Abstract: Metazoan organisms are dependent on a continuous supply of O(2) for survival. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that regulates oxygen homeostasis and plays key roles in development, physiology, and disease. HIF-1 activity is induced in response to continuous hypoxia, intermittent hypoxia, growth factor stimulation, and Ca(2+) signaling. HIF-1 mediates adaptive responses to hypoxia, including erythropoiesis, angiogenesis, and metabolic reprogramming. In each case, HIF-1 regulates the expression of multiple genes encoding key components of the response pathway. HIF-1 also mediates maladaptive responses to chronic continuous and intermittent hypoxia, which underlie the development of pulmonary and systemic hypertension, respectively.
Abstract: White adipose (fat) tissues regulate metabolism, reproduction, and life span. Adipocytes form throughout life, with the most marked expansion of the lineage occurring during the postnatal period. Adipocytes develop in coordination with the vasculature, but the identity and location of white adipocyte progenitor cells in vivo are unknown. We used genetically marked mice to isolate proliferating and renewing adipogenic progenitors. We found that most adipocytes descend from a pool of these proliferating progenitors that are already committed, either prenatally or early in postnatal life. These progenitors reside in the mural cell compartment of the adipose vasculature, but not in the vasculature of other tissues. Thus, the adipose vasculature appears to function as a progenitor niche and may provide signals for adipocyte development.
Abstract: Every organ depends on blood vessels for oxygen and nutrients, but the vasculature associated with individual organs can be structurally and molecularly diverse. The central nervous system (CNS) vasculature consists of a tightly sealed endothelium that forms the blood-brain barrier, whereas blood vessels of other organs are more porous. Wnt7a and Wnt7b encode two Wnt ligands produced by the neuroepithelium of the developing CNS coincident with vascular invasion. Using genetic mouse models, we found that these ligands directly target the vascular endothelium and that the CNS uses the canonical Wnt signaling pathway to promote formation and CNS-specific differentiation of the organ’s vasculature.
Abstract: The dorsal striatum plays a role in consummatory food reward, and striatal dopamine receptors are reduced in obese individuals, relative to lean individuals, which suggests that the striatum and dopaminergic signaling in the striatum may contribute to the development of obesity. Thus, we tested whether striatal activation in response to food intake is related to current and future increases in body mass and whether these relations are moderated by the presence of the A1 allele of the TaqIA restriction fragment length polymorphism, which is associated with dopamine D2 receptor (DRD2) gene binding in the striatum and compromised striatal dopamine signaling. Cross-sectional and prospective data from two functional magnetic resonance imaging studies support these hypotheses, which implies that individuals may overeat to compensate for a hypofunctioning dorsal striatum, particularly those with genetic polymorphisms thought to attenuate dopamine signaling in this region.
Abstract: CONTEXT: Serum LH levels decrease with increasing body mass index (BMI) in women with polycystic ovarian syndrome (PCOS). OBJECTIVE: The objective of this study was to determine whether pharmacokinetic factors contribute to the effect of obesity on LH in PCOS. PARTICIPANTS/INTERVENTIONS/SETTING: Twenty-one women with PCOS underwent frequent blood sampling, iv administration of GnRH (75 ng/kg), and sc administration of the NAL-GLU GnRH antagonist (150 microg/kg) followed by iv recombinant human LH (rhLH; 300 IU) in the General Clinical Research Center at an academic medical center. MAIN OUTCOME MEASURES: Pharmacokinetic parameters were estimated by modeling the LH serum concentration profiles after administration of GnRH and rhLH and related to BMI. RESULTS: Serum levels of LH and rhLH decreased in a distinctly monoexponential fashion in all patients. The apparent biological half-life of rhLH was not influenced by BMI, nor was the total body clearance or apparent volume of distribution. However, the apparent half-life of endogenous LH was inversely related to BMI (r=-0.46; P\textless0.04), and the estimated total body clearance of endogenous LH was positively related to BMI (r=0.53; P\textless0.02). CONCLUSION: Estimated clearance and apparent half-life of endogenous LH are influenced by BMI in women with PCOS, contributing to the inverse relationship between LH and BMI in this population. The absence of an effect of BMI on the pharmacokinetics of rhLH in these subjects suggests that the effect of obesity on clearance of endogenous LH is the result of alterations in the isoform composition of LH secreted by the pituitary.
Abstract: We developed a mathematical model of human respiration in the awake state that can be used to predict changes in ventilation, blood gases, and other critical variables during conditions of hypocapnia, hypercapnia and these conditions combined with hypoxia. Hence, the model is capable of describing ventilation changes due to the hypocapnic-hypoxia of high altitude. The basic model is that of Grodins et al. [Grodins, F. S., J. Buell, and A. J. Bart. J. Appl. Physiol. 22:260-276, 1967]. We updated the descriptions of (1) the effects of blood gases on cardiac output and cerebral blood flow, (2) acid-base balance in blood and tissues, (3) O2 and CO2 binding to hemoglobin and most importantly, (4) the respiratory-chemostat controller. The controller consists of central and peripheral sections. The central chemoceptor-induced ventilation response is simply a linear function of brain P(CO2) above a threshold value. The peripheral response has both a linear term similar to that for the central chemoceptors, but dependent upon carotid body P(CO2) and with a different threshold and a complex, nonlinear term that includes multiplication of separate terms involving carotid body P(O2) and P(CO2). Together, these terms produce ’dogleg’-shaped curves of ventilation plotted against P(CO2) which form a fan-like family for different values of P(CO2). With this chemical controller, our model closely describes a wide range of experimental data under conditions of solely changes in P(CO2) and for short-term hypoxia coupled with P(CO2) changes. This model can be used to accurately describe changes in ventilation and respiratory gases during ascent and during short-term residence at altitude. Hence, it has great applicability to studying O2-delivery systems in aircraft.
Abstract: Prolonged periods of skeletal muscle inactivity due to bed rest, denervation, hindlimb unloading, immobilization, or microgravity can result in significant muscle atrophy. The muscle atrophy is characterized as decreased muscle fiber cross-sectional area and protein content, reduced force, increased insulin resistance as well as a slow to fast fiber type transition. The decreases in protein synthesis and increases in protein degradation rates account for the majority of the rapid loss of muscle protein due to disuse. However, we are just beginning to pay more attention on the identification of genes involved in triggering initial responses to physical inactivity/microgravity. Our review mainly focuses on the signaling pathways involved in protein loss during disuse atrophy, including two recently identified ubiquitin ligases: muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx). Recent reports suggest that inhibition of the IGF-1/PI3K/Akt pathway in muscle may be involved in the progression of disuse atrophy. NF-kappaB seems to be a key intracellular signal transducer in disuse atrophy. Factors such as myostatin, p38 and calcineurin can induce muscle protein loss under specified conditions, but further experiments are needed to determine whether they are necessary components of disuse atrophy. Where possible, the molecular mechanisms underlying the slow to fast fiber type transition and increased insulin resistance in atrophic muscles are discussed as well. Collectively, the disuse-induced muscle atrophy is a highly ordered process that is controlled by interactions between intracellular signaling pathways rather than isolated pathways.
Abstract: The aspartyl-protease renin is the key regulator of the renin-angiotensin-aldosterone system, which is critically involved in salt, volume, and blood pressure homeostasis of the body. Renin is mainly produced and released into circulation by the so-called juxtaglomerular epithelioid cells, located in the walls of renal afferent arterioles at the entrance of the glomerular capillary network. It has been known for a long time that renin synthesis and secretion are stimulated by the sympathetic nerves and the prostaglandins and are inhibited in negative feedback loops by angiotensin II, high blood pressure, salt, and volume overload. In contrast, the events controlling the function of renin-secreting cells at the organ and cellular level are markedly less clear and remain mysterious in certain aspects. The unravelling of these mysteries has led to new and interesting insights into the process of renin release.
Abstract: Coronary artery disease (CAD) is the leading cause of death worldwide and is commonly caused by a constellation of risk factors called the metabolic syndrome. We characterized a family with autosomal dominant early CAD, features of the metabolic syndrome (hyperlipidemia, hypertension, and diabetes), and osteoporosis. These traits showed genetic linkage to a short segment of chromosome 12p, in which we identified a missense mutation in LRP6, which encodes a co-receptor in the Wnt signaling pathway. The mutation, which substitutes cysteine for arginine at a highly conserved residue of an epidermal growth factor-like domain, impairs Wnt signaling in vitro. These results link a single gene defect in Wnt signaling to CAD and multiple cardiovascular risk factors.
Abstract: Luteolysis is defined as the loss of function and subsequent involution of the luteal structure. The luteolytic process is usually subdivided, whereby the decline in progesterone is described as functional luteolysis and the structural involution is described as structural luteolysis. After the corpus luteum ceases to produce progesterone, it decreases in size, experiences a loss of cellular integrity, and then disappears from the ovary as a result of apoptosis of luteal cells. However, the control mechanisms responsible for initiating and mediating apoptosis during structural luteolysis seem more complex than originally envisioned. Furthermore, efforts to elucidate the apoptotic mechanisms have been complicated by the fact that different mammalian species have different mechanisms for controlling luteal function. Therefore, it is of interest to know whether different mammalian species have different apoptotic mechanisms. The goal of this review was to focus on species-related differences in the mechanism of apoptosis during structural luteolysis in rodents, cattle and humans, the species that are used most for luteolysis research.
Abstract: The mechanisms controlling ATP generation in the transition from normal resting conditions to either high work states or ischemia are poorly understood. ATP generation depends upon compartmentation between the mitochondria and cytosol of metabolic pathways and key energy transfer species that cannot be easily assessed experimentally. We developed a multicompartment mathematical model of cardiac metabolism to simulate the metabolic responses to ischemia and increased workload. The model is based on mass balances, transport, and metabolic processes in cardiac tissue, and has three distinct compartments (blood, cytosol, and mitochondria). In addition to distinguishing between cytosol and mitochondria, the model includes a cytosolic subcompartment for glycolytic metabolic channeling. The model simulations predict the rapid activation of glycogenolysis and lactate production at the onset of ischemia, and support the concept of localization of glycolysis to a cytosolic subcompartment. In addition, simulations show that mitochondrial NADH/NAD(+) is primarily determined by oxygen consumption during ischemia, while cytosolic NADH/NAD(+) and lactate production are largely a function of glycolytic flux during the initial phase, and is controlled by mitochondrial NADH/NAD(+) and the malate-aspartate shuttle during the steady state. Finally, the model predicts that metabolic activation with an abrupt increase in workload requires parallel activation of ATP hydrolysis, glycolysis, mitochondrial dehydrogenases, the electron transport chain, and ADP phosphorylation. Taken together, these studies demonstrate the importance of metabolic compartmentation in the regulation of cardiac energetics in response to acute stress, and they highlight the usefulness of computational models in this line of investigation.
Abstract: While the role of the ubiquitin-proteasome system (UPS) in regulating cellular processes continues to expand, the elucidation of its role in cardiac disease is just beginning. The UPS regulates pivotal processes at all levels of cardiac biology: from membrane-associated ion channels and receptors to downstream signaling intermediates and transcription factors. Moreover, the role of the UPS in maintaining cardiac protein quality control is emerging, as exemplified by its multiple interactions with the cardiac sarcomere and role in familial cardiomyopathies. The diversity of UPS regulation lies in E3 ligases, which specifically recognize targets and direct the ubiquitination process. In the context of disease, E3 ligase expression affects the severity of disease in both ischemia reperfusion injury and cardiac hypertrophy in vivo by modulating signaling intermediates. In ischemia-reperfusion injury, the activities of CHIP and MDM2 (both with E3 ligase activity) profoundly affect apoptosis regulation and severity of disease. In cardiac hypertrophy, Atrogin1 and MuRF1 attenuate cardiac hypertrophy by interacting with calcineurin and PKCepsilon, respectively. Additionally, MuRF1 and MDM2 interact with sarcomeric proteins (cTnI and Tcap, respectively) which may prove to be mechanisms by which hypertrophy is attenuated or protein quality modulated. All of these exciting new findings, however, must be taken in the context of disease regulation of the UPS components themselves. Key UPS components (e.g. ubiquitin, E1, E2, E3, proteasome) are themselves transcriptionally regulated in cardiac disease. Our understanding of the precise nature by which the UPS regulates key biological functions in cardiac disease has just begun.
Abstract: Defining optimal nutrient requirements is critical for ensuring crew health during long-duration space exploration missions. Data pertaining to such nutrient requirements are extremely limited. The primary goal of this study was to better understand nutritional changes that occur during long-duration space flight. We examined body composition, bone metabolism, hematology, general blood chemistry, and blood levels of selected vitamins and minerals in 11 astronauts before and after long-duration (128-195 d) space flight aboard the International Space Station. Dietary intake and limited biochemical measures were assessed during flight. Crew members consumed a mean of 80% of their recommended energy intake, and on landing day their body weight was less (P = 0.051) than before flight. Hematocrit, serum iron, ferritin saturation, and transferrin were decreased and serum ferritin was increased after flight (P \textless 0.05). The finding that other acute-phase proteins were unchanged after flight suggests that the changes in iron metabolism are not likely to be solely a result of an inflammatory response. Urinary 8-hydroxy-2’-deoxyguanosine concentration was greater and RBC superoxide dismutase was less after flight (P \textless 0.05), indicating increased oxidative damage. Despite vitamin D supplement use during flight, serum 25-hydroxycholecalciferol was decreased after flight (P \textless 0.01). Bone resorption was increased after flight, as indicated by several markers. Bone formation, assessed by several markers, did not consistently rise 1 d after landing. These data provide evidence that bone loss, compromised vitamin D status, and oxidative damage are among critical nutritional concerns for long-duration space travelers.
Abstract: Decrements in left ventricular (LV) mass observed after microgravity exposure have been previously postulated to be a central component of spaceflight-induced cardiovascular deconditioning. In this study, echocardiographic measurements of LV mass in astronauts demonstrated a comparative 9.1% reduction in postflight LV mass that returned to preflight values by the third day of recovery. A ground-based study in normal subjects determined that these pre- to postflight LV mass changes could be reproduced by simple dehydration. Reductions in LV mass observed immediately after spaceflight may be secondary to simple physiologic fluid exchanges.
Abstract: The role of heart-type cytosolic fatty acid-binding protein (H-FABP) in mediating whole body and muscle-specific long-chain fatty acid (LCFA) and glucose utilization was examined using exercise as a phenotyping tool. Catheters were chronically implanted in a carotid artery and jugular vein of wild-type (WT, n = 8), heterozygous (H-FABP(+/-), n = 8), and null (H-FABP(-/-), n = 7) chow-fed C57BL/6J mice, and mice were allowed to recover for 7 days. After a 5-h fast, conscious, unrestrained mice were studied during 30 min of treadmill exercise (0.6 mph). A bolus of [(125)I]-15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid and 2-deoxy-[(3)H]glucose was administered to obtain rates of whole body metabolic clearance (MCR) and indexes of muscle LCFA (R(f)) and glucose (R(g)) utilization. Fasting, nonesterified fatty acids (mM) were elevated in H-FABP(-/-) mice (2.2 +/- 0.9 vs. 1.3 +/- 0.1 and 1.3 +/- 0.2 for WT and H-FABP(+/-)). During exercise, blood glucose (mM) increased in WT (11.7 +/- 0.8) and H-FABP(+/-) (12.6 +/- 0.9) mice, whereas H-FABP(-/-) mice developed overt hypoglycemia (4.8 +/- 0.8). Examination of tissue-specific and whole body glucose and LCFA utilization demonstrated a dependency on H-FABP with exercise in all tissues examined. Reductions in H-FABP led to decreasing exercise-stimulated R(f) and increasing R(g) with the most pronounced effects in heart and soleus muscle. Similar results were seen for MCR with decreasing LCFA and increasing glucose clearance with declining levels of H-FABP. These results show that, in vivo, H-FABP has reciprocal effects on glucose and LCFA utilization and whole body fuel homeostasis when metabolic demands are elevated by exercise.
Abstract: The Peutz-Jegher syndrome tumor-suppressor gene encodes a protein-threonine kinase, LKB1, which phosphorylates and activates AMPK [adenosine monophosphate (AMP)-activated protein kinase]. The deletion of LKB1 in the liver of adult mice resulted in a nearly complete loss of AMPK activity. Loss of LKB1 function resulted in hyperglycemia with increased gluconeogenic and lipogenic gene expression. In LKB1-deficient livers, TORC2, a transcriptional coactivator of CREB (cAMP response element-binding protein), was dephosphorylated and entered the nucleus, driving the expression of peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha), which in turn drives gluconeogenesis. Adenoviral small hairpin RNA (shRNA) for TORC2 reduced PGC-1alpha expression and normalized blood glucose levels in mice with deleted liver LKB1, indicating that TORC2 is a critical target of LKB1/AMPK signals in the regulation of gluconeogenesis. Finally, we show that metformin, one of the most widely prescribed type 2 diabetes therapeutics, requires LKB1 in the liver to lower blood glucose levels.
Abstract: These experiments examined changes in the chemoreflex control of breathing and acid-base balance after 5 days at altitude (3480 m) in six healthy males. The partial pressures of carbon dioxide (P(CO2)) at which ventilation increased during isoxic hypoxic and hyperoxic modified rebreathing tests at sea level fell significantly at altitude by mean+/-S.E.M. of 12.8+/-2.51 mmHg and 9.5+/-1.77 mmHg, respectively, but response slopes above threshold were unchanged. Altitude exposure produced a respiratory alkalosis evidenced by a decrease in mean resting end-tidal P(CO2) from 41+/-0.84 mmHg at sea level to 32+/-2.04 mmHg at altitude, but pH did not increase significantly from its sea level value. Blood samples were analyzed to discover acid-base changes, using a modification of the equations for acid-base balance proposed by [Stewart, P.A., 1983. Modern quantitative acid-base chemistry. Can. J. Physiol. Pharmacol. 61, 1444-1461]. While strong ion difference at altitude was not significantly different from its sea level value, albumin concentration was increased significantly from 38.6+/-0.30 g L(-1) to 49.8+/-0.76 g L(-1). We suggest that the respiratory alkalosis was produced by a fall in the chemoreflex threshold and pH was corrected by an elevation in the concentration of weakly dissociated protein anions.
Abstract: Echocardiographic measurements of astronaut cardiac function have documented an initial increase, followed by a progressive reduction in both left ventricular end-diastolic volume index and stroke volume with entry into microgravity (micro-G). The investigators hypothesize that the observed reduction in cardiac filling may, in part, be due to the absence of a gravitational acceleration dependent, intraventricular hydrostatic pressure difference in micro-G that exists in the ventricle in normal gravity (1-G) due to its size and anatomic orientation. This acceleration-dependent pressure difference, DeltaP(LV), between the base and the apex of the heart for the upright posture can be estimated to be 6660 dynes/cm(2) ( approximately 5 mm Hg) on Earth. DeltaP(LV) promotes cardiac diastolic filling on Earth, but is absent in micro-G. If the proposed hypothesis is correct, cardiac pumping performance would be diminished in micro-G. To test this hypothesis, ventricular function experiments were conducted in the 1-G environment using an artificial ventricle pumping on a mock circulation system with the longitudinal axis anatomically oriented for the upright posture at 45 degrees to the horizon. Additional measurements were made with the ventricle horizontally oriented to null DeltaP(LV)along the apex-base axis of the heart as would be the case for the supine posture, but resulting in a lesser hydrostatic pressure difference along the minor (anterior-posterior) axis. Comparative experiments were also conducted in the micro-G environment of orbital space flight on board the Space Shuttle. This paper reviews the use of an automated cardiovascular simulator flown on STS-85 and STS-95 as a Get Away Special payload to test this hypothesis. The simulator consisted of a pneumatically actuated, artificial ventricle connected to a closed-loop, fluid circuit with adjustable compliance and resistance elements to create physiologic pressure and flow conditions. Ventricular instrumentation included pressure transducers in the apex and base as well as immediately upstream of the inflow valve and downstream of the outflow valve, and a flow probe downstream of the outflow valve. By varying the circulating fluid volume, ventricular function could be determined for varying preload pressures at a regulated, mean afterload pressure of 95 mm Hg. This variation in preload condition permitted the construction of a ventricular function curve for the micro-G environment for comparison to the same curve for the 1-G environment. Data were collected from both missions at the upper end of the ventricular function curve. Experiment operation in the 1-G, supine orientation or in the micro-G environment eliminated the DeltaP(LV) observed in the 1-G, upright orientation. Consistent with the hypothesis, additional atrial pressure was required in micro-G to obtain stroke volumes and flow rates similar to those measured in 1-G for the upright posture. The necessary increase in atrial pressure was approximately 5 mm Hg in these experiments. In the same range of flow rates and stroke volumes, similar flows were observed in the 1-G supine posture for atrial pressures intermediate to the 1-G upright and micro-G values, also consistent with the hypothesis. Additional experiments on board the Space Shuttle are in preparation to gather data across the rest of the normal physiologic range of the ventricular function curve.
Abstract: Inhibin is secreted in two distinct heterodimeric forms, A and B, but the mechanism for the differential control of these two forms is unclear. To evaluate the relationship between secretion of inhibin forms and folliculogenesis, the effects of gonadotropins on inhibin concentrations were studied in parallel with stereological enumeration of ovarian follicle types in gonadotropin-deficient hypogonadal (hpg) female mice treated with recombinant human FSH (10 IU/day), hCG (1 IU/day), or both for 20 days. Treatment with FSH alone significantly increased blood concentrations of both inhibin A and inhibin B, whereas hCG alone had no effect on either inhibin. The combination of FSH and hCG further increased the concentration of inhibin A but had no effect on the concentration of inhibin B beyond that of FSH. The number of primordial follicles per ovary was significantly reduced in FSH-treated hpg mice, but was not affected by hCG treatment. Antral follicles were absent in the untreated hpg mice, present following treatment with FSH, and were present in only limited numbers following hCG treatment alone. Preovulatory follicles were observed only in the wild-type and combined FSH and hCG treatment groups. These results demonstrate that secretion of both inhibins is associated with the presence of antral follicles. Inhibin A secretion is increased by the presence of preovulatory follicles, whereas the concentration of inhibin B is not affected. The observed effects of gonadotropins on inhibin A and B secretion may be explained by corresponding gonadotropin effects on follicle development.
Abstract: Lipoprotein lipase (LPL) is the only known enzyme in the capillary endothelium of peripheral tissues that hydrolizes plasma triglycerides and provides fatty acids (FAs) for their subsequent tissue uptake. Previously, we demonstrated that mice that express LPL exclusively in muscle develop essentially normal fat mass despite the absence of LPL and the deprivation of nutritionally derived FAs in adipose tissue (AT). Using this mouse model, we now investigated the metabolic response to LPL deficiency in AT that enables maintenance of normal AT mass. We show that the rate of FA production was 1.8-fold higher in LPL-deficient AT than in control AT. The levels of mRNA and enzymatic activities of important enzymes involved in FA and triglyceride biosynthesis were induced concomitantly. Increased plasma glucose clearing and (14)C-deoxyglucose uptake into LPL-deficient mouse fat pads indicated that glucose provided the carbon source for lipid synthesis. Leptin expression was decreased in LPL-deficient AT. Finally, the induction of de novo FA synthesis in LPL-deficient AT was associated with increased expression and processing of sterol regulatory element binding protein 1 (SREBP-1), together with an increase in INSIG-1 expression. These results suggest that in the absence of LPL in AT, lipogenesis is activated through increased SREBP-1 expression and processing triggered by decreased availability of nutrition-derived FAs, elevated insulin, and low leptin levels.
Abstract: Ghrelin is a recently identified growth hormone (GH) secretogogue whose administration not only induces GH release but also stimulates food intake, increases adiposity, and reduces fat utilization in mice. The effect on food intake appears to be independent of GH release and instead due to direct activation of orexigenic neurons in the arcuate nucleus of the hypothalamus. The effects of ghrelin administration on food intake have led to the suggestion that inhibitors of endogenous ghrelin could be useful in curbing appetite and combating obesity. To further study the role of endogenous ghrelin in appetite and body weight regulation, we generated ghrelin-deficient (ghrl(-/-)) mice, in which the ghrelin gene was precisely replaced with a lacZ reporter gene. ghrl(-/-) mice were viable and exhibited normal growth rates as well as normal spontaneous food intake patterns, normal basal levels of hypothalamic orexigenic and anorexigenic neuropeptides, and no impairment of reflexive hyperphagia after fasting. These results indicate that endogenous ghrelin is not an essential regulator of food intake and has, at most, a redundant role in the regulation of appetite. However, analyses of ghrl(-/-) mice demonstrate that endogenous ghrelin plays a prominent role in determining the type of metabolic substrate (i.e., fat vs. carbohydrate) that is used for maintenance of energy balance, particularly under conditions of high fat intake.
Abstract: BACKGROUND: Little is known about the regional distribution of cerebral blood flow (CBF) in nonanesthetized animals during periods of lowered blood pressure. The present investigation addresses the specific reaction patterns of local cerebral blood flow (LCBF) in comparison with mean CBF during graded pressure-controlled hemorrhagic shock in conscious rats. METHODS: Conscious rats were subjected to graded pressure-controlled hemorrhage (to 85, 70, 55, or 40 mm Hg) by arterial blood withdrawal. After a period of 30 minutes, blood pressure was stabilized by withdrawal or reinfusion of blood. LCBF was determined autoradiographically by the iodo(14C)antipyrine method in 34 brain structures, and mean CBF was calculated and compared with the values of nonhemorrhaged control animals. RESULTS: Mean CBF remained unchanged except for the group with the lowest blood pressure of 40 mm Hg (decrease in CBF of 28%). Otherwise, LCBF was increased in some brain structures at an unchanged mean CBF. Congruently, at 40 mm Hg, the decrease in mean CBF did not show up in all brain structures, the local pattern of CBF varying between an unchanged and a profoundly decreased CBF. The mean coefficient of variation of CBF was increased with the severity of hemorrhagic shock, which indicates an enhanced heterogeneity of CBF. CONCLUSION: Because of the substantial heterogeneity in the responses of LCBF to pressure-controlled hemorrhage, autoregulation of CBF during pressure-controlled hemorrhagic shock has to be reconsidered on a regional basis.
Abstract: Obesity and noninsulin-dependent diabetes mellitus are globally epidemic. Insulin resistance is a major contributor to the pathogenesis of type II diabetes and plays a role in numerous other metabolic disorders including hypertension, dyslipidaemia and atherosclerosis. Obesity, in particular visceral adiposity, is positively correlated with insulin resistance. Although this correlation between adiposity and insulin resistance is well established in human beings as well as in rodent models, the mechanisms involved in obesity-related insulin resistance are not fully defined. One mechanism is that factors secreted from adipocytes can affect peripheral insulin resistance. One candidate for such a factor is resistin, an adipocyte-secreted hormone that impairs glucose homeostasis and insulin action in the mouse. This review will summarize our current understanding of resistin and will attempt to provide a framework for future study of its role in rodent and human physiology.
Abstract: Although recent models offer realistic descriptions of the human respiratory system, they do not fulfill all characteristics of a stable, comprehensive model, which would allow us to evaluate a variety of hypotheses on the control of breathing. None of the models offer completely realistic descriptions of the gaseous components of blood, and their description of delays associated with the propagation of changes in partial pressures of respiratory gases between the lungs and brain and tissue compartments have shortcomings. These deficiencies are of particular significance in an analysis of periodic breathing where dynamic alterations in the circulation and in blood chemical stimuli are likely to assume considerable importance. We developed a computational model of the human respiratory control system which is an extension of the model of Grodins et al. (F. S. Grodins, J. Buell, and A. J. Bart. J. Appl. Physiol. 22(2):260-276, 1967). Our model combines an accurate description of a plant with a novel controller design that treats minute ventilation as a sum of central and peripheral components. To ensure that the developed model is stable and sufficiently robust to act as a test platform for hypotheses about control of ventilation, we simulated a series of challenging physiological conditions, specifically, the response to eucapnic hypoxia, the development of periodic breathing during hypocapnic hypoxia, and the open loop response to hypercapnic step. These steady state and transient responses of the model were compared with results from similar physiological experiments. Our simulations suggest that for a particular value of arterial Po2, the steady state difference between brain and arterial Pco2 remains approximately constant as a function of arterial Pco2. The model indicates that hypoxia-induced changes in cerebral blood flow contribute significantly to the ventilatory decline observed during eucapnic hypoxia. The model exibits hypoxic-induced periodic breathing, which can be eliminated by small increases in F(I)co2. The dynamics of the model’s open loop hypercapnic ventilatory response approximates experimental data well.
Abstract: Mounting evidence exists for a role of the CRH system in energy balance, including a direct influence on human adipocytes, the regulation of adipose 11 beta-hydroxysteroid dehydrogenase type 1 activity, and cortisol formation. We characterized the expression of CRH receptors 1 and 2 and CRH-like peptides stresscopin and urocortin in human adipose tissue in comparison with other peripheral tissues, adrenal, and heart. The effect of CRH on CRH receptor and CRH-like peptide expression was analyzed in isolated human adipocytes using quantitative TaqMan PCR. CRH receptors were detectable in fat tissue at mRNA and protein levels. CRH-R2 expression in fat was comparable with its expression in the heart, the organ with the highest CRH-R2 expression known. CRH-R1:CRH-R2 ratio varied according to fat-depot type; whereas CRH-R1 expression was higher in sc fat than in visceral fat, the opposite was true for CRH-R2. Adipose tissue also expressed urocortin and stresscopin, the predominant ligands of peripheral CRH-R2. CRH down-regulated CRH-R1 and CRH-R2 mRNA expression in isolated adipocytes. These data, together with the recently published observation that CRH regulates adipocyte metabolism by down-regulating 11 beta-hydroxysteroid dehydrogenase, indicate that a CRH system exists within human adipose tissue. This system could be implicated in energy homeostasis and in mediating the anorexic effects of CRH at adipose level.
Abstract: Muscle biopsies were obtained from the vastus lateralis before and after 84 days of bed-rest from six control (BR) and six resistance-exercised (BRE) men to examine slow- and fast-twitch muscle fibre contractile function. BR did not exercise during bed-rest and had a 17 and 40% decrease in whole muscle size and function, respectively. The BRE group performed four sets of seven maximal concentric and eccentric supine squats 2-3 days per week (every third day) that maintained whole muscle strength and size. Slow (MHC I) and fast (MHC IIa) muscle fibres were studied at 15 degrees C for diameter, peak force (P(o)), contractile velocity (V(o)) and force-power parameters. SDS-PAGE was performed on each single fibre after the functional experiments to determine MHC isoform composition. MHC I and IIa BR fibres were, respectively, 15 and 8% smaller, 46 and 25% weaker (P(o)), 21 and 6% slower (V(o)), and 54 and 24% less powerful after bed-rest (P \textless 0.05). BR MHC I and IIa P(o) and power normalized to cell size were lower (P \textless 0.05). BRE MHC I fibres showed no change in size or V(o) after bed-rest; however, P(o) was 19% lower (P \textless 0.05), resulting in 20 and 30% declines (P \textless 0.05) in normalized P(o) and power, respectively. BRE MHC IIa fibres showed no change in size, P(o) and power after bed-rest, while V(o) was elevated 13% (P \textless 0.05). BRE MHC IIa normalized P(o) and power were 10 and 15% lower (P \textless 0.05), respectively. MHC isoform composition shifted away from MHC I fibres, resulting in an increase (P \textless 0.05) in MHC I/IIa (BR and BRE) and MHC IIa/IIx (BR only) fibres. These data show that the contractile function of the MHC I fibres was more affected by bed-rest and less influenced by the resistance exercise protocol than the MHC IIa fibres. Considering the large differences in power of human MHC I and IIa muscle fibres (5- to 6-fold), the maintenance of whole muscle function with the resistance exercise programme is probably explained by (1). the maintenance of MHC IIa power and (2). the shift from slow to fast (MHC I –\textgreater MHC I/IIa) in single fibre MHC isoform composition.
Abstract: Appetite is controlled by a complicated system with hunger and satiety signals interacting in complex pathways both peripherally and centrally. Insulin, leptin and ghrelin are key hormonal regulators of food intake. Ghrelin enhances appetite while leptin is a satiety signal. A novel peripheral regulator of food intake, peptide YY(3-36), is released from the gastrointestinal tract postprandially. In this review old and new peripheral signals and their interaction in the control of food intake are briefly discussed.
Abstract: Resistin is an adipokine with putative prodiabetogenic properties. Like other hormones secreted by adipose tissue, resistin is being investigated as a possible etiologic link between excessive adiposity and insulin resistance. Although there is growing evidence that circulating levels of this adipokine are proportional to the degree of adiposity, an effect on insulin resistance in humans remains unproven. To evaluate the relations among resistin, obesity, and insulin resistance, we measured fasting serum resistin levels in 113 nondiabetic (75-g oral glucose tolerance test) Pima Indians (ages 29 +/- 7 years, body fat 31 +/- 8%, resistin 3.7 +/- 1.1 ng/ml [means +/- SD]), who were characterized for body composition (assessed by hydrodensitometry or dual-energy X-ray absorptiometry), whole-body insulin sensitivity (M; assessed by hyperinsulinemic clamp), basal hepatic glucose output (BHGO) and hepatic glucose output during low-dosage insulin infusion of a hyperinsulinemic clamp (HGO; a measure of hepatic insulin resistance), and acute insulin secretory response (AIR; assessed by 25-g intravenous glucose tolerance test). Follow-up measurements of M, BHGO, HGO, and AIR were available for 34 subjects who had normal glucose tolerance at baseline and remained nondiabetic at follow-up. The average time to follow-up was 4.5 +/- 2.7 years. In cross-sectional analyses, serum resistin levels were positively associated with percent body fat (r = 0.37, P = 0.0001) and 2-h glucose (r = 0.19, P = 0.04), respectively. Serum resistin levels were not associated with fasting glucose and insulin levels, M, BHGO, HGO, or AIR (r = 0.17, 0.12, -0.13, -0.06, -0.03, and -0.04, respectively; all P \textgreater 0.05). After adjusting for percent body fat, there was no association between serum resistin levels and 2-h glucose (r = 0.06, P = 0.6). In prospective analyses, high serum resistin levels at baseline were not associated with a decline in M (r = -0.1, P \textgreater 0.5). Resistin levels were, however, associated with increases in percent body fat, fasting plasma insulin, and HGO (r = 0.34, 0.36, and 0.37; all P \textless 0.05) after adjusting for sex, age, and time to follow-up. After additional adjustment for the change in percent body fat, there was no association between baseline serum resistin levels and changes in plasma insulin or HGO (r = 0.26 and 0.23; both P \textgreater 0.1). We conclude that in Pima Indians, like other human populations, circulating resistin levels are proportional to the degree of adiposity, but not the degree of insulin resistance. We unexpectedly found that high serum resistin levels do predict future increases in percent body fat. Our data suggest that resistin promotes obesity but not obesity-associated insulin resistance in humans.
Abstract: Synthetic agonists of the growth hormone secretagogue receptor (GHSR) rejuvenate the pulsatile pattern of GH-release in the elderly, and increase lean but not fat mass in obese subjects. Screening of tissue extracts in a cell line engineered to overexpress the GHSR led to the identification of a natural agonist called ghrelin. Paradoxically, this hormone was linked to obesity. However, it had not been directly shown that the GHSR is a physiologically relevant ghrelin receptor. Furthermore, ghrelin’s structure is significantly different from the synthetic agonist (MK-0677) used to expression-clone the GHSR. To address whether the GHSR mediates ghrelin’s stimulatory effects on GH release and appetite, we generated Ghsr-null mice. In contrast to wild-type mice, acute treatment of Ghsr-null mice with ghrelin stimulated neither GH release nor food intake, showing that the GHSR is a biologically relevant ghrelin receptor. Nevertheless, Ghsr-null mice are not dwarfs; their appetite and body composition are comparable to that of wild-type littermates. Furthermore, in contrast to suggestions that ghrelin regulates leptin and insulin secretion, fasting-induced changes in serum levels of leptin and insulin are identical in wild-type and null mice. Serum insulin-like growth factor 1 levels and body weights of mature Ghsr-null mice are modestly reduced compared to wild-type littermates, which is consistent with ghrelin’s property as an amplifier of GH pulsatility and its speculated role in establishing an insulin-like growth factor 1 set-point for maintaining anabolic metabolism. Our results suggest that chronic treatment with ghrelin antagonists will have little effect on growth or appetite.
Abstract: Low density lipoprotein (LDL) apheresis provides a safe and effective means of treating patients with homozygous familial hypercholesterolaemia (FH). It also has a role in preventing the progression of coronary artery disease in heterozygotes and others with severe dyslipidaemia who are refractory to or intolerant of high doses of lipid-lowering drugs. Established methods involve either adsorption of apolipoprotein B-containing lipoproteins by affinity columns containing anti-apolipoprotein B antibodies or dextran sulphate, or their precipitation at low pH by heparin, in each instance after first separating plasma from blood cells with a cell separator. The most recently developed method enables lipoproteins to be adsorbed directly from whole blood, using polyacrylate columns. All 4 methods have proved to be similarly efficient when used weekly or biweekly to lower LDL cholesterol and Lp(a) without unduly reducing HDL cholesterol. Economic constraints restrict the use of LDL apheresis to the treatment of potentially fatal disorders such as FH, where there is clear evidence of benefit compared with conventional therapy. Widening the indications to include the treatment of other dyslipidaemic disorders such as steroid-resistant nephrotic syndrome, post-transplant donor vessel disease, stroke and prevention of re-stenosis after coronary angioplasty requires evidence from controlled trials that is currently lacking.
Abstract: It has been observed previously that hormone-sensitive lipase-deficient (HSL-ko) mice have reduced white adipose tissue (WAT) stores compared to control mice. These findings contradict the expectation that the decreased lipolytic activity in WAT of HSL-ko mice would cause accumulation of triglycerides (TGs) in that tissue. Here we demonstrate that the cellular TG synthesis in HSL-deficient WAT is markedly reduced due to downregulation of the enzymatic activities of glycerophosphate acyltransferase, dihydroxyacetonphosphate acyltransferase, lysophosphatidate acyltransferase, and diacylglycerol acyltransferase. Fatty acid de novo synthesis is also decreased due to reduced cellular glucose uptake, reduced glucose incorporation into adipose tissue lipids, and reduced activities of acetyl:CoA carboxylase and fatty acid synthase. Finally, the activities of phosphoenolpyruvate carboxykinase (PEPCK), acyl:CoA synthetase (ACS), and glucose 6-phosphate dehydrogenase, the enzymes that provide glycerol-3-phosphate, acyl-CoA, and NADPH for TG synthesis, respectively, are decreased in HSL-ko mice. The reduced expression of the peroxisome proliferator-activated receptor gamma (PPAR gamma) target genes PEPCK, ACS, and aP2, as well as reduced mRNA levels of PPAR gamma itself, suggest the involvement of this transcription factor in the downregulation of lipogenesis. Taken together, these results establish that in the absence of HSL, the reduced NEFA production is counteracted by a drastic reduction of NEFA reesterification that provides sufficient quantities of NEFA for release into the circulation. These metabolic adaptations result in decreased fat mass in HSL-ko mice.
Abstract: The number of known glucose transporters has expanded considerably over the past 2 years. At least three, and up to six, Na+-dependent glucose transporters (SGLT1-SGLT6; gene name SLC5A) have been identified. Similarly, thirteen members of the family of facilitative sugar transporters (GLUT1-GLUT12 and HMIT; gene name SLC2A) are now recognised. These various transporters exhibit different substrate specificities, kinetic properties and tissue expression profiles. The number of distinct gene products, together with the presence of several different transporters in certain tissues and cells (for example, GLUT1, GLUT4, GLUT5, GLUT8, GLUT12 and HMIT in white adipose tissue), indicates that glucose delivery into cells is a process of considerable complexity.
Abstract: A pathogenic role of the kidney in hypertension has been strongly supported by experimental studies by Guyton and Dahl since the 1960s. In the early 1980s, de Wardener and MacGregor proposed that in hypertensive patients the ability of the kidneys to excrete a sodium load could be genetically impaired. Since then, "sodium-sensitive" hypertension has been the object of numerous studies, mostly on animal models because of the difficulty to investigate the renal handling of sodium in humans. More recently, considerable progress in this field has been made thanks to the in vivo study of segmental renal tubular function by the clearance of lithium and to the growing knowledge of the genetics of renal tubular sodium transport systems. The scope of this review is to briefly review the most relevant information gathered by the investigation of segmental renal tubular sodium handling in humans as related to blood pressure regulation and hypertension. In aggregate, the results of these studies strongly support the association between altered renal sodium handling and high blood pressure and suggest a causal role of genetic, nutritional, metabolic, and neurohormonal factors. All of these factors, alone or in combination, may be able to impair the normal renal tubular sodium handling and influence blood pressure homeostasis. The paradigm of the pathogenic role of the kidney in hypertension is thus relentlessly shifting toward the definition of inherited as well as acquired renal tubular defects and molecular alterations, providing a plausible explanation for the alteration in blood pressure levels.
Abstract: The ventilatory response to mild-to-moderate exercise in humans is isocapnic, or ’error-free’. It has been suggested that this response is learned over many repetitions of exercise through the process of minimising any deviations from normal in the blood gas tensions, as sensed by the chemoreceptors. However, relatively limited training programmes have failed to produce any convincing evidence in humans that forcibly altering the blood gas tensions during repeated periods of exercise alters the subsequent steady-state ventilatory response to exercise. In this study, eight healthy young subjects were exposed, over a 7 day training period, to a total of 70 repeated bouts of exercise paired with a simultaneous airway CO2 load to stimulate the chemoreceptors (protocol EX + CO2). The ventilatory response to exercise was measured before and after training to determine whether it had been modified. Two further training protocols were undertaken as controls. One employed repeated exercise without an airway CO2 load, and the other employed repeated airway CO2 loading without exercise. On the 1st and 2nd days following training with protocol EX + CO2, end-tidal PCO2 was regulated at a lower level during steady-state exercise than following training with the control protocols and than before training (mean +/- S.E.M. reduction in end-tidal PCO2 = 1.32 +/- 0.36 Torr, ANOVA, P \textless 0.05). In contrast to previous studies, this finding demonstrates that the steady-state ventilatory response to exercise can be modified by a prior period of altered chemoreception during exercise. This suggests that ventilation is matched to metabolic rate during exercise by a mechanism that involves learning and memory.
Abstract: OBJECTIVE: Adipose tIssue regulates insulin sensitivity via the circulating adipocytokines, leptin, resistin and adiponectin. The objective of this study was to compare the levels of resistin, adiponectin and leptin in lean and obese subjects and determine the relationship between circulating adipocytokines and insulin resistance. METHODS: We examined plasma levels of resistin, adiponectin and leptin in 17 lean subjects with a mean body mass index (BMI) of approximately 23 and 34 non-diabetic obese individuals with a mean BMI approximately 33. Insulin resistance was assessed using the homeostasis model assessment ratio (HOMA-R) formula derived from fasting insulin and glucose levels. RESULTS: Resistin levels were not significantly different between the two groups but were significantly higher in women compared with men, 35.4+/-6.5 (s.e.) vs 15.4+/-2.9 microg/L, P\textless0.01. Resistin did not correlate with BMI but did significantly correlate with HOMA-R, P\textless0.01, and this correlation remained significant after adjustment for gender and BMI. Adiponectin levels were significantly lower in obese compared with lean subjects, P\textless0.005, and higher in women, P\textless0.001, but showed no significant correlation with HOMA-R. Leptin levels were significantly higher in obese subjects and women and correlated with HOMA-R and resistin. DISCUSSION: In this small group of patients we demonstrated that insulin resistance correlated most strongly with leptin levels. A significant correlation between resistin levels and insulin resistance was also observed. Although a similar trend was apparent for adiponectin, the correlation with insulin resistance did not achieve statistical significance.
Abstract: PURPOSE: To analyze anatomoclinic and evolutive aspects of the renal involvement associated to the Behçet’s disease through 6 observations collected in the nephrology department from 1985 to 2000 and to make a review of the literature. METHODS: Retrospective study, diagnosis of Behçet’s disease according to the Classification of the International Group Study on the Behçet’s disease and renal damage confirmed by histology. RESULTS: Our patients all male are aged between 25 to 55 years with a mean at 34 years old. The renal damage was revelated by a nephrotic syndrome in 3 cases and by a proteinuria at 1 to 2.7 g/day in 3 cases. Microscopic hematuria was present in 2 cases and arterial hypertension in 2 cases. The renal insufficiency has been noted in 2 cases of which severe in one of them. The renal biopsy showed an amyloidosis AA type in 3 cases, a segmental and focal glomerulonephritis in 2 cases and a thrombotic microangiopathy associated to a moderate tubulo-interstitiel lesions by toxicity of ciclosporine in 1 case. The extrarenal signs were dominated by bipolar aphtosis in all cases, necrotic pseudofolliculitis and the no specific cutaneous hyperreactivity in 5 cases and the erythema nodosum in 1 case. The ocular manifestation has been noted in 4 cases and articular manifestation in 3 cases. The vascular manifestation has been noted in one case. The treatment was colchicine in 4 cases and prednisone and cyclophosphamide in 1 case. Three patients were lost of view and a patient died in hemodialysis. The 2 other patients with amylosis had persistent proteinuria with a normal renal function. CONCLUSION: The kidney is one of organs that can alter the prognosis of the Behçet’s disease; so, its screening must be realised in each patient with this disease.
Abstract: Anesthetics, widely used in magnetic resonance imaging (MRI) studies to avoid movement artifacts, could have profound effects on cerebral blood flow (CBF) and cerebrovascular coupling relative to the awake condition. Quantitative CBF and tissue oxygenation (blood oxygen level-dependent [BOLD]) were measured, using the continuous arterial-spin-labeling technique with echo-planar-imaging acquisition, in awake and anesthetized (2% isoflurane) rats under basal and hypercapnic conditions. All basal blood gases were within physiologic ranges. Blood pressure, respiration, and heart rates were within physiologic ranges in the awake condition but were depressed under anesthesia (P \textless 0.05). Regional CBF was heterogeneous with whole-brain CBF values of 0.86 +/- 0.25 and 1.27 +/- 0.29 mL. g-1. min-1 under awake and anesthetized conditions, respectively. Surprisingly, CBF was markedly higher (20% to 70% across different brain conditions) under isoflurane-anesthetized condition compared with the awake state (P \textless 0.01). Hypercapnia decreased pH, and increased Pco(2) and Po(2). During 5% CO(2) challenge, under awake and anesthetized conditions, respectively, CBF increased 51 +/- 11% and 25 +/- 4%, and BOLD increased 7.3 +/- 0.7% and 5.4 +/- 0.4%. During 10% CO(2) challenge, CBF increased 158 +/- 28% and 47 +/- 11%, and BOLD increased 12.5 +/- 0.9% and 7.2 +/- 0.5%. Since CBF and BOLD responses were substantially higher under awake condition whereas blood gases were not statistically different, it was concluded that cerebrovascular reactivity was suppressed by anesthetics. This study also shows that perfusion and perfusion-based functional MRI can be performed in awake animals.
Abstract: Ghrelin is a newly discovered peptide hormone produced by the stomach that displays potent growth hormone-releasing activity and a stimulatory effect on food intake and digestive function while reducing energy expenditure. The isolation of ghrelin has led to new insights into how this gastric hormone links the endocrine control of nutritional homeostasis with growth hormone secretion and gastrointestinal motility through gut-brain interactions.
Abstract: Hormone-sensitive lipase (HSL) is a major enzyme for triglyceride (TG) lipolysis in adipose tissue. In HSL-knockout mice, plasma free fatty acid and TG levels are low, associated with low liver TG content. Because a decreased hepatic insulin sensitivity has been reported to be associated with high liver TG levels, our aim was to determine whether a hepatic TG content lower than normal, as observed in HSL-knockout mice, leads to increased hepatic insulin sensitivity. Therefore, hyperinsulinemic clamp experiments in combination with D-(3)H-glucose were used. Furthermore, hepatic insulin receptor and phosphorylated protein kinase B (PKB-P)/akt were analyzed by Western blotting. No significant differences where observed in insulin-mediated whole-body glucose uptake between HSL-knockout and control mice. Interestingly, hepatic insulin sensitivity of HSL-knockout mice was increased, because insulin caused a greater reduction in endogenous glucose production ( approximately 71% compared with approximately 31% in control mice; P \textless 0.05), despite decreased plasma adiponectin levels. PKB/akt phosphorylation and phosphatidylinositol-3-kinase activity was significantly higher in livers of HSL-knockout mice after insulin stimulation. In HSL-knockout mice, reduced hepatic TG stores result in an increased suppressive effect of insulin on hepatic glucose production, in line with an increased hepatic PKB-P/akt and phosphatidylinositol-3 kinase activity. Thus, hepatic insulin sensitivity is indeed increased after reducing hepatic TG stores below normal.
Abstract: AIMS: To investigate resistin concentrations in patients with essential hypertension and different glucose tolerance and the relationship between serum resistin level and blood glucose. METHODS: Sixty-five patients with essential hypertension [13 with Type 2 diabetes mellitus (DM), 26 with impaired glucose tolerance (IGT), and 26 with normal glucose tolerance (NGT); 30 males, 35 females] were studied. Fasting serum resistin concentrations were measured by enzyme immunoassay (EIA). Oral glucose tolerance tests and insulin release tests were used to calculate glucose area under the curve (AUCG), the ratio of insulin to glucose (DeltaI30/DeltaG30), and insulin sensitivity index (ISI) according to Cederholm’s formula. RESULTS: Fasting serum resistin concentrations (microg/l) in DM (34.9 +/- 10.2) patients were significantly higher than those in IGT (25.1 +/- 10.4) (P \textless 0.05) and in NGT (21.5 +/- 7.9) (P \textless 0.05) patients. Pearson correlation showed that fasting serum resistin concentration was correlated with AUCG (r = 0.445, P \textless 0.001), ISI (r = -0.322, P \textless 0.01) and DeltaI30/DeltaG30 (r = -0.366, P \textless 0.01), but not body mass index and waist-hip ratio. After adjustment for gender, age and body mass index (BMI), partial correlation analysis showed that the fasting serum resistin concentrations were still correlated with AUCG (r = 0.327, P \textless 0.01) and DeltaI30/DeltaG30 (r = -0.348, P \textless 0.01), but ISI. CONCLUSION: Resistin may be involved in the development of diabetes in humans.
Abstract: Diabetes mellitus contributes greatly to morbidity, mortality, and overall health care costs. In major part, these outcomes derive from the high incidence of progressive kidney dysfunction in patients with diabetes making diabetic nephropathy a leading cause of end-stage renal disease. A better understanding of the early dysfunctions observed in the diabetic kidney may permit the development of new strategies to prevent diabetic nephropathy. This review proposes a "tubulo-centric" view of glomerular function in early type I diabetes mellitus. The following are particularly discussed (1) the primary role of an increase in reabsorption by the proximal tubule in early glomerular hyperfiltration, (2) the role of sodium-glucose cotransport and tubular growth under these conditions, and (3) the primary role of reabsorption by the proximal tubule for the paradoxical relationship between dietary salt and glomerular filtration rate. Finally, an outline is presented of potential therapeutic implications for the prevention of diabetic kidney disease.
Abstract: Nephrotic syndrome is a clinical and laboratory syndrome caused by the increased permeability of the glomerular capillary wall for macromolecules. Nephrotic syndrome is a potentially life-threatening state and persistent nephrotic syndrome has a poor prognosis with a high risk of progression to end-stage renal failure and a high risk of cardiovascular complications due to severe hyperlipidemia. Pathogenesis of increased glomerular permeability in different glomerular diseases has not been fully elucidated. Recently, identification of the mutated genes for some podocyte proteins (nephrin, podocin, alpha-actinin-4) in rare familial forms of nephrotic syndrome shed has new light on the molecular mechanisms of glomerular permselectivity. Gradually it becomes apparent that sporadic mutations of podocyte proteins (e.g., podocin) may be present even in some patients with acquired nephrotic syndrome. Expression of other podocyte proteins may change during the course of experimental nephrotic syndrome, possibly as a response to podocyte damage resulting either in apoptosis or stimulation of proliferation and some form of repair, including glomerular sclerosis. Better understanding of these mechanisms could clearly also have therapeutic implications. Glomerular permeability factors are believed to play a role in some noninflammatory glomerular diseases, mainly minimal change disease and focal segmental glomerulosclerosis, but their molecular identification remains elusive, possibly due to the nonhomogeneous nature of the underlying diseases. As an example, focal segmental glomerulosclerosis possibly can be caused by the sporadic mutation of some genes for podocyte proteins, increased production of glomerular permeability factor (possibly by T lymphocytes), or the loss of inhibitors of glomerular permeability factors in nephrotic urine. Clearly the factors causing increased glomerular permeability and factors perpetuating glomerular sclerosis are not necessarily the same. Proteinuria does not seem to be only the consequence of glomerular damage, but it may possibly cause tubular damage and initiate interstitial fibrosis and thus contribute to the progression of chronic renal failure in proteinuric renal diseases. Recent insights into the mechanisms of tubular protein reabsorption may give new tools for preventing the progression of chronic renal disease. Cubilin inhibitors could potentially ameliorate tubular and interstitial damage in patients with heavy proteinuria refractory to treatment. Nephrotic hyperlipidemia is accompanied with increased risk of cardiovascular complications and should be treated in all patients with persistent nephrotic syndrome. The putative positive effect of hypolipidemic drugs (namely statins) on the cardiovascular risk and potentially also on the rate of progression of chronic renal failure remains to be demonstrated in prospective controlled studies. Recent progress in understanding podocyte biology in rare inherited glomerular diseases gives the chance to understand in the near future the molecular pathogenesis of increased glomerular permeability in the much more common acquired forms of nephrotic syndrome.
Abstract: The human red cell has proved to be an invaluable model cell for the study of many aspects of membrane structure and function. It has a series of transport pathways which mediate the movements of the univalent cations Na and K, which are either identical or similar to systems in other human tissues, including the human kidney. The balance between the energy-consuming NaK pump and a ’passive leak’ component maintains a net deficit of cations within the cell, which defends the cell volume against osmotic swelling. There exist a series of dominantly inherited human red cell conditions, gathered under the generic title ’hereditary stomatocytoses’, in which the so-called ’passive leak’ to Na and K is pathologically increased. In the more severe variants this compromises the integrity of the cell and the patients suffer haemolytic anaemia. Some less severe variants present with pseudohyperkalaemia caused by loss of K from red cells on storage of blood at room temperature. The most severe variants show a deficiency in a widely distributed ’raft’ protein known as stomatin. The stomatin protein is homologous to the ’podocin’ protein, the gene for which is mutated in a recessively inherited form of nephrotic syndrome. Among other possible functions, both proteins could be involved in the trafficking of membrane proteins to and from the plasma membrane.
Abstract: In every nephron the glomerular filtration rate is adapted to changes in the salt concentration of early distal tubular fluid through the mechanism of tubuloglomerular feedback. Recent studies indicate that adenosine and possibly ATP mediate this mechanism and demonstrate its role in glomerular hemodynamic alterations in the early diabetic kidney.
Abstract: Our previous work indicates that myocardial ischemia could be the mechanism responsible for the left ventricular (LV) dysfunction that frequently develops after massive sympathetic nervous system (SNS) activation. In this study, coronary blood flow (CBF) and myocardial ATP, creatine phosphate, and lactate concentrations were measured after massively activating the SNS of anesthetized rabbits with an intracisternal injection of veratrine. CBF was measured at time 0 (baseline), and at 2, 10, and 20 min after SNS activation in one group, and at 0, 45, 90, and 150 min in a second group. Myocardial ATP, creatine phosphate, and lactate were measured at 0, 2, 10, 20, 90, and 150 min in separate groups of rabbits. SNS activation caused LV dysfunction in approximately 60% of the rabbits. SNS-related increases in CBF kept pace with the increases in myocardial energy demand as determined from the systolic pressure-heart rate product. The subendocardial-to-subepicardial blood flow ratio did not change significantly. Myocardial creatine phosphate concentration was depressed 2 min after SNS activation and remained depressed for at least 20 min. ATP fell continuously and was significantly lower than baseline by 20 min. Tissue lactate concentration was elevated at this time. By 90 min, the concentrations of all three metabolites had recovered. These results indicate that myocardial high-energy phosphate compounds fall after massive SNS activation, but ischemia does not appear to be the underlying mechanism.
Abstract: About 20% of astronauts suffer postspaceflight presyncope. We studied pre- to postflight (5- to 16-day missions) cardiovascular responses to standing in 35 astronauts to determine differences between 1) men and women and 2) presyncopal and nonpresyncopal groups. The groups were presyncopal women, presyncopal men, and nonpresyncopal men based on their ability to stand for 10 min postflight. Preflight, women and presyncopal men had low vascular resistance, with the women having the lowest. Postflight, women experienced higher rates of presyncope (100 vs. 20%; P = 0.001) and greater losses of plasma volume (20 vs. 7%; P \textless 0.05) than men. Also, presyncopal subjects had lower standing mean arterial pressure (P \textless or = 0.001) and vascular resistance (P \textless 0.05), smaller increases in norepinephrine (P \textless or = 0.058) and greater increases in epinephrine (P \textless or = 0.058) than nonpresyncopal subjects. Presyncopal subjects had a strong dependence on plasma volume to maintain standing stroke volume. These findings suggest that postflight presyncope is greatest in women, and this can be ascribed to a combination of inherently low-resistance responses, a strong dependence on volume status, and relative hypoadrenergic responses. Conversely, high vascular resistance and postflight hyperadrenergic responses prevent presyncope.
Abstract: GFR varies inversely with dietary NaCl in patients with early type I diabetes and in streptozotocin (STZ)-diabetic rats. To explain this paradox within the laws of physiology, it was hypothesized that it results from heightened sensitivity of the diabetic proximal tubule to dietary salt because changes in proximal reabsorption (Jprox) elicit reciprocal adjustments in GFR through the normal actions of tubuloglomerular feedback (TGF). Micropuncture was done in rats after 5 wk of moderately hyperglycemic STZ-diabetes and 1 wk of different NaCl diets. First, single-nephron GFR (SNGFR) and early distal tubular Na(+), Cl(-) and K(+) concentration (representing the TGF signal) were measured by collecting from early distal nephrons. In nondiabetics, dietary salt did not affect SNGFR or the TGF signal. In diabetics, the TGF signal varied directly with dietary salt while SNGFR varied inversely with dietary salt. Next, Jprox was measured by collecting from late proximal tubules. To control for different SNGFR, SNGFR was manipulated by perfusing Henle’s loop to alter TGF activity. Controlling for SNGFR, dietary salt did not affect Jprox in nondiabetics but exerted a major inverse impact on Jprox in diabetics. In conclusion, normal rats acclimate to dietary NaCl by primarily adjusting transport downstream of the macula densa. In contrast, diabetes renders reabsorption in the proximal tubule sensitive to dietary NaCl with subsequent effects on the TGF signal. This explains the paradoxical effect of dietary NaCl on GFR in early diabetes.
Abstract: Increased glomerular permeability of the glomerular capillary wall for macromolecules caused by the changes of the structure of the glomerular basement membrane, or podocytes and slit diaphragm between foot processes of podocytes is the main cause of nephrotic syndrome. Recently new information about podocyte proteins emerged. Mutation of the basic structural protein of slit diaphragm, nephrin, results in the Finnish type of the congenital nephrotic syndrome, mutations of other podocyte proteins, e.g. podocin, or alpha-actinin-4 result in congenital focal segmental glomerulosclerosis. Primary focal segmental glomerulosclerosis is a clinical syndrome, caused either by the mutation of podocyte proteins, or by circulating permeability factors, or by the deficiency of their circulating inhibitors. New information about the role of cubilin and megalin in the reabsorption of filtered albumin in the proximal tubule may contribute to the elucidation of the mechanisms of the tubulotoxicity of proteinuria; inhibition of albumin reabsorption in nephrotic subjects could lower the risk of interstitial fibrosis and progressive renal insufficiency.
Abstract: We determined whether interindividual variation in hepatic insulin sensitivity could be attributed to variation in liver fat content (LFAT) independent of obesity. We recruited 30 healthy nondiabetic men whose LFAT (determined by proton spectroscopy); intraabdominal, sc, and total (determined by magnetic resonance imaging) fat; and insulin sensitivity of endogenous glucose rate of production (R(a)) and suppression of serum FFA [euglycemic insulin clamp combined with [3-(3)H]glucose (0-300 min); insulin infusion rate, 0.3 mU/kg.min, 120-300 min] were measured. The men were divided into groups of low (mean +/- SD, 1.7 +/- 0.2%) and high (10.5 +/- 2.0%) LFAT based on their median fat content. The low and high LFAT groups were comparable with respect to age (44 +/- 2 vs. 42 +/- 2 yr), body mass index (25 +/- 1 vs. 26 +/- 1 kg/m(2) ), waist to hip ratio (0.953 +/- 0.013 vs. 0.953 +/- 0.013), maximal oxygen uptake (35.6 +/- 1.5 vs. 33.5 +/- 1.5 ml/kg.min), and intraabdominal, sc, and total fat. The high compared with the low LFAT group had several features of insulin resistance, including fasting hyperinsulinemia (7.3 +/- 0.6 vs. 5.3 +/- 0.6 mU/liter; P \textless 0.02, high vs. low LFAT) hypertriglyceridemia (1.4 +/- 0.2 vs. 0.9 +/- 0.1 mmol/liter; P \textless 0.02), a low high density lipoprotein (HDL) cholesterol concentration (1.4 +/- 0.1 vs. 1.6 +/- 0.1 mmol/liter; P \textless 0.05), and a higher ambulatory 24-h systolic blood pressure (130 +/- 3 vs. 122 +/- 3 mm Hg; P \textless 0.05). Basal glucose R(a) and serum FFA were comparable between the groups, whereas insulin suppression of glucose R(a) [51 +/- 8 vs. 20 +/- 12 mg/m(2).min during 240-300 min (P \textless 0.05) or -55 +/- 7 vs. -85 +/- 12% below basal (P \textless 0.05, high vs. low LFAT)] and of serum FFA (299 +/- 33 vs. 212 +/- 13 micromol/liter; 240-300 min; P \textless 0.02) were impaired in the high compared with the low LFAT group. Insulin stimulation of glucose Rd were comparable in the men with high LFAT (141 +/- 12 mg/m(2).min) and those with low LFAT (156 +/- 14 mg/m(2).min; P = NS). Fat accumulation in the liver is, independent of body mass index and intraabdominal and overall obesity, characterized by several features of insulin resistance in normal weight and moderately overweight subjects.
Abstract: 1. This review is presented with the intent of illustrating the representative studies of functional and myocardial energetic consequences of hearts with postinfarction left ventricular (LV) remodelling or with concentric hypertrophy and diastolic LV dysfunction in porcine models. 2. Both eccentric and concentric cardiac hypertrophy are associated with the abnormal myocardial energetics that are most severe in hearts with congestive heart failure (CHF). Presently, these abnormalities cannot be satisfactorily explained to be the cause(s) of the dysfunction of failing hearts or cause the progress from compensated cardiac hypertrophy to CHF. 3. Mechanisms governing abnormal myocardial high-energy phosphate (HEP) metabolism in hearts with cardiac hypertrophy and CHF are unclear. Myocardial energy metabolism studies use both kinetic and thermodynamic models. The thermodynamic studies examine the myocardial steady state levels of high- and low-energy phosphate, which indicate myocardial energy state or phosphorylation potential that is defined by the ratio of [ATP]/([ADP][Pi]). The kinetics studies examine the reaction velocity that is regulated by: (i) quantity and activity of the key enzymes; (ii) the concentrations of all the substrates and products; and (iii) the Michaelis-Menten constants of each substrate of the reaction. 4. Significant alterations in myocardial concentrations of phosphocreatine (PCr), ATP and ADP, myocardial oxidative phosphorylation (OXPHOS) protein expression and substrate preference are found in hearts with postinfarction LV remodelling and CHF. However, to define a causal relationship is a different matter. 5. Future studies of animal models of LV hypertrophy or heart failure using gene manipulation may provide additional insights to answer the persisting question of whether limitations of ATP synthetic or transport capacities contribute to the pathogenesis of LV remodelling or failure.
Abstract: Rapid minimization of energy consumption in excitable tissues is effective protection from lethal effects of extreme metabolic stress. The ATP-sensitive K(+) channels in the brain respond in ATP-depleted metabolic states such as hypoxia and may be involved in the protection mechanism against energy-consuming generalized seizure.
Abstract: 1. Metabolic processes are acutely and chronically regulated in response to changes in the workload of the heart. Acute changes in cardiac work result in activation and inactivation of existing enzymes and in altered fluxes through existing metabolic pathways. Sustained or chronic changes in cardiac work result in both trophic and transcriptional alterations. 2. The metabolic consequences of a sustained increase or decrease in the workload of the heart are surprisingly uniform and consist of a switch from the predominant oxidation of fatty acids to oxidation of glucose. 3. This switch is reflected in the changes of the transcript levels of three key regulators of mitochondrial function: pyruvate dehydrogenase kinase 4 (PDK4), which phosphorylates and inactivates the pyruvate dehydrogenase complex, malonyl-CoA decarboxylase (MCD), which regulates malonyl-CoA levels and, therefore, rates of beta-oxidation of long-chain fatty acids, and uncoupling protein 3 (UCP-3), which uncouples the oxidative phosphorylation of ADP. 4. The transcript levels of all three proteins are downregulated in hypertrophy as well as in atrophy of rat heart. All three transcripts are transcriptionally regulated by the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha). 5. Diminished expression of PPARalpha and PPARalpha-regulated genes constitutes an adaptive mechanism in response to altered workload, because reactivation of PPARalpha in hypertrophied heart results in severe contractile dysfunction.
Abstract: Orthostatic intolerance following prolonged exposure to microgravity continues to be a primary concern of the human space program. Reduced autonomic tone has been demonstrated to contribute to this phenomenon, and the heart rate baroreflex, in particular, has been repeatedly shown to be impaired. However, only the works of Yelle et al. have attempted to address the role of the total peripheral resistance (TPR) baroreflex, a potentially more significant contributor to blood pressure regulation. We applied a previously developed method for estimating the static gains of both the arterial and cardiopulmonary TPR baroreflexes to data obtained before and after 16-day bed rest. Reductions in the estimated static gains of the arterial (statistically significant) and cardiopulmonary TPR baroreflexes were found after bed rest. This study supports the works of Yelle et al, which imply that the TPR baroreflex is reduced after spaceflight.
Abstract: Intracellular acidosis due mainly to lactic acid accumulation has been regarded as the most important cause of skeletal muscle fatigue. Recent studies on mammalian muscle, however, show little direct effect of acidosis on muscle function at physiological temperatures. Instead, inorganic phosphate, which increases during fatigue due to breakdown of creatine phosphate, appears to be a major cause of muscle fatigue.
Abstract: When evaluating dyspnea in patients with heart or lung disease it is useful to measure the quantity of ventilation needed to eliminate metabolically produced CO2 (i.e., the ventilatory efficiency). Mathematically, the relationship between ventilation (VE) and CO2 output is determined by the arterial CO2 pressure and the physiologic dead space-tidal volume ratio. We decided to determine how age, sex, size, fitness, and the type of ergometer influenced ventilatory efficiency in normal subjects. Three methods were compared for expressing this relationship: (1) the VE versus CO2 output slope below the ventilatory compensation point, commonly used by cardiologists for estimating the severity of heart failure; (2) the VE/CO2 output ratio at the anaerobic threshold, commonly used by pulmonologists; and (3) the lowest VE/CO2 output ratio during exercise, the latter parameter not previously reported. We studied 474 healthy adults, between 17 and 78 years of age during incremental cycle and treadmill cardiopulmonary exercise tests at three test sites, correcting the total VE for the equipment dead space. The lowest VE/CO2 output ratio was insignificantly different from the ratio at the anaerobic threshold, less variable than that for the slope relationship, and unaffected by the site, ergometer, and gas exchange measurement systems. The regression equation for the lowest VE/CO2 output ratio was 27.94 + 0.108 x age + (0.97 = F, 0.0 = M) - 0.0376 x height, where age is in years and height is in centimeters. We conclude that the lowest VE/CO2 output ratio is the preferred noninvasive method to estimate ventilatory inefficiency.
Abstract: OBJECTIVE : Several studies have shown that arginine vasopressin (AVP) potentiates the sympathetic nervous transmission in isolated vessels. The present study investigates such a potentiation in the pithed rat model. METHODS : Male Wistar rats weighing 270-310 g were used. Spinal-cord stimulation was applied, with frequencies of 0.25-4 Hz, in the presence or absence of a subpressor dose of intravenous (i.v.) AVP (1 pmol/kg per min). In addition, the effect of AVP on postsynaptic alpha-adrenoceptor-mediated responses was studied using exogenously administered noradrenaline (NA). For this purpose dose-response curves (DRCs) for NA (i.v.) were constructed. RESULTS : In the pithed rat model endogenously generated angiotensin II facilitates neurally mediated increments in vascular resistance. Without the administration of the angiotensin II type 1 (AT1) antagonist, irbesartan, the facilitating effect of AVP was not visible. However, after the administration of the AT1 antagonist, irbesartan, the facilitating effect of AVP became apparent. The stimulation-induced rise in diastolic blood pressure (DBP) was enhanced in the presence of AVP from 63.7 +/- 4.5 to 78.6 +/- 4.2 mmHg, at a stimulation frequency of 4 Hz. The vasopressin receptor V1 antagonist, SR-49059, completely inhibited this AVP-induced facilitation, whereas the V2 antagonist, SR-121463B, or the V2 agonist, desmopressin, did not. The DRC of exogenously administered NA was not influenced by AVP. CONCLUSION : The stimulating effect of AVP on sympathetic neurotransmission is completely dependent on the stimulation of presynaptically located V1 receptors. The facilitating effect of angiotensin II on the sympathetic nervous system (SNS) in the pithed rat model masks the facilitating effect of AVP in this preparation.
Abstract: OBJECTIVE : Arginine vasopressin (AVP) not only acts directly on blood vessels through vasopressin V1 receptor stimulation but also may modulate adrenergic-mediated responses in animal experiments. The aim of the present study was to assess whether subpressor concentrations of AVP could contribute to an abnormal adrenergic contractile response of human renal arteries. METHODS : Renal artery rings were obtained from 27 patients undergoing nephrectomy. The rings were suspended in organ bath chambers for isometric recording of tension. RESULTS : AVP (10(-10) mol/l) and the vasopressin V1 receptor agonist [Phe2, Orn8]-vasotocin (10(-10) mol/l) produced a leftward shift of the concentration-response curve to noradrenaline (half-maximal effective concentration decreased from 1.1 x 10(-6) mol/l to 3.1 x 10(-7) mol/l). The enhancement of noradrenaline-induced contractions was inhibited by the vasopressin V1 receptor antagonist d(CH2)5Tyr(Me)AVP (10-8 mol/l) and unaffected by endothelium removal or pretreatment with the inhibitor of nitric oxide (NO) synthase NG-monomethyl-l-arginine (l-NMMA). The vasopressin V2 receptor agonist 1-desamino-8-D-arginine vasopressin (dDAVP) (10(-10)-10(-8) mol/l) did not modify contractile responses to noradrenaline. In the presence of the dihydropyridine calcium antagonist nifedipine (10(-6) mol/l), vasopressin failed to enhance the contractile response to noradrenaline. CONCLUSIONS : The results demonstrate that subpressor concentrations of vasopressin potentiate the contractile effects of noradrenaline without intervention of the NO system. The effects appear to be mediated by vasopressin V1 receptor stimulation, which brings about an increase in calcium entry through dihydropyridine-sensitive calcium channels.
Abstract: Glucose is cleared from the bloodstream by a family of facilitative transporters (GLUTs), which catalyze the transport of glucose down its concentration gradient and into cells of target tissues, primarily striated muscle and adipose. Currently, there are five established functional facilitative glucose transporter isoforms (GLUT1-4 and GLUTX1), with GLUT5 being a fructose transporter. GLUT1 is ubiquitously expressed with particularly high levels in human erythrocytes and in the endothelial cells lining the blood vessels of the brain. GLUT3 is expressed primarily in neurons and, together, GLUT1 and GLUT3 allow glucose to cross the blood-brain barrier and enter neurons. GLUT2 is a low-affinity (high Km) glucose transporter present in liver, intestine, kidney, and pancreatic beta cells. This transporter functions as part of the glucose sensor system in beta cells and in the basolateral transport of intestinal epithelial cells that absorb glucose from the diet. A new facilitative glucose transporter protein, GLUTX1, has been identified and appears to be important in early blastocyst development. The GLUT4 isoform is the major insulin-responsive transporter that is predominantly restricted to striated muscle and adipose tissue. In contrast to the other GLUT isoforms, which are primarily localized to the cell surface membrane, GLUT4 transporter proteins are sequestered into specialized storage vesicles that remain within the cell’s interior under basal conditions. As postprandial glucose levels rise, the subsequent increase in circulating insulin activates intracellular signaling cascades that ultimately result in the translocation of the GLUT4 storage compartments to the plasma membrane. Importantly, this process is readily reversible such that when circulating insulin levels decline, GLUT4 transporters are removed from the plasma membrane by endocytosis and are recycled back to their intracellular storage compartments. Therefore, by establishing an internal membrane compartment as the default localization for the GLUT4 transporters, insulin-responsive tissues are poised to respond rapidly and efficiently to fluctuations in circulating insulin levels. Unfortunately, the complexity of these regulatory processes provides numerous potential targets that may be defective and eventually result in peripheral tissue insulin resistance and possibly diabetes. As such, understanding the molecular details of GLUT4 expression, GLUT4 vesicle compartment biogenesis, GLUT4 sequestration, vesicle trafficking, and fusion with the plasma membrane has become a major focus for many laboratories. This chapter will focus on recently elucidated insulin signal transduction pathways and GLUT4 vesicle trafficking components that are necessary for insulin-stimulated glucose uptake and GLUT4 translocation in adipocytes.
Abstract: BACKGROUND: Cardiac dysfunction after brain death has been documented, but its mechanisms remain unclear. Myocardial ischemia has been suggested as a possible cause. The aim of the present study was to investigate the existence of an imbalance between myocardial oxygen delivery and demand as a possible cause of myocardial dysfunction in brain-dead pigs. METHODS AND RESULTS: Interstitial myocardial lactate and adenosine concentrations were assessed with cardiac microdialysis in 2 groups of animals: brain-dead pigs (n=7) and brain-dead pigs treated with labetalol (10+/-3 mg/kg) (n=7). Heart rate (HR), left ventricular (LV) dP/dt(max), rate-pressure product (RPP), cardiac output (CO), and left anterior descending coronary artery blood flow (QLAD) were continuously monitored. Brain-dead pigs exhibited a transient significant increase in HR, LV dP/dt(max), RPP, and CO and a limited increase in QLAD. This resulted in functional myocardial ischemia attested to by the significantly increased adenosine and lactate microdialysate concentrations. In brain-dead pigs treated with labetalol, there was a moderate increase in HR, QLAD, and adenosine microdialysate concentrations; LV dP/dt(max), RPP, CO, and myocardial lactate concentrations remained stable, confirming the preservation of aerobic metabolism. CONCLUSIONS: Brain death was associated with an increase in myocardial interstitial adenosine and lactate concentrations, as well as with myocardial dysfunction; all were attenuated by labetalol, suggesting an imbalance between oxygen consumption and oxygen delivery as a possible cause of myocardial dysfunction after brain death.
Abstract: OBJECTIVE: To test the hypothesis that altered loading conditions play a key role in hemodynamic instability and cardiac dysfunction in the brain dead (BD) organ donor. METHODS: BD was induced by inflation of a subdural balloon catheter. In the first part of the study, left ventricular function was assessed in a canine in situ cross-circulated heart model (n=6). Pre- and afterload and coronary perfusion pressure were kept identical in all hearts throughout the experiment. In the second part of the study, hearts (n=6) were investigated in vivo allowing the interaction between left ventricular contractility and arterial load. Left ventricular pressure–volume loops were obtained by a combined conductance-pressure catheter and the slope of the endsystolic pressure–volume relationship (Ees), arterial elastance (Ea), stroke work (SW), pressure–volume area, ventriculo–arterial coupling ratio (VAC) and mechanical efficiency (Eff) were calculated. RESULTS: Induction of BD led to a hyperdynamic response in both models with a significant increase of most hemodynamic parameters. In the in situ isolated heart model, left ventricular contractility returned to baseline without any further deterioration. In contrast, in the intact circulation the hemodynamic parameters declined significantly in comparison to baseline 4 h after BD (Ees: 4.07+/-0.51 vs. 8.06+/-1.09 mmHg/ml, P\textless0.05, Ea: 3.17+/-0.39 vs. 4.42+/-0.30 mmHg/ml, P\textless0.05). However, VAC (0.78+/-0.09 vs. 0.65+/-0.14 n.s.) and Eff (73.4+/-2.1 % vs. 76.8+/-3.7 %, n.s.) remained constant over the time. CONCLUSION: BD induction leads to an initial hyperdynamic reaction followed by hemodynamic instability. The facts that no cardiac dysfunction occurred if loading conditions were kept constant and the ventriculo–arterial coupling ratio and mechanical efficiency remained constant in the intact animal model indicate that decreased contractility reflects to decreased arterial elastance after brain death. Therefore, reduced contractile function after brain death at a decreased afterload may contribute to stroke work optimization.
Abstract: Based on observations in 110 children with nephrotic syndrome (NS) and data from the literature, existing concepts on the pathogenesis of edema formation in the NS have been modified. The data suggest that the basic abnormality is a primary disturbance in renal sodium excretion. Depending on the stage in the development of the NS, the rate of progression in the development of hypoproteinemia, and the absolute levels of plasma oncotic pressure, functional hypovolemia may develop, resulting in stimulation of hemostatic mechanisms and secondary sodium retention. This applies as much to patients with minimal change NS as to patients with histological lesions. Alterations in kidney function (glomerular filtration rate, renal plasma flow, filtration fraction) in the NS cannot be explained by hypo- or hypervolemia, but reflect variations in plasma oncotic pressure and glomerular basement membrane permeability. These abnormalities will also influence sodium excretion. Evaluation of the presence of functional hypovolemia will have therapeutic consequences. A quick diagnosis can be made by assessment of FENa+ and UK+/ (UK+ + UNa+) Sodium retention associated with increased distal Na/K exchange indicates functional hypovolemia, and may be treated by albumin infusion if clinically required.
Abstract: To calculate cardiac output by the indirect Fick principle, CO(2) concentrations (CCO(2)) of mixed venous (Cv(CO(2))) and arterial blood are commonly estimated from PCO(2), based on the assumption that the CO(2) pressure-concentration relationship (PCO(2)-CCO(2)) is influenced more by changes in Hb concentration and blood oxyhemoglobin saturation than by changes in pH. The purpose of the study was to measure and assess the relative importance of these variables, both in arterial and mixed venous blood, during rest and increasing levels of exercise to maximum (Max) in five healthy men. Although the mean mixed venous PCO(2) rose from 47 Torr at rest to 59 Torr at the lactic acidosis threshold (LAT) and further to 78 Torr at Max, the Cv(CO(2)) rose from 22.8 mM at rest to 25.5 mM at LAT but then fell to 23.9 mM at Max. Meanwhile, the mixed venous pH fell from 7.36 at rest to 7.30 at LAT and to 7.13 at Max. Thus, as work rate increases above the LAT, changes in pH, reflecting changes in buffer base, account for the major changes in the PCO(2)-CCO(2) relationship, causing Cv(CO(2)) to decrease, despite increasing mixed venous PCO(2). Furthermore, whereas the increase in the arteriovenous CCO(2) difference of 2.2 mM below LAT is mainly due to the increase in Cv(CO(2)), the further increase in the arteriovenous CCO(2) difference of 4.6 mM above LAT is due to a striking fall in arterial CCO(2) from 21.4 to 15.2 mM. We conclude that changes in buffer base and pH dominate the PCO(2)-CCO(2) relationship during exercise, with changes in Hb and blood oxyhemoglobin saturation exerting much less influence.
Abstract: The effects of posture on the lymphatic outflow pressure and lymphatic return of albumin were examined in 10 volunteers. Lymph flow was stimulated with a bolus infusion of isotonic saline (0.9%, 12.6 ml/kg body wt) under four separate conditions: upright rest (Up), upright rest with lower body positive pressure (LBPP), supine rest (Sup), and supine rest with lower body negative pressure (LBNP). The increase in plasma albumin content (Delta Alb) during the 2 h after bolus saline infusion was greater in Up than in LBPP: 82.9 +/- 18.5 vs. -28.4 mg/kg body wt. Delta Alb was greater in LBNP than in Sup: 92.6 vs. -22.5 +/- 18.9 mg/kg body wt (P \textless 0.05). The greater Delta Alb in Up and Sup with LBNP were associated with a lower estimated lymphatic outflow pressure on the basis of the difference in central venous pressure (Delta CVP). During LBPP, CVP was increased compared with Up: 3.8 +/- 1.4 vs. -1.2 +/- 1.2 mmHg. During LBNP, CVP was reduced compared with Sup: -3.0 +/- 2.2 vs. 1.7 +/- 1.0 mmHg. The translocation of protein into the vascular space after bolus saline infusion reflects lymph return of protein and is higher in Up than in Sup. Modulation of CVP with LBPP or LBNP in Up and Sup, respectively, reversed the impact of posture on lymphatic outflow pressure. Thus posture-dependent changes in lymphatic protein transport are modulated by changes in CVP through its mechanical impact on lymphatic outflow pressure.
Abstract: Leptin deficiency, found in transgenic lipodystrophic mice and in obese (ob/ob) mice, was shown to cause increased lipogenesis in liver, through action of the sterol regulatory element-binding protein-1c, and increased liver gluconeogenesis, through a decline in the insulin receptor substrate-2. The resulting stimulation of insulin secretion by the pancreas owing to high blood glucose initiates a vicious cycle of insulin resistance.
Abstract: 1. We recently showed that fatigue of the inspiratory muscles via voluntary efforts caused a time-dependent increase in limb muscle sympathetic nerve activity (MSNA) (St Croix et al. 2000). We now asked whether limb muscle vasoconstriction and reduction in limb blood flow also accompany inspiratory muscle fatigue. 2. In six healthy human subjects at rest, we measured leg blood flow (.Q(L)) in the femoral artery with Doppler ultrasound techniques and calculated limb vascular resistance (LVR) while subjects performed two types of fatiguing inspiratory work to the point of task failure (3-10 min). Subjects inspired primarily with their diaphragm through a resistor, generating (i) 60 % maximal inspiratory mouth pressure (P(M)) and a prolonged duty cycle (T(I)/T(TOT) = 0.7); and (ii) 60 % maximal P(M) and a T(I)/T(TOT) of 0.4. The first type of exercise caused prolonged ischaemia of the diaphragm during each inspiration. The second type fatigued the diaphragm with briefer periods of ischaemia using a shorter duty cycle and a higher frequency of contraction. End-tidal P(CO2) was maintained by increasing the inspired CO(2) fraction (F(I,CO2)) as needed. Both trials caused a 25-40 % reduction in diaphragm force production in response to bilateral phrenic nerve stimulation. 3. .Q(L) and LVR were unchanged during the first minute of the fatigue trials in most subjects; however, .Q(L) subsequently decreased (-30 %) and LVR increased (50-60 %) relative to control in a time-dependent manner. This effect was present by 2 min in all subjects. During recovery, the observed changes dissipated quickly (\textless 30 s). Mean arterial pressure (MAP; +4-13 mmHg) and heart rate (+16-20 beats min(-1)) increased during fatiguing diaphragm contractions. 4. When central inspiratory motor output was increased for 2 min without diaphragm fatigue by increasing either inspiratory force output (95 % of maximal inspiratory pressure (MIP)) or inspiratory flow rate (5 x eupnoea), .Q(L), MAP and LVR were unchanged; although continuing the high force output trials for 3 min did cause a relatively small but significant increase in LVR and a reduction in .Q(L). 5. When the breathing pattern of the fatiguing trials was mimicked with no added resistance, LVR was reduced and .Q(L) increased significantly; these changes were attributed to the negative feedback effects on MSNA from augmented tidal volume. 6. Voluntary increases in inspiratory effort, in the absence of diaphragm fatigue, had no effect on .Q(L) and LVR, whereas the two types of diaphragm-fatiguing trials elicited decreases in .Q(L) and increases in LVR. We attribute these changes to a metaboreflex originating in the diaphragm. Diaphragm and forearm muscle fatigue showed very similar time-dependent effects on LVR and .Q(L).
Abstract: BACKGROUND: A critical point in oxygen supply for microvascular oxygenation during normovolemic hemodilution has not been identified. The relation between organ microvascular oxygen partial pressure (microPO2) and organ oxygen consumption (VO2) during a decreasing oxygen delivery (DO2) is not well understood. The present study was designed to determine the systemic hematocrit and organ DO2 values below which organ microPO2 and VO2 cannot be preserved by regulatory mechanisms during normovolemic hemodilution. METHODS: Eighteen male Wistar rats were randomized between an experimental group (n = 12), in which normovolemic hemodilution was performed with pasteurized protein solution (PPS), and a control group (n = 6). Systemic hemodynamic and intestinal oxygenation parameters were monitored. Intestinal microPO2 was measured using the oxygen-dependent quenching of palladium-porphyrin phosphorescence. RESULTS: Baseline values in hemodilution and control group were similar. Hemodilution decreased hematocrit to 6.2 +/- 0.8% (mean +/- SD). Constant central venous pressure measurements suggested maintenance of isovolemia. Despite an increasing mesenteric blood flow, intestinal DO2 decreased immediately. Initially, microPO2 was preserved, whereas mesenteric venous PO2 (P(mv)O2) decreased; below a hematocrit of 15%, microPO2 decreased significantly below P(mv)O2. Critical DO2 was 1.5 +/- 0.5 ml x kg(-1) x min(-1) for VO2, and 1.6 +/- 0.5 ml x kg(-1) x min(-1) for microPO2. Critical hematocrit values for VO2 and microPO2 were 15.8 +/- 4.6% and 16.0 +/- 3.5%, respectively. CONCLUSIONS: Intestinal microPO2 and VO2 were limited by a critical decrease in DO2 and hematocrit at the same time. Beyond these critical points not only shunting of oxygen from the microcirculation could be demonstrated, but also a significant correlation between intestinal microPO2 and VO2.
Abstract: The renin-angiotensin system is one of the most widely studied endocrine systems. It has an important role in the regulation of normal homeostasis, and disturbances in this system may be important in numerous pathological states. This review will focus on the major insights and important questions raised from gene targeting of this system.
Abstract: Many astronauts after being weightless in space become hypotensive and presyncopal when they assume an upright position. This phenomenon, known as orthostatic intolerance, may interfere with astronaut function during reentry and after spaceflight and may limit the ability of an astronaut to exit a landed spacecraft unaided during an emergency. Orthostatic intolerance is more pronounced after long-term spaceflight and is a major concern with respect to the extended flights expected aboard the International Space Station and for interplanetary exploration class missions, such as a human mission to Mars. Fully effective countermeasures to this problem have not yet been developed. To test the hypothesis that alpha-adrenergic stimulation might provide an effective countermeasure, we conducted a 16-day head-down-tilt bed-rest study (an analog of weightlessness) using normal human volunteers and administered the alpha(1)-agonist drug midodrine at the end of the bed-rest period. Midodrine was found to significantly ameliorate excessive decreases in blood pressure and presyncope during a provocative tilt test. We conclude that midodrine may be an effective countermeasure for the prevention of orthostatic intolerance following spaceflight.
Abstract: Findings from recent bed rest and spaceflight human studies have indicated that the inability to adequately elevate the peripheral resistance and the altered autoregulation of cerebral vasculature are important factors in postflight orthostatic intolerance. Animal studies with rat model have revealed that simulated microgravity may induce upward and downward regulations in the structure, function, and innervation of the cerebral and hindquarter vessels. These findings substantiate in general the hypothesis that microgravity-induced redistribution of transmural pressures and flows across and within the arterial vasculature may well initiate differential adaptations of vessels in different anatomic regions. Understanding of the mechanisms involved in vascular adaptation to microgravity is also important for the development of multisystem countermeasures. However, future studies will be required to further ascertain the peripheral effector mechanism of postflight cardiovascular dysfunction.
Abstract: Chronic microgravity may modify adaptations of the leg circulation to gravitational pressures. We measured resting calf compliance and blood flow with venous occlusion plethysmography, and arterial blood pressure with sphygmomanometry, in seven subjects before, during, and after spaceflight. Calf vascular resistance equaled mean arterial pressure divided by calf flow. Compliance equaled the slope of the calf volume change and venous occlusion pressure relationship for thigh cuff pressures of 20, 40, 60, and 80 mmHg held for 1, 2, 3, and 4 min, respectively, with 1-min breaks between occlusions. Calf blood flow decreased 41% in microgravity (to 1.15 +/- 0.16 ml x 100 ml(-1) x min(-1)) relative to 1-G supine conditions (1.94 +/- 0.19 ml x 100 ml(-1) x min(-1), P = 0.01), and arterial pressure tended to increase (P = 0.05), such that calf vascular resistance doubled in microgravity (preflight: 43 +/- 4 units; in-flight: 83 +/- 13 units; P \textless 0.001) yet returned to preflight levels after flight. Calf compliance remained unchanged in microgravity but tended to increase during the first week postflight (P \textgreater 0.2). Calf vasoconstriction in microgravity qualitatively agrees with the "upright set-point" hypothesis: the circulation seeks conditions approximating upright posture on Earth. No calf hemodynamic result exhibited obvious mechanistic implications for postflight orthostatic intolerance.
Abstract: Studies in which GLUT4 has been overexpressed in transgenic mice provide definitive evidence that glucose transport is rate limiting for muscle glucose disposal. Transgenic overexpression of GLUT4 selectively in skeletal muscle results in increased whole body glucose uptake and improves glucose homeostasis. These studies strengthen the hypothesis that the level of muscle GLUT4 affects the rate of whole body glucose disposal, and underscore the importance of GLUT4 in skeletal muscle for maintaining whole body glucose homeostasis. Studies in which GLUT4 has been ablated or ’knocked-out’ provide proof that GLUT4 is the primary effector for mediating glucose transport in skeletal muscle and adipose tissue. Genetic ablation of GLUT4 results in impaired insulin tolerance and defects in glucose metabolism in skeletal muscle and adipose tissue. Because impaired muscle glucose transport leads to reduced whole body glucose uptake and hyperglycaemia, understanding the molecular regulation of glucose transport in skeletal muscle is important to develop effective strategies to prevent or reduce the incidence of Type II diabetes mellitus. In patients with Type II diabetes mellitus, reduced glucose transport in skeletal muscle is a major factor responsible for reduced whole body glucose uptake. Overexpression of GLUT4 in skeletal muscle improves glucose homeostasis in animal models of diabetes mellitus and protects against the development of diabetes mellitus. Thus, GLUT4 is an attractive target for pharmacological intervention strategies to control glucose homeostasis. This review will focus on the current understanding of the role of GLUT4 in regulating cellular glucose uptake and whole body glucose homeostasis.
Abstract: Blood substitutes (modified hemoglobin solutions, perfluorocarbon emulsions) serve as artificial oxygen carriers and are alternatives to blood transfusions. Hemoglobin solutions mimic the sigmoidal oxygen dissociation curve of natural blood. Perfluorocarbon emulsions exhibit a linear relation between PO2 and dissolved oxygen. The most advanced substances may enter medicine in few years.
Abstract: Diabetes mellitus is a chronic disease that leads to complications including heart disease, stroke, kidney failure, blindness and nerve damage. Type 2 diabetes, characterized by target-tissue resistance to insulin, is epidemic in industrialized societies and is strongly associated with obesity; however, the mechanism by which increased adiposity causes insulin resistance is unclear. Here we show that adipocytes secrete a unique signalling molecule, which we have named resistin (for resistance to insulin). Circulating resistin levels are decreased by the anti-diabetic drug rosiglitazone, and increased in diet-induced and genetic forms of obesity. Administration of anti-resistin antibody improves blood sugar and insulin action in mice with diet-induced obesity. Moreover, treatment of normal mice with recombinant resistin impairs glucose tolerance and insulin action. Insulin-stimulated glucose uptake by adipocytes is enhanced by neutralization of resistin and is reduced by resistin treatment. Resistin is thus a hormone that potentially links obesity to diabetes.
Abstract: We studied the role of cardiac and arterial baroreceptors in the reflex control of arginine vasopressin (AVP) and renin secretion during graded hypotension in conscious dogs. The dogs were prepared with Silastic cuffs on the thoracic inferior vena cava and catheters in the pericardial space. Each experiment consisted of a control period followed by four periods of inferior vena caval constriction, during which mean arterial pressure (MAP) was reduced in increments of approximately 10 mmHg. The hormonal responses were measured in five dogs under four treatment conditions: 1) intact, 2) acute cardiac denervation (CD) by intrapericardial infusion of procaine, 3) after sinoaortic denervation (SAD), and 4) during combined SAD+CD. The individual slopes relating MAP to plasma AVP and plasma renin activity (PRA) were used to compare the treatment effects using a 2 x 2 factorial analysis. There was a significant (P \textless 0.01) effect of SAD on the slope relating plasma AVP to MAP but no effect of CD and no SAD x CD interaction. In contrast, the slope relating PRA and MAP was increased (P \textless 0.05) by SAD but was not affected by CD. These results support the hypothesis that stimulation of AVP secretion in response to graded hypotension is primarily driven by unloading arterial baroreceptors in the dog.
Abstract: Vasodilator responses were assessed in resistance arteries (100-200 microm) isolated from the gracilis muscle of normotensive rats after changes in dietary salt intake. Sprague-Dawley rats were maintained on either a high-salt (HS) diet (4.0% NaCl) or a low-salt (LS) diet (0.4% NaCl) for 4-8 wk (chronic) or 3 days (short-term) with water ad libitum. One group of short-term HS rats received a continuous intravenous infusion of a low dose (5 ng x kg(-1) x min(-1)) of ANG II to prevent the ANG II suppression that occurs with HS diet. Short-term and chronic HS diet eliminated arterial dilation in response to ACh and reduced PO(2) (30-40 mmHg) and the stable prostacyclin analog iloprost. ANG II infusion preserved the response to these vasodilator stimuli in short-term HS animals. Dilator responses to sodium nitroprusside and forskolin were unaffected by HS diet. These findings suggest that ANG II suppression during HS diet impairs vascular relaxation mechanisms upstream from the cAMP and cGMP second messenger systems.
Abstract: Mice null for adipocyte fatty acid binding protein (AFABP) compensate by increasing expression of keratinocyte fatty acid binding protein (KFABP) (Hotamisligil et al. Science 274:1377-1379, 1996). In the present study, AFABP knockout (KO) and wild-type (WT) mice became equally obese on a high-fat diet, as judged by fat pad weights, adipocyte size, and body composition analysis. High-fat feeding led to moderate insulin resistance in both WT and AFABP knockout mice, as indicated by an approximately 2-fold increase in plasma insulin. However, in the high fat-fed mice, plasma glucose levels were approximately 15% lower in the AFABP-KO mice. Adipocytes isolated from AFABP-KO and WT mice fed high- or low-fat diets exhibited similar rates of basal and norepinephrine-stimulated lipolysis and insulin-stimulated rates of glucose conversion to fatty acids and glyceride-glycerol. However, basal glucose conversion to fatty acids was higher in adipocytes of AFABP-KO mice. Adipocyte tumor necrosis factor-alpha release was similarly increased by high-fat diet-induced obesity in both WT and AFABP-KO mice. As assessed by Western blot analysis, the level of KFABP protein in AFABP-KOs was approximately 40% of the level of AFABP in WT controls. The binding affinities of KFABP for long-chain fatty acids were 2- to 4-fold higher than those of AFABP, but the relative affinities for different fatty acids were similar. As for AFABP, the rate of fatty acid transfer from KFABP to model phospholipid vesicles was increased with acceptor membrane concentration and by inclusion of acidic phospholipids, indicating a similar mechanism of transfer. We conclude KFABP can functionally compensate for the absence of AFABP, resulting in no major alterations in adipocyte metabolism or fat accumulation in response to short-term feeding of high-fat diets that result in moderate hyperinsulinemia.
Abstract: We investigated the relationship between pericardial pressure and the volumetric lymphatic clearance rate of pericardial fluid in sheep. A single catheter perfusion system was established to deliver tracer to the pericardial cavity and control pericardial pressure. In addition, catheters were placed into the thoracic duct and into the jugular vein at the base of the neck. (125)I-human serum albumin (HSA) was administered into the pericardial perfusate to serve as the lymph flow marker and its concentration monitored in the effluent from the outflow end of the perfusion system. (131)I-HSA was injected intravenously to permit calculation of plasma tracer loss and tracer recirculation into lymphatics. From mass balance equations, estimates of total pericardial clearance into lymphatics increased significantly as pericardial pressures were elevated in 2. 5 cm H(2)O increments from 2.5 to 12.5 cm H(2)O (P = 0.018). Pericardial lymph transport ranged from 0.89 +/- 0.10 to 3.09 +/- 0. 66 ml/h at 2.5 and 12.5 cm H(2)O pericardial pressure, respectively. The majority of transport occurred through mediastinal vessels with a small proportion (10.3 to 23.9%) being cleared into lymphatics leading to the thoracic duct. We conclude that lymphatic pericardial fluid transport increases approximately 3.5-fold over a pericardial pressure range that encompasses the transition between the shallow and steep portions of the pericardial pressure-volume relationship.
Abstract: BACKGROUND: Little is known about the onset and degree of biochemical and functional alterations in calcium metabolism during microgravity. OBJECTIVE: To evaluate the effect of microgravity on intestinal calcium absorption and calcium-regulating hormones under metabolic ward conditions. MATERIALS AND METHODS: Fractional calcium absorption (Fc240 in percentage of dose administered) was determined pre-flight, in-flight and post-flight, by use of a stable strontium test in one cosmonaut who spent 20 days in space. Moreover, a sequence of blood samples was collected for the determination of serum parathyroid hormone (PTH), 25-hydroxyvitamin D, calcitriol and serum C-telopeptide (CTx, biomarker of bone resorption) levels. During all periods of data collection, calcium intake was held constant at a minimum level of 1.000 mg day(-1) and a daily supplement of 16.6 microg vitamin D2 was given. Personal ultraviolet (UV) light exposure was measured during the whole mission using a biologically weighting UV dosimeter. RESULTS: Fc240 was markedly reduced on flight day 19 (4.4%) as compared to pre-flight and post-flight data (13.4% and 17.2%, respectively). Serum calcitriol levels fell from 40.6 pg mL(-1) (mean pre-flight level) to 1.3 pg mL(-1) on flight day 18 and returned into the normal range after recovery. Serum CTx increased during the flight, while serum PTH and 25-hydroxyvitamin D levels did not change significantly. CONCLUSIONS: Intestinal calcium absorption can be diminished after only three weeks of microgravity. Changes are associated with a severe suppression of circulating calcitriol levels, but are independent of exogenous vitamin D supply and serum PTH levels.
Abstract: Space flight is associated with the loss of skeletal muscle, principally from muscles with anti-gravity functions. Examination of data across different missions can permit a distinction to be made between true microgravity responses and what are mission-specific responses. Protein metabolism has been investigated on six missions, four short-term [Shuttle missions Space Life Sciences 1 (1991, SLSI), Space Life Sciences 2 (1993, SLS2), Deutsche-2 (1993, D2) and the Life and Microgravity Sciences (1996, LMS)] and two long-term missions (Skylab 1993 and NASA/MIR, 1996-1998). Measurements made include dietary intake (six missions), nitrogen balance (four missions), whole-body protein kinetics with [15N]glycine as the tracer (four missions) and cortisol excretion (three missions). Also available for comparison are bed rest studies with and without exercise. The purpose of this paper is to see what can be learnt about the muscle loss problem by comparing metabolic results across the six missions for which data are available and against bed rest. The analysis suggests that there is a linkage between the inability to maintain energy balance and exercise, and the connection is the decreased efficiency of removal of the metabolic by-products of exercise (heat, CO2) during space flight.
Abstract: Acute and long-term effects of resistance exercise combined with vascular occlusion on muscular function were investigated. Changes in integrated electromyogram with respect to time (iEMG), vascular resistive index, and plasma lactate concentration were measured in five men either during or after elbow flexion exercises with the proximal end of the arm occluded at 0-100 mmHg. The mean iEMG, postexercise hyperemia, and plasma lactate concentration were all elevated with the increase in occlusion pressure at a low-intensity exercise, whereas they were unchanged with the increase in occlusion pressure at high-intensity exercise. To investigate the long-term effects of low-intensity exercise with occlusion, older women (n = 24) were subjected to a 16-wk exercise training for elbow flexor muscles, in which low-intensity [ approximately 50-30% one repetition maximum (1 RM)] exercise with occlusion at approximately 110 mmHg (LIO), low-intensity exercise without occlusion (LI), and high- to medium-intensity ( approximately 80-50% 1 RM) exercise without occlusion (HI) were performed. Percent increases in both cross-sectional area and isokinetic strength of elbow flexor muscles after LIO were larger than those after LI (P \textless 0.05) and similar to those after HI. The results suggest that resistance exercise at an intensity even lower than 50% 1 RM is effective in inducing muscular hypertrophy and concomitant increase in strength when combined with vascular occlusion.
Abstract: Recent evidence suggests that energy substrate metabolism forms the link between gene expression and contractile function of the heart. This hypothesis draws on three seemingly unconnected observations, made in 1941 by three different investigators. The first gave rise to the concept of the dynamic nature of body constituents, the second to the concept of one gene for one enzyme, and the third to the concept of energy conservation in the phosphate bond of adenosine triphosphate (ATP), the "approximate P." The heart employs different mechanisms to adapt to acute and to sustained changes in energy demand. While acute changes in energy demand are met by the coordinated activation or inactivation of enzymes, chronic changes in energy demand are met by adjustments in the rate of "metabolic" gene expression which are often isoform specific. Transcriptional analysis by quantitative polymerase chain reaction (PCR) defines changes in energy substrate metabolism in response to an altered physiologic environment at the transcriptional level. The paradigm of cardiac hypertrophy and atrophy has revealed a surprisingly uniform and rapid response in cardiac gene expression including the reactivation of fetal metabolic genes. The physiologic consequences are revealed in a shift in substrate utilization from fatty acids to glucose. Clinical consequences include a change in metabolic gene expression of the failing human heart, including the downregulation of glucose transporters and the enzymes of fatty acid metabolism. Although it is possible to study regulation of metabolism at the level of gene expression, the complexities of the interactions between metabolic intermediates and transcription factors may be difficult to elucidate by simple reductionist approaches. A model of feedback/feedforward between genes and proteins is needed to explain the principle of reestablishing homeostatic control of metabolism as cellular and external environments change.
Abstract: Altered glucose homeostasis in the different diabetic states often results from a combination of insulin deficiency (absolute or relative), and impaired hormone action. The latter involves alterations in the expression and/or function of glucose transporters in insulin responsive peripheral tissues - skeletal muscle and adipose tissue. Since whole body glucose utilization depends mainly on controlled changes in glucose transport in these tissues, this review focuses on the role of glucose transporters in the regulation of insulin-stimulated glucose transport activity. The molecular mechanisms by which several inducers of insulin resistance inhibit insulin action on glucose uptake are also discussed. Better understanding of the complex regulation of glucose transport and transporters will hopefully shed light on potential sites for new pharmaceutical interventions. Several excellent reviews have been published in the past 2 years detailing various aspects which are discussed only briefly in this review. They are mentioned in the text to allow further reading.
Abstract: PURPOSE: This paper examines the production of lactate in human skeletal muscle over a range of power outputs (35-250% VO2max) from an enzymatic flux point of view. The conversion of pyruvate and NADH to lactate and NAD in the cytoplasm of muscle cells is catalyzed by the near-equilibrium enzyme lactate dehydrogenase (LDH). As flux through LDH is increased by its substrates, pyruvate and NADH, the factors governing the production of these substrates will largely dictate how much lactate is produced at any exercise power output. In an attempt to understand lactate production, flux rates through the enzymes that regulate glycogenolysis/glycolysis, the transfer of cytoplasmic reducing equivalents into the mitochondria, and the various fates of pyruvate have been measured or estimated. RESULTS: At low power outputs, the rates of pyruvate and NADH production in the cytoplasm are low, and pyruvate dehydrogenase (PDH) and the shuttle system enzymes (SS) metabolize the majority of these substrates, resulting in little or no lactate production. At higher power outputs (65, 90, and 250% VO2max), the mismatch between the ATP demand and aerobic ATP provision at the onset of exercise increases as a function of intensity, resulting in increasing accumulations of the glycogenolytic/glycolytic activators (free ADP, AMP, and Pi). The resulting glycolytic flux, and NADH and pyruvate production, is progressively greater than can be handled by the SS and PDH, and lactate is produced at increasing rates. Lactate production during the onset of exercise and 10 min of sustained aerobic exercise may be a function of adjustments in the delivery of O2 to the muscles, adjustments in the activation of the aerobic ATP producing metabolic pathways and/or substantial glycogenolytic/glycolytic flux through a mass action effect.
Abstract: Adipocyte fatty acid-binding protein, aP2, is a member of the intracellular fatty acid binding protein family. Previously, studies have shown increased insulin sensitivity in aP2-deficient mice with dietary obesity. Here, we asked whether aP2-related alterations in lipolytic response and insulin production are features of obesity-induced insulin resistance and investigated the effects of aP2-deficiency on glucose homeostasis and lipid metabolism in ob/ob mice, a model of extreme obesity. ob/ob mice homozygous for the aP2 null allele (ob/ ob-aP2-/-) became more obese than ob/ob mice as indicated by significantly increased body weight and fat pad size but unaltered body length. However, despite their extreme adiposity, ob/ob-aP2-/- animals were more insulin-sensitive compared with ob/ob controls, as demonstrated by significantly lower plasma glucose and insulin levels and better performance in both insulin and glucose tolerance tests. These animals also showed improvements in dyslipidemia and had lower plasma triglyceride and cholesterol levels. Lipolytic response to beta-adrenergic stimulation and lipolysis-associated insulin secretion was significantly reduced in ob/ob-aP2-/- mice. Interestingly, glucose-stimulated insulin secretion, while virtually abolished in ob/ob controls, was significantly improved in ob/ob-aP2-/- animals. There were no apparent morphological differences in the structure or size of the pancreatic islets between genotypes. Taken together, the data indicate that in obesity, aP2-deficiency not only improves peripheral insulin resistance but also preserves pancreatic beta cell function and has beneficial effects on lipid metabolism.
Abstract: Testosterone production rates were determined in 16 patients with Cushing’s syndrome (4 men and 12 women) using the stable-isotope dilution technique and mass spectrometry. 1alpha,2alpha-D-Testosterone was infused for 10 hours at a dose of 20 microg/h (men) and 0.4 microg/h (women) and blood samples were obtained at 20-minute intervals during the last 4 hours of the observation period. Estimated production rates in men with Cushing’s syndrome were 27, 73, 150, and 180 microg/h (mean, 106 +/- 70 microg/h; healthy men [n = 12], 210 +/- 70 microg/h). In the 12 women with Cushing’s syndrome, testosterone production rates were 0.3 to 22.3 microg/h (healthy women [n = 5], 4.3 +/- 1.9 microg/h). There was no difference in testosterone production rates in female patients with central (n = 8) versus adrenal (n = 4) Cushing’s syndrome. In summary, testosterone production rates are subnormal or low-normal in male patients with endogenous hypercortisolism, but not in female patients with the same disorder. We conclude that testosterone production in men, but not in women, is predominantly of gonadal origin and hence susceptible to a glucocorticoid-induced suppression of gonadotropin secretion.
Abstract: In mice with too little fat (lipodystrophy) or too much fat (ob/ob), leptin deficiency leads to hyperglycemia, hyperinsulinemia, and insulin resistance. In both disorders, the liver overproduces glucose as a result of resistance to the normal action of insulin in repressing mRNAs for gluconeogenic enzymes. Here we show that chronic hyperinsulinemia downregulates the mRNA for IRS-2, an essential component of the insulin-signaling pathway in liver, thereby producing insulin resistance. Despite IRS-2 deficiency, insulin continues to stimulate production of SREBP-1c, a transcription factor that activates fatty acid synthesis. The combination of insulin resistance (inappropriate gluconeogenesis) and insulin sensitivity (elevated lipogenesis) establishes a vicious cycle that aggravates hyperinsulinemia and insulin resistance in lipodystrophic and ob/ob mice.
Abstract: OBJECTIVES AND METHODS: Brain death related hemodynamic instability and/or cardiac dysfunction is frequently described in the potential organ donor which may lead to exclusion of the heart from transplantation. The underlying mechanisms are controversely discussed. Therefore, in the present study, potential brain death associated cardiodepressant factors were evaluated separately in cross-circulated canine heart models. Brain death was induced by inflation of a subdural balloon catheter. Loading conditions and coronary perfusion pressure were kept identical in all cross-circulated hearts throughout the experiment. RESULTS: Induction of brain death led to a significant hyperdynamic response in all groups, with a maximal effect by the combination of neural and humoral pathways. After the initial reaction all hemodynamic parameters returned to baseline and remained stable until the end of experiments. Even if the hearts were explanted from brain dead donors with typical hemodynamic deterioration in vivo, they showed no significant differences in comparison to the other groups including healthy controls ex vivo. CONCLUSIONS: Therefore we conclude, that hemodynamic instability in the potential donor may rather reflect altered loading conditions and impaired coronary perfusion than neuro-humorally mediated direct myocardial injury.
Abstract: The mechanisms of sodium retention in edema-forming minimal change nephrotic syndrome (MCNS) have not been completely evaluated. The aim of this study was to characterize the transmembrane sodium transport in nephrotic syndrome by measuring the erythrocyte sodium-lithium countertransport (SLC) in vitro. Eighteen children with MCNS were studied in the edema-forming state, and subsequently at the beginning of remission. Nephrotic children with edema retained sodium (10+/-12 micromol/day) and had a higher SLC [426+/-118 vs. 281+/-60 micromol/l red blood cells (RBC) per hour, P=0.003). The intracellular sodium concentration of nephrotics was 6.1+/-2.1 mmol/l RBC, which did not differ from that of controls (6.42+/-2.24, n=13). In remission sodium balance became negative (-30+/-21 mmol/day), and the SLC decreased but still differed significantly from control values (P=0.009). The intracellular sodium content decreased to 4.4+/-0.9 mmol/l RBC (P=0.002). There was a negative correlation between erythrocyte SLC and plasma albumin concentration (r=0.48, P=0.003), and urinary sodium excretion rate (r=0.66, P=0.001). In conclusion, erythrocyte SLC is high in the edema-forming state of childhood nephrotic syndrome and decreases with the onset of remission. A role for the SLC in the altered sodium homeostasis of nephrotic syndrome is suggested.
Abstract: Adult Ren-2 gene transgenic rats, TGR(mRen-2)27, exhibit elevated circulating and kidney angiotensin II (Ang II) levels in the presence of severe hypertension. The aim of this study was to examine whether AT1 and AT2 receptors in the kidney and renal hemodynamic and tubular responses to blockade of these receptors were altered in the Ren-2 gene transgenic rats during the maintenance phase of hypertension. Renal AT1 and AT2 receptors were mapped by in vitro autoradiography (n=8), and the effects of blockade of these receptors on mean arterial pressure (MAP), heart rate (HR), and renal cortical (CBF) and medullary blood flows (MBF) were studied in anaesthetized, adult age-matched male homozygous TGR rats (n=12) and Sprague-Dawley (SD) rats (n=7). TGR rats showed higher basal MAP (P\textless0.001), heart and kidney weight (P\textless0.001), plasma renin activity (P\textless0.05) and plasma Ang II level (P\textless0.05), and CBF (P\textless0.05) and MBF (P\textless0.05) than SD rats. AT1 receptor binding was significantly increased in the glomeruli, proximal tubules, and the inner stripe of the outer medulla of TGR rats (P\textless0.01), while the AT2 receptor binding was low at all renal sites of TGR and SD rats. Immunohistochemistry revealed that this increased AT1 receptor labeling occurred mainly in vascular smooth muscle layer of intrarenal blood vessels including afferent and efferent arterioles, juxtaglomerular apparatus, glomerular mesangial cells, proximal tubular cells, and renomedullary interstitial cells (RMICs) in the transgenic rats. Blockade of AT1 receptors with losartan in TGR rats markedly reduced MAP to the normotensive level (P\textless0.001) without altering HR. Both CBF (P\textless0.005) and MBF (P\textless0.05) were significantly increased by losartan in the transgenic rats. By contrast, losartan only caused a smaller decrease in MAP and an increase in renal CBF in SD rats (P\textless0.05). PD 123319 was without any renal effect in both SD and TGR rats. These findings suggest that markedly increased AT1 receptors in renal vasculature, glomerular mesangial cells, and RMICs in the presence of fulminant hypertension and elevated circulating and tissue Ang II levels may play an important role in the maintenance of hypertension in the Ren-2 gene transgenic rats.
Abstract: We hypothesized that nitric oxide (NO) opposes regional vasoconstriction caused by acute angiotensin II (ANG II) infusion in conscious rats. Mean arterial pressure (MAP), blood flow, and vascular conductance (regional blood flow/ MAP; ml/min/100 g/mm Hg) were measured and/or calculated before and at 2 min of ANG II infusion (0.05 or 1 microg/kg/min, i.a.) in the absence and presence of NO synthase (NOS) inhibition [N(G)-nitro-L-arginine methyl ester (L-NAME), 0.25 or 1 mg/kg, i.a.]. ANG II reduced stomach and hindlimb conductance only after NOS inhibition. For example, whereas 0.05 microg/kg/min ANG II did not attenuate conductance in the stomach (i.e., 1.04+/-0.08 to 0.93+/-0.12 ml/min/100 g/mm Hg), this variable was reduced (i.e., 0.57+/-0.14 to 0.34-/+0.05 ml/min/100 g/mm Hg; p \textless 0.05) when ANG II was infused after 0.25 mg/kg L-NAME. In addition, whereas hindlimb conductance was similar before and after administering 1 microg/kg/min ANG II (i.e., 0.13+/-0.01 and 0.09+/-0.02, respectively), this variable was reduced (i.e., 0.07+/-0.01 and 0.02+/-0.00, respectively; p \textless 0.05) when ANG II was infused after 1 mg/kg L-NAME. These findings indicate that NO opposes ANG II-induced vasoconstriction in the stomach and hindlimb. In contrast, whereas both doses of ANG II decreased (p \textless 0.05) vascular conductance in the kidneys and small and large intestine regardless of whether NOS inhibition was present, absolute vascular conductance was lower (p \textless 0.05) after L-NAME. For example, 1 microg/kg ANG II reduced renal conductance from 3.34+/-0.31 to 1.22+/-0.14 (p \textless 0.05). After 1 mg/kg L-NAME, renal conductance decreased from 1.39+/-0.18 to 0.72+/-0.16 (p \textless 0.05) during ANG II administration. Therefore the constrictor effects of NOS inhibition and ANG II are additive in these circulations. Taken together, our results indicate that the ability of NO to oppose ANG II-induced constriction is not homogeneous among regional circulations.
Abstract: Plasma TGs, FFAs, and muscle TG are oxidizable lipid fuel sources for skeletal muscle metabolism during prolonged exercise. Plasma FFAs are a major fuel oxidized by skeletal muscle, and their rate of use by muscle depends on several factors, including plasma FFA availability, transport from plasma to the mitochondria, and intracellular metabolism. Mobilization of FFAs from adipose tissue is the first committed step in FFA metabolism, and it depends on the rate of adipose tissue lipolysis. Adipose tissue lipolysis increases with exercise duration and exercise intensity up to intensities of approximately 60% to 65%. Evidence suggests that FFAs are transported from plasma to the mitochondria by FFA transporter proteins that include the plasma membrane and cytosolic FABPPM and FABPC. Plasma FFA use can also be regulated at the mitochondrial transport step by changing the activity of carnitine palmitoyltransferase (CPT-1). Although results from biopsy and tracer studies indicate that muscle TG contribute to skeletal muscle oxidative metabolism during exercise, their exact contribution is difficult to ascertain. Evidence shows that muscle TG use depends on exercise intensity, duration, and mode. The contribution of plasma TG to skeletal muscle metabolism is small. The rate of use of plasma TG is dependent on lipoprotein lipase activity, which is correlated with the oxidative capacity of the muscle fibers. Dietary manipulations can modulate substrate use during exercise and can potentially affect exercise performance. High carbohydrate availability before exercise is associated with an increase in blood glucose and plasma insulin concentrations, which can ultimately decrease the rate of adipose tissue lipolysis and the availability of plasma FFAs. Increased glucose flux has also been shown to decrease lipid oxidation by directly inhibiting the transport of FFAs across the mitochondrial membranes. High lipid availability can be changed by short-term or long-term exposure to high-fat diets. Because carbohydrate reserves are diminished with exposure to high-fat diets, improvements in exercise performance have been difficult to measure under these conditions.
Abstract: Most mammalian cell types, including endothelial cells, respond to cell swelling by activating a Cl- current termed ICl,swell, but it is not known how the physical stimulus of cell swelling is transferred to the channels underlying ICl,swell. We have investigated the precise relation between cell volume and ICl,swell in endothelial cells by performing whole-cell current recordings while continuously monitoring cell thickness (Tc) as a measure for cell volume. The time course of Tc was accurately predicted by a theoretical model that describes volume changes of patch-clamped cells in response to changes in the extracellular osmolality (OSMo). This model also predicts significant changes in intracellular ionic strength (Gammai) when OSMo is altered. Under all experimental conditions ICl,swell closely followed the changes in Gammai, whereas ICl,swell and cell volume were often found to change independently. These results do not support the hypothesis that Gammai regulates the volume set point for activation of ICl,swell. Instead, they are in complete agreement with a model in which a decrease of Gammai rather than an increase in cell volume is the initial trigger for activation of ICl,swell.
Abstract: BACKGROUND: Brain death results in a rapid decline in left ventricular function, which has clinical relevance for organ transplantation. The aim of the present study was to investigate coronary perfusion changes during brain death and their role in cardiac dysfunction. METHODS: In an in situ isolated canine heart model, brain death was induced by inflation of a subdural balloon catheter. The heart was perfused separately with the animal’s own blood by a pressure-controlled roller pump that was coupled to the measured aortic pressure. Myocardial contractility was estimated by the slope of the end-systolic pressure-volume relation. RESULTS: Induction of brain death resulted in a transient hyperdynamic response, followed by a significant decrease in systemic vascular resistance, coronary blood flow, and the end-systolic pressure-volume relation (p\textless0.05). However, if coronary perfusion pressure was decoupled from aortic pressure and elevated to pre-brain death levels, coronary blood flow and the end-systolic pressure-volume relation were also restored to baseline levels. CONCLUSION: Severe impairment of coronary blood flow may contribute to decreased contractility after brain death that can be reversed by modulation of coronary perfusion pressure.
Abstract: Our current understanding of the mechanism of fluid transport by epithelia relies upon mathematical models developed 30 years ago to explain the mechanism of solute-solvent coupling and the pathways taken by water across an epithelium. The validity of these models is reconsidered in light of recent findings, and it is concluded that a simple three-compartment model system is adequate to explain fluid absorption and secretion by epithelia.
Abstract: We examined whether the altered orthostatic tolerance following 14 days of head-down tilt bed rest (HDBR) was related to inadequate sympathetic outflow or to excessive reductions in cardiac output during a 10- to 15-min head-up tilt (HUT) test. Heart rate, blood pressure (BP, Finapres), muscle sympathetic nerve activity (MSNA, microneurography), and stroke volume blood velocity (SVV, Doppler ultrasound) were assessed during supine 30 degrees (5 min) and 60 degrees (5-10 min) HUT positions in 15 individuals who successfully completed the pre-HDBR test without evidence of orthostatic intolerance. Subjects were classified as being orthostatically tolerant (OT, n = 9) or intolerant (OI, n = 6) following the post-HDBR test. MSNA, BP, and SVV during supine and HUT postures were not altered in the OT group. Hypotension during 60 degrees HUT in the post-bed rest test for the OI group (P \textless 0.05) was associated with a blunted increase in MSNA (P \textless 0.05). SVV was reduced following HDBR in the OI group (main effect of HDBR, P \textless 0.02). The data support the hypothesis that bed rest-induced orthostatic intolerance is related to an inadequate increase in sympathetic discharge that cannot compensate for a greater postural reduction in stroke volume.
Abstract: Insulin receptor substrates (Irs proteins) mediate the pleiotropic effects of insulin and Igf-1 (insulin-like growth factor-1), including regulation of glucose homeostasis and cell growth and survival. We intercrossed mice heterozygous for two null alleles (Irs1+/- and Irs2+/-) and investigated growth and glucose metabolism in mice with viable genotypes. Our experiments revealed that Irs-1 and Irs-2 are critical for embryonic and post-natal growth, with Irs-1 having the predominant role. By contrast, both Irs-1 and Irs-2 function in peripheral carbohydrate metabolism, but Irs-2 has the major role in beta-cell development and compensation for peripheral insulin resistance. To establish a role for the Igf-1 receptor in beta-cells, we intercrossed mice heterozygous for null alleles of Igf1r and Irs2. Our results reveal that Igf-1 receptors promote beta-cell development and survival through the Irs-2 signalling pathway. Thus, Irs-2 integrates the effects of insulin in peripheral target tissues with Igf-1 in pancreatic beta-cells to maintain glucose homeostasis.
Abstract: Space travel causes rapid and pronounced skeletal muscle wasting in humans that reduces their long-term flight capabilities. To develop effective countermeasures, the basis of this atrophy needs to be better understood. Space travel may cause muscle atrophy indirectly by altering circulating levels of factors such as growth hormone, glucocorticoids, and anabolic steroids and/or by a direct effect on the muscle fibers themselves. To determine whether skeletal muscle cells are directly affected by space travel, tissue-cultured avian skeletal muscle cells were tissue engineered into bioartificial muscles and flown in perfusion bioreactors for 9 to 10 days aboard the Space Transportation System (STS, i.e., Space Shuttle). Significant muscle fiber atrophy occurred due to a decrease in protein synthesis rates without alterations in protein degradation. Return of the muscle cells to Earth stimulated protein synthesis rates of both muscle-specific and extracellular matrix proteins relative to ground controls. These results show for the first time that skeletal muscle fibers are directly responsive to space travel and should be a target for countermeasure development.
Abstract: The natriuretic and diuretic action of a highly selective adenosine A1 receptor (A1AdoR) antagonist, 1,3-dipropyl-8-[2-(5,6-epoxy)norbornyl]xanthine (CVT-124), was investigated in anesthetized rats. CVT-124 (0.1 to 1 mg/kg) caused dose-dependent increases in urine flow and fractional and absolute sodium excretion of by six- to 10-fold and, at 0.1 mg/kg, increased the GFR (1.6+/-0.1 to 2.5+/-0.2 ml/min; P\textless0.01). There were no changes in BP or heart rate. CVT-124 reduced absolute proximal reabsorption (26+/-3 to 20+/-2 nl/min; P\textless0.05) despite unchanged proximally measured, single-nephron GFR (SNGFR) (42+/-5 to 44+/-4 nl/min; NS) and thereby decreased fractional proximal reabsorption (60+/-3 to 46+/-4%; P\textless0.05). Despite increasing distal tubular fluid flow rate (5.4+/-0.7 to 9.7+/-0.9 nl/min; P\textless0.001), it reduced the proximal-distal difference in SNGFR (before: 9.4+/-1.0 versus during CVT-124: 4.6+/-1.5 nl/min; P\textless0.01), suggesting that it had blunted the effects of the macula densa on SNGFR. Direct measurements of maximal tubuloglomerular feedback (TGF) responses were made from proximal stop flow pressure (PSF) during orthograde loop perfusion from the proximal tubule with artificial tubular fluid at 40 nl/min. TGF was blunted by intravenous CVT-124 (0.5 mg/kg; deltaPSF with vehicle: 8.3+/-0.6 versus CVT-124: 6.5+/-0.3 mm Hg; n = 9; P\textless0.01). In conclusion, A1AdoR blockade reduces proximal reabsorption and uncouples it from glomerular filtration. It increases distal delivery of fluid yet does not activate a macula densa-dependent fall in SNGFR because it blunts the TGF response. Natriuresis accompanied by blockade of proximal glomerulotubular balance and TGF characterizes a new class of diuretic drugs.
Abstract: The impact of sodium intake and changes in total body sodium (TBS) for the setting of pressure-dependent renin release (PDRR) was studied in freely moving dogs. An aortic cuff allowed servo control of renal perfusion pressure (RPP) at preset values. Protocols were 1) high sodium intake (HSI), 2) low sodium intake (LSI), 3) TBS moderately increased (+3.1 mmol Na/kg body wt) by 20% reduction of RPP for 2-4 days, 4) large increase of TBS (+8.2) by combining protocol 3 with aldosterone infusion, and 5) TBS reduced (-3.1) by peritoneal dialyses. Twenty-four-hour time courses of arterial plasma renin activity (PRA) revealed that LSI increased PRA for the first 10 h only; afterward PRA did not differ between LSI and HSI. Reduced TBS increased PRA constantly, and the large increase of TBS constantly reduced PRA. PDRR stimulus-response curves (assessed 20 h after last sodium intake) revealed an exponential relationship in each protocol. PDRR was not changed by different sodium intake. Conversely, reduced TBS increased PDRR markedly, whereas the large increase of TBS suppressed it. Thus an inverse relationship between TBS and PRA, i.e., a TBS-dependent renin release, was found. This relationship was enhanced by decreasing RPP. This interplay between TBS-dependent renin release and PDRR allows the organism a differentiated reaction to changes in TBS and arterial pressure.
Abstract: The contributions of increases in circulating catecholamines, changes in central command, and muscle afferents on baroreflex control of the sinus node during exercise are unclear. We used a dobutamine infusion to induce hemodynamic changes comparable to those of moderate physical exercise in the absence of changes in central command and muscle afferents in 13 healthy subjects. Dobutamine (up to 9 microg/kg body weight per minute) increased systolic blood pressure, shortened the RR interval, increased systolic blood pressure variability, but blunted RR interval variability (P\textless0.05 versus placebo). Consequently, dobutamine decreased the coherence between variations in systolic blood pressure and RR interval and decreased arterial baroreflex sensitivity from 12+/-2 to 3+/-1 ms/mm Hg (P\textless0.01). The largest increases in systolic blood pressure with dobutamine were paralleled by the greatest impairments in arterial baroreflex sensitivity (0. 50\textlessr\textless0.56, P\textless0.01). The chronotropic effects of dobutamine prevented a reflex bradycardia in response to the blood pressure increase. However, less predominant low-frequency oscillations in systolic blood pressure (P\textless0.0001) suggested preserved sympathetic withdrawal in response to the blood pressure increase induced by dobutamine. In conclusion, this study revealed that a shift in the operating point of the arterial baroreceptors and the chronotropic effects of adrenergic stimulation impair baroreflex control of the sinus node during dobutamine exercise stress testing. Baroreflex control of the sinus node is not reset when hemodynamic characteristics of exercise are reproduced in the absence of modifications in central command and muscles afferents.
Abstract: PURPOSE: Hyponatremia ([plasma sodium] \textless135 mmol x L(-1)) is a potentially serious complication of ultraendurance sports. However, the etiology of this condition is still uncertain. This observational cohort study aimed to determine prospectively the incidence and etiology of hyponatremia in an ultradistance triathlon. METHODS: The subjects consisted of 605 of the 660 athletes entered in the New Zealand Ironman triathlon (3.8-km swim, 180-km cycle, and 42.2-km run). Subjects were weighed before and after the race. A blood sample was drawn for measurement of plasma sodium concentration after the race. RESULTS: Complete data on pre- and postrace weights and plasma sodium concentrations were available in 330 race finishers. Postrace plasma sodium concentrations were inversely related to changes in body weight (P = 0.0001). Women (N = 38) had significantly lower plasma sodium concentrations (133.7 vs 137.4 mmol x L(-1); P = 0.0001) than men (N = 292) and lost significantly less relative weight (-2.7 vs -4.3%; P = 0.0002). Fifty-eight of 330 race finishers (18%) were hyponatremic; of these only 18 (31%) sought medical care for the symptoms of hyponatremia (symptomatic). Eleven of the 58 hyponatremic athletes had severe hyponatremia ([plasma sodium] \textless 130 mmol x L(-1)); seven of these 11 severely hyponatremic athletes were symptomatic. The relative body weight change of the 11 severely hyponatremic athletes ranged from 2.4% to +5%; eight (73%) of these athletes either maintained or gained weight during the race. In contrast, relative body weight changes in the 47 athletes with mild hyponatremia ([plasma sodium] 130-134 mmol x L(1)) were more variable, ranging from -9.25% to +2.2%. CONCLUSIONS: Hyponatremia is a common biochemical finding in ultradistance triathletes but is usually asymptomatic. Although mild hyponatremia was associated with variable body weight changes, fluid overload was the cause of most (73%) cases of severe, symptomatic hyponatremia.
Abstract: When whole body insulin-stimulated glucose disposal rate is measured in man applying the euglycaemic, hyperinsulinaemic clamp technique it has been shown that approximately 75% of glucose is taken up by skeletal muscle. After the initial transport step, glucose is rapidly phosphorylated to glucose-6-phosphate and routed into the major pathways of either glucose storage as glycogen or the glycolytic/tricarboxylic acid pathway. Glucose uptake in skeletal muscle involves-the activity of specific glucose transporters and hexokinases, whereas, phosphofructokinase and glycogen synthase hold critical roles in glucose oxidation/glycolysis and glucose storage, respectively. Glucose transporters and glycogen synthase activities are directly and acutely stimulated by insulin whereas the activities of hexokinases and phosphofructokinase may primarily be allosterically regulated. The aim of the review is to discuss our present knowledge of the activities and gene expression of hexokinase II (HKII), phosphofructokinase (PFK) and glycogen synthase (GS) in human skeletal muscle in states of altered insulin-stimulated glucose metabolism. My own experimental studies have comprised patients with disorders characterized by insulin resistance like non-insulin-dependent diabetes mellitus (NIDDM) and insulin-dependent diabetes mellitus (IDDM) before and after therapeutic interventions, patients with microvascular angina and patients with severe insulin resistant diabetes mellitus and congenital muscle fiber type disproportion myopathy as well as athletes who are in a state of improved insulin sensitivity. By applying the glucose insulin clamp method in combination with nuclear magnetic resonance 31P spectroscopy to normoglycaemic or hyperglycaemic insulin resistant subjects impairment of insulin-stimulated glucose transport and/or phosphorylation in skeletal muscle has been shown. In states characterized by insulin resistance but normoglycaemia, the activity of HKII measured in needle revealed any genetic variability that contributes to explain the decreased muscle levels of GS mRNA or the decreased activity and activation of muscle GS in NIDDM patients and their glucose tolerant but insulin resistant relatives. Thus, the causes of impaired insulin-stimulated glycogen synthesis of skeletal muscle in normoglycaemic insulin resistant subjects are likely to be found in the insulin signalling network proximal to the GS protein. In insulin resistant diabetic patients the impact of these yet unknown abnormalities may be accentuated by the prevailing hyperglycaemia and hyperlipidaemia. Endurance training in young healthy subjects results in improved insulin-stimulated glucose disposal rates, predominantly due to an increased glycogen synthesis rate in muscle, which is paralleled by an increased total GS activity, increased GS mRNA levels and enhanced insulin-stimulated activation of GS. These changes are probably due to local contraction-dependent mechanisms. Likewise, one-legged exercise training has been reported to increase the basal concentration of muscle GS mRNA in NIDDM patients to a level similar to that seen in control subjects although insulin-stimulated glucose disposal rates remain reduced in NIDDM patients. In the insulin resistant states examined so far, basal and insulin-stimulated glucose oxidation rate at the whole body level and PFK activity in muscle are normal. In parallel, no changes have been found in skeletal muscle levels of PFK mRNA and immunoreactive protein in NIDDM or IDDM patients. In endurance trained subjects insulin-stimulated whole body glucose oxidation rate is often increased. However, depending on the intensity and frequency, physical exercise may induce an increased, a decreased or an unaltered level of muscle PFK activity. In athletes the muscle PFK mRNA is similar to what is found in sedentary subjects whereas the immunoreactive PFK protein concentration is decreased.
Abstract: It is often said that the introduction of insulin into clinical medicine made a ’dramatic’ difference to the mortality resulting from diabetic coma. This is true in the sense that before 1922 it was almost uniformly fatal, but until the 1950s the mortality in many large hospitals was as high as 30-50%. Often autopsy did not establish a cause of death. Many may have been a result of hypokalaemia, a complication which was not recognized until 1946; in that year in the Journal of the American Medical Association, Jacob Holler described a patient who developed respiratory paralysis 12h into treatment that, after several hours in an iron lung, was cured by potassium infusion. In the 5 years after Holler’s paper there were many reports of deaths resulting from hypokalaemia, as well as several ’near misses’, but clinicians were extremely cautious about early replacement probably, as an editorialist in The Lancet suggested, because ’the frightening effects of intravenous injections of potassium made clinicians reluctant to believe in a lack of potassium as a cause of trouble, except in very rare conditions such as familial periodic paralysis’. It had been known since 1923 that insulin lowered serum potassium, but this was not of great interest because the symptoms of hypokalaemia were not known. Also, potassium was not an electrolyte with which clinicians were familiar. Until the introduction of flame photometry in 1950, it was only measured in research studies as chemical methods took several hours to complete.
Abstract: OBJECTIVES: The depressed myocardial function observed in brain dead organ donors has been attributed to massive sympathetic discharge and catecholamine cardiotoxicity. Because elevated catecholamines are associated with altered myocardial gene expression, we investigated whether acute brain death from increased intracranial pressure alters the expression of myocardial gene products important in contractility. METHODS: A balloon expansion model was used to increase intracranial pressure in rabbits (n = 22). At timed intervals after brain death, mean arterial pressure, heart rate, electrocardiograms, histologic myocardial injury, and systemic catecholamines were assessed. Messenger RNA levels encoding myofilaments, adrenergic receptors, sarcoplasmic reticulum proteins, transcription factors, and stress-induced programs were measured with blot hybridization of total left ventricular RNA. RESULTS: Increased intracranial pressure induced an immediate pressor response that temporally coincided with diffuse electrocardiographic ST segment changes. Systemic epinephrine and norepinephrine levels concurrently increased (5- to 8-fold within 1 minute), then fell below baseline within 2 hours, and remained depressed at 4 hours. By 1 hour, histologic injury was evident. Four hours after the induction of increased intracranial pressure, levels of messenger RNA-encoding skeletal and cardiac alpha-actins, egr-1, and heat shock protein 70 were significantly increased. Sham-operated animals did not exhibit these changes. CONCLUSIONS: Select changes in myocardial gene expression occur in response to increased intracranial pressure and implicate ventricular remodeling in the myocardial dysfunction associated with acute brain death.
Abstract: A substantial body of work has been recently directed toward elucidation of the relationships between body weight, blood pressure, and renal and vascular function. In this review only a few of the myriad studies are highlighted in order to survey areas of current investigation and controversy. Epidemiologic studies have confirmed the blood pressure-body weight relationship but suggest a link to insulin resistance. The majority of investigative work in the mechanism and abnormalities in obesity and their link to blood pressure have focused on the kidney as the primary organ of interest. In addition to alterations in renal blood flow and function, the sympathetic nervous system has also been implicated. The role of the major adrenal steroid dehydroepiandrosterone (DHEA) has been examined, as have the roles of bradykinin and leptin, the exiting new polypeptide thought to play a role in obesity.
Abstract: Human spaceflight is associated with a loss of body protein. Bed rest studies suggest that the reduction in the whole body protein synthesis (PS) rate should be approximately 15%. The objectives of this experiment were to test two hypotheses on astronauts and cosmonauts during long-duration (\textgreater3 mo) flights on MIR: that 1) the whole body PS rate will be reduced and 2) dietary intake and the PS rate should be increased postflight because protein accretion is occurring. The 15N glycine method was used for measuring whole body PS rate before, during, and after long-duration spaceflight on the Russian space station MIR. Dietary intake was measured together with the protein kinetics. Results show that subjects lost weight during flight (4.64 +/- 1.0 kg, P \textless 0.05). Energy intake was decreased inflight (2,854 +/- 268 vs. 2,145 +/- 190 kcal/day, n = 6, P \textless 0.05), as was the PS rate (226 +/- 24 vs. 97 +/- 11 g protein/day, n = 6, P \textless 0.01). The reduction in PS correlated with the reduction in energy intake (r2 = 0.86, P \textless 0.01, n = 6). Postflight energy intake and PS returned to, but were not increased over, the preflight levels. We conclude that the reduction in PS found was greater than predicted from ground-based bed rest experiments because of the shortfall in dietary intake. The expected postflight anabolic state with increases in dietary intake and PS did not occur during the first 2 wk after landing.
Abstract: It has been shown that children with nephrotic syndrome due to minimal change disease (MCD) can present with avid salt retention and stimulated vasoactive hormones, as well as with stable edema. The present study examines these conditions in children with nephrotic syndrome not due to MCD (non-MCD). In six children with hypovolemic symptoms (congenital nephrotic syndrome in four), strong sodium retention (fractional sodium excretion, FE(Na), 0.2 +/- 0.2%) was found. Lithium clearance (FE(Li)) and maximal water excretion (Vmax) were suppressed, suggesting avid sodium reabsorption throughout the nephron. Aldosterone, renin, and norepinephrine were elevated. Sixteen other children with non-MCD had stable edema. FE(Na) was 1.8 +/- 1.1%, whereas FE(Li), Vmax, and hormones were normal, and not different from data in 35 nonproteinuric children. In children with MCD, 12 presented with hypovolemic symptoms and strong sodium retention (FE(Na) 0.3 +/- 0.3%), whereas 15 were stable (FE(Na) 1.1 +/- 0.7%). Regarding tubular sodium handling and hormones, the same distinction could be made as for the children with non-MCD. However, hypoproteinemia differed. In the children with non-MCD lesions, plasma colloid osmotic pressure was significantly lower in the hypovolemic types (4.2 +/- 0.4 mmHg) than in those with stable edema (13.0 +/- 3.8 mmHg; P \textless 0.05); in MCD, no such difference existed (respectively, 8.1 +/- 3.0 and 9.9 +/- 2.2 mmHg). In summary, children with nephrotic syndrome may present with pathophysiologic pictures of decreased effective circulating volume or of stable edema, regardless of whether they have non-MCD or MCD. The pathogenesis of the hypovolemic picture seems to be different, since it is associated with extreme hypoproteinemia only in the children with non-MCD.
Abstract: The objectives of this study were as follows: 1) to measure human energy expenditure (EE) during spaceflight on a shuttle mission by using the doubly labeled water (DLW) method; 2) to determine whether the astronauts were in negative energy balance during spaceflight; 3) to use the comparison of change in body fat as measured by the intake DLW EE, 18O dilution, and dual energy X-ray absorptiometry (DEXA) to validate the DLW method for spaceflight; and 4) to compare EE during spaceflight against that found with bed rest. Two experiments were conducted: a flight experiment (n = 4) on the 16-day 1996 life and microgravity sciences shuttle mission and a 6 degrees head-down tilt bed rest study with controlled dietary intake (n = 8). The bed rest study was designed to simulate the flight experiment and included exercise. Two EE determinations were done before flight (bed rest), during flight (bed rest), and after flight (recovery). Energy intake and N balance were monitored for the entire period. Results were that body weight, water, fat, and energy balance were unchanged with bed rest. For the flight experiment, decreases in weight (2.6 +/- 0.4 kg, P \textless 0.05) and N retention (-2. 37 +/- 0.45 g N/day, P \textless 0.05) were found. Dietary intake for the four astronauts was reduced in flight (3,025 +/- 180 vs. 1,943 +/- 179 kcal/day, P \textless 0.05). EE in flight was 3,320 +/- 155 kcal/day, resulting in a negative energy balance of 1,355 +/- 80 kcal/day (-15. 7 +/- 1.0 kcal. kg-1. day-1, P \textless 0.05). This corresponded to a loss of 2.1 +/- 0.4 kg body fat, which was within experimental error of the fat loss determined by 18O dilution (-1.4 +/- 0.5 kg) and DEXA (-2.4 +/- 0.4 kg). All three methods showed no change in body fat with bed rest. In conclusion, 1) the DLW method for measuring EE during spaceflight is valid, 2) the astronauts were in severe negative energy balance and oxidized body fat, and 3) in-flight energy (E) requirements can be predicted from the equation: E = 1.40 x resting metabolic rate + exercise.
Abstract: Previous reports from our group demonstrated that about one-half of the total volume of cerebrospinal fluid (CSF) removed from the cranial vault in sheep is transported into extracranial lymphatics, especially cervical lymphatic vessels in the neck. In this study, we tested the hypothesis that an elevation of intracranial pressure (ICP) would increase cervical lymphatic pressure and lymph flow rates in anesthetized sheep. Catheters were inserted into both lateral ventricles, the cisterna magna, cervical lymphatics, and the jugular vein. A ventriculo-cisternal perfusion system was employed to regulate ICP. Mean (P = 0.008), peak (P = 0.007), and baseline (P = 0.013) cervical lymphatic pressures increased as ICP was elevated from 10 to 70 cmH2O in 20-cmH2O increments. Similarly, cervical lymph flow rates increased (P \textless 0.001), with flows at 70 cmH2O ICP observed to be approximately fourfold higher than those at 10 cmH2O ICP. No changes were observed in mesenteric lymph flow rates (vessels not expected to drain CSF). We conclude that cervical lymphatic vessels play an important role in the transport of CSF from the cranial vault when ICP is elevated.
Abstract: In these experiments, we used a strain of angiotensin converting enzyme (ACE) germline null mutant mice, generated by J. H. Krege and co-workers (J. H. Krege, S. W. M. John, L. L. Langenbach, J. B. Hodgin, J. R. Hagaman, E. S. Bachman, J. C. Jennette, D. A. O’Brien, and O. Smithies. Nature 375: 146-148, 1995), to examine the effect of chronic ACE deficiency on the magnitude of tubuloglomerular feedback (TGF) responses. The genotype was determined by PCR on DNA extracted from the tail and was verified after each experiment by assessment of the blood pressure response to an injection of ANG I. To assess TGF responsiveness, we determined the change in stop-flow pressure (PSF) caused by increasing NaCl concentration at the macula densa by using micropuncture techniques. When loop of Henle flow rate was increased from 0 to 40 nl/min, PSF fell from a mean of 42.3 +/- 1.95 to 33.6 +/- 2.09 mmHg (n = 6, P = 0.005) in wild-type mice (+/+), fell from 40.6 +/- 2.35 to 38.6 +/- 1.93 mmHg in heterozygous (+/-) mice (n = 7, P = 0.014), and did not change in homozygous ACE (-/-) mice [36.7 +/- 2.02 mmHg vs. 36.4 +/- 2.01 mmHg; n = 4, P = not significant (NS)]. During an infusion of ANG II at a dose that did not significantly elevate blood pressure (70 ng. kg-1. min-1), TGF response magnitude (PSF 0 - PSF 40) increased from 6.5 +/- 1.4 to 9.8 +/- 1.19 mmHg in +/+ (P = 0.006), from 1.14 +/- 0.42 to 4.6 +/- 1.3 mmHg in +/- (P = 0.016), and from 0.42 +/- 0.25 to 4.02 +/- 1.06 in -/- mice (P = 0.05). Absence of TGF responses in ACE null mutant mice and restoration of near-normal responses during an acute infusion of ANG II supports previous conclusions that ANG II is an essential component in the signal transmission pathway that links the macula densa with the glomerular vascular pole.
Abstract: We have investigated the effectiveness of human recombinant inhibin A (hr-inhibin A) to suppress the secretion of follicle-stimulating hormone (FSH) in ram lambs from 1 to 18 months of age. Seventeen rams (nine castrated, eight intact) were used. At 1, 3, 6, 9, 12 and 18 months of age the rams were given an i.v. injection of either vehicle or hr-inhibin A (0.64 microgram/kg). Blood samples were taken over 24 h. Plasma concentrations of FSH were suppressed in castrated and intact rams following injection of hr-inhibin A with maximal suppression occurring 6 h after injection. Vehicle injection had no effect. At 12 months of age the suppression in FSH was most rapid in castrated rams and was maximal in intact rams. The clearance rate of inhibin was greatest at older ages but during the period of seasonally induced testicular activity, there was a significant decrease in the inhibin clearance. The testicular weight was reduced in rams treated with hr-inhibin A, indicating the importance of FSH for testicular development during the pubertal period. There was no effect of hr-inhibin A on plasma concentrations of luteinizing hormone. We conclude that inhibin is capable of suppressing the secretion of FSH in rams from 1 month of age onwards and that the pituitary gland becomes maximally responsive to the actions of inhibin by the age of puberty.
Abstract: The present study was performed to test the hypothesis that orally administered essential amino acids, in combination with carbohydrate, will stimulate net muscle protein synthesis in resting human muscle in vivo. Four volunteers ingested 500 mL of a solution containing 13.4 g of essential amino acids and 35 g sucrose (EAA). Blood samples were taken from femoral arterial and venous catheters over a 2-hour period following the ingestion of EAA to measure arteriovenous concentrations of amino acids across the muscle. Two muscle biopsies were taken during the study, one before administration of the drink and one approximately 2 hours after consumption of EAA. Serum insulin increased from normal physiologic levels at baseline (9.2 +/- 0.8 microU/mL) and peaked (48 +/- 7.1 microU/mL) 30 minutes after EAA ingestion. Arterial essential amino acid concentrations increased approximately 100 to 400% above basal levels between 10 and 30 minutes following drink ingestion. Net nitrogen (N) balance changed from negative (-495 +/- 128 nmol/mL) prior to consumption of EAA to a peak positive value (416 +/- 140 nmol/mL) within 10 minutes of ingestion of the drink. EAA resulted in an estimated positive net N uptake of 307.3 mg N above basal levels over the 2-hour period. Muscle amino acid concentrations were similar prior to and 2 hours following ingestion of EAA. We conclude that ingestion of a solution composed of carbohydrates to stimulate insulin release and a small amount of essential amino acids to increase amino acid availability for protein synthesis is an effective stimulator of muscle protein anabolism.
Abstract: The aim of this study was to determine the role of renal innervation in the prolonged stimulation of renin secretion and renin synthesis accompanying renal artery stenosis. Male Sprague-Dawley rats, in which the left kidney had been denervated or sham denervated 4 days earlier, received a left renal artery clip (ID 0.2 mm). Plasma renin activity and renin mRNA were assayed 1, 2, or 4 days after clipping. The stimulation of both plasma renin activity and renin mRNA was blunted markedly in the rats with the denervated clipped kidney. The typical suppression of renin mRNA in the intact right kidney, however, was not different between rats with sham-denervated or denervated left kidneys, nor was the increase of blood pressure in response to renal artery clipping different between the experimental groups. To test whether the suppression of renin mRNA in the contralateral kidney was related to the increase of blood pressure, another group of rats with denervated clipped left kidneys was treated additionally with the T-type calcium channel blocker mibefradil (15 mg. kg(-1). d(-1)). Despite blood pressure normalization by mibefradil, plasma renin activities and renin mRNA levels in the clipped denervated kidneys and in the intact right kidneys remained unchanged. These findings suggest that renal nerves are responsible for marked background stimulation of both renin secretion and renin mRNA expression, which is normally masked by the inhibitory effect of renal perfusion pressure on the renin system. Renal nerve activity is therefore an important determinant of the gain of renin stimulation during reduced renal arterial pressure.
Abstract: It is well known that, in a state of weightlessness, body fluids shift toward the head site, but the actual rates of the migration of fluids has never been measured. In order to identify the causes of reduced orthostatic tolerance and the reduction in circulating blood volume after returning from a space mission, it is necessary to measure the changes in body fluid distribution. Although the methods for measuring changes in body fluids include the use of isotopes or pigments, such methods cannot be employed in space due to their invasive properties. Therefore, we directed our attention toward the impedance method, for which we developed a non-invasive apparatus for measuring the distribution of body fluids. We therefore measured the actual distribution of body fluids using the bed-rest method, a model of the zero gravity state.
Abstract: In this study we assessed different magnetic resonance imaging (MRI) scanning regimes and examined some of the assumptions commonly made for measuring body fat content by MRI. Whole body MRI was used to quantify and study different body fat depots in 67 women. The whole body MRI results showed that there was a significant variation in the percentage of total internal, as well as visceral, adipose tissue across a range of adiposity, which could not be predicted from total body fat and/or subcutaneous fat. Furthermore, variation in the amount of total, subcutaneous, and visceral adipose tissue was not related to standard anthropometric measurements such as skinfold measurements, body mass index, and waist-to-hip ratio. Finally, we show for the first time subjects with a percent body fat close to the theoretical maximum (68%). This study demonstrates that the large variation in individual internal fat content cannot be predicted from either indirect methods or direct imaging techniques, such as MRI or computed tomography, on the basis of a single-slice sampling strategy.
Abstract: PURPOSE: The purpose of this study was to investigate the relationship between training-induced alterations in plasma volume (PV) and changes in fluid and electrolyte regulatory hormones during prolonged exercise. METHODS: Seven male subjects (VO2peak 49.2 +/- 2.4 mL.kg-1.min-1, X +/- SE) performed a cycling test before (C) and after (T) 6 d of training and after 6 d of detraining (DT). Training was conducted for 2 h.d-1 at 68% VO2peak at a room temperature between 26-28 degrees C. The 60-min exercise challenge included 20 min at 50%, 65%, and 75% VO2peak workloads. RESULTS: Training resulted in a calculated 13.8 +/- 1.6% PV expansion (P \textless 0.05) which recovered to C levels with DT (1.8 +/- 2.3%, P \textgreater 0.05). Compared with that at C, training resulted in a reduction of aldosterone (ALDO) concentration at all exercise intensities (P \textless 0.05) which normalized to C levels with DT. With T, epinephrine (EPI) concentrations were reduced at the highest power output only (365 +/- 51 vs 113 +/- 22 pg.mL-1; P \textless 0.05) and returned to C levels with DT. Arginine vasopressin (AVP) concentrations were also reduced at the highest workload only (20.2 +/- 3.2 pg.mL-1 vs 10.4 +/- 0.7 pg.mL-1; P \textless 0.05) and remained depressed after DT (11.8 +/- 1.3 pg.mL-1; P \textless 0.05). Atrial natriuretic factor (ANF) and norepinephrine (NOREPI) were not affected by T or DT. CONCLUSIONS: The results suggest that concentrations of ALDO, and to a lesser extent EPI, during exercise are related to PV levels, whereas ANF and NOREPI concentrations are not. AVP concentrations are related to other adaptive factors, the effects of which persist for a longer time course than do PV changes.
Abstract: This study gives the first quantitative analysis of net steady-state transmural fluxes of water, urea, and NaCl in a numerical model of the rat renal medulla in antidiuresis, revealing the model’s predictions of water, urea, and NaCl cycling patterns. These predictions are compared both to in vivo micropuncture data from the literature and to earlier qualitative proposals (e.g., K. V. Lemley and W. Kriz. Kidney Int. 31: 538-548, 1987) of cycling and exchange patterns based on medullary anatomy and available permeability and transport parameter measurements. The analysis is based on our most recent three-dimensional model [X. Wang, S. R. Thomas, and A. S. Wexler. Am. J. Physiol. 274 (Renal Physiol. 43): F413-F424, 1998]. In general agreement with earlier proposed patterns, this analysis predicts the following: 1) important water short-circuiting from descending structures to ascending vasa recta in most medullary regions, 2) massive urea recycling in the upper inner medulla, 3) a progressive increase of the ratio of urea to total osmoles along the corticopapillary axis, 4) urea dumped from the collecting ducts (CD) into the deep papilla is returned to the cortex essentially via outer medullary short vasa recta, bearing witness to a shift from the long descending limbs and vasa recta of the inner medulla (IM) to short structures in the outer medulla (OM). The analysis also shows that the known radial heterogeneity of the inner stripe (IS) implies unequal osmolalities in long descending limbs, vasa recta, and CDs entering the IM across the OM/IM border and explains the model’s unorthodox osmolality profile along the CD. In conflict with micropuncture evidence of a doubling of urea flow in superficial Henle’s loops (SHL) between the end proximal and early distal tubule (T. Armsen and H. W. Reinhardt. PflÃŒgers Arch. 326: 270-280, 1971), the model predicts net urea loss from SHL due to the model’s inclusion of nonneglible measured urea permeability of medullary thick ascending limbs [M. A. Knepper, Am. J. Physiol. 245 (Renal Fluid Electrolyte Physiol. 14): F634-F639, 1983]. We present a suite of adjusted model permeabilities that improves agreement with the micropuncture data on this point. In conclusion, this modeling analysis of solute and water recycling serves as a quantitative check on qualitative propositions in the literature and allows closer critical comparison of model behavior with published experimental results than was heretofore possible.
Abstract: OBJECTIVE: A major cause of early postoperative morbidity and mortality after cardiac transplantation is right ventricular (RV) failure which is attributed to the inability of the donor’s RV to acutely compensate for the recipient’s elevated pulmonary vascular resistance. This study was performed to determine: (1) the acute effects of brain death on the RV function; and (2) the adaptation potential of the RV to a progressive increase in RV afterload. METHODS: In 13 anesthetized, open-chest dogs (eight with brain death vs. five control with sham operation), brain death was induced by inflation of a subdural balloon catheter. Heart rate, RV systolic and end-diastolic pressure (RVSP, RVEDP), pulmonary arterial pressure (PAP), and cardiac output (CO), and pressure-length loops (sonomicrometry) were recorded. Afterload increase was induced 2 h after brain death induction by constriction of the pulmonary artery with an increase in RVP from 25 to 50 mmHg in 5 mmHg steps. RESULTS: Cushing phenomenon occurred within a few minutes after brain death induction, with a significant increase of HR (229 +/- 10 vs. 89 +/- 6 min(-1), P \textless 0.001), CO (3.2 +/- 0.2 vs. 1.7 +/- 0.1 l/min, P \textless 0.001), PAP (30.4 +/- 2.5 vs. 15.5 +/- 1.3 mmHg, P \textless 0.01) RVSP (55 +/- 5 vs. 23 +/- 2 mmHg, P \textless 0.001) and RVEDP (7.4 +/- 0.9 vs. 3.3 +/- 0.6 mmHg, P \textless 0.001). All these values were also significantly (P \textless 0.01) higher than the time corresponding values of the control group. The analysis of the pressure-length loops showed a hypercontractile state. Within 15-60 min, all parameters turned to baseline and remained stable for up to 2 h. When afterload was increased progressively, RVEDP increased markedly in the brain death and slightly in the control group (9.4 +/- 0.7 vs. 4.2 +/- 1.1 mmHg, P \textless 0.01, at RVSP = 50 mmHg). On the other hand, the increase of peak positive dP/dt was significantly higher in the control group (430 +/- 37 vs. 644 +/- 55 mmHg/s, P \textless 0.01, at RVP = 50 mmHg). However, global RV pump function characterized by CO and stroke work was similar in both groups. While regional RV contractility remained unchanged in the brain death group in terms of pressure-length relationships, RV contractility significantly increased in the control group. CONCLUSION: (1) Brain death per se does not result in an acute impairment of RV function. (2) While control animals adapt to an increased afterload by the homeometric, as well as the heterometric regulation, after brain death, an increase in RV preload follows elevations in RV afterload by the Frank-Starling mechanism subserving the increased stroke work required to ensure unchanged pump function.
Abstract: The uptake of blood glucose by skeletal muscle is a complex process. In order to be metabolized, glucose must travel the path from blood to interstitium to intracellular space and then be phosphorylated to glucose 6-phosphate (G6P). Movement of glucose from blood to interstitium is determined by skeletal muscle blood flow, capillary recruitment and the endothelial permeability to glucose. The influx of glucose from the interstitium to intracellular space is determined by the number of glucose transporters in the sarcolemma and the glucose gradient across the sarcolemma. The capacity to phosphorylate glucose is determined by the amount of skeletal muscle hexokinase II, hexokinase II compartmentalization within the cell, and the concentration of the hexokinase II inhibitor G6P. Any change in glucose uptake occurs due to an alteration in one or more of these steps. Based on the low calculated intracellular glucose levels and the higher affinity of glucose for phosphorylation relative to transport, glucose transport is generally considered rate-determining for basal muscle glucose uptake. Exercise increases both the movement of glucose from blood to sarcolemma and the permeability of the sarcolemma to glucose. Whether the ability to phosphorylate glucose is increased in the working muscle remains to be clearly shown. It is possible that the accelerated glucose delivery and transport rates during exercise bias regulation so that muscle glucose phosphorylation exerts more control on muscle glucose uptake. Conditions that alter glucose uptake during exercise, such as increased NEFA concentrations, decreased oxygen availability and adrenergic stimulation, must work by altering one or more of the three steps involved in glucose uptake. This review describes the regulation of glucose uptake during exercise at each of these sites under a number of conditions, as well as describing muscle glucose uptake in the post-exercise state.
Abstract: Plasma leptin concentration is increased in hypertensive obese humans, but whether leptin contributes to the increased arterial pressure in obesity is not known. In this study, we tested whether chronic increases in leptin, to levels comparable to those in obesity, could cause a sustained increase in arterial pressure and also the importance of central nervous system (CNS) versus systemic mechanisms. Five male Sprague-Dawley rats were implanted with chronic nonoccluding catheters in the abdominal aorta and both carotid arteries for CNS infusion, and five other rats were implanted with an abdominal aorta catheter and femoral vein catheter for intravenous (I.V.) infusion. After 7 days of control, leptin was infused into the carotid arteries or femoral vein at 0.1 microg/kg/min for 5 days and 1.0 microg/kg/min for 7 days, followed by a 7-day recovery period. The carotid artery and i.v. infusions of leptin at 1 microg/kg/min significantly increased plasma leptin levels, from 1.2+/-0.4 ng/mL to 91+/-5 ng/mL and from 0.9+/-0.1 ng/mL to 94+/-9 ng/mL, respectively, but there was no significant increase in either group at the low dose. Food intake also did not change at the low dose but decreased by approximately 65% in the carotid group and 69% in the i.v. group after 7 days of the 1 microg/kg/min infusion. Mean arterial pressure (MAP) increased slightly at the low dose only in the carotid group, but this was not statistically significant. At the higher dose, however, MAP increased significantly from 86+/-1 mm Hg to 94+/-1 mm Hg in the carotid group and from 87+/-1 mm Hg to 93+/-1 mm Hg in the i.v. group. Heart rate also increased significantly in both groups at 1 microg/kg/min leptin infusion. Fasting blood glucose and insulin levels decreased significantly at 1 microg/kg/min in both the carotid artery group (-10.5% and -82.5%, respectively) and the i.v. group (-13.6% and -80.4%, respectively). All variables returned to control levels after leptin infusion was stopped. These results indicate that chronic increases in circulating leptin cause sustained increases in arterial pressure and heart rate and are consistent with a possible role for leptin in obesity hypertension.
Abstract: The effect of -6 degrees head-down-tilt bed rest (HDBR) for 14 days on supine sympathetic discharge and cardiovascular hemodynamics at rest was assessed. Mean arterial pressure, heart rate (n = 25), muscle sympathetic nerve activity (MSNA; n = 16) burst frequency, and forearm blood flow (n = 14) were measured, and forearm vascular resistance (FVR) was calculated. Stroke distance, our index of stroke volume, was derived from measurements of aortic mean blood velocity (Doppler) and R-R interval (n = 7). With these data, an index of total peripheral resistance was determined. Heart rate at rest was greater in the post (71 +/- 2 beats/min)- compared with the pre-HDBR test (66 +/- 2 beats/min; P \textless 0.003), but mean arterial pressure was unchanged. Aortic stroke distance during post-HDBR (15.5 +/- 1.1 cm/beat) was reduced from pre-HDBR levels (20.0 +/- 1.5 cm/beat) (P \textless 0.03). Also, MSNA burst frequency was reduced in the post (16.7 +/- 2.8 beats/min)- compared with the pre (25.2 +/- 2.6 beats/min)-HDBR condition (P \textless 0.01). Bed rest did not alter forearm blood flow, FVR, or total peripheral resistance. Thus reductions in MSNA with HDBR were not associated with a decrease in FVR.
Abstract: The first studies of space flown rats revealed that in m.soleus (SOL) slow-twitch fibers (ST) were reduced in size more pronouncedly than fast-twitch fibers (FT). The same differences in the fiber atrophy levels were found in rats after hind-limb suspension. At the same time, the studies on humans exposed to real and simulated weightlessness demonstrated that at least in m.vastus lateral (VL) the ST and FT fibers’ levels of atrophy were almost similar. The discrepancies in the results of human and rat studies are believed to be explained by: i/species-specificity in muscle plasticity pattern; ii/differences in characteristics of muscles usually being under rat and human studies (SOL vs VL); iii/observation of different stages of the atrophy development in different species; The study was aimed to test these hypotheses.
Abstract: The lung is particularly vulnerable to injury because the blood-gas barrier is so extremely thin. Furthermore, the mechanical stresses in the barrier become very high when capillary pressure is raised, or when the lung is inflated to a high volume. The strength of the blood-gas barrier on the thin side can be attributed to the type IV collagen in the basement membranes. Abnormally high stresses in the walls of the pulmonary capillaries result in ultrastructural changes including disruptions of both the alveolar epithelial and capillary endothelial layers. All Thoroughbred racehorses break their pulmonary capillaries when they gallop. Also, elite human athletes develop changes in the permeability of the blood-gas barrier at high levels of exercise. Pathological conditions resulting in stress failure include: 1) high-altitude pulmonary edema; 2) neurogenic pulmonary edema; 3) severe left ventricular failure; 4) mitral stenosis; and 5) overinflation of the lung. There is a spectrum of low permeability to high permeability edema as the capillary pressure is raised. Remodeling of pulmonary capillaries apparently occurs at high capillary pressures. It is likely that the extracellular matrix of the capillaries is continuously regulated in response to capillary wall stress.
Abstract: We evaluated the blood pressure-lowering activity, tolerability, and safety of losartan in 112 hypertensive (sitting diastolic blood pressure, 90 to 115 mm Hg) patients with chronic renal insufficiency including mild renal insufficiency (30 to 60 mL/min per 1.73 m2; n=51), moderate to severe renal insufficiency (10 to 29 mL/min per 1.73 m2; n=33), or hemodialysis (n=28). After a 3-week placebo period, once-daily losatan was administered for 12 weeks. The daily dose of 50 mg was increased to 100 mg after 4 weeks in patients whose sitting diastolic blood pressure remained \textgreater or = 90 mm Hg or was reduced by \textless 5 mm Hg. A second, non-angiotensin-converting enzyme inhibitor, antihypertensive drug was added after 8 weeks as needed. Twenty-four-hour creatinine clearance was determined and renal clearance studies of inulin and para-aminohippurate were done in a subset of 11 patients. Trough sitting blood pressures were reduced at the end of the first week in all groups. At weeks 4, 8, and 12, the reductions in systolic blood pressure/diastolic blood pressure averaged -11.9/-8.7, -10.8/-9.4, and -14.7/-12.1 mm Hg in patients with mild renal insufficiency; -7.7/-6.3, -13.1/-11.8, and -14.1/-10.6 mm Hg, in moderate to severe renal insufficiency; -17.0/-12.7, -19.1/-14.4, and -22.7/-18.0 mm Hg in hemodialysis. Creatinine clearance, glomerular filtration rate, and effective renal plasma flow were stable. Losartan was withdrawn in only 6 patients because ofa clinical or laboratory adverse experience. Hyperkalemia (\textgreater 6 mEq/L) requiring discontinuation of losartan occurred in only one (group 2) patient. We conclude that once-daily losartan, given as monotherapy at doses of 50 or 100 mg or in combination with other antihypertensive drugs, was effective in reducing blood pressure in hypertensive patients with chronic renal disease and that losartan regimens were well tolerated in all groups, including those on hemodialysis.
Abstract: Early in spaceflight, an apparently paradoxical condition occurs in which, despite an externally visible headward fluid shift, measured central venous pressure is lower but stroke volume and cardiac output are higher, and heart rate is unchanged from reference measurements made before flight. This paper presents a set of studies in which a simple three-compartment, steady-state model of cardiovascular function is used, providing insight into the contributions made by the major mechanisms that could be responsible for these events. On the basis of these studies, we conclude that, during weightless spaceflight, the chest relaxes with a concomitant shape change that increases the volume of the closed chest cavity. This leads to a decrease in intrapleural pressure, ultimately causing a shift of blood into the vessels of the chest, increasing the transmural filling pressure of the heart, and decreasing the central venous pressure. The increase in the transmural filling pressure of the heart is responsible, through a Starling-type mechanism, for the observed increases in heart size, left ventricular end-diastolic volume, stroke volume, and cardiac output.
Abstract: Insulin resistance is associated with hyperleptinemia, whilst exposure of hepatoma cells and isolated adipocytes to high concentrations of leptin has been demonstrated to result in attenuated insulin response and a reduced suppression of gluconeogenesis. To determine the acute metabolic effects of hyperleptinemia, we measured whole body glucose uptake (WBU) and hepatic glucose production rate (HGP) in rats using the euglycemic hyperinsulinemic clamping technique. Anesthetised male rats received recombinant murine leptin (1 microg/min) or vehicle into the jugular vein for 90 min. After 30 min of leptin infusion, insulin was infused to a level of 70 microU/ml and a variable-rate glucose infusion was adjusted to maintain blood glucose levels to 4-4.5 mmol/l. Glucose infusion rates during clamping were not different between leptin-infused and control rats, and there were no significant effects on the HPR or WBU measured using [6-(3)H]glucose under basal or clamped conditions. In summary, our data demonstrate that acute hyperleptinemia in normal weight Wistar rats does not appear to reduce insulin sensitivity, in vivo, or to affect HPR under clamp conditions.
Abstract: We assessed the effects of sustained weightlessness on chest wall mechanics in five astronauts who were studied before, during, and after the 10-day Spacelab D-2 mission (n = 3) and the 180-day Euromir-95 mission (n = 2). We measured flow and pressure at the mouth and rib cage and abdominal volumes during resting breathing and during a relaxation maneuver from midinspiratory capacity to functional residual capacity. Microgravity produced marked and consistent changes (Delta) in the contribution of the abdomen to tidal volume [DeltaVab/(DeltaVab + DeltaVrc), where Vab is abdominal volume and Vrc is rib cage volume], which increased from 30.7 +/- 3. 5 (SE)% at 1 G head-to-foot acceleration to 58.3 +/- 5.7% at 0 G head-to-foot acceleration (P \textless 0.005). Values of DeltaVab/(DeltaVab + DeltaVrc) did not change significantly during the 180 days of the Euromir mission, but in the two subjects DeltaVab/(DeltaVab + DeltaVrc) was greater on postflight day 1 than on subsequent postflight days or preflight. In the two subjects who produced satisfactory relaxation maneuvers, the slope of the Konno-Mead plot decreased in microgravity; this decrease was entirely accounted for by an increase in abdominal compliance because rib cage compliance did not change. These alterations are similar to those previously reported during short periods of weightlessness inside aircrafts flying parabolic trajectories. They are also qualitatively similar to those observed on going from upright to supine posture; however, in contrast to microgravity, such postural change reduces rib cage compliance.
Abstract: This article examines the role of the autonomic nervous system in mediating the increase of glucagon secretion observed during insulin-induced hypoglycemia (IIH). In the first section, we briefly review the importance of the alpha-cell response in recovery from hypoglycemia under both physiologic conditions and pathophysiologic conditions, such as type 1 diabetes. We outline three possible mechanisms that may contribute to increased glucagon secretion during hypoglycemia but emphasize autonomic mediation. In the second section, we review the critical experimental data in animals, nonhuman primates, and humans suggesting that, in the absence of diabetes, the majority of the glucagon response to IIH is mediated by redundant autonomic stimulation of the islet alpha-cell. Because the glucagon response to hypoglycemia is often impaired in patients with type 1 diabetes, in the third section, we examine the possibility that autonomic impairment contributes to the impairment of the glucagon response in these patients. We review two different types of autonomic impairment. The first is a slow-onset and progressive neuropathy that worsens with duration of diabetes, and the second is a rapid-onset, but reversible, autonomic dysfunction that is acutely induced by antecedent hypoglycemia. We propose that both types of autonomic dysfunction can contribute to the impaired glucagon responses in patients with type 1 diabetes. In the fourth section, we relate restoration of these glucagon responses to restoration of the autonomic responses to hypoglycemia. Finally, in the fifth section, we summarize the concepts underlying the autonomic hypothesis, the evidence for it, and the implications of the autonomic hypothesis for the treatment of type 1 diabetes.
Abstract: The lymphatic vessels of the lung provide an important route for clearance of interstitial edema fluid filtered from pulmonary blood vessels. However, the importance of lung lymphatics for the removal of airway liquid filtered from the systemic circulation of the lung has not been demonstrated. We studied the contribution of the bronchial vasculature to lung lymph flow in anesthetized, ventilated sheep (n = 35). With the bronchial artery cannulated and perfused (control flow = 0.6 ml. min-1. kg-1), lymph flow from the efferent duct of the caudal mediastinal lymph node was measured 1) during increased bronchial vascular perfusion (300% of control flow); 2) with a hydrated interstitium induced by a 1-h period of left atrial hypertension and subsequent recovery, both with and without bronchial perfusion; and 3) during infusion (directly into the bronchial artery) of bradykinin, an inflammatory mediator known to cause changes in bronchial vascular permeability. Increased bronchial perfusion for 90 min resulted in an average 35% increase in lung lymph flow. During left atrial hypertension, the increase in lung lymph flow was significantly greater with bronchial perfusion (339% increase over baseline) than without bronchial perfusion (138% increase). Furthermore, recovery after left atrial hypertension was more complete after 90 min without bronchial perfusion (91%) than with bronchial perfusion (63%). Infusion of bradykinin into the bronchial artery resulted in a prompt and prolonged 107% increase in lung lymph flow. This was not seen if the same dose was infused into the pulmonary artery. Thus bronchial vascular transudate contributes significantly to lymph flow from the efferent duct of the caudal mediastinal lymph node. These results demonstrate that lymph vessels clear excess fluid from the airway wall and should be considered when evaluating the effect of vascular leak in airway obstruction.
Abstract: In metabolic acidosis, the capacity of the proximal tubule for bicarbonate absorption is enhanced, whereas NaCl reabsorption is inhibited. Recent evidence indicates that transcellular NaCl absorption in the proximal tubule is mediated by apical membrane Cl/formate exchange and Cl/oxalate exchange, in parallel with recycling of these organic anions. We evaluated whether the effect of metabolic acidosis to inhibit NaCl reabsorption in the proximal tubule is due at least in part to inhibition of organic anion-dependent NaCl transport in this nephron segment. Absorption rates of bicarbonate (JHCO3), chloride (JCl), and fluid (Jv) were measured in rat proximal tubule segments microperfused in situ. We confirmed that metabolic acidosis stimulates JHCO3 in tubules microperfused with 25 mM HCO3, pH 7.4. For measurements of JCl, tubules were microperfused with a low-bicarbonate (5 mM), high-chloride solution, simulating conditions in the late proximal tubule. Under these conditions, baseline JCl and Jv measured in the absence of formate and oxalate were not significantly different between control and acidotic rats. However, whereas addition of 50 ¿M formate or 1 ¿M oxalate to luminal and capillary perfusates markedly stimulated JCl and Jv in control rats, formate and oxalate failed to stimulate JCl and Jv in acidotic rats. We conclude that metabolic acidosis markedly downregulates organic anion-stimulated NaCl absorption, thereby allowing differential regulation of proximal tubule NaHCO3 and NaCl transport.
Abstract: The effects of three isoforms derived from recombinant human FSH on ovarian follicle development in vitro were characterized for the first time. The three subfractions comprised discrete pI ranges of 3. 6-4.6 (acid), 4.5-5.0 (mid), and 5.0-5.6 (least acidic). Follicular growth, estradiol secretion, and antral formation were assessed for each fraction of isoforms in a range of concentrations over a 5-day culture period. Least acidic FSH produced, at and above 1.5 ng/ml, a high percentage of follicles growing above the size threshold necessary for antral formation, whereas mid and acid FSH induced similar growth only at higher concentrations (7.5 ng/ml and 50 ng/ml, respectively). Least acidic FSH specifically induced the most rapid growth of follicles during preantral development. Acid FSH at all concentrations stimulated estradiol-17ss secretion later during culture and antral formation in a lower proportion of follicles than did least acidic and mid FSH. It can be concluded 1) that the least acidic isoform induced fastest preantral growth, producing the largest antral follicles at the lowest dose of all three fractions and 2) that the less and mid acidic isoforms had more impact on stimulation of estradiol production and antral formation than the acid isoform.
Abstract: Cerebral blood flow velocity (CBFv) was measured by insonating the middle cerebral arteries of four subjects using a 2 Mhz transcranial Doppler. Ambient CO2 was elevated to 0.7% for 23 d in the first study and to 1.2% for 23 d in the same subjects in the second study. By non-parametric testing CBFv was elevated significantly by +35% above pre-exposure levels during the first 1-3 d at both exposure levels, after which CBFv progressively readjusted to pre-exposure levels. Despite similar CBFv responses, headache was only reported during the initial phase of exposure to 1.2% CO2. Vascular reactivity to CO2 assessed by rebreathing showed a similar pattern with the CBFv increases early in the exposures being greater than those elicited later. An increase in metabolic rate of the visual cortex was evoked by having the subjects open and close their eyes during a visual stimulus. Evoked CBFv responses measured in the posterior cerebral artery were also elevated in the first 1-3 d of both studies returning to pre-exposure levels as hypercapnia continued. Cerebral vascular autoregulation assessed by raising head pressure during 10 degrees head-down tilt both during the low-level exposures and during rebreathing was unaltered. There were no changes in the retinal microcirculation during serial fundoscopy studies. The time-dependent changes in CO2 vascular reactivity might be due either to retention of bicarbonate in brain extracellular fluid or to progressive increases in ventilation, or both. Cerebral vascular autoregulation appears preserved during chronic exposure to these low levels of ambient CO2.
Abstract: The majority of modern epilepsy research has focused on possible abnormalities in synaptic and intrinsic neuronal properties–as likely epileptogenic mechanisms as well as the targets for developing novel antiepileptic treatments. However, many other processes in the central nervous system contribute to neuronal excitability and synchronization. Regulation of ionic balance is one such set of critical processes, involving a complex array of molecules for moving ions into and out of brain cells–both neurons and glia. Alterations in extracellular-to-intracellular ion gradients can have both direct and indirect effects on neuronal discharge. We have found, for example, that when hippocampal slices are exposed to hypo-osmotic bathing medium, the cells not only swell, but there is also a significant increase in the amplitude of a delayed rectifier potassium current in inhibitory interneurons–an effect that may contribute to the increase in tissue excitability associated with hypo-osmolar treatments. In contrast, antagonists of the chloride co-transporter, furosemide or bumetanide, block epileptiform activity in both in vitro and in vivo preparations. This antiepileptic effect is presumably due to the drugs’ ability to block chloride co-transport. Indeed, prolonged tissue exposure to low levels of extracellular chloride have a parallel action. These experiments indicate that manipulation of ionic balance may not only facilitate epileptiform activities, but may also provide insight into new therapeutic strategies to block seizures.
Abstract: Human type 2 diabetes is characterized by defects in both insulin action and insulin secretion. It has been difficult to identify a single molecular abnormality underlying these features. Insulin-receptor substrates (IRS proteins) may be involved in type 2 diabetes: they mediate pleiotropic signals initiated by receptors for insulin and other cytokines. Disruption of IRS-1 in mice retards growth, but diabetes does not develop because insulin secretion increases to compensate for the mild resistance to insulin. Here we show that disruption of IRS-2 impairs both peripheral insulin signalling and pancreatic beta-cell function. IRS-2-deficient mice show progressive deterioration of glucose homeostasis because of insulin resistance in the liver and skeletal muscle and a lack of beta-cell compensation for this insulin resistance. Our results indicate that dysfunction of IRS-2 may contribute to the pathophysiology of human type 2 diabetes.
Abstract: We tested the hypotheses that, in hypoxic young pigs, reductions in cardiac output restrict systemic oxygen transport to a greater extent than does hypoxia alone and that compensatory responses to this restriction are more effective in higher than in lower priority vasculatures. To study this, 10- to 14-day-old instrumented awake hypoxic (arterial oxygen tension = 39 Torr) pigs were exposed to reduced venous return by inflation of a right atrial balloon-tipped catheter. Blood flow was measured with radionuclide-labeled microspheres, and oxygen metabolism was determined with arterial and venous oxygen contents from appropriate vessels. Hypoxia resulted in a reduction in oxygen tension; increases in cardiac output and perfusion to brain (72% over baseline), heart, adrenal glands, and liver without reductions to other organs except for the spleen; reductions in systemic and intestinal oxygen delivery; and increases in systemic and intestinal oxygen extraction without changes in systemic, cerebral, or intestinal oxygen uptake. During hypoxia, decreasing venous return was associated with increases in arterial lactic acid concentration and central venous pressure; attenuation of the hypoxia-related increase in cardiac output; sustained increases in brain (72% over baseline) and heart perfusion; reductions in lung (bronchial artery), pancreatic, renal, splenic, and intestinal (-50% below baseline) perfusion; decreases in systemic and gastrointestinal oxygen delivery; sustained increases in systemic and intestinal oxygen extraction; and decreases in intestinal oxygen uptake, without changes in cerebral oxygen metabolism. We conclude that when venous return to the heart is reduced in hypoxic young pigs, the hypoxia-related increase in cardiac output was attenuated and the relative reduction in cardiac output was associated with preserved cerebral oxygen uptake and compromised intestinal oxygen uptake. Regional responses to hypoxia combined with relative reductions in cardiac output differ from that of hypoxia alone, with the greatest effects on lower priority organs such as the gastrointestinal tract.
Abstract: We investigated the effects of the nature of the flooding amino acid on the rate of incorporation of tracer leucine into human skeletal muscle sampled by biopsy. Twenty-three healthy young men (24.5 +/- 5. 0 yr, 76.2 +/- 8.3 kg) were studied in groups of four or five. First, the effects of flooding with phenylalanine, threonine, or arginine (all at 0.05 g/kg body wt) on the incorporation of tracer [13C]leucine were studied. Then the effects of flooding with labeled [13C]glycine [0.1 g/kg body wt, 20 atoms percent excess (APE)] and [13C]serine (0.05 g/kg body wt, 15 APE) on the incorporation of simultaneously infused [13C]leucine were investigated. When a large dose of phenylalanine or threonine was administered, incorporation of the tracer leucine was significantly increased (from 0.036 to 0. 067 %/h and 0.037 to 0.070 %/h, respectively; each P \textless 0.01). However, when arginine, glycine, or serine was administered as a flooding dose, no stimulation of tracer leucine incorporation could be observed. These results, together with those previously obtained, suggest that large doses of individual essential, but not nonessential, amino acids are able to stimulate incorporation of constantly infused tracer amino acids into human muscle protein.
Abstract: Recent reviews have claimed that the majority of patients with the nephrotic syndrome have plasma volume expansion (that is, they are overfilled). Here we attempt to re-establish balance to the debate on body fluid volume status in nephrotic patients by: (a) discussing the conflicting literature on plasma volume measurements in the nephrotic syndrome; (b) providing alternate explanations for data purporting to support an overfill hypothesis in the nephrotic syndrome; (c) emphasizing secondary neurohumoral responses that support underfilling at least as frequently as overfilling; and (d) emphasizing the clinical importance of fluid assessment in the individual patient with the nephrotic syndrome particularly in relation to diuretic use.
Abstract: This study was undertaken to examine the effects of 12 weeks of skeletal unloading on parameters of calcium homeostasis, calcitropic hormones, bone histology, and biochemical markers of bone turnover in 11 normal subjects (9 men, 2 women; 34 +/- 11 years of age). Following an ambulatory control evaluation, all subjects underwent 12 weeks of bed rest. An additional metabolic evaluation was performed after 12 days of reambulation. Bone mineral density declined at the spine (-2.9%, p = 0.092) and at the hip (-3.8%, p = 0.002 for the trochanter). Bed rest prompted a rapid, sustained, significant increase in urinary calcium and phosphorus as well as a significant increase in serum calcium. Urinary calcium increased from a pre-bed rest value of 5.3 mmol/day to values as high as 73 mmol/day during bed rest. Immunoreactive parathyroid hormone and serum 1,25-dihydroxyvitamin D declined significantly during bed rest, although the mean values remained within normal limits. Significant changes in bone histology included a suppression of osteoblastic surface for cancellous bone (3.1 +/- 1.3% to 1.9 +/- 1.5%, p = 0.0142) and increased bone resorption for both cancellous and cortical bone. Cortical eroded surface increased from 3.5 +/- 1.1% to 7.3 +/- 4.0% (p = 0.018) as did active osteoclastic surface (0.2 +/- 0.3% to 0.7 +/- 0.7%, p = 0.021). Cancellous eroded surface increased from 2.1 +/- 1.1% to 4.7 +/- 2.2% (p = 0.002), while mean active osteoclastic surface doubled (0.2 +/- 0.2% to 0.4 +/- 0.3%, p = 0.020). Serum biochemical markers of bone formation (osteocalcin, bone-specific alkaline phosphatase, and type I procollagen extension peptide) did not change significantly during bed rest. Urinary biochemical markers of bone resorption (hydroxyproline, deoxypyridinoline, and N-telopeptide of type I collagen) as well as a serum marker of bone resorption (type I collagen carboxytelopeptide) all demonstrated significant increases during bed rest which declined toward normal during reambulation. Thus, under the conditions of this study, the human skeleton appears to respond to unloading by a rapid and sustained increase in bone resorption and a more subtle decrease in bone formation.
Abstract: We measured the urine amino acid distribution patterns before, during and after space flight on the Space Shuttle. The urine samples were collected on two separate flights of the space shuttle. The first flight lasted 9.5 days and the second flight 15 days. Urine was collected continuously on 8 subjects for the period beginning 10 d before launch to 6 d after landing. Results: In contrast to the earlier Skylab missions where a pronounced amino aciduria was found, on shuttle the urinary amino acids showed little change with spaceflight except for a marked decrease in all of the amino acids on FD (flight day) 1 (p\textless0.05) and a reduction in isoleucine and valine on FD3 and FD4 (p\textless0.05). Conclusions: (i) Amino aciduria is not an inevitable consequence of space flight. (ii) The occurrence of amino aciduria, like muscle protein breakdown is a mission specific effect rather than part of the general human response to microgravity.
Abstract: OBJECTIVE: This review is an account of the physiological issues involved in the effects of pH on vascular smooth muscle tone. The following criteria were considered when reviewing the literature: (i) the type of smooth muscle, i.e. either tonic or phasic, (ii) the source of the smooth muscle i.e. pulmonary, systemic, large artery, resistance artery, vein or cell line, (iii) the effects of changing intracellular or extracellular pH alone, (iv) the acute or chronic effects of altered pH (v) the influence of extracellular pH on intracellular pH and (vi) the influence of altered intracellular pH on basal or agonist induced tone. Studies of the effects of pH on the individual intracellular components of vascular tone, specifically sarcoplasmic reticulum and contractile proteins function are considered. Finally, the pH sensitivity of molecular components that contribute to smooth muscle cell tone are reviewed. CONCLUSIONS: There appear to be distinct differences in the response of large arteries and resistance arteries to altered intracellular pH which may be based on the different properties of the smooth muscle within the wall of each blood vessel. Similarly, systemic and pulmonary vessels may respond differently, but no systematic study exists to allow a more definitive conclusion. Factors controlling intracellular pH such as intracellular buffering power and sarcolemmal pH regulating mechanisms may differ across the vascular bed and may contribute to some of the differences observed in response to altered extracellular pH. Finally, few studies have examined the pH sensitivity the intracellular processes involved in basal tone and pharmaco-mechanical coupling in vascular smooth muscle. More information concerning these latter aspects of smooth muscle function is required to progress the understanding of the modulator action on pH on vascular tone.
Abstract: In 1866, Carl Ludwig together with Elias Cyon created the first isolated perfused frog heart preparation. Perfusion systems for the isolated mammalian heart were developed by H. Newell Martin in 1883 and by Oscar Langendorff in 1895. In its working mode, the isolated perfused rat heart was established in the 1960s.
Abstract: OBJECTIVE: To determine the best therapeutic strategy for the use of midodrine in patients with neurogenic orthostatic hypotension (NOH). BACKGROUND: Midodrine is a peripherally acting alpha-adrenergic agonist useful in the treatment of NOH. However, neither the most effective dosage of midodrine nor the required frequency of administration is established. DESIGN/METHODS: Midodrine dose-blood pressure response, pharmacokinetics, and duration of action were examined in a double-blind, placebo-controlled, four-way crossover trial. Twenty-five patients with NOH were randomized to receive on successive days placebo or midodrine 2.5, 10, or 20 mg. Blood pressures of patients in the supine and standing positions were measured sequentially. A global assessment of the patient’s overall symptom improvement after each leg of the study was performed. Blood levels of midodrine and its active metabolite, desglymidodrine, were assayed. RESULTS: Midodrine significantly increased standing systolic blood pressure, with the increase peaking at 1 hour. There was a significant linear relation between midodrine dosage and mean systolic blood pressure. The mean score for global improvement of symptoms was significantly higher for midodrine (10 and 20 mg) compared with placebo. The half-life of desglymidodrine was approximately 4 hours. CONCLUSION: A 10-mg dose of midodrine prescribed two to three times daily is effective in increasing orthostatic blood pressure and ameliorating symptoms in patients with NOH.
Abstract: The sodium-potassium ATPase (Na+/K+-ATPase or Na+/K+-pump) is an enzyme present at the surface of all eukaryotic cells, which actively extrudes Na+ from cells in exchange for K+ at a ratio of 3:2, respectively. Its activity also provides the driving force for secondary active transport of solutes such as amino acids, phosphate, vitamins and, in epithelial cells, glucose. The enzyme consists of two subunits (alpha and beta) each expressed in several isoforms. Many hormones regulate Na+/K+-ATPase activity and in this review we will focus on the effects of insulin. The possible mechanisms whereby insulin controls Na+/K+-ATPase activity are discussed. These are tissue- and isoform-specific, and include reversible covalent modification of catalytic subunits, activation by a rise in intracellular Na+ concentration, altered Na+ sensitivity and changes in subunit gene or protein expression. Given the recent escalation in knowledge of insulin-stimulated signal transduction systems, it is pertinent to ask which intracellular signalling pathways are utilized by insulin in controlling Na+/K+-ATPase activity. Evidence for and against a role for the phosphatidylinositol-3-kinase and mitogen activated protein kinase arms of the insulin-stimulated intracellular signalling networks is suggested. Finally, the clinical relevance of Na+/K+-ATPase control by insulin in diabetes and related disorders is addressed.
Abstract: BACKGROUND. The effect of vasoconstrictors on intracerebral hemodynamics in anesthetized patients is controversial. The influence of phenylephrine and norepinephrine on the cerebral circulation was investigated in isoflurane- or propofol-anesthetized patients using transcranial Doppler ultrasonography. METHODS: Forty patients were randomly assigned to have vasoconstrictor tests with norepinephrine or phenylephrine during either isoflurane or propofol anesthesia. Blood flow velocities were simultaneously measured in the middle cerebral artery and ipsilateral extracranial internal carotid artery. Baseline recordings were done during stable anesthesia in a supine position (test 0). A second series of measurements were performed after norepinephrine or phenylephrine had increased mean arterial blood pressure by about 20% (test 1). With maintained norepinephrine or phenylephrine infusion, a final series of results were obtained after the increased mean arterial blood pressure was counteracted by a slightly head-up patient position (test 2). RESULTS: Both vasoconstrictors significantly increased mean flow velocities in the middle cerebral artery (norepinephrine: 43 +/- 11 cm/s to 49 +/- 11 cm/s; phenylephrine: 43 +/- 8 cm/s to 48 +/- 9 cm/s; +/- SD) and internal carotid artery (norepinephrine: 27 +/- 7 cm/s to 31 +/- 8 cm/s; phenylephrine: 27 +/- 9 cm/s to 31 +/- 10 cm/s) in the isoflurane-but not in the propofol-anesthetized patients. In the head-up position, only small and insignificant flow velocity changes were observed in both cerebral arteries independent of the vasoconstrictor or background anesthetic. CONCLUSIONS: The results of the present study indicate that norepinephrine and phenylephrine do not directly affect intracranial hemodynamics in anesthetized patients, but rather that hemodynamic changes observed with vasoconstrictors reflect the effect of the background anesthetic agents on cerebral pressure autoregulation.
Abstract: This study examined the effect of intravenous infusion of subpressor doses of angiotensin (Ang II) on renal medullary blood flow (MBF), medullary partial oxygen pressure (PO2), and nitric oxide (NO) concentration under normal conditions and during reduction of the medullary nitric oxide synthase (NOS) activity in anesthetized rats. With laser Doppler flowmetry and polarographic measurement of PO2 with microelectrodes, Ang II (5 ng/kg per minute) did not alter renal cortical and medullary blood flows or medullary PO2. N(omega)-nitro-L-arginine methyl ester (L-NAME) was infused into the renal medullary interstitial space at a dose of 1.4 microg/kg per minute, a dose that did not significantly alter basal levels of MBF or PO2. Intravenous infusion of Ang II at the same dose in the presence of L-NAME decreased MBF by 23% and medullary PO2 by 28%, but it had no effect on cortical blood flow or arterial blood pressure. An in vivo microdialysis-oxyhemoglobin NO trapping technique was used in other rats to determine tissue NO concentrations using the same protocol. Ang II infusion increased tissue NO concentrations by 85% in the renal cortex and 150% in the renal medulla. Renal medullary interstitial infusion of L-NAME (1.4 microg/kg per minute) reduced medullary NO concentrations and substantially blocked Ang II-induced increases in NO concentrations in the renal medulla, but not in the renal cortex. Tissue slices of the renal cortex and medulla were studied to determine the effects of Ang II and L-NAME on the nitrite/nitrate production. Ang II stimulated the nitrite/nitrate production predominately in the renal medulla, which was significantly attenuated by L-NAME. We conclude that small elevations of circulating Ang II levels increase medullary NO production and concentrations, which plays an important role in buffering the vasoconstrictor effects of this peptide and in maintaining a constancy of MBF.
Abstract: In vivo energy production results largely from the oxidative metabolism of either glucose or fatty acids. Under diverse physiologic and nutritional conditions, the oxidation of either glucose or fatty acids may predominate. The nature of the control of the availability and oxidation of each substrate has been studied extensively for \textgreater or = 30 y. The most popular and enduring hypothesis was proposed by Randle et al in 1963 and is termed the glucose-fatty acid cycle. This proposal places great significance on the regulation of lipolysis as a factor controlling substrate metabolism. Our work has led to an opposite perspective, which could be called the glucose-fatty acid cycle reversed. According to our hypothesis, the rate of glycolysis, determined by the intracellular availability of glucose-6-phosphate, is the predominant factor determining the rate of glucose oxidation. Whereas the rate of lipolysis may have some effect on the availability of glucose, both via a fatty acid-mediated inhibition of plasma glucose uptake and also by supplying glycerol for gluconeogenesis, there is little evidence for a direct inhibitory effect of fatty acid oxidation on the intracellular oxidation of glucose. In contrast, increased glucose oxidation limits oxidation of long-chain fatty acids directly by inhibiting their transport into the mitochondria. Consequently, whereas there is a close coupling between glucose availability and oxidation, fatty acids are generally available in greater quantities than are required for oxidation. We propose that fatty acid oxidation is largely controlled at the site of oxidation, which is in turn determined by the availability of glucose, rather than by its availability via lipolysis.
Abstract: The purposes of this review were twofold: to apply modern physicochemical principles to explain changes in acid-base regulation and the control of ventilation in human pregnancy; and to demonstrate the value of pregnancy as a model for the study of endocrine effects on physiological control systems. Application of P.A. Stewart’s approach (P.A. Stewart. Can. J. Physiol. Pharmacol. 61: 1444-1461, 1983) shows that lower values of plasma hydrogen ion concentration ([H+]) observed at rest and in association with exercise in pregnancy are the result of lower values for carbon dioxide tension (Pco2) and total weak acid ([A(tot)]). This effect is partly offset by a lower strong ion difference ([SID]). The ability to predict plasma [H+] at rest and following strenuous exercise in pregnancy (J.G. Kemp, F.A. Greer, and L.A. Wolfe. J. Appl. Physiol. 83: 644-651, 1997) supports the validity of Stewart’s approach. Jennings and associates (D.B. Jennings. Can. J. Physiol. Pharmacol. 72: 1499-1512, 1994) have further demonstrated in animal models the involvement of plasma osmolality and circulating levels of angiotensin II (ANG II) and arginine vasopressin (AVP) in the chemical control of ventilation. We hypothesize that pregnancy-induced increases in respiratory sensitivity to carbon dioxide are the combined result of reduced plasma osmolality, reduced cerebrospinal fluid [SID], and augmented circulating levels of progesterone, ANG II, and AVP.
Abstract: OBJECTIVE: To assess the effects of supplementation with oral potassium on blood pressure in humans. DESIGN: Meta-analysis of randomized controlled trials. DATA SOURCES: English-language articles published before July 1995. STUDY SELECTION: Thirty-three randomized controlled trials (2609 participants) in which potassium supplementation was the only difference between the intervention and control conditions. DATA EXTRACTION: Using a standardized protocol, 2 of us independently abstracted information on sample size, duration, study design, potassium dose, participant characteristics, and treatment results. RESULTS: By means of a random-effects model, findings from individual trials were pooled, after results for each trial were weighted by the inverse of its variance. An extreme effect of potassium in lowering blood pressure was noted in 1 trial. After exclusion of this trial, potassium supplementation was associated with a significant reduction in mean (95% confidence interval) systolic and diastolic blood pressure of -3.11 mm Hg (-1.91 to -4.31 mm Hg) and -1.97 mm Hg (-0.52 to -3.42 mm Hg), respectively. Effects of treatment appeared to be enhanced in studies in which participants were concurrently exposed to a high intake of sodium. CONCLUSIONS: Our results support the premise that low potassium intake may play an important role in the genesis of high blood pressure. Increased potassium intake should be considered as a recommendation for prevention and treatment of hypertension, especially in those who are unable to reduce their intake of sodium.
Abstract: Steady-state insulin resistance results in a fasting hyperinsulinemia and is a common feature of type II diabetes mellitus and obesity. In this study, a systems analysis approach was used to study glucose homeostasis which is considered as the dynamic balance between glucose release by the liver and its uptake by the peripheral tissues as regulated by insulin and glucagon. A series of computer simulation studies were performed utilizing a mathematical model of glucose homeostasis. The purpose of the study was to better understand the factors which control glucose balance and to ascertain their relative importance in the development of steady state, fasting hyperinsulinemia. When peripheral cellular insulin receptors which regulate glucose uptake were reduced to 25% of normal, the steady state plasma insulin concentration showed little change from the basal level of 8 microU/ml. When insulin receptors in the liver were also reduced to 25% of normal, the steady state insulin concentration increased from the basal levels to 32 microU/ml. Reducing pancreatic alpha cell insulin receptors to 25% of normal further increased the hyperinsulinemia to 80 microU/ml. Hence, this study suggests that the liver and its release of glucose, as controlled by insulin and glucagon, plays a central role in the development of a steady-state insulin resistance and hyperinsulinemia.
Abstract: Hypoxia activates erythropoietin-producing cells, chemoreceptor cells of the carotid body and pulmonary artery smooth muscle cells (PSMC) with a comparable arterial PO2 threshold of some 70 mmHg. The inhibition by CO of the hypoxic responses in the two former cell types has led to the proposal that a haemoprotein is involved in the detection of the PO2 levels. Here, we report the effect of CO on the hypoxic pulmonary vasoconstriction (HPV). Pulmonary arterial pressure (PAP) was measured in an in situ, blood-perfused lung preparation. PAP in normoxia (20% O2, 5% CO2) was 15.2+/-1.8 mmHg, and hypoxia (2% O2, 5% CO2) produced a DeltaPAP of 6.3+/-0.4 mmHg. Addition of 8% or 15% CO to the hypoxic gas mixture reduced the DeltaPAP by 88.3+/-2.7% and 78.2+/-6.1% respectively. The same levels of CO did not affect normoxic PAP nor reduced the DeltaPAP produced by angiotensin II. The effect of CO was studied after inhibition of the NO-cyclic guanosine monophosphate (cGMP) cascade with N-methyl-l-arginine (5.10(-5) M) or methylene blue (1.4.10(-4) M). It was found that both inhibitors more than doubled the hypoxic DeltaPAP without altering the effectiveness of CO to inhibit the HPV. In in vitro experiments we verified the inhibition of guanylate cyclase by measuring the levels of cGMP in segments of the pulmonary artery. Cyclic GMP levels were 1.4+/-0.2 (normoxia), 2.5+/-0.3 (hypoxia) and 3.3+/-0.5 pmole/mg tissue (hypoxia plus 8% CO); sodium nitroprusside increased normoxic cGMP levels about fourfold. Methylene blue reduced cGMP levels to less than 10% in all cases, and abolished the differences among normoxic, hypoxic and hypoxic plus CO groups. It is concluded that CO inhibits HPV by a NO-cGMP independent mechanism and it is proposed that a haemoprotein could be involved in O2-sensing in PSMC.
Abstract: BACKGROUND: The ob gene product leptin is secreted by fat cells and reflects the content of fat in the body. Leptin and insulin concentrations as well as body weight are interrelated and a direct correlation has been found between these concentrations in humans with normal renal function. Markedly elevated serum leptin concentrations have recently been reported in patients with chronic renal failure (CRF). The aim of the present study was to investigate the relation between serum leptin and plasma insulin in patients with advanced CRF. METHODS: Serum leptin, plasma insulin, as well as body fat content (determined with dual-energy X-ray absorptiometry) were determined in a cohort of 46 patients (mean age 54 +/- 2 years) with advanced CRF (creatinine clearance 8 +/- 1 ml/min). RESULTS: In 23 CRF patients with plasma insulin below the median value (14 mU/l), serum leptin concentrations were no higher than in healthy controls (8.0 +/- 1.2 vs 8.4 +/- 0.9 ng/ml). However, in CRF patients with plasma insulin \textgreater 14 mU/l (n = 23) the serum leptin concentrations were much higher (38.2 +/- 11.0 ng/ml; P \textless 0.0001). In CRF patients, serum leptin (normalized for the per cent body fat content) correlated significantly (r = 0.64; P \textless 0.0001) with plasma insulin concentrations. However, the increase in plasma insulin was blunted in patients with very high serum leptin concentrations in relation to the per cent body fat content. CONCLUSIONS: The present results demonstrate that serum leptin concentrations are markedly elevated in CRF patients with higher plasma insulin than in those with lower plasma insulin concentrations. This suggests that insulin resistance and hyperinsulinaemia contribute to elevated serum leptin concentrations in CRF. The present results also demonstrate that, when circulating serum leptin concentrations are much higher in relation to the per cent body fat content, no additional increase in plasma insulin occurs. This latter observation suggests that the secretion of insulin by the pancreas is lower in hyperleptinaemic patients. Consequently, extremely elevated serum leptin may play a role in reducing glucose-stimulated insulin secretion and glucose intolerance in CRF.
Abstract: Twenty-seven halothane-anaesthetized, mechanically ventilated adult mongrel dogs were randomly assigned to either respiratory acidosis group [pHa 7.22 (0.03, SD), PaCO2 9.6 (1.1) kPa, base excess -0.5 (1.4) mmol.l-1, n = 9], metabolic acidosis group [pHa 7.20 (0.05), PaCO2 5.5 (0.4) kPa, base excess -11.1 (2.1) mmol.l-1, n = 9], or nonacidosis group [pHa 7.37 (0.07), PaCO2 5.2 (0.4) kPa, base excess -1.1 (1.5) mmol.l-1, n = 9]. Respiratory acidosis and metabolic acidosis were induced by decreasing respiratory rate and continuous infusion of 2 mmol.l-1 hydrochloric acid, respectively. Sodium bicarbonate solution 1 mmol.kg-1 was injected into the right atrium over five seconds when haemodynamic stability was obtained. In all three groups, acute administration of sodium bicarbonate produced transient decreases in mean arterial pressure and RV dP/dtmax, and transient increase in right atrial pressure 30 seconds after injections, but these variables returned to the pre-injection values by the end of the three minutes observation period. Although no significant differences were seen in haemodynamic variables among the three groups at 30 seconds, one and three minutes, maximum reductions in both RV dP/dtmax and PBF in the metabolic acidosis group (260 (143) mmHg.s-1 and 0.38 (0.26) l.min-1) were significantly greater than those in the non-acidosis group (127 (34) mmHg.s-1 and 0.08 (0.09) l.min-1; P \textless 0.05).
Abstract: A protocol achieving for long-term hemodynamic stability enabled us to evaluate pancreatic endocrine function for up to 1 wk following brain death. The glucose disappearance rate was significantly lower in brain-dead patients (N = 21) than in normal controls (N = 10) (p \textless 0.001). In 19 brain-dead patients whose plasma epinephrine concentrations exceeded 0.4 ng/ml, the mean early insulin release was significantly lower than in controls, while early insulin release was markedly higher in the remaining two patients. It is possible that early insulin released may be due to increased plasma epinephrine concentrations following brain death. Late insulin release in brain-dead patients was not lower, but was higher than controls and was accompanied by a decrease in the glucose disappearance rate. No evidence of abnormalities in histopathology of pancreas was detected at autopsy. Our results indicate that intrinsic insulin secretory function can be preserved during the first week following brain death.
Abstract: Inhibition of renal carbonic anhydrase reduces proximal reabsorption and activates tubuloglomerular feedback (TGF). The TGF response is saturable, with highest gain focused near the natural flow rate. Therefore, any large change imposed on ambient tubular flow should reduce the TGF response to subequent flow perturbations. However, TGF tends to align with ambient flow regardless of the rate of ambient flow, suggesting that TGF resets to accommodate changes in flow while maintaining feedback efficiency. We used micropuncture and videometric flow velocitometry to test for TGF resetting in free-flowing nephrons during systemic infusion of the carbonic anhydrase inhibitor benzolamide (BNZ, 5 mg x kg(-1) x h(-1)) in euvolemic rats. Late proximal flow (V(LP)) and the fractional compensation (C) of TGF for perturbations in V(LP) were assessed repeatedly before and during BNZ. Early on, BNZ reduced C, consistent with TGF saturation. Over the next 45-60 min, V(LP) increased gradually by approximately 5 nl/min as C recovered to pre-BNZ levels. BNZ also increased V(LP) by approximately 5 nl/min when TGF was rendered inoperative by intratubular wax block, but this increase occurred rapidly. These data demonstrate rightward resetting of TGF during reduced proximal reabsorption.
Abstract: OBJECTIVE: To identify cerebral hemispheric lateralization in cardiac autonomic control. PATIENTS: Eight patients undergoing an intracarotid amobarbital sodium test as a presurgical evaluation of temporal lobe epilepsy. DESIGN: Power spectral analysis of heart rate variability before and after intracarotid amobarbital injection. SETTING: University hospital and research center. MAIN OUTCOME MEASURE: The changes in the ratio of low-frequency (LF) (sympathetic) to high-frequency (HF) (parasympathetic) power (LF/HF ratio), a measure of sympathovagal balance, after hemispheric inactivation. RESULTS: The LF/HF ratio changed as follows: right preinactivation = 3.81 +/- 0.96, postinactivation = 3.40 +/- 1.23; left preinactivation = 2.74 +/- 0.49, postinactivation = 4.34 +/- 0.59 (mean +/- SEM). The test of interaction between laterality and inactivation using a 2-way repeated-measures analysis of variance was statistically significant (P = .001). The increased ratio on the left side (1.61 +/- 0.70) was statistically significant (P = .03), but the decrease on the right side (-0.40 +/- 0.46) was not (P \textless or = .70). CONCLUSIONS: These findings suggest that there is a cerebral lateralization in cardiac autonomic control and that the right cerebral hemisphere predominantly modulates sympathetic activity. This study may help identify subgroups of patients with intracranial disease at high risk of cardiac complications.
Abstract: In microgravity (microG) humans have marked changes in body fluids, with a combination of an overall fluid loss and a redistribution of fluids in the cranial direction. We investigated whether interstitial pulmonary edema develops as a result of a headward fluid shift or whether pulmonary tissue fluid volume is reduced as a result of the overall loss of body fluid. We measured pulmonary tissue volume (Vti), capillary blood flow, and diffusing capacity in four subjects before, during, and after 10 days of exposure to microG during spaceflight. Measurements were made by rebreathing a gas mixture containing small amounts of acetylene, carbon monoxide, and argon. Measurements made early in flight in two subjects showed no change in Vti despite large increases in stroke volume (40%) and diffusing capacity (13%) consistent with increased pulmonary capillary blood volume. Late in-flight measurements in four subjects showed a 25% reduction in Vti compared with preflight controls (P \textless 0.001). There was a concomittant reduction in stroke volume, to the extent that it was no longer significantly different from preflight control. Diffusing capacity remained elevated (11%; P \textless 0.05) late in flight. These findings suggest that, despite increased pulmonary perfusion and pulmonary capillary blood volume, interstitial pulmonary edema does not result from exposure to microG.
Abstract: The objective of the present study was to develop a physiologically based pharmacokinetic (PBPK) model for a ternary mixture of alkyl benzenes [toluene (TOL), m-xylene (XYL), and ethylbenzene (EBZ)] in rats and humans. The approach involved the development of the mixture PBPK model in the rat and extrapolation to humans by substituting rat physiological parameters and blood:air partition coefficients in the model with those of humans, scaling maximal velocity for metabolism on the basis of body weight0.75 and keeping all other model parameters species-invariant. The development of the PBPK model for the ternary mixture in the rat was accomplished by initially validating or refining the existing PBPK models for TOL, XYL, and EBZ and linking the individual chemical models via the hepatic metabolism term. Accordingly, the Michaelis-Menten equation for each solvent was modified to test four possible mechanisms of metabolic interaction (i.e., no interaction, competitive inhibition, noncompetitive inhibition, and uncompetitive inhibition). The metabolic inhibition constant (Ki) for each binary pair of alkyl benzenes was estimated by fitting the binary chemical PBPK model simulations to previously published data on blood concentrations of TOL, XYL, and EBZ in rats exposed for 4 hr to a binary combination of 100 or 200 ppm of each of these solvents. Competitive metabolic inhibition appeared to be the most plausible mechanism of interaction at relevant exposure concentrations for all binary mixtures of alkyl benzenes in the rat (Ki,TOL-XYL = 0.17; Ki,TOL-EBZ = 0.79; Ki,XYL-TOL = 0.77; Ki,XYL-EBZ = 1.50; Ki,EBZ-TOL = 0.33; Ki,EBZ-XYL = 0.23 mg/L). Incorporating the Ki values obtained with the binary chemical mixtures, the PBPK model for the ternary mixture simulated adequately the time course of the venous blood concentrations of TOL, XYL, and EBZ in rats exposed to a mixture containing 100 ppm each of these solvents. Following the validation of the ternary mixture model in the rat, it was scaled to predict the kinetics of TOL, XYL, and EBZ in blood and alveolar air of human volunteers exposed for 7 hr to a combination of 17, 33, and 33 ppm, respectively, of these solvents. Model simulations and experimental data obtained in humans indicated that exposure to atmospheric concentrations of TOL, XYL, and EBZ that remain within the permissible concentrations for a mixture would not result in biologically significant modifications of their pharmacokinetics. Overall, this study demonstrates the utility of PBPK models in the prediction of the kinetics of components of chemical mixtures, by accounting for mechanisms of binary chemical interactions.
Abstract: Analogue scales are relatively easy to interpret for the assessment of exercise-induced dyspnea although certain standardization points remain to be established. We discuss the pathophysiological basis correlating dyspnea with exercise parameters. In clinical practice, the curve of the dyspnea/ventilation ratio plotted during exercise is a useful parameter, focusing attention on the notion of a dyspnea threshold (near the ventilatory threshold) and slope (which could be modified, for example, by treatment or a rehabilitation program). Evaluation of exercise-induced dyspnea must of course be an integral part or the overall analysis of all other parameters studied during exercise.
Abstract: Allometric scaling relations, including the 3/4 power law for metabolic rates, are characteristic of all organisms and are here derived from a general model that describes how essential materials are transported through space-filling fractal networks of branching tubes. The model assumes that the energy dissipated is minimized and that the terminal tubes do not vary with body size. It provides a complete analysis of scaling relations for mammalian circulatory systems that are in agreement with data. More generally, the model predicts structural and functional properties of vertebrate cardiovascular and respiratory systems, plant vascular systems, insect tracheal tubes, and other distribution networks.
Abstract: To isolate the impact of GnRH pulse frequency on FSH secretion and to examine the effect of differing levels of FSH on inhibin B secretion during the luteal-follicular transition, exogenous GnRH was administered to GnRH-deficient women using one of two regimens, and the results were compared to those in normal women. In the GnRH-deficient women, the GnRH pulse frequency was increased from every 4 h in the late luteal phase to every 90 min on the day of menses to mimic normal cycling women (physiological frequency transition; n = 8 studies) or the GnRH pulse frequency was kept constant at a late luteal phase frequency of every 4 h through the first 6 days of the subsequent early follicular phase of cycle 2 (slow frequency transition; n = 6 studies). The differential rise in FSH secretion induced in these studies allowed us to examine the subsequent contribution of varying levels of FSH to inhibin B secretion. A physiological regimen of GnRH during the luteal-follicular transition resulted in a rise in FSH and inhibin B levels that did not differ from that in normal cycling women and a normal follicular phase length. On the other hand, maintaining a luteal frequency of GnRH for 6 days into the subsequent early follicular phase produced FSH levels significantly lower than those in the physiological transition (P \textless 0.05), with the greatest difference seen on the day after menses (9.1 +/- 1.0 vs. 16.4 +/- 1.4 IU/L for the slow and physiological transition groups, respectively; P \textless 0.005), but no difference in LH. This slower rise of FSH secretion in the slow frequency group was associated with significantly lower inhibin B levels (43.3 +/- 21.5 vs. 140.0 +/- 24.4 pg/mL, mean days 1, 3, and 5; P \textless 0.02), a later doubling of estradiol from baseline (day 9.6 +/- 0.9 vs. day 5.6 +/- 0.1; P \textless 0.02), and a longer follicular phase length (16.0 +/- 1.4 vs. 11.6 +/- 0.9 days; P \textless 0.05) compared with those in the physiological transition group. In conclusion, during the luteal-follicular transition, the GnRH pulse frequency contributes to but is not solely responsible for the FSH rise that initiates folliculogenesis. Alteration of FSH dynamics induced by changes in GnRH pulse frequency in GnRH-deficient women provides evidence that FSH stimulates inhibin B production in the human. Timely follicular development indicated by both estradiol and inhibin B secretion appears to be dependent on the pattern of increase in FSH during the luteal-follicular transition.
Abstract: The effects of pericardial constraint on cardiac chamber interactions were evaluated by mathematical model analyses based on a novel concept of coupled vs. uncoupled pericardial constraint. We hypothesized that the nature of pericardial constraint can be classified as a "coupled" constraint exerted by uniform liquid pressure or an "uncoupled" constraint exerted by regional surface pressure. The numerical solution of the model of atrioventricular interaction produced the characteristic waveforms in venous flows and right atrial/ventricular pressures in classical pericardial diseases. Coupled constraint accounted for the patterns in cardiac tamponade; uncoupled constraint accounted for those in constrictive pericarditis. Analytic solution of the model of ventricular interdependence demonstrated that coupled constraint (tamponade) produced greater gains in ventricular interdependence, increasing the occurrence of pulsus paradoxus, whereas uncoupled constraint (constriction) produced a greater effective right ventricular elastance, increasing the likelihood of Kussmaul’s sign. Thus the concept of coupled vs. uncoupled constraint may offer a coherent framework to understand the characteristic steady-state and respiratory-induced hemodynamic events in multiple forms of pericardial diseases.
Abstract: Our aim was to determine whether the adaptation to simulated microgravity (microG) impairs regulation of cerebral blood flow (CBF) during orthostatic stress and contributes to orthostatic intolerance. Twelve healthy subjects (aged 24 +/- 5 yr) underwent 2 wk of -6 degrees head-down-tilt (HDT) bed rest to simulate hemodynamic changes that occur when humans are exposed to microG. CBF velocity in the middle cerebral artery (transcranial Doppler), blood pressure, cardiac output (acetylene rebreathing), and forearm blood flow were measured at each level of a ramped protocol of lower body negative pressure (LBNP; -15, -30, and -40 mmHg x 5 min, -50 mmHg x 3 min, then -10 mmHg every 3 min to presyncope) before and after bed rest. Orthostatic tolerance was assessed by using the cumulative stress index (CSI; mmHg x minutes) for the LBNP protocol. After bed rest, each individual’s orthostatic tolerance was reduced, with the group CSI decreased by 24% associated with greater decreases in cardiac output and greater increases in systemic vascular resistance at each level of LBNP. Before bed rest, mean CBF velocity decreased by 14, 10, and 45% at -40 mmHg, -50 mmHg, and maximal LBNP, respectively. After bed rest, mean velocity decreased by 16% at -30 mmHg and by 21, 35, and 39% at -40 mmHg, -50 mmHg, and maximal LBNP, respectively. Compared with pre-bed rest, post-bed-rest mean velocity was less by 11, 10, and 21% at -30, -40, and -50 mmHg, respectively. However, there was no significant difference at maximal LBNP. We conclude that cerebral autoregulation during orthostatic stress is impaired by adaptation to simulated microG as evidenced by an earlier and greater fall in CBF velocity during LBNP. We speculate that impairment of cerebral autoregulation may contribute to the reduced orthostatic tolerance after bed rest.
Abstract: OBJECTIVE: To assess the relevance of sympathetic nerves for the stimulation of renin secretion and renin gene expression during effective angiotensin II type 1 receptor blockade in vivo. METHODS: Male Sprague-Dawley rats were treated with the angiotensin II type 1-receptor blocker losartan (40 mg/kg) for 3 days. To examine the role of renal sympathetic nerves in the stimulation of the renin system by losartan, left kidneys were denervated 4 days prior to the treatment with losartan. Also, to examine the role of circulating catecholamines in the stimulation of the renin system by losartan, the animals were administered a combination treatment of losartan with the beta1-adrenoreceptor blocker metoprolol (50 mg/kg per day) for 3 days. RESULTS: Losartan treatment increased plasma renin activity about sevenfold and renal renin messenger RNA (mRNA) levels about fivefold and decreased systolic blood pressure from 118 to 95 mmHg. Administration of losartan elevated renin mRNA both in the innervated and in the denervated kidneys to the same level as it did in kidneys of normal animals. Losartan treatment increased plasma renin activity and renal renin mRNA levels in the beta1-blocker-treated rats to the same extent as it did in animals administered losartan only. CONCLUSION: These findings suggest that, under sub-chronic treatment with hypotensive doses of angiotensin II receptor blockers, sympathetic outflow plays no important mediator role in the characteristic stimulation of renin secretion and renin gene expression, suggesting that it is mainly a direct disinhibition of angiotensin II’s action on the level of juxtaglomerular cells that accounts for the effect.
Abstract: Our aim was to elucidate why astronaut’s exercise capacity after spaceflight is reduced. Therefore, the kinetics of oxygen uptake (VO2) as a measure for muscular aerobic capacity, as well as maximal oxygen uptake (VO2peak), and anaerobic threshold (PAT) as overall measures for exercise capacity were determined. Measurements of VO2peak and AT were restricted to pre- and postflight sessions. METHODS: Four crew-members of the D-2 mission (10 d) were cycling with steady state phases at 20 W and 80 W, followed by 450s of pseudo random binary sequence (PRBS) changes between 20 W and 80 W, and an incremental exercise test (10 W every 30 s) up to subjective exhaustion. Breath-by-breath VO2, VCO2, ventilation, HR, and blood pressure were continuously recorded. Blood lactate samples were drawn only during the incremental phase. The VO2 kinetics were determined by evaluation of the relationship between the workload and the instantaneous oxygen uptake of each subject. The cross-correlation function between both variables showed two characteristic items, the maximum as a measure for the muscular aerobic capacity, and its lag representing time consuming processes. RESULTS AND DISCUSSION: Each subject showed an individual characteristic of VO2 kinetics. In flight, no significant changes were detected compared to preflight data. Decreases in lags of cross-correlation function maxima and decreases in mean blood pressure during exercise indicate lowered blood volumes 2 d after the flight. Lowered blood volumes can explain the losses in exercise capacity. The maximum of the cross-correlation function did not change significantly which indicates unchanged muscular oxidative capacity.
Abstract: STUDY OBJECTIVES: To identify the relative contribution of hydrostatic and permeability mechanisms to the development of human neurogenic pulmonary edema. DESIGN: Retrospective review of patients with neurogenic pulmonary edema who had pulmonary edema fluid analysis. SETTING: University hospital ICU. PATIENTS: Twelve patients with neurogenic pulmonary edema in whom the associated neurologic condition was subarachnoid hemorrhage (n = 8, 67%), postcraniotomy (n = 2), and stroke (n = 2). MEASUREMENTS: Protein concentration was measured from pulmonary edema fluid and plasma samples obtained shortly after the onset of clinical pulmonary edema. RESULTS: The mechanism of pulmonary edema was classified according to the initial alveolar edema fluid to plasma protein concentration ratio. A hydrostatic mechanism (ratio \textless or = 0.65) was observed in seven patients, none of whom had cardiac failure or intravascular volume overload. Five patients had evidence for increased permeability (ratio \textgreater 0.70). Patients with a hydrostatic mechanism had better initial oxygenation (mean +/- SD PaO2/FIO2 [fraction of inspired oxygen] = 233 +/- 132) compared with patients with increased permeability (PaO2/FIo2 = 80 +/- 42), and oxygenation improved more rapidly in the hydrostatic patients. Overall mortality (58%) was high, but it was related to unresolved neurologic deficits, not to respiratory failure. CONCLUSION: Many of our patients had a hydrostatic mechanism for neurogenic pulmonary edema. This is a novel observation in humans since prior clinical case reports have emphasized increased permeability as the usual mechanism for neurogenic pulmonary edema. These findings are consistent with pulmonary venoconstriction or transient elevation in left-sided cardiovascular pressures as contributing causes to the development of human neurogenic pulmonary edema.
Abstract: The ability of mitochondria to oxidize substrates and generate energy is integral to normal homeostasis and to the ability of cells to survive in the face of impending energy failure. Lactic acidosis is a common and readily apparent biochemical marker for mitochondrial dysfunction. However, lactic acidosis represents only the most obvious example in which acquired or congenital abnormalities of mitochondrial oxidative phosphorylating capacity contribute to the pathobiology and phenotypic expression of a broad spectrum of clinical disorders. Consequently, interventions that improve mitochondrial function or prevent mitochondrial energy failure may have widespread therapeutic implications.
Abstract: It is unclear whether sympathetic tone opposes dilator influences in exercising skeletal muscle. We examined high levels of sympathetic tone, evoked by lower body negative pressure (LBNP, -60 mmHg) on intramuscular pH and phosphocreatine (PCr) levels (31P-nuclear magnetic resonance spectroscopy) during graded rhythmic handgrip (30 contractions/min; approximately 17, 34, 52 and 69% maximal voluntary contraction). Exercise was performed with LBNP and without LBNP (Control). At the end of exercise, LBNP caused lower levels of muscle pH (6.59 +/- 0.09) compared with Control (6.78 +/- 0.05; P \textless 0.05). PCr recovery, an index of mitochondrial respiration, was less during the recovery phase of the LBNP trial. Exercise mean arterial pressure was not altered by LBNP. The protocols were repeated with measurements of forearm blood flow velocity and deep venous samples (active forearm) of hemoglobin (Hb) saturation, pH, and lactate. With LBNP, mean blood velocity was reduced at rest, during exercise, and during recovery compared with Control (P \textless 0.05). Also, venous Hb saturation and pH levels during exercise and recovery were lower with LBNP and lactate was higher compared with Control (P \textless 0.05). We conclude that LBNP enhanced sympathetic tone and reduced oxygen transport. At high workloads, there was a greater reliance on nonoxidative metabolism. In other words, sympatholysis did not occur.
Abstract: Elevated blood glucose concentrations result in increased intracellular levels of glucose 6-phosphate in liver, skeletal muscle, and adipose tissue. In liver, blood glucose concentrations are the main factor in control of the synthesis of glycogen; insulin has only a potentiating effect. In skeletal muscle and adipocytes, glucose alone has little effect on the activity of glycogen synthase, the limiting enzyme in glycogen synthesis. However, insulin released as a result of elevated blood glucose stimulates the translocation of specific glucose transporters to the cell membrane, increases the uptake of glucose, and causes the covalent, dephosphorylation-mediated activation of glycogen synthase. We present evidence that elevated intracellular contents of glucose 6-phosphate provoke the activation of glycogen synthase in liver, muscle, and adipose tissue. In addition, glucose 6-phosphate may inhibit the phosphorylation of glycogen synthase by cyclic AMP-stimulated protein kinase. We show that the stimulated glucose uptake and phosphorylation appear to play a major role in the control by insulin of the enzymes involved in glycogen synthesis.
Abstract: The hypothesis was tested that human cardiac filling pressures increase and the left atrium is distended during 20-s periods of microgravity (microG) created by parabolic flights, compared with values of the 1-G supine position. Left atrial diameter (n = 8, echocardiography) increased significantly during microG from 26.8 +/- 1.2 to 30.4 +/- 0.7 mm (P \textless 0.05). Simultaneously, central venous pressure (CVP; n = 6, transducer-tipped catheter) decreased from 5.8 +/- 1.5 to 4.5 +/- 1.1 mmHg (P \textless 0.05), and esophageal pressure (EP; n = 6) decreased from 1.5 +/- 1.6 to -4.1 +/- 1.7 mmHg (P \textless 0.05). Thus transmural CVP (TCVP = CVP - EP; n = 4) increased during microG from 6.1 +/- 3. 2 to 10.4 +/- 2.7 mmHg (P \textless 0.05). It is concluded that short periods of microG during parabolic flights induce an increase in TCVP and left atrial diameter in humans, compared with the results obtained in the 1-G horizontal supine position, despite a decrease in CVP.
Abstract: To gain insight into the mechanism(s) by which cells sense volume changes, specific predictions of the macromolecular crowding theory (A. P. Minton. In: Cellular and Molecular Physiology of Cell Volume Regulation, edited by K. Strange. Boca Raton, FL: CRC, 1994, p. 181-190. A. P. Minton, C. C. Colclasure, and J. C. Parker. Proc. Natl. Acad. Sci. USA 89: 10504-10506, 1992) were tested on the volume of internally perfused barnacle muscle cells. This preparation was chosen because it allows assessment of the effect on cell volume of changes in the intracellular macromolecular concentration and size while maintaining constant the ionic strength, membrane stretch, and osmolality. The predictions tested were that isotonic replacement of large macromolecules by smaller ones should induce volume decreases proportional to the initial macromolecular concentration and size as well as to the magnitude of the concentration reduction. The experimental results were consistent with these predictions: isotonic replacement of proteins or polymers with sucrose induced volume reductions, but this effect was only observed when the replacement was \textgreater or = 25% and the particular macromolecule had an average molecular mass of \textless or = 20 kDa and a concentration of at least 18 mg/ml. Volume reduction was effected by a mechanism identical with that of hypotonicity-induced regulatory volume decrease, namely, activation of verapamil-sensitive Ca2+ channels.
Abstract: Narrowed afferent arteriolar diameter in young, spontaneously hypertensive rats (SHR) may be a contributor to later development of high blood pressure. Thus, treatment that causes dilation of the afferent arterioles in SHR may inhibit the redevelopment of high blood pressure when treatment is withdrawn. We treated SHR with an ACE inhibitor (cilazapril, 5 to 10 mg/kg per day, high; 1 mg/kg per day, low), a calcium antagonist (mibefradil, 20 to 30 mg/kg per day), and an endothelin receptor antagonist (bosentan, 100 mg/kg per day) from age 4 to 20 weeks. Untreated SHR and Wistar-Kyoto rats were also investigated. At 20 weeks, the rats were killed, and morphology of the afferent arterioles was studied. Other SHR (untreated, high cilazapril, low cilazapril, mibefradil) were treated in exactly the same way and then followed to 32 weeks without treatment. The morphometric studies showed that cilazapril increased the lumen diameter in the afferent arterioles and decreased the media-lumen ratio in a dose-dependent manner. On withdrawal of cilazapril treatment, the reduction in blood pressure persisted. Mibefradil tended to increase afferent arteriolar diameter, whereas it did not alter media-lumen ratio. The persistent effect on blood pressure was only moderate after withdrawal of mibefradil. Bosentan had no effect on renal afferent arteriolar structure or blood pressure. In conclusion, cilazapril was more effective than mibefradil in altering afferent arteriolar structure and caused the most persistent effect on blood pressure after treatment withdrawal. The association of increased afferent arteriolar diameter and lower blood pressure level after withdrawal of treatment may suggest a pathogenic role for afferent arteriolar diameter in the development of high blood pressure in SHR.
Abstract: Cardiac output (Q), heart rate (HR), blood pressure, and oxygen consumption (VO2) were measured repeatedly both at rest and at two levels of exercise in six subjects during microgravity exposure. Exercise was at 30 and 60% of the workload producing the individual’s maximal VO2 in 1 G. Three of the subjects were on a 9-day flight, Spacelab Life Sciences-1, and three were on a 15-day flight, Spacelab Life Sciences-2. We found no temporal differences during the flights. Thus we have combined all microgravity measurements to compare in-flight values with erect or supine control values. At rest, Q in flight was 126% of Q erect (P \textless 0.01) but was not different from Q supine, and HR in flight was 81% of HR erect (P \textless 0.01) and 91% of HR supine (P \textless 0.05). Thus resting stroke volume (SV) in flight was 155% of SV erect (P \textless 0.01) and 109% SV supine (P \textless 0.05). Resting mean arterial blood pressure and diastolic pressure were lower in flight than erect (P \textless 0.05). Exercise values were considered as functions of VO2. The increase in Q with VO2 in flight was less than that at 1 G (slope 3.5 vs. 6.1 x min-1.l-1.min-1). SV in flight fell with increasing VO2, whereas SV erect rose and SV supine remained constant. The blood pressure response to exercise was not different in flight from erect or supine. We conclude that true microgravity causes a cardiovascular response different from that seen during any of its putative simulations.
Abstract: We tested the hypothesis that glucose plus insulin determine the rate of fat oxidation in humans by controlling the rate of fatty acid entrance into the mitochondria. We gave constant infusions of [1-13C]oleate, a long-chain fatty acid, and [1-14C]octanoate, a medium-chain fatty acid, for 3 h in seven volunteers (basal). Immediately after the basal period, a hyperinsulinemic (insulin infusion = 120 mU x m(-2) min(-1)), hyperglycemic (plasma glucose = 140 mg/dl) clamp was started and continued for 5 h. During the last 3 h of the clamp, the infusions of [1-13C]oleate and [1-14C]octanoate were repeated. Intracellular acylcarnitine concentrations were measured in muscle biopsies obtained before and after the clamp. Plasma oleate enrichment and FFA concentration were kept constant by means of variable infusions of lipids and heparin. Oleate, but not octanoate, requires carnitine binding to gain access to the mitochondrial matrix; hence, if glucose and/or insulin limit long-chain fatty acid entrance into the mitochondria, then, during the clamp, long-chain acylcarnitine formation should be decreased, causing a decrease in oleate, but not octanoate, oxidation. Oleate oxidation decreased from the basal value of 0.7+/-0.1 to 0.4+/-0.1 micromol x kg(-1) x min(-1) (P \textless 0.05). In contrast, octanoate oxidation remained unchanged. Long-chain acylcarnitine concentration decreased from 855+/-271 in the basal state to 376+/-83 nmol/gram dry weight during the clamp (P \textless 0.05). We conclude that glucose and/or insulin determine fatty acid oxidation by controlling the rate of long-chain fatty acid entrance into the mitochondria.
Abstract: In this study we have investigated a hypothesis that proposes the reverse of the so-called "glucose-fatty acid cycle, " i.e., that accelerated carbohydrate metabolism directly inhibits fatty acid oxidation. We studied normal volunteers in the basal state and during a hyperinsulinemic, hyperglycemic clamp (plasma insulin = 1,789 +/- 119 pmol/l, plasma glucose = 7.7 +/- 0.2 mmol/l). We quantified fat oxidation using indirect calorimetry and stable isotopes ([1-13C]oleate). Plasma oleate enrichment and free fatty acid (FFA) concentration were kept constant by means of infusion of lipids and heparin. Glucose oxidation increased from basal 6.2 +/- 0.8 to 22.3 +/- 1.4 mumol.kg-1.min-1 during the clamp (P \textless 0.01). Total (indirect calorimetry) and plasma fatty acid oxidation (isotopic determination) decreased from 2.6 +/- 0.2 to 0.4 +/- 0.3 (P \textless 0.01) and 2.2 +/- 0.2 to 1.4 +/- 0.1 mumol.kg-1.min-1 (P \textless0.05), respectively. We conclude that under the conditions of the present experiment, glucose and/or insulin directly inhibits fatty acid oxidation. Our findings suggest that, contrary to the prediction of the glucose-fatty acid cycle, the intracellular availability of glucose (rather than FFA) determines the nature of substrate oxidation in human subjects.
Abstract: As single-nephron glomerular filtration rate (SNGFR) and late proximal flow (VLP) increase during growth or following volume expansion, the tubuloglomerular feedback (TGF) function (defined as the decrement in SNGFR due to the process of TGF) shifts rightward in the plane defined by VLP and SNGFR as required to maintain the homeostatic efficiency of TGF. It is not known whether this resetting of TGF requires changes in the systemic hormonal milieu or results from prolonged activation of TGF itself. We employed micropuncture and videometric flow velocitometry (an optical technique for measuring flow in unobstructed nephrons) to address this issue in Inactin-anesthetized euvolemic rats. The fractional compensation (C) of TGF for perturbations [late proximal flow perturbation (VH) = +/- 5 nl/min] in VLP was assessed repeatedly before and during a sustained increase in flow imposed by adding 20 nl/min to early proximal flow (VEP). Augmenting VEP initially saturated TGF, thus suppressing C. Over the next 30 min, C recovered to 70% of its original value, suggesting a rightward resetting of the TGF function to match the increase imposed on VLP. Resetting was confirmed by documenting an evolving asymmetry of C about VH = 0 by testing C vs. VH for -12 \textless or = VH \textless or = 12 in increments of 4 nl/min. Beyond 30 min of augmented VEP, C gradually declined due to desensitization of TGF. A sustained increase in VLP is sufficient to include TGF resetting, independent of any change in the systemic neurohumoral milieu.
Abstract: INTRODUCTION: The objective of this study was to investigate possible gender differences in the hemodynamic responses of the lower body during lower body negative pressure (LBNP). METHODS: In this study, 17 women (mean age = 56 yrs) and 15 men (mean age = 55 yrs) underwent a 15 min exposure to -50 mm Hg LBNP. A Beckman (BR-100) Impedance Plethysmograph was used to measure each subject’s leg and pelvic blood flow and pooling during the LBNP test. RESULTS: The women had an 83% greater increase in blood volume in the pelvic region than men as a result of the LBNP exposure. Women and men had similar increases in leg blood volume as a result of the 15 min exposure to -50 mm Hg. There was no significant gender difference in the decreased amount of blood flow to the leg or pelvic regions by the end of -50 mm Hg LBNP. CONCLUSIONS: These results demonstrate that women have greater blood pooling in the pelvic region compared to men when exposed to -50 mm Hg LBNP. These results should be considered when designing life-support equipment for men and women pilots and astronauts, especially the designing of anti-G and Space Shuttle re-entry garments.
Abstract: 1. In a group of 40 patients with orthostatic intolerance due to hypotension and/or tachycardia, we have compared the pathogenetic roles of impaired contractility of the arterioles and the veins by measuring contractile responsiveness of the arterioles, reflected by increases in diastolic blood pressure and of the veins reflected by measurements of reduction in venous diameter during intravenous noradrenaline infusions. 2. Compared with 27 healthy subjects, patients with diffuse autonomic insufficiency showed striking supersensitivity in diastolic blood pressure (six out of eight) and venous constrictive responses (seven out of eight patients) to noradrenaline, consistent with impaired arteriolar and venous innervation. 3. In contrast, the patients with hyperadrenergic orthostatic hypotension (n = 16) and orthostatic tachycardia (n = 16) showed diastolic blood pressure responses to noradrenaline that were almost invariably within the 95% confidence limits of the changes in normal subjects but supersensitive constrictive responses of foot veins in 22 of 32 subjects and subnormal venous responses in two individuals. The rate of noradrenaline infusion calculated to cause 50% of maximal venous constriction (the ED50) was significantly lower in the patients [mean (SEM) 6.8 (1.9) ng/min] than in the normal subjects [mean (SEM) 23.2 (3.0) ng/min, P \textless 0.025]. 4. The finding of significantly supersensitive foot vein constrictive responses to noradrenaline infusion in the patients of all three groups and supersensitive blood pressure responses exclusively in the patients with diffuse autonomic insufficiency indicates that venous pooling in the legs was the predominant pathogenetic mechanism of orthostatic intolerance in all three types of patients studied. 5. Correction of the orthostatic hypotension and/or tachycardia by external compression in virtually all patients confirmed this conclusion.
Abstract: We recently observed a time-dependent resetting of the tubuloglomerular feedback (TGF) sensitivity to a subnormal level after acute unilateral renal denervation (aDNX). The present investigation compares the effects of aDNX with those of chronic unilateral renal denervation (cDNX), i.e one week after aDNX. All experiments were performed in anaesthetized rats prepared for micropuncture. cDNX led to increases in urine, sodium and potassium excretion in denervated kidneys, while contralateral kidneys showed reduced excretion of these parameters. GFR was increased in denervated kidneys, but unchanged on the contralateral side. TGF activity was determined by measuring the maximal stop-flow pressure response (delta Psf) and the tubular flow rate at which 50% of the maximal response occurred (turning point; TP). cDNX decreased TGF sensitivity, as indicated by an increased TP from 19.1 nL/min in sham-DNX to 26.1 nL/min. Concomitantly, TP in contralateral kidneys was significantly decreased to 15.9 nL/min, aDNX led to a greater sensitivity reduction: TP increased from 19.8 to 34.0 nL/min and contralaterally TP decreased to 14.0 nL/min. delta Psf in cDNX increased by 63% compared to sham-DNX, while on the contralateral side this was unchanged. No difference in delta Psf was found between control, DNX and contralateral kidneys in the aDNX group. In summary, these experiments show that the previously reported decrease in TGF sensitivity in aDNX kidneys still persists after one week, although less pronounced. As a result of the decreased TGF sensitivity, GFR is kept on a high level in cDNX kidneys. Contralateral kidneys show reversed resetting.
Abstract: A rapid (within 0-5 s) increase in skeletal muscle blood flow has been demonstrated following muscle contraction, yet the mechanism remains unresolved. Recently, it was suggested that the entire rapid exercise hyperemia could be attributed to the mechanical muscle pump effect. Other evidence indicates that the muscle pump cannot increase arterial flow. We measured human forearm blood flow with the arm positioned above or below heart level during 1) simulation of rhythmic muscle pump function via repeated inflation/deflation of a forearm cuff to 100 mmHg to achieve mechanical emptying of forearm veins, and 2) 1-s single-cuff inflations, 1-s voluntary forearm contractions, and 1-s contractions performed within a cuff inflation. Rhythmic cuff inflation increased blood flow with the arm below heart level (P \textless 0.05) but not above. Flow following single contractions was higher than flow following cuff inflation within 2 s (P \textless 0.05). Peak flow increases due to a single mechanical venous emptying (7.7 +/- 0.7 ml.100 ml(-1) min(-1)) could account for 60% of the peak flow increase due to muscle contraction (12.8 +/- 1.0 ml.100 ml(-1).min(-1)) with the arm below heart level, whereas above heart level mechanical venous emptying accounted for 46% of the flow increase due to contraction (3.0 +/- 0.4 vs. 6.5 +/- 0.6 ml.100 ml(-1).min(-1)). We conclude that a functional muscle pump does exist in the human forearm in vivo, but that a rapid vasodilation detectable within 2 s also contributes to the early exercise hyperemia.
Abstract: In our study we have examined the mRNA levels of nitric-oxide-(NO-)synthases in rat kidneys during states of stimulated and reduced renin gene expression, to find out whether renal mRNA levels of NO-synthases are correlated with the activity of the renin system. Stimulation of the renin system was achieved by unilateral renal artery clipping (2-kidney/1-clip rats), treatment with the angiotensin II (ANG II) antagonist losartan (40 mg/kg), application of furosemide (12 mg x kg-1 x day-1) and a low-sodium diet (0.02% w/w Na+), which increased renin mRNA levels to 464%, 495%, 309% and 219% of those of control animals, respectively. Inhibition of the renin system was achieved in the nonclipped (contralateral) kidneys of 2-kidney/1-clip rats and in the kidneys of rats which were fed a high-sodium diet (4% w/w Na+); in both cases renin mRNA levels decreased to about 50% of the control values. First screening of the gene expression of brain-type NO-synthase (b-NOS), endothelial NOS (e-NOS) and inducible NOS (i-NOS) during all these alterations of the renin system was done using the reverse transcriptase-polymerase chain reaction (RT-PCR) technique. Results from such noncompetitive PCR experiments indicated that only b-NOS mRNA levels change concordantly with the levels of renin. These changes in b-NOS mRNA levels were checked by the more reliable method of RNase protection assay. Results of the RNase protection assay proved that the renal levels of b-NOS mRNA were significantly increased by about 50% after a low-sodium diet and hypoperfusion of the kidney. Given a stimulatory role of endothelium-derived relaxing factor (EDRF)/NO on the renin system our findings may provide the first evidence that increases of renal levels of b-NOS mRNA and, as a consequence, of renal EDRF/NO formation could be important mediators of the well-known effect of salt intake and hypoperfusion on the renin system.
Abstract: Human spaceflight is associated with a loss of body protein. To investigate this problem, dietary intake, nitrogen balance, the whole body protein, and fibrinogen protein synthesis rates were measured on the crews of two Spacelab Life Sciences (SLS) shuttle missions before, during, and after spaceflight. The first mission, SLS-1, lasted 9.5 days, and the second, SLS-2, lasted 15 days. The 15N-glycine method was used for the protein synthesis measurements. The following results were obtained. 1) There was a rapid decline in weight for the first 5 days and then the body weight appeared to stabilize. 2) The mean energy intake preflight was 39.0 +/- 2.5 kcal x kg-1 x day-1 (n = 10). There was a sharp drop in dietary intake on flight day 1, with recovery by the second day, and then energy intake was constant at 30.4 +/- 1.5 kcal x kg-1 x day-1 (n = 12) for the remainder of the flight period (P \textless 0.05). 3) Nitrogen retention was decreased during flight, with the magnitude of the decrease lessening toward the end of the mission. The daily mean nitrogen balance changed from 58 +/- 9 mg x kg-1 x day-1 (n = 9) preflight to 16 +/- 3 mg N x kg-1 x day-1; P \textless 0.05; n = 11) in flight, corresponding to a loss of approximately 1 kg of lean body mass over 14 days. 4) Whole body protein synthesis was increased early in flight and on recovery, as was fibrinogen synthesis. We conclude that 1) the rapid readjustment and stabilization of energy intake and the improved nitrogen retention with increasing flight duration are consistent with a rapid metabolic accommodation to the novel environment; and that 2) the increased protein turnover indicates that a metabolic stress response is an important factor in this adjustment process.
Abstract: Ammonium (NH4+) excretion varies appropriately with changes in acid-base balance and represents the major regulatable component of net acid excretion. The transport of ammonium can occur by ’diffusion trapping’, or active H+ secretion in parallel with passive NH3 diffusion. In addition, direct NH4+ transport is important in many nephron segments. Since NH4+ and K+ have a similar hydrated radius, these ions share common transport pathways in many renal and nonrenal cell types. For example, these ions compete for a common binding site on the Na,K-ATPase. In addition to Na+ pump-mediated NH4+ transport, the Na,K-ATPase generates an electrochemical gradient across the cell membrane which affects other H+ and NH4+ transport pathways. In this review, the role of the Na+ pump on each of these renal ammonium transport mechanisms will be reviewed.
Abstract: Studies of the cardiovascular response to lower body negative pressure (LBNP) in men and women have suggested that women may have less tolerance to LBNP than men, although tolerance per se was not determined. To investigate the effect of gender on tolerance to LBNP, 10 men 10 women were subjected to increasing levels of LBNP until presyncopal symptoms developed. The cumulative stress index (CSI) score was determined, as were cardiovascular variables. Women had 62% less tolerance to LBNP with a CSI of 412 +/- 43 mmHg/min compared with a CSI of 1,070 +/- 149 mmHg/min for men. Cardiovascular changes associated with LBNP were similar for men and women when expressed relative to the occurrence of presyncope, but women had a higher heart rate response when the data were expressed at absolute levels of LBNP (-30 and -50 mmHg LBNP). Thus men and women had similar cardiovascular adjustments to the LBNP, with the changes in women occurring lower levels of LBNP. These data are important in a consideration of the development of antigravitational countermeasures for women. These data raise questions as to the manner in which blood pools within the lower body in men and women under LBNP.
Abstract: The renin-angiotensin-aldosterone system plays a major role in renovascular hypertension, but the relationship between renin release and the renal fractional extraction of atrial natriuretic peptide (ANP) in this condition is not well defined. We measured ANP levels in the renal veins and aortas of 49 untreated hypertensive patients studied under standardized conditions immediately before renal angiography. Twenty-one patients had renal artery stenosis, 13 of which were unilateral and 8 bilateral. Five of the 13 patients with unilateral renal artery stenosis had an elevated renin ratio (\textgreater or = 1.5). Patients with renal artery stenosis were older (P \textless .01) and had higher systolic pressures (P \textless .05) than patients with essential hypertension. Arterial levels of ANP were significantly higher in patients with unilateral or bilateral renal artery stenosis than in patients with essential hypertension (P \textless .05). Patients with hypertension and left ventricular hypertrophy had significantly higher arterial ANP levels than those with no hypertrophy (40 versus 26 pmol/L, P \textless .05), but in patients with renal artery stenosis, arterial ANP levels were similar in those with or without hypertrophy. Renal venous ANP levels were significantly higher in stenotic than in normal kidneys. Moreover, in unilateral renal artery stenosis, stenotic kidneys of patients with an elevated renin ratio (stenotic kidney/contralateral kidney \textgreater or = 1.5) had a significantly higher renal venous ANP level than stenotic kidneys of patients with normal renin ratio (30 versus 17 pmol/L, P \textless .05). However, the median fractional extraction of ANP was similar, around 0.50 (range, 0 to 0,83), in normal kidneys of hypertensive patients and in stenotic and contralateral kidneys of patients with renal artery stenosis. A significant inverse correlation between arterial ANP and renal venous active plasma renin concentration was found for normal kidneys (r= -.62, P \textless .01) of hypertensive patients without hypertrophy. However, for stenotic kidneys, no such relationship was apparent. A significant correlation between arterial ANP and the arteriovenous difference of ANP (r = +.92, P \textless .001) was found. This relationship was similar for normal and stenotic kidneys. In conclusion, an inverse relationship between arterial ANP and renal venous active plasma renin concentration exists in normal kidneys of essential hypertensive patients without left ventricular hypertrophy. Furthermore, data of ANP extraction through normal and stenotic kidneys suggest that saturation of ANP extraction does not occur. Increased levels of ANP in renal artery stenosis are likely caused by enhanced cardiac secretion of this peptide.
Abstract: This paper quantifies the fluxes of fatty acids through the pathways supplying muscle mitochondria with oxidative fuel in exercising dogs and goats. We used continuous infusions of 1-[14C]palmitate and indirect calorimetry to measure fatty acid supply from two sources: the circulation and the triglyceride stores within the muscle cells. Our goal was to determine maximal flux through these two branches of the lipid pathway as key functional parameters for testing the principle of symmorphosis, i.e. that structural capacity is quantitatively matched to functional demand in the oxidative substrate pathways. It is under these rate-limiting conditions that we predict that all of the structural capacity will be used. Maximal rates of fatty acid oxidation were reached at low exercise intensities of 40% Mo2max. Fatty acids from the circulation supplied only a small fraction (15-25%) of the total fat oxidized under these conditions. Although dogs were able to oxidize circulatory fatty acids faster than goats, maximal rates were not in proportion to the 2.2-fold difference in aerobic capacity between the two species. Dogs compensated for their relatively lower use of circulatory fatty acids by oxidizing more triglycerides from lipid droplets in their muscle cells. We conclude that fatty acids from intramuscular triglyceride stores are a major source of fuel during maximal rates of lipid oxidation. Furthermore, it is this branch of the fatty acid pathway that is adapted to the large difference in aerobic capacity between dogs and goats.
Abstract: Insulin-dependent diabetes mellitus in poor control, alcohol intake associated with extracellular fluid volume contraction, or hypoglycemia may each lead to an increased rate of production of ketoacids. Generally, several days of illness are required before ketoacidosis becomes severe. Two clinical examples are presented to suggest that a severe degree of ketoacidosis may develop over a short period of time, literally overnight. In both examples, there was the ingestion of a modest amount of ethanol. From a quantitative analysis of factors that may influence the rate of production and removal of ketoacids, the following were deduced. Contributing factors to the very rapid development of maximal ketoacidosis could include the absence of a lag period for the conversion of ethanol to acetyl-coenzyme A in the liver and an impaired ability of the brain and kidneys to oxidize ketoacids, especially if these ketoacids are produced very rapidly and/or if less metabolic work is performed by these organs. In special settings, ketoacidosis may develop more rapidly than is generally appreciated.
Abstract: The present article is concerned with mechanisms which are responsible for the exaggerated brain damage observed in hyperglycemic animals subjected to transient global or forebrain ischemia. Since hyperglycemia enchances the production of lactate plus H+ during ischemia, it seems likely that aggravation of damage is due to exaggerated intra- and extracellular acidosis. This contention is supported by results showing a detrimental effect of extreme hypercapnia in normoglycemic rats subjected to transient ischemia or to hypoglycemic coma. Enhanced acidosis may exaggerate ischemic damage by one of three mechanisms: (i) accelerating free radical production via H(+)-dependent reactions, some of which are catalyzed by iron released from protein bindings by a lowering of pH, (ii) by perturbing the intracellular signal transduction pathway, leading to changes in gene expression or protein synthesis, or (iii) by activating endonucleases which cause DNA fragmentation. While activation of endonucleases must affect the nucleus, the targets of free radical attack are not known. Microvessels are considered likely targets of such attack in sustained ischemia and in trauma; however, enhanced acidosis is not known to aggravate microvascular dysfunction, or to induce inflammatory responses at the endothelial-blood interface. A more likely target is the mitochondrion. Thus, if the ischemia is of long duration (30 min) hyperglycemia triggers rapidly developing mitochondrial failure. It is speculated that this is because free radicals damage components of the respiratory chain, leading to a secondary deterioration of oxidative phosphorylation.
Abstract: The pathogenesis of brain swelling and neurological deterioration after rapid hemodialysis (dialysis disequilibrium syndrome) is controversial. The "reverse urea hypothesis" suggests that hemodialysis removes urea more slowly from the brain than from the plasma, creating an osmotic gradient that results in cerebral edema. The "idiogenic osmole hypothesis" proposes that an osmotic gradient between brain and plasma develops during rapid dialysis because of newly formed brain osmoles. In this review, the experimental basis for the two hypotheses are critically examined. Based on what is known about the physiology of urea and water diffusion across the blood-brain barrier, and empiric observations of brain solute composition after experimental hemodialysis, we conclude that the "reverse urea hypothesis" remains a viable explanation for dialysis disequilibrium and that rapid reduction of a high urea level in and of itself predisposes to this condition.
Abstract: This paper integrates the results of a series of studies on the supply of O2 and substrates for oxidative muscle metabolism and draws conclusions on the role of structural design in partitioning and limiting substrate supply. The studies compared dogs and goats exercising at different intensities and combined physiological, biochemical and morphometric investigations. In both species, the rate of fatty acid oxidation reached an upper limit at low exercise intensities, and only glucose consumption was increased at higher exercise intensities. The supply of both glucose and fatty acids from the capillaries reached maximal rates at low exercise intensities; this limitation is related to the design of the sarcolemma as calculations suggest that the endothelium introduces only a small resistance to substrate flux. From these findings, it appears that the capillaries are designed to satisfy O2 supply up to maximal O2 demand. The increase in substrate supply to the mitochondria at higher exercise intensities is achieved by drawing on intracellular stores of glycogen and lipids. The size of these stores is larger in dogs than in goats, providing the athletic species with twice the fuel reserves. These findings are interpreted on the basis of a network model with fluxes partitioned between direct and indirect pathways and with some structures shared by more than one function. Whereas O2 is supplied through a direct pathway, the supply of both substrates is split temporally to allow, during exercise, immediate fuel supply to the mitochondria from intracellular stores; these are replaced from the vasculature, during periods of rest, to a size commensurate with high rates of combustion. Considering this complexity, we conclude that the results are compatible with the principle of symmorphosis applied to a network structure and that the adjustment of design to functional demand involves different structures for O2 and for substrates.
Abstract: We studied renal sodium handling during water diuresis in children in the early phase of relapse of minimal lesion nephrotic syndrome (MLNS). Findings were related to presence or absence of symptoms suggestive of hypovolaemia, and to neurohumoral factors, and were compared to results of similar studies in the same children in remission. Nine children (aged 7.8 +/- 3.1 years) presented with hypovolaemic symptoms, and 10 (7.4 +/- 4.3 years) without such symptoms. Both groups displayed severe proteinuria, hypoproteinaemia and oedema. Symptomatic patients showed tendency for a low glomerular filtration rate, and significantly impaired urine dilution, decreased fractional sodium and lithium excretions, and elevated diluting segment reabsorption [CH2O/(CH2O + CNa)] and sodium/potassium exchange [UK/(UK + UNa)]. In the non-symptomatic patients these parameters were normal. Plasma renin and aldosterone were significantly elevated in the symptomatic children, and strongly correlated with all parameters of tubule sodium reabsorption. Weaker associations were found for plasma noradrenaline and atrial natriuretic peptide. Vasopressin was also relatively high in the symptomatic group, but showed no association with impaired urine dilution. The diffusely stimulated tubular sodium reabsorption in the symptomatic children, in association with stimulated neurohumoral factors, indicates that secondary sodium retention contributes to oedema formation in at least a subset of children developing a nephrotic relapse. This may be limited to the early stage, and be more pronounced in some patients than in others. The tubular defect responsible for maintenance of oedema in stabilized MLNS remains unclear.
Abstract: The contribution of preglomerular resistance changes to the tubuloglomerular feedback (TGF) effector response was evaluated by micropuncture in hydropenic rats. Studies were performed in free-flowing nephrons to compare the fractional compensation (C) for perturbations in late proximal flow (VLP) with associated changes in glomerular capillary hydrostatic pressure (PGC). VLP was monitored by a noninvasive optical technique, and PGC was monitored by direct capillary micropuncture. Data were employed in conjunction with a model of glomerular filtration to analyze the TGF effector mechanism. C varied with the applied perturbation (VH), showing a single peak near the natural operating point. In contrast, the effect of TGF on PGC was asymmetric about the operating point, such that PGC was sensitive only to large positive perturbations. The model predicts that changes in preglomerular resistance account for only a small fraction of the integrated TGF response to small disturbances in the ambient state of the nephron but account for a greater share of the response to larger increments in flow. The TGF response in hydropenic rats is mediated by both pre- and postglomerular vascular elements.
Abstract: This paper quantifies maximal fluxes through the pathway supplying carbohydrates to the mitochondria of muscle cells. Continuous infusions of D-[3-(3)H]glucose together with indirect calorimetry were used to investigate the partitioning of the supply of carbohydrates through the two branches of the pathway: from circulating glucose and from glycogen stores within the muscle cells to the mitochondria. The relative contribution of circulating glucose to total carbohydrate oxidation was small, accounting for only 13% and 23% of the carbohydrate oxidized at exercise intensities approaching MO2max in dogs and goats, respectively. Unexpectedly, maximal rates of circulating glucose oxidation were nearly the same in the two species (when expressed in absolute terms; dog:goat ratio = 1.2), despite the 2.2-fold difference in aerobic capacity. We conclude that the glycogen stores in the muscle cells are the major source of substrates at maximal rates of oxidation, supplying 60-70% of the total energy. Furthermore, it is this branch of the carbohydrate pathway that is adapted to the large difference in aerobic capacity between dogs and goats.
Abstract: OBJECTIVES: Earlier studies demonstrated that hypertonic buffer agents administered during cardiopulmonary resuscitation (CPR) altered neither myocardial pH nor cardiac resuscitability. The rationale for the routine use of buffer agents for CPR has therefore been challenged. However, when these buffer agents are administered during CPR, they may have favorable effects on the postresuscitation course. Postresuscitation myocardial dysfunction has more recently emerged as a potentially fatal complication after successful cardiac resuscitation. Options for prevention and management of this complication have prompted the present studies, in which the effects of buffer agents administered during CPR are evaluated as to their effects on postresuscitation myocardial function and survival. DESIGN: Prospective, randomized, controlled animal study. SETTING: University animal laboratory. SUBJECTS: Forty male Sprague-Dawley rats (450 to 570 g). INTERVENTIONS: Ventricular fibrillation was induced electrically. Mechanical Ventilation and percordial compression were initiated after either a 4- or an 8-min interval of untreated cardiac arrest. Sodium bicarbonate as a CO2-generating buffer, Carbicarb and tromethamine as CO2-consuming buffers, or hypertonic saline placebo were injected as a bolus into the right atrium during CPR. Defibrillation after 10 mins of cardiac arrest and CPR was successful in each instance. No differences in the electric power required for successful resuscitation were documented. Left ventricular pressure, rate of left ventricular pressure increase measured at a left ventricular pressure of 40 mm Hg (dP/dt40), rate of left ventricular pressure decline (-dP/dt), and end-tidal PCO2 were continuously measured for 240 mins after successful resuscitation. MEASUREMENTS AND MAIN RESULTS: Decreases in coronary perfusion pressure were observed after each buffer or placebo injection. As anticipated, end-tidal PCO2 increased after bicarbonate and decreased after Carbicarb or tromethamine. Postresuscitation left ventricular function was significantly decreased in all animals. However, there was significantly less depression in rate of left ventricular pressure increase measured at a left ventricular pressure of 40 mm Hg (dP/dt40), rate of left ventricular pressure decline (-dP/dt), and a lower left ventricular diastolic pressure with both Carbicarb and tromethamine in association with significant increases in postresuscitation survival rate. When the duration of untreated cardiac arrest was increased to 8 mins, the severity of postresuscitation left ventricular dysfunction was magnified and postresuscitation myocardial function and survival were significantly improved with both CO2-generating and CO2-consuming buffer agents. CONCLUSION: Although buffer agents may not improve the success of resuscitation when administered during CPR, they may ameliorate postresuscitation myocardial dysfunction and thereby improve postresuscitation survival.
Abstract: OBJECTIVE: Recently, we reported evidence for genetic linkage between human essential hypertension and the angiotensinogen gene (AGT) and an association with a common molecular variant of this gene (methionine 235 –\textgreater threonine or T235). Other studies had led us to hypothesize that blunted renal plasma flow responses to infused angiotensin II (Ang II) when in high salt balance may reflect increased intrarenal formation of Ang II, a condition that might promote hypertension. Here we examine the relationship between AGT genotype and renal vascular response to infused Ang II. METHODS: Hypertensive (n = 34, all off medication) and normotensive (n = 57) members of families with a history of hypertension (age 18-60 years) as well as 29 normotensive volunteers without a family history of hypertension were studied after controlled diets with 200 mequiv./day sodium. Ang II was infused at a mildly pressor dose (3 ng/kg/min) and renal plasma flow was determined by steady-state plasma para-aminohippurate concentration. RESULTS: After correction for covariates in multivariate analyses, participants homozygous for the T235 variant had significantly diminished renal plasma flow responses to the Ang II infusion (P = 0.005). Changes in renal arterial resistance were also blunted in the T235 homozygotes. Similar results were found when analysis was restricted to normotensive participants or subdivided based on family history of hypertension. No confounding factors associated with AGT genotype that could explain these differences were found. Furthermore, obesity, which also suppressed renovascular response to Ang II, was found to interact significantly (P = 0.017) with genotype such that, among T235 homozygotes, obesity had a greater blunting effect on renal vascular response. CONCLUSIONS: Expected renovascular response to infused Ang II was blunted in persons with the AGT TT genotype. This is the first report of an association between a specific gene variant and altered renal physiology in humans with particular relevance to essential hypertension.
Abstract: Correction of the obese state induced by genetic leptin deficiency reduces elevated levels of both blood glucose and hypothalamic neuropeptide Y (NPY) mRNA in ob/ob mice. To determine whether these responses are due to a specific action of leptin or to the reversal of the obese state, we investigated the specificity of the effect of systemic leptin administration to ob/ob mice (n = 8) on levels of plasma glucose and insulin and on hypothalamic expression of NPY mRNA. Saline-treated controls were either fed ad libitum (n = 8) or pair-fed to the intake of the leptin-treated group (n = 8) to control for changes of food intake induced by leptin. The specificity of the effect of leptin was further assessed by 1) measuring NPY gene expression in db/db mice (n = 6) that are resistant to leptin, 2) measuring NPY gene expression in brain areas outside the hypothalamus, and 3) measuring the effect of leptin administration on hypothalamic expression of corticotropin-releasing hormone (CRH) mRNA. Five daily intraperitoneal injections of recombinant mouse leptin (150 micrograms) in ob/ob mice lowered food intake by 56% (P \textless 0.05), body weight by 4.1% (P \textless 0.05), and levels of NPY mRNA in the hypothalamic arcuate nucleus by 42.3% (P \textless 0.05) as compared with saline-treated controls. Pair-feeding of ob/ob mice to the intake of leptin-treated animals produced equivalent weight loss, but did not alter expression of NPY mRNA in the arcuate nucleus. Leptin administration was also without effect on food intake, body weight, or NPY mRNA levels in the arcuate nucleus of db/db mice. In ob/ob mice, leptin did not alter NPY mRNA levels in cerebral cortex or hippocampus or the expression of CRH mRNA in the hypothalamic paraventricular nucleus (PVN). Leptin administration to ob/ob mice also markedly reduced serum glucose (8.3 +/- 1.2 vs. 24.5 +/- 3.8 mmol/l; P \textless 0.01) and insulin levels (7,263 +/- 1,309 vs. 3,150 +/- 780 pmol/l), but was ineffective in db/db mice. Pair-fed mice experienced reductions of glucose and insulin levels that were \textless 60% of the reduction induced by leptin. The results suggest that in ob/ob mice, systemic administration of leptin inhibits NPY gene overexpression through a specific action in the arcuate nucleus and exerts a hypoglycemic action that is partly independent of its weight-reducing effects. Furthermore, both effects occur before reversal of the obesity syndrome. Defective leptin signaling due to either leptin deficiency (in ob/ob mice) or leptin resistance (in db/db mice) therefore leads directly to hyperglycemia and the overexpression of hypothalamic NPY that is implicated in the pathogenesis of the obesity syndrome.
Abstract: Monitoring of the secretory dynamics of FSH during the human menstrual cycle has demonstrated conflicting results between the amounts of FSH measured by dimer-specific immunoassays and previous heterologous in vitro bioassays. These differences suggest somewhat different models of the steroidal and nonsteroidal regulation of FSH secretion and its control of folliculogenesis in the human. We have developed a homologous in vitro bioassay, using the recombinant human FSH receptor cotransfected into Chinese hamster ovary cells with a cAMP-responsive luciferase reporter gene, that overcomes many of the theoretic shortfalls of previous assays and allows reevaluation of the changes in bioactive FSH across the menstrual cycle. Bioactive FSH levels measured across 12 menstrual cycles in 11 normal women ranged from 4-40 IU/L. FSH bioactivity was constant during the menstrual cycle, with elevations noted only during the mid- to late luteal phase. Bioactive FSH levels were similar to immunoactive FSH levels across the cycle as indicated by a ratio of bioactive to immunoreactive FSH (FSH B/I) of 1.10 +/- 0.04 across the follicular and early luteal phases. However, during the mid- to late luteal phase, the mean FSH B/I rose to 1.65 +/- 0.07, which significantly exceeded that during the rest of the cycle (P \textless 0.001). This change in FSH B/I occurs at a critical time during folliculogenesis when the next cohort of follicles is being recruited and appears to be secondary to a decrease in immunoreactive FSH unaccompanied by a similar decrease in in vitro bioactivity. There was good agreement between immunoassay and bioassay results on the day of the midcycle gonadotropin surge (FSH B/I = 1.07 +/- 0.14), which was not different from that in the follicular phase (days -17 to -2; FSH B/I = 1.06 +/- 0.05) or the FSH B/I measured in postmenopausal women (0.93 +/- 0.2). These observations using a novel homologous human FSH in vitro bioassay indicate that bioactive FSH levels are not declining during the time of active corpus luteum formation and secretory activity. Thus, there is a previously undetected increased biologic signal during the mid- to late luteal phase, suggesting that the influence of elevated FSH on the cohort of developing follicles (including the subsequent dominant follicle) begins earlier during the luteal-follicular transition than previously predicted by FSH immunoreactivity.
Abstract: We tested the hypothesis that the ability of the tubuloglomerular feedback (TGF) to stabilize renal function is impaired in rats with 7-8 wk of insulin-treated streptozotocin-diabetes. Proximal tubular flow was measured in free-flowing nephrons using a noninvasive optical technique. The homeostatic efficiency of TGF was determined from the fractional compensation for perturbations in ambient flow. Fractional compensation was substantially reduced in diabetic rats. To assess the roles of the proximal tubule and loop of Henle as determinants of TGF efficiency, we tested the effect of diabetes on proximal tubular reabsorption as determined by standard micropuncture and on the ionic content of early distal tubular fluid by employing a microelectrode for on-line measurement of electrical conductivity (TED). Diabetes caused glomerular hyperfiltration and increased fractional proximal tubular reabsorption (FPR), such that late proximal tubular flow (VLP) and early distal tubular flow were unaffected. The increase in FPR was a minor contributor to the overall effect on fractional compensation. Diabetes decreased the ambient TED without affecting the slope of the relationship between VLP and TED. These results demonstrate that the homeostatic, efficiency of the TGF system is reduced in diabetes and that this cannot be fully accounted for by changes in tubular reabsorption. Impaired TGF efficiency renders the diabetic glomerular microvasculature more susceptible to impact from fluctuations in systemic hemodynamics.
Abstract: The influence of microgravity on the myosin phenotype of skeletal muscle fibers in the vastus lateralis of eight crew members was studied before and after 5-day (n = 3) and 11-day (n = 5) spaceflights (space shuttle flights: STS-32, -33 and -34). Single-fiber electrophoresis analyses showed that the proportion of fibers expressing only slow (type I) myosin heavy chain (MHC) in the vastus lateralis was significantly lower after than before 11 days of spaceflight. Although the family of type II MHC isoforms was elevated post- compared with preflight, the distribution among the isoforms of type II MHC was not statistically different. Based on monoclonal and polyclonal antibodies specific for three adult MHC isoforms and single-fiber electrophoresis, approximately 3% of the fibers analyzed coexpressed all three adult MHC isoforms. The results from immunohistochemical staining with two different sets of antibodies indicate a reduction in the percentage of fibers expressing type I MHC as a result of spaceflight. The mean difference, however, was significant only when the fibers were categorized simply as type I or II. These changes appeared to be highly individualized among the astronauts. These results suggest that a rapid change in MHC isoform expression can occur in some muscle fibers after a relatively brief exposure to spaceflight.
Abstract: The aim of this study was to examine the influence of the systemic renin-angiotensin system on the gene expression of atrial natriuretic peptide in rat hearts. The renin-angiotensin system was stimulated (1) by unilateral renal artery clipping (0.2-mm clip, 2 days), producing a fourfold increase of circulating plasma renin activity and increasing blood pressure; (2) by furosemide infusion with simultaneous salt substitution, increasing plasma renin activity values to 45 ng angiotensin I/h per milliliter without changing blood pressure; or (3) by administration of the calcium antagonist amlodipine, which increased plasma renin activity values to 42 ng angiotensin I/h per milliliter and lowered blood pressure. Unilateral renal artery clipping increased atrial natriuretic peptide mRNA levels approximately 20-fold in the left ventricles and approximately twofold in the right ventricles and atria. Furosemide infusion had no effect on cardiac atrial natriuretic peptide mRNA levels, and in amlodipine-treated rats, cardiac atrial natriuretic peptide mRNA levels decreased to 30% of control values. The increase of atrial natriuretic peptide mRNA in the ventricles during renal artery clipping was blunted by the administration of the angiotensin-converting enzyme inhibitor ramipril, which also attenuated the blood pressure rise. In clipped rats amlodipine did not change elevated plasma renin activity values but abolished the rise of blood pressure and also attenuated the rise of atrial natriuretic peptide mRNA in the hearts. These findings indicate that an increase of the activity of the systemic renin-angiotensin system does not result in an obligatory change in cardiac atrial natriuretic peptide gene expression.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: The present study tested the hypothesis that, during acute bleeding, the development of tissue hypoxia might be reflected by an abrupt widening in arteriovenous gradient for PCO2 (AV PCO2) and for pH (AV pH) as accurately as by an increase in blood lactate levels. Twenty-four anesthetized (isoflurane 1.4% end-tidal), paralyzed, and mechanically ventilated dogs submitted to progressive hemorrhage were studied. Oxygen uptake (VO2) was derived from expired gas analysis and oxygen delivery (DO2) was calculated by the product of the thermodilution cardiac index and the arterial O2 content. During the first part of the protocol, VO2 remained stable as the progressive reduction in DO2 was associated with a corresponding increase in O2 extraction (O2ER). Blood lactate increased slightly but not significantly. AV PCO2 and AV pH increased significantly, essentially related to venous respiratory acidosis. The critical value of DO2 below which VO2 decreased was 8.95 +/- 1.60 mL.min-1.kg-1. Below this value, there was a marked increase in blood lactate and an abrupt widening in AV PCO2 and AV pH gradients. The critical value of DO2 obtained from blood lactate, AV PCO2 and AV pH were similar to those obtained from VO2 (8.60 +/- 1.12; 8.73 +/- 1.40; 8.78 +/- 1.37, respectively; P = not significant). A significant correlation was found, during the hemorrhage protocol, between blood lactate and AV PCO2 (r = 0.84; P \textless 0.001) or AV pH (r = 0.78; P \textless 0.001). Therefore, AV PCO2 and AV pH represent simple but reliable indicators of tissue hypoxia during hemorrhagic shock.
Abstract: The popularity of routine temperature correcting of pH, PCO2 and PO2 values is based on the observation that large differences in the blood gas values are present when the patient’s temperature is profoundly hypo- or hyperthermic. This observation leads some clinicians to the unsubstantiated conclusion that uncorrected 37 degrees C values are "wrong." The danger in this superficial thought process is that one might reach the unfounded conclusion that temperature-corrected values are "right." The simple truth is: With significant changes in patient temperature, we do not fully understand the complexity of the effects on metabolism, vascular function, and respiration. Both corrected and uncorrected blood gas values, therefore, are of uncertain usefulness in patients with significant deviations in body temperature. There is no logical or scientific basis for the assumption that temperature-corrected values are better than the values obtained at 37 degrees C. In fact, the available technical and biological data lead to the conclusion that, in almost all circumstances, there is no clinical advantage to using values other than those at 37 degrees C. In addition, the routine process of temperature correction of blood gases involves several practical disadvantages. First, interpretation of the corrected values demands deviation from the familiar and well-documented guidelines for interpreting 37 degrees C values. Second, temperature correction assumes the laboratory has received the patient’s true temperature at the time of sampling. My experience is that the patient’s true temperature often is not reported or is reported erroneously. Third, temperature-corrected values can be confused with uncorrected values and vice versa. Available data support the practice that only uncorrected (37 degrees C) blood gas values should be used and reported routinely. Temperature-corrected values should be calculated only when specifically requested and the onus for clinical use of temperature-corrected values lies with the clinician who requests them.
Abstract: The cause of sodium retention in nephrotic syndrome is unclear. Hypovolaemia has traditionally been labelled as the cause but there is evidence in adults of a renal disturbance as the main cause. We aimed to find out whether children with early nephrosis can be classified as hypovolaemic by objective measures. We measured blood volume, kidney function, and hormone concentrations in children with early relapse of minimal-change nephrosis. Three presentations could be defined. The first was patients with incipient proteinuria and normal plasma protein, characterised by sodium retention, increased renal plasma flow, and slightly increased aldosterone, but normal noradrenaline. The second was patients with severe proteinuria, hypoproteinaemia, and hypovolaemic symptoms, who had oedema, sodium retention, and high concentrations of plasma renin, aldosterone, and noradrenaline, low atrial natriuretic peptide, and low glomerular filtration rate. The third was patients with equally severe proteinuria and hypoproteinaemia, but without hypovolaemic symptoms; they had oedema, but no active sodium retention, and normal plasma hormones and glomerular filtration. Neither blood pressure nor blood volume discriminated patients with or without hypovolaemic symptoms. These findings show that children with early full-blown nephrosis can present both with and without hypovolaemic symptoms and laboratory signs, despite equally severe hypoproteinaemia, and also that sodium retention precedes the reduction in serum protein.
Abstract: In anesthetized dogs, the amount of fatty acyl moieties in the fatty acid, triacylglycerol, and phospholipid fractions of arterial blood and biceps femoris muscle has been determined to delineate the presence of a fatty acid gradient from blood to skeletal muscle tissue, if any. The content of fatty acids in biceps femoris muscle was found to be very low (approximately 0.1% of total amount of unesterified and esterified fatty acyl moieties in the tissue sample). The ratio of the content of fatty acids (nmol/ml) in arterial plasma and the tissue level of fatty acids (nmol/g wet weight) was approximately 17. This finding supports the notion that a fatty acid gradient from the vascular compartment to the skeletal muscle fibers might be one of the driving forces of net extraction of fatty acids by skeletal muscle.
Abstract: We investigated renal and peripheral forearm extraction of atrial natriuretic peptide in patients with primary aldosteronism to determine whether alterations in extraction may contribute to the elevated levels of circulating atrial natriuretic peptide observed in primary aldosteronism. We obtained simultaneous venous blood samples from the left renal vein and a peripheral vein and from the radial artery in 28 patients with primary aldosteronism and 10 patients with essential hypertension. Renal extraction of atrial natriuretic peptide was significantly (P \textless .001) reduced (40 +/- 2%) in primary aldosteronism compared with essential hypertensive patients (62 +/- 3%). Peripheral forearm extraction was also reduced (P \textless .01) in primary aldosteronism compared with essential hypertensive patients (24 +/- 3% versus 38 +/- 4%). These findings are consistent with widespread downregulation of atrial natriuretic peptide receptors in primary aldosteronism. Consistent with reports that marked reduction in glomerular filtration rate is required before the renal extraction of atrial natriuretic peptide is reduced, no significant relationship between renal extraction of atrial natriuretic peptide and plasma creatinine was seen in primary aldosteronism or essential hypertension. Although the major regulators of atrial natriuretic peptide secretion in primary aldosteronism are presumably alterations in arterial blood pressure and plasma volume, reduced renal and peripheral extraction of atrial natriuretic peptide in primary aldosteronism may also contribute significantly to the elevated circulating levels observed.
Abstract: Recent studies suggest a significant contribution of the pulmonary circulation to the perfusion of large airways. In this study we used anesthetized ventilated sheep (n = 19) to determine the functional contribution of the pulmonary circulation to airway smooth muscle. We performed sequential intravenous challenge with methacholine chloride (MCh; 0.25-2.5 mg/ml) to determine airway resistance (Raw) changes in the intact animal, after bronchial artery cannulation that essentially removed bronchial arterial delivery of MCh, and in an isolated lung preparation. After blocking the vagal reflex component of this response, we found that intravenous MCh in the intact preparation resulted in an average 2.2 +/- 0.5 cmH2O.l-1.s increase (181%) in Raw. After prevention of bronchial arterial delivery of MCh, Raw increased by 0.8 +/- 0.3 cmH2O.l-1.s (64%; P \textless 0.01 compared with intact preparation). In the isolated lung preparation, Raw increased by 0.6 +/- 0.2 cmH2O.l-1.s (63%; P \textless 0.01 compared with intact preparation). These results demonstrate that in sheep, the bronchial artery provides the major route for delivery of intravenously administered agonists to airway smooth muscle. Considering the large dilutional effect of an intravenously administered agonist by the time it reaches the bronchial artery, we conclude that the pulmonary component of agonist delivery to large airways is \textless 10% and unlikely to play a major physiological role.
Abstract: The total-body red blood cell mass (RBCM) decreases during the first few days of spaceflight; however, the pathophysiology of "spaceflight anemia" noted on return to earth is poorly understood. In studies before, during, and after a 9-day mission we determined the rates of removal and replacement of RBCs by using chromium 51. The rate and efficiency of RBC production were assessed with iron 59. Serial measurements were made of plasma volume (PV), RBCM, serum ferritin level, and erythropoietin level. PV decreased within hours, resulting in an increased total body hematocrit during the first few days of the mission. Serum erythropoietin level decreased within 24 hours and remained low. Circulating RBCs disappeared at a normal rate during flight, but few new cells replaced those destroyed, resulting in a decrease in RBCM of 11% during the mission. After 22 hours in space, intramedullary formation of cells continued at near preflight levels as measured by erythron iron turnover. The coexistence of new cell formation in the bone marrow and failure of cells to be released into the blood is consistent with ineffective erythropoiesis. Microgravity causes blood located in gravity-dependent spaces to shift to a central volume. We conclude that the initial adaptation is a reduction in PV resulting in plethora. Increase in total body hematocrit causes a decrease in erythropoietin production. RBCM decreases because RBCs destroyed at a normal rate are not replaced.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Idiopathic edema is usually orthostatic. It is most evident in the feet or abdomen after prolonged standing or sitting and in the fingers and eyelids after recumbency overnight. It occurs almost exclusively in post-pubertal women and is associated with discomfort in the areas of fluid accumulation (including symptoms of the carpal tunnel syndrome, nonarticular rheumatism, and headaches, sometimes with pseudotumor cerebri), and weight gain with excessive increments from morning to evening. The pathogenesis, diagnosis, and treatment of idiopathic edema are discussed.
Abstract: A compartmental model consisting of the circulation, a general interstitium, and the lymphatics, is formulated to describe the transport and distribution of fluid and plasma proteins (albumin) in the human microvascular exchange system. Transcapillary mass exchange is assumed to occur via a coupled Starling mechanism. Unknown or poorly quantified model parameters are estimated by statistical fitting of simulation predictions to five different sets of experimental data. The data consist of steady-state and transient plasma and interstitial volumes and colloid osmotic pressures measured under laboratory or clinical conditions for normal humans and for patients with nephrotic syndrome or mild heart disease. In all cases, it is assumed that the system response to perturbations imposed either artificially or through illness is due to changes in the Starling driving forces. The three best-fit parameters were found to be normal capillary hydrostatic pressure, Pc,o = 11.0 mm Hg; albumin reflection coefficient, sigma = 0.99; and lymph flow sensitivity, LS = 43.1 ml/mm Hg.hr. Three other parameters, which were unknown but related to the estimated parameters through steady-state mass balance equations, were determined to be fluid filtration coefficient, KF = 121.1 ml/mm Hg.hr; albumin permeability-surface area product, PS = 73.0 ml/hr; and normal lymph flow, JL,o = 75.7 ml/hr. The fully described model was validated by comparisons between (1) simulation predictions and data used in parameter estimation, (2) estimated transport parameters and available literature values, and (3) model predictions and an additional set of experimental data.
Abstract: OBJECTIVE: Right ventricular (RV) dysfunction remains the leading cause of early mortality after cardiac transplantation. The effect of brain death and subsequent hypothermic cardioplegic arrest and storage on subsequent post-transplant right ventricular function was examined. SUMMARY BACKGROUND DATA: Right ventricular dysfunction in the donor heart usually is attributed to failure of the donor right ventricle to adapt to the sudden increase in afterload (pulmonary vascular resistance) in the recipient. Strategies to improve ventricular mechanics in the postoperative period are aimed at reducing pulmonary vascular resistance with vasodilators or augmenting right ventricular contractility with inotropic agents. Events occurring in the donor heart (brain death, hypothermic cardioplegic arrest, and storage) also may be directly related to post-transplant RV dysfunction. METHODS: A canine model of brain death and orthotopic cardiac transplantation was used. A dynamic pressure-volume analysis of RV mechanics was performed using micromanometers and sonomicrometric dimension transducers. Systolic function was assessed by measurement of preload recruitable stroke work (PRSW). Brain death was induced in 17 dogs by inflation of an intracranial balloon. Right ventricular function then was assessed serially to 6 hours (PRSW). Right ventricular adrenergic beta receptor density and function was sampled at control and after 6 hours of brain death. The effect of cardioplegic arrest and hypothermic storage was assessed in a second group of 17 dogs, using the same instrumentation and method of RV analysis. RESULTS: A significant decrease in right ventricular PRSW occurred after brain death, with the average decrease being 37% +/- 10.4% from the control. The RV myocardial beta adrenergic receptor density did not significantly change (253 +/- 34 fmol/ng control vs. 336 +/- 54 fmol/ng after brain death). The adenylyl cyclase activity of the RV beta receptor was assessed and was not altered by brain death. Orthotopic transplantation after cardioplegic arrest and hypothermic storage significantly decreased RV PRSW from 23.6 +/- 2.0 x 10(3) erg to 13.5 +/- 1.4 x 10(3) erg. CONCLUSIONS: These data indicate that the donor right ventricle is exposed to factors significantly detrimental to its mechanical performance well before facing an increased afterload in the recipient. Strategies to reduce RV dysfunction associated with brain death and hypothermic storage could positively impact post-transplant survival.
Abstract: This study was undertaken to determine oxygen consumption at rest and constant graded work loads while exercising on a bicycle ergometer and to compute mechanical efficiency of sportsmen. Thirteen healthy, active, well trained young sportsmen from sports hostel, Sports Authority of India, Hyderabad, were selected and were requested to pedal the bicycle ergometer at 50 watts and 100 watts (300 and 600 kpm) work loads for 18-20 min. The energy cost of the activity at the respective work loads was measured by means of indirect, open circuit respiratory exchange method. The workouts resulted in the oxygen consumption of about 920.4 +/- 77.5 ml and 1475.2 +/- 101.7 ml at 300 and 600 kpm respectively. The gross or absolute mechanical efficiency (AME) were calculated at these work loads. The delta mechanical efficiency (DME) was also computed for the work increment from 300 to 600 kpm by using the amount of oxygen consumed at these work loads. The AME was about 23-24 per cent in both the loads while the DME was found to be 26 per cent. The relationship between anthropometry, resting metabolic rate (RMR), AME and DME was assessed. It was observed that both AME and DME values of these subjects were in the normal range of Swedish and Canadian active young men. These parameters can be used as indicators for assessing sports persons efficiency both in the active and lean periods.
Abstract: The metabolic acidosis resulting from poor tissue perfusion is considered to have several significant hemodynamic effects. Correction of the acidosis with sodium bicarbonate seems to be a rational approach to this problem. However, the current medical literature shows little clinical benefit to this tactic. In fact, indiscriminate bicarbonate administration may, itself, have deleterious effects. Concurring with the absence of a consistent therapeutic advantage to the use of sodium bicarbonate in the treatment of lactic acidosis due to inadequate tissue perfusion, the American Heart Association removed the routine use of sodium bicarbonate from the treatment of cardiac arrest in the algorithms of the Advanced Cardiac Life Support course. Although the debate continues, a detailed review of the medical literature does not support the use of sodium bicarbonate in this setting.
Abstract: Digoxin intoxication occurs frequently and may require treatment with digoxin-specific Fab therapy. Little is known, however, regarding the biological fate of this compound. Pharmacokinetic studies have not been performed in healthy volunteers, but there are limited kinetic data from patients who have received therapy for the treatment of digoxin toxicity. Digoxin-specific Fab is eliminated via renal and nonrenal routes, having a volume of distribution slightly exceeding extracellular volume (0.40 L/kg) and an elimination half-life of 16 to 20 hours. Patients with renal impairment and end-stage renal disease have elimination half-life values that are prolonged up to 10-fold in magnitude, while volume of distribution is unaffected. Systemic clearance of digoxin-specific Fab is approximately 0.32 ml/min/kg in digoxin-toxic patients with preserved renal function. Renal failure also decreases Fab clearance by up to 75%. Therefore, Fab may reside in the serum of anephric patients for 2 to 3 weeks after administration. More important is the effect of Fab on the disposition of digoxin. Because digoxin-specific Fab has a stronger digoxin-binding affinity than do biological membranes, it can sequester tissue-bound and intracellular digoxin into the extracellular spaces. This results in a rapid increase in digoxin serum concentrations in the central compartment. Since the majority of digoxin is bound by Fab, it cannot interact with its biological receptor and thus reverses digoxin toxicity. The pharmacokinetic fate of total digoxin after administration of digoxin-specific Fab follows that of Fab. However, it appears that the elimination half-life of Fab is slightly shorter than that of total digoxin in patients with end-stage renal disease, suggesting that the clearance of Fab is slightly faster than that of total digoxin. Free digoxin concentrations fall rapidly after Fab administration and then rebound upwards within 12 to 24 hours. This rebound in free digoxin concentrations, however, is delayed by 12 to 130 hours in patients with renal dysfunction and end-stage renal disease. Rebound in free digoxin concentrations occurs during the initial phase of the biexponential decline of the serum concentration-time profile for digoxin-specific Fab, suggesting that distribution from the vascular spaces is the likely cause. Following the increase, free digoxin concentrations decline in a manner that is dependent on renal and nonrenal routes of elimination. During this time period it is evident that Fab retains it capability of binding digoxin while it resides in plasma. There is no evidence to support a dissociation between the Fab-digoxin complex over extended periods of time.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: This investigation was designed to evaluate the changes in arterial and mixed venous acid-base conditions during untreated ventricular fibrillation and after institution of cardiopulmonary resuscitation (CPR). Fifty-two swine (weight: 25-40 kg) were studied after induction of ventricular fibrillation. In a subgroup of 10 animals, 10-min CPR trials were performed. Arterial and mixed venous blood gases were monitored at baseline, after 5 min of untreated ventricular fibrillation (nonintervention interval) and after 10 min of mechanical CPR. Standard CPR was performed at compression rates of 100/min with a 60% duty cycle. Arterial pH, Pco2, and HCO3 were unchanged when baseline values were compared with those obtained after 5 min of untreated ventricular fibrillation, while arterial Po2 decreased from 81 to 69 torr. Mixed venous pH decreased from 7.41 to 7.35, Pco2 increased from 43 to 48 torr, Po2 decreased from 40 to 38 torr and HCO3 decreased from 28 to 26 mEq/l (P \textless 0.05). Although these changes were statistically significant, many remain in the normal range. Both arterial and mixed venous pH and HCO3 fell further after 9 min of CPR and Pco2 increased (P \textless 0.05). Alterations in mixed venous pH and Pco2 were more apparent than corresponding changes in arterial blood gas composition. We conclude that untreated cardiac arrest may be accompanied by normal arterial and mixed venous blood gas levels. Tissue acidosis is only revealed after tissue perfusion is restored and is most accurately reflected in the mixed venous blood gas composition. This apparent paradox provides insight into the relationship between tissue perfusion and arterial and mixed venous acid-based composition.
Abstract: Simultaneous administration of the diuretic furosemide (10 mg/kg sc) and a low dose of the angiotensin-converting enzyme inhibitor captopril (5 mg/kg sc) reduced mean arterial blood pressure (MAP) and increased ingestion of water and 0.3 M NaCl within 2 h. Administration of either agent alone did not reduce MAP or cause significant fluid intakes. The increased ingestion of water and saline after furosemide plus captopril 1) was not due to increased excretion of water and sodium compared with losses after furosemide alone, 2) was abolished by the AT1-receptor blocker, losartan (10 mg/kg sc), and 3) was abolished by administration of a greater dose of captopril (100 mg/kg sc). Intravenous infusion of phenylephrine (3-4 micrograms.kg-1 x min-1) prevented the reduction in MAP after furosemide plus captopril and blunted the saline intake but not water intake. Simultaneous administration of the vasodilator minoxidil and captopril also stimulated robust salt appetite in association with reduced MAP. It is concluded that the integrity of renin-angiotensin mechanisms is necessary for the rapid ingestion of water and saline after furosemide and captopril and that arterial pressure modulates the behavioral responses.
Abstract: The possibility that the decreased urinary flow during continuous positive-pressure breathing (CPPB) may be a consequence of a reflex mediated via the cardiopulmonary baroreceptors to increase neurohumoral secretion or to change the sympathetic outflow was assessed. Muscle sympathetic nerve activity (MSNA) on the right peroneal nerve, vasoactive hormones, and renal and cardiovascular responses were measured during CPPB (+12 mmHg) in 10 male subjects (22.0 +/- 0.6 yr, 66.8 +/- 1.5 kg body wt). The experiments consisted of a 1-h control, 1 h with CPPB (experimental) or without CPPB (a time control), and a 1-h recovery period. Two blood samples were taken during each period for measurements of arginine vasopressin (AVP), plasma aldosterone (PAldo), plasma renin activity (PRA), norepinephrine, and atrial natriuretic peptide (ANP), and urine was collected hourly for the measurement of urine volume and electrolytes and clearances. MSNA rapidly increased (P \textless 0.05) at the onset of CPPB, continued to increase during exposure, and rapidly returned to the normal level at recovery. The MSNA changes coincided with increased plasma NE and were concurrent with a reduced (P \textless 0.05) urine output associated with a reduction of both free water and osmolal clearances, Na+ and osmolal excretions, and creatinine clearance (glomerular filtration rate). AVP and PRA increased (P \textless 0.05), whereas PAldo and ANP were unchanged. The results are consistent with the concept that increased sympathetic outflow may play a role in the reduction of urinary output and Na+ excretion during unloading of the cardiopulmonary receptors.
Abstract: The prevailing theory of sodium depletion-induced salt appetite states that angiotensin (ANG) of cerebral origin, not of renal origin, causes the behavior. This assertion depends partly on an experiment that suppressed salt appetite using an intravenous infusion of a dose of angiotensin-converting enzyme (ACE) inhibitor (captopril, 2.5 mg/h) that supposedly blocked both central and peripheral enzyme (17). The present experiments used the same dose of captopril to suppress salt appetite both in 24-h and in 3-h models of sodium depletion-induced behavior. The captopril-infused rats 1) increased water intake normally after central injections of ANG I given immediately after each salt appetite test, 2) had no arterial pressor response after intravenously injected ANG I, and 3) had normal arterial pressor responses after either intravenously injected ANG II or centrally injected ANG I. Thus, although the peripheral ACE was completely blocked in captopril-infused rats, the central ACE was not, because the central thirst and arterial pressor responses to ANG I were indistinguishable from controls. This demonstrates that ANG of renal origin is necessary for the expression of sodium depletion-induced salt appetite.
Abstract: The role of the macula densa in the control of renin synthesis during sodium depletion was studied in Balb/c mice which had their left kidney made hydronephrotic 6 weeks earlier. The role of the nervous system was studied by giving the mice propranolol or by denervation of the left kidney. There was no net secretion of renin from the left hydronephrotic kidney on control or low sodium diet. All plasma renin came from the right kidney. Sodium depletion caused similar rises in renin content of the normal and hydronephrotic kidney. These rises were accompanied by increases in mRNA for renin in both kidneys. Denervation of the left hydronephrotic kidney caused a fall in renal renin content. However, sodium depletion caused a significant rise in both renin mRNA and renal renin in the control and denervated hydronephrotic kidney. Propranolol decreased the renin content of normal and hydronephrotic kidneys. Sodium depletion caused a rise in mRNA and renal renin in both kidneys although the absolute final amount was less than in the control animals. Sodium depletion stimulates renin synthesis in a normal kidney and a kidney without a macula densa. This response is not affected by the nervous supply to the kidney. In the hydronephrotic mouse subjected to sodium depletion the synthesis and secretion of renin appear to be disassociated.
Abstract: Atrial natriuretic peptide is an important peptide hormone of cardiac origin that functions to regulate cardiac preload via the regulation of sodium excretion. This natriuretic action occurs through activation of the particulate guanylyl cyclase-linked natriuretic peptide-A receptor. HS-142-1 is a newly discovered antagonist of the natriuretic peptide-A receptor that permits insight into the functional role of atrial natriuretic peptide in cardiorenal homeostasis. The first objective of this study was to define for the first time the intrarenal action of HS-142-1 on exogenous atrial natriuretic peptide-mediated natriuresis in anesthetized normal dogs. In group 1 (n = 6), which received intravenous atrial natriuretic peptide at 100 ng/kg per minute, intrarenal HS-142-1 (0.5 mg/kg bolus) attenuated atrial natriuretic peptide-induced increases in glomerular filtration rate, urine flow, sodium excretion, and renal cyclic GMP generation and decreases in distal tubular sodium reabsorption. The second objective was to determine whether endogenous atrial natriuretic peptide participates in the regulation of basal sodium excretion. In group 2 (n = 6), intrarenal HS-142-1 alone decreased both absolute and fractional sodium excretion and renal cyclic GMP generation and increased distal tubular sodium reabsorption. These studies demonstrate that HS-142-1 markedly attenuates exogenous atrial natriuretic peptide-mediated natriuresis via enhancement of distal tubular reabsorption and blunting of increases in glomerular filtration rate. Second, the current studies support a functional role for endogenous atrial natriuretic peptide in the regulation of basal sodium excretion.
Abstract: This study was designed to examine whether macula densa function is involved in the changes of renal renin gene expression upon acute hypoperfusion of one kidney. To block macula densa function, rats with free access to salt and water were subcutaneously infused with furosemide (12 mg/day) for 6 days. Then, 4 days after the start of the infusion, the left renal arteries were clipped with 0.2-mm silver clips and renin mRNA levels in ipsilateral and contralateral kidneys, as well as plasma renin activities (PRA), were determined 48 h after clipping. In non-clipped animals furosemide increased PRA from 10 to 47 ng angiotensin I.h-1.ml-1 and raised renin mRNA levels in both kidneys 2.5-fold. In vehicle-infused animals, clipping of the left renal artery increased PRA to 37 ng angiotensin I.h-1.ml-1 and led to a 5-fold rise of renin mRNA levels in the ipsilateral kidneys and to a suppression to 20% of the control values in the contralateral kidneys. PRA values in clipped and furosemide-infused animals were 45 ng angiotensin I.h-1.ml-1. In these animals renin mRNA levels increased in the ipsilateral kidneys to similar absolute values as in vehicle-infused rats, whilst contralateral renin mRNA levels fell to about 25% of the respective controls. These findings indicate that the stimulations of renin gene expression by inhibition of macula densa salt transport and by renal artery clipping are not additive, suggesting that the macula densa mechanism may participate in the stimulation of renin gene expression upon hypoperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: To investigate the effects of an angiotensin II type 1 receptor antagonist (CV-11974) on renal blood flow and renal sympathetic nerve activity compared with a calcium antagonist (nicardipine), we measured both parameters in conscious spontaneously hypertensive rats aged 13 to 15 weeks. One to 2 days after surgery, CV-11974 (n = 9) and nicardipine (n = 8) were intravenously administered to decrease arterial pressure in a similar time course and degree of hypotension. CV-11974 increased renal blood flow by 23 +/- 4% at the maximal fall in mean arterial pressure (-32 +/- 1 mm Hg), and renal nerve activity increased by 70 +/- 7%. The maximal increase in renal blood flow (+27 +/- 4%) was observed when mean pressure was reduced by approximately 20 mm Hg. The maximal reduction of renal vascular resistance (-33 +/- 3%) correlated significantly with pretreatment levels of plasma renin concentration (r = -.792). In contrast, nicardipine produced a progressive reduction of renal blood flow and marked increases in heart rate and renal nerve activity. Increases in heart rate and nerve activity were greater than those with CV-11974 treatment (P \textless .001). At the maximal fall in mean pressure (-32 +/- 1 mm Hg), renal blood flow decreased by 23 +/- 4%, which was significantly correlated with percent changes in renal nerve activity (+150 +/- 11%, r = -.744). Renal denervation in another set of rats (n = 6) improved renal blood flow and renal vascular resistance responses to nicardipine.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: To determine the role of arterial O2 content (CaO2) in the cerebral blood flow (CBF) responses to hypoxemia and hemodilution, CaO2 was progressively reduced from approximately 18 to approximately 6 ml O2/dl in normocapnic, normothermic, pentobarbital-anesthetized rabbits. This was done either by reducing PaO2 (hypoxemia, minimum PaO2 approximately 26 mmHg) or arterial hematocrit (isovolemic hemodilution with hetastarch, minimum hematocrit approximately 14%) while CBF was measured with radioactive microspheres. As CaO2 decreased, CBF increased in both groups but was greater in hypoxemic animals at CaO2 values \textless or = 9 ml O2/dl. For example, at a CaO2 approximately 6 ml O2/dl, CBF in hypoxemic animals was 110 +/- 38 ml.100 g-1.min-1 (means +/- SD) compared with 82 +/- 22 ml.100 g-1.min-1 in hemodiluted animals (means +/- SD). While calculated cerebral O2 delivery (cerebral DO2) was well maintained in hypoxemic animals, it decreased significantly during hemodilution (from 7.95 +/- 2.92 baseline to 5.08 +/- 1.10 ml O2/dl.100 g-1.min-1 at the lowest CaO2 value). This decrease in cerebral DO2 was offset by an increase in oxygen extraction ratio during hemodilution. By contrast, the small increase in oxygen extraction ratio seen with hypoxemia did not achieve significance. These results suggest that there are different adaptive responses to acute hypoxemia or hemodilution . They also imply that at similar CBF and CaO2 values, tissue O2 availability may be greater during hemodilution than during hypoxemia.
Abstract: The secretion and synthesis of renin were studied in mice by measuring aortic, right and left renal vein renin, renal renin, and mRNA for renin. The role of the macula densa was evaluated in a kidney made hydronephrotic by tying the ureter 6 weeks earlier. There was no net secretion of renin from the left hydronephrotic kidney even when the mice were placed in a high secretory state by sodium restriction or enalapril. Sodium restriction and enalapril increased renin content to a similar extent in the normal and hydronephrotic kidney. High sodium intake decreased renin content in the normal and hydronephrotic kidney and also decreased the enalapril-stimulated renin content. Changes in mRNA in the same direction to renal renin implied that this was due to increased synthesis. Thus secretion and synthesis of renin can be disassociated. The macula densa is important for renin secretion but not for the stimulation of synthesis.
Abstract: We examined the active and passive contributions of the alpha- and beta-adrenergic receptor mechanisms to the changes in systemic vascular capacitance caused by the carotid sinus baroreflex system in anesthetized, vagotomized dogs. The carotid sinuses were isolated from the systemic circulation and perfused with controlled pressures. To determine the changes in vascular capacitance, a constant flow, constant venous pressure cardiopulmonary bypass was used. The changes in unstressed vascular volume were calculated when carotid sinus pressure was reduced from 200 to 50 mmHg without any adrenergic receptor antagonist, with either an alpha- (phentolamine) or a beta- (propranolol) antagonist and then with both. The reflex change in unstressed vascular volume in the systemic circulation (22.6 +/- 9.0 ml/kg without any antagonist) was reduced by 72% with phentolamine, by 35% with propranolol, and by 73% with both antagonists. Our results suggest that the alpha-adrenergic mechanisms contribute significantly to active changes in systemic venous capacity. In addition, the beta-adrenergic system has very little effect on active changes in venous vessels but does contribute to the overall capacity changes by dilating the hepatic outflow resistance when the carotid sinus baroreflex system is activated.
Abstract: The mechanisms that balance food intake and energy expenditure determine who will be obese and who will be lean. One of the molecules that regulates energy balance in the mouse is the obese (ob) gene. Mutation of ob results in profound obesity and type II diabetes as part of a syndrome that resembles morbid obesity in humans. The ob gene product may function as part of a signalling pathway from adipose tissue that acts to regulate the size of the body fat depot.
Abstract: BACKGROUND: Increases in brain glucose will worsen outcome after global cerebral ischemia, and some experimental evidence suggests that the duration of hyperglycemia also may influence outcome. Different types of hyperglycemia were studied to identify metabolic differences that might account for alterations in postischemic outcome. METHODS: Ninety pentobarbital-anesthetized Sprague-Dawley rats were divided into three groups: normoglycemic nondiabetic rats (N) (n = 30), chronically hyperglycemic diabetic rats (HD) (n = 30), and acutely hyperglycemic, glucose-infused nondiabetic rats (HN) (n = 30). These groups were further subdivided into groups of six rats each that received 0, 2.5, 5, 10, or 15 min of complete cerebral ischemia (potassium chloride–induced cardiac arrest). Brains were excised after 10-kW focused microwave radiation and metabolites were measured using enzymatic fluorometric techniques. RESULTS: At all study intervals, plasma glucose concentrations in HD and HN were fourfold greater than in N. Before ischemia, brain glucose concentrations in all groups were proportional to plasma glucose concentrations; however, brain glycogen concentrations did not differ among groups. After the onset of ischemia, there was an immediate diminution of brain glucose, glycogen, adenosine triphosphate (ATP), and phosphocreatine that in all cases was most pronounced during the initial 2.5 min of ischemia. Consumption of carbohydrate stores and lactate production were greater in HD and HN than in N. HD had lesser preischemic ATP concentrations and energy charges relative to N and HN (P \textless 0.05), perhaps reflecting their disease state; however, at 2.5 min of ischemia, the relationship of ATP concentrations and energy charges was HN \textgreater HD \textgreater N (P \textless 0.05 among all). In all groups, ATP and phosphocreatine were more than 96% depleted by 10 min of ischemia. With few exceptions (ATP concentrations and energy charges before ischemia and at 2.5 min, and lactate concentration in HD \textless HN at 15 min), there were no measured metabolic differences between HD and HN. CONCLUSIONS: In these studies, the duration of hyperglycemia did not affect intraischemic carbohydrate consumption. At short durations of ischemia (2.5 min), both HD and HN groups had greater intraischemic ATP concentrations and energy charges than N; however, at longer durations of ischemia (\textgreater 5.0 min), high-energy phosphate depletion was similarly severe in all groups. These studies suggest that energy failure is not the origin of worse postischemic neurologic injury in hyperglycemic subjects, nor does energy failure readily explain reported differences between acutely and chronically hyperglycemic subjects exposed to global cerebral ischemia.
Abstract: Glucagon-like peptide-1 (GLP-1) is a hormone derived from the preproglucagon molecule that is secreted by intestinal L cells and stimulates insulin secretion from beta cells. The GLP-1 receptor is a candidate gene for diabetes mellitus, as mutations may induce the impaired insulin response that is a characteristic feature of NIDDM. To study the relationship between the GLP-1 receptor gene and NIDDM, linkage of a microsatellite polymorphism flanking the GLP-1 receptor gene with diabetes was investigated in three Caucasian families with MODY and in the nuclear families of 12 NIDDM probands. A cumulative LOD score -8.50 excludes linkage in these MODY pedigrees. A LOD score of -1.24 in the NIDDM nuclear pedigrees makes linkage improbable. Mutations in or near the GLP-1 receptor gene are unlikely to be the major cause of the inherited predisposition to NIDDM in Caucasian pedigrees, but we cannot exclude a role for this locus in a polygenic model or a major role in some pedigrees.
Abstract: Hypoxemia is a major comorbid factor for permanent brain damage in several metabolic encephalopathies. To determine whether hypoxia impairs brain adaptation to hyponatremia, worsening brain edema, we performed in vitro and in vivo studies in cats and rats with hyponatremia plus either ischemic or hypoxic hypoxia. Mortality with hypoxic hypoxia was 0%; with hyponatremia, 22%; and with hyponatremia+hypoxia, 100%. Hyponatremia in cats produced brain edema, with a compensatory decrease of brain sodium. Ischemic hypoxia also resulted in brain edema, but with elevation of brain sodium. However, when ischemic hypoxia was superimposed upon hyponatremia, there was elevation of brain sodium with further elevation of water. Outward sodium transport in cat cerebral cortex synaptosomes was measured via three major pathways through which brain osmolality can be decreased. After hyponatremia, sodium transport was significantly altered such that brain cell osmolality would decrease: 44% increase in Na(+)-K(+)-ATPase transport activity (ouabain inhibitable); 26% decrease in amiloride-sensitive sodium uptake. The change in veratridine-stimulated sodium uptake was not significant (P \textgreater 0.05). When ischemic hypoxia was superimposed upon hyponatremia, all of the cerebral adaptive changes induced by hyponatremia alone were eliminated. Thus, hypoxia combined with hyponatremia produces a major increase in brain edema and mortality, probably by eliminating the compensatory mechanisms of sodium transport initiated by hyponatremia that tend to minimize brain swelling.
Abstract: We studied the responses of total renal blood flow (RBF) and renal medullary blood flow (RMBF) to changes in renal perfusion pressure (RPP) within and below the range of renal autoregulation in the anesthetized dog (n = 7). To measure RMBF, we developed a technique in which the medulla is exposed by excising a section of infarcted cortex and a multiple optical fiber flow probe, connected to a laser-Doppler flowmeter, is placed on the medulla. At the baseline RPP of 120 +/- 1 mmHg, RBF was 2.58 +/- 0.33 ml.min-1.g perfused kidney wt-1, and RMBF was 222 +/- 45 perfusion units. RPP was then decreased in consecutive 20-mmHg steps to 39 +/- 1 mmHg. At 80 +/- 1 mmHg, RBF remained at 89 +/- 4% of the baseline value; however, RMBF had decreased significantly (P \textless 0.05) to 73 +/- 4% of its baseline value. The efficiency of autoregulation of RBF and of RMBF within the RPP range of 120 to 80 mmHg was determined by calculating an autoregulatory index (AI) for each parameter using the formula AI = (%delta blood flow)/(%delta RPP). An AI of 0 indicates perfect autoregulation, and an index of 1 indicates a system with a fixed resistance. The AI for RBF averaged 0.33 +/- 0.12 over this pressure range and showed a significantly greater (P \textless 0.05) autoregulatory ability than did the RMBF (0.82 +/- 0.13). Decreasing perfusion pressure \textless 80 mmHg produced significant decreases in both RBF and RMBF.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Sprinting performances rely strongly on a fast acceleration at the start of a sprint and on the capacity to maintain a high velocity in the phase following the start. Simulations based on a model developed in which the generation of metabolic power is related to the mechanical destinations of power showed that for short-lasting sprinting events, the best pacing strategy is an all out effort, even if this strategy causes a strong reduction of the velocity at the end of the race. Even pacing strategies should only be used in exercises lasting longer than 80 to 100 seconds. Sprint runners, speed skaters and cyclists need a large rate of breakdown of energy rich phosphates in the first 4 to 5 seconds of the race (mechanical equivalent \textgreater 20 W/kg) in order to accelerate their body, and a power output of more than 10 W/kg in the phase following the start to maintain a high velocity. Maximal speed in running is mainly limited by the necessity to rotate the legs forwards and backwards relative to the hip joint. The acceleration phase, however, relies on powerful extensions of all leg joints. Through a comparison of the hindlimb design of highly specialised animal sprinters (as can be found among predators) and of long distance animal runners (as found among hoofed animals), it is illustrated that these 2 phases of a sprint rely on conflicting requirements: improvement of maximal speed would require lower moments of inertia of the legs whereas a faster acceleration would require the involvement of more muscle mass (not only of the hip and knee extensors but also of the plantar flexors). Maximal speed in cycling and speed skating is not limited by the necessity to move leg segments but rather on air friction and rolling or ice friction. Since the drag coefficients found for speed skaters and cyclists (about 0.8) are considerably higher than those of more streamlined bodies, much progress can still be expected from the reduction of air friction. Speed skaters and especially cyclists show much smaller accelerations during the start than do sprint runners. Skaters might try to improve their very first push off by developing a start technique that allows a much more horizontally directed propulsive force. The small propulsive force at the onset of a cycling sprint is due to the gearing system.(ABSTRACT TRUNCATED AT 400 WORDS)
Abstract: 1. Previous work has demonstrated a positive relationship between experimentally induced changes in arterial pressure (AP) and renal interstitial hydrostatic pressure (RIHP). The purpose of the present study was to test the hypothesis that RIHP is positively correlated with the normal changes in AP that occur spontaneously in conscious rats. 2. Rats were chronically instrumented for the recording of AP (via an aortic catheter) and RIHP. RIHP was measured by implanting a Millar microtransducer, whose tip had been encapsulated in a 35 microns pore polyethylene matrix (5 mm long, 2 mm o.d.), approximately 5 mm below the renal cortical surface. 3. A total of 56 h of simultaneous analog recording of AP and RIHP was obtained from ten rats. Each 1 h segment was digitized and evaluated at frequencies of 1, 0.1, 0.02 and 0.01 Hz. 4. In forty-nine out of fifty-six of these 1 h recordings taken at 1 Hz, there were significant positive linear correlations between AP and RIHP (mean r = 0.32) with a mean slope of 0.11 mmHg RIHP/1 mmHg AP. Low-pass filtering to 0.01 Hz significantly increased the r value to 0.48. 5. These results demonstrate that spontaneous changes in AP and RIHP are positively correlated. The spontaneous coupling of AP and RIHP may be of importance in the regulation of salt and water excretion by the pressure diuresis mechanism.
Abstract: Male Sprague-Dawley rats, treated with either saline (n = 14) or guanethidine (n = 12) from 1 to 13 wk of age, were instrumented for the measurement of mean arterial pressure (MAP) and indexes of regional blood flows (pulsed Doppler flow probes) in the subdiaphragmatic aorta, superior mesenteric artery, and distal aorta (hindquarters). Hemodynamic parameters were simultaneously recorded in the conscious rats on a beat-to-beat basis by a computer. Chronic sympathectomy did not change the MAP level but nearly doubled its spontaneous variability, mainly due to large decreases in MAP associated with regional vasodilations that were slightly delayed with respect to the onset of the decreases in pressure, especially in the aortic and mesenteric circulations. In the hindquarters vascular bed, the onset of vasodilations sometimes coincided with the onset of the decreases in MAP. During depressor episodes, blood flow varied little (aortic and mesenteric circulations) or even increased (hindquarters). This hemodynamic pattern was not affected by acute beta-adrenoceptor blockade. We conclude that chronic sympathectomy sensitizes the cardiovascular system to decreases in arterial pressure mainly by unmasking local autoregulatory responses of regional circulations. The sympathetic control of vascular tone overrides these responses and considerably limits the MAP variability.
Abstract: Vagal stimulation (VS) decreases heart rate and alters the loading conditions of the left ventricle (LV). However, its effects on LV performance are not clearly defined. To evaluate the effects of VS on LV performance, 20 anesthetized open-chest dogs were instrumented to measure LV pressure (LVP) and volume. VS resulted in a decrease in the slope of the end-systolic pressure-volume relationship, without pacing and with pacing, after ansae subclaviae resection and after ansae subclaviae resection plus beta-adrenergic blockade. VS did not alter the time constant of isovolumic relaxation (tau) or the LV end-systolic pressure-tau relationship during vena caval occlusion. No change was noticed in the LV chamber stiffness constant without and with pacing. However, a significant increase in the LV filling fraction at one-third and one-half of diastole was observed. We examined the mechanism of this increase by examining the relationship of left atrial pressure (LAP) and LVP. VS increased mean LAP 44% and increased the LAP-LVP gradient 42%. These data suggest that VS exerts a significant negative inotropic effect that is independent of its bradycardiac effect and the level of sympathetic tone. Despite the absence of lusitropic effects of VS, early filling of the LV is augmented most likely as a result of an increase in LAP.
Abstract: BACKGROUND. The results of trials of the primary prevention of coronary heart disease have suggested that treating hypertension with high doses of thiazide diuretic drugs might increase the risk of sudden death from cardiac causes. In contrast, treatment with low doses of thiazide reduces the risk of coronary heart disease. METHODS. To examine the association between thiazide treatment for hypertension and the occurrence of primary cardiac arrest, we conducted a population-based case-control study among enrollees of a health maintenance organization. The case patients were 114 persons with hypertension who had a primary cardiac arrest from 1977 through 1990. The control patients were a stratified random sample of 535 persons with hypertension. The patients’ treatment was assessed with the use of a computerized pharmacy data base. Records of their ambulatory care were reviewed to determine other clinical characteristics. RESULTS. The risk of primary cardiac arrest among patients receiving combined thiazide and potassium-sparing diuretic therapy was lower than that among patients treated with a thiazide without potassium-sparing therapy (odds ratio, 0.3; 95 percent confidence interval, 0.1 to 0.7). As compared with low-dose thiazide therapy (25 mg daily), moderate-dose therapy (50 mg daily) was associated with a moderate increase in risk (odds ratio, 1.7; 95 percent confidence interval, 0.7 to 4.5), and high-dose therapy (100 mg daily) was associated with a larger increase in risk (odds ratio, 3.6; 95 percent confidence interval, 1.2 to 10.8) (P value for trend, 0.02). The addition of a potassium-sparing drug to low-dose thiazide therapy was associated with a reduced risk of cardiac arrest (odds ratio, 0.4; 95 percent confidence interval, 0.1 to 1.5). CONCLUSIONS. Both the dose of thiazide drugs and the addition of potassium-sparing drugs influence the risk of primary cardiac arrest. These results may explain the differences in the effect of antihypertensive therapy on mortality from coronary heart disease in previous clinical trials.
Abstract: To assess the mechanisms whereby muscular work stimulates glucose uptake and metabolism in vivo, dogs were studied during rest (-40-0 min), moderate exercise (0-90 min), and exercise recovery (90-180 min) with plasma glucose clamped at 5.0, 6.7, 8.3, and 10.0 mM (n = 5 at 5.0 mM and n = 4 at all other levels) using a variable glucose infusion. Basal insulin was maintained with somatostatin and insulin replacement. Whole-body glucose uptake, limb glucose uptake, and oxidative and nonoxidative glucose plus lactate metabolism, were assessed with tracers ([3H]glucose and [14C]glucose) and arteriovenous differences. The combined effects of glucose and exercise on the increment above resting values for limb glucose uptake, arteriovenous glucose difference, LGO, LGNO, and rate of glucose disappearance were synergistic (approximately 112, 90, 125, 76, and 90% greater than the additive values, respectively). Neither exercise nor recovery affected the Km for limb glucose uptake (4.7 +/- 1.1, 4.8 +/- 0.4, and 5.2 +/- 0.3 mM during rest, exercise, and recovery, respectively), but both conditions increased the Vmax (44 +/- 16, 217 +/- 30, and 118 +/- 14 mumol/min during rest, exercise, and recovery, respectively). Similarly, the Km for arteriovenous glucose differences were unaffected by exercise recovery (4.9 +/- 0.6, 5.0 +/- 0.4, and 5.3 +/- 0.3 mM during rest, exercise, and recovery, respectively), but the maximum rose (272 +/- 50, 650 +/- 78, and 822 +/- 111 microM during rest, exercise, and recovery, respectively). The LGO was unchanged by glycemia at rest (15 +/- 4 mumol/min at 10.0 mM). The Km for LGO during exercise was 5.1 +/- 0.3 mM, and the Vmax was 163 +/- 15. The capacity for LGO returned to basal during recovery. LGNO increased gradually with increasing glycemia during rest, exercise, and recovery and did not approach saturation (38 +/- 13, 105 +/- 36, and 132 +/- 45 mumol/min during rest, exercise, and recovery, respectively, at 10.0 mM). In general, the LGNO was elevated at every glucose level during exercise (approximately twofold) and recovery (approximately threefold) compared with rest. Arterial free fatty acid and glycerol levels decreased with increasing glycemia within all periods. Free fatty acids were suppressed by a greater amount during exercise compared with rest and recovery.(ABSTRACT TRUNCATED AT 400 WORDS)
Abstract: Previous studies have shown that the right ventricle (RV) appears to tolerate volume overloading better than does the left ventricle (LV). To determine whether this dichotomous response is due to intrinsic differences in the contractile performance of volume hypertrophied RV vs. LV cardiac muscle cells, or cardiocytes, we characterized the contractile performance of cardiocytes isolated from an experimental feline model of biventricular volume overload (n = 7 cats), wherein a peripheral arteriovenous fistula (AVF) produced an identical duration and degree of volume overload for both ventricles; sham-operated cats served as the appropriate controls (n = 7). Cardiocyte contractile function was defined by laser diffraction measurement of sarcomere motion. For the AVF cats, there was a 2.4-fold increase in cardiac output, a significant increase in the RV and LV weight-to-body weight ratios, and a significant increase in cell surface area for the RV and LV cardiocytes. Despite this, cardiocyte contractile function in the AVF cats was entirely normal. Thus there was no significant difference between RV and LV cardiocytes from control cats in the extent or velocity of sarcomere shortening either in 1 cP superfusate or in higher viscosity superfusates, and comparison of RV and LV cells from the AVF cats to those from sham-operated cats again revealed no significant differences. Furthermore, cardiocyte relengthening properties showed no significant differences between AVF and control groups. In summary, this study shows that contractile dysfunction is not an inherent property of either RV or LV cardiac muscle cells hypertrophying in response to substantial volume overloading when preload is increased but afterload is normal.
Abstract: The pathogenesis of nervous system-induced pulmonary edema remains incompletely understood. There are two major causes: elevated intravascular pressure and pulmonary capillary leak. Thus, both hemodynamic (cardiogenic) or nonhemodynamic (noncardiogenic) components exist. These components often occur together in settings such as pulmonary edema following epileptic convulsions or intracranial pressure elevation. The hemodynamic component is relatively brief and may unmask a "pure" noncardiogenic pulmonary edema such as that seen in experimental seizures (see Fig. 6). Whether the hemodynamic changes produce a pulmonary capillary leak through pressure-induced mechanical injury to the pulmonary capillaries or whether some direct nervous system control over pulmonary capillary permeability exists remains uncertain. The neuroeffector site for nervous system-induced pulmonary edema appears relatively well established in regions about the caudal medulla, where nuclei regulating systemic arterial pressure and afferent and efferent pathways to and from the lungs are located.
Abstract: BACKGROUND. Even in the absence of a previous myocardial infarction, patients with coronary artery disease often present with chronic regional wall motion abnormalities that are reversible spontaneously or after coronary revascularization. In these patients, regional dysfunction has been proposed to result either from prolonged postischemic dysfunction (myocardial "stunning") or from adaptation to chronic hypoperfusion (myocardial "hibernation"). This study examines which of these two mechanisms is responsible for the chronic regional dysfunction often detected in patients with angina and noninfarcted collateral-dependent myocardium. METHODS AND RESULTS. Twenty-six anginal patients (19 men; mean age, 60 +/- 9 years old) with chronic occlusion of a major coronary artery but without previous infarction were studied. Positron emission tomography was performed to measure absolute regional myocardial blood flow with 13N-ammonia at rest (n = 26) and after intravenous dipyridamole (n = 11). The kinetics of 18F-deoxyglucose and 11C-acetate were measured to calculate the rate of exogenous glucose uptake and the regional oxidative metabolism (n = 15). Global and regional left ventricular function was evaluated by contrast ventriculography at baseline (n = 26) and after revascularization (n = 12). Transmural myocardial biopsies from the collateral-dependent area were obtained in seven patients during bypass surgery and analyzed by optical and electron microscopy. According to resting regional wall motion, patients were separated into groups with and without dysfunction of the collateral-dependent segments. In patients with normal wall motion (n = 9), regional myocardial blood flow, oxidative metabolism, and glucose uptake were similar among collateral-dependent and remote segments. By contrast, in patients with regional dysfunction (n = 17), collateral-dependent segments had lower myocardial blood flow (77 +/- 25 versus 95 +/- 27 mL.min-1.100 g-1, p \textless 0.001), smaller k values (slope of 11C clearance reflecting oxidative metabolism, 0.049 +/- 0.015 versus 0.068 +/- 0.020 min-1, p \textless 0.001) and higher glucose uptake (relative 18F-deoxyglucose-to-flow ratio of 1.9 +/- 1.6 versus 1.2 +/- 0.2, p \textless 0.05) compared with remote segments. However, myocardial blood flow and k values were similar among collateral-dependent segments of patients with and without segmental dysfunction. After intravenous dipyridamole, collateral-dependent myocardial blood flow increased from 78 +/- 5 to 238 +/- 54 mL.min-1.100 g-1 in three patients with normal wall motion and from 88 +/- 17 to only 112 +/- 44 mL.min-1.100 g-1 in eight patients with regional dysfunction. There was a significant (r = -0.85, p \textless 0.001) inverse correlation between wall motion abnormality and collateral flow reserve. Analysis of the tissue samples obtained at the time of bypass surgery showed profound structural changes in dysfunctioning collateral-dependent areas, including cellular swelling, loss of myofibrillar content, and accumulation of glycogen. Despite these alterations, the regional wall motion score improved significantly in the patients studied before and after revascularization (from 3.8 +/- 1.3 to 0.8 +/- 0.9, p \textless 0.005). CONCLUSIONS. In a subgroup of patients with noninfarcted collateral-dependent myocardium, immature or insufficiently developed collaterals do not provide adequate flow reserve. Despite nearly normal resting flow and oxygen consumption, these collateral-dependent segments exhibit chronically depressed wall motion and demonstrate marked ultrastructural alterations on morphological analysis. We propose that these alterations result from repeated episodes of ischemia as opposed to chronic hypoperfusion and represent the flow, metabolic, and morphological correlates of myocardial "hibernation."
Abstract: Vasopressin is a powerful vasoconstrictor that is released into the systemic circulation during exercise. We tested the hypothesis that this peptide contributes to the cardiovascular response during treadmill exercise in the pig. Seventeen miniswine were instrumented with epicardial electrocardiogram leads, left atrial and aortic catheters, and a left ventricular pressure transducer for measurement of heart rate (HR), regional blood flow, arterial blood pressure (MAP), and myocardial contractility [first derivative of left ventricular pressure (dP/dt) at 40 mmHg developed pressure] at rest and during exercise. At a work intensity of 80% of each animal’s maximal HR reserve, exercise-induced increases in MAP, HR, dP/dt at 40 mmHg developed pressure, and cardiac output were measured. On a separate day, the workload performed by each animal was replicated in the presence of selective vasopressin V1-receptor inhibition using the specific V1 antagonist, [d(CH2)5Tyr(Me)]arginine vasopressin (10-14 micrograms/kg iv). During exercise, MAP was lower (96 +/- 3 vs. 104 +/- 2 mmHg) and cardiac output was higher (13.5 +/- 0.6 vs. 12.6 +/- 1.0 l/min) in the presence of V1-receptor blockade than during unblocked conditions, respectively. Furthermore, we observed an attenuation of exercise-induced decreases in blood flow to the colon. Increases in vascular resistance in the stomach, small intestine, colon, and pancreas also were diminished by V1-receptor inhibition. However, HR and myocardial contractile responses to exercise were not affected. These results suggest that vasopressin contributes to increases in MAP and to the redistribution of cardiac output during dynamic exercise in the miniswine.
Abstract: To test the hypothesis that a significant proportion of transcapillary water flow occurs through solute-restricting channels, we investigated the effects of transcapillary water movement on plasma electrolytes in isolated perfused cat skeletal muscle. The lower hindlimbs of anesthetized cats were perfused with a plasma-albumin solution and were weighed to determine transcapillary water movement. Osmolality was increased 60-70 mosmol/kgH2O with sucrose, creating water fluxes of 8-10 ml.min-1.100 g-1, and the changes in the venous concentrations of sodium, potassium, and chloride were determined. The ion concentrations were all reduced by 6-7% with no significant difference between them. The amount of reduction was quantitatively explained by the flow of ion-free water from the interstitial space into plasma and the diffusion of electrolyte in the same direction. These findings support the hypothesis that important water-only transcapillary channels exist in mammalian skeletal muscle. The observations may also explain some of the electrolyte changes seen in intense exercise.
Abstract: A method for estimating total body fat (TBF) and the amount and distribution of adipose tissue in humans by using magnetic resonance imaging (MRI) is described. Thirty transaxial images of subjects were taken by a nuclear magnetic imager (0.02 T). Adipose tissue volume was calculated from adipose tissue area in each image and from the distances between images. The CV when estimating total volume of body adipose tissue was 1.5%. TBF of healthy Swedish women was estimated by the MRI method (n = 25), by underwater weighing (UWW) (n = 20), and by body-water dilution (BWD) (n = 23). When assessed by MRI and BWD, women contained 1.4 +/- 2.9% less and 4.7 +/- 4.0% more TBF, respectively, than when assessed by UWW. On average, 74.2% of total adipose tissue volume was situated subcutaneously. Subcutaneous fat:fat-free body weight and nonsubcutaneous fat:fat-free body weight were both significantly correlated with percent TBF but the women stored excess fat subcutaneously rather than nonsubcutaneously.
Abstract: Glucagon and the glucagon receptor are a primary source of control over blood glucose concentrations and are especially important to studies of diabetes in which the loss of control over blood glucose concentrations clinically defines the disease. A complementary DNA clone for the glucagon receptor was isolated by an expression cloning strategy, and the receptor protein was expressed in several kidney cell lines. The cloned receptor bound glucagon and caused an increase in the intracellular concentration of adenosine 3’, 5’-monophosphate (cAMP). The cloned glucagon receptor also transduced a signal that led to an increased concentration of intracellular calcium. The glucagon receptor is similar to the calcitonin and parathyroid hormone receptors. It can transduce signals leading to the accumulation of two different second messengers, cAMP and calcium.
Abstract: Recent reports have suggested that increases in venoarterial difference in PCO2 (VAPCO2) and arteriovenous difference in pH (AVpH) represent valuable markers of tissue hypoxia in shock states associated with low cardiac output. We compared the values of VAPCO2 and AVpH with that of blood lactate in their relationship to changes in O2 uptake (VO2) and O2 delivery (DO2) during an acute reduction in blood flow induced by cardiac tamponade. In 13 anesthetized and mechanically ventilated dogs, a catheter was inserted into the pericardium to inject saline and to measure the intrapericardial pressure. VO2 was derived from expired gas analysis. DO2 was calculated by the product of the thermodilution cardiac index and the arterial O2 content. The critical DO2 (DO2crit) was found at 9.9 +/- 1.8 ml/kg.min. VAPCO2 and AVpH, which were 7.1 +/- 4.6 mm Hg and 0.028 +/- 0.025 U, respectively, at baseline, progressively increased to reach 17.5 +/- 6.6 mm Hg and 0.114 +/- 0.054 U, respectively, at DO2crit (both p \textless 0.01). Below DO2crit they increased more dramatically. These changes were related to both arterial hypocapnia and mixed venous hypercapnia. CO2 excretion decreased from 5.8 +/- 2.0 ml/kg-min at baseline to 3.9 +/- 0.9 ml/kg.min at DO2crit (p \textless 0.01). End-tidal CO2 tension significantly fell below DO2crit. Lactate levels increased from 2.1 +/- 0.5 to 3.5 +/- 0.5 mmol/L at DO2crit (P \textless 0.01) and to 6.9 +/- 2.1 mmol/L (p \textless 0.01) at the end of the study. There was no statistically significant difference between the DO2crit calculated for VAPCO2, AVpH, lactate, or VO2.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Lactic acidosis is the most common metabolic acidosis. At clinical presentation, several causes usually can be identified. The liver is a major site of removal of lactate and hydrogen ions, and abnormalities in the aerobic metabolism of lactate by mitochondria in hepatocytes and other cells may contribute to many clinical conditions in which overproduction and underuse of lactate occur. To date, no therapy specifically designed to lower arterial blood lactate levels has reduced mortality significantly. Prompt recognition and treatment of the underlying causes of lactic acidosis remain the cornerstone of treatment.
Abstract: Isolated vasodilated cat hindlimb skeletal muscles were perfused at constant flow and stimulated at 4 Hz for 2-4 min in three studies. Water uptake rates were measured gravimetrically or calculated from venous protein concentration changes. Venous plasma sodium, potassium, chloride, and osmolality were also measured. Maximum water uptake rates averaged 1.8 +/- 0.2 (SE) ml.min-1 x 100 g-1, reaching twice that in some experiments. Water uptake continued after stimulation had ceased. Constant-flow perfusion maintained a constant capillary pressure that was corroborated by measurements of arterial and venous perfusate pressures. Water uptake rate was not influenced by hematocrit but was highly correlated with plasma flow rate. The evidence strongly suggests that small-molecule osmotic pressure was the primary pressure causing the transcapillary water flux. Venous plasma sodium and chloride concentrations increased almost as much as protein (108 and 87% of the protein increase, respectively), as would be expected when water fluxes are driven by small-molecule osmotic pressure. Peak potassium efflux averaged 36 +/- 3 mu eq.min-1 x 100 g-1, but potassium did not contribute significantly to the osmotic gradient.
Abstract: The relationship of myocardial O2 consumption (MVO2) to its potential hemodynamic and mechanical determinants was investigated in eight healthy normal volunteers at rest and during infusion of dobutamine (5-10 micrograms.kg-1.min-1). MVO2 was calculated from the monoexponential myocardial clearance of [1-11C]acetate with positron emission tomography, and left ventricular mechanical function was assessed by two-dimensional echocardiography. Infusion of dobutamine increased heart rate by 53%, the tension-time index by 31%, and the rate-pressure product by 116%. Cardiac output (+70%), left ventricular ejection fraction (+24%), total mechanical energy [systolic pressure-volume area, (PVA) +84%], and left ventricular pressure-work index (+100%) also increased during infusion of dobutamine. During infusion of dobutamine, MVO2 increased from 96 +/- 17 to 233 +/- 19 J.min-1.100 g left ventricle-1, while myocardial efficiency (the ratio of PVA to MVO2) decreased from 46 +/- 8 to 35 +/- 4% (P \textless 0.001 each). MVO2 was best correlated (P \textless 0.001) with the PVA (r = 0.92) and the pressure-work index (r = 0.92). Infusion of dobutamine also resulted in a significant parallel upward shift of the PVA-MVO2 relationship, indicative of an increase in PVA-independent MVO2. Our data indicate that, in human subjects, MVO2 is mainly related to systolic PVA and that inotropic stimulation with dobutamine results in decreased efficiency of contraction, such as that previously described in isolated hearts.
Abstract: Postprandial storage of carbohydrate as glycogen in muscle was quantitated in normal subjects (n = 8) by natural abundance 13C-nuclear magnetic resonance spectroscopy with proton decoupling in a 4.7-tesla magnet. After an overnight fast three basal measurements of gastrocnemius muscle glycogen were made and a mixed meal was given. Muscle glycogen concentration rose from 83.3 +/- 5.2 to a maximum of 100.2 +/- 6.7 mmol/l muscle at 4.9 h (P \textless 0.01) and fell thereafter to 90.6 +/- 5.9 mmol/l muscle at 7 h postprandially (P \textless 0.006). The meal brought about an increase in plasma glucose from 5.4 +/- 0.2 to 7.3 +/- 0.4 mmol/l at 30 min but this was followed by a rapid fall to 6.2 +/- 0.4 mmol/l at 75 min. Plasma insulin rose from 62.4 +/- 11.4 to 900 +/- 216 pmol/l at 30 min and declined steadily thereafter. It was calculated from total muscle mass measurements and estimation of carbohydrate absorption rates that at peak muscle glycogen concentrations between 26 and 35% of the absorbed carbohydrate was stored as muscle glycogen. These data quantitate the role of skeletal muscle glycogen synthesis in postprandial carbohydrate storage and demonstrate that this tissue acts as a dynamic buffer to maintain glucose homeostasis during postprandial substrate storage.
Abstract: 1. To investigate the effects of angiotensin-converting enzyme inhibition (ACEI) on exercise performance, the following were measured in eight normal rabbits performing graded treadmill exercise during intravenous vehicle saline or enalaprilat infusion: haemodynamics, noradrenaline (NA) spillover, hindlimb oxygen consumption and lactate release. 2. Blood pressure, heart rate (HR), femoral blood flow (FBF), hindlimb lactate release, hindlimb oxygen consumption and hindlimb NA spillover rate were all significantly increased during exercise and the changes during enalaprilat infusion were similar to control responses. 3. At submaximal exercise (6 m/min), ACEI did not significantly alter the responses of hindlimb lactate release, NA spillover rate or oxygen consumption. At the higher exercise load (12 m/min), ACEI reduced hindlimb NA spillover rate (33.1 +/- 4.2 vs 61.3 +/- 17.1 ng/min) and significantly increased oxygen consumption (241 +/- 53.4 vs 133 +/- 23.3%, P \textless 0.05). The ratio of hindlimb NA spillover rate to total NA spillover rate was markedly increased during exercise, with similar changes being observed in ACEI and control experiments. 4. This study indicates that acute ACEI has a favourable effect on oxygen utilization in exercising muscle in the normal rabbit. Suppression of local sympathetic activation during exercising stress, as reflected in a reduced NA spillover response, may benefit the microcirculation in exercising muscles.
Abstract: We evaluated the relationship between end-capillary and systemic venous PO2 values in the retractor muscle of 14 anesthetized hamsters during both nonhypoxic and hypoxic ventilation to ascertain whether the level of tissue oxygenation could be reliably estimated from the systemic parameter. End-capillary PO2 was estimated from measurements of oxygen saturation in capillaries at the venular end of the network obtained using in vivo video microscopy and computer-aided image-analysis techniques at three different levels of inspired oxygen (0.3, 0.21, and 0.1). Measurements of systemic arterial and venous blood gases were made in conjunction with these capillary determinations. In addition, in a portion of the study we utilized an oxygen microelectrode to determine the PO2 in the first-order venule draining the portion of the muscle containing the capillaries under study. We found that only when the animals were made acutely hypoxic was there any correspondence between the systemic venous and end-capillary PO2 values. In addition, these data provide support for the presence of arteriovenous shunting of oxygen during nonhypoxic ventilation.
Abstract: This study was performed to test the hypothesis that tissue O2 extraction capabilities during hemorrhage may be greater when hematocrit (Hct) is initially reduced. Twenty-four anesthetized and splenectomized dogs were randomly assigned in three groups of eight dogs each: group 1 (Hct 40), 40-45% Hct; group 2 (Hct 30), 30-35% Hct; and group 3 (Hct 20), 20-25% Hct. In each animal, the desired Hct was obtained by normovolemic hemodilution using hydroxyethyl starch 450/0.7 and maintained throughout the experiment. O2 delivery (DO2) was progressively reduced by hemorrhage. At each step, DO2 and O2 consumption (VO2) were measured separately. Critical DO2 obtained from a plot of VO2 vs. DO2 was lower in the Hct 30 and Hct 20 groups than in the Hct 40 group [(in ml.min-1.kg-1) Hct 30, 7.9 +/- 2.2; Hct 20, 7.8 +/- 1.0; Hct 40, 10.4 +/- 1.1; P \textless 0.05]. Critical DO2 obtained from blood lactate levels was also significantly lower in the Hct 30 and Hct20 groups than in the Hct 40 group. Critical O2 extraction ratio was also greater in the Hct 30 and Hct 20 groups than in the Hct 40 group (Hct 30, 73.0 +/- 13.9%; Hct 20, 70.1 +/- 9.6%; Hct 40, 57.1 +/- 11.5%; P \textless 0.05). In the conditions of our study, moderate hemodilution was associated with an improvement of the O2 extraction capabilities of the body, probably related to the reduction in blood viscosity.
Abstract: Lower body positive pressure (LBPP) was applied at 4 and 30 Torr to increase central venous pressure (CVP). CVP increased with LBPP (r = 0.55, P \textless 0.01), and the increases were significant at 4 and 30 Torr (7.4 and 7.8 mmHg) from the control (6.0 mmHg). During LBPP cardiac output increased, which was significantly related to the increase in CVP (r = 0.63, P \textless 0.01). The carotid baroreflex was elicited by trains of neck pressure and suction from 40 to -65 Torr. The carotid-cardiac and carotid-vasomotor baroreflex responses were assessed by determining the maximal gains of heart rate (HR) interval and intraradial mean arterial pressure (MAP) to changes in carotid sinus pressure using a logistic model. The carotid-cardiac and carotid-vasomotor baroreflex gains were negatively related to LBPP, and at 30 Torr, both gains (5.6 ms/mmHg and -0.14 mmHg/mmHg) were significantly smaller than the control (12.4 ms/mmHg and -0.24 mmHg/mmHg). The decreases in carotid-cardiac and carotid-vasomotor baroreflex sensitivity during LBPP were primarily associated with the increases in CVP (r = -0.52, P \textless 0.01, and r = -0.74, P \textless 0.01, respectively). These data suggest that the increases in CVP and/or central blood volume diminish the sensitivity of the carotid baroreflex control of HR and MAP by enhancing the tonic inhibitory influence from the cardiopulmonary baroreceptors.
Abstract: Endocrine regulation of fluids and electrolytes during 7 days of -6 degrees head-down bed rest (HDBR) was compared in male (n = 8) and, for the first time, female (n = 8) volunteers. The subjects’ responses to quiet standing for 2 h before and after HDBR were also tested. In both sexes, diuresis and natriuresis were evident during the first 2-3 days of HDBR, resulting in a marked increase in the urinary Na(+)-to-K+ ratio and significant Na+ retention on re-ambulation. After the 1st day of HDBR, plasma renin activity (PRA) was increased relative to aldosterone (Aldo), plasma volume was decreased, and the renal response to Aldo appeared to be appropriate. Circulating levels of arginine vasopressin, cortisol, and ACTH were unchanged during HDBR. Plasma testosterone decreased slightly on day 2 of HDBR in males. The ratio of early morning ACTH to cortisol was lower in females than in males because ACTH was lower in females. Urinary cortisol increased and remained elevated throughout the HDBR in males only. There were no gender differences in the responses to 7 days of HDBR, except those in the pituitary-adrenal system; those differences appeared unrelated to the postural change. The provocative cardiovascular test of quiet standing before and after HDBR revealed both sex differences and effects of HDBR. There were significant sex differences in cardiovascular responses to standing before and after HDBR. Females had greater PRA and Aldo responses to standing before HDBR and larger Aldo responses to standing after HDBR than males.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: 1. Vasomotor tone and reactivity were investigated in feed arteries of the extensor digitorum longus and soleus muscles. Feed arteries are located external to the muscle and give rise to the microcirculation within each muscle. Resting diameter was smaller in feed arteries of the soleus muscle. 2. Feed arteries of both muscles dilated to similar peak values with sodium nitroprusside. 3. Micropressure measurements demonstrated resistance to blood flow in the feed arteries supplying both muscles. Feed arteries supplying soleus muscle demonstrated greater resistance to blood flow compared to feed arteries of extensor digitorum longus muscle. 4. Greater resting tone and larger pressure drop for feed arteries of soleus muscle suggest greater range of flow control compared to feed arteries of extensor digitorum longus muscle. 5. In both muscles, feed artery diameter increased with muscle contraction (functional dilatation) and in response to transient ischaemia (reactive dilatation). The magnitude of these responses varied between muscles. 6. Feed arteries are active sites of blood flow control in extensor digitorum longus and soleus muscles of the rat. These muscles differ in fibre type and recruitment properties. Differences in feed artery reactivity may contribute to differences in blood flow between these muscles observed at rest and during exercise.
Abstract: To determine the individual contributions of the right and left carotid sinus baroreflex control of the cardiac interval, we measured heart rate [as expressed by R-R interval (RRI)] and mean arterial pressure (MAP) responses elicited by pulsed trains of neck suction or pressure in 20 healthy men. Pulses were delivered using a customized neck collar device partitioned to allow for stimulation of only one side of the neck. Maximal cardiac gains for right, left, and bilateral baroreflexes were determined from the logistic function of RRI responses to changes in estimated carotid sinus pressure (ECSP). Maximal gains for right (5.44 +/- 1.33 ms/Torr ECSP) and left (4.22 +/- 1.44 ms/Torr ECSP, P \textgreater 0.05) carotid-cardiac responses did not differ. However, the bilateral gain (6.89 +/- 1.80 ms/Torr ECSP) was less than the simple sum of the right and left gains (9.67 +/- 2.20 ms/Torr ECSP, P \textless 0.01). We suggest that the right and left carotid-cardiac reflex responses are quantitatively similar in humans and exhibit an inhibitory interaction when compared with the bilateral response under conditions of supine rest in normotensive subjects.
Abstract: 1. The effects of nifedipine and Bay-K-8644 on the release of adrenal catecholamines were examined in anaesthetized dogs. 2. Splanchnic nerve stimulation (SNS) at 1 and 3 Hz produced frequency-dependent increases in adrenaline (ADR) and noradrenaline (NA) output determined from adrenal venous blood. 3. Neither nifedipine (10 and 30 micrograms/kg, i.v.) nor Bay-K-8644 (10 and 30 micrograms/kg, i.v.) modified the SNS-induced increases in catecholamine output. Basal catecholamine output tended to be increased and decreased by nifedipine and Bay-K-8644, respectively. 4. Nifedipine produced significant decreases in arterial pressure and renal blood flow rate. Bay-K-8644 produced a significant increase in arterial pressure associated with a decrease in renal blood flow rate. 5. These results suggest that dihydropyridine-sensitive calcium channels do not play a major role in adrenal catecholamine release evoked by SNS.
Abstract: We studied the effects of brain stem and spinal lesions on the 10-Hz rhythms in left and right inferior cardiac sympathetic nerve discharge (SND) of baroreceptor-denervated, decerebrate cats. Unilateral medullary lesions [parasagittal section 1.5 mm lateral to midline, radiofrequency lesion of the rostral ventrolateral medulla (RVLM), or chemical inactivation (muscimol) of the RVLM] dramatically reduced the 10-Hz rhythmic discharges in the two nerves. Power in the 10-Hz band of ipsilateral inferior cardiac SND was reduced more than that in contralateral SND. In contrast, bilateral parasagittal medullary sections or microinjection of muscimol into the medullary raphe uniformly reduced the 10-Hz rhythmic discharges of both nerves. Unlike unilateral medullary lesions, rostral pontine or cervical spinal hemisection reduced the 10-Hz discharges of only the ipsilateral inferior cardiac nerve. The chemical inactivation experiments demonstrate that the 10-Hz rhythm in SND is dependent on medullary raphe and RVLM neurons. Moreover the experiments with unilateral lesions demonstrate a mutually facilitatory interaction of medullary circuits that are responsible for the 10-Hz rhythmic discharges in sympathetic nerves located on opposite sides of the body.
Abstract: We tested the hypothesis that rapid increases in muscle blood flow and vascular conductance (C) at onset of dynamic exercise are caused by the muscle pump. We measured arterial (AP) and central venous pressure (CVP) in nine awake dogs, eight with atrioventricular block, pacemakers, and ascending aortic flow probes for control of cardiac output (CO) (2 also had terminal aortic flow probes). One dog had only an iliac artery probe. At exercise onset (0 and 10% grade, 4 mph) C and CVP rose to early plateaus, and AP reached a nadir, all in 2-5 s. At 20% grade and 4 mph, C increased continuously after its initial sudden rise. Timing and magnitude of initial change in conductance (delta C) were independent of CO, AP, work rate (change in grade at constant speed), or autonomic function (blocked by hexamethonium). Speed of initial delta C and its independence from work rate and blood flow ruled out metabolic vasodilation as its cause; insensitivity to AP and autonomic blockade ruled out myogenic relaxation and sympathetic vasodilation as causes of sudden delta C. Sensitivity to contraction frequency (not work per se) implicates the muscle pump. When reflexes were blocked, a large secondary rise in C, presumably caused by metabolic vasodilation, began after 10 s of mild exercise. When reflexes were intact in mild exercise, C was lowered below its initial plateau by sympathetic vasoconstriction, which partially raised AP from its nadir toward its preexercise level. Our conclusion is that dynamic exercise has a large rapid effect on C that is not explained by known neural, metabolic, myogenic, or hydrostatic influences.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Sympathetically mediated changes in blood pressure are thought to occur through changes in arterial resistance (Ra). To test whether the critical closing pressure (Pcrit) could also play a role, we pump-perfused the vascularly isolated canine hindlimb at constant flow. Carotid sinuses were isolated and both vagus nerves cut. Carotid sinus (Pcar), arterial, perfusion (Pper), and venous (Pv) pressures and flow to the hindlimb (Q, electromagnetic flow probe) were measured. By decreasing pump flow to zero over time periods of 1-10 s and measuring the pressure at zero-flow, it was possible to estimate arterial compliance and Pcrit. Ra was calculated as (Pper - Pcrit)/Q. Venous resistance was calculated as (Pel - Pv)/Q, where Pel is the pressure in the compliant region obtained by the double-occlusion technique. Raising Pcar from 115 +/- 7 to 203 +/- 10 mmHg (n = 6) decreased Pcrit from 49.7 +/- 4.3 to 25.9 +/- 2.6 mmHg and Ra from 10.7 +/- 1.2 to 6.8 +/- 0.9 mmHg.min.100 g-1.ml-1 (P \textless 0.05). Lowering Pcar from 119 +/- 6 to 71 +/- 6 mmHg (n = 6) increased Pcrit from 37.0 +/- 3.3 to 61.0 +/- 8.5 mmHg and Ra from 10.0 +/- 1.6 to 14.0 +/- 2.4 mmHg.min.100 g.ml-1 (P \textless 0.05). Arterial compliance increased when Pcar was raised (P \textless 0.05) and decreased when Pcar was decreased (P \textless 0.1). Venous resistance did not change when Pcar was altered. In conclusion, changes in carotid sinus stimulation alters blood flow to the hindlimb through changes in both Pcrit and Ra.
Abstract: The dynamic pressure-flow relationship in the canine hindlimb at normal arterial pressure is best explained by modeling a Starling resistor (critical pressure, Pcrit) at the level of the arterioles. Regulation of flow can therefore occur at the Starling resistor through changes in Pcrit or along the length of the vessel through changes in arterial resistance (Ra). We hypothesized that increasing perfusion pressure (Pper) would increase Pcrit due to the myogenic response but would decrease Ra because of flow-mediated vasodilation and passive effects. We pump-perfused vascularly isolated hindlimbs of anesthetized dogs and then measured Pcrit and calculated Ra over Pper range of 75-175 mmHg. When Pper was increased from 75 to 175 mmHg, Pcrit increased from 33 +/- 2 to 48 +/- 6 (means +/- SE) mmHg, whereas Ra decreased from 10.1 +/- 1.2 to 7.86 +/- 0.7 mmHg.min.100 g.ml-1 (P \textless 0.01). Thus the responses of Pcrit and Ra to an increase in Pper were dissociated. In a second part of the study, we lowered carotid sinus pressure to determine the effects of central factors on local autoregulation. A decrease in carotid sinus pressure increased Pcrit and Ra at each Pper (P \textless 0.05). We conclude that an increase in Pper causes the arterial vasculature to constrict at the level of the Starling resistor and dilate more proximally. The carotid baroreflex causes an increase in tone throughout the arterial vasculature but does not alter the local response to increases in Pper.
Abstract: OBJECTIVES: To evaluate whether a spontaneous increase in cerebral blood flow (CBF) could be observed in subjects with severe hypertension and to study the effect of a calcium antagonist, felodipine, on blood pressure and CBF after acute and chronic administration. DESIGN: Patients with severe hypertension were recruited at the emergency ward. Patients with previous treatment with calcium antagonists, women of child-bearing potential, severe uraemia, nephrotic syndrome, heart failure, manifest cerebrovascular lesions and pathological liver function tests were excluded. METHODS: CBF was measured by single-photon emission computed tomography after intravenous administration of xenon-133 before (CBF1) and after intravenous infusion of felodipine, 0.01 mg/min during 40-60 min (CBF2) in 12 patients aged 25-67 years with no antihypertensive treatment except for beta-blockers in four patients and beta-blockers plus a diuretic in one patient. CBF was repeated after 3 weeks of oral therapy with felodipine, 5-10 mg twice a day with the addition of beta-blockers in 10/12 patients (CBF3). RESULTS: During the felodipine infusion blood pressure decreased. There were no neurological symptoms or signs before or during the felodipine administration. CBF1 was within normal limits with no significant differences between previously treated and untreated patients. There was a non-significant tendency to increase in global CBF after felodipine administration, associated with a significant reduction in the physiological side differences in blood flow. CONCLUSIONS: In spite of the initially very high blood pressure, no general or focal hyperaemia was observed, and thus no evidence for a ’breakthrough’ of the cerebral autoregulation. Felodipine gives a smooth blood pressure reduction with a maintained CBF.
Abstract: Several recent observations suggest that atrial natriuretic peptides (ANP) can modulate steroidogenesis in isolated rat Leydig cells and in young men. Other observations suggest that catechol estrogen can inhibit prostaglandin (PGI2) release in the endothelium, and we had found that androgen can relieve angina pectoris and improve myocardial ischemia in elderly men with coronary heart disease (CHD), possibly through relieving coronary artery smooth muscle spasm. Because ANP and PGI2 are vasoactive peptides which regulate vasomotion, there must be an interaction between steroidogenesis hormones and vasoactive peptides. We evaluated the effects of androgen (Sustanon 250) administration on plasma ANP, PGI2 and thromboxane (TXA2) levels in elderly men with CHD. Thirty 60-75-year-old men with CHD received 250 mg (1 ml) Sustanon 250 injection, and 30 age- and sex-matched CHD patients received 1 ml saline. Plasma ANP, PGI2, TXA2, estradiol (E2) and testosterone (T) were determined before injection and 3 weeks thereafter. The results showed that Sustanon 250 administration increased plasma ANP levels, decreased TXA2 and increased PGI2 levels significantly, and thereby improved the TXA2/PGI2 imbalance in CHD patients (all P \textless 0.01). Meanwhile, serum T levels rose (P \textless 0.01), but E2 levels remained unchanged, and thus the E2/T ratio decreased (P \textless 0.05). Our findings demonstrate that androgen exerts its regulatory role by altering plasma ANP levels and the TXA2/PGI2 ratio.
Abstract: Maintenance of the ionic and osmotic composition and volume of intra- and extracellular fluids in the brain is crucial for normal functioning of the central nervous system (CNS). Osmoregulation in the CNS is mediated by solute and water transport across the blood-brain barrier, choroid plexus and plasma membrane of glial cells and neurons. Despite its clinical and physiological significance, however, little is known about the underlying cellular and molecular mechanisms by which CNS osmotic and ionic balance is maintained. In this review, I will discuss our current understanding of cell volume regulation in the CNS and how it relates to various disease processes, such as hyponatremia, renal failure and hypernatremia. A detailed understanding of brain osmoregulatory processes represents a fundamental physiological problem and is required for the treatment of numerous disease states, particularly those encountered in the practice of nephrology.
Abstract: The purpose of the present investigation was to examine coronary flow and vasodilator reserve in conscious, chronically instrumented dogs with pacing-induced heart failure, a model of severe biventricular cardiomyopathy devoid of significant hypertrophy. Twelve dogs were studied after 28 days of rapid right ventricular pacing and were compared with six sham-operated controls. Left ventricular (LV) average transmural flow was significantly less in conscious dogs with pacing-induced heart failure, whereas the endocardial-to-epicardial flow ratio was not significantly different. In response to near maximal coronary vasodilation with adenosine, subepicardial coronary flow and vasodilator reserve were preserved in congestive heart failure (CHF), yet there was evidence of impaired subendocardial flow and vasodilator reserve, and the endocardial-to-epicardial ratio was significantly less. When the markedly elevated LV end-diastolic pressure was normalized in heart failure, there was restoration of subendocardial coronary flow reserve and a normalization of the endocardial-to-epicardial ratio. Thus, in CHF, there is impaired coronary flow and vasodilator reserve that is selective to the subendocardium of the LV. At this point in the heart failure process, this impairment is not associated with structural changes but is a consequence of the marked elevation in LV end-diastolic pressure.
Abstract: Renal pressure-flow (P-F) relationships are usually evaluated by measuring effects of mechanically induced changes in renal arterial pressure (AP) on renal blood flow (RBF). We devised a method allowing evaluation of renal P-F relationships during normal changes in AP occurring spontaneously in a conscious animal rather than during artificially induced changes in AP. In 18 trials in 6 dogs standing at rest, we measured average AP and RBF for each cardiac cycle over periods of approximately 35 min (approximately 3,100 cardiac cycles/trial). AP and RBF values for each cardiac cycle were expressed as percent change (%delta) from the 35-min average (beat-to-beat changes). Slope and angle of each consecutive beat-to-beat P-F change were calculated and collated into one of eight zones representing the possible physiological mechanisms responsible for concurrent, spontaneous changes in RBF and AP. In a predominance of the cardiac cycles (approximately 43%), the spontaneous AP-RBF relationship was consistent with being mediated by arterial baroreflexes (i.e., increases in AP were accompanied by proportionately greater increases in RBF during 44.4% of cardiac cycles in which AP increased, and decreases in AP were accompanied by proportionately greater decreases in RBF during 41.4% of cardiac cycles in which AP decreased). Blockade of autonomic ganglionic transmission with hexamethonium markedly attenuated this pattern. Our results indicate that renal circulation participates in moment-to-moment control of AP via a predominant baroreflex-like pattern.
Abstract: We tested the effect of certain newly synthesized allosteric modifiers of hemoglobin on the dilation induced by arterial hypoxia, arterial hypotension, and arterial hypercapnia in cerebral arterioles of anesthetized cats equipped with cranial windows for the observation of the cerebral microcirculation. The allosteric modifiers of hemoglobin are isomers of 2-(aryloxy)-2-methylpropionic acid. They shift the oxygen dissociation of hemoglobin to the right, thereby facilitating the local release of oxygen. When these compounds were applied topically by superfusion at a rate of 1 ml/min in a concentration of 0.1 mM, they had no significant effect on baseline arteriolar diameter but reduced significantly the vasodilation from arterial hypoxia and arterial hypotension. They did not influence the vasodilation from arterial hypercapnia. Spectrophotometric measurements of optical densities from pial veins 50-80 microns in diameter indicated that the superfusion with the allosteric compounds reduced hemoglobin oxygen saturation both during room air breathing and during hypoxia. We conclude that the vasodilations from arterial hypoxia and arterial hypotension are mediated by local oxygen-dependent mechanisms. The allosteric modifiers of hemoglobin may be useful as tools in investigating oxygen-dependent mechanisms.
Abstract: The techniques of in vivo magnetic resonance (MR) imaging and spectroscopy have been established over the past two decades. Recent applications of these methods to study human brain function have become a rapidly growing area of research. The development of methods using standard MR contrast agents within the cerebral vasculature has allowed measurements of regional cerebral blood volume (rCBV), which are activity dependent. Subsequent investigations linked the MR relaxation properties of brain tissue to blood oxygenation levels which are also modulated by consumption and blood flow (rCBF). These methods have allowed mapping of brain activity in human visual and motor cortex as well as in areas of the frontal lobe involved in language. The methods have high enough spatial and temporal sensitivity to be used in individual subjects. MR spectroscopy of proton and carbon-13 nuclei has been used to measure rates of glucose transport and metabolism in the human brain. The steady-state measurements of brain glucose concentrations can be used to monitor the glycolytic flux, whereas subsequent glucose metabolism–i.e., the flux into the cerebral glutamate pool–can be used to measure tricarboxylic acid cycle flux. Under visual stimulation the concentration of lactate in the visual cortex has been shown to increase by MR spectroscopy. This increase is compatible with an increase of anaerobic glycolysis under these conditions as earlier proposed from positron emission tomography studies. It is shown how MR spectroscopy can extend this understanding of brain metabolism.
Abstract: Although much is known about fibrin polymerization, because it is complex, the effects of various modifications are not intuitively obvious and many experimental observations remain unexplained. A kinetic model presented here that is based on information about mechanisms of assembly accounts for most experimental observations and allows hypotheses about the effects of various factors to be tested. Differential equations describing the kinetics of polymerization were written and then solved numerically. The results have been related to turbidity profiles and electron microscope observations. The concentrations of intermediates in fibrin polymerization, and fiber diameters, fiber and protofibril lengths have been calculated from these models. The simplest model considered has three steps; fibrinopeptide A cleavage, protofibril formation, and lateral aggregation of protofibrils to form fibers. The average number of protofibrils per fiber, which is directly related to turbidity, can be calculated and plotted as a function of time. The lag period observed in turbidity profiles cannot be accurately simulated by such a model, but can be simulated by modifying the model such that oligomers must reach a minimum length before they aggregate. Many observations, reported here and elsewhere, can be accounted for by this model; the basic model may be modified to account for other experimental observations. Modeling predicts effects of changes in the rate of fibrinopeptide cleavage consistent with electron microscope and turbidity observations. Changes only in the rate constants for initiation of fiber growth or for addition of protofibrils to fibers are sufficient to account for a wide variety of other observations, e.g., the effects of ionic strength or fibrinopeptide B removal or thrombospondin. The effects of lateral aggregation of fibers has also been modeled: such behavior has been observed in turbidity curves and electron micrographs of clots formed in the presence of platelet factor 4. Thus, many aspects of clot structure and factors that influence structure are directly related to the rates of these steps of polymerization, even though these effects are often not obvious. Thus, to a large extent, clot structure is kinetically determined.
Abstract: Our purpose was to test the hypothesis that human aging alters sympathoadrenal-circulatory control of arterial blood pressure during orthostasis. Plasma catecholamine and hemodynamic adjustments to two different forms of orthostatic stress, lower body suction (-10 to -50 mmHg) and standing, were determined in 14 young (26 +/- 1 yr) and 13 older (64 +/- 1) healthy, normally active men. During quiet supine rest, cardiac output tended to be lower and systemic vascular resistance higher in the older men, but no other differences were observed. On average, arterial blood pressure was well maintained during both forms of orthostasis in the two groups; the older men actually demonstrated better maintenance of pressure (P \textless 0.05) and a lesser incidence of orthostatic hypotension than the young men during lower body suction. Despite a blunted reflex tachycardia during orthostatic stress (P \textless 0.05), cardiac output tended to decrease less in the older men because of a smaller decline in stroke volume (P \textless 0.05, suction only), whereas the reflex increases in systemic vascular resistance were not different in the two groups. The whole forearm vasoconstrictor response tended to be attenuated in the older men during lower body suction, but was identical in the two groups with standing. Forearm skin vascular resistance was unaltered during lower body suction in both groups. Orthostasis-evoked increases in antecubital venous plasma norepinephrine concentrations were similar in the young and older men, whereas little or no increases in plasma epinephrine concentrations were observed in either group.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: This study was designed to determine how several factors interact to modify the cerebral ischemic pressor response (CIR) in anesthetized rabbits. After the carotid sinus and aortic nerves were bilaterally sectioned, blood flow through the left internal carotid artery (ICF), which was surgically restricted as the sole route of blood supply to the brain, was reduced by a servo-controller during ventilation with room air, and 8% and 90% O2 and 2 and 5% CO2 gas mixtures. Blood flow (MBF), tissue PO2, PCO2, and interstitial pH were measured in the rostral ventrolateral medulla. Internal carotid arterial pressure, tissue PO2, and MBF decreased proportionately as ICF decreased in the range from 4 to 0 ml/min. Hypoxia significantly increased the rise in renal nerve activity (RNA) and CIR caused by cerebral ischemia, while hyperoxia significantly decreased them. Hypercapnia had almost no influence on the increases in RNA and mean arterial pressure produced by cerebral ischemia. CIR showed a much higher correlation with changes in tissue PO2 than with the other factors. We examined how these factors interact to modify CIR and found that central hypoxia is the main factor in producing CIR.
Abstract: Cerebral cell volume regulatory mechanisms are activated by sustained disturbances in plasma osmolality. Acute hypernatremia causes a predictable shrinkage of brain cells due to the sudden imposition of a plasma-to-cell osmolal gradient. However, during chronic hypernatremia cerebral cell volume is maintained close to the normal range as a result of the accumulation of electrolytes and organic osmolytes including myo-inositol, taurine, glutamine, glycerophosphorylcholine, and betaine. The increased cytosolic level of these molecules is generally accomplished via increased activity of sodium (Na+)-dependent cotransport systems. The slow dissipation of these additional osmotically active solutes from the cell during treatment of hypernatremia necessitates gradual correction of this electrolyte abnormality. Acute hyponatremia leads to cerebral cell swelling and severe neurological dysfunction. However, prolonged hyponatremia is associated with significant reductions in brain cell electrolyte and organic osmolyte content so that cerebral cell volume is restored to normal. While acute hyponatremia can be treated with the administration of moderate doses of hypertonic saline in order to control seizure activity, chronic hyponatremia should be corrected slowly in order to prevent subsequent neurological deterioration. If the rate of correction exceeds 0.5 mmol/l per hour, or if the total increment in serum [Na+] exceeds 25 mmol/l in the first 48 h of therapy, then there is an increased risk of the development of cerebral demyelinating lesions. Chronic hyperglycemia activates the brain cell volume regulatory adaptations in the same manner as hypernatremia. Therefore, during the treatment of diabetic ketoacidosis, it is imperative to restore normoglycemia gradually in order to prevent the occurrence of cerebral edema.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Twenty-seven patients in cardiopulmonary arrest had simultaneous measurements of arterial and central venous blood gases during cardiopulmonary resuscitation (CPR) with a pneumatic chest comparison and ventilation device. Mean central venous and arterial hydrogen ion concentrations, PCO2 and calculated bicarbonate concentrations were significantly different (P less than 0.01) at all sampling times (0, 10 and 20 min). Central venous blood samples predominantly showed a respiratory acidosis in contrast to a mixed disturbance in arterial samples inclined towards a metabolic acidosis. The mean difference between central venous PCO2 (pcv CO2) and arterial PCO2 (pa CO2) ranged from 5.18 to 5.83 kPa reflecting the low blood flow in patients undergoing CPR. Measurement of arterial Po2 indicated adequate oxygenation using the pneumatic device. Arterial blood gas analysis alone does not reflect tissue acid base status. Bicarbonate administration during CPR may have adverse effects and any decision as to its use should be based on central venous blood gas estimations.
Abstract: Rat C6 glial cells undergo rapid regulatory volume increase (5-10 min) via electrolyte uptake when exposed to a hypertonic medium. With chronic exposure to hypertonicity (greater than 8 h), accumulated electrolyte is replaced partly by inositol. Inositol accumulation is brought about by upregulation of Na(+)-dependent inositol transport. When C6 cells acclimated chronically to hypertonic NaCl medium were returned to isotonic conditions, inositol levels dropped slowly from 478 nmol/mg protein towards control values (117 nmol/mg protein) in 18-24 h. Inositol loss occurred in part by efflux to the external medium via a pathway distinct from the uptake mechanism. Laser light-scattering measurements demonstrated that regulatory volume decrease (RVD) is slow under these experimental conditions. In contrast, cells exposed acutely to hypertonicity swell and then undergo a rapid and nearly complete RVD when returned to isotonic medium. These results suggest that slow inositol loss is rate limiting for RVD during recovery from chronic hypertonic stress. The slow inositol loss and RVD may be due to slow turnover of the efflux mechanism and/or slow downregulation of the hypertonically stimulated inositol uptake pathway.
Abstract: During peritoneal dialysis, fluid is transported out of the peritoneal cavity by lymphatic and nonlymphatic pathways, thereby decreasing net ultrafiltration by 40-50% and reducing small solute clearance by 15-20%. The direct lymphatic pathway consists of the diaphragmatic lymphatics, which directly connect the peritoneal cavity to the bloodstream. The interstitial lymphatic and direct blood entry pathways convey fluid that has been driven into the interstitial space of the tissue surrounding the peritoneal cavity by the increased intraperitoneal pressure, and return it to the bloodstream. Since flow through lymphatic pathways is only a portion of the flow through all pathways, total fluid loss is greater than lymph flow. The best technique for estimating lymph flow is direct measurement by cannulation of lymphatic vessels, a technique that is not clinically feasible. The tracer disappearance technique, which measures the rate at which macromolecules leave the peritoneal cavity, is an indirect measure of fluid loss. The tracer appearance technique, which measures the rate at which macromolecules reach the blood from the peritoneal cavity, slightly overestimates lymph flow because some tracer may enter the bloodstream directly from the tissues. Much of the previous controversy over the contribution of the lymphatic pathways to total fluid loss can be resolved by understanding the differences in what these techniques measure.
Abstract: In the presence of Cl-, K+ secretion by the distal tubule saturates with increasing luminal Na+ concentration. Apparent maximal K+ secretion is attained with luminal Na+ concentrations of 40 mM. The results of the present study show that lowering the Cl- concentration of luminal fluid can increase the level of Na(+)-stimulated K+ secretion beyond the maximal level attained in the presence of Cl-. The effect of lowering luminal Cl- concentration to less than 10 mM on K+ secretion is greater with higher Na+ concentration. Under these conditions, chlorothiazide decreases K+ secretion. When chlorothiazide is present, changing the Na+ concentration does not affect K+ secretion. Because in rats a thiazide effect is attributed primarily to the distal convoluted tubule (DCT), we postulate that it is primarily DCT cells that increase K+ secretion when Na+ concentration is raised in the presence of low luminal Cl- concentration. We propose that the rat DCT cells have both an absorptive Na(+)-Cl- cotransport mechanism and a secretory K(+)-Cl- cotransport mechanism in the luminal membrane that can mediate the apparent exchange of Na+ for K+.
Abstract: The authors describe evidence of communication between the two pleural cavities after major cardiothoracic surgery (combined heart and lung transplantation, heart transplantation, and correction of complex congenital heart disease) performed in three patients. In two patients, unilateral lung biopsy caused a symptomatic bilateral pneumothorax. This was successfully treated with insertion of a single chest tube in one patient and two chest tubes in the other patient. In the third patient, simultaneous evacuation of large bilateral pleural effusions was performed by means of unilateral thoracentesis because of the presence of a common pleural cavity.
Abstract: Systemic acidemia may impair cardiac contractility and predispose to arrhythmias. Moreover, bicarbonate treatment may further depress cardiac performance and increase mortality. Whether changes in myocardial intracellular pH or energy metabolism underlie this diminished performance has not been clarified in the in vivo setting. Thus we investigated the effect of lactic acidosis and two proposed treatments on myocardial energetics and intracellular pH in anesthetized living rats. A previously validated 31P-labeled nuclear magnetic resonance (31P-NMR) spectroscopic technique using saturating pulses was used to follow myocardial intracellular pH, phosphocreatine (PCr), ATP, and inorganic phosphate (Pi). After obtaining baseline values, we infused lactic acid to achieve a level greater than 5 mM. We then added an infusion of either bicarbonate (n = 7) or saline (n = 5). During lactic acid infusion, arterial pH declined (from 7.27 to 7.07, P less than 0.0001), but myocardial intracellular pH did not change (7.13 vs. 7.07, P not significant). The ratio of PCr to Pi, however, decreased with acidemia (from 3.13 to 2.24, P = 0.004), suggesting impaired energy metabolism. Compared with saline, bicarbonate infusion restored systemic pH (from 7.08 to 7.29), but myocardial pH was unaltered. In addition, PCr/Pi declined further following bicarbonate treatment (1.41 vs. 2.42, P = 0.08) but not following saline. Thus, despite reversal of systemic acidemia, bicarbonate treatment was associated with more severe impairment of energy metabolism than saline. This suggests a mechanism for previously reported adverse cardiac effects of bicarbonate treatment.
Abstract: The possibility that spontaneous oscillations in microvessel caliber, called vasomotion, arise from the activity of the local myogenic mechanism is analyzed in this work using an original mathematical model. According to experimental results, the model assumes that the myogenic response in microcirculation (transverse arterioles and terminal precapillary-postcapillary microvessels) is characterized by both a static and a dynamic (i.e., rate-dependent) component. Computer simulations demonstrate that the myogenic mechanism of action, thanks to its strong rate-dependent component in terminal arterioles, can produce vascular instability and oscillations of vessel caliber without the need to assume the existence of a local pacemaker in smooth muscle cells. Moreover, these oscillations turn out similar, both in frequency and in shape, to those experimentally observed in microvascular networks. Finally, according to experimental data, several kinds of vasodilatory stimuli (such as arterial hypotension, increase in the tissue metabolic rate, and postischemic reactive hyperemia) cause stoppage of vasomotion and stabilization of vessel caliber.
Abstract: Voluntary wheel running induces an increase in the concentration of the regulatable glucose transporter (GLUT4) in rat plantaris muscle but not in soleus muscle (K. J. Rodnick, J. O. Holloszy, C. E. Mondon, and D. E. James. Diabetes 39: 1425-1429, 1990). Wheel running also causes hypertrophy of the soleus in rats. This study was undertaken to ascertain whether endurance training that induces enzymatic adaptations but no hypertrophy results in an increase in the concentration of GLUT4 protein in rat soleus (slow-twitch red) muscle and, if it does, to determine whether there is a concomitant increase in maximal glucose transport activity. Female rats were trained by treadmill running at 25 m/min up a 15% grade, 90 min/day, 6 days/wk for 3 wk. This training program induced increases of 52% in citrate synthase activity, 66% in hexokinase activity, and 47% in immunoreactive GLUT4 protein concentration in soleus muscles without causing hypertrophy. Glucose transport activity stimulated maximally with insulin plus contractile activity was increased to roughly the same extent (44%) as GLUT4 protein content in soleus muscle by the treadmill exercise training. In a second set of experiments, we examined whether a swim-training program increases glucose transport activity in the soleus in the presence of a maximally effective concentration of insulin. The swimming program induced a 44% increase in immunoreactive GLUT4 protein concentration. Glucose transport activity maximally stimulated with insulin was 62% greater in soleus muscle of the swimmers than in untrained controls. Training did not alter the basal rate of 2-deoxyglucose uptake.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Addition of 5 mM sodium azide to Clone 9 cells, a rat liver cell line characterized by intracellular glucose concentrations of less than 10% that of the external medium and limited glycogen stores, results in a 50-80% reduction in cell ATP content within 20 min which then recovers to near-basal levels within 1 h and is subsequently maintained at normal levels for 24 h despite continuing the presence of the inhibitor. Associated with this adaptive response is a striking stimulation of facilitated glucose transport, mediated by the GLUT-1 transporter, that exhibits "early" and "late" phases that appear to be mechanistically different. During the early phase of the response (0-2 h), glucose transport rate is enhanced 12-fold in the absence of any change in cell GLUT-1 or GLUT-1 mRNA content. In contrast, the late phase of the response (8-24 h) is characterized by a further large stimulation of glucose transport (to 1.6 times the 2-h value) that is associated with 2- to 3- and 6- to 10-fold increments in cell GLUT-1 and GLUT-1 mRNA content, respectively. In time course studies an increase in GLUT-1 mRNA content was observed at 4 h and preceded the increment in GLUT-1 which became detectable after 8 h of exposure to azide. A marked induction of GLUT-1 mRNA by azide was also demonstrable in cells incubated in medium containing higher concentrations of glucose (10.6 mM), although the increment was approximately 20% less than when cells were incubated in standard medium (containing 5.6 mM glucose).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: To determine the impact of i.v. endothelin-1 on systemic, pulmonary and splanchnic circulation, as well as the peptide’s regional clearance, hepatic venous and right heart catheterization was performed in healthy volunteers. During the peptide’s continuous i.v. administration (0.4 pmol x kg-1 x min-1, 60 min) its plasma concentration rose from 2.1 +/- 0.5 to 9.5 +/- 5.3 pmol/l (pulmonary artery), from 2.1 +/- 0.9 to 5.0 +/- 1.6 pmol/l (femoral artery), and from 1.5 +/- 0.6 to 2.9 +/- 1.2 pmol/l (hepatic vein). This was accompanied by an increase in mean systolic arterial pressure from 127 +/- 14 to 131 +/- 12 mmHg (P less than 0.05). Concomitantly, cardiac output and heart rate decreased from 7.0 +/- 1.1 to 5.8 +/- 1.0 l/min and from 63 +/- 6 to 56 +/- 5 beats/min, respectively, while total vascular resistance increased from 964 +/- 273 to 1204 +/- 338 dyn x cm x s-5 (P less than 0.01). No major changes in pulmonary circulation were observed, while splanchnic vascular resistance increased from 4472 +/- 1056 to 5361 +/- 1420 dyn x cm x s-5 (P less than 0.01) and estimated hepatic blood flow decreased from 1403 +/- 218 to 1218 +/- 219 ml min-1 (P less than 0.01). During endothelin-1 infusion the pulmonary vascular bed accounted for approximately 53% of the peptide’s overall disposal.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Portable power tools and appliances can be identified as the source of injury in approximately 9% of occupational electrocutions. A search of fatality records for 1984 through 1986 in National Institute for Occupational Safety and Health (NIOSH) and Occupational Safety and Health Administration (OSHA) data bases identified 102 electrocutions involving portable appliances and tools that used 110-volt AC and 33 deaths involving welding equipment, which usually operates on 220-volt AC or higher. Of these 102 deaths, 51 occurred in the construction industry, 13 in services, 13 in manufacturing, and 25 in other industries. Plumbing contractors (Standard Industrial Classification [SIC] 1711) had the largest number of deaths (15) in construction. Powered hand-tools were involved in 58 deaths, with electric drills (23) and saws (13) the two largest classes. Proper provision of ground-fault circuit interrupter protection, particularly at temporary work sites, could have prevented most of the deaths from 110-volt AC. Engineering controls for preventing electrocution from portable arc-welding equipment should be evaluated.
Abstract: Proximal tubular pressure, glomerular filtration rate, and early distal tubule Cl- oscillate at 35 mHz in normotensive rats because of tubuloglomerular feedback (TGF); the oscillation bifurcates to chaos in spontaneously hypertensive rats (SHR). To examine the importance of TGF-initiated vascular interactions between nephrons in these dynamics, we measured tubular pressure simultaneously in two or more nephrons. The oscillations were synchronized in nephrons supplied by a common cortical radial artery. The correlation coefficient of pressure records from coupled nephrons was 0.86 +/- 0.02. Intratubular furosemide perfusion diminished the oscillation in both the perfused and the coupled nephron; total autospectral power in each of the nephrons and cross-spectral power were reduced to 45% of control. The correlation between noncoupled nephrons was not significant, and intratubular furosemide perfused in one nephron had no effect on adjacent but noncoupled nephrons. In SHR, the correlation coefficient of tubular pressure records was high from coupled nephrons only; furosemide diminished the autospectral power of pressure fluctuations to approximately 60-75% of control in both perfused and coupled nephrons, and cross-spectral power was affected by a similar amount. Nephron-nephron interactions, specific to vascular connectivity, persist in SHR and appear to be stronger than in normotensive rats.
Abstract: The local influence of sympathetic stimulation on the cerebral circulation during acute hypertension was investigated in anesthetized rats. From initial studies, intravenously administered angiotensin II was selected as the pressor agent. Local cerebral blood flow was measured with [14C]iodoantipyrine autoradiography during 1) unilateral electrical stimulation of the superior cervical ganglion plus moderate hypertension [mean arterial blood pressure (MABP) 162 +/- 2 mmHg], 2) unilateral stimulation plus severe hypertension (MABP 177 +/- 4 mmHg), and 3) unilateral preganglionic sympathetic nerve section (denervated) plus severe hypertension (MABP 186 +/- 4 mmHg). During moderate hypertension, blood flow was rather homogeneous and sympathetic stimulation produced modest (7-15%) regionally specific reductions in flow ipsilateral to the stimulation (P less than 0.05). During severe hypertension: 1) focal areas of marked hyperemia occurred throughout the brain, 2) local blood flow was similar within innervated and denervated hemispheres, and 3) with sympathetic stimulation the volume of hyperemic tissue was reduced ipsilaterally and blood flow was decreased by 7-25% in areas of basal ganglia, cerebral cortex, limbic system and thalamus. To conclude, 1) the local cerebral autoregulatory response is highly dependent on whether the area becomes hyperperfused and 2) sympathetic stimulation decreases brain blood flow by modestly reducing local tissue perfusion and by lessening the volume of extreme hyperemia.
Abstract: In several species, the ovulatory LH surge is preceded by a surge of GnRH. Although a role for estradiol in the initiation of the LH surge is well established in the primate, several observations in the rhesus monkey have questioned whether such an estradiol-induced neurosecretory event takes place. We report on GnRH measurements in cerebrospinal fluid (CSF) samples obtained from the third ventricle of intact and ovariectomized (OVX) conscious rhesus monkeys during control periods and throughout the estradiol-induced positive feedback phase. In the first experiment, we measured control GnRH concentrations in CSF collected at 15-min intervals uninterruptedly for a period of 1-5 days in tethered OVX monkeys (n = 4) in their cages without steroid priming. As had been demonstrated previously with the same method in restrained animals, CSF from the third ventricle contained detectable amounts of GnRH. Spontaneous GnRH secretion was pulsatile; overall mean pulse interval was 67.4 (+/- 2.2 SE) min for a total of 177 GnRH pulses. During 2 periods (8 and 6 h) when simultaneous blood and CSF samples were obtained, 14 out of 15 GnRH pulses were accompanied by an LH pulse. To evaluate the effects of an estrogen challenge on GnRH secretion, estradiol benzoate (E2B; 330 micrograms) was given to 4 intact (5 experiments) and to 2 OVX monkeys. CSF collection was initiated 8-24 h before E2B injection and continued for 72-84 h thereafter. E2B administration resulted in a surge of LH and of GnRH in all but one experiment. The mean time of onset of the GnRH surge was 22.0 (+/- 4.0) h after E2B, whereas that of the LH surge was 24.7 (+/- 3.4) h. In contrast to LH, which declined after a peak at 35.2 +/- 3.9 h, the increase in GnRH secretion persisted throughout most of the observation period. The magnitude of the GnRH response differed in the 2 groups; in the intact animals, mean peak GnRH concentration increased 8.9-fold but only 3.8-fold in the OVX monkeys. A similar GnRH surge was observed in 1 OVX monkey, receiving an iv infusion of E2, which produced more physiological concentrations of E2. In this animal, an initial suppression of GnRH concentration in the 24-48 h period after E2 (GnRH control, 14.6 +/- 1.9; post-E2, 4.0 +/- 0.5 pg/ml) preceded the initiation of the GnRH surge which occurred at 54 h after E2.(ABSTRACT TRUNCATED AT 400 WORDS)
Abstract: 1. Renin synthesis and secretion were studied in Balb/c mice with a denervated left kidney. 2. Denervation inhibited renin secretion. 3. Denervation reduced the renal renin content. 4. Denervation reduced renal renin mRNA. 5. Renal denervation inhibits renin secretion by blocking the synthetic system prior to mRNA formation.
Abstract: 1. The effects of change from a high to low sodium diet upon renal sodium and water excretion and hormone responses were studied in patients with dissociated sympathetic control (DS, tetraplegic) and controls with sympathetic control largely intact (IS, paraplegic). 2. Total and fractional urinary sodium excretion fell in response to sodium restriction in both groups, but the fall in fractional sodium excretion was greater in the DS group compared with the IS group (DS, 1.34 +/- 0.12 to 0.42 +/- 0.05%; IS, 0.96 +/- 0.08 to 0.52 +/- 0.06%). 3. Supine mean arterial pressure fell during the low salt period in the DS group (80.2 +/- 2.7 to 74.4 +/- 2.3 mmHg) but was unaffected by salt restriction in the IS group (101 +/- 2.3 to 98.8 +/- 2.7 mmHg). In the DS group, creatinine clearance remained constant throughout the low salt period (103.7 +/- 7.9 to 98.3 +/- 9.7 ml min-1), but fell during salt restriction in the IS group (101.4 +/- 8.5 to 83.2 +/- 5 ml min-1). 4. Plasma renin activity was lower during salt loading in DS subjects but increased more rapidly and to higher levels in response to salt restriction (DS, 1021 +/- 142 to 4439 +/- 355; IS, 1765 +/- 269 to 3683 +/- 465 pg angiotensin I ml-1 h-1). Plasma atrial natriuretic peptide concentration was higher in the DS group during salt loading and salt restriction (DS, 37.6 +/- 5.6 to 22 +/- 3.8; IS, 20.2 +/- 2.3 to 11 +/- 1.6 pg ml-1).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: The objective of the present study was to elucidate the dynamics of parathyroid hormone regulation, with particular reference to the mechanism controlling the acute parathyroid hormone release. Through utilization of the citrate clamp technique and the calcium clamp technique we were able, in a standardized way, to stimulate and suppress the parathyroid hormone secretion. Precise bedside measurements of blood ionized calcium and measurements of intact parathyroid hormone were performed. Twelve healthy young volunteers participated in two trials 6-12 wk apart, a citrate clamp (delta-blood ionized calcium -0.19 mmol/l) and a calcium plus citrate clamp (delta-blood ionized calcium +0.22 mmol/l and -0.19 mmol/l). During the citrate clamp, preceded by normal calcemia, serum intact parathyroid hormone peaked to a maximum after 5-10 min, four to six times above baseline concentration and then declined to a steady state two to three times above baseline concentration. During the citrate clamp, preceded by hypercalcemia induced by a calcium clamp, serum intact parathyroid hormone also peaked immediately to about five to nine times above its suppressed level, approximately two times above the baseline concentration. Subsequently, serum intact parathyroid hormone declined to a steady state just below the baseline concentration. In conclusion, within the range studied, the mechanism eliciting the acute serum intact parathyroid hormone release from its depot is a fall in blood ionized calcium, not the absolute concentration of ionized calcium.
Abstract: Previous studies have demonstrated that renal nerve activity has acute effects on renal function in rats with cervical spinal cord transection (CST). The present study tested the hypothesis that renal nerves chronically influence renal and cardiovascular function in CST rats. Three groups of conscious Sprague-Dawley rats were studied: renal denervated plus CST (RDNX + CST), sham RDNX plus CST (sham + CST), and sham RDNX plus sham CST (intact). CST or sham CST surgeries were performed 8 days after RDNX or sham RDNX. Sodium and water intakes were fixed by intravenous infusion. Mean arterial pressure (MAP) and plasma renin activity (PRA) were measured before and for 9 days after CST/sham CST. In addition, urine flow, urinary sodium excretion, and urine pH were measured in the two groups of CST rats. One day after CST, MAP decreased approximately 25 mmHg in both RDNX + CST and sham + CST groups. PRA had fallen approximately 50% 1 day after CST and was not different between CST groups. PRA remained depressed throughout the study. There were no differences between sham + CST and RDNX + CST rats in any of the renal or cardiovascular variables measured after CST. In summary, we found no evidence for a chronic effect of renal nerves on renal function or arterial pressure in CST rats.
Abstract: Hypothalamic hormones as well as anterior pituitary hormones were detected in the peripheral plasma after the diagnosis of brain death. It is possible that residual hypothalamic tissue was functioning after satisfying the usual criteria of total brain death. To examine this possibility, endocrinological and morphological alterations of the hypothalamic-pituitary system was evaluated in 28 brain dead patients. Intrinsic ADH was depleted in the plasma shortly after the diagnosis of brain death. Anterior pituitary hormones were initially detected in all patients, but gradually disappeared. The direct TRH (thyrotropin releasing hormone) stimulation to the anterior lobe was responded to well. Morphological studies showed a partial necrosis of the anterior lobe and the preservation of the posterior lobe for as long as a week. These data prove that the pituitary is partially preserved after brain death. LH-RH (luteinizing hormone releasing hormone) was detected in the peripheral plasma of all patients and GRF (growth hormone releasing factor) was detected in half of the patients for as long as 15 days, but autopsy revealed the fact that the brain tissue including the hypothalamus became extensively necrotic after the sixth day of brain death. In order to solve this controversy it is proposed that these hormones originate from extracranial tissues such as pancreas. The detection of hypothalamic hormones after the diagnosis of brain death therefore is not contradictory to the concept of total brain death.
Abstract: The mechanism for cardiovascular deconditioning and skeletal muscle atrophy during microgravity is not known. The purpose of the present study was to determine whether a decrease in contractile protein gene expression in the muscle of rats occurred after 14 days of microgravity. No differences existed in the profile of myosin protein isoforms or beta-myosin heavy chain mRNA in hearts between the flight and synchronous control groups. On the other hand, differences in the expression of beta-myosin heavy chain mRNA relative to the 18S and 28S rRNA in the heart between flight and synchronous control groups were noted with a covariance mapping analysis. Both the vastus intermedius and lateral gastrocnemius muscles exhibited significant (P less than 0.05) decreases in skeletal alpha-actin mRNA per unit of extractable RNA in the flight group compared with the synchronous control group. However, no significant difference for skeletal alpha-actin mRNA occurred in the triceps brachii muscle between these groups. Cytochrome c mRNA per unit of extractable RNA decreased (P less than 0.05) only in the vastus intermedius but not in the lateral gastrocnemius or triceps brachii muscles. In summary, changes in the pretranslational regulation of contractile protein gene expression occur in both heart and skeletal muscle after 14 days of microgravity.
Abstract: The network of lymphatic capillaries of the human skin was depicted at the distal part of the tibial plateau by fluorescence microlymphography (fluorescein isothiocyanate-dextran 150,000). Intralymphatic pressure was determined in 28 lymphatic capillaries of 21 healthy volunteers (mean diameter 56.0 +/- 10.0 microns) by a servo-nulling pressure system. It averaged 4.0 +/- 4.5 mmHg (range: -6.8 to +10.7 mmHg). These are the first measurements of pressure in the initial lymphatics of human skin and form a basis with which to compare measurements made in patients with different forms of edema.
Abstract: The development of atrial fibrillation in 2 patients, following an electrical shock is reported. One patient, with an underlying pre-excitation syndrome, had to be cardioverted due to rapid ventricular rate and hypotension. The other, with normal conduction, tolerated the arrhythmia well and atrial fibrillation reverted spontaneously after 24 hours.
Abstract: It is well-known that cardiac function in cerebrally dead patients rapidly deteriorates, leaving the organ unfit for donation. This study investigated whether or not cardiac function in patients with cerebral death can be maintained in a desirable condition with hormonal supplementation. In studies of changes in hormones before and after cerebral death, insulin, glucagon, triiodothyronine, thyroxine, cortisol, vasopressin, epinephrine, and norepinephrine values were measured with a lapse of time after cerebral death. Among them, triiodothyronine and cortisol levels were markedly reduced after cerebral death; therefore, these two hormones were selected as hormonal supplements. The average period from the judgment of cerebral death to cardiac arrest was 4.3 days in 12 patients with no hormonal supplement (group I) and more than 11.5 days in 4 patients with hormonal supplement (group II). This period for patients in group II was significantly longer (p less than 0.05). In 2 of the group II patients the hormonal supplementation was discontinued at the family’s request, and in the other 2 patients, it was discontinued because of proposed renal donation. Hemodynamic comparisons between the two groups showed that the mean arterial pressure and the left ventricular maximum dp/dt were significantly higher (p less than 0.01) as was the cardiac index (p less than 0.05) on the 3rd day after cerebral death in members of group II. Thereafter, in group II, an excellent hemodynamic state was maintained until hormonal supplements were discontinued. We conclude that the triiodothyronine and cortisol supplements were effective in the maintenance of cardiac function in patients after cerebral death.
Abstract: The continuous measurement of jugular venous oxygen saturation (SjvO2) with a fiberoptic catheter is evaluated as a method of detecting cerebral ischemia after head injury. Forty-five patients admitted to the hospital in coma after severe head injury had continuous and simultaneous monitoring of SjvO2, intracranial pressure, arterial oxygen saturation, and end-tidal CO2. Cerebral blood flow, cerebral metabolic rates of oxygen and lactate, arterial and jugular venous blood gas levels, and hemoglobin concentration were measured every 8 hours for 1 to 11 days. Whenever SjvO2 dropped to less than 50%, a standardized protocol was followed to confirm the validity of the desaturation and to establish its cause. Correlation of SjvO2 values obtained by catheter and with direct measurement of O2 saturation by a co-oximeter on venous blood withdrawn through the catheter was excellent after in vivo calibration when there was adequate light intensity at the catheter tip (176 measurements: r = 0.87, p less than 0.01). A total of 60 episodes of jugular venous oxygen desaturation occurred in 45 patients. In 20 patients the desaturation value was confirmed by the co-oximeter. There were 33 episodes of desaturation in these 20 patients, due to the following causes: intracranial hypertension in 12 episodes, hypocarbia in 10, arterial hypoxia in six, combinations of the above in three, systemic hypotension in one, and cerebral vasospasm in one. The incidence of jugular venous oxygen desaturations found in this study suggests that continuous monitoring of SjvO2 may be of clinical value in patients with head injury.
Abstract: Little published information exists regarding the magnitude and time course of cephalad fluid shift resulting from microgravity simulations. Six subjects were exposed to 150 min each at horizontal bed rest, 6 degrees head-down tilt, and horizontal water immersion. Fluid shift was estimated by calculating leg volumes from eight serial girth measurements from groin to ankle before, during, and after exposure. Results were compared with data from the first 3 h of spaceflight. By the end of exposure, total leg volume for the six subjects decreased by 2.6 +/- 0.8%, 1.7 +/- 1.2%, and 4.0 +/- 1.6% for horizontal, head-down, and immersion, respectively. Changes had plateaued for horizontal and head-down and had slowed for immersion. Relatively more fluid was lost from the lower leg than the thigh for all three conditions, particularly head-down. During the first 3 h of spaceflight, total leg volume decreased by 8.6%, and relatively more fluid was lost from the thigh than the lower leg. The difference in volume changes in microgravity and simulated microgravity may be caused by the small transverse pressures still present in ground-based simulations and the extremely nonlinear compliance of tissue.
Abstract: A review is given of the normal regulation of cerebral blood flow (CBF) and its pathophysiology in hypertension and stroke. In otherwise healthy hypertensive patients, the absolute level of CBF is the same as in normal subjects. CBF autoregulation, however, is shifted towards higher pressure, thus impairing the tolerance to hypotension. In most patients, this does not interfere with the beneficial effect of treatment, i.e., stroke prevention. Cerebral ischemia, however, may be provoked by overzealous pressure lowering in selected clinical settings: initial or intensified treatment of very severe hypertension, treatment of hypertension in the elderly, and treatment of hypertension in acute stroke. In the latter, a complicated sequence of brain ischemia and hyperemia makes antihypertensive intervention difficult in the early phase, when blood pressure is probably best allowed to decrease spontaneously.
Abstract: This study investigates whether walking or running prevents the formation of edema in the lower leg. In 18 volunteers changes in calf volume were measured using strain gauge plethysmography during slow (3 km/h) and fast (6 km/h) walking or running (10 km/h) on a treadmill for 20 min each. Venous pressure was measured in a superficial vein near the ankle. Low-pass filtering removed motion artifacts from the signals. Slow walking reduced the calf volume in a biphasic manner: a rapid decrease was followed by a slow decline, lasting from about minute 2 to minute 20, its mean rate being -0.073%/min. Besides a rapid initial decrease, no significant change was observed during fast walking. During running, the calf volume first increased within 7 min to a maximum of 2.5% and subsequently decreased with a mean rate of -0.096%/min. The medians of venous pressure were 84.0, 23.5, 30.4, and 29.5 mmHg during quiet standing, slow and fast walking, and running, respectively. The experimental results prove the hypothesis that walking prevents dependent edema formation. This effect, however, cannot be fully explained by the lowered venous pressures.
Abstract: The ability of human skeletal muscle to provide anaerobically derived ATP during short-term, intense activity is examined. The paper emphasizes the information obtained from direct measurements of substrates, intermediates, and products of the pathways in muscle that provide anaerobically derived ATP. The capacity of muscle to provide ATP via anaerobic pathways is approximately 370 mmol/kg dry muscle (dm) during dynamic exercise lasting approximately 3 min. Anaerobic glycolysis provided approximately 80%, phosphocreatine (PCr) degradation approximately 16%, and depletion of the ATP store approximately 4% of the total ATP provided. When the blood flow to the working muscles is reduced or occluded, the anaerobic capacity decreases to approximately 300 mmol/kg dm. This reduction is due to a lower glycolytic capacity associated with an inability to remove lactate from the muscles. Directly measured maximal rates of anaerobically derived ATP provision from PCr degradation and glycolysis during intense muscular activity are each approximately 9-10 mmol.kg-1 dm.s-1. Evidence suggests that both of these pathways are activated instantaneously at the onset of maximal activity. Spring training does little to the capacity or rates of the pathways, although a 10-20% increase in glycolytic ATP provision has been reported. The only study comparing direct and indirect estimates of the anaerobic capacity in humans suggests that O2 deficit measured at the mouth accurately predicts the anaerobic capacity of a single muscle group and that O2 debt does not. There are many unresolved issues regarding the capacity of the PCr and glycogenolytic–glycolytic systems to provide ATP during short-term intense muscular activity in humans.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: The influence of combined replenishment of L-3,5,3’-triiodothyronine (T3) and vasopressin (antidiuretic hormone [ADH]) on both hepatic metabolism and systemic hemodynamics was assessed in brain-dead dogs. Arterial ketone body ratio (AKBR) was measured as a parameter of hepatic metabolism, which reflects the redox state (free nicotinamide adenine dinucleotide/reduced nicotinamide adenine dinucleotide) of liver mitochondria. Mean arterial blood pressure (MAP) was significantly decreased from 110.4 +/- 3.8 to 44.4 +/- 1.7 mmHg, at 1 hr after completion of brain death (P less than 0.01). In the control group AKBR was maintained thereafter at near control value of 1.0 with a significant decrease in serum lactate concentration in spite of marked hypotension. T3 infusion at a rate of 1 microgram/kg/hr elevated the AKBR but did not elevate MAP. Vasopressin infusion at a rate of 0.1 U/kg/hr sustained AKBR and elevated MAP significantly at 1 hr after administration but tended to decrease thereafter. Combined administration of T3 and ADH elevated the AKBR to about 2.0, and MAP was restored to near-normal level. Other parameters such as glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and lactic dehydrogenase, reflecting liver cell injury and serum creatinine, and blood urea nitrogen as renal function, were maintained within normal range. These results indicate that combined T3 and vasopressin administration has a beneficial synergistic effect on both hepatic energy metabolism and systemic hemodynamics without any detrimental influence to other conventional parameters. Therefore, it is suggested that this combined administration may contribute to the management of potential multiorgan donors.
Abstract: Experimental nephrotic syndrome results in sodium retention, reflecting, at least in part, an intrinsic defect in renal sodium handling in the distal nephron. We studied the relationships among plasma atrial natriuretic peptide (ANP) concentration, sodium excretion (UNaV), and urinary cyclic GMP excretion (UcGMPV) in vivo, and the responsiveness of isolated glomeruli and inner medullary collecting duct (IMCD) cells to ANP in vitro, in rats with adriamycin nephrosis (6-7 mg/kg body weight, intravenously). 3-5 wk after injection, rats were proteinuric and had a blunted natriuretic response to intravenous infusion of isotonic saline, 2% body weight given over 5 min. 30 min after onset of the infusion, plasma ANP concentrations were elevated in normals and were even higher in nephrotics. Despite this, nephrotic animals had a reduced rate of UcGMPV after the saline infusion, and accumulation of cGMP by isolated glomeruli and IMCD cells from nephrotic rats after incubation with ANP was significantly reduced compared to normals. This difference was not related to differences in binding of 125I-ANP to IMCD cells, but was abolished when cGMP accumulation was measured in the presence of 10(-3) M isobutylmethylxanthine or zaprinast (M&B 22,948), two different inhibitors of cyclic nucleotide phosphodiesterases (PDEs). Infusion of zaprinast (10 micrograms/min) into one renal artery of nephrotic rats normalized both the natriuretic response to volume expansion and the increase in UcGMPV from the infused, but not the contralateral, kidney. These results show that, in adriamycin nephrosis, blunted volume expansion natriuresis is associated with renal resistance to ANP, demonstrated both in vivo and in target tissues in vitro. The resistance does not appear related to a defect in binding of the peptide, but is blocked by PDE inhibitors, suggesting that enhanced cGMP-PDE activity may account for resistance to the natriuretic actions of ANP observed in vivo. This defect may represent the intrinsic sodium transport abnormality linked to sodium retention in nephrotic syndrome.
Abstract: The influence of isovolemic hemodilution with 6% hetastarch [hematocrits (Hct) ranging from 43 to 20%] on cerebral blood flow (CBF), cerebral red blood cell and plasma volumes, total cerebral blood volume (CBV), and cerebral Hct was examined in normothermic, normocarbic, halothane-anesthetized Sprague-Dawley rats. CBF was measured via the indicator-fractionation method ([3H]nicotine), red blood cell volume was measured using 99mTc-labeled red blood cells, while plasma volume was measured using [14C]dextran. Brain tissue was fixed in situ by microwave irradiation. All data plots (e.g., CBF vs. Hct) were fitted by linear regression methods. Hemodilution was associated with a progressive increase in forebrain CBF (from a fitted value of 78 ml.100 g-1.min-1 at Hct = 43%, to 171 ml.100 g-1.min-1 at 20%). Cerebral plasma volume also rose, while red blood cell volume decreased. Total CBV (i.e., the sum of red blood cell and plasma volumes) increased in parallel with CBF (from 2.51 ml/100 g at Hct = 43 to 4.94 ml/100 g at Hct = 20%). This increase is larger than can be explained by a simple increase in the diameter of arterial/arteriolar resistance vessels and may be due to either capillary recruitment or to an increase in the volume of postarteriolar structures. Calculated cerebral tissue hematocrit decreased. The magnitude of this decrease was larger than the reduction in arterial Hct; the ratio of cerebral to arterial Hct decreased from 0.780 at an arterial Hct equaling 43% to 0.458 at Hct equaling 20%.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Bronchial artery blood flow index (BFI) was measured in an unanesthetized sheep model using a chronically implanted ultrasonic flow probe. The bronchial circulation was monitored during changes of the concentrations of oxygen and carbon dioxide in inhaled air. Control BFI was 15.9 +/- 3.8 ml/min/m2 during normoxic breathing with 0% CO2 (n = 6) and 18.0 +/- 1.6 ml/min/m2 while breathing 28% O2 and 0% carbon dioxide (n = 6). Hypoxia (FIO2 = 0.10) significantly increased BFI to 25.8 +/- 4.9 ml/min/m2 with a decrease in the bronchovascular resistance index (BVRI) from a baseline of 7.85 +/- 1.73 to 4.75 +/- 0.86 mm Hg/(ml/min)/m2. Hyperoxia (FIO2 = 1.0) raised BFI to 30.5 +/- 10.1 ml/min/m2 without a significant decrease in BVRI. Changing the inhaled carbon dioxide concentration from 0 to 10% resulted in a significant increase in BFI from 18.0 +/- 1.6 to 43.6 +/- 10.3 ml/min/m2 and a decrease in BVRI from 5.56 +/- 0.44 to 4.63 +/- 2.18 mmHg/(ml/min)/m2 (not significant). The change in BFI varies directly with lymph flow for hypoxia and hypercarbia. This is consistent with changes in cardiac index, indicating probable changes in surface area being perfused in the lung. Changes in BFI with hyperoxia did not follow changes in systemic vascular resistance or cardiac index. Similarly, lymph flow elevation did not occur during hyperoxia. These data suggest that BFI changes with hyperoxia are not related to changes in total systemic vascular resistance, or cardiac index, and a different mechanism may control bronchovascular flow for this condition.
Abstract: We had reported that the systemic administration of N omega-methyl-L-arginine (L-NMA), a specific inhibitor of nitric oxide (NO) synthesis from L-arginine (ARG), raises arterial blood pressure (BP) while paradoxically enhancing central sympathetic outflow. Cervical spinal cord transection abolishes the increase in sympathetic outflow and attenuates the pressor effect of L-NMA. Thus, in addition to lowering BP by direct vasorelaxation, NO may also act in the central nervous system to reduce vascular sympathetic tone. To test this hypothesis we have injected L-NMA directly into the central nervous system in anesthetized rats. Intracisternally (i.c.), L-NMA elicited a small pressor response accompanied by a marked increase in sympathetic renal nerve activity (RNA). In contrast, the inactive stereoisomer N omega-methyl-D-arginine had neither pressor nor neural effects. The increases in RNA and BP elicited by i.c. L-NMA were abolished by spinal cord transection at C1 to C2 and by the i.v. administration of ARG. When administered i.c., ARG also abolished the increase in RNA elicited by i.v. L-NMA and significantly attenuated the pressor response. Thus, our findings indicate that L-NMA acts centrally by an ARG-reversible mechanism in the anesthetized rat to stimulate sympathetic nerve activity. Inasmuch as centrally synthesized NO has been postulated to play a second messenger and/or neurotransmitter role, our findings suggest that one such function would be the central regulation of sympathetic outflow and hence, BP.
Abstract: STUDY OBJECTIVE–The aim was to evaluate the influence that centrally administered angiotensin-II has on the intrarenal renin-angiotensin system and renal sympathetic nerve activity. DESIGN–Renal responses to centrally administered angiotensin-II (10 micrograms) or saralasin (50 micrograms) were measured in anaesthetised rats. The right kidney was vascularly isolated (but neurally intact) and perfused with artificial plasma at either a constant pressure (13.3 kPa) or constant flow (600 microliters.min-1) and renal vascular resistance was measured. Renal perfusate was collected at 10 min intervals after central administration of peptides and intrarenal concentrations of noradrenaline and renin were determined. SUBJECTS–Adult female Sprague-Dawley rats (200-225 g) were used. Rats were given thermal (or sham) lesions of the medial basal forebrain (MBF) 24 h prior to renal perfusion studies. RESULTS–Sham lesioned animals: central administration of angiotensin-II caused an increase in renal vascular resistance and intrarenal noradrenaline concentration in both the constant pressure and constant flow renal perfusion models. Central administration of angiotensin-II increased intrarenal renin concentration in the constant pressure model, while it decreased intrarenal renin concentration in the constant flow model. These effects of intracerebroventricular angiotensin-II were blocked by the concomitant administration of saralasin. Saralasin had no agonist actions on the responses measured. Medial basal forebrain lesioned animals: baseline levels of intrarenal noradrenaline concentration in both the constant flow and constant pressure perfusion models were significantly reduced compared to sham lesioned rats. Baseline intrarenal renin concentration was increased relative to sham lesioned rats in the constant flow perfusion model, but decreased relative to sham lesioned rats in the constant pressure perfusion model. Lesions of the medial basal forebrain block responses to intracerebroventricular angiotensin-II in both models. CONCLUSIONS–Angiotensin-II appears to act on neurones within the medial basal forebrain to increase renal sympathetic nerve activity. Renal nerve activity interacts with the prevailing intrarenal pressure to modulate the release of renin.
Abstract: The purpose of the present study was to examine whether intensity of exercise affects skin blood flow response to exercise. For this purpose, six healthy men cycled, in a random order on different days, for 15 min at 50, 60, 70, 80, and 90% of their maximum oxygen consumption (VO2max) at a room temperature of 25 degrees C. At the end of exercise, esophageal temperature (Tes) averaged 37.4 +/- 0.2, 37.7 +/- 0.2, 37.9 +/- 0.2, 38.6 +/- 0.3, and 38.9 +/- 0.4 degrees C (SE) at the 50, 60, 70, 80, and 90% work loads, respectively. At the two highest work loads, no steady state was observed in Tes. Skin blood flow was estimated by measuring forearm blood flow (FBF) with strain-gauge plethysmography and by laser-Doppler flowmetry on the upper back. Both techniques showed that skin blood flow response to rising Tes was markedly reduced at the 90% work load compared with other work loads. At the end of exercise, FBF averaged 7.5 +/- 1.7, 10.7 +/- 3.1, 9.6 +/- 2.1, 11.3 +/- 2.6, and 5.4 +/- 1.3 (SE) ml.min-1.100 ml-1 (P less than 0.01) at the 50, 60, 70, 80, and 90% VO2max work loads, respectively. The corresponding values for Tes threshold for cutaneous vasodilation (FBF) were 37.42 +/- 0.16, 37.48 +/- 0.13, 37.59 +/- 0.13, 37.79 +/- 0.19, and 38.20 +/- 0.22 degrees C (P less than 0.05) at 50, 60, 70, 80, and 90% VO2max, respectively. In two subjects, no cutaneous vasodilation was observed at the 90% work load.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: A method is introduced for quantitating cycling between hepatic glycogen and glucose-1-P in humans. It depends on the administration of trace [2-3H,6-14C]galactose, a glucose load, and acetaminophen. The ratio of 3H to 14C in the glucuronide of the acetaminophen excreted in urine to that in the administered galactose provides the measure of the fraction of glycogen synthesized that is synthesized from glucose-1-P formed from glycogen. The quantity of glucose-1-P formed from glycogen that is not reconverted to glycogen is not measured. It is assumed that the glucuronide samples the UDP-glucose pool in liver from which glycogen is formed, the last glucosyl units formed from UDP-glucose in glycogen synthesis are the first broken down, and the equilibration of [2-3H]glucose-1-P with fructose-6-P is rapid relative to its conversion to UDP-glucose. During a 5-hour period, while three normal subjects and three non-insulin-dependent diabetics, who had fasted overnight, were infused with 4 mg/kg/min of glucose, the rate of glycogen breakdown, as measured using the method, was only a small percentage of the rate of glycogen synthesis.
Abstract: The objective of this study was to examine effects of nonpeptide angiotensin II (Ang II) receptor antagonists on renal vasoconstrictor responses to renal nerve stimulation (RNS) and intrarenal injection of norepinephrine in pentobarbital-anesthetized dogs. The subtype 1-selective Ang II receptor antagonists, DuP 753 (2-n-butyl-4-chloro-5-(hydroxymethyl)-1-[(2’-(1H- tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole, potassium salt) and EXP3174 (2-n-butyl-4-chloro-1-[(2’-(1H-tetrazol-5-yl) biphenyl-4-yl)methyl]imidazole-5-carboxylic acid) given intra-arterially to the kidney caused dose-dependent reductions of renal vasoconstrictor responses to RNS but not to norepinephrine. In contrast, the subtype 2-selective Ang II receptor specific ligand, PD 123177 (1-[(4-amino-3-methylphenyl)methyl]-5-(diphenylacetyl)-4,5,6,7- tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid), did not alter the renal vasoconstrictor responses to RNS, norepinephrine, and Ang II in doses of 10-100 micrograms/kg/min i.a. Captopril also reduced the renal vasoconstrictor responses to RNS but not to norepinephrine. However, saralasin did not alter the renal vasoconstrictor responses to RNS and norepinephrine, although it was as effective as DuP 753 and EXP3174 in blocking the renal vasoconstrictor response to Ang II. These results suggest that endogenous Ang II enhances renal adrenergic function at the prejunctional site in anesthetized dogs. Analogous to the Ang II receptor in vascular smooth muscle, the prejunctional Ang II receptor appears to be of subtype 1. Mechanisms accounting for the absence of the inhibition of Ang II-mediated renal adrenergic response by saralasin remain to be determined.
Abstract: The need for cadaveric organs for transplantation is increasing. To decrease the shortage of organs, identification of potential donors and conditioning of these donors must improve. We present a review of relevant data on body and tissue alterations due to brain death and summarize the recent literature covering experimental and clinical studies on optimal donor management.
Abstract: Sodium and water retention is characteristic of edematous disorders including cardiac failure, cirrhosis, nephrotic syndrome, and pregnancy. Nonosmotic vasopressin release has been implicated in the water retention of these edematous disorders. The nonosmotic release of vasopressin is consistently associated with activation of the sympathetic nervous and renin-angiotensin-aldosterone systems in both experimental animals and in edematous patients. Moreover, the sympathetic nervous system has been shown to be involved in the nonosmotic release of vasopressin and activation of the renin-angiotensin system. These findings have led to our proposal that body fluid volume regulation involves the dynamic interaction between cardiac output and peripheral arterial resistance. Neither total extracellular fluid volume nor blood volume is a determinant of renal sodium and water excretion. Rather, renal sodium and water retention is initiated by a decrease in effective arterial blood volume (EABV) due to either a fall in cardiac output or peripheral arterial vasodilation. The acute response to a decrease in EABV involves vasoconstriction mediated by angiotensin, sympathetic mediators, and vasopressin. The slower response to restoring EABV involves vasopressin-mediated water retention and aldosterone-mediated sodium retention. The resultant renal vasoconstriction limits the distal tubular delivery of sodium and water, thus maximizing the water-retaining effect of vasopressin and impairing the normal escape from the sodium-retaining effects of aldosterone. The elevated glomerular filtration rate and filtered sodium load in pregnancy allows increased distal sodium and water delivery in spite of a decrease in EABV, thus limiting edema formation during gestation.
Abstract: Effective and practical preventive procedures for postflight orthostatic intolerance are highly desirable. The current practice of attempts to expand plasma volume by ingestion of salt and fluids before reentry has proven benefits. This study evaluated alternative options using fludrocortisone (F) to expand plasma volume (PV), dextroamphetamine (Dex) to enhance norepinephrine (NE) release and atropine (A) to reduce the effects of vagal stimulation. Seven subjects with proven post-bedrest orthostatic intolerance returned for a 7-day 6 degrees head-down bedrest study. F (0.2 mg) was given at 8:00 AM and 8:00 PM the day before and 8:00 AM the day the subjects got out of bed (2 hours before standing). PV was measured before and 1 hour after the last dose of F. D (5 mg) and A (0.8 mg) were then taken orally 1 hour before the stand test. F expanded PV by 16% and caused sodium retention. Four of the 7 subjects stood for 1 hour post-bedrest and HR, plasma NE and PRA responses to standing were greatly enhanced and sustained. Although there was a narrowing of pulse pressure, the ability to overcome orthostatic intolerance with these countermeasures was largely due to vasoconstriction and sustained high heart rate. The existing literature on pharmacologic countermeasures for post-flight and post-bedrest orthostatic hypotension is reviewed, and the results are discussed in that context.
Abstract: The present studies were performed to examine the vasoconstrictor effect of angiotensin II (ANG II), angiotensin III (ANG III), and vasopressin in isolated afferent arterioles of the rabbit kidney. Afferent arterioles were dissected together with their glomerulus and perfused with a pressure head of 120 cmH2O. Changes in vasomotor tone were assessed as diameter changes on videotaped recordings. Afferent arterioles responded to the angiotensins and vasopressin with dose-dependent reductions in vascular diameters with half-maximum responses being observed at concentrations between 10(-9) and 10(-8) M. Responses to ANG II and III were inhibited by saralasin. Contractile responses to ANG II and vasopressin were not altered by prior occlusion of the efferent arteriole, suggesting that afferent vasoconstriction does not represent a myogenic reaction to an increase in efferent resistance. The vasoconstrictor response to ANG II was largely eliminated by removal of the glomerulus and the distal-most portion of the afferent arteriole, whereas the response to vasopressin remained intact. Our data are consistent with the notion that the juxtaglomerular apparatus (JGA) and/or glomerulus may control proximal afferent arteriolar contractility by electrotonic or myogenic coupling mechanisms or by producing cofactors that modulate vasomotor responses.
Abstract: The low solubility of sevoflurane in blood suggests that this agent should enter and leave the body more rapidly than isoflurane. However, the closeness of sevoflurane and isoflurane tissue/blood partition coefficients suggests that the rates of equilibration with and elimination from tissues should be similar. We tested both predictions, comparing sevoflurane with isoflurane and nitrous oxide in seven volunteers. We measured the rate at which the alveolar (end-tidal) (FA) concentration of nitrous oxide increased toward an inspired (FI) concentration of 65%-70%, then measured the concurrent rise in FA and mixed expired concentrations (FM) of sevoflurane and isoflurane at respective FI values of 1.0% sevoflurane and 0.6% isoflurane for 30 min. Minute ventilation (VE) was measured concurrently with the measurements of anesthetic concentrations. For the potent agents, we also measured VE, FA, and FM for 6-7 days of elimination. FA/FI values at 30 min of administration were as follows: nitrous oxide, 0.986 +/- 0.003 (mean +/- SD); sevoflurane, 0.850 +/- 0.018; and isoflurane, 0.733 +/- 0.027. FA/FA0 (FA0 = the last FA during administration) values after 5 min of elimination were as follows: sevoflurane, 0.157 +/- 0.020; isoflurane, 0.223 +/- 0.024. Recovery (volume of anesthetic recovered during elimination/volume taken up) of sevoflurane (101% +/- 7%) equaled recovery of isoflurane (101% +/- 6%). Time constants for a five-compartment mammillary model for sevoflurane were smaller than those for isoflurane for the lungs but were not different from isoflurane for the other compartments.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: A comprehensive diagnostic evaluation was administered to 162 closed head-injured patients within 1 to 21 days (mean, 7.5 days) after injury. Each evaluation consisted of (1) power spectral analyses of electroencephalogram (EEG) recorded from 19 scalp locations referenced to age-matched norms, (2) brainstem auditory evoked potentials, (3) computed tomography (CT)-scan, and (4) Glasgow Coma Score (GCS) at time of admission (GCS-A) and at time of EEG test (GCS-T). Functional outcome at one year following injury was assessed using the Rappaport Disability Rating Scale (DRS), which measures the level of disability in the six diagnostic categories of (1) eye opening, (2) best verbal response, (3) best motor response, (4) self-care ability for feeding, grooming, and toileting, (5) level of cognitive functioning, and (6) employability. The ability of the different diagnostic measures to predict outcome at one year following injury was assessed using stepwise discriminant analyses to identify patients in the extreme outcome categories of complete recovery versus death and multivariate regression analyses to predict patients with intermediate outcome scores. The best combination of predictor variables was EEG and GCS-T, which accounted for 74.6% of the variance in the multivariate regression analysis of intermediate outcome scores and 95.8% discriminant accuracy between good outcome and death. The best single predictors of outcome in both the discriminant analyses and the regression analyses were EEG coherence and phase. A gradient of prognostic strength of diagnostic measures was EEG phase greater than EEG coherence greater than GCS-T greater than CT-scan greater than EEG relative power. The value of EEG coherence and phase in the assessment of diffuse axonal injury was discussed.
Abstract: To assess the effect of vasopressin (VP) on systemic capacity (SC), blood was drained from the venae cavae to an oxygenator and returned to the aorta at a constant rate so that changes in SC could be measured as the inverse of changes in oxygenator volume in 17 anesthetized pigs. After 10 min of VP administration (1.1 U/min ia), mean arterial pressure increased from 67 +/- 2 to 144 +/- 7 mmHg (P less than 0.001). SC decreased promptly and reached a nadir of 110 +/- 32 ml (P less than 0.02, 5.5 ml/kg) below control at 5 min but returned to 35 +/- 65 ml (P = not significant, 1.8 ml/kg) below control at 10 min. Portal venous pressure decreased from 19.3 +/- 2.6 to 16.6 +/- 2.7 mmHg (P less than 0.001), and portal flow decreased from 828 +/- 68 to 458 +/- 92 ml/min (P less than 0.001). Transhepatic venous resistance increased. After evisceration, VP caused only an increase in SC. Thus VP causes an initial SC decrement due entirely to a decrease in splanchnic capacity. The decrease in splanchnic capacity must be caused, at least in part, by the decrease in gastrointestinal arterial inflow and subsequent decrease in portal venous pressure. These initial effects of VP on SC would be expected to enhance ventricular filling and cardiac output in the intact animal and could be important in the acute compensatory response to hemorrhage.
Abstract: The low solubility of desflurane in blood and tissues suggests that the partial pressures of this agent in blood and tissues should approach the inspired partial pressure more rapidly than would the blood and tissue partial pressures of other potent inhaled anesthetics. We tested this prediction, comparing the pharmacokinetics of desflurane with those of isoflurane, halothane, and nitrous oxide in eight volunteers. We measured the rate at which the alveolar (endtidal) (FA) concentration of nitrous oxide increased towards an inspired (FI) concentration of 65-70%, and then measured the concurrent increase in FA and mixed expired concentrations (FM) of desflurane, isoflurane, and halothane at respective FI values of 2.0%, 0.4%, 0.2%. Minute ventilation (VE) was measured concurrently with the measurements of anesthetic concentrations. The potent vapors were administered for 30 min; administration of nitrous oxide continued throughout the period of anesthesia. For the potent agents, we also measured VE, FA, and FM for 5-7 days of elimination. We used FA/FI and FA/FA0 (FA0 = the last FA during the administration of each anesthetic) to define the rate of increase of anesthetic in the lungs and the rate of elimination of anesthetic, respectively. FA/FI values at 30 min of administration were: (mean +/- SD) nitrous oxide 0.99 +/- 0.01, desflurane 0.90 +/- 0.01, isoflurane 0.73 +/- 0.03, and halothane 0.58 +/- 0.04. FA/FA0 values after 5 min of elimination were: desflurane 0.14 +/- 0.02, isoflurane 0.22 +/- 0.02, and halothane 0.25 +/- 0.02. Recovery (volume of anesthetic recovered during elimination per volume taken up) of desflurane (105 +/- 25%) equalled recovery of isoflurane (102 +/- 13%) and exceeded recovery of halothane (64 +/- 9%). Time constants for a five-compartment mammillary model for halothane and isoflurane differed for the lungs, fat group, and hepatic metabolism, and exceeded those for desflurane for all compartments. In summary, we found that FA/FI of desflurane increases more rapidly and that FA/FA0 decreases more rapidly in humans than do these variables with other available potent anesthetics. We also found that desflurane resists biodegradation in humans and so may have little or no toxic potential.
Abstract: To elucidate the underlying mechanisms of the initial fall in blood pressure on standing upright from the supine position, we measured the beat-to-beat changes in intra-arterial pressure in eight healthy male subjects in response to standing. Changes in stroke volume, cardiac output, and total peripheral resistance were computed from the pressure waveform using a pulse contour method. To determine possible mechanisms for the changes observed on standing, similar measures were made on passive tilting and a brief (3-s) bout of cycle exercise. Standing elicited a transient 25% (23-mmHg) fall in mean blood pressure as a result of a 36% fall in total peripheral resistance. Head-up tilt elicited a gradual change in haemodynamic parameters, which reached plateau levels in 20-30 s. Cycling elicited a transient 17% (18-mmHg) fall in blood pressure and a 41% fall in total peripheral resistance. In addition, we measured right atrial and esophageal pressures in two subjects on standing and cycling and found a 10- to 15-mmHg rise in right atrial pressure without a corresponding change in esophageal pressure. This points to the cardiopulmonary reflex as the primary effector of peripheral vasodilation, but we cannot exclude the possibility that 1) local metabolic vasodilation and 2) central command-mediated cholinergic vasodilation contributed to the fall in vascular resistance.
Abstract: To study the time-dependent changes in the secretion of atrial natriuretic peptide (ANP) in response to chronic stimulation by controlled increments in atrial pressure, we developed methodology for precise control of right atrial pressure (RAP) in dogs by employing an externally adjustable occluder around the pulmonary artery and a servo-control system. During 7 days of servo-control of RAP at 6.3 +/- 0.1 mmHg above control levels (1.3 +/- 0.1 mmHg), the 24-h coefficient of variation in RAP was 1/45 the variation that occurred under control conditions. After 30 min of increased RAP, mean arterial pressure (MAP) was reduced from 101 +/- 4 to 84 +/- 3 mmHg in association with increments in plasma renin activity (PRA) from 0.6 +/- 0.1 to 2.5 +/- 0.9 ng angiotensin I (ANG I).ml-1.h-1 and in the plasma concentrations of ANP, arginine vasopressin (AVP), and epinephrine from 93 +/- 18 to 484 +/- 61 pg/ml, from 0.5 +/- 0.1 to 9.2 +/- 2.4 pg/ml, and from 82 +/- 27 to 585 +/- 133 pg/ml, respectively. In comparison, on day 7 of servo-control of RAP, sodium balance was achieved and MAP remained depressed (82 +/- 4 mmHg) along with sustained increments in both plasma ANP concentration (482 +/- 67 pg/ml) and PRA (1.7 +/- 0.6 ng ANG I.ml-1.h-1); on the other hand, the plasma concentrations of AVP and epinephrine returned to control levels. This quantitative study indicates that ANP secretion does not chronically adapt to stimulation by increased atrial pressure and suggests that the plasma levels of ANP achieved in heart failure markedly increase renal excretory capability and allow fluid balance to be achieved at a substantial fall in renal perfusion pressure.
Abstract: Immobilization is associated with increased bone resorption. To investigate the early onset of increased bone resorption, we evaluated 14 patients who were immobilized for 10 days because of lumbar disc protrusion. The fasting urinary hydroxyproline/creatinine ratio increased significantly after four days (P less than 0.01), reached a peak after 10 days (16.4 +/- 3.3 mumol/mmol, 27.6 +/- 8.8 mumol mmol, P less than 0.01) and returned slowly to baseline values after mobilization. The fasting urinary calcium creatinine ratio followed a similar pattern. Serum calcium and phosphate increased during immobilization (P less than 0.01). Serum 1,25-dihydroxyvitamin D decreased significantly during immobilization (98 +/- 33 pmol/l vs. 79 +/- 36 pmol/l, P less than 0.05), and reached a nadir one week after mobilization (P less than 0.01). We conclude that there is an early significant increment in resorption parameters, with a slow return during the mobilization period. Serum 1,25-dihydroxyvitamin D is suppressed as a result of the increased serum calcium and serum phosphate levels.
Abstract: The objective of the present study was to describe the time courses of renal responses during renal sympathetic stimulation and to determine whether the kidney can provide a sustained response to sympathetic stimulation for 3 h. In four pentobarbital sodium-anesthetized dogs, stimulation (3.3 Hz) of a greater splanchnic nerve (GSN) on one side caused reductions in renal blood flow (RBF) and sodium excretion (UNaV) of both stimulated and contralateral-denervated kidneys, plus an increase in plasma renin activity (PRA). During continued stimulation, RBF partially recovered, but UNaV fell to less than 5% of control and PRA rose and remained at least eight times above control. In nine dogs, a single GSN was stimulated after ipsilateral adrenal medullectomy and ligation of the splanchnic circulation. The acute response to GSN stimulation was now confined to the ipsilateral kidney. Ipsilateral RBF fell by 32 +/- 10% but returned to 85 +/- 5% of control values by the end of the stimulation period. Contralateral RBF fell slowly by approximately 10%. Ipsilateral and contralateral UNaV fell to 34 +/- 10 and 43 +/- 11% of control values, respectively. PRA increased rapidly at the onset of GSN stimulation and remained at least 2.8 times control levels. After stimulation, RBF, UNaV, and PRA returned toward control levels. These results confirm the findings of others that the response of the renal vasculature to sympathetic stimulation is mainly transient. However, they additionally demonstrate a strong and sustained decrease in UNaV lasting for the total 3-h period of sympathetic stimulation.
Abstract: A simulation model for the production of thrombin in plasma is presented. Values of the reaction rate constants as determined in purified systems are used and the model is tested by comparison of simulations of factor Xa, factor Va and thrombin generation curves with experimental data obtained in thromboplastin-activated plasma. Simulations of the effect of hirudin indicate that factor V is predominantly activated by thrombin and not by factor Xa. The model predicts a threshold value for the factor Xa production which, if exceeded, results in explosive and complete activation of prothrombinase. The dependence of this threshold value on different negative feedback reactions, e.g. the inactivation of thrombin and factor Xa by antithrombin III (+ heparin), is investigated. The threshold value, for control plasma in the range of 1-10 pM total factor Xa production, can be raised two orders of magnitude by accelerated inactivation of factor Xa and prothrombinase but is hardly affected by a tenfold increase in the rate of thrombin inactivation or by increased production of activated protein C. This latter effect, however, results in a more gradual input-response relation between factor Xa input and the extent of prothrombinase activation.
Abstract: In anesthetized rats with sinoaortic denervation, intracerebroventricular (icv) injection of atrial natriuretic peptide (ANP) resulted in decreased mean arterial blood pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) (depressor effects), whereas icv angiotensin II (ANG II) produced increases in these variables (pressor effects). The depressor effects of ANP were slower in onset and longer in duration than the pressor effects of ANG II. Intracerebroventricular injection of the ANG II-receptor blocker sarthran or the ANG II-synthesis inhibitor captopril resulted in a significant reduction in MAP; HR and RSNA were not affected. Both sarthran and captopril abolished the depressor responses to icv ANP. In contrast, injection of an anti-rat ANP antibody, which blocked the depressor effects of icv ANP, did not by itself modify MAP, HR, or RSNA, nor did the antibody affect the pressor responses to icv ANG II. These data suggest that, in this animal model, the depressor effects of icv ANP are mediated by the inhibition of brain ANG II-dependent neural activity. These results also demonstrate that, in this preparation, the endogenous ANG II system actively contributes to the maintenance of basal MAP, whereas the central ANP system, at least in regions accessible to the antirat ANP antibody, plays little role in this maintenance.
Abstract: Prospective measurements of cerebral blood flow (CBF) and Cognitive Capacity Screening Examination (CCSE) were obtained following head injury among 42 patients for a mean total follow-up interval of 10 years. Clinical data obtained at the time of injury and detailed neurological examinations at each follow-up visit were correlated with serial CBF and CCSE scores. Comparisons of the group of patients who cognitively improved (n = 32) were made with the group that did not (n = 10). Of the total group, 76% showed cognitive improvements for as long as 10 years after injury, with CBF increases toward normal. Predictors for long-term cognitive improvements include: higher initial Glasgow Coma Scales, earlier recovery from coma, absence of signs of brain stem injury, and improvements of cerebral perfusion and autoregulation. Failure to improve correlated with low initial Glasgow Coma Scales, signs of brain stem injury, and persistent impairments of cerebral perfusion.
Abstract: Electrocardiographic changes and cardiac arrhythmias have been reported frequently in patients suffering high tension (greater than 1,000 V) electrical injuries as well as low tension (less than 350 V) electrical injuries. An association of atrial fibrillation with low tension electrical injury from a household appliance, however, has not been described in the recent literature. We describe a patient with atrial fibrillation induced by a shock from a household toaster. Pathophysiologic mechanisms and approach to treatment are reviewed, emphasizing the transient nature of most electrically induced arrhythmias.
Abstract: Two-dimensional echocardiography was performed during a head-up tilt test in 11 control subjects (group I) and 18 patients with recurrent unexplained syncope. In four patients (group II), the head-up tilt test was negative at baseline and after isoproterenol infusion. Syncope was induced during baseline head-up tilt in nine patients (group III) and after isoproterenol challenge in five (group IV). The echocardiographic variables assessed were left ventricular end-systolic and end-diastolic areas and percent fractional shortening. At the end of head-up tilt, end-systolic area decreased by 4.5 +/- 1.3 and 3.0 +/- 1.2 cm2 in groups III and IV, respectively, compared with 0.5 +/- 0.7 and 0.2 +/- 0.1 cm2 in groups I and II, respectively (p less than 0.04). Similarly, end-diastolic area decreased by 5.5 +/- 2.6 cm2 in group III compared with 2.7 +/- 1.9 and 1.75 +/- 0.4 cm2 in group I and II, respectively (p less than 0.04). Additionally, at the end of the baseline study, fractional shortening was significantly greater in group III and group IV (43 +/- 5%) than in groups I and II (p less than 0.01). In conclusion, syncope induced by head-up tilt is associated with vigorous myocardial contraction and a significant decrease in left ventricular end-systolic dimensions. This left ventricular hypercontractility may play an important role in the pathogenesis of syncope induced by head-up tilt.
Abstract: Recent investigations using direct (microneurographic) recordings of MSNA have provided a substantial amount of new information on the regulation of sympathetic nervous system control of nonactive skeletal muscle blood flow during exercise in humans. Some of the new conclusions from these studies discussed in this review include: 1. The direction, pattern and magnitude of the MSNA response to exercise depend on the collective influence of a number of factors, including the mode (isometric or rhythmic), intensity, and duration of the exercise, the size of the contracting muscle mass, and possibly the level of conditioning (physical training) of the exercising muscles. The MSNA response also appears to be tightly coupled with the onset and progression of muscle fatigue, at least during sustained, isometric contractions. 2. Increases in MSNA evoked during exercise with the arms are fairly uniform among different skeletal muscle nerves, and these responses correlate strongly with changes in venous plasma norepinephrine concentrations, limb vascular resistance and arterial blood pressure. Thus, increases in this neural activity during exercise are associated with the expected physiological responses. 3. The MSNA response to the same level of exercise varies markedly among healthy subjects but appears to be consistent over time within a particular subject. 4. The muscle metaboreflex (muscle chemoreflex) is the primary-mechanism by which MSNA is stimulated during small-muscle, isometric exercise in humans. In contrast, central command has a relatively weak influence on MSNA during this type of exercise. 5. Muscle metaboreflex-stimulation of MSNA also occurs during dynamic exercise, but only at or above moderate, submaximal intensities (i.e., not during mild exercise). 6. Muscle metaboreflex-evoked increases in MSNA during exercise are strongly associated with glycogenolysis and the consequent cellular accumulation of hydrogen ions in the contracting muscles. 7. Sympathoinhibitory cardiopulmonary reflexes do not appear to modulate the MSNA responses to isometric exercise in the healthy human. However, arterial baroreflexes exert a potent inhibitory effect on MSNA during this form of exercise. The mechanisms involved in the regulation of MSNA during large-muscle, dynamic leg exercise is an important topic for future investigations, as is the relationship between MSNA and sympathetic outflow to other regional circulations (e.g., heart, viscera, skin) during various forms of exercise.
Abstract: 1. Myogenic responses may account for control of organ blood flow. The study of these responses without interference from the organ requires an isolation technique for vessels which contribute significantly to flow resistance. This study reports on experiments on isolated small mesenteric arteries. 2. Distal rat mesenteric arcade arteries and first-order branches (diameter range 145-365 microns, mean 293 microns) were manually dissected and cannulated using a double-barrelled micro-cannula. Luminal cross-sectional area of these vessels was continuously monitored by means of a fluorescence technique. 3. Nine out of eighteen vessels developed basal tone at 80 mmHg distending pressure, resulting in a 45.2 +/- 5.1% (mean +/- S.E.M) decrease of cross-sectional area. Tone was induced in the other vessels by 0.3-1 microM-noradrenaline, resulting in a 59.5 +/- 7.1% decrease in cross-sectional area. 4. In vessels with either spontaneous or induced tone, stepwise changes of pressure resulted in passive effects, followed by myogenic responses. 5. Steady-state pressure-cross-sectional area relations of vessels with basal tone showed a significant negative slope (-0.5% mmHg-1), while pressure-cross-sectional area relations of vessels with induced tone were essentially flat between 40 and 120 mmHg. 6. Five vessels with basal tone and eight vessels with induced tone developed vasomotion at 80 mmHg. Frequencies of spontaneous and induced vasomotion were 14 (range 4-31) and 21 (9-25) cycles min-1 respectively. Amplitudes were 5 (1-10) and 8 (3-17)% of the passive cross-sectional area. In both groups, frequency was positively, and amplitude negatively correlated with pressure. 7. These data show that myogenic responses are induced by wall stress, rather than by distension of the vascular wall. Basal tone is not a prerequisite for the appearance of myogenic responses.
Abstract: To provide experimental verification to Stewart’s quantitative approach to acid-base analysis, the effects of acute maximal treadmill exercise (VO2max test) on venous acid base status were studied in 17 male subjects aged 18-23 yr. Venous CO2 tension (PCO2) total plasma proteins ([PTOT]), [H+], and concentrations of strong ions [( Na+], [K+], [Cl-] and lactate ion concentration ([La-]) were measured before and within 1 min post-exercise. Mean post-exercise PCO2, [PTOT], [K+], and [La-] were significantly higher than the corresponding pre-exercise values (P less than 0.05), there was a strong tendency for a significant change in [Na+] (P less than 0.056), and no changes were found in [Cl-]. Changes in venous acid-base status were analyzed quantitatively by applying relevant physicochemical theory. Altered values measured in the independent variables ([PTOT], PCO2, and net strong ion difference, [SID]) were used to calculate the corresponding changes in the dependent quantities. Comparison of individual measured and calculated values for the only one of these that is normally measured, ([H+]), yielded the theoretically expected agreement. PCO2 and [SID] changes accounted for most [H+] changes. These results demonstrate the usefulness of the quantitative approach (i.e., [H+]-PCO2 diagram) in the analysis and in understanding of plasma acid base changes with exercise and in clinical situations.
Abstract: Twenty-four-hour urine kallikrein excretion (Uka), urine protein excretion, renal sodium handling, and the activity of the renin-angiotensin-aldosterone system were serially studied in 11 children at three different stages of the minimal change nephrotic syndrome (MCNS)-edema forming state, proteinuric steady state in which a relapse of the disease was just starting but no edema as yet and remission. The value for Uka was significantly increased in the edema forming state in contrast to the normal values of proteinuric steady state and remission. Serum sodium concentration was only decreased in the edema forming state and the degree of hypoalbuminemia and proteinuria did not differ between the edema forming and proteinuric steady states. Urine volume, absolute and fractional sodium excretion were significantly decreased in the edema forming and proteinuric steady states as compared with those in remission, suggesting that sodium retention was present in both states of the disease although the change in these parameters was more profound in the edema forming state than in the proteinuric steady state. Creatinine clearance did not differ among each stage of the disease. Plasma renin activity and plasma aldosterone concentration were significantly increased in the edema forming state as compared with those in the proteinuric steady state and remission. Plasma renin activity and plasma aldosterone concentration were significantly correlated directly with Uka and plasma aldosterone concentration was correlated inversely with urine sodium excretion. No relation was noted between Uka and other variables.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: We have examined the mechanisms underlying reduced circulating GH concentrations in the obese human. Computer-assisted (deconvolution) analysis was used to determine endogenous GH secretory and clearance rates quantitatively from entire 24-h plasma GH concentration profiles. These analyses revealed that the half-life (t 1/2) of endogenous GH was significantly shorter in obese (11.7 +/- 1.6 min) than in normal weight subjects (15.5 +/- 0.81 min; P less than 0.01). The accelerated blood disposal rate of GH was not due to decreased circulating concentrations of GH-binding protein, since the latter were similar in obese (25 +/- 1.0%) and normal weight (24 +/- 2.3%) men. However, obese men had significantly fewer GH secretory bursts (3.2 +/- 0.53 vs. 9.7 +/- 0.67/day; P less than 0.01). Among the rare GH secretory bursts that occurred in obese subjects, there were significantly prolonged mean intersecretory burst intervals (282 +/- 65 vs. 131 +/- 11 min; P less than 0.05). The resultant daily GH production rate in obese men was reduced to one fourth that in normal weight individuals. Both GH secretion rate and burst frequency were negatively correlated with the degree of obesity (ponderal index). The decreases in GH burst frequency and half-life were specific, since GH secretory pulse amplitude (maximal rate of GH release), the mass of GH released per burst, and the duration of computer-resolved GH secretory bursts were not different in obese and normal weight men. We conclude that obese men harbor a double defect in GH dynamics involving both GH secretion and clearance, and that the severity of the GH secretory deficiency is proportionate to the degree of obesity.
Abstract: Individuals greater than or equal to 60 yr of age are more susceptible to hyperthermia than younger people. However, the mechanisms involved remain unclear. To gain further insight, we examined the heat loss responses of 7 young (24-30 yr) and 13 older (58-74 yr) men during 20 min of cycle exercise [67.5% maximal O2 uptake (VO2max)] in a warm environment (30 degrees C, 55% relative humidity). Forearm blood flow (FBF) and chest sweat rate (SR) were plotted as a function of the weighted average of mean skin and esophageal temperatures [Tes(w)] during exercise. The sensitivity and threshold for each response were defined as the slope and Tes(w) at the onset of the response, respectively. When the young sedentary men were compared with a subgroup (n = 7) of the older physically active men with similar VO2max, the SR and FBF responses of the two groups did not differ significantly. However, when the young men were compared with a subgroup of older sedentary men with a similar maximal O2 pulse, the SR and FBF sensitivities were significantly reduced by 62 and 40%, respectively. These findings suggest that during a short exercise bout either 1) there is no primary effect of aging on heat loss responses but, rather, changes are associated with the age-related decrease in VO2max or 2) the decline in heat loss responses due to aging may be masked by repeated exercise training.
Abstract: The primary aim of this study was to determine the influence of systemic hyperoxia on sympathetic nervous system behavior at rest and during submaximal exercise in humans. In seven healthy subjects (aged 19-31 yr) we measured postganglionic sympathetic nerve activity to skeletal muscle (MSNA) in the leg, antecubital venous norepinephrine concentrations, heart rate, and arterial blood pressure during normoxic rest (control) followed by 3- to 4-min periods of either hyperoxic (100% O2 breathing) rest, normoxic exercise (rhythmic handgrips at 50% of maximum force), or hyperoxic exercise. During exercise, isocapnia was maintained by adding CO2 to the inspirate as necessary. At rest, hyperoxia lowered MSNA burst frequency (12-42%) and total activity (6-42%) in all subjects; the average reductions were 25 and 23%, respectively (P less than 0.05 vs. control). Heart rate also decreased during hyperoxia (6 +/- 1 beats/min, P less than 0.05), but arterial blood pressure was not affected. During hyperoxic compared with normoxic exercise, there were no differences in the magnitudes of the increases in MSNA burst frequency or total activity, plasma norepinephrine concentrations, or mean arterial blood pressure. In contrast, the increase in heart rate during hyperoxic exercise (13 +/- 2 beats/min) was less than the increase during normoxic exercise (20 +/- 2 beats/min; P less than 0.05). We conclude that, in healthy humans, systemic hyperoxia 1) lowers efferent sympathetic nerve activity to skeletal muscle under resting conditions without altering venous norepinephrine concentrations and 2) has no obvious modulatory effect on the nonactive muscle sympathetic nerve adjustments to rhythmic exercise.
Abstract: Six healthy subjects were given endothelin-1, intravenously in a dose of 4 pmol.kg-1.min-1 for 20 min. Blood samples were drawn from arterial, hepatic and renal vein catheters for determinations of splanchnic and renal blood flows and the extraction of endothelin-1 in these vascular beds. Intravenous infusion of endothelin-1 increased the mean arterial blood pressure by 6.8 +/- 2.0 mm Hg (p less than 0.05) and reduced splanchnic and renal blood flows by 34% (p less than 0.005) and 26% (p less than 0.001) respectively. Return to basal flow values occurred after about 1 hr for the splanchnic and 3 hrs for the renal blood flow. The fractional extractions of endothelin-1-like immunoreactivity corresponded to 75 +/- 2% and 60 +/- 2% in the splanchnic and renal vascular beds, respectively. The disappearance curve in plasma and two half-lives of 1.4 +/- 0.1 min and 35 +/- 2.8 min respectively.
Abstract: Renal ammonia production and distribution and ammonia precursor utilization were evaluated in eight patients with chronic potassium depletion (CPD) and aldosterone-producing adenoma and in 20 controls. In CPD, urinary ammonia excretion and ammonia added to renal venous blood were about twofold higher than in controls; thus, total ammonia production was significantly augmented (88.0 +/- 10.3 mumol/min.1.73 m2 vs. 45.0 +/- 2.6 in controls). Total ammonia production was inversely correlated with serum potassium and directly correlated with urine flow. Stepwise multiple regression analysis showed that both factors, mainly serum potassium, significantly influence ammonia production and account for 61.4% of variations in ammonia production. Renal extraction of glutamine was significantly increased (56.6 +/- 5.9 mumol/min.1.73 m2 vs. 34.6 +/- 3.1 in controls), and this could account for ammonia production. The ratio of urinary ammonia excretion to total ammonia production, an index of the intrarenal ammonia distribution, was similar in patients and controls, and was significantly correlated with urine pH and true renal blood flow (RBF). Stepwise multiple regression analysis showed that RBF, urine pH and urine flow also significantly affected ammonia distribution. However, these factors accounted for only 41.7% of variations in intrarenal ammonia partition, urine pH having a minor role. We conclude that in patients with CPD other factors besides urine pH, urine flow and RBF intervene in the ammonia partition between urine and blood.
Abstract: Control of cell size within defined limits is vital for maintenance of normal organ function. This important feature of cell physiology can be disturbed by changes in membrane transport in epithelial cells. In addition, fluctuations in the osmolality of the extracellular fluid, caused by an abnormal plasma concentration of sodium, glucose, or urea can lead to derangements in cell size. Cell volume regulation is especially important in the brain because the brain is confined within a non-compliant vault and cannot tolerate significant perturbations in cell size. Therefore, brain cells have developed a coordinated array of adaptive mechanisms designed to modulate the cytosolic content of osmotically active solutes in response to alterations in the osmolality of the extracellular fluid. This process is controlled by various hormones including arginine vasopressin, insulin, and estrogen, and is subject to changes during development. The bulk of the change in cell content of osmolytes involves inorganic electrolytes. However, excessive variation in the cytosolic ionic strength has deleterious effects on protein structure and enzyme function. Therefore, brain cells have developed the capacity to accumulate or extrude various organic osmolytes in order to adjust the cytosolic osmolality without adversely affecting cell function. These solutes are termed non-perturbing osmolytes and belong to one of three classes of molecules: amino acids, carbohydrates and polyhydric sugar alcohols, or methylamines. Cerebral cells regulate the cytosolic content of organic osmolytes primarily by altering the transmembrane flux of these solutes. There are features of the cell volume regulatory response that are shared by the brain and kidney cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: We have investigated the role of triglyceride-fatty acid cycling in amplifying control of the net flux of fatty acids in response to exercise and in recovery from exercise. Five normal volunteers were infused with [1-13C]palmitate and D-5-glycerol throughout rest, 4 h of treadmill exercise at 40% maximum O2 consumption, and 2 h of recovery. Total fat oxidation was quantified by indirect calorimetry. Lipolysis (rate of appearance of glycerol) increased from 2.1 +/- 0.3 to 6.0 +/- 1.2 mumol.kg-1.min-1 after 30 min of exercise and progressively increased thereafter to a value of 10.5 +/- 0.8 mumol.kg-1.min-1 after 4 h. Lipolysis decreased rapidly during the first 20 min of recovery, but it was still significantly elevated after 2 h of recovery. The rate of appearance of free fatty acids followed the same pattern of response. Seventy percent of released fatty acids were reesterified at rest, and this value decreased to 25% within the first 30 min of exercise. Reesterification remained less than 35% of lipolysis until the start of recovery, at which time the value rose to 90%. In exercise, more than one-half the increase in fat oxidation could be attributed to the reduction in the percent reesterification. Most of the change in percent reesterification during exercise and recovery was caused by changes in extracellular cycling of fatty acids released into plasma. We conclude that triglyceride-fatty acid cycling plays an important role in enabling a rapid response of fatty acid metabolism to major changes in energy metabolism.
Abstract: We examined the proposal that preischemic hyperglycemia causes exaggerated brain damage by decreasing intracellular or extracellular pH to below a specified threshold value. We also provide a critical appraisal of two related hypotheses. The first is that hyperglycemia enhances brain damage by causing excessive intraglial acidosis; the second, that the critical degree of acidosis is reached not during the ischemia but when recirculation is instituted. The following conclusions are drawn. First, the evidence is inconclusive in favor of marked compartmentation of H+ during ischemia, based on a discontinuous delta lactate/delta PCO2 relation and on direct intracellular pH measurements. In fact, results obtained with identical techniques in normoglycemic animals suggest that the acid compartment assumed to be glia is very small and may be of another origin. Second, although recirculation may give rise to a further increase in either extracellular or intracellular acidosis under certain conditions, this acidosis is not a prerequisite for increased tissue damage or infarction. Third, a critical appraisal of reports supports the contention that enhanced damage is triggered below a specified threshold pH value. In complete or near-complete ischemia, this value corresponds to a tissue lactate content of 17-20 mM.kg-1 wet wt. No correlation exists between subthreshold values for delta lactate and the severity of tissue damage. Furthermore, hyperglycemia cannot be expected to enhance damage if conditions prevent lactate from reaching threshold values or if they uncouple changes in lactate and pH.
Abstract: The effect of an intravenous infusion of human endothelin-1 on blood pressure and plasma concentrations of endothelin-1, potassium, sodium, renin, aldosterone, and atrial natriuretic factor was investigated in six healthy, sodium-loaded men. During the peptide’s exogenous application (1.0, 2.5, and 5.0 ng/kg.min), its plasma concentrations rose from a basal value of 1.2 +/- 0.3 to 3.2 +/- 1.9, 9.9 +/- 7.6, and 56.5 +/- 50.3 pmol/l (p less than 0.01), respectively, and mean blood pressure rose from a basal value of 87.1 +/- 7.3 to 92.6 +/- 8.2 mm Hg (p less than 0.01). A rise in serum concentrations of potassium (from 4.0 +/- 0.3 to 4.6 +/- 0.2 mmol/l; p less than 0.005) and a concomitant fall in serum concentrations of sodium (from 142.7 +/- 1.0 to 139.5 +/- 2.3 mmol/l; p less than 0.05) was seen in each subject. Plasma concentrations of renin, aldosterone, and atrial natriuretic factor did not change during the infusion of endothelin-1. Thus, in the doses used, endothelin-1 induces a rise in blood pressure and serum potassium concentrations.
Abstract: The role of the hypothalamic paraventricular nucleus (PVN) in thyroid hormone regulation of TSH synthesis during hypothyroidism was studied in adult male rats that were normal (n = 10), had primary hypothyroidism with sham lesions in the hypothalamus (n = 17), and had primary hypothyroidism with PVN lesions (n = 14). Two and 4 weeks after initiation of treatment, plasma levels of thyroid hormones (TSH, corticosterone and PRL) and pituitary content of TSH beta and alpha-subunit mRNA were measured. TRH mRNA levels in the PVN were determined by in situ hybridization histochemistry. At 2 weeks, despite a decrease in plasma free T4 in both hypothyroid groups, plasma TSH levels increased, but to a lesser degree, in the hypothyroid PVN lesioned compared to hypothyroid sham-lesioned group (7.8 +/- 1.3 vs. 20.5 +/- 1.1 ng/dl; P less than 0.05). Similarly, at 4 weeks, the hypothyroid PVN-lesioned group demonstrated a blunted TSH response compared to the hypothyroid sham-lesioned group (6.8 +/- 0.7 vs. 24.0 +/- 1.3 ng/dl; P less than 0.05). Plasma corticosterone and PRL did not significantly differ between sham-lesioned and PVN-lesioned groups. TSH beta mRNA levels markedly increased in hypothyroid sham-lesioned rats compared to those in euthyroid controls at 2 weeks (476 +/- 21% vs. 100 +/- 39%; P less than 0.05) and 4 weeks (1680 +/- 270% vs. 100 +/- 35%; P less than 0.05). In contrast, TSH beta mRNA levels did not increase with hypothyroidism in the PVN-lesioned group compared to those in euthyroid controls at 2 weeks (140 +/- 16%, P = NS) and only partially increased at 4 weeks (507 +/- 135; P less than 0.05). alpha mRNA levels at 4 weeks markedly increased in hypothyroid sham-lesioned rats compared to those in euthyroid controls (1121 +/- 226% vs. 100 +/- 48%; P less than 0.05), but did not increase in the hypothyroid PVN-lesioned rats (61 +/- 15%; P = NS). TRH mRNA in the PVN increased in the hypothyroid sham-lesioned rats compared to those in euthyroid controls (16.6 +/- 1.3 vs. 4.8 +/- 1.2 arbitrary densitometric units; P less than 0.05), and TRH mRNA was not detectable in the PVN of hypothyroid-lesioned rats at 2 weeks. In summary, lesions in rat PVN prevented the full increase in plasma TSH, pituitary TSH beta mRNA, and alpha mRNA levels in response to hypothyroidism. Thus, factors in the PVN are important in thyroid hormone feedback regulation of both TSH synthesis and secretion.
Abstract: The currently available automatic implantable cardioverter-defibrillator has proven highly successful for termination of ventricular tachycardia and fibrillation. Newer devices, however, permit lower energy shocks to be delivered initially and longer episodes of arrhythmia to occur before shocks are delivered. These changes may result in longer durations of arrhythmia before successful termination. Little is known about the effects of the duration of ventricular fibrillation on the efficacy of defibrillating shocks. In this study, we examined the efficacy of defibrillating shocks in 22 patients undergoing automatic implantable cardioverter-defibrillator implantation or generator change. Defibrillating shocks ranging from 300 to 600 V (5.9-24.2 J) were delivered in matched pairs after 5 and 15 seconds of ventricular fibrillation. For the 300-V shocks (5.9 J), defibrillation was accomplished in 82% of patients when the shocks were given after 5 seconds of ventricular fibrillation and in only 45% of patients when the shocks were delivered after 15 seconds (p less than 0.01). At higher energies, there was no difference in the efficacy of defibrillation shocks delivered after 5 compared with 15 seconds of ventricular fibrillation. The postshock aortic, systolic, and diastolic blood pressures were significantly lower when the shocks were given after 15 seconds of ventricular fibrillation than after only 5 seconds. We conclude that the duration of ventricular fibrillation affects defibrillation efficacy especially at energies that are relatively low compared with maximal device outputs and that longer episodes of ventricular fibrillation cause more postshock hemodynamic depression. These observations have implications for defibrillation threshold testing at the time of device implantation and for the design and programming of future automatic implantable antitachycardia devices.
Abstract: Hypoperfusion states cause lactic acidosis, and the acidemia further reduces the inadequate cardiac output. Conceivably, the adverse effect of lactic acidemia on cardiac output is due to depressed contractility demonstrated in isolated myocardium. Alternatively, factors governing venous return cause a relative hypovolemic state and/or acidemic pulmonary vasoconstriction-induced right ventricular dysfunction. We reasoned that examination of left ventricular pressure-volume relationships at end systole and end diastole would determine which of these potential mechanisms accounted for reduced cardiac output during progressive lactic acidosis in anesthetized, mechanically ventilated dogs. Left ventricular (LV) volume was estimated from two pairs of epicardial ultrasonic crystals placed in the anterior-posterior and longitudinal planes, and LV pressure was obtained rom a catheter-tipped transducer. During progressive acidemia induced by a continuous intravenous infusion of 0.5 N lactic acid, cardiac output, stroke volume, and mean systemic arterial pressure fell significantly while mean pulmonary artery pressure and right atrial pressure increased significantly. These variables did not change with time in control (no-acid infusion) dogs. Lactic acidemia caused a 40% reduction in stroke volume, which could be attributed to depressed LV contractility, characterized by a decrease in maximum dP/dt as well as a fall in slope (Emax) with no change in volume intercept (Vo) of the left ventricular pressure-volume relationship at end systole. Neither the measured left ventricular end-diastolic pressure nor the estimated left ventricular end-diastolic volume (LVEDV) decreased with acidemia, suggesting that the reduced venous return did not result from relative hypovolemia. However, acidemic pulmonary hypertension may have interfered with the expected response to myocardial depression, which is an increase in LVEDV.
Abstract: Seventeen essential hypertensive patients with normal renal function were treated with a new non-sulphydryl orally active angiotensin converting enzyme (ACE) inhibitor, benazepril, 10 mg given once or twice daily, according to diastolic blood pressure levels, for 6 weeks. In all patients, changes in blood pressure, systemic and renal hemodynamics, plasma renin activity and urinary aldosterone and albumin excretions were assessed at the end of a 2-week placebo run-in period and at the end of the study. Benazepril monotherapy controlled blood pressure well. No changes in cardiac output, heart rate or stroke volume were observed, while peripheral vascular resistance was significantly decreased (-11%, P less than 0.05). Plasma volume was unaltered. The glomerular filtration rate was stable, but effective renal plasma flow was increased because of the marked reduction in renal vascular resistance (-35%) and, therefore, the filtration fraction was decreased. Urinary albumin excretion remained unchanged. A significant increase in plasma renin activity (P less than 0.001) and a decrease in urinary aldosterone excretion were seen. No side effects were observed during the treatment period. In conclusion, our results suggest that benazepril alone is an effective antihypertensive agent in patients with essential hypertension. The blood pressure lowering effect is due mainly to systemic vasodilation and is observed up to 24 h after administration of the drug. The vasodilation appears to be more consistent in the renal than in the systemic circulation.
Abstract: The changes in plasma immunoreactive atrial natriuretic factor (iANF) and urinary Na excretion that occur in response to an oral load of Na and to infusion of synthetic atrial natriuretic factor (ANF) were examined in conscious dogs with an arteriovenous (AV) fistula and chronic compensated high-output heart failure. After ingestion of a meal containing 125 meq Na, plasma iANF and right atrial pressure increased from high basal levels of 506 +/- 46 pg/ml and 96 +/- 5 mmH2O to peak responses of 728 +/- 43 pg/ml (P less than 0.05) and 104 +/- 6 mmH2O (P less than 0.05). These increases were associated with a brisk postprandial natriuresis and diuresis of a magnitude previously observed in normal dogs. Synthetic ANF infusions that achieved plasma iANF levels of similar and higher magnitude to those observed during the feeding experiments did not produce a significant natriuresis in these AV fistula dogs. In separate series of experiments, chronic effects of normal and low-Na diets on daily Na excretion and postabsorptive plasma iANF, renin, and aldosterone were studied in normal and AV fistula dogs. During the normal Na diet of 40 meq/day, both groups had normal levels of renin and aldosterone, but Na balance was achieved in AV fistula animals in the presence of a fourfold elevation in plasma iANF compared with normal dogs (P less than 0.05). During 2 wk of Na restriction, cumulative negative Na balance and marked stimulation of renin and aldosterone were similar in normal and AV fistula animals, but plasma iANF did not change significantly in either group.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Since thromboxane (Tx) can mediate the actions of angiotensin II (ANG II), we investigated interaction between these systems on the tubuloglomerular feedback (TGF) response. TGF was assessed from proximal stop-flow pressure (PSF) during orthograde perfusion of the loop of Henle (LH) between 0 and 40 nl/min. In the basal state, TGF was 11.3 +/- 0.8 mmHg. In series 1 experiments, it was unaltered by vehicle (+0.3 +/- 0.9 mmHg, n = 9, NS), was reduced by an ANG II antagonist, saralasin (-2.4 +/- 1.1 mmHg, n = 8, P less than 0.0005), and by a TxA2 antagonist SQ 29,548 (-4.8 +/- 0.6 mmHg, n = 11, P less than 0.0001). Both drugs together produced an additive blunting of TGF of -6.9 +/- 0.7 mmHg. In series 2 experiments, TGF was again unchanged by vehicle (+0.2 +/- 0.6 mmHg). It was reduced by -4.4 +/- 0.2 mmHg (P less than 0.0001) by an angiotensin-converting enzyme inhibitor CGS-14,824A (50 mg/kg, n = 5) and by -4.0 +/- 0.4 mmHg (P less than 0.001) by a Tx synthesis inhibitor CGS-13,080 (50 mg/kg, n = 7). Although both drugs together produced a further blunting of the response of -6.1 +/- 0.4 mmHg, this was significantly (P less than 0.001) less than additive. In both series, a response (averaging 3.5 +/- 0.3 mmHg) persisted in all rats given combined antagonists or inhibitors. In conclusion, both ANG II and TxA2 can modulate TGF-induced changes in PSF independently, and the response probably requires other system(s) in addition to ANG II and TxA2.
Abstract: Exquisite sensitivity of normal parathyroid glands to small changes in ambient calcium concentrations and impaired sensitivity in primary hyperparathyroidism have been shown in vitro. Using an assay for PTH that detects rapid changes in PTH secretion (N-terminal-specific RIA; normal range, less than 3-33 pg/mL), we determined PTH suppressibility in response to a standardized dose of oral calcium in normal subjects and patients with primary hyperparathyroidism. Nine normal subjects were given oral calcium (25 mg/kg), and blood was analyzed half-hourly for 3 h for calcium and N-terminal PTH (N-PTH). Serum calcium rose by 0.34 +/- 0.06 mg/dL (0.085 +/- 0.015 mmol/L), and N-PTH levels declined rapidly from 15.3 +/- 1.4 to 4.2 +/- 1.1 pg/mL (-73 +/- 6%; P less than 0.01). In six subjects N-PTH concentrations became undetectable. Nine patients with primary hyperparathyroidism were tested in the same manner. Serum calcium rose by 0.53 +/- 0.1 mg/dL (0.13 +/- 0.025 mmol/L), and N-PTH levels declined less, from 66 +/- 14 to 52 +/- 12 pg/mL (-21 +/- 4%; P less than 0.05). In none of the patients was the PTH reduced to less than 20 pg/mL. These results illustrate in vivo that the PTH response to oral calcium in primary hyperparathyroidism is markedly different from that in normal subjects.
Abstract: The use of pulsatile GnRH to treat infertile women who do not ovulate has been shown to be safe, simple, and effective and the preferred method of inducing ovulation in appropriately selected patients who are resistant to treatment with clomiphene citrate. Treatment with GnRH is particularly effective for restoring ovulation in patients with idiopathic hypogonadotrophic hypogonadism and partially recovered weight-related amenorrhoea, but less successful in patients with polycystic ovary syndrome and organic hypothalamic pituitary disease. Based on personal experience, we advocate routine use of the subcutaneous route, using 15 micrograms per pulse every 90 min, and we monitor the patient’s progress by serial ultrasound scanning and measurement of serum gonadotrophin and oestradiol concentrations. If the patient does not respond we recommend adding treatment with clomiphene citrate (Homburg et al, 1988b). Treatment with intravenous GnRH is reserved for women who do not respond to the above combination of drugs. We do not treat patients with GnRH until their body mass index is in the normal range (between 20-25) and we avoid GnRH treatment in patients with hypersecretion of LH during the follicular phase. If LH concentrations are raised, an alternative method of treatment is recommended, such as ovarian diathermy (Armar et al, 1990). Finally, the question of whether GnRH deficiency in patients with hypogonadotrophic hypogonadism is caused by a specific genetic lesion is not yet fully resolved. Yang-Feng et al (1986) used a cDNA clone encoding the human GnRH precursor molecule in order to assign the GnRH gene to a particular human chromosome. They found a single site for GnRH sequences in the human genome and that the gene coding for GnRH is located on the short arm of chromosome 8. Experiments in the congenitally hypogonadal mouse have shown that it is possible to restore gonadal development and gametogenesis by gene transfer (Mason et al, 1987). Clearly an abnormality at the level of the genome may be responsible for the secretory defect in patients with hypogonadotrophic hypogonadism, but it has yet to be defined (Weiss et al, 1989). Presumably elucidation awaits the development of more refined methods because both the genetics and the clinical associations of GnRH deficiency are most persuasive. Meanwhile replacement treatment with GnRH provides a simple and safe form of treatment for managing the clinical syndromes of GnRH deficiency.
Abstract: We studied the bronchial vascular response to downstream pressure elevation by increasing left atrial pressure (Pla) and mean airway pressure (Paw) with positive end-expiratory pressure (PEEP). In seven pentobarbital-anesthetized ventilated sheep, we cannulated and perfused the bronchial branch of the bronchoesophageal artery. Steady-state bronchial artery pressure- (Pba) flow (Qba) relationships were obtained as Pla was increased by inflating a balloon catheter in the left atrium. Bronchial vascular resistance (BVR), determined by the inverse slope of the Pba-Qba relationship, increased significantly from 3.2 +/- 0.3 (SE) mmHg.ml-1.min-1 at a Pla of 2.9 +/- 0.7 mmHg to 5.1 +/- 0.5 mmHg.ml-1.min-1 at a Pla of 20.1 +/- 2.0 mmHg (P = 0.0007). Under control Qba (23.3 +/- 1.2 ml/min), these changes in BVR represent a 3.6 +/- 0.7-mmHg increase in Pba per mmHg increase in Pla. The zero-flow pressure increased 1.3 +/- 0.2 mmHg/mmHg increase in Pla. After infusion of papaverine, a smooth muscle paralytic agent, directly into the bronchial artery, BVR decreased significantly to 1.3 +/- 0.7 mmHg.ml-1.min-1 (P = 0.0004). Under these dilated conditions, BVR was unaltered by increases in Pla. After papaverine administration, Pba increased 0.9 +/- 0.1 and 1.2 +/- 0.1 mmHg/mmHg increase in Pla during control and zero-flow conditions, respectively. Thus the effect of Pla elevation on BVR appears to be dependent on active smooth muscle responses. Paw elevation had similar effects on Pba. Under control Qba, Pba increased 2.2 +/- 0.4 mmHg/mmHg increase in Paw.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Mechanisms of accelerated proteolysis were compared in denervated and unweighted (by tail-cast suspension) soleus muscles. In vitro and in vivo proteolysis were more rapid and lysosomal latency was lower in denervated than in unweighted muscle. In vitro, lysosomotropic agents (eg, chloroquine, methylamine) did not lessen the increase in proteolysis caused by unweighting, but abolished the difference in proteolysis between denervated and unweighted muscle. Leucine methylester, an indicator of lysosome fragility, lowered latency more in denervated than in unweighted muscle. 3-Methyladenine, which inhibits phagosome formation, increased latency similarly in all muscles tested. Mersalyl, a thiol protease inhibitor, and 8-(diethylamino)octyl-3,4,5-trimethoxybenzoate hydrochloride (TMB-8), which antagonizes sarcoplasmic reticulum release of Ca2+, reduced accelerated proteolysis caused by unweighting without diminishing the faster proteolysis due to denervation. Calcium ionophore (A23187) increased proteolysis more so in unweighted than control muscles whether or not Ca2+ was present. Different mechanisms of accelerated proteolysis were studied further by treating muscles in vivo for 24 hours with chloroquine or mersalyl. Chloroquine diminished atrophy of the denervated but not the unweighted muscle, whereas mersalyl prevented atrophy of the unweighted but not of the denervated muscle, both by inhibiting in vivo proteolysis. These results suggest that (1) atrophy of denervated, but not of unweighted, soleus muscle involves increased lysosomal proteolysis, possibly caused by greater permeability of the lysosome, and (2) cytosolic proteolysis is important in unweighting atrophy, involving some role of Ca2(+)-dependent proteolysis and/or thiol proteases.
Abstract: The role of the medullary collecting duct in pressure natriuresis has not been established. In vivo microcatheterization was used to study the effect of an acute increase in blood pressure induced by bilateral carotid artery and vagal nerve ligation on medullary collecting duct function in anaesthetized rats. Increased fluid and electrolyte excretion during pressure natriuresis were accompanied by increased delivery of water, sodium, chloride, and potassium to the beginning of the medullary collecting duct, a change that was significantly greater than in a second series of time-control animals. These increases in delivery were within the range for which constant fractional NaCl reabsorption had been found previously. However, during increased perfusion pressure, reabsorption of both sodium and chloride in the medullary collecting duct as a fraction of delivered load were reduced from 81 +/- 4.1 to 51 +/- 9.3% (p less than 0.01) and from 65.7 +/- 6.0 to 42.7 +/- 9.1% (p less than 0.01), respectively. No significant changes in medullary collecting reabsorption were seen in the time controls. We conclude that increased perfusion pressure, in addition to increasing delivery to the medullary collecting duct, also inhibits sodium chloride reabsorption in this nephron segment.
Abstract: This study was carried out to determine whether hepatic glucose production (HGP) could be suppressed in normal subjects by infusing different amounts of glucose, in the absence of significant changes in steady state plasma glucose (SSPG) or insulin (SSPI) concentrations. Consequently, subjects were infused with somatostatin (215 nmol/h), insulin (28.7 pmol/m2.min), and amounts of glucose varying from 0-200 mumol/m2.min in the absence or presence of glucagon (5.2 pmol/m2.min). SSPI concentrations were constant (60-70 pmol/L) during these studies, and values for the total glucose appearance rate (glucose infusion rate plus HGP) and SSPG did not vary significantly as a function of the rate of exogenous glucose infusion. However, values for HGP fell in response to increases in glucose infusion rate and could be suppressed to approximately 50% of the original value despite the fact that SSPG, SSPI, and glucose appearance rate did not change significantly. These data indicate that HGP can be regulated by varying the rate of exogenous glucose infusion during glucose clamp studies.
Abstract: Changes in intra- and extracellular free calcium concentration were evaluated with ion-selective microelectrodes during periods of anoxia and ischemia in three different regions of intact rat brain. Recordings stable for at least 2 min and in most cases for 4-6 min were chosen for analysis. Under normoxic conditions neuronal [Ca2+]i varied between less than 10(-8) and 10(-7) M from cell to cell but no systematic regional differences were observed. Elimination of O2 or interruption in blood flow caused, within 30-60 s, slight intracellular alkalinization followed by a small rise in [Ca2+]i, a mild degree of hyperpolarization, and disappearance of electrical activity in the cortex, in that order. It is postulated that a decline in cellular energy levels, as manifested by H+ uptake associated with creatine phosphate hydrolysis, leads to an increase in [Ca2+]i, which activates Ca2(+)-dependent K+ channels and consequently enhances gK. 2-4 min later there was a sudden, large rise in [K+]e, a fall in [Ca2+]e and a rapid elevation of [Ca2+]i. The magnitude of the latter was greatest in a high proportion of hippocampal neurons in area CA1 and some cortical cells, while it was smallest and relatively delayed in thalamic neurons. In the hippocampus area CA1 increases in [Ca2+]i to as much as 6-8 x 10(-4) were observed; some of these could be reversed when O2 or blood flow were restored to normal. Pretreatment of animals with ketamine and MK-801, antagonists of excitatory amino acid transmitters, markedly slowed and decreased the rises in [Ca2+]i. The effects of the two agents were most pronounced in the hippocampus. It is concluded that the receptor-operated channels are largely responsible for Ca2+ entry into certain cells during hypoxia/ischemia. This pathway may be of primary importance in parts of the hippocampus and cortex, regions of the brain that are particularly vulnerable to O2 deprivation and which receive high glutamatergic input and have an abundance of excitatory amino acid receptors.
Abstract: In Vero cells, Na(+)-H+ antiport as well as Na(+)-coupled and Na(+)-independent Cl(-)-HCO3- antiport are involved in regulation of cytosolic pH (pHi) after large (unphysiological) deviations from neutrality. In this paper we have studied to which extent each of the three antiports is involved in regulation of pHi after small deviations from neutrality expected to occur under physiological conditions. At physiological extracellular pH (pHo), inhibition of Na(+)-H+ exchange by amiloride did not alter pHi. At neutral and alkaline pHo, pHi was found to be lower in the presence of HCO3- than in its absence, whereas at acidic pHo, pHi was higher in the presence of HCO3- than in its nominal absence. Above pHi 6.5, the activity of the Na(+)-coupled Cl(-)-HCO3- antiport was higher than the Na(+)-H+ antiport. After a small reduction of pHi, the recovery of steady-state pHi was entirely dependent on Na(+)-coupled Cl(-)-HCO3- antiport, whereas after more pronounced acidification, also Na(+)-H+ exchange contributed to the acid extrusion. The Na(+)-independent Cl(-)-HCO3- antiport, which acts as an acidifying mechanism, was strongly activated at pHi greater than 7.1. The results indicate that at physiological pHo the steady-state pHi is largely determined by the activity of the two Cl(-)-HCO3- antiports, and they suggest that Na(+)-H+ exchange does not influence the resting pHi under these conditions.
Abstract: Stimulation of proximal tubular fluid reabsorption by peritubular angiotensin II (Ang II) was examined by split-drop micropuncture in 5- and 12-week-old spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto rats (WKY). In WKY, the maximum stimulation occurred at 10(-11) mol/l and the response did not vary with age. In 5-week-old SHR, the dose-response relationship was similar in shape and in the extent of the maximum response but was shifted one half-logarithmic step to the right, indicating decreased sensitivity to Ang II. In contrast, the dose-response relationship was shifted one half-logarithmic step to the left in 12-week-old SHR compared with WKY. Alterations in the responsiveness of the proximal tubule to Ang II in young SHR could contribute to sodium retention observed during development of hypertension in these rats.
Abstract: The relation between hypertensive glomerular damage and arteriolar diameter was examined in a microvascular cast study in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. The blood pressure and urinary protein excretion increased progressively in the DOCA rats. In controls afferent arteriolar diameters increased during the course of the experiment, and efferent arteriolar diameters remained unchanged. In the DOCA rats, however, afferent arteriolar diameters did not change significantly, while efferent arteriolar diameters increased. Histological studies showed severe arteriolosclerosis and glomerulosclerosis in the DOCA rats. The results show that these arteriolar changes might contribute to the reduction of glomerular capillary pressure in the development of DOCA-salt hypertension. However, they are not sufficient to protect glomeruli from hypertensive damage.
Abstract: Acute saline volume expansion (VE) in the developing animal is associated with a blunted natriuretic response when compared with that in adults. Recent studies have suggested that renal interstitial hydrostatic pressure (RIHP) plays an important role in mediating VE-induced natriuresis in the adult. The purpose of our study was to determine whether abnormalities in the RIHP response to VE could be involved in the blunted natriuretic response in the developing animal. The effect of an acute saline load (5% body wt) on RIHP and sodium excretion was examined in adult pigs (greater than 70 d) and piglets (26-43 d). In response to an acute saline load, the piglets excreted significantly less sodium than the adults (1.7 +/- 0.5 versus 3.8 +/- 0.7 mumol/min/g kidney wt). The increase in fractional excretion of sodium in response to VE was also significantly less in the piglets. There was no significant change in GFR in either group. Associated with the blunted natriuretic response in the piglet was an absence of an increase in RIHP (6.1 +/- 1.1 versus 6.1 +/- 1.6 mm Hg) in response to VE. In contrast, the adult pig, which exhibited a normal natriuretic response, showed a significant increase in RIHP (8.8 +/- 1.3 to 12.3 +/- 1.5 mm Hg) during VE. When RIHP was prevented from increasing during VE in the adult pigs, the natriuretic response was significantly attenuated, as it was in the piglets.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: One hundred ninety-nine patients with out-of-hospital cardiac arrest persisted in ventricular fibrillation after the first defibrillation attempt and were then randomly assigned to receive either epinephrine or lidocaine before the next two shocks. The resulting electrocardiographic rhythms and outcomes for each group of patients were compared for each group and also compared with results during the prior 2 years, a period when similar patients primarily received sodium bicarbonate as initial adjunctive therapy. Asystole occurred after defibrillation with threefold frequency after repeated injection of lidocaine (15 of 59, 25%) compared with patients treated with epinephrine (four of 55, 7%) (p less than 0.02). There was no difference in the proportion of patients resuscitated after treatment with either lidocaine or epinephrine (51 of 106, 48% vs. 50 of 93, 54%) and in the proportion surviving (18, 19% vs. 21, 20%), respectively. Resuscitation (64% vs. 50%, p less than 0.005) but not survival rates (24% vs. 20%) were higher during the prior 2-year period in which initial adjunctive drug treatment for persistent ventricular fibrillation primarily consisted of a continuous infusion of sodium bicarbonate. The negative effect of lidocaine or epinephrine treatment was explained in part by their influence on delaying subsequent defibrillation attempts. Survival rates were highest (30%) in a subset of patients who received no drug therapy between shocks. We conclude that currently recommended doses of epinephrine and lidocaine are not useful for improving outcome in patients who persist in ventricular fibrillation.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Regulation of urea transport by vasopressin in inner medullary collecting duct (IMCD) cells is thought to be important for the urinary concentrating mechanism. Isolated tubule perfusion studies suggest the existence of a saturable urea carrier. We have measured 14C-urea efflux in IMCD cells which were freshly isolated and grown in primary culture. Cells were isolated from rat papilla by collagenase digestion and hypotonic shock. In suspended cells, 14C-urea efflux (Jurea) from loaded cells was exponential with time constant 59 +/- 3 sec (SEM, n = 6, 23 degrees C). Jurea had an activation energy of 4.1 kcal/mole and was inhibited 42 +/- 7% by 0.25 mM phloretin and 30-40% by the high affinity urea analogues dimethylurea and phenylurea. Jurea was increased 40-60% by addition of vasopressin (10(-8) M) or 8-bromo-cAMP (1 mM); stimulated Jurea was inhibited 55 +/- 8% by the kinase A inhibitor H-8. Phorbol esters and epidermal growth factor did not alter Jurea. IMCD cells grown in primary culture were homogeneous in appearance with greater than fivefold stimulation of cAMP by vasopressin. The exponential time constant for urea efflux was 610 +/- 20 sec (n = 3). Jurea was not altered by vasopressin, cAMP or phloretin. Another function of in vivo IMCD cells, vasopressin-dependent formation of endosomes containing water channels, was absent in the cultured cells. These results demonstrate presence of a urea transporter on suspended IMCD cells which is activated by cAMP and inhibited by phloretin and urea analogues. The urea transporter and its regulation by cAMP, and cAMP-dependent apical membrane endocytosis, are lost after growth in primary culture.
Abstract: In conclusion, the pathogenesis of electrical injury is more complex than previously thought. Cellular damage occurs both by heating and electroporation. The relative contributions of heat and electroporation depend on the duration of electric current passage, the orientation of the cells, their location, and other factors. If the contact is brief, nonthermal mechanisms of cell damage may be most important. If the contact is much longer, heat damage will be most destructive. The characteristic time before heat damage predominates is probably a function of the electrical field strength in the tissue. If heat damage predominates, the injury may not be limited just to the plasma membrane but to other cell membranes as well. This is unlikely to be reversible. These parameters should also determine the pattern of injury. Damage by Joule heating is not known to be dependent on cell size, whereas larger cells are more vulnerable to membrane breakdown by electroporation. Cells do survive transient plasma membrane rupture under appropriate circumstances. Thus, if electroporation is the mechanism of damage, injured tissue may be salvageable; the challenge is to identify a technique that promptly reseals the damaged membranes. Current therapy requires a fully staffed and equipped intensive care unit, available operating suites, and the full range of available medical specialists. Major teaching hospitals are usually the prime candidates for operating an electric trauma unit. After initial resuscitation, efforts should be directed primarily toward preventing additional tissue loss mediated through a compartment syndrome. Renal and cardiac failure resulting from the release of intracellular muscle contents into the circulation must be prevented. Attention can then be directed toward maximizing tissue salvage and preventing late skeletal and neuromuscular complications. Finally, complex reconstructive procedures are needed to optimize the functional value of the remaining tissue. The eventual reconstructive goals should be kept in mind throughout the acute care of the patient.
Abstract: This study examined whether variability among healthy young adults in resting metabolic rate, normalized for the amount of metabolically active tissue (assessed by total body potassium), is related to protein turnover. Resting metabolic rate was measured by indirect calorimetry for 2 h in 26 men and 21 women, 19-33 yr old, with simultaneous estimation of protein turnover during a 4-h infusion of L-[1-13C]leucine. After adjusting metabolic rate for total body potassium, the standard deviation was only 89 kcal/day, or 5.5% of the average value. There was a high correlation between leucine flux (an index of proteolysis) and metabolic rate (r = 0.84) and between the nonoxidized portion of leucine flux (an index of protein synthesis) and metabolic rate (r = 0.83). This relationship was weaker, but still significant, after adjusting leucine metabolism and metabolic rate for total body potassium (r = 0.36 for leucine flux vs. metabolic rate, r = 0.33 for nonoxidized portion of leucine flux vs. metabolic rate, P less than 0.05). The regression analysis suggested that the contribution of protein turnover to resting metabolic rate was approximately 20% in an average subject. Metabolic rate and protein turnover were highest in the subjects with the greatest amount of body fat, even after accounting for differences in whole body potassium. Neither resting metabolic rate nor protein turnover was related to total or free concentrations of thyroxine or triiodothyronine, within the euthyroid range.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: The chronic reserve for the secretion of atrial natriuretic factor (ANF) was studied in conscious dogs with an arteriovenous (a-v) fistula, a model of high-output heart failure. After the first 7 days of marked sodium retention after creation of the a-v fistula, the animals regained sodium balance for the subsequent 3 wk. This compensatory natriuresis occurred in the presence of significant increases in right atrial pressure and was associated with marked and sustained elevations in plasma ANF and with the return of plasma renin and aldosterone to base-line values. The cardiac reserve for ANF secretion was further evaluated in these dogs with compensated high-output heart failure during additional progressive elevations in cardiac filling pressures induced by 3 wk of deoxycorticosterone acetate (DOCA) administration. During the DOCA regimen, plasma ANF increased an additional twofold from its high base line. Arterial blood pressure increased by 6-12 mmHg, and plasma renin activity was suppressed. However, the animals consistently retained sodium, and the high plasma levels of ANF were unable to counterbalance the sodium-retaining actions of DOCA. After termination of DOCA, the dogs exhibited a marked natriuresis, and all the hemodynamic and hormonal parameters returned to pre-DOCA control levels. This longitudinal study demonstrates that the cardiac reserve for chronic ANF secretion is well maintained in dogs with an a-v fistula during progressive cardiac volume overload. The present results suggest that the ANF endocrine system may represent one chronic compensatory mechanism to achieve sodium balance in heart failure when there is concomitant normalization of the renin-aldosterone system.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: In this study we measured (n = 6) the phosphocreatine-to-inorganic phosphate ratio (PCr/Pi), Pi, and pH with 31P-nuclear magnetic resonance (31P-NMR) in the human forearm during static work at 30% of maximal voluntary contraction (MVC) for 2 min followed immediately by 3 min of circulatory arrest (forearm arterial occlusion). Static exercise, with its central volitional and skeletal muscle metabolic and mechanical afferent components, caused a rise in heart rate (HR, 32%), blood pressure (BP, 29%), and calf vascular resistance (calf R, 30%). During forearm occlusion after static exercise, HR returned to base line, the increase in BP was attenuated by 30%, and calf R remained elevated and unchanged. The percent change in calf R was correlated with forearm cellular pH (R = 0.56, P less than 0.001) but only weakly associated with PCr/Pi (R = 0.33, P less than 0.042). 30% MVC for 1 min followed by arterial occlusion (3 min) reduced PCr/Pi by 65% and pH by 0.16 U (P less than 0.05). Calf R was unchanged. Circulatory arrest alone (20 min) caused no change in either pH or calf R but large changes in PCr/Pi (50% reduction). We conclude that 1) there is an association between forearm cellular acidosis and calf vasconstriction during static forearm exercise and 2) large changes in PCr/Pi without concomitant changes in pH are not associated with changes in calf R.
Abstract: We studied the effect of ouabain (digitalis) on the relation between left ventricular (LV) O2 consumption (VO2) and pressure-volume (P-V) area (PVA) in 7 excised cross-circulated canine heart preparations. PVA is a measure of the total mechanical energy generated by LV contraction and was obtained as the specific area in the P-V diagram circumscribed by the end-systolic P-V line, end-diastolic P-V curve, and the systolic P-V trajectory. Ouabain (0.11 mg, intracoronary-arterially) increased Emax (LV contractility index) by 58 +/- 44% (mean +/- SD) from 7.8 +/- 3.4 to 12.0 +/- 4.8 mmHg/(ml/100 g LV). PVA correlated linearly with LV VO2 per beat in either the control (r greater than 0.97) or the ouabain run (r greater than 0.96) in individual hearts. Ouabain increased the VO2-axis intercept of the regression line of VO2 on PVA from 0.029 +/- 0.004 in the control run to 0.036 +/- 0.009 ml O2/beat/100 g LV without significantly changing the slope [(1.53 +/- 0.24).10(-5) ml O2/(mmHg/ml)] of the regression line. This slope is equivalent to the contractile efficiency value of 44 +/- 6% from the excess VO2 above unloaded VO2 to PVA. The parallel elevation of the VO2-PVA relation with ouabain was similar to the results produced by epinephrine and Ca2+ in our previous studies. Ouabain, like epinephrine and Ca2+, did not change the contractile efficiency from the PVA-dependent fraction of VO2 to PVA.
Abstract: We examined the clinical relevance of a rise in fasting blood glucose (BG) between 0300 and 0600 in 97 patients with insulin-dependent diabetes mellitus (IDDM) receiving sequentially conventional (CT) and basal-bolus (BBIT) insulin therapies and assessed the impact of one potential causal factor, i.e., posthypoglycemic hyperglycemia, with 231 BG profiles (97 during CT, 134 during BBIT) in which BG was measured every 3 h over a 24-h period. A rise in BG between 0300 and 0600 occurred in 157 of 231 (68%) profiles. The mean magnitude of this rise was 56 +/- 39 mg/dl and was lower (P less than .05) during BBIT (48 +/- 35 mg/dl, n = 97) than CT (62 +/- 43 mg/dl, n = 97). A dawn rise (between 0300 and 0600) greater than 50 mg/dl occurred in 40 of 97 (41%) profiles during CT and 26 of 97 (27%) during BBIT (P less than .05). When all profiles were grouped according to the magnitude of this rise in BG, the mean daytime BG (from 0900 to 1800) was higher (P less than .05) after an 0300-0600 BG rise greater than 50 mg/dl compared with groups of profiles showing either a fall in BG or a rise less than 50 mg/dl; a rise in BG between 0300 and 0600 correlated (r = .38, P less than .0001) with the subsequent mean daytime BG. Nocturnal hypoglycemia (BG less than 60 mg/dl) recorded at 2400 and/or 0300 occurred in 57 of 231 (25%) profiles.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Renal blood flow, renal sympathetic nerve activity, and renin release responses to mental stress (Stroop’s color-word conflict test; CWT) and intravenously infused epinephrine (Epi) were evaluated in 12 healthy volunteers. The overflows of norepinephrine (NE) and dopamine (DA) to renal venous plasma were measured as indexes of nerve activity; the fractional extraction of Epi was used to assess renal catecholamine extraction from arterial plasma. At rest, NE and DA levels were higher in renal venous plasma than in arterial plasma. Arterial Epi levels were 0.26 +/- 0.04 nmol/l, and the fractional extraction of Epi by the kidney was 46 +/- 4%. CWT increased renal vascular resistance (RVR) by 48%, renal venous NE overflow by 214% (to 708 +/- 79 pmol/min), and DA overflow by 42% (to 34 +/- 4 pmol/min). Arterial Epi increased by 197%. The vasoconstrictor response was correlated with the NE overflow response. The increased renin release (from 75 to 247 U/min, median values; P less than 0.001) was correlated to increases in mean arterial pressure and NE and DA overflows. Epi infusion increased arterial plasma Epi and renin release dose dependently to 6.43 +/- 0.27 nmol/l and by 664%, respectively. RVR and NE and DA overflows were unchanged. Renal venous DA data support the existence of a subset of renal dopaminergic nerves. Mental stress causes renal vasoconstriction, apparently due to increased renal sympathetic nerve activity. Physiological increments of circulating Epi do not affect renal blood flow but enhance renin release markedly without apparent activation of the renal nerves in humans.
Abstract: The reflex mechanisms that produce the neurocirculatory adjustments to hemorrhagic hypotension are incompletely understood. The goal of this study was to determine if hemorrhagic hypotension in rats produces differential effects on sympathetic outflow to the adrenal gland and kidney and if the two sympathetic nerve responses are governed by different reflex mechanisms. We performed simultaneous multifiber recordings of adrenal and renal sympathetic nerve activity (SNA) during 8 minutes of sustained hemorrhagic hypotension to a mean arterial pressure of 50 mm Hg in chloralose-anesthetized Sprague-Dawley rats with a) baroreceptors intact, b) cervical vagotomy, c) sinoaortic baroreceptor denervation, and d) combined vagotomy plus sinoaortic denervation. During hemorrhagic hypotension in rats with intact baroreceptors, renal SNA decreased by 31 +/- 10% (mean +/- SEM, p less than 0.05 vs. control) and heart rate decreased from 384 +/- 13 to 365 +/- 16 beats per minute (p less than 0.05), but adrenal SNA increased by 69 +/- 10% over control (p less than 0.05). The decreases in renal SNA and heart rate were reversed by cervical vagotomy but not by atropine, which indicates vagal afferent mediation. In contrast, the increases in adrenal SNA during hemorrhage were not affected by vagotomy alone or by sinoaortic denervation alone but were markedly attenuated by combined sinoaortic denervation and vagotomy, which indicates redundancy in the baroreflex control of adrenal SNA.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Pseudorabies virus (PRV) injections of various sympathetic ganglia and the adrenal gland were made in rats. These produced immunohistochemically detectable retrograde viral infections of ipsilateral sympathetic preganglionic neurons (SPNs) and transneuronal infections of the specific sets of second order neurons in the spinal cord and brain that innervate the infected SPNs. Five cell groups in the brain appear to regulate the entire sympathetic outflow: the paraventricular hypothalamic nucleus (PVH), A5 noradrenergic cell group, caudal raphe region, rostral ventrolateral medulla, and ventromedial medulla. In addition, local interneurons in laminae VII and X of the spinal cord are also involved. Other CNS areas also became transneuronally labeled after infections of certain sympathetic ganglia, most notably the superior cervical and stellate ganglia. These areas include the central gray matter and lateral hypothalamic area. The zona incerta was uniquely labeled after stellate ganglion infections. The cell body labeling was specific. This specificity was demonstrated in the PVH where the neurons of the parvocellular PVH that form the descending sympathetic pathway were labeled in a topographic fashion. Finally, we demonstrate that the retrograde transneuronal viral cell body labeling method can be used simultaneously with either neuropeptide transmitter or transmitter synthetic enzyme immunohistochemistry.
Abstract: The CNS cell groups that innervate the sympathoadrenal preganglionic neurons of rats were identified by a transneuronal viral cell body labeling technique combined with neurotransmitter immunohistochemistry. Pseudorabies virus was injected into the adrenal gland. This resulted in retrograde viral infections of the ipsilateral sympathetic preganglionic neurons (T4-T13) and caused retrograde transneuronal cell body infections in 5 areas of the brain: the caudal raphe nuclei, ventromedial medulla, rostral ventrolateral medulla, A5 cell group, and paraventricular hypothalamic nucleus (PVH). In the spinal cord, the segmental distribution of virally infected neurons was the same as the retrograde cell body labeling observed following Fluoro-gold injections in the adrenal gland except there was almost a 300% increase in the number of cells labeled and a shift in cell group distribution. These results imply there are local interneurons that regulate the sympathoadrenal preganglionic neurons. In the medulla oblongata, serotonin (5-HT)-, substance P (SP)-, thyrotropin-releasing hormone-, Met-enkephalin-, and somatostatin-immunoreactive neurons of the raphe pallidus and raphe obscurus nuclei and the ventromedial medulla were infected. In the ventromedial and rostral ventrolateral medulla, immunoreactive phenylethanolamine-N-methyltransferase, SP, neuropeptide Y, somatostatin, and enkephalin neurons were infected. The A5 noradrenergic cells were labeled, as were some somatostatin-immunoreactive neurons in this area. In the were infected. The A5 noradrenergic cells were labeled, as were some somatostatin-immunoreactive neurons in this area. In the hypothalamus, tyrosine hydroxylase- and SP-immunoreactive neurons of the dorsal parvocellular PVH were infected. Only a few immunoreactive vasopressin, oxytocin, Met-enkephalin, neurotensin, and somatostatin PVH neurons were labeled.
Abstract: The purpose of this study was to determine the relationship between changes in efferent muscle sympathetic nerve activity (MSNA) to the lower leg and calf vascular resistance (CVR) during isometric exercise in humans. We made intraneural (microneurographic) determinations of MSNA in the right leg (peroneal nerve) while simultaneously measuring calf blood flow to the left leg, arterial pressure, and heart rate in 10 subjects before (control), during, and after (recovery) isometric handgrip exercise performed for 2.5 min at 15, 25, and 35% of maximal voluntary contraction (MVC). Heart rate and arterial pressure increased above control within the initial 30 s of handgrip at all levels, and the magnitudes of the increases at end contraction were proportional to the intensity of the exercise. In general, neither MSNA nor CVR increased significantly above control levels during handgrip at 15% MVC. Similarly, neither variable increased above control during the initial 30 s of handgrip at 25 and 35% MVC; however, during the remainder of the contraction period, progressive, parallel increases were observed in MSNA and CVR (P less than 0.05). The correlation coefficients relating changes in MSNA to changes in CVR for the individual subjects averaged 0.63 +/- 0.07 (SE) (range 0.30-0.91) and 0.94 +/- 0.06 (range 0.80-0.99) for the 25 and 35% MVC levels, respectively. During recovery, both MSNA and CVR returned rapidly toward control levels. These findings demonstrate that muscle sympathetic nerve discharge and vascular resistance in the lower leg are tightly coupled during and after isometric arm exercise in humans. Furthermore, the exercise-induced adjustments in the two variables are both contraction intensity and time dependent.
Abstract: Various theories about the genesis of dyspnea have often assumed that the sensation is similar from patient to patient and is generated by a single underlying mechanism. To investigate whether breathlessness induced in normal volunteers by different stimuli represents one or more than one sensation, we studied 30 subjects in whom breathlessness was induced by each of 8 different stimuli: breath-holding, CO2 inhalation, inhalation of CO2, with ventilation voluntarily targeted below the level dictated by chemical drive, breathing with a resistive load, breathing with an elastic load, voluntary elevation of functional residual capacity, voluntary limitation of tidal volume, and exercise. For each stimulus, subjects were asked to choose description of their sensation(s) of breathlessness from a questionnaire listing 19 descriptors. The responses from this questionnaire were evaluated using cluster analysis to search for relationships among descriptors and to identify natural groupings. We found that distinct groups of descriptors emerged, i.e., subjects could distinguish different sensations of breathlessness. In addition, we found an association between certain descriptor groups and stimuli. We conclude that the term breathlessness may encompass multiple sensations, and, therefore, may not be explainable by a single physiologic mechanism.
Abstract: Rats subjected to ammonium chloride-induced metabolic acidosis or respiratory acidosis caused by hypercapnia were given alkalinization therapy with either sodium bicarbonate or Carbicarb. Ammonium chloride induced dose-dependent systemic acidosis but did not affect intracellular brain pH. Hypercapnia caused dose-dependent systemic acidosis as well as decreases in intracellular brain pH. Sodium bicarbonate treatment resulted in systemic alkalinization and increases in arterial PCO2 in both acidosis models, but it caused intracellular brain acidification in rats with ammonium chloride acidosis. Carbicarb therapy resulted in systemic alkalinization without major changes in arterial PCO2 and intracellular brain alkalinization in both acidosis models. These data demonstrate that bicarbonate therapy of systemic acidosis may be associated with "paradoxical" intracellular brain acidosis, whereas Carbicarb causes both systemic and intracellular alkalinization under conditions of fixed ventilation.
Abstract: Nineteen males (aged 45-68 yr) were studied before and after either a period of regular endurance exercise [walk/jog 3-4 days/wk for 30 +/- 1 (SE) wk, n = 11] or unchanged physical activity (38 +/- 2 wk, n = 8) (controls) to determine the influence of physical training on cardiac parasympathetic (vagal) tone and baroreflex control of heart rate (HR) and limb vascular resistance (VR) at rest in middle-aged and older men. Training resulted in a marked increase in maximal O2 uptake (31.6 +/- 1.2 vs. 41.0 +/- 1.8 ml.kg-1.min-1, 2.56 +/- 0.16 vs. 3.20 +/- 0.18 l/min, P less than 0.05) and small (P less than 0.05) reductions in body weight (81.2 +/- 3.5 vs. 78.7 +/- 4.0 kg) and body fat (23.8 +/- 1.3 vs. 20.9 +/- 1.3%). HR at rest was slightly, but consistently, lower after training (63 +/- 2 vs. 58 +/- 1 beats/min, P less than 0.05). In general, HR variability (index of cardiac vagal tone) was greater after training. Chronotropic responsiveness to either brief carotid baroreflex stimulation (neck suction) or inhibition (neck pressure), or to non-specific arterial baroreflex inhibition induced by a hypotensive level of lower body suction, was unchanged after training. In contrast, the magnitude of the reflex increase in forearm VR in response to three levels of lower body suction was markedly attenuated after training (38-59%; P less than 0.05 at -10 and -30 mmHg; P = 0.07 at -20 mmHg). None of these variables or responses was altered over time in the controls. These findings indicate that in healthy, previously sedentary, middle-aged and older men, strenuous and prolonged endurance training 1) elicits large increases in maximal exercise capacity and small reductions in HR at rest, 2) may increase cardiac vagal tone at rest, 3) does not alter arterial baroreflex control of HR, and 4) results in a diminished forearm vasoconstrictor response to reductions in baroreflex sympathoinhibition.
Abstract: Technologic aid is available for the three central problems of hemorrhage, lung damage, and cardiac damage. Autotransfusion, new modes of ventilator support, extracorporeal oxygenation, balloon pumping, and left ventricular assist are available for the trauma patient. The author explains these new devices and their role in thoracic trauma cases.
Abstract: Insulin hypoglycaemia causes a rise in plasma vasopressin concentrations in man and the rat, and vasopressin stimulates glucagon secretion and increases hepatic glucose output in man. Vasopressin has also been suggested to have an important synergistic role with corticotrophin releasing factor in the release of adrenocorticotrophin hormone, and a counter-regulatory role for the hormone has been proposed. As diminished anterior pituitary hormone responses to hypoglycaemia have been reported in diabetes mellitus, we studied the plasma vasopressin responses to insulin-induced hypoglycaemia in 10 patients with established Type 1 diabetes and 10 matched control subjects. Blood glucose fell from 4.5 +/- 0.3 to 1.6 +/- 0.1 mmol l-1 (p less than 0.001) in the diabetic group and from 4.6 +/- 0.2 to 1.5 +/- 0.2 mmol l-1 (p less than 0.001) in control subjects, with delayed blood glucose recovery in the diabetic patients. Plasma vasopressin rose in the diabetic patients from 0.9 +/- 0.2 to 6.9 +/- 2.8 pmol l-1 (p less than 0.001), a significantly greater rise (p less than 0.05) than in the control subjects, 0.8 +/- 0.1 to 2.4 +/- 1.0 pmol l-1 (p less than 0.001). Plasma osmolalities remained unchanged and haemodynamic changes were similar in both groups. There is an exaggerated rise in plasma vasopressin concentrations in diabetic patients in response to insulin-induced hypoglycaemia. The putative mechanisms and potential significance of the exaggerated rise are discussed.
Abstract: Arcading arterioles (average diam 68 microns ID) connecting adjacent triangular vascular sectors in the rat mesentery were examined in vivo for the presence of flow-dependent vasodilation. When a feed artery to one of these sectors was occluded, the affected sector was supplied by collateral flow through the arcading arteriole, and red cell velocity in the arteriole increased by 10-66 mm/s. The velocity increase was followed (with an average delay of 7.7 s) by dilation of the arcading arteriole, which averaged 68%. The dilation was closely correlated with red cell velocity (r = 0.96), volume flow (r = 0.96), and wall shear rate (r = 0.89). The dilation was sustained for the duration of increased velocity (1-10 min) and was not affected when direction of flow in the arteriole was reversed. The flow-induced dilation was equal to the maximal dilation attained with topically applied papaverine. Dilation of the arcading arteriole could be almost completely abolished if the arteriole was also occluded during occlusion of a feed artery. These observations indicate that a potent flow-dependent dilator mechanism is present in arcading arterioles of rat mesentery and may play an important role in local regulation.
Abstract: The effects of rapid atrial pacing on central hemodynamics, plasma hormones, and renal function were investigated in eight control and nine cardiac-denervated dogs under chloralose anesthesia. Pacing at approximately 250 ppm for 60 min caused similar increases in pulmonary wedge and right atrial pressures, systemic vascular resistance, and plasma atrial natriuretic peptide (ANP) in both groups. In control dogs, pacing produced a fall in both plasma vasopressin (AVP) and plasma renin activity (PRA) and a rise in urine flow rate associated with an increase in free water but not sodium clearance. In contrast, in cardiac-denervated dogs, both plasma AVP and PRA increased during pacing; urine flow rate did not change, and marked sodium retention occurred. This study supports the concept that the increase in urine flow during rapid atrial pacing is mediated by inhibition of renin and AVP secretion through intact cardiac nerves. The secretion of ANP is unaffected by cardiac denervation. The natriuretic and vasodilator actions of high plasma ANP concentrations during rapid atrial pacing can be inhibited either by neurally mediated cardiorenal effects in normal animals or by stimulation of the renin-angiotensin system after cardiac denervation.
Abstract: Poorly controlled insulin-dependent diabetes mellitus is associated with considerable elevations of plasma vasopressin concentrations, although well-controlled diabetics have normal osmoregulated thirst and vasopressin release. We studied the effect of blood glucose concentration on osmoregulated thirst and vasopressin secretion in insulin-dependent diabetes mellitus. Blood glucose was maintained overnight, and for the duration of the study, in either the euglycemic (4-5 mmol/l) or hyperglycemic (10-12 mmol/l) range, and patients underwent infusion of hypertonic (855 mmol/l) sodium chloride solution. Plasma sodium was lower during the hyperglycemic study, but elevation in plasma sodium concentration by infusion of saline caused progressive linear increases in both thirst and plasma vasopressin concentrations in both studies. Linear regression analysis defined lowered plasma sodium thresholds for both thirst appreciation and vasopressin release during the hyperglycemic study, although the sensitivity of the osmoreceptors remained unchanged. Analysis of the data in terms of plasma osmolality, corrected for the increase in blood glucose in the hyperglycemic study, revealed no differences in the osmotic thresholds for thirst or vasopressin release; sensitivity of the osmoreceptors also remained the same. Drinking abolished thirst and lowered plasma vasopressin concentrations before major changes in plasma sodium were observed. These results show that insulin-dependent diabetic patients osmoregulate appropriately when moderately hyperglycemic but that the threshold plasma sodium for vasopressin secretion and thirst appreciation is lowered by an unknown mechanism.
Abstract: Tissue/blood partition coefficients of anesthetics are important indicators of the rate of tissue wash-in and wash-out, and wash-in and wash-out are determinants of the rates of induction of and recovery from anesthesia. In the present study of human tissues, we found that the tissue/blood partition coefficients (for brain, heart, liver, kidney, muscle, and fat) for the new anesthetic I-653 were smaller than those for isoflurane, sevoflurane, and halothane (anesthetics listed in order of increasing tissue/blood partition coefficients). For example, the respective brain/blood partition coefficients were 1.29 +/- 0.05 (mean +/- SD); 1.57 +/- 0.10; 1.70 +/- 0.09; and 1.94 +/- 0.17. This indicates that induction of and recovery from anesthesia with I-653 should be more rapid than with the other agents. The finding of a lower tissue/blood partition coefficient for I-653 parallels the previous finding of a lower blood/gas partition coefficient.
Abstract: The role of intra- and extrarenal factors in oedema formation in children with nephrotic syndrome is reviewed. Oedema reflects an abnormal accumulation of fluid within the interstitial tissue. At the capillary level oedema develops when increased lymph flow is no longer effective for the removal of interstitial fluid and the maintenance of intravascular volume. Alterations of intrarenal haemodynamics and tubular sodium reabsorption contribute to sodium retention. Recent studies suggest that during oedema formation reduced effective circulatory volume triggers changes in various hormonal systems, such as renin-angiotensin-aldosterone, noradrenaline, dopamine, vasopressin, prostaglandins and natriuretic factors, which contribute to sodium and water retention. It appears that the release of atrial natriuretic peptide following central volume expansion is responsible for the increased urine flow and natriuresis after intravenous administration of albumin.
Abstract: To investigate the relative influence of protein synthetic and degradative control mechanisms in vivo during skeletal muscle atrophy, we measured myofibril and total mixed protein synthesis rates in muscles of rats prevented from hindlimb weight-bearing for 5 h and 7 days. Protein synthesis rates were determined by infusing the animals with [3H]Leu for 5 h and measuring the specific activity of [3H]Leu in the aminoacyl-tRNA precursor and protein product fractions of the muscles. In the soleus muscle, myofibril protein synthesis rates decreased from a control value of 5.9 to 4.6%/day during 5 h of hindlimb unweighting and to 2.4%/day after 7 days of hindlimb unweighting. The relatively more phasic muscles (plantaris, medial gastrocnemius, quadriceps) showed a tendency for increased myofibril protein synthesis rates (117-127% of control) during the first 5 h followed by a decrease (46-62% of control) at 7 days of hindlimb unweighting. A predicted time course of soleus muscle myofibril protein degradation rate was obtained from a numerical model of the decrease in soleus myofibril protein synthesis rate as a first-order process [half-time (t1/2) = 0.3 day by least-squares fit] and the time course of soleus muscle myofibril protein previously observed with hindlimb unweighting (Thomason et al., J. Appl. Physiol. 63: 130-137, 1987). The degradation rate model makes specific, testable predictions for the mechanism of myofibril protein degradation during soleus muscle atrophy: 1) the first-order degradation rate constant does not obtain a fixed value over a 24-day period but is continuously changing throughout atrophy, and 2) the first-order degradation rate constant changes on a time scale slower than protein synthesis rate.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: The acute effects on kidney function of acetazolamide (250 mg) given intravenously were evaluated in seven healthy subjects. Glomerular filtration rate was measured as the renal clearance of 51Cr-EDTA, and fluid flow rate out of the proximal tubules was assessed by measurement of the renal lithium clearance. An 18% decline in glomerular filtration rate (ml/min) was observed after acetazolamide administration (109 +/- 16 vs 89 +/- 14, p less than 0.02), while lithium clearance (ml/min) increased by 35% (30 +/- 5 vs 38 +/- 8, p less than 0.02). Absolute proximal tubular reabsorption of water (ml/min) was reduced by about one third (79 +/- 12 vs 51 +/- 9, p less than 0.02), and fractional proximal reabsorption of water and sodium (%) declined (73 +/- 2 vs 58 +/- 6, p less than 0.02). Renal sodium clearance and absolute distal reabsorption of sodium increased, while fractional distal reabsorption of sodium declined. Acetazolamide reduces absolute and fractional proximal tubular reabsorption of sodium and water, and glomerular filtration rate. Primarily, this induces an increase in the output of fluid from the proximal tubules accounting for the diuretic effect of the drug. The acute fall in glomerular filtration rate is probably mediated by a temporary increase in proximal intratubular pressure and activation of the tubuloglomerular feedback mechanism.
Abstract: In this review, we assess the role of nuclear magnetic resonance (NMR) spectroscopy as a noninvasive method of studying metabolism in cerebral ischaemia. Phosphorus-31 NMR provides a monitor of intracellular pH and energy metabolites, including ATP, phosphocreatine, and inorganic phosphate, while other nuclei, including 1H, 13C, 19F, and 23Na can give additional information about several aspects of brain metabolism and physiology. For example, 1H NMR not only provides excellent images, but may also be used to monitor a range of metabolites, including lactate and several amino acids. Comparisons are made with the large body of information that is available from more traditional methods of studying metabolism. Emphasis is placed on the correlation of NMR data with parallel measurements of regional blood flow, tissue oxygenation, oedema, electrical activity, and tissue damage. Technical aspects of NMR are discussed where appropriate; for example, in relation to the range of metabolites that are accessible to study, the spatial resolution that is available for studies of focal lesions, problems arising from tissue heterogeneity, and quantification of metabolite levels. Applications in animal models and in humans are discussed; these primarily involve the 31P nucleus, but for the future it appears that 1H NMR studies offer particular promise.
Abstract: Microwave fixation in situ was used to assess regional glycogen and glucose stores in normal rat brain. Glycogen levels were highest in the cerebellum and pons/medulla (38.0 and 35.6 nmol/mg protein), and lowest in the striatum and cerebral cortex (17.4 and 23.6 nmol/mg protein respectively). Glucose concentrations paralleled glycogen, ranging from 5.9 to 10.8 nmol/mg protein. Glycogen, glucose, and lactate were measured during complete global ischaemia (decapitation) to assess regional differences in ischaemic metabolism. Those regions which in normal brain contain higher glycogen and glucose stores were found to maintain significantly higher levels of glycogen and glucose for at least 2 minutes of ischaemia. Lactate accumulated to highest levels after 30 minutes of ischaemia in those regions with highest glucose and glycogen stores. Lactate levels did not, however, rise above 90 nmol/mg protein in any brain region, a level well below that considered potentially neurotoxic. The data indicate considerable regional differences in normal and ischaemic glycogen metabolism that might contribute to known regional differences in vulnerability to global ischaemia.
Abstract: The purpose of the present study was to investigate whether, in humans, hypoxia results in an elevated lactate production from exercising skeletal muscle. Under conditions of both hypoxia [inspired oxygen fraction (F1O2): 11.10%] and normoxia (F1O2: 20.94%), incremental exercise of a forearm was performed. The exercise intensity was increased every minute by 1.6 kg.m.min-1 until exhaustion. During the incremental exercise the partial pressure of oxygen (PO2) and carbon dioxide (PCO2), oxygen saturation (SO2), pH and lactate concentration [HLa] of five subjects, were measured repeatedly in blood from the brachial artery and deep veins from muscles in the forearm of both the active and inactive sides. The hypoxia (arterial SO2 approximately 70%) resulted in (1) the difference in [HLa] in venous blood from active muscle (values during exercise-resting value) often being more than twice that for normoxia, (2) a significantly greater difference in venous-arterial (v-a) [HLa] for the exercising muscle compared to normoxia, and (3) a difference in v-a [HLa] for non-exercising muscle that was slightly negative during normoxia and more so with hypoxia. These studies suggest that lower O2 availability to the exercising muscle results in increased lactate production.
Abstract: The focus of this review is on the role of the renal nerves in contributing to the sodium retention associated with cirrhosis, congestive heart failure, and nephrotic syndrome. With respect to these three disease state information is presented which indicates that conditions exist which would be predicted to activate the sympathetic nervous system. Consistent with this, indirect indices of increased peripheral and renal sympathetic nerve activity are observed in these diseases. Acute experiments have indicated that the renal nerves are influencing sodium excretion in these sodium-retaining disorders. The renal nerves have the capacity to influence tubular sodium transport, renal hemodynamics, and renal endocrine release, all of which may affect the renal handling of sodium. Experiments are discussed which have implicated all three mechanisms of action in cirrhosis and congestive heart failure. Despite the fact that studies are demonstrating an increasing importance of the renal nerves, experiments have not been conducted to definitively implicate the renal nerves as being responsible for the long-term sodium retention in these disease conditions.
Abstract: The lack of a reliable quantitative description of blood flow in man has hampered the development of accurate biokinetic models of essential elements, drugs, imaging agents, and carcinogens. In this paper we review and analyse data on blood flow and identify representative percentages of cardiac output and absolute blood flow rates to organs and tissues of man for use as reference values for biokinetic models. To keep the review and analysis to a manageable size we have limited attention to the resting state and have suggested reference values for absolute and relative flow rates only for adult males and females.
Abstract: Simultaneous microneurographic recordings were made of muscle sympathetic activity (MSA) in the radial and the peroneal nerves of seven healthy subjects during 2-min static handgrip (30% of maximal voluntary contraction) followed by 2 min of forearm ischemia induced by arterial occlusion. At rest sympathetic burst frequency was similar in both nerves, but relative burst strengths differed between the two neurograms, suggesting that sympathetic outflows to arm and leg were not identical. Both radial and peroneal MSA were unchanged during the first minute of handgrip and increased to a similar degree during the second minute. Thus previously reported differences in vascular resistance between forearm and calf during static handgrip cannot be explained by differences in MSA to arm and leg muscles. During forearm ischemia after handgrip, peroneal MSA remained at the same level as during the second minute of handgrip but there was a further increase of radial MSA. This shows that stimulation of chemosensitive endings in forearm muscles induces differentiation of sympathetic neural outflow to muscles in the leg and the contralateral arm.
Abstract: As the second of a two-part research project, this study attempted to build three clinically useful prediction equations; these equations would be used to predict three long-term functional outcomes: productivity status, living arrangement status, number of hours of assistance required per week. There were ten predictor variables used in each analysis. These ten variables belonged to four theoretical classes: pre-injury demographics, pre-injury social characteristics, severity of injury, and post-injury environmental variables. The analytical method used was the General Linear Model of multiple regression, rather than the most often used Stepwise regression procedure. The results indicate that in none of the three prediction equations was more than 28% of the criterion variance accounted for, and only a minority of the predictor variables were significant predictors. It is concluded that, while the equations are of only very limited utility, the theoretical model and the analytical technique will be useful for future investigators.
Abstract: The renal vascular actions of atrial natriuretic peptide (ANP) remain incompletely understood. The purpose of this study is to evaluate the effects of ANP on microvascular structures of the normal kidney. The in vitro blood-perfused juxtamedullary nephron technique was utilized to allow visualization of arcuate arteries and afferent and efferent arterioles. Donor rats were pretreated with captopril to eliminate possible interactions between angiotensin II and atriopeptin III (AP III). The effects of topical administration of 3 nM AP III were determined by videometric analysis of vessel inside diameters. Under control conditions, arcuate arterial diameter averaged 83 +/- 14 microns (n = 7), afferent arteriolar diameter was 20 +/- 4 microns (n = 7), and efferent arteriolar diameter was 16 +/- 2 microns (n = 7). During superfusion with AP III, arcuate arteries and afferent arterioles dilated 73 +/- 9 and 23 +/- 5%, respectively. Both returned to their control values when AP III was removed from the superfusate. Further experiments on arcuate arteries (n = 5) revealed that 0.3 nM AP III also vasodilated these vessels (26 +/- 9%); however, no significant effect was elicited by 0.03 nM AP III. In contrast to the vasodilator influence of AP III on preglomerular vessels, efferent arteriolar diameter was not altered by AP III exposure. These observations reveal that AP III can induce selective preglomerular vasodilation involving arcuate arteries as well as afferent arterioles, while efferent arteriolar diameter is not perceptibly influenced.
Abstract: A method for maintaining chronic severe hypoosmolality in rats is described utilizing subcutaneous infusions of the antidiuretic vasopressin analogue 1-deamino-[8-D-arginine] vasopressin (DDAVP) at rates of 1 or 5 ng/hr via osmotic minipumps in combination with self-ingestion of a concentrated, nutritionally-balanced liquid diet. Using these methods, 97.3% of all rats studied achieved stable levels of severe hyponatremia (plasma [Na+] = 111.6 +/- 0.5 mEq/liter, N = 213), which was sustained for periods of time ranging from two to five weeks. Mortality was low (1.8%) and observable morbidity was not noted over a series of studies encompassing 4,628 rat days of sustained hypoosmolality. Analysis of food intake and body weight revealed no evidence of tissue catabolism at any time with the lower (1 ng/hr) DDAVP infusion rate, and only during the first week with the higher (5 ng/hr) rate. Metabolic balance studies during 13 days of sustained hypoosmolality demonstrated the dilutional nature of the hypoosmolality, and only a limited degree of renal escape from the antidiuretic effects of DDAVP (urine osmolalities 800 to 1200 mOsm/kg H2O). Studies of brain water and electrolyte contents demonstrated complete normalization of brain volume after 14 to 28 days of sustained hypoosmolality, the major part of which (70%) could be accounted for by loss of brain electrolytes. Both natriuresis and kaliuresis occurred during the first five days of hypoosmolality, and were of sufficient magnitude to suggest some degree of adaptation of other body fluid compartments via electrolyte losses as well. These results indicate that rats have substantial capacity to tolerate prolonged severe hypoosmolality with little morbidity and mortality as long as proper attention is paid to their nutritional requirements, and provide further evidence that brain volume regulation likely represents the major adaptive mechanism that allows survival despite sustained hypoosmolality.
Abstract: We tested whether translocation of glucose transporters between subcellular membrane fractions is involved in the stimulation of glucose transport by anoxia by perfusing rat hearts in the presence or absence of oxygen. The hearts were then fractionated by a modification of the procedures of Watanabe, et al. (Watanabe, T., Smith, M. M., Robinson, F. W., and Kono, T. (1984) J. Biol. Chem. 259, 13117-13122), who previously demonstrated translocation in response to insulin in heart, to give plasma membrane and high-speed pellet fractions. The contents of glucose transporters in the two fractions were determined by reconstitution of transport activity, D-glucose-reversible binding of cytochalasin B, and labeling with antibodies against the erythrocyte transporter. The heart transporter was also recognized by antibodies against the COOH-terminal peptide of the glucose transporter. All three types of assays revealed a decrease (20-30%) in the high-speed pellet fraction and an increase (20-70%) in the plasma membranes in response to anoxia. Treatment of hearts with insulin produced a similar extent of translocation and a similar stimulation (about 2-fold) of glucose uptake, indicating that translocation plays a role of similar importance in the stimulation of transport by both of these effectors.
Abstract: To assess mechanisms leading to the ’dawn phenomenon’ in type 1 diabetes mellitus, overnight insulin clearance, hepatic blood flow and insulin sensitivity of glucose metabolism were determined in 9 type 1 diabetic subjects treated with continuous subcutaneous insulin infusions. Glucose clamp studies were performed twice, once after midnight (from 24.00 to 02.00 h), and once in the early morning (from 06.00 to 08.00 h) during insulin infusion at 15 mU/m2/min. Insulin clearance was 482 +/- 57 ml/m2/min during the first, and 528 +/- 56 ml/m2/min during the second clamp (nonsignificant). Hepatic plasma flow assessed by measuring indocyanine green clearance was 984 +/- 115 and 1,040 +/- 163 ml/min, after the first and after the second clamp, respectively (nonsignificant). Glucose uptake during the two clamps was not significantly different. Since hepatic blood flow is known to influence insulin clearance and hepatic glucose metabolism, the data demonstrate that overnight changes in hepatic blood flow and insulin clearance do not contribute to the previously described early morning increase in insulin requirements in type 1 diabetic subjects (dawn phenomenon).
Abstract: The purpose of this study was to examine the relationship between plasma norepinephrine concentrations (PNE) and efferent muscle sympathetic nerve activity to noncontracting muscle (MSNA) during graded, rhythmic exercise in humans. In the initial study, six healthy men (ages 20-30 yr) performed 2-min bouts of two-arm cycling exercise at power outputs of 0, 10, 20, 40, 60 (n = 6), and 80 (n = 3) W. Heart rate (HR) was recorded and intraneural measurements of MSNA (right peroneal nerve) were made continuously for 2 min before (control) and during exercise at each work load. At least 2 wk later, subjects performed the same exercise bouts at which time HR was measured and a venous (forearm) blood sample was obtained for the subsequent determination of PNE by high-performance liquid chromatography. During exercise, HR increased progressively from 0 to 80 W. Neither MSNA nor PNE increased above control in response to arm cycling at 0, 10, and 20 W [0-16 +/- 1% (SE) of peak work load], but both variables increased progressively at the 40-, 60-, and 80-W (33 +/- 1 to 67 +/- 2% of peak work load) levels (all P less than 0.05). The individual MSNA and PNE responses (% change from control) over the six work loads were directly related (r = 0.80, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: We examined the effects of the neuropeptide substance P on pulmonary hemodynamic and transvascular fluid filtration in isolated Ringer’s-perfused and blood-enriched Ringer’s-perfused guinea pig lung and on albumin flux across bovine pulmonary artery endothelial monolayer. Mean pulmonary artery, left atrial, and capillary pressures were determined and used to calculate arterial and venous resistances, and lung weight was continuously monitored. Substance P (0.01-1.0 microM) caused marked increases in pulmonary arterial pressure, capillary pressure, venous resistance, and lung weight within 3-5 minutes after administration. These responses remained elevated above baseline at the end of the 30-minute experimental period in the Ringer’s-perfused lungs but not in the blood-enriched Ringer’s-perfused lungs. Substance P did not alter the capillary filtration coefficient in isolated lungs and transendothelial albumin permeability in the endothelial monolayer. Substance P resulted in an increase in venous effluent thromboxane B2 concentrations in perfused lungs but had no effect on 6-keto-prostaglandin F1 alpha concentrations. Papaverine (0.27 mM) (a smooth-muscle relaxant) abolished the pulmonary microvascular response to substance P in Ringer’s-perfused lungs, and meclofenamate (0.15 mM) (a cyclooxygenase inhibitor) attenuated the pulmonary vasoconstriction and lung weight increase. Pyrilamine (1.0 microM) (a histamine1-receptor antagonist) did not alter the responses to substance P. In conclusion, substance P does not affect pulmonary vascular permeability to water and protein. Substance P induces an intense pulmonary vasoconstriction (due to greater constriction of postcapillary vessels) and an elevation in pulmonary capillary pressure that increases net transvascular fluid filtration.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: We used phosphorus nuclear magnetic resonance spectroscopy (31P-NMR) to probe the cellular events in contracting muscle that initiate the reflex stimulation of sympathetic outflow during exercise. In conscious humans, we performed 31P-NMR on exercising forearm muscle and simultaneously recorded muscle sympathetic nerve activity (MSNA) with microelectrodes in the peroneal nerve to determine if the activation of MSNA is coupled to muscle pH, an index of glycolysis, or to the concentrations (II) of inorganic phosphate (Pi) and adenosine diphosphate (ADP) which are modulators of mitochondrial respiration. During both static and rhythmic handgrip, the onset of sympathetic activation in resting muscle coincided with the development of cellular acidification in active muscle. Furthermore, increases in MSNA were correlated closely with decreases in intracellular pH but dissociated from changes in phosphocreatine [( PCr]), [Pi], and [ADP]. The principal new conclusion is that activation of muscle sympathetic outflow during exercise in humans is coupled to the cellular accumulation of protons in contracting muscle.
Abstract: Plasma vasopressin, vasopressin-induced platelet aggregation, and platelet vasopressin receptors were investigated in 10 normal subjects and 14 diabetic patients free of microangiopathy. Basal plasma vasopressin concentration was identical in two groups. Platelet aggregation induced by vasopressin as well as by epinephrine was not significantly altered in the diabetic patients. However, exploration of platelet V1-vasopressin receptors revealed in the diabetic group a dramatic reduction in the number of binding sites without alteration of the receptor affinity for tritiated vasopressin. Thus vasopressin-induced platelet aggregation in uncomplicated diabetes mellitus remains normal despite a decrease in the number of vasopressin receptors presumably due to alterations of the platelet membrane structure.
Abstract: High-fidelity hemodynamic recordings of aortic and right atrial pressures and the coronary perfusion gradient (the difference between aortic and atrial pressure) were made in nine patients during cardiopulmonary resuscitation (CPR). Findings during conventional manual CPR were compared with those during high-impulse CPR (rate, 120 cycles/min with a shorter compression:relaxation ratio) as well as during pneumatic vest CPR with and without simultaneous ventilation and abdominal binding. Aortic peak pressure during conventional CPR averaged 61 +/- 29 mm Hg but varied widely (range, 39-126 mm Hg) among patients. Although the magnitude of improvement was modest, the high-impulse method was the only technique tested that significantly elevated both aortic peak pressure and the coronary perfusion gradient during cardiac arrest. During conventional CPR, aortic pressure rose from 61 +/- 29 to 80 +/- 39 mm Hg during high-impulse CPR, and the gradient rose from 9 +/- 11 to 14 +/- 15 mm Hg, respectively; p less than 0.01. The pneumatic vest method significantly improved peak aortic pressure but not the coronary perfusion gradient. Simultaneous ventilation and chest compression created high end-expiratory pressure and lowered the coronary perfusion gradient. Abdominal binding had no significant hemodynamic effects. This evaluation of experimental resuscitation methods in humans shows that the high-impulse chest compression method augments aortic pressure over levels achieved during conventional CPR methods; however, the improvement in pressure is modest and may not be clinically important. Simultaneous ventilation as well as abdominal binding during CPR were associated with no benefit; in fact, simultaneous ventilation appears to adversely affect cardiac perfusion and, therefore, should not be used during clinical resuscitation.
Abstract: In vitro studies indicating an inverse relationship between free fatty acid (FFA) availability and glucose oxidation led to proposal of the glucose-fatty acid cycle. In vivo studies have yielded conflicting results regarding the effect of FFA on glucose oxidation. In the present study the effect of FFA on glucose oxidation was determined in six normal volunteer subjects. The rate of glucose uptake was fixed by using a constant glucose infusion to suppress endogenous glucose production. Glucose was infused continuously overnight and during the four hour study at 8 mg/kg X min to ensure use of glucose as an energy substrate by virtually all tissues. Following a two-hour baseline glucose infusion, infusion of 20% IV fat emulsion at 1.0 mL/min plus heparin was added to the constant glucose infusion for two additional hours. Total carbohydrate oxidation was determined by indirect calorimetry, and the direct oxidation of the infused (plasma) glucose was measured by the use of U-13C-glucose. Glycogen oxidation was calculated as the difference between total carbohydrate oxidation and the oxidation of plasma glucose. Glucose uptake was calculated from the infusion rate, corrected for any changes in plasma and/or urine glucose concentration. Glucose uptake closely approximated the rate of IV glucose infusion and was unchanged by fat infusion. The percent of CO2 production from U-13C-glucose oxidation (74.5 +/- 12.3, mean +/- SD) was not affected by FFA, nor was the percent of glucose uptake oxidized (37.5 +/- 4.0).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: An endothelium-derived 21-residue vasoconstrictor peptide, endothelin, has been isolated, and shown to be one of the most potent vasoconstrictors known. Cloning and sequencing of preproendothelin complementary DNA shows that mature endothelin is generated through an unusual proteolytic processing, and regional homologies to a group of neurotoxins suggest that endothelin is an endogenous modulator of voltage-dependent ion channels. Expression of the endothelin gene is regulated by several vasoactive agents, indicating the existence of a novel cardiovascular control system.
Abstract: Aldosterone is part of a complex system that regulates plasma potassium concentration by affecting the renal excretion of the ion as well as its distribution within the body. Because there are other components of the system, it has been difficult to determine the physiological significance of aldosterone in potassium regulation by attempting to study the hormone’s effects in isolation. In this presentation a quantitative analysis of the potassium control system is used to provide information concerning the physiological role of aldosterone in potassium regulation under normal and pathological conditions, as well as during pharmacological interventions.
Abstract: 1. The game of squash has recently been associated with a high incidence of ventricular arrhythmias and sudden death. To investigate this further, plasma catecholamines and potassium (K+) were monitored during a game of squash in six normal volunteers. 2. No cardiac arrhythmias were seen in this study despite the subjects reaching maximum heart rates of 181 +/- 5 beats/min (mean +/- SEM). 3. During exercise, plasma K+ rose from 3.82 +/- 0.16 to 4.29 +/- 0.2 mmol/l, but after 90 s rest this fell to 3.68 +/- 0.28 mmol/l and after 180 s to 3.44 +/- 0.17 mmol/l. This rapid K+ shift could not be accounted for by generalized changes in venous acid-base status or by changes in venous plasma catecholamines. Although pretreatment with a beta 2-antagonist caused the overall plasma K+ levels to be higher, it had no significant effect on the fall in plasma K+ after exercise. 4. Such rapid K+ shifts after exercise might contribute to arrhythmogenesis in susceptible individuals. The precise mechanism of the fall in K+ after exercise remains undetermined, but it seems not to involve catecholamines stimulating beta 2-adrenoceptors and is more likely to be due to increased skeletal muscle blood flow and/or intracellular acidosis.
Abstract: Since the role of aldosterone in mediating extrarenal potassium transport remains uncertain, the effect of mineralocorticoid on potassium metabolism was assessed in anephric patients. Seven anephric patients underwent three identical 72-hour periods between hemodialyses during which treatment with either 10 mg/day deoxycorticosterone acetate (DOCA) intramuscularly or 300 mg/day spironolactone orally was compared to a baseline control period. The serum potassium rise, plasma aldosterone, salivary and stool electrolytes were measured in response to potassium loading over 48 hours with a metabolic diet containing 38 mEq/day followed by an "acute" oral potassium load of 0.5 mEq/kg. Acute potassium loading with DOCA resulted in a lower increment in serum potassium than with spironolactone (P less than 0.01). The volume of distribution of the acute potassium load at three hours was 55% of body weight with DOCA, which was significantly greater (P less than 0.05) than with either spironolactone (35%) or control (34%). However, with the dietary load of potassium, the increments in serum potassium measured at 24 and 48 hours (13 hours post-prandial) were similar in all three periods. The volume of distribution of the dietary potassium was not altered by DOCA or spironolactone but had risen to an average of 172% at 24 hours and 243% at 48 hours in the three periods. Plasma aldosterone levels were low, positively correlated to the serum potassium and similar in all three periods without evidence of feedback inhibition by DOCA or stimulated by spironolactone.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: 1. Xamoterol is a cardioselective beta-adrenoceptor partial agonist which may have a role in the management of cardiac failure. Excretion is mainly by the renal route. 2. The kinetics of a single 200 mg oral dose of xamoterol were studied in eight elderly (age 67-82 years) volunteers, eight young (age 21-43 years) volunteers; eight patients with mild to moderate cardiac failure and eight age and sex matched controls. 3. Elderly volunteers had a significantly longer time to reach peak concentration (mean +/- s.e. mean 2.1 +/- 0.2 vs 1.1 +/- 0.1 h) and elimination half-life time (27.0 +/- 2.8 vs 16.4 +/- 3.1 h) compared with young volunteers. The renal clearance of xamoterol was lower in the elderly (115 +/- 12 vs 185 +/- 19 ml min-1) and showed a significant correlation with creatinine clearance (r = 0.85, P less than 0.001). 4. There was no significant difference in any of the pharmacokinetic parameters measured in patients with cardiac failure compared with healthy age and sex matched controls. 5. These results suggest that the maintenance dose of xamoterol could be reduced in elderly patients in relation to impairment of renal function.
Abstract: Smooth muscle performs many functions that are essential for the normal working of the human body. Changes in pH are thought to affect many aspects of smooth muscle. Despite this, until recently little was known about either intracellular pH (pHi) values or pHi regulation in smooth muscle. Recent work measuring pHi with either microelectrodes or nuclear magnetic resonance spectroscopy is now providing some of this much needed information for smooth muscles. From these studies, it can be concluded tentatively that pHi is the same in different smooth muscles, approximately 7.06 (37 degrees C). This value is very close to those obtained in cardiac and skeletal muscle. It is clear that H+ is not in equilibrium across the smooth muscle membrane; i.e., pHi is regulated. Preliminary results in smooth muscle suggest that certain aspects of this regulation are different from that described for other muscle types. Changes in pHi have been found to produce marked effects on contraction in smooth muscle. Of particular interest is the fact that, unlike striated muscles, some smooth muscles can product more force during an intracellular acidification.
Abstract: The concept of centrifugal renal development is based on renal embryogenesis. It implies a relationship between nephron age and nephron position along a cortical to medullary axis. In common usage, however, it often also implies a relationship between nephron age or position and nephron maturity. We consider here whether the ideas of centrifugal development and centrifugal maturation should in fact be considered as separate and distinct concepts. That is, we consider the possibility that nephron maturity does not necessarily correlate with nephron age. Unfortunately, pertinent reported data give no clear answer. We conclude only that further study will be required before definitive conclusions about renal developmental stages can be stated with certainty.
Abstract: The effects of acidosis on renal function and morphology were examined in the isolated perfused rat kidney (IPK). Kidneys were perfused with oxygenated Krebs-Henseleit-albumin medium for 60 minutes at pH 7.4 or pH 7.0. At the lower pH, GFR was reduced by 25%, TRNa by 32% and oxygen consumption by 41% as compared to perfusion at pH 7.4 (all P less than 0.05). In addition, the usual hypoxic injury observed in the medullary thick ascending limb of the Loop of Henle (TAL) in the IPK at pH 7.4 (consisting of nuclear pyknosis and focal fragmentation necrosis) was reduced by acidosis from 62% to 14% of tubules involved (P less than 0.005). This cytoprotection was not the result of improved oxygenation since O2 delivery was actually slighty reduced at pH 7.0 compared to pH 7.4. Furthermore, acidosis was protective even after perfusion with non-oxygenated media (42% tubules damaged at pH 7.0 vs. 95% of tubules damaged at pH 7.4; P less than 0.01), making it very unlikely that the effect of acidosis is to improve TAL oxygenation. Since previous studies indicate that the TAL lesion is transport dependent and prevented in the non-filtering kidney, it was possible that the decrease in GFR associated with acidosis could account for decreased injury. The GFR was manipulated by alterations in perfusion pressure or albumin concentration, and no consistent relationship between the extent of injury and GFR could be shown at either pH over a wide range of GFR values. Therefore, acidosis protected the TAL from hypoxic injury by a mechanism apparently independent of oxygen or solute delivery.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Experiments were performed to test for a possible role of arginine vasopressin (AVP) in the renal vascular responses to the combination of hypoxia and varying levels of CO2 in the conscious rat. Animals were instrumented with pulsed Doppler flow probes on the left renal artery and with arterial and venous catheters. Renal blood flow (RBF) and mean arterial blood pressure (MABP) were determined in conscious, unrestrained rats under the following conditions: 1) hypocapnic hypoxia [arterial PO2 (PaO2) = 26 Torr; arterial PCO2 (PaCO2) = 21 Torr]; 2) isocapnic hypoxia (PaO2 = 34 Torr; PaCO2 = 36 Torr); 3) hypercapnic hypoxia (PaO2 = 42 Torr; PaCO2 = 57 Torr); and 4) room air control (PaO2 = 93 Torr; PaCO2 = 38 Torr). MABP fell from 104 +/- 2 to 83 +/- 5 mmHg during hypocapnic hypoxia but was unaffected by the other stimuli. RBF was significantly reduced by both hypocapnic and hypercapnic hypoxia and unchanged in the other protocols, whereas renal vascular resistance (RVR) was elevated only in the hypercapnic hypoxia group. Additional experiments were performed to test whether activation of V1-vasopressinergic receptors during hypoxia might mediate the observed changes in renal hemodynamics. Experiments were performed as before except that at the midpoint of hypoxic or room air exposure, 10 micrograms/kg of the specific V1 vasopressinergic antagonist d(CH2)5Tyr(Me)AVP was administered. However, administration of the V1 antagonist had no effect on the observed renal hemodynamic responses to hypoxia. Therefore, although intense chemoreceptor stimulation by hypercapnic hypoxia may increase RVR and decrease renal perfusion, these renal hemodynamic responses do not appear to be mediated by increased circulating levels of AVP.
Abstract: These studies have revealed that the delivery and actions of beta receptor antagonist drugs are controlled by a cascade of stereoselective processes involving multiple enzymes, transport proteins and receptors. In essence, the free concentration of the pharmacologically active (-)-enantiomer species of these drugs presented to cell surface beta receptors appears to be a function of the stereoselective clearance by hepatic cytochrome P-450 isoenzymes, enantiomer selective binding to alpha 1-acid glycoprotein and albumin and perhaps predominantly by stereoselective sequestration (and release) by the vesicular amine transport protein within adrenergic neurons. Stereoselectivity in the clearance of beta blocking drugs, which can favor either the (+)- or (-)-enantiomer, only appears to be important for the lipophilic drugs which are cleared by hepatic metabolism. Such stereoselectivity is due to differential stereochemical substrate requirements of individual hepatic cytochrome P-450 isoenzymes. Interindividual variations in the stereoselectivity can occur as a result of differences in the amount and expression of cytochrome P-450 isoenzymes due to genetic predisposition or other factors. In the same context, we have observed a significant correlation between the extent and stereoselectivity of binding of beta blocking drugs to plasma proteins. This is another finding which suggests that variability in the expression of individual proteins involved in the beta blocking drug-protein cascade determines the free concentration of the pharmacologically active enantiomer. However, since most observations have been made in young normal subjects, the extent of stereoselectivity in metabolism, binding and other processes is unknown in the general population where steady-state plasma concentrations can vary widely due to multiple biological factors. The observations from neural studies support the concept that adrenergic nerve endings provide a depot for the stereoselective storage and release of the active enantiomer of beta receptor antagonists. The mechanism of this release appears to involve exocytotic secretion of drug that has been stereoselectively accumulated by the neurotransmitter storage vesicles. In terms of this idea, beta receptor antagonists released during nerve stimulation may achieve concentrations of the (-)-enantiomer within the adrenergic synapse greatly in excess of those found in plasma. Such a mechanism could significantly influence both the intensity and duration of beta receptor blockade in the heart, blood vessels, brain and other target tissues.(ABSTRACT TRUNCATED AT 400 WORDS)
Abstract: The elderly segment of our society may triple by the year 2050. Specific cardiovascular data on the normal aging heart will be needed to provide proper medical and surgical therapy for this patient group. This report reviews normal aging changes of the very elderly heart. Expected or normal aging changes include brown atrophy of the myocardium, increased subepicardial fat, focal amyloid deposits, sigmoid-shaped ventricular septum, and calcific deposits in the aortic valve, mitral annulus and epicardial coronary arteries. Certain normal aging changes may produce clinical heart disease: aortic valve calcium (aortic stenosis), mitral valve annular calcium (mitral stenosis), amyloid deposits (amyloid heart disease). Certain normal aging changes may mimic heart disease: sigmoid-shaped ventricular septum (hypertrophic cardiomyopathy), mitral leaflet "buckling" (floppy mitral valve).
Abstract: We studied the effect of systemic hypoxia on the bronchial vascular pressure-flow relationship in anesthetized ventilated sheep. The bronchial artery, a branch of the bronchoesophageal artery, was cannulated and perfused with a pump with blood from a femoral artery. Bronchial blood flow was set so bronchial arterial pressure approximated systemic arterial pressure. For the group of 25 sheep, control bronchial blood flow was 22 ml/min or 0.7 ml.min-1.kg-1. During the hypoxic exposure, animals were ventilated with a mixture of N2 and air to achieve an arterial PO2 (PaO2) of 30 or 45 Torr. For the more severe hypoxic challenge, bronchial vascular resistance (BVR), as determined by the slope of the linearized pressure-flow curve, decreased acutely from 3.8 +/- 0.4 mmHg.ml-1.min to 2.9 +/- 0.3 mmHg.ml-1.min after 5 min of hypoxia. However, this vasodilation was not sustained, and BVR measured at 30 min of hypoxia was 4.2 +/- 0.8 mmHg.ml-1.min. The zero flow intercept, an index of downstream pressure, remained unaltered during the hypoxic exposure. Under conditions of moderate hypoxia (PaO2 = 45 Torr), BVR decreased from 4.6 +/- 0.3 to 3.8 +/- 0.4 mmHg.ml-1.min at 5 min and remained dilated at 30 min (3.6 +/- 0.5 mmHg.ml-1.min). To determine whether dilator prostaglandins were responsible for the initial bronchial vascular dilation under conditions of severe hypoxia (PaO2 approximately equal to 30 Torr), we studied an additional group of animals with pretreatment with the cyclooxygenase inhibitors indomethacin (2 mg/kg) and ibuprofen (12.5 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Contractile failure during various types of exercise has been attributed to intramuscular metabolic changes. We examined the temporal changes in force-generating capacity and metabolic state during intermittent isometric contractions in humans. One-legged quadriceps contractions at 30% maximum voluntary contraction (MVC) were executed for 6 s, with 4 s of rest between. The decrease in force-generating capacity was tested from brief MVC’s and short bursts of 50-Hz stimulation applied at 5-min intervals. After 1 min of exercise, the MVC force declined linearly and in parallel to the 50-Hz stimulation force, indicating that the contractile failure was due to intramuscular processes. After 30 min of exercise the MVC force had declined by approximately 40% compared with the value obtained after 1 min. In separate experiments the same contraction protocol was followed, but two-legged contractions were used. Muscle biopsies taken after 5, 15, and 30 min of exercise showed only minor changes in the concentrations of glycogen, lactate, creatine phosphate (CrP), and ATP. However, at exhaustion, defined as loss of ability to sustain the target force, the concentrations of CrP and glycogen were reduced by 73 and 32%, and muscle lactate concentration had increased to 4.8 mmol/kg wet wt. Thus the gradual decline in force-generating capacity was not due to lactacidosis or lack of substrates for ATP resynthesis and must have resulted from excitation/contraction coupling failure, whereas exhaustion was closely related to phosphagen depletion, without significant lactacidosis.
Abstract: Study Objective: To determine whether antibodies to vasopressin play a role in the development of diabetes insipidus or interfere with diagnosis and treatment. Design: Random plasma or serum samples for determining of antibodies to vasopressin were collected from patients and controls. Setting: Referral university hospital with most patients studied in the clinical research center. Patients: Twenty-nine healthy controls and 113 patients with polyuria (15 with primary polydipsia; 86 with neurogenic diabetes insipidus [60 studied before, 28 during, and 10 after antidiuretic hormone treatment]; and 12 with nephrogenic diabetes insipidus). Interventions: Antibodies were detected by incubating samples with radiolabeled 125I-arginine vasopressin. The effect of antibodies on diagnosis was studied by examining the relation of plasma vasopressin to osmolality measured during dehydration or infusion of hypertonic saline and the relation of urine osmolality to plasma vasopressin measured during dehydration. Measurements and Main Results: Antibodies to vasopressin were not detected in patients with primary polydipsia, nephrogenic diabetes insipidus, or neurogenic diabetes insipidus studied before therapy with antidiuretic hormone. Antibodies were detected in 6 of 28 patients studied during such treatments. All 6 patients reported decreased antidiuretic response to previously effective therapy with arginine or lysine vasopressin but had normal response to desmopressin or chlorpropamide. Conclusion: Diabetes insipidus does not result from spontaneously occurring antibodies to vasopressin. The antibodies occasionally develop during treatment with antidiuretic hormone and, when they do, almost always result in secondary resistance to its antidiuretic effect. Antibodies usually do not impair the response to other forms of therapy; they only rarely interfere with the diagnosis of diabetes insipidus, by falsely suggesting the presence of the partial nephrogenic form.
Abstract: Changes in osmoregulation during normal menstrual cycle were examined in 15 healthy women. In 10 women, studied repetitively during two consecutive menstrual cycles, basal plasma osmolality, sodium, and urea decreased by 4 mosmol/kg, 2 meq/l, and 0.5 mM, respectively (all P less than 0.02) from the follicular to luteal phase. Plasma vasopressin, protein, hematocrit, mean arterial pressure, and body weight did not change. In five other women, diluting capacity and osmotic control of thirst and vasopressin release were assessed in follicular, ovulatory, and luteal phases. Responses of thirst and/or plasma vasopressin, urine osmolality, osmolal and free water clearance to water loading, and infusion of hypertonic saline were normal and similar in the three phases. However, the plasma osmolality at which plasma vasopressin and urine osmolality were maximally suppressed as well as calculated osmotic thresholds for thirst and vasopressin release were lower by 5 mosmol/kg in the luteal than in the follicular phase. This lowering of osmotic thresholds for thirst and vasopressin release, which occurs in the luteal phase, is qualitatively similar to that observed in pregnancy and should be taken into account when studying water balance and regulation of vasopressin secretion in healthy cycling women.
Abstract: Both proximal renal tubule cells and cultured Madin-Darby canine kidney (MDCK) cells are capable of regulating their volume in hypotonic media. Regulatory cell volume decrease in proximal straight tubules is impaired by barium, amiloride and acetazolamide and depends on the presence of bicarbonate and of sodium, whereas it is unaffected by complete removal of extracellular chloride. The observations may point to parallel loss of potassium through potassium channels as well as of bicarbonate and sodium via a bicarbonate-sodium cotransport. Alternatively, potassium/hydrogen ion exchange or potassium bicarbonate cotransport could be involved. In MDCK cells, exposure to hypotonic media apparently leads to the activation of an anion channel, while potassium conductance is rather decreased. In both proximal tubules and MDCK cells, volume regulatory decrease is possibly triggered by leucotrienes, which may be released during cell swelling. Cell volume is altered in a variety of conditions even at isotonic extracellular fluid and cell volume-regulatory mechanisms are likely to participate in regulation of renal transepithelial transport.
Abstract: 1. Pulsed bidirectional Doppler-ultrasound equipment was used to measure changes in blood velocities in the femoral artery on a beat to beat basis for consecutive contraction and relaxation phases during voluntary rhythmic exercise of the quadriceps muscle group in man. 2. Rapid and large fluctuations of blood velocities were found, being high during relaxation and low during contraction phases. At the onset of contraction phase, negative velocities were present, indicating retrograde flow. During the rest of the contraction phase, forward flow occurred comparable to the resting flow level even at high loads. 3. Estimated maximal flow to the whole leg during relaxation phase, calculated from these blood velocity measurements and vessel diameter (measured with echo-ultrasound equipment with high resolution) was in two of the subjects 3.32 l min-1 (female) and 5.97 l min-1 (male). When using computer tomography to estimate the volume of the quadriceps muscle group, the calculated maximum flow to this muscle group was 243 (female) and 257 (male) ml min-1 100 ml muscle-1. The time-averaged flow during exercise to the whole leg was 1.51 l min-1 (female) and 2.47 l min-1 (male). The calculated time-averaged flow to the quadriceps muscle group was 101 (female) and 98 (male) ml min-1 100 ml muscle-1. 4. The duration of post-contraction hyperaemia following such rhythmic exercise of up to 6 min duration and up to 75% maximum voluntary contraction was never in excess of 150 s.
Abstract: Three hundred eighty-eight of 7,283 (5.3%) admitted trauma patients underwent urgent thoracotomy. In 61 patients (15.7%), pulmonary or tracheobronchial injury prompted thoracotomy (11, blunt; 50, penetrating). Pulmonary hemorrhage necessitated thoracotomy in 54 patients (88.5%); tracheobronchial injury in five patients (8.2%). The mortality was 27.9%. Nine patients (14.8%) underwent pneumonectomy: eight died of intractable hemorrhagic shock during thoracotomy despite rapid control of pulmonary hemorrhage: one died of sepsis. Eleven patients (18.0%) underwent lobectomy: six (54.5%) died of concomitant injuries. Thirty-six patients (59.0%) underwent pneumonorrhaphy: one died of concomitant injuries. Five (8.2%) patients underwent tracheobronchial repair: one died of concomitant injuries. Pneumonectomy was uniformly fatal and should be a procedure of last resort in the treatment of pulmonary injury, as lobectomy and pneumonorraphy are better tolerated by these critically ill patients.
Abstract: Successful cardioversion is dependent on the delivery of sufficient current. Current is determined by energy and transthoracic impedance (TTI). Our purpose was to assess factors affecting TTI in humans. Twenty-eight patients undergoing elective cardioversion were monitored up to 48 hours after shock delivery. We also studied 10 normal subjects, who did not receive shocks, for comparison. TTI declined 8% in the first hour in patients who received shocks, but also 6% in the normal subjects who wore the same pads for 1 hour but received no shocks. Twenty-four hours later, TTI returned to baseline in the nonshocked subjects but remained reduced (93% of control, p less than 0.05) in the shocked patients. There was a correlation between the total energy delivered and the decline in TTI (r = 0.69). TTI was 9% lower at end-expiration than at end-inspiration (55 +/- 3 vs 50 +/- 3 ohms, mean +/- standard error of the mean, p less than 0.01, paired t test). In the normal subjects, when a nonsalt-containing coupling agent (ultrasound coupling gel) was compared with a salt-containing gel (Redux paste), TTI was 20% higher (65 +/- 5 vs 54 +/- 4 ohms, p less than 0.01) with the nonsalt-containing gel. When no coupling agent was used, TTI was markedly higher, 160 +/- 18 ohms (p less than 0.01 vs control). After 1 hour, TTI decreased 6% in the normal subjects when salt-containing gel was used, but did not change when a nonsalt gel was used.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Dyspnea, the sensation of feeling breathless, is a symptom experienced under conditions in which there is an inordinately high ventilatory demand relative to the ability to breathe. Its major physical sign is tachypnea. New developments in monitoring ventilation during exercise have improved our ability to evaluate the symptom of dyspnea and to understand pathophysiological mechanisms contributing to the symptom. We briefly describe the range of mechanisms that determine exercise ventilation and their possible relationship to dyspnea. Questionnaires and psychophysical testing have been used to quantify dyspnea, but there is variability in dyspnea grade from these methods. Dyspnea-producing stimuli and the mechanisms by which they act are reviewed. Disorders producing dyspnea and the pathophysiological mechanisms underlying each are discussed. Perception of dyspnea is obviously through the central nervous system, where dyspnea-producing stimuli are integrated. The specific integration site is probably in the region of the brain stem, since occasional patients with brain stem lesions do not experience dyspnea despite the presence of a number of dyspnea-producing stimuli.
Abstract: This study examined the time course of adult rodent soleus muscle myofibril and myosin isoform protein expression after 4, 8, 16, 28, and 56 days of hindlimb unweighting by tail suspension (S). The time course of soleus muscle recovery (R) was also examined after 28 days of hindlimb unweighting with an additional 4, 8, 16, and 28 days of unrestricted cage activity. During suspension, soleus muscle myofibril protein rapidly decreased from 34.3 +/- 3.1 (1.96SE) mg/pair in the control (C) group to 6.9 +/- 1.4 (1.96SE) mg/pair in S (t = 56 days). The calculated first-order degradation rate constant for this loss was kd = 0.17 days-1 [half time (t1/2) = 4.1 days]. The estimated slow myosin (SM) isoform content decreased from 13.4 +/- 2.0 (1.96SE) mg/pair in C to 2.1 +/- 0.2 (1.96SE) mg/pair in S (kd = 0.19 days-1, t1/2 = 3.6 days). The relative proportion of other myosin isoforms was increased at 28 and 56 days of suspension, reflecting an apparent de novo synthesis and the loss of SM. Recovery of contractile protein after 28 days of suspension was slower for both the myofibril protein and the SM isoform (kd = 0.07 days-1, t1/2 = 10 days). These data suggest that loss of weight bearing specifically affected the mechanisms of contractile protein expression reflected in soleus muscle protein degradation processes. In addition, the expression of the myosin isoforms were apparently differentially affected by the loss of weight-bearing activity.
Abstract: The glucagon-suppressing activity of insulin and somatostatin were compared at high and low glucose concentrations. In normal dogs made hyperglucagonemic by phloridzin pretreatment, insulin and somatostatin suppressed glucagon at rates of 47 +/- 8 and 35 +/- 8%/h (NS), respectively, despite profound hypoglycemia. In severely hyperglycemic alloxan-diabetic dogs, insulin and somatostatin suppressed glucagon at rates of 48 +/- 13 and 54 +/- 6%/h, respectively, not different from the nondiabetic dogs. After phloridzin pretreatment to eliminate hyperglycemia in the diabetic dogs, insulin and somatostatin suppressed 51 +/- 8 and 31 +/- 10%/h (NS), respectively. Glucose infused in the phloridzin-pretreated insulin-deprived group suppressed glucagon only partially; insulin was required to reduce it further. We conclude that insulin and somatostatin suppress glucagon at similar rates irrespective of ambient glucose levels, and that diabetic hyperglucagonemia represents the summation of stimulation by insulin lack minus suppression by the associated hyperglycemia.
Abstract: An in vitro method has been used to examine whether secretion of renin from the juxtaglomerular apparatus is affected by changes in the sodium chloride concentration of the tubular fluid at the macula densa. Single juxtaglomerular apparatuses were microdissected from rabbits and the tubule segment containing the macula densa was perfused, while simultaneously the entire juxtaglomerular apparatus was superfused, and the fluid was collected for renin measurement. In this preparation, in which influences from renal nerves and local hemodynamic effects are eliminated, a decrease in the tubular sodium chloride concentration at the macula densa results in a prompt stimulation of the renin release rate.
Abstract: Studies of leg volumes in space by multiple girth measurements showed reductions of 1.9 L (12.8% of leg volume) with 1.1 L from the non-dominant leg on Skylab 4. On landing, 65% of postflight leg volume increase was complete at 1.5 h. Measurement of the dominant leg during the equivalent period on Shuttle showed a mean loss of 0.9 L which was 90% complete at 150 min. Postflight increases were 87% complete at 1.5 h postlanding. Mass measurements during and after Skylab 4 showed a loss of 2.5 kg over the first 4 d on-orbit with a gain of 2.7 kg over the first 4 d of recovery. These changes are assumed to be tissue fluids secondary to changes in hydrostatic pressures and are much greater than those seen in bed rest. Rate and magnitude of inflight and postflight changes have significant operational impact.
Abstract: Ischaemia has profound effects on myocardial metabolism and cell function in general. High energy phosphate and glycogen stores are depleted. Lactate, inorganic phosphate and hydrogen ions accumulate, exerting negative effects on the initially accelerated glycolytic flux. Fatty acid oxidation is inhibited. The cellular content of lipid intermediates, such as hydroxy-fatty acids, acyl CoA and acylcarnitine, increases in low-flow ischaemia hearts. Non-esterified fatty acid (NEFA) accumulation occurs after 30-60 min ischaemia. Endogenous triacylglycerol and phosphoglyceride turnover is most likely impaired, ultimately resulting in accumulation of lipid droplets in the oxygen deprived cells and in degradation of myocardial membranes. Accumulated lipid substances such as NEFA, acyl CoA, acylcarnitine and lysophosphoglycerides, are likely to be involved in the mechanism underlying ischaemia-induced damage to myocardial cells.
Abstract: To assess myocardial lymphatics during the evolution of myocardial infarction we performed lymphangiographic studies thirty and three hundred sixty minutes after occlusion of the left anterior descending coronary artery in 92 dogs. A morphometric index was employed on a coded basis to assess the lymphangiograms. Well before myocardial necrosis was evident, at thirty minutes, a striking reduction was evident in lymphatic filling in the ischemic zone: similar changes were seen three hundred sixty minutes after occlusion. Heparin in doses that rendered blood incoagulable did not prevent the lymphatic occlusion or collapse, but they were prevented by two agents that act as cardiac lymphagogues, hyaluronidase and CLS 2210. Lymph flow from the heart was assessed in another 23 dogs. Lymph flow fell sharply after coronary artery occlusion in placebo-treated dogs but was well maintained in dogs treated with hyaluronidase and with CLS 2210. The reduction in cardiac lymphatic filling and lymph flow occurred too early to be a consequence of myocardial necrosis. To the extent that reduced lymphatic drainage allows the local accumulation of potentially toxic products, it could contribute to the local damage. Treatment with the lymphagogues not only maintained lymphatic patency but also reduced evidence of myocardial damage evident on examination by light and electron microscopy. These studies provide an alternative to commonly held concepts on how hyaluronidase reduces myocardial infarction after coronary artery occlusion and support the concept that lymphatic occlusion or collapse plays a role in myocardial infarction.
Abstract: The effects of atriopeptin III on the renal response to changes in renal perfusion pressure (RPP) were examined in uninephrectomized and adrenalectomized rats. Neural influences on the kidney were eliminated by renal denervation. Plasma levels of antidiuretic hormone (ADH), angiotensin II, aldosterone, corticosterone, and norepinephrine were controlled by intravenous infusion. Infusion of atriopeptin III at a dose of 30 or 100 ng X kg-1 X min-1 increased plasma levels of atrial natriuretic peptide from 101 +/- 8 pg/ml to 424 +/- 16 and 2,553 +/- 308 pg/ml, respectively. In control rats, increasing RPP in two steps from 100 to 125 to 150 mmHg produced sixfold increases in sodium and water excretion. The slopes of the relationships between fractional sodium and water excretion and RPP were enhanced by approximately 10, 20, and 40% in the rats infused with the 30, 100, and 500 ng X kg-1 X min-1 dose of atriopeptin III. Renal blood flow and glomerular filtration rate were not significantly different in vehicle- and atriopeptin III-infused rats at any RPP studied. Papillary blood flow measured with a laser-Doppler flowmeter increased 15% within the first 5 min of infusion of atriopeptin III at a dose of 100 ng X kg-1 X min-1. Cortical blood flow was not significantly altered. The rise in papillary blood flow during atriopeptin III infusion, however, may be a consequence and not the cause of the natriuresis and diuresis, since urine flow increased before significant changes in papillary blood flow were detected. These studies suggest that atrial natriuretic factor could influence the long-term control of arterial pressure by altering renal medullary hemodynamics and promoting the elimination of sodium and water. The plasma levels of atrial natriuretic peptide needed to alter the pressure-natriuresis relationship, however, may exceed levels that can be attained in vivo with endogenous release.
Abstract: The experimental model of central pontine myelinolysis–chronic (4-day) hyponatremia induced by daily injections of hypotonic dextrose solutions and vasopressin followed by rapid correction with saline–was used in young fasted and thirsted mice. In normal controls chronic fasting and thirsting lowered plasma and brain glucose levels and cerebral glycolytic and tricarboxylic acid cyclic metabolic fluxes. The fasting state had little effect on brain amino acids. Clinically, the animals became semistuporous; about one-third died. Chronic hyponatremia in fasted mice almost tripled the plasma glucose concentrations and increased the brain carbohydrate reserve. Levels of other brain glycolytic and Krebs citric acid cycle intermediates were similar to those of controls. Severe hyponatremia and hypoosmolality induced profound decreases in levels of brain electrolytes, amino acids (especially taurine), and creatine. These changes permitted a new osmotic balance between blood and brain and a normal brain water content. The behavior and mortality of the hyponatremic animals were not different from those of the fasted control mice. Correction of hyponatremia to normonatremic levels over a 9-hr period returned brain Na+ and K+ levels to normal but the contents of the measured amino acids and creatine were still reduced one-third or more. As a result, treatment produced a significant degree of dehydration and shrinkage of the brain. The findings stress the importance of amino acids (taurine in particular) and creatine levels, as well as electrolytes, in brain osmoregulation and suggest a role for an osmotic disequilibrium–blood osmolality higher than brain–in the production of brain lesions following rapid correction of chronic hyponatremia in animals and possibly in humans. Replenishment of depleted brain K+ and amino acid levels, as well as slow elevation of the chronically depressed level of plasma Na+, is recommended.
Abstract: The effect of bicarbonate on the ability of cells to regulate the internal pH after acid and alkali loads was studied. In the presence of Na+, the normalization of the internal pH after acid loads occurred more rapidly in the presence than in the absence of bicarbonate. DIDS (4,4’-diisothiocyano-2,2’-stilbene-disulfonic acid) strongly inhibited the pH increase, whereas amiloride inhibited it to a lesser extent. The Na+-linked, bicarbonate-dependent pHi increase after an acid load was strongly reduced in cells depleted of Cl-. When cells were transferred to gluconate or mannitol balanced buffers containing bicarbonate, there was a rapid alkalinization of the cytosol, apparently due to influx of bicarbonate induced by chloride efflux. When the internal pH was below 7.0, the pH increase was much more rapid in the presence than in the absence of Na+, whereas at higher internal pH, there was no measurable effect of Na+. The ability of the cells to reduce the internal pH after an alkali load was increased in the presence of bicarbonate. The data indicate that both Na+-linked and Na+-independent bicarbonate/chloride exchange occur in Vero cells.
Abstract: We used microelectrode recordings of muscle sympathetic nerve activity (MSNA) from the peroneal nerve in the leg during arm exercise in conscious humans to test the concept that central command and muscle afferent reflexes produce mass sympathetic discharge at the onset of exercise. Nonischemic rhythmic handgrip and mild arm cycling produced graded increases in heart rate and arterial pressure but did not increase MSNA, whereas ischemic handgrip and moderate arm cycling dramatically increased MSNA. There was a slow onset and offset of the MSNA responses, which suggested metaboreceptor mediation. When forearm ischemia was continued after ischemic handgrip, MSNA remained elevated (muscle chemoreflex stimulation) but heart rate returned to control (elimination of central command). The major new conclusions are that: the onset of dynamic exercise does not produce mass, uniform sympathetic discharge in humans, and muscle chemoreflexes and central command appear to produce differential effects on sympathetic and parasympathetic responses.
Abstract: The effects of immobilization on bone mass and bone remodeling in patients with spinal cord injuries are known to simulate weightlessness-induced bone changes in astronauts. Nevertheless, immobilization has never been investigated using histomorphometric studies in healthy volunteers. Twenty healthy male volunteers participated in a ’120 day bed-rest’ experiment in the USSR. Bone biopsy cores of iliac crest were taken before and at the end of the period of bed-rest. The subjects were divided into five groups. Five subjects underwent a normal ambulatory life (control subjects); three subjects were placed on continuous bed-rest for 120 days (complete immobilization); four subjects were immobilized and underwent a controlled training program; four subjects were immobilized and received treatment with potassium diphosphonate (ethane-1,hydroxy-1,diphosphonate 900 mg/day, per os); and four subjects were immobilized and received diphosphonate plus physical exercise. Parameters of bone mass and bone cellular activities (osteoblastic formation and osteoclastic resorption) were measured using automatic and semi-automatic image analysis systems. Bone mass remained constant in each group. Cellular activity measurements showed that in completely immobilized men, the mineralization rate was lower than in controls without change in osteoid parameters; in contrast, osteoclastic parameters were increased. In immobilized men given the training program, bone formation was normal and bone resorption was increased. In immobilized men treated with diphosphonate, osteoid parameters and resorption activity were decreased. In immobilized men with diphosphonate plus training, the osteoid parameters and the resorption activity were reduced but to a lesser degree than in immobilized men with diphosphonate alone. Failure of bone loss in normal immobilized subjects differed from results found in paraplegic patients. However, a decrease in mineralization rate and an increase in bone resorption activity were found in both studies. Exercise stimulated bone resorption and diphosphonate inhibited the osteoclastic activity. These data emphasize the difficulties in finding good models to stimulate spaceflight conditions on earth. Comparative studies must be done using bone biopsies to determine more precisely the effects of weightlessness on the human skeleton.
Abstract: We have determined the effect of various rates of glucose infusion on the rates of release of glycerol (Ra glycerol), free fatty acids (Ra FFA), and on energy metabolism in normal human volunteers. Plasma kinetics were determined with use of the stable isotopic tracers D-5-glycerol and [1-13C]palmitate, and energy metabolism was determined by indirect calorimetry. The effect of glucose infusion on Ra glycerol and Ra FFA was dose-dependent. At an infusion rate of 1 mg X kg-1 X min-1, no effect on either kinetic factor was noted. At 4 mg X kg-1 X min-1, both Ra glycerol and Ra FFA were suppressed; at 8 mg X kg-1 X min-1, Ra FFA was even more depressed, but Ra glycerol was similar to the value during the 4 mg X kg-1 X min-1 infusion. At all infusion rates tested, the amount of potential energy available from the sum of the glucose infusion and endogenously mobilized fat was always greater than when no glucose was infused. Glucose decreased fat mobilization by both inhibiting lipolysis and stimulating reesterification, thus causing a significant increase in triglyceride-fatty acid substrate cycling within the adipose tissue.
Abstract: The authors studied the relative contribution of cerebrospinal fluid (CSF) and vascular parameters to the level of intracranial pressure (ICP) in 34 severely head-injured patients with a Glasgow Coma Scale score of less than 8. This was accomplished by first characterizing the temporal course of CSF formation and outflow resistance during the 5-day period postinjury. The CSF formation and outflow resistance were obtained from pressure responses to bolus addition and removal of fluid from an indwelling ventricular catheter. The vascular contribution to the level of ICP was assessed by withdrawing fluid at its rate of formation and observing the resultant change in equilibrium ICP level. It was found that, with the exception of patients with subarachnoid hemorrhage, CSF parameters accounted for approximately one-third of the ICP rise after severe head injury, and that a vascular mechanism may be the predominant factor in elevation of ICP.
Abstract: To determine the relative importance of the peripheral and central chemoreceptors in the ventilatory response to acute metabolic acid-base disturbances we measured the normoxic ventilatory response to acute respiratory and metabolic acidosis and alkalosis in 10 chloralose-urethane anesthetized cats using a technique of vertebral artery perfusion that allows one to independently manipulate the PaCO2, PaO2 and the H+ concentration of the blood in the systemic circulation (peripheral) and the blood perfusing the brain stem (central) (Berkenbosch et al., 1979). The ventilation could be satisfactorily described by a linear function of the peripheral and central arterial H+ concentration and the central PaCO2. Mean values (+/- SEM) found for the peripheral arterial H+ sensitivity and the isocapnic central arterial H+ sensitivity were 26.0 +/- 3.2 and 12.7 +/- 1.8 ml X min-1 X nM-1, respectively; the isohydric central arterial CO2 sensitivity was 545.9 +/- 96.7 ml X min-1 X kPa-1. We conclude that in the ventilatory response to an acute metabolic acid-base disturbance both the peripheral and central chemoreceptors play a role. However, the sensitivity of the peripheral chemoreceptors to isocapnic changes in the arterial H+ concentration is twice as large as the sensitivity of the central chemoreceptors. It is argued that in the adaptation of the ventilation to an acute metabolic acidosis the stimulatory effect of the peripheral chemoreceptors is counteracted by a diminished stimulation of the central chemoreceptors.
Abstract: To define glycemic thresholds for activation of glucose counterregulatory systems and for symptoms of hypoglycemia, we measured these during stepped reductions in the plasma glucose concentration (in six 10-mg/dl hourly steps) from 90 to 40 mg/dl under hyperinsulinemic clamp conditions, and compared these with the same measurements during euglycemia (90 mg/dl) under the same conditions over 6 h in 10 normal humans. Arterialized venous plasma glucose concentrations were used to calculate glycemic thresholds of 69 +/- 2 mg/dl for epinephrine secretion, 68 +/- 2 mg/dl for glucagon secretion, 66 +/- 2 mg/dl for growth hormone secretion, and 58 +/- 3 mg/dl for cortisol secretion. In contrast, the glycemic threshold for symptoms was 53 +/- 2 mg/dl, significantly lower than the thresholds for epinephrine (P less than 0.001), glucagon (P less than 0.001), and growth hormone (P less than 0.01) secretion. Thus, the glycemic thresholds for activation of glucose counterregulatory systems during decrements in plasma glucose lie within or just below the physiologic plasma glucose concentration range, and are substantially higher than the threshold for hypoglycemic symptoms in normal humans. These findings provide further support for the concept that glucose counterregulatory systems are involved in the prevention, as well as the correction, of hypoglycemia.
Abstract: The precise patterns of LH, FSH, and PRL secretion and their correlation with estradiol (E2) and progesterone (P) secretion during the entire luteal phase have not been elucidated. To analyze in detail the secretory patterns of these hormones we performed 29 consecutive studies in 5 healthy, regularly menstruating women throughout their luteal phase [days 0 (ovulation), 2, 6, 10, and 14] and subsequent early follicular phase (day 2F). During each study plasma LH, FSH, PRL, E2, and P were measured at 10-min intervals for 6 h. Both plasma LH concentrations and LH pulse frequency declined from days 0 to 10 and increased thereafter, whereas LH pulse amplitude continued to decline throughout the luteal and early follicular phases. Plasma FSH concentrations followed a pattern similar to that of LH; however, there was a larger increase in the FSH level on days 14 and 2F. Plasma PRL levels declined initially on day 2 and again on day 14. Regression analysis indicated a positive correlation between LH concentrations and LH pulse frequency (r = 0.715; P less than 0.001) and between PRL and E2 concentrations (r = 0.528; P less than 0.01). A negative correlation was found between plasma P concentrations and both LH concentrations (r = -0.521; P less than 0.01) and LH pulse frequency (r = -0.633; P less than 0.001) and between plasma E2 and FSH concentrations (r = -0.762; P less than 0.001). Thirty-six (65%) PRL pulses and only 11 (39%) FSH pulses coincided with LH pulses. There was no clear pulsatile pattern of secretion of either E2 or P. We conclude that 1) the plasma LH, FSH, PRL, E2, and P concentrations vary markedly throughout the luteal phase; 2) the plasma LH level is largely dependent on the frequency of LH pulses; 3) plasma P decreases plasma LH by reducing the frequency of LH pulses; 4) the remarkable synchrony between PRL pulses and LH pulses implies that their secretion may be regulated by a common neuroendocrine mechanism; and 5) the preferential increase in FSH during the late luteal phase may play an important role in follicular recruitment for the subsequent cycle.
Abstract: The mesangial changes in 92 renal biopsy specimens from 81 children with IgA nephropathy were correlated with the clinical and the other renal biopsy findings. Three types of mesangial changes were identified: mesangial hypercellularity was predominant compared with the increase in matrix in 34 biopsy specimens (type A), the degrees of mesangial hypercellularity and matrix increase were similar in 36 (type B) and matrix increase was predominant in 22 (type C). The interval between the onset of disease and biopsy was significantly shorter in biopsies with type A mesangial changes (P less than 0.01) and significantly longer in those with type C (P less than 0.01). Serial pathologic observations revealed that predominant mesangial hypercellularity was almost exclusively seen in the initial biopsy but predominant matrix increase was usually seen in the follow-up biopsy. The percentage of glomeruli showing sclerosis was significantly higher in biopsies with type C mesangial changes (P less than 0.05). At the latest follow-up, 58% of the patients showing type A and 57% showing type B lost their proteinuria, whereas only 9% showing type C lost their proteinuria (P less than 0.01). These findings suggest that predominant mesangial hypercellularity is characteristic of the early lesion of childhood IgA nephropathy, and progression of disease leads to gradual decrease of mesangial cellularity and increase of matrix with sclerosis.
Abstract: Peroneal muscle sympathetic activity (MSA) was recorded during 2 min of isometric handgrip at 30% of maximal power and correlated with plasma levels of noradrenaline (NA) in venous blood from the contralateral forearm in 16 normotensive subjects and 15 previously untreated patients with essential hypertension. Resting values for MSA and NA were similar in the two groups and there was a significant positive correlation between the level of MSA (expressed either as bursts per 100 heart beats or bursts min-1) and the concentration of NA. Changes of MSA and NA during handgrip were similar in both groups. When monitored every minute in a subgroup of the material (n = 12), the number of sympathetic bursts min-1 increased maximally by 23% and total MSA (bursts min-1 X mean burst amplitude) by 67% during the second minute of handgrip. The maximal increase of venous NA concentrations was 21% and occurred 2 min later, probably reflecting a slow wash-out of NA from the neuroeffector junctions. It is concluded that: there is no difference in MSA between normotensive and hypertensive subjects at rest or during isometric handgrip, MSA is an important determinant of the concentration of NA in forearm venous plasma, and the relative change of the venous plasma NA concentration during isometric handgrip is considerably smaller than the change in total MSA.
Abstract: Mechanisms of ventilatory acclimatization to chronic hypoxia remain unclear. To determine whether the sensitivity of peripheral chemoreceptors to hypoxia increases during acclimatization, we measured ventilatory and carotid sinus nerve responses to isocapnic hypoxia in seven cats exposed to simulated altitude of 15,000 ft (barometric pressure = 440 Torr) for 48 h. A control group (n = 7) was selected for hypoxic ventilatory responses matched to the preacclimatized measurements of the experimental group. Exposure to 48 h of hypobaric hypoxia produced acclimatization manifested as decrease in end-tidal PCO2 (PETCO2) in normoxia (34.5 +/- 0.9 Torr before, 28.9 +/- 1.2 after the exposure) as well as in hypoxia (28.1 +/- 1.9 Torr before, 21.8 +/- 1.9 after). Acclimatization produced an increase in hypoxic ventilatory response, measured as the shape parameter A (24.9 +/- 2.6 before, 35.2 +/- 5.6 after; P less than 0.05), whereas values in controls remained unchanged (25.7 +/- 3.2 and 23.1 +/- 2.7; NS). Hypoxic exposure was associated with an increase in the carotid body response to hypoxia, similarly measured as the shape parameter A (24.2 +/- 4.7 in control, 44.5 +/- 8.2 in acclimatized cats). We also found an increased dependency of ventilation on carotid body function (PETCO2 increased after unilateral section of carotid sinus nerve in acclimatized but not in control animals). These results suggest that acclimatization is associated with increased hypoxic ventilatory response accompanied by enhanced peripheral chemoreceptor responsiveness, which may contribute to the attendant rise in ventilation.
Abstract: To determine whether chloride repletion without sodium could correct chronic chloride depletion metabolic alkalosis (CDA) in Sprague-Dawley rats without volume expansion and without increasing glomerular filtration rate (GFR), CDA was generated by peritoneal dialysis (PD) against 0.15 M NaHCO3 and maintained for 7-10 days by a chloride-restricted diet supplemented with sodium and potassium salts. Control animals were dialyzed against Ringer bicarbonate. The maintenance period of chronic CDA, compared with control, was characterized by hypokalemic metabolic alkalosis (serum TCO2 31.9 +/- 0.6 vs. 23.1 +/- 0.5 meq/l, P less than 0.05), volume contraction (plasma volume 3.76 +/- 0.08 vs. 4.19 +/- 0.22 ml/100 g body wt, P less than 0.05), decreased GFR (838 +/- 84 vs. 1045 +/- 45 microliters.min-1.100 g body wt-1, P less than 0.05), increased plasma renin activity (PRA) (63 +/- 13 vs. 12 +/- 3 ng.ml-1.h-1, P less than 0.05), but unchanged plasma aldosterone concentrations (PAC) (4.1 +/- 1.0 vs. 3.4 +/- 1.6 ng/dl, P = NS). Complete correction of chronic CDA was accomplished by 24 h of ingestion of choline chloride drink, and despite negative sodium balance, neutral potassium balance, continued bicarbonate ingestion, and persistent volume contraction (plasma volume 3.76 +/- 0.08 vs. 3.73 +/- 0.12 ml/100 g body wt pre- and postcorrection, P = NS), GFR remained decreased (659 +/- 87 vs. 1,045 +/- 45 microliters.min-1.100 g body wt-1, P less than 0.05), PRA decreased (63 +/- 13 vs. 33 +/- 5 ng.ml-1.h-1, P less than 0.05), but PAC did not change (4.1 +/- 1.0 vs. 6.1 +/- 1.6 ng/dl, P = NS) after correction of CDA.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Patients with membranous glomerulonephritis (MGN), impaired renal function and the nephrotic syndrome are at high risk of developing renal failure. Twenty-six such patients were studied with serum creatinine concentrations exceeding 135 microM, and 24-hour urine protein excretion of at least 3.5 g/day to determine the potential benefit of cyclophosphamide therapy. Cyclophosphamide (mean 1.5 mg/kg/day) was given to nine patients for 23 +/- 4 months. These patients were compared with 17 concurrent controls. The two groups did not differ in clinical or laboratory features at the time of biopsy or start of treatment or its equivalent. Six of the nine cyclophosphamide treated patients and 15 of the 17 controls had received prednisone therapy. The total follow-up was 49 +/- 10 months in the treated group and 50 +/- 6 months in the controls. At last observation, serum creatinine values exceeded 400 microM in eight controls (4 on dialysis) and in none of the treated patients. The mean serum creatinine level was significantly lower (P less than 0.02) in the treated group (173 +/- 24 microM) than in controls (433 +/- 71 0.02) in the treated group (173 +/- 24 microM) than in controls (433 +/- 71 microM). The mean serum albumin level and 24-hour urine protein excretion both improved significantly with treatment as compared with controls. There were four complete remissions, five partial remissions and no patient with persistent nephrotic syndrome after treatment. In the controls, there were no complete remissions, six partial remissions and 11 patients had persistent nephrotic syndrome (P less than 0.001). Thus, cyclophosphamide therapy appears to be of benefit in patients with MGN, the nephrotic syndrome and impaired renal function.
Abstract: The role of angiotensin II in the hormonal and renal responses to maximal exercise was investigated by using the angiotensin-converting enzyme inhibitor captopril. Nine male subjects performed a standardized maximal treadmill test with and without acute captopril treatment (25 mg orally). At rest, captopril elevated plasma renin activity and lowered aldosterone levels. With maximal exercise, captopril treatment reduced the increase in mean arterial blood pressure by 8 mmHg and the increase in plasma renin activity by 3.0 ng ANG I.ml-1.h-1. The responses of adrenocorticotropin (ACTH), cortisol, and vasopressin to maximal exercise were not altered by captopril treatment. Although aldosterone levels were reduced at rest with captopril, during maximal exercise no difference was noted between treatments. Captopril treatment had no effects on the renal handling of salts or water during exercise. In conclusion, angiotensin II plays a role in the increase in mean blood pressure during maximal exercise in normal subjects but has no effect on the exercise responses of ACTH, vasopressin, and aldosterone or on the renal handling of salts and water.
Abstract: 1. Considerable data from animal studies suggest that angiotensin II exerts a facilitatory effect on noradrenaline release. We sought evidence for such an effect in man by examining how a subpressor dose of angiotensin II (1.5 ng kg-1 min-1) influences the haemodynamic and plasma noradrenaline responses to physiological stimulation of the sympathetic nervous system. 2. The physiological stimuli investigated were a cold pressor test, the response to standing from lying, bicycle exercise and forearm isometric exercise. 3. The presence of the angiotensin II infusion had no effect on the systolic blood pressure, diastolic blood pressure, heart rate or plasma noradrenaline responses to stimulation of the sympathetic nervous system. 4. We have therefore found no evidence to support the enhancement of noradrenaline release by this low dose of angiotensin II in man.
Abstract: Patients with uncontrolled insulin-dependent diabetes mellitus have elevations in plasma vasopressin that cannot be completely accounted for by recognized stimuli. To determine whether insulin deficiency per se increases plasma vasopressin, we investigated the effect of acute insulin depletion on the osmoregulation of plasma vasopressin in insulin-dependent diabetics. When intravenous insulin infusion was stopped, plasma vasopressin, osmolality, and glucose increased over the ensuing 5 h, whereas plasma sodium decreased, and blood volume and pressure did not change. This increase in vasopressin was not due to a loss of osmoregulation, because changes in plasma osmolality and sodium, induced by infusion of hypertonic saline or water loading, induced appropriate vasopressin responses under insulin deplete as well as replete conditions. However, when plasma osmolality and glucose were raised by infusion of hypertonic dextrose, plasma vasopressin increased significantly in diabetic patients under insulin-deplete but not under insulin-replete conditions and actually decreased in healthy controls. These results indicate that acute insulin depletion increases vasopressin secretion by sensitizing the osmoreceptor to stimulation by hyperglycemia. This change in osmoreceptor specificity may be explained by postulating that glucose transport by osmoreceptor neurons as insulin dependent.
Abstract: To explore the mechanism of glomerular permselectivity defect in passive Heymann nephritis, an experimental model of human membranous glomerulopathy, Munich-Wistar rats were subjected to both micropuncture assessment of glomerular hemodynamics and whole kidney clearance measurements of graded size dextrans 10 days after injection of sheep anti-rat tubular antigen (anti-Fx1A). Compared with normal control rats, anti-Fx1A-treated animals were characterized by marked proteinuria (65 +/- 8 micrograms/min versus 6 +/- 1, p less than 0.001), markedly and significantly higher glomerular transcapillary hydraulic pressure difference (40 +/- 1 mm Hg versus 33 +/- 1, p less than 0.001), depressed ultrafiltration coefficient and impaired glomerular size-selective function as determined by fractional clearance of dextrans. Calculation of membrane parameters based on a recently defined heteroporous membrane model revealed abnormally high availability of non-size selective, large pore pathways in the glomerular capillary wall of the rats with passive Heymann nephritis. To ascertain the role of the altered hemodynamic pattern in the observed defect in the size-selective function of the glomerular capillary wall, glomerular transcapillary hydraulic pressure difference was manipulated experimentally in these proteinuric rats by intra-aortic infusion of acetylcholine or angiotensin II. These agents respectively suppressed and augmented glomerular transcapillary hydraulic pressure difference and brought about a decline of and a further rise in fractional clearance of larger dextrans along with parallel changes in both urine protein excretion rate and availability of nonselective channels. These results indicate that the permselectivity defect in passive Heymann nephritis is attributable, at least in part, to impaired size selectivity of the glomerular capillary wall caused by a prevailing abnormally high transcapillary hydraulic pressure difference.
Abstract: Thyroid hormone is important in the regulation of synthesis and secretion of thyroid-stimulating hormone (TSH) in the anterior pituitary, but its role in the control of hypothalamic thyrotropin-releasing hormone (TRH) is controversial. To determine whether thyroid hormone regulates the function of TRH in the hypothalamic tuberoinfundibular system, a study was made of the effect of hypothyroidism on thyrotropin-releasing hormone messenger RNA (proTRH mRNA) and TRH prohormone in the rat paraventricular nucleus. Extracts of rat hypothalamic paraventricular nucleus were examined by quantitative Northern blot analysis, and coronal sections of rat brain were examined by in situ hybridization histochemistry and immunocytochemistry. A nearly twofold increase in proTRH mRNA was observed in hypothyroid animals; this increase could be obliterated by levothyroxine treatment, suggesting an inverse relation between circulating thyroid hormone and proTRH mRNA. In situ hybridization showed that this response occurred exclusively in medial parvocellular neurons of the paraventricular nucleus. A simultaneous increase in proTRH mRNA and immunoreactive TRH prohormone in this region suggests that hypothyroidism induces both transcription and translation of the TRH prohormone in the paraventricular nucleus.
Abstract: Thiazide diuretics increase salt and water excretion primarily by inhibiting mechanisms for electroneutral sodium and chloride transport by distal convoluted tubule cells. This might be termed the ’specific’ effect of this class of diuretics and accounts for the ’chlorouretic’ effectiveness of the drug. Secondary to this inhibition of sodium and chloride absorption, potassium secretion is stimulated most likely because of the resultant increase in distal tubule fluid flow rate, and calcium absorption is stimulated possibly via a decrease in distal convoluted tubule cell sodium activity and an increase in basolateral sodium/calcium exchange. To a varying degree, thiazides also inhibit carbonic anhydrase. This effect can contribute to the diuresis, but is largely buffered by the reserve transport capacity of the loop of Henle. To the extent that the effects of transport inhibition in the proximal tubule are transmitted to the distal tubule, tubuloglomerular feedback may be activated and effect a reduction in the glomerular filtration rate.
Abstract: The temporal changes in the plasma concentration of immunoreactive atrial natriuretic factor (iANF) were studied in six conscious dogs with an arteriovenous (AV) fistula, a model of chronic high-output heart failure. Following the creation of the AV fistula, the dogs retained sodium avidly for 5 days, and plasma renin activity, plasma aldosterone concentration, and right atrial pressure increased significantly from controls. During this initial stage, iANF increased only modestly. From day 6 to 14, the dogs increased their daily sodium excretion and approached sodium balance. This natriuretic response was associated with a significant rise in iANF, with the return of renin and aldosterone levels to base line, and with a progressive significant elevation in right atrial pressure. Thus, in dogs with an AV fistula and cardiac volume overload, chronic increases in atrial pressure appear to be a sustained stimulus for the release of ANF. It is suggested that following the initial period of sodium retention in this experimental mental model of heart failure, chronic endocrine adjustments for the reestablishment of sodium balance involve an increase in ANF which subsequently can exert a tonic inhibitory action on the renin-aldosterone axis. It is concluded that the ANF endocrine system might function as an effective chronic compensatory mechanism to help promote sodium and water excretion in dogs with an AV fistula through the suppression of the renin-aldosterone system and possibly through its direct renal actions.
Abstract: The use of the creatinine height index (CHI) as a measure of protein nutrition is reviewed. Any such cross-sectional measurement is inherently limited. Using published values for urinary creatinine excretion per kilogram body weight in adult subjects of varying age and values for "ideal" weight as a function of height, we have derived normal values for expected creatinine excretion in men and women of varying height. These permit the derivation of an age-corrected CHI. Possible explanations for the normal decrease in creatinine excretion with age include (1) decreasing lean body mass with age, (2) decreasing proportion of muscle in lean body, and (3) lower meat intake in older persons. Diet has an important influence if meat intake is substantial or if consumption of a creatine-free diet is prolonged. Creatinine metabolism and extrarenal excretion are minor, except in subjects with reduced renal function. Application of a correction for constant extrarenal clearance of creatinine in patients with chronic renal failure probably is not valid. Further observations of creatinine excretion in normal subjects of varying age and height are needed.
Abstract: In dogs running on a treadmill at 2 or 4 mph or 4 mph plus 10% incline, graded reductions in hindlimb perfusion reflexly elicited pressor responses. To test the idea that systemic arterial pressure (SAP) is raised by accumulation in muscle of a nerve-activating "pressor substance" release when O2 delivery becomes inadequate, arterial O2 content (CaO2) was reduced 29.1% by carbon monoxide (CO) inhalation before repeating exercise at 2 mph. We reasoned that the pressor substance, or related substances, should appear in femoral venous blood and be correlated to SAP. [K+] behaved inappropriately as a signal to raise SAP, i.e., when flow was reduced, SAP rose markedly with little or no change in [K+]. SAP was well correlated to pH and [lactate] over the three work loads. Compared with the same work load with normal CaO2, CO shifted the relation between SAP and terminal aortic flow rightward 0.30 l/min (34.5%) and the relation between SAP and PO2 leftward 7.7 mmHg. CO did not affect the relation of SAP to terminal aortic O2 delivery, hindlimb O2 uptake index, pH, or [lactate]. Thus pressor responses are apparently generated when O2 delivery falls below some critical level causing accumulation of a pressor substance the release of which is linked to a metabolic event that precipitates lactate accumulation.
Abstract: Previous studies in adrenalectomized (Adx) rats suggest that aldosterone may regulate ion transport in the ascending portion of Helen’s loop. In order to examine directly the effect of adrenalectomy on transport, medullary thick ascending limb (Mtal) segments were isolated from Adx, Adx replaced with aldosterone (Adx + Ald, 0.5 micrograms X 100 g X body wt X d), and control Sprague-Dawley rats. Both net sodium and net chloride fluxes were significantly less in the Mtal segments from Adx rats compared with those in the control or Adx + Ald group. Physiologic levels of exogenous aldosterone increased net sodium chloride flux toward control values in the Adx + Ald group. Net potassium flux was not different among the three groups. We conclude that adrenalectomy impairs reabsorptive NaCl but not K transport in the Mtal, and that aldosterone restores this process. This reabsorptive defect may contribute to the urinary concentrating and diluting abnormality associated with adrenal insufficiency.
Abstract: Because of the central role of the sympathetic nervous system in mediating the stress response, plasma norepinephrine (NE), epinephrine (E), and dopamine (DA) levels were measured in 61 traumatically brain-injured patients to determine whether catecholamine (CA) levels obtained within 48 hours after injury provide reliable prognostic markers of outcome. Patient outcome was determined at 1 week using the Glasgow Coma Scale (GCS) and at the time of discharge using the Glasgow Outcome Scale (GOS). Levels of NE, E, and DA correlated highly with the admission GCS score (NE: r = 0.58, p less than 0.0001; E: r = 0.46, p less than 0.0025; DA: r = 0.27, p less than 0.04). Moreover, in the 21 patients with GCS scores of 3 or 4 on admission, NE levels predicted outcome at 1 week. All six patients with NE levels less than 900 pg/ml (normal level less than 447 pg/ml) improved to GCS scores of greater than 11, while 12 of 15 with NE values greater than 900 pg/ml remained with GCS scores of 3 to 6 or died. Levels of E and DA were not as useful. Catecholamine levels also increased significantly as the GOS score worsened. Levels of NE and E were significantly higher in patients who died or remained persistently vegetative than in those with better outcomes. In the 54 patients who survived beyond 1 week, significant correlations were present between the length of hospitalization and NE (r = 0.71, p less than 0.0001) and E (r = 0.61, p less than 0.0001) levels. Concentrations of NE (r = 0.61, p less than 0.0004) and E (r = 0.48, p less than 0.01) were also highly correlated with the duration of ventilatory assistance. Analysis of the interactions of CA levels and GCS scores, duration of ventilatory assistance, and length of hospitalization revealed that the CA’s either enhanced the reliability of the GCS score or were independent predictors of outcome. Thus, these findings indicate that alterations in circulating CA levels reflect the severity of the neurological insult and provide support for the use of CA measurements as a physiological marker of patient outcome in both the acute and chronic phases of traumatic brain injury.
Abstract: The purpose of this study was to test the hypothesis that hyperglycemia, comparable with that found in uncontrolled diabetes mellitus, increases renal blood flow (RBF) and glomerular filtration rate (GFR) through a tubuloglomerular feedback (TGF) mechanism. We infused glucose intrarenally (0.1-0.3 g/min) into anesthetized dogs with normal kidneys (NK), with nonfiltering kidneys (NFK) in which changes in TGF were blocked, and with normal kidneys in which renal perfusion pressure (RAP) was lowered to the limits of renal autoregulation (LPK). Calculated intrarenal plasma glucose levels rose to 250-400 mg/dl. In NK (n = 6) RBF and GFR increased by 18 +/- 3 and 19 +/- 5%, respectively, and renal vascular resistance fell by 17 +/- 2% after 90 min. The renal hemodynamic responses to glucose were abolished in NFK (n = 8); RBF averaged 96 +/- 4% of control after 60 min of hyperglycemia. RBF and GFR did not change during hyperglycemia in LPK (n = 5), averaging 96 +/- 1 and 100 +/- 8% of control, respectively, after 60 min. Autoregulation of RBF and GFR during reductions in RAP was impaired during hyperglycemia in NK; RBF and GFR were effectively autoregulated between RAP of 126 and 70-85 mmHg during the control period, whereas during glucose infusion RBF and GFR fell by 31 +/- 9 and 47 +/- 10%, respectively, when RAP was reduced in steps to 70 mmHg. These data suggest that hyperglycemia impairs renal autoregulation and may increase renal blood flow and GFR through a tubuloglomerular feedback mechanism.
Abstract: In healthy tissues, decreases in oxygen delivery (QO2 = cardiac output X arterial O2 content) do not lower oxygen consumption (VO2) because tissue O2 extraction increases proportionately. When delivery is reduced below a critical threshold, VO2 falls because tissue extraction exceeds a critical threshold, and cannot compensate for the reduction in delivery. In the adult respiratory distress syndrome and perhaps in septicemia, tissue extraction capacity is impaired, leading to O2 supply dependency despite normal or increased overall delivery. This pathologic supply dependency could be caused by a loss in autoregulatory capacity, by disrupted blood flow distribution secondary to peripheral microembolization, or to other factors interfering with efficient tissue distribution of QO2 with respect to VO2. Alternatively, the increased VO2 may be consumed in biochemical pathways not associated with ATP production, or in the production of oxygen radicals or hydrogen peroxide. To the extent this abnormal dependence of VO2 on QO2 reflects tissue hypoxia, clinical interventions which decrease systemic delivery should be evaluated with regard to possible deleterious effects on organ system function.
Abstract: Coronary vasoconstriction was examined in response to the selective stimulation of alpha 1- and alpha 2-adrenoceptors in chronically instrumented conscious dogs. Norepinephrine (NE, 0.05 and 0.1 micrograms X kg-1 X min-1), a mixed alpha 1- to alpha 2-adrenoceptor agonist, phenylephrine (PE, 0.5 and 1.0 micrograms X kg-1 X min-1), a preferential alpha 1-adrenoceptor agonist, and B-HT 920 (1.0 micrograms X kg-1 X min-1), a preferential alpha 2-adrenoceptor agonist, were infused intravenously after ganglionic (hexamethonium, 30 mg/kg iv), beta-adrenoceptor (propranolol, 1.0 mg/kg iv), and muscarinic receptor (atropine methylbromide, 0.1 mg/kg iv) antagonism. Equipressor doses of the alpha-adrenoceptor agonists caused similar increases in calculated late diastolic coronary resistance (NE, 0.57 +/- 0.10 mmHg X ml-1 X min; PE, 0.61 +/- 0.13 mmHg X ml-1 X min; B-HT 920, 0.64 +/- 0.09 mmHg X ml-1 X min). Mechanically increasing aortic root pressure to levels similar to those observed in response to alpha-adrenoceptor stimulation did not increase coronary resistance. Preferential antagonism of alpha 1-adrenoceptors with prazosin (1 mg/kg iv) abolished the vasoconstrictor response to PE but had a lesser effect on the response to B-HT 920. Antagonism of alpha 2-adrenoceptors with rauwolscine (alpha-yohimbine, 0.1 mg/kg iv) abolished the vasoconstrictor response to B-HT 920 but had a lesser effect on the response to PE. The response to NE was reduced to a similar degree by either alpha 1- or alpha 2-adrenoceptor antagonism.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: In shrinking-drop micropuncture studies in anaesthetized rats proximal tubular fluid reabsorption (JVa) decreased by 36% following intravenous infusion of enalapril. In a separate group of rats enalapril reduced fractional lithium clearance indicating decreased proximal fluid reabsorption. Following enalapril, GFR rose by 46% but absolute proximal reabsorption rose by 22% indicating 48% effectiveness of proximal glomerulo-tubular balance (GTB). Since renal blood flow and glomerular filtration rate (GFR) increased in parallel and arterial pressure fell, fluid uptake and proximal GTB were unlikely to have been decreased by peritubular physical forces. In anaesthetized rats proximal fluid reabsorption and proximal GTB are modulated by endogenous AII through direct stimulation of proximal tubular transport.
Abstract: In contrast to chronic metabolic acidosis, chronic respiratory acidosis does not result in an adaptation in either renal ammonia or glucose production. To examine the possibility that this might be explained by a difference in proximal tubule intracellular pH, the response of two pH-sensitive metabolites, citrate and alpha-ketoglutarate, were assessed. Metabolic acidosis of 3 days duration, induced by drinking 1.5% NH4Cl, significantly reduced urinary citrate excretion (172 to 15 mumol/day) and renal cortical citrate (1.33 to 0.88 mumol/g) and alpha-ketoglutarate (0.90 to 0.46 mumol/g) concentrations in comparison with normal rats. Chronic respiratory acidosis, produced by 3 days in a 10% CO2 environment, lowered systemic pH similar to metabolic acidosis but had no effect on either urinary citrate excretion or renal cortical citrate and alpha-ketoglutarate concentrations. By contrast, acute respiratory acidosis (3, 6, or 24 h duration) reduced urinary citrate excretion and renal cortical citrate and alpha-ketoglutarate concentrations in a fashion similar to acute metabolic acidosis. These data suggest that acute acidosis of either respiratory or metabolic origin lowers the intracellular pH of the proximal tubule. However, when the acid-base abnormality enters the chronic phase, proximal tubular intracellular pH remains low with metabolic acidosis but returns to normal values with respiratory acidosis.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Studies were conducted to examine the effects of adrenalectomy (ADX) and selective, physiological adrenal corticosteroid replacement on sodium and potassium transport by the superficial loop of Henle and distal tubule of rat kidney in vivo. In the loop of Henle, ADX inhibited sodium reabsorption by 33%. Whereas dexamethasone had no effect on reabsorption, aldosterone increased sodium transport to control levels. Thus, physiological levels of mineralocorticoids, but not glucocorticoids, control a fraction of sodium reabsorption in the loop of Henle. ADX also inhibited potassium reabsorption in the loop of Henle. Both dexamethasone and aldosterone reversed the inhibition, although only aldosterone increased reabsorption to control levels. In the distal tubule, ADX reduced sodium reabsorption by 44%. Both aldosterone and dexamethasone stimulated reabsorption: however, only aldosterone increased transport to control. Potassium secretion by the distal tubule was also reduced 34% by ADX. Aldosterone, but not dexamethasone, stimulated secretion. Thus, physiological levels of aldosterone regulate a fraction of sodium reabsorption and potassium secretion in the distal tubule.
Abstract: The disappearance and metabolic clearance rate (MCR) of alpha human atrial natriuretic peptide (alpha h-ANP) has been studied in normal man by radioimmunoassay of the atrial peptide in plasma and plasma extracts. After an intravenous (iv) bolus injection of 100 micrograms alpha h-ANP, levels of immunoreactive alpha h-ANP (IR-alpha hANP) in unextracted plasma fell rapidly and exponentially during the first 10 min (t1/2 = 2.5 min), after which levels declined more slowly to reach basal values 30 min after injection. Venous plasma extracts, purified by Sep Pak cartridges, were used to calculate the MCR of IR-alpha hANP under steady state conditions of constant iv infusion (200 micrograms over 60 min) in healthy volunteers. Calculated MCR from venous samples was 2.4 L/min and volume of distribution 10.7 L. After cessation of infusions, the disappearance rate (rapid phase) of IR-alpha hANP was 3.1 min. These studies show that alpha h-ANP is rapidly metabolized at rates similar to other vasoactive hormones such as angiotensin II and vasopressin.
Abstract: Effects of angiotensin II on rat, rabbit, and bovine proximal tubular reabsorption have been demonstrated with a variety of techniques, including in vivo microperfusion, free-flow micropuncture of surface and juxtamedullary nephrons, perfusion of isolated tubules in vitro, and cell culture. Blockade of endogenous angiotensin production in vivo with converting-enzyme inhibition, or of receptors with saralasin, consistently inhibits proximal reabsorption of fluid in both superficial and juxtamedullary proximal tubules. Angiotensin effects on the proximal tubule are not neurally mediated, for they persist in denervated kidneys and are seen in nerve-free isolated tubules. Physiological concentrations of angiotensin (10(-11)-10(-9) M) stimulate electroneutral sodium transport from the basolateral membrane, whereas pharmacological doses (10(-7) M and above) inhibit reabsorption. The stimulatory effects appear to be receptor mediated. In addition to these direct effects of angiotensin on the proximal tubule epithelium, endogenous angiotensin may also alter peritubular physical forces to further enhance proximal reabsorption. These effects of angiotensin may represent an important homeostatic mechanism during states of extracellular fluid volume depletion.
Abstract: Survival to hospital discharge was related to the clinical history and emergency care system factors in 285 patients with witnessed cardiac arrest due to ventricular fibrillation. Only the emergency care factors were associated with differences in outcome. Both the period from collapse until initiation of basic life support and the duration of basic life support before delivery of the first defibrillatory shock were shorter in patients who survived compared with those who died (3.6 +/- 2.5 versus 6.1 +/- 3.3 minutes and 4.3 +/- 3.3 versus 7.3 +/- 4.2 minutes; p less than 0.05). A linear regression model based on emergency response times for 942 patients discovered in ventricular fibrillation was used to estimate expected survival rates if the first-responding rescuers, in addition to paramedics, had been equipped and trained to defibrillate. Expected survival rates were higher with early defibrillation (38 +/- 3%; 95% confidence limits) than the observed rate (28 +/- 3%). Because outcome from cardiac arrest is primarily influenced by delays in providing cardiopulmonary resuscitation and defibrillation, factors affecting response time should be carefully examined by all emergency care systems.
Abstract: Therapy of elevated ventricular filling pressures in patients with dilated heart failure may be limited by concern that cardiac output will be further compromised. Twenty-five patients with severe symptoms and ejection fractions of 25% or less were studied to determine the lowest ventricular filling pressures that could be achieved with vasodilator and diuretic therapy while maintaining cardiac output. In 20 of 25 patients normal pulmonary capillary wedge pressures (PCWs) were achieved (mean 10 mm Hg compared with 30 mm Hg at baseline). Stroke volume was 60 vs 39 ml at baseline. Stroke work index was 30 vs 19 g-m/m2. For each patient, over the range of PCWs, stroke volume and stroke work index were maintained and were often maximal at the lowest PCW achieved. The upright position was well tolerated in patients with normal supine PCW. Normal filling pressures can be achieved in patients with congestive heart failure without compromise of cardiac output. While congestive symptoms should be improved, the feasibility and benefit of maintaining normal filling pressures over a long term must be established.
Abstract: This study presents a description of aerobic capacity in a large US population comprised of 1,514 men and 375 women. Such influencing factors as age, training state, occupation, and body composition were evaluated. The population consisted of new recruits entering the US Army from civilian life as well as soliders in a variety of assignments and physical training programs. Age ranged from 17 to 55 yr. With the exception of one older group, aerobic capacity was determined as maximal O2 uptake measured directly by the Douglas bag technique during a standard discontinuous treadmill running procedure. New male and female recruits representing a young civilian population entered the service with maximal O2 uptake of 51 and 37 ml X kg body wt-1 X min-1, respectively, and thereafter increased 5% during initial basic training. The difference between genders, 30% on an absolute basis, was 14% when expressed as a function of fat-free weight. Aerobic capacity was less after occupational training and continued to decrease with age at an average yearly rate of 10%, or 0.5 ml X kg body wt-1 X min-1. Aerobic capacity varied with intensity of the occupational physical demand, except in groups with significant physical training programs. This first large US population study of aerobic capacity, using a direct treadmill procedure, demonstrates levels consistent with any previously reported population.
Abstract: A method is described to partition measured values of steady-state ventilatory response into an estimation of the blood flow in the respiratory controller and the sensitivity of the controller to CO2 assuming proportional control. The analysis is derived from the describing equations of a computer model and leads to the definition of a grid of lines emanating from a hypothetical reference point at negative ventilation and zero central nervous system metabolism. Data from the literature reporting differences in CO2 response among normal subjects and changes in resting ventilation and cerebral blood flow with age are reinterpreted from this perspective. Use of a structural model to interpret physiological data is shown to give a different meaning to data reduction in contrast to interpretation using statistical models like regression.
Abstract: Right ventricular volume affects left ventricular volume via direct interaction across the interventricular septum and series interaction because the right and left hearts are connected in series through the lungs. Because it is difficult to sort out complex physiological mechanisms in the intact circulation, the relative importance of these two effects is unknown. We used statistical analyses of transient changes in left and right ventricular pressures and dimensions following pulmonary artery and venae caval constrictions to separate and quantitate the direct (immediate) from the series (delayed) interaction effects on left ventricular size at end systole and end diastole. With the pericardium closed, direct interaction was one-half as important as series interaction at end diastole and was one-third as important at end systole. With the pericardium removed, direct interaction was one-fifth as important as series interaction at end diastole and one-sixth as important at end systole. These results suggest that differences between transient and steady-state end-systolic pressure-volume relationships are largely explained by direct interaction and that direct end-systolic interaction is important for maintaining balanced right and left heart outputs.
Abstract: The degree by which atrial natriuretic factor (ANF)-induced renal hemodynamic changes account for its natriuretic effect was determined by early clamp experiments in six anesthetized dogs. After control periods, perfusion pressure of the left kidney (LK) was reduced to 80-90 mmHg, and synthetic ANF (auriculin A) was infused intravenously (0.3 micrograms X min-1 X kg body wt). After recovery, furosemide (F) was administered as a bolus injection (1 mg/kg body wt). In the right kidney (RK), which served as a time control, ANF increased (P less than 0.05) glomerular filtration rate (GFR) 16 +/- 4% and Na excretion (UNa V) 261 +/- 63%, whereas it decreased urine osmolality (Uosm) 36 +/- 7% without changing free water clearance. ANF also increased diuresis (V) and kaliuresis (UKV). F produced qualitatively the same results without changing GFR. In the clamped LK, ANF failed to increase GFR (22 +/- 4 vs. 26 +/- 4 ml/min), UNaV (30 +/- 9 vs. 33 +/- 11 mueq/min), V, and UKV or to decrease Uosm (841 +/- 97 vs. 840 +/- 114 mosmol/kg H2O). F had similar effects in LK as in RK. The data demonstrate that the natriuretic effect of ANF is abolished when its renal hemodynamic actions are impeded. In addition, the results demonstrate that ANF antagonizes renal vasoconstriction in the dog. The results are consistent with the view that the ANF-induced natriuresis is due in great part to an increase in the filtered load of Na into a washed-out inner medulla.
Abstract: The effect of transient cerebral ischaemia connected with acute orthostatic hypotension on plasma adrenaline and noradrenaline levels was studied in seven healthy male volunteers during tilt. Sublingual administration of 1 mg nitroglycerin was used to block peripheral vascular reflexes and thus to provoke orthostatic intolerance. A consistent increase in plasma adrenaline concentrations (from 19.2 to 104.3 pg/ml on average, P less than 0.01) was found in six subjects who developed clinical signs of collapse after tilting. Plasma adrenaline never changed after tilting without collapse. Posturally stimulated plasma noradrenaline increases were similar yet irrespective of the presence of collapse.
Abstract: In a previous study of normal subjects exercising at sea level and simulated altitude, ventilation-perfusion (VA/Q) inequality and alveolar-end-capillary O2 diffusion limitation (DIFF) were found to increase on exercise at altitude, but at sea level the changes did not reach statistical significance. This paper reports additional measurements of VA/Q inequality and DIFF (at sea level and altitude) and also of pulmonary arterial pressure. This was to examine the hypothesis that VA/Q inequality is related to increased pulmonary arterial pressure. In a hypobaric chamber, eight normal subjects were exposed to barometric pressures of 752, 523, and 429 Torr (sea level, 10,000 ft, and 15,000 ft) in random order. At each altitude, inert and respiratory gas exchange and hemodynamic variables were studied at rest and during several levels of steady-state bicycle exercise. Multiple inert gas data from the previous and current studies were combined (after demonstrating no statistical difference between them) and showed increasing VA/Q inequality with sea level exercise (P = 0.02). Breathing 100% O2 did not reverse this increase. When O2 consumption exceeded about 2.7 1/min, evidence for DIFF at sea level was present (P = 0.01). VA/Q inequality and DIFF increased with exercise at altitude as found previously and was reversed by 100% O2 breathing. Indexes of VA/Q dispersion correlated well with mean pulmonary arterial pressure and also with minute ventilation. This study confirms the development of both VA/Q mismatch and DIFF in normal subjects during heavy exercise at sea level. However, the mechanism of increased VA/Q mismatch on exercise remains unclear due to the correlation with both ventilatory and circulatory variables and will require further study.
Abstract: Pressures in the primary arterioles of the cremaster muscle are reported to be approximately 50% of systemic, indicating that arterial resistance proximal to microvessels is high and may limit maximal blood flow. With no change in arterial resistance, increases in perfusion normally associated with muscle work either could not occur or would require increments in systemic pressure far greater than those actually observed in vivo. Therefore, we hypothesized that the small arteries feeding the muscle may participate in the hyperemic response. To test this hypothesis, male golden hamsters (n = 31, 118 g) were anesthetized (pentobarbital, 70 mg/kg i.p.), and the right cremaster was opened to expose its feed arteries, which originated from the iliac artery. Preparations were superfused and maintained at 35 +/- 1 degree C. Feed arteries had substantial tone, as shown by the fact that topical acetylcholine, applied at supramaximal concentration, dilated these vessels from 115 +/- 8 microns at rest to 158 +/- 9 microns (mean +/- SE; n = 38 vessels; p less than 0.01), corresponding to an estimated 4.4-fold increase in conductance. Stimulation of the sectioned motor nerve (8 Hz, 30 seconds) induced striated muscle contraction and increased feed vessel diameter from 93 +/- 5 microns to 116 +/- 5 microns (n = 14; p less than 0.01), consistent with a 2.6-fold increase in conductance. A 5-minute occlusion of the iliac artery resulted in feed artery dilation of similar magnitude. Supramaximal doses of acetylcholine applied topically to the distal portions of the cremaster resulted in striated muscle contraction and a dilation that propagated upstream to increase feed artery diameter by 25%.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Right ventricular loading leads to diastolic septal flattening in man without necessarily requiring right ventricular pressure to exceed left ventricular pressure. This observation suggested that the unstressed septal configuration is flat and that its normal concave shape is due to the left-to-right transseptal pressure gradient. To examine this hypothesis, we studied septal configuration by two-dimensional echocardiography in nine patients with normal global and regional left ventricular function during surgery for coronary artery disease. The transseptal pressure gradient was obtained from pulmonary capillary wedge pressure minus right atrial pressure. Measurements were obtained at control (open chest, intact pericardium [C]), with the pericardium open (OP), on cardiopulmonary bypass (CPB), and after cardiac arrest (CA). There were no changes in any measurements between C and OP or between CPB and CA. Left ventricular end-diastolic cavity area decreased from 16.5 +/- 2.1 cm2 at C to 11.1 +/- 4.5 cm2 after CPB, and further decreased to 8.9 +/- 3.5 cm2 after CA (p less than .001), yet the septum flattened, as shown by an increase in its radius of curvature from 1.7 +/- 0.5 cm during C to 2.5 +/- 0.7 cm after CPB, and to 2.9 +/- 1.0 cm after CA (p less than .001), or from 0.4 +/- 0.1 to 0.8 +/- 0.4 to 1.1 +/- 0.5 U (p less than .001) when normalized for cavity area. Diastolic transseptal pressure gradient was reduced from 4.1 +/- 2.3 mm Hg during C to 1.1 +/- 1.8 mm Hg after CPB, and to 0.5 +/- 1.4 mm Hg after CA (p less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: The lactate increase during exercise is a critically important biochemical and physiological event that leads to decreasing cell pH, an accelerated rate of glycogen depletion in the muscle, and important changes in ventilatory and gas exchange dynamics. Lactate increases only slightly at low work rates, and this increase is proportional to pyruvate increase (i.e. compatible with accelerated glycolysis without a change in redox state). At high work rates lactate increases disproportionately to pyruvate, the increased rate of lactate accumulation and lactate/pyruvate ratio appearing to occur at a threshold O2 consumption for a given individual. This symposium addresses the biochemical origin and physiological consequences of the increased lactate production during exercise.
Abstract: Plasma levels of ANP were measured in normal subjects and in three conditions associated with disturbed volume homeostasis. Levels of ANP were appropriately raised in seven patients with primary aldosteronism, and fell to normal following removal of an aldosterone-producing adenoma in six and dexamethasone treatment in one patient with glucocorticoid-suppressible hyperaldosteronism. The level of ANP in one patient with Gordon’s syndrome (a condition associated with plasma volume expansion) was lower than in the patients with primary aldosteronism, both before and after saline infusion. This is consistent with reduced ANP responsiveness in this condition. responsiveness in this condition. Levels of ANP were inappropriately elevated in three patients with Bartter’s syndrome (a condition with plasma volume contraction) and rose further during saline infusion. This is consistent with primary hypersecretion of ANP.
Abstract: Since mammalian atria were recently found to contain vasoactive and natriuretic peptides, we investigated the following in normal humans: plasma human atrial natriuretic peptide concentrations, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), urinary water and electrolyte excretion, blood pressure (BP), and catecholamine, antidiuretic hormone (ADH), angiotensin II, and aldosterone levels before, during, and after intravenous administration of the newly synthetized alpha-human atrial natriuretic peptide (alpha hANP). In 10 subjects alpha hANP given as an initial bolus of 50 micrograms followed by a 45-min maintenance infusion at 6.25 micrograms/min increased plasma alpha hANP from 58 +/- 12 to 625 +/- 87 (mean +/- SEM) pg/ml; caused an acute fall in diastolic BP (-12%, P less than 0.001) and a hemoconcentration (hematocrit +7%, P less than 0.01) not fully explained by a negative body fluid balance; increased GFR (+15%, P less than 0.05) despite unchanged or decreased ERPF (filtration fraction +37%, P less than 0.001); augmented (P less than 0.05- less than 0.001) urinary chloride (+317%), sodium (+224%), calcium (+158%), magnesium (+110%), phosphate excretion (+88%), and free water clearance (from -0.76 to +2.23 ml/min, P less than 0.001) with only little change in potassium excretion; and increased plasma norepinephrine (P less than 0.001) while plasma and urinary epinephrine and dopamine, and plasma ADH, angiotensin II, and aldosterone levels were unchanged. The magnitude and pattern of electrolyte and water excretion during alpha hANP infusion could not be accounted for by increased GFR alone. Therefore, in normal man, endogenous alpha hANP seems to circulate in blood. alpha hANP can cause a BP reduction and hemoconcentration which occur, at least in part, independently of diuresis and are accompanied by sympathetic activation. An increase in GFR that occurs in the presence of unchanged or even decreased total renal blood flow is an important but not sole mechanism of natriuresis and diuresis induced by alpha hANP in man.
Abstract: We investigated the acid-base condition of arterial and mixed venous blood during cardiopulmonary resuscitation in 16 critically ill patients who had arterial and pulmonary arterial catheters in place at the time of cardiac arrest. During cardiopulmonary resuscitation, the arterial blood pH averaged 7.41, whereas the average mixed venous blood pH was 7.15 (P less than 0.001). The mean arterial partial pressure of carbon dioxide (PCO2) was 32 mm Hg, whereas the mixed venous PCO2 was 74 mm Hg (P less than 0.001). In a subgroup of 13 patients in whom blood gases were measured before, as well as during, cardiac arrest, arterial pH, PCO2, and bicarbonate were not significantly changed during arrest. However, mixed venous blood demonstrated striking decreases in pH (P less than 0.001) and increases in PCO2 (P less than 0.004). We conclude that mixed venous blood most accurately reflects the acid-base state during cardiopulmonary resuscitation, especially the rapid increase in PCO2. Arterial blood does not reflect the marked reduction in mixed venous (and therefore tissue) pH, and thus arterial blood gases may fail as appropriate guides for acid-base management in this emergency.
Abstract: The development of shock initiates a cascade of responses in an effort to reestablish homeostasis. Three of the most important hormonal and neurohumoral changes are the secretion of glucocorticoids, catecholamines, and vasopressin. Regulation of adrenal function is much more complex than originally thought. Hemorrhage is a potent stimulus for cortisol release, and both ACTH and ACTH-independent mechanisms have been described. The ACTH response to its releasing hormone, corticotropin releasing hormone (CRF), is itself amplified by vasopressin, which appears to have intrinsic CRF properties. Because ACTH is synthesized as part of a large precursor molecule (pro-opiomelanocortin) containing the amino acid sequences for several important proteins, stimulation of ACTH release has far-ranging effects, the specifics of which are just being clarified. Norepinephrine and epinephrine levels increase manyfold above baseline within minutes of the onset of hemorrhagic shock. Only patients experiencing cardiac arrest or the rare patient with a very active pheochromocytoma have higher concentrations. The levels reached are far in excess of those required to cause both cardiovascular and metabolic alterations. Because of the presence of the endogenous opiates leucine and methionine enkephalin in the neurosecretory granule, it is very likely that the enkephalins are coreleased with the catecholamines, modifying their cardiovascular effects and producing analgesia. Hypovolemia is also a potent stimulus for vasopressin secretion, which overrides hypotonicity, presenting a clinical picture quite compatible with the syndrome of inappropriate antidiuretic hormone secretion, from which it must be differentiated. Vasopressin also is released by pain, nausea, and hypoxia, all of which are likely to be present in the patient with shock.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Aortic depressor nerve discharge (AND), lumbar sympathetic nerve discharge (SND), and single-unit activity of medullospinal pressure-sensitive neurons of nucleus paragigantocellularis lateralis (PGCL neurons) were recorded in halothane-anesthetized 16-wk-old spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats. The relationship between these variables and mean arterial pressure (MAP) was investigated. The gain of baroreceptor afferents was not significantly different between the strains, but corner MAP (intersection between linear ascending portion of curve and noise) was 38 mmHg higher in SHRs. The relationship between SND and MAP and that between PGCL neuronal activity and MAP were both characterized by a plateau (maximal activity) at low MAP followed by a linear reduction reaching zero at a level called cutoff MAP. The theoretical intersection between the plateau and the linear decremental portion of these curves was defined as a corner MAP. Values of corner MAP determined at the three levels (AND, SND, PGCL) were identical in a given strain and reset by a common value in SHRs (38-40 mmHg). The gain of baroreceptor reflex measured at all three sites as the slope of the linear incremental (AND) or decremental (PGCL and sympathetic chain) portion of the activity-MAP relationship was the same in WKY rats and in SHRs. Cutoff MAP measured in PGCL was identical to that measured in peripheral sympathetic system for a given strain. There was no significant difference in maximal discharge rate of PGCL neurons nor in lumbar SND and no interstrain difference in the proportion of SND that was suppressible by arterial baroreceptor feedback.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: The basal and plus insulin states of glucose transport activity in adipocytes are known to show different responses to changes in the pH or osmolarity of the incubation mixture. When the pH was raised from 7 to 8, the basal glucose transport activity (assessed from the rate of 3-O-methyl-D-glucose uptake) was increased approximately 3-fold while the plus insulin activity remained virtually unaffected. Likewise, when cells were exposed to 300 mM sorbitol, the basal glucose transport activity, but not the plus insulin activity, was considerably increased. In both cases, the change in the transport activity was ATP-dependent and was completed in approximately 60 min. The increase in the cellular glucose transport activity was accompanied, in both cases, by an increase in the glucose transport activity in the plasma membrane fraction and a decrease in the activity in the high-speed pellet fraction. The transport activity in the subcellular fractions was determined after reconstitution into egg lecithin liposomes. Both isotonic buffer at pH 8.0 and hypertonic buffer at pH 7.4 significantly stimulated membrane-bound cAMP phosphodiesterase in adipocytes. It is concluded that the above two experimental conditions may induce insulin-like effects in fat cells and may facilitate translocation of the glucose transport activity from an intracellular site to the plasma membrane.
Abstract: Hemodynamic and hormonal factors were monitored in nine patients with nephrotic syndrome who were evaluated relative to their capacity to excrete a 20-mL/kg water load (normal greater than 80%). In five "nonexcretor" patients (37% of water load excreted in five hours), as compared to four normal excretors (105% of water load excreted in five hours; P less than .01 v nonexcretors), neither BP (131/88 v 119/79 mm Hg), pulse (74 v 77 beats/min), cardiac index (3.7 v 3.1 L/min/m2), pulmonary wedge pressure (9.3 v 7.3 mm Hg), systemic vascular resistance (1537 v 1254 dynes-sec-cm-5), nor plasma volume (41.3 v 40.1 mL/kg) were different. Similarly, plasma renin activity (2.6 v 3.7 ng/mL/h), plasma aldosterone (12 v 10.9 ng/dL), and plasma norepinephrine (403 v 312 pg/mL) were not different between nonexcretor v excretor patients with nephrotic syndrome. Plasma vasopressin concentrations were also similar both before (3.1 +/- 0.8 v 2.4 +/- 1.2 pg/mL) and during the water load (0.9 +/- 0.3 v 1.0 +/- 0.4 pg/mL). Inulin clearances, however, were lower in the nonexcretor v the excretor nephrotic patients (37 v 78 mL/min/1.73 m2; P less than .02) and correlated with water excretion (r = .68; P less than .05). Head-out water immersion increased sodium (40 to 110 microEq/min; P less than .01) and water excretion (37% to 82%; P less than .025) in the nonexcretors; the improvement correlated with the increase in inulin clearance during immersion (r = .70; P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: The relationship between thirst perception and plasma osmolality was studied during hypertonic and physiological saline infusion in ten healthy volunteers. Thirst perception was quantified using a linear visual analogue scale which volunteers marked at intervals during the infusion periods. Infusion of hypertonic saline caused a steady rise in plasma osmolality together with a progressive linear increase in thirst perception and also plasma arginine vasopressin. No significant changes in thirst, plasma osmolality or plasma arginine vasopressin occurred during infusion of physiological saline. Linear regression analysis of the results defined the functions. Thirst (cm) = 0.3 (plasma osmolality-281) (r = +0.92, P less than 0.001) and plasma arginine vasopressin (pmol/l) = 0.4 (plasma osmolality-285) (r = +0.96, P less than 0.001). The osmolar threshold for thirst onset thus defined (281 mosmol/kg) was much lower than in previous studies and similar to the theoretical osmolar threshold for vasopressin release (285 mosmol/kg). We conclude that thirst perception rises in a progressive fashion throughout a wide range of plasma osmolality and that the osmolar threshold for thirst onset is similar to the theoretical osmolar threshold for vasopressin release. The results are compatible with the concept of either a single osmoreceptor subserving both thirst and vasopressin release, or two osmoreceptors sharing similar functional characteristics.
Abstract: The development of shock initiates a cascade of responses in an effort to reestablish homeostasis. Three of the most important hormonal and neurohumoral changes are the secretion of glucocorticoids, catecholamines, and vasopressin. Regulation of adrenal function is much more complex than originally thought. Hemorrhage is a potent stimulus for cortisol release, and both ACTH and ACTH-independent mechanisms have been described. The ACTH response to its releasing hormone, corticotropin releasing hormone (CRF), is itself amplified by vasopressin, which appears to have intrinsic CRF properties. Because ACTH is synthesized as part of a large precursor molecule (pro-opiomelanocortin) containing the amino acid sequences for several important proteins, stimulation of ACTH release has far-ranging effects, the specifics of which are just being clarified. Norepinephrine and epinephrine levels increase manyfold above baseline within minutes of the onset of hemorrhagic shock. Only patients experiencing cardiac arrest or the rare patient with a very active pheochromocytoma have higher concentrations. The levels reached are far in excess of those required to cause both cardiovascular and metabolic alterations. Because of the presence of the endogenous opiates leucine and methionine enkephalin in the neurosecretory granule, it is very likely that the enkephalins are coreleased with the catecholamines, modifying their cardiovascular effects and producing analgesia. Hypovolemia is also a potent stimulus for vasopressin secretion, which overrides hypotonicity, presenting a clinical picture quite compatible with the syndrome of inappropriate antidiuretic hormone secretion, from which it must be differentiated. Vasopressin also is released by pain, nausea, and hypoxia, all of which are likely to be present in the patient with shock.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Diuretic drugs were used to characterize mechanisms involved in transporting sodium, chloride, and potassium across the wall of surface distal tubules of the rat kidney using in vivo microperfusion techniques. Both furosemide and chlorothiazide inhibited sodium and chloride absorption but did not affect the rate of potassium secretion or the transepithelial voltage. However, chlorothiazide inhibited sodium and chloride absorption more completely than furosemide and was additive to the effect of furosemide; furosemide was ineffective if chlorothiazide was already present. In contrast to the effect of furosemide, bumetanide did not affect sodium and chloride absorption but did increase potassium secretion. Amiloride reduced sodium absorption and potassium secretion without affecting net chloride absorption. These effects were additive to those of chlorothiazide. In the loop of Henle bumetanide was more effective than furosemide in inhibiting net sodium potassium and chloride absorption. It appears that cells of the distal tubule in the rat possess an Na-Cl cotransport mechanism that differs from the Na-K-2Cl cotransport mechanism found in the thick ascending limb. Sodium transport also proceeds via a conductive pathway that is inhibited by amiloride. The two modes of sodium transport, conductive and coupled to chloride, may occur in different cell types along the distal tubule.
Abstract: Polycythaemia was corrected by erythrapheresis in ten patients with hypoxic cor pulmonale who were stable on regular diuretic therapy. Renal haemodynamics, renal function and the renin-angiotensin-aldosterone system were assessed before and afterwards. Before erythrapheresis effective renal plasma flow (ERPF) was reduced (63% predicted) but glomerular filtration rate (GFR) was preserved (88% predicted) by a rise in filtration fraction (FF) (138% predicted). A negative correlation existed between ERPF and packed cell volume (r = -0.723; P less than 0.02) and also between ERPF and PaCO2 (r = -0.710; P less than 0.05). Polycythaemia was sufficient to maintain renal oxygen delivery (97% predicted). After erythrapheresis systemic blood pressure, blood volume and blood viscosity all decreased. ERPF increased by 18% (P less than 0.02). FF fell by 11% (P less than 0.05) and GFR was unchanged. Renal oxygen delivery diminished by 25% (P less than 0.001). Plasma renin activity was increased in five patients and plasma aldosterone increased in two patients before erythrapheresis. No sustained fall occurred in plasma renin activity or plasma aldosterone, possibly because the haemodynamic consequences of the procedure had opposing actions on renin secretion. Although the reduction in FF would per se tend to enhance renal sodium and water excretion, a diuresis or natriuresis did not occur consistently.
Abstract: Midodrine is an orally active adrenergic agonist useful in the treatment of hypotension. We have investigated the pharmacodynamics of its active metabolite after oral midodrine therapy in nine patients with severe orthostatic hypotension. Peak plasma levels of the metabolite were reached in 60 to 90 minutes and ranged from 25 to 56 ng/ml. The mean values for distribution volume, plasma clearance, and t1/2 were 4.0 L/kg, 23 ml/min/kg, and 2.1 hours, respectively. Heart rate increased after 5 to 10 mg doses and the increases were statistically significant (P less than 0.05) at 120 minutes. An apparent increase in blood pressure was not statistically significant. The patients said that they felt better.
Abstract: Ten patients with end-stage renal failure and anaemia (mean haemoglobin 6.1 g/dl, range 4.6-8.8 g/dl) on thrice-weekly haemodialysis were treated with human erythropoietin derived from recombinant DNA (rHuEPO). This was given as an intravenous bolus after each dialysis in rising doses within the range 3-192 IU/kg. All patients showed increases in reticulocyte numbers and haemoglobin concentration and after the first week of treatment none of the four previously transfusion-dependent patients needed further transfusions. In nine patients treated for 12 weeks haemoglobin rose to a mean of 10.3 g/dl, range 9.5 to 12.8 g/dl. Thereafter the dose of erythropoietin was adjusted to avoid a further rise in haemoglobin. During treatment one patient had an episode of hypertensive encephalopathy and two had clotting in their arteriovenous fistulas (complete in one). rHuEPO is an effective treatment for the anaemia of end-stage renal failure but longer-term observations are needed on the consequences of increasing the haematocrit.
Abstract: Characteristics of sodium transport in the inner medullary collecting duct were determined in anesthetized rats before and during intravenous infusion of synthetic atrial natriuretic factor (atriopeptin II). Infusion of the factor was associated with increased sodium delivery and reduced fractional reabsorption in the duct. Increasing delivery to the same extent by KCl infusion had no effect on fractional reabsorption. The results demonstrate that atrial natriuretic factor has a specific inhibitory effect on net sodium transport in this part of the nephron. The mechanism of this inhibition may involve induction of sodium permeability and consequent backflux into the tubular lumen.
Abstract: This review has focused on the influence of several diuretic drugs on potassium handling by the kidney. One class of drugs (loop diuretics) acts by directly inhibiting a potassium absorptive mechanism in the luminal membrane of cells of the thick ascending limb of Henle’s loop. Two other groups of diuretics affect potassium transport indirectly by inhibiting salt and water absorption upstream from the potassium secretory site in the late distal tubule: carbonic anhydrase inhibitors act in the proximal tubule; thiazides act in the early distal tubule. The subsequent increase in lumen flow rate then stimulates net potassium secretion by the distal tubule. A fourth class of drugs (spironolactone) acts by antagonizing the response of the distal tubule to aldosterone. These drugs decrease the ability of aldosterone to stimulate distal potassium secretion. Finally, a fifth group of drugs (potassium-sparing diuretics) decreases potassium secretion by increasing the luminal membrane voltage and thus decreasing the electrochemical gradient for potassium exit from the cell.
Abstract: The dynamic increase in oxygen uptake (VO2) at the start of exercise reflects the circulatory adjustments to metabolic changes induced by the exercise. Because VO2 measured at the lungs is the product of pulmonary blood flow and arteriovenous oxygen difference, pathologic conditions affecting the capacity of these factors to change would be expected to alter VO2 kinetics. To determine whether measurement of VO2 kinetics can detect conditions in which the pulmonary blood flow response to exercise is abnormal, VO2 was measured, breath-by-breath, during the transition from rest to exercise in 13 adults with cyanotic congenital heart disease (central venoarterial shunting) and in nine normal subjects. The increase in VO2 above baseline during the first 20 sec of exercise (phase I), reflecting the immediate increase in pulmonary blood flow, was diminished in the patients compared with that in normal subjects (14.8 +/- 10.9 vs. 49.8 +/- 19.2 ml of oxygen) (p less than .001). The patients’ phase I responses correlated with their reported physical activity tolerance (p less than .01). In addition, the second phase of the VO2 response kinetics was prolonged in patients compared with normal subjects (half-time = 63 +/- 13 vs 15 +/- 13 sec) (p less than .001). We conclude that striking disturbances in VO2 kinetics occur in patients with cyanotic congenital heart disease and that these measurements provide a useful noninvasive means of evaluating the degree to which the increase in pulmonary blood flow is constrained in response to exercise.
Abstract: In summary, we propose: that renal ammoniagenesis is regulated both by factors dependent and independent of the acid-base status, the net effect of the ammoniagenic process on the proton balance being directly related to the rate of urinary ammonium excretion; that the renal metabolism of glutamine should not be examined independently of the metabolism of other substrate physiologically taken up by the kidney; that different pathways for glutamine metabolism will change during acid-base disorders of organic or nonorganic origin; that, among the main glutamine utilizing pathways, only the GLDH pathway is influenced directly by the acid-base status; the ammoniagenic transamination pathways is regulated by substrate availability in the kidney; that the lowest ammoniagenic flux in the kidney coincides with the rate of alanine production since alanine appears to derive directly from glutamine. When this pathway is stimulated without concomitant acidosis, most of the ammonia produced is not excreted in urine but released in the renal venous blood: thus, no significant effect on the acid-base balance is produced; that glutamine is metabolized by proximal kidney tubules of acidotic dogs probably through net oxidation; that the quantitative analysis of the metabolic consequence of this process indicates that the rate of ATP turnover at this site may effectively place an upper limit to the rate of glutamine oxidation, and ammonia production by the kidney, and that this limit is nearly reached in chronically acidotic animals.
Abstract: The present study attempted long term hemodynamic maintenance in 16 adult brain-dead patients, 14 with head injury and 2 with cerebrovascular accidents. In addition to respiratory and fluid management, 10 were treated with continuous infusion of epinephrine to maintain systolic blood pressure above 90 mm Hg. The remaining 6 patients each received a continuous infusion of synthetic arginine vasopressin (ADH) at a rate of 1 or 2 units/hour (285 +/- 45 microunits/kg/minute) simultaneously with epinephrine. The 10 patients treated with epinephrine alone all succumbed to cardiac arrest within 48 hours of brain death, with a mean survival time of 24.1 +/- 17.2 hours. In the patients who received simultaneous ADH infusion, a minimal dose of epinephrine of no more than 0.5 mg/hr in most instances sufficed to maintain blood pressure. Their mean survival time after brain death was remarkably prolonged to 23.1 +/- 19.1 days. In brain death, ADH plays a critical role in hemodynamic maintenance, and ADH administration permits long term hemodynamic stabilization of brain-death patients, offering increasing opportunities for organ transplantation.
Abstract: Clinical techniques for artificial perfusion have not previously been examined directly for their effects on brain high-energy metabolism. Our study involved 24 large mongrel dogs that were anesthetized, instrumented for central venous intravenous access, and subjected to craniotomy to expose the dura and underlying parietal cortex. The animals were divided into the following six experimental groups of four animals each: nonischemic controls; 15-minute cardiac arrest without resuscitation; 45-minute cardiac arrest without resuscitation; 15-minute cardiac arrest plus 30 minutes resuscitation with conventional cardiopulmonary resuscitation (CPR); 15-minute cardiac arrest plus 30 minutes resuscitation with interposed abdominal compression (IAC) CPR; and 15-minute cardiac arrest plus 30 minutes resuscitation with internal cardiac massage. Cardiac arrest was induced by central venous injection of KCl 0.6 mEq/kg, and it was confirmed by continuous ECG monitoring. The three active resuscitation models included administration of NaHCO3 and epinephrine, but no attempt was made to restart the heart by defibrillation during resuscitation. At the indicated time in each group, a 4- to 5-g sample of brain was removed through the craniotomy, immediately cooled to 0 C and processed for isolation of mitochondria. The mitochondria were studied for their content of superoxide dismutase and for quantitative oxygen consumption with glutamate/malate substrate during resting and ADP-stimulated respiration. Our results show a significant drop in brain mitochondrial superoxide dismutase activity during the first 15 minutes of cardiac arrest. There is minimal injury to brain mitochondrial oxygen consumption during both 15 and 45 minutes of complete ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Previous studies demonstrated selective increases in mixed venous carbon dioxide tension (PvCO2) during CPR in a porcine model of cardiac arrest. This was associated with a decrease in end-tidal carbon dioxide concentration (ETCO2), possibly due to a critical reduction in cardiac output and therefore pulmonary blood flow during CPR. We investigated the relationship between ETco2 and cardiac output before cardiac arrest and during CPR. Observations in 19 minipigs confirmed a high linear correlation between ETco2 and cardiac output. We conclude that the increase in Pvco2 and the concurrent decrease in ETco2 reflect a critical reduction in cardiac output, which reduces alveolar blood flow to the extent that carbon dioxide clearance by the lung fails to keep pace with systemic CO2 production.
Abstract: Following a survey of existing mathematical models of running, a new analysis is developed, based on the first law of thermodynamics. The method properly accounts for each term in the energy balance, and avoids the use of mechanical efficiency factors. A relationship is derived between race distance and the time taken to run that distance. An excellent correlation of results from recent Olympic Games is established for events over distances from 100 m to 10,000 m. The velocity-time relationship for a sprinter running 100 m at maximum available power is obtained by numerical integration of the power equation. It is shown that the peak velocity is achieved in the middle stages of the race, a result which is consistent with practice, but which previous calculations based on Newton’s laws have failed to predict. Further applications of the analysis are indicated.
Abstract: The role of arginine vasopressin (AVP) in the regulation of renal medullary blood flow is uncertain. To determine if AVP has a direct vasoconstrictive action on vasa recta, the effect of AVP on erythrocyte velocity (VRBC), diameter, and blood flow (QVR) in descending vasa recta (DVR) and ascending vasa recta (AVR) was studied in the exposed renal papilla of four groups of chronically water diuretic rats using fluorescence videomicroscopy. There were three periods: control (period 1), experimental (period 2), and recovery (period 3). In periods 1 and 3, all groups received hypotonic saline. In period 2, group I rats (AVP) received AVP (45 ng/h per kg body wt); group II (time) received hypotonic saline alone; group III (AVP plus V1-inhibitor) received AVP plus its vascular antagonist, d(CH2)5Tyr(Me)AVP; and group IV (V1-inhibitor) received the vascular antagonist alone. Another group of rats (group V) was employed to demonstrate that the rise in blood pressure induced by a 3- or 10-ng/kg injection of AVP was virtually abolished by the prior infusion of the V1-inhibitor. The urine of group III as well as group I rats was concentrated (Uosm = 721 +/- 62 H2O vs. 670 +/- 39 mosM/kg), while urine remained dilute in groups II and IV. In period 2, VRBC and QVR in DVR and AVR decreased in group I, did not decrease in group III, and increased in groups II and IV. The vascular antagonist thus completely abolished the AVP-induced decrease in QVR in group III. These findings unequivocally establish that AVP in physiological amounts reduces medullary blood flow, at least in part, by a direct vasoconstrictive action on the medullary microcirculation. They also show that an effect of AVP on medullary blood flow is not necessary for its antidiuretic effect.
Abstract: Fluid uptake by vasa recta was determined by two independent methods, videomicroscopy and the micropuncture technique, in the exposed papilla of nine antidiuretic rats to reconcile differences in values previously obtained by the two techniques. Erythrocyte velocity (Vrbc) and diameter (D) in descending vasa recta (DVR) (n = 22) and ascending vasa recta (AVR) (n = 31) near the "base" of the papilla were measured. Using a conversion function determined in vitro, Vrbc was transformed into mean blood velocity (Vblood). From D and Vblood, mean blood flow (Q) in DVR and AVR was calculated. In DVR, mean Vrbc, D, and Q were 1.06 +/- 0.01 mm/s, 16.3 +/- 0.4 micron, and 10.6 +/- 1.4 nl/min, respectively. In AVR, each corresponding value differed significantly, 0.47 +/- 0.06 mm/s (P less than 0.001), 19.8 +/- 0.8 micron (P less than 0.001), and 5.65 +/- 1.3 nl/min (P less than 0.025), respectively. Blood samples from DVR and AVR were obtained by micropuncture from the same location. Plasma protein concentration (g/dl) was 5.1 +/- 0.6 in DVR, 4.0 +/- 0.4 (P less than 0.05) in AVR, and 3.6 +/- 0.3 (P less than 0.025) in the renal vein. Assuming no net transcapillary loss of protein, total plasma outflow exceeded inflow by 29%, the excess representing fluid uptake; and to reconcile the blood flow and plasma protein concentrations found, functioning AVR should outnumber functioning DVR by a ratio of 2.1-2.4 to 1, depending on local hematocrit. Given the total number of AVR + DVR = 2,944 (at the base), capillary fluid uptake was calculated to range between 1.5 and 2.6 microliter/min.
Abstract: The American Heart Association’s current standards for CPR indicate that acid-base therapy should be guided by measurements of arterial blood gases. However, we have discovered a striking discrepancy between arterial and venous blood gases during CPR: severe venous hypercarbia and acidosis may coexist with simultaneous arterial alkalosis. Arterial blood gases during CPR, therefore, may not accurately reflect the acid-base status of mixed venous blood and thus may fail to indicate systemic acid-base status.
Abstract: Plasma potassium rises during muscular exercise and falls rapidly when exercise is stopped. Since the sympathoadrenal system is stimulated with exertion and both alpha- and beta-adrenergic agonists affect internal potassium homeostasis, we studied the influence of catecholamines on potassium shifts during and after exercise. Six healthy subjects were given maximal exercise stress tests under three conditions: with no medication (control), during beta-blockade with propranolol, and during alpha-blockade with phentolamine. Compared with a peak rise in plasma potassium of 1.23 +/- 0.27 mmol per liter (mean +/- S.E.M.) during the control study, propranolol caused a rise of 1.89 +/- 0.35 (P less than 0.01) and a sustained elevation during recovery. Phentolamine diminished the rise of potassium (0.70 +/- 0.21 mmol per liter; P less than 0.01) and lowered the potassium level throughout recovery. These effects of catecholamines were independent of the venous pH, the plasma bicarbonate and serum glucose levels, and urinary potassium excretion, and they did not appear to be due to insulin. High norepinephrine and epinephrine levels confirmed the release of catecholamines capable of stimulating alpha- and beta-receptors. Exercise work did not differ among the groups. beta-Adrenergic receptors appear to moderate the acute hyperkalemia of exercise, whereas alpha-adrenergic receptors act to enhance hyperkalemia and may protect against hypokalemia when exertion ceases.
Abstract: Vasopressin induces a concentration-dependent increase in atriopeptin immunoreactivity in plasma. Rat plasma, rat atrial extract, and synthetic atriopeptin III (APIII) produced parallel displacement curves of iodine-125-labeled APIII binding to specific antiserum. Fractionation of plasma atriopeptin immunoreactivity by reverse-phase high-performance liquid chromatography showed that the major portion consists of two species of low molecular weight peptides in a ratio of 10 to 1. Both peaks exhibited potent vasorelaxant activity, suggesting the presence of the carboxyl terminal Phe-Arg sequence of atriopeptin in each species. Sequence determination of the purified peptides indicated that the major peptide is Ser-Leu-Arg-Arg-APIII and the minor peptide APIII. It appears that the former is the major species of atrial peptide in the rat circulation and that it is the product of selective cleavage of the high molecular weight precursor.
Abstract: To clarify the central nervous and the cardiovascular mechanisms mediating the Cushing response (CR) during intracranial hypertension, the effects of continuous and prolonged expansion of an epidural supratentorial balloon was studied in six dogs. Regional cerebral blood flow, cardiac output, extracerebral tissue blood flow and regional vascular resistance were measured with radioactive microspheres before and during the CR while heart rate, arterial blood pressure and ECG were continuously recorded. The results showed that balloon expansion led progressively to cerebrospinal ischemia beginning in the cerebrum and progressing to the pons, medulla oblongata and spinal cord in an orderly rostro-caudal fashion. This progressing ischemia was closely associated with patterned and stereotyped changes in cardiovascular indices. Thus, respiration ceased, heart rate decreased, blood pressure increased and cardiac output fell when the ischemia appeared in the lower pons. Further advancement of the ischemic front to the lower medulla oblongata led to an abrupt switch-over from bradycardia to tachycardia, which persisted until the experiment was terminated. Since bradycardia disappeared when ischemia reached the vagal cardiomotor nucleus, the initial bradycardia appeared to be the result of increased vagal discharge. When ischemia reached the pons, the mean arterial pressure rose to a maximum of 245 mm Hg (+/- 45) but then fell progressively when the ischemia reached the spinal cord. The decrease in cardiac output persisted throughout the CR and was associated with decreased flow in most extracerebral organs. Exceptions were the heart muscle and the adrenal medulla in which blood flow increased considerably. Changes in regional vascular resistance reciprocated the changes in flow. These results suggest that the vasomotor component of the CR is brought about entirely by peripheral vasoconstriction.
Abstract: To define the role of insulin in blood pressure regulation, the hormone’s action on renal sodium handling, potassium balance, pressor reactivity, and the release of catecholamines and aldosterone are summarized. Insulin-stimulated renal sodium reabsorption induces expansion of the extracellular volume, increase in cardiac output, and ultimately, hypertension. On the other hand, the insulin-induced shift of potassium into the cell interior is transient and appears to be of little consequence for long-term blood pressure control. Although the release of norepinephrine is stimulated by insulin, a norepinephrine-mediated pressor effect is prevented in healthy men by a simultaneous norepinephrine-antagonistic action of insulin. The latter causes the fall in blood pressure seen after intravenous insulin in patients with autonomic dysfunction who lack the rise in norepinephrine release. Both in healthy and in diabetic men, exogenous insulin does not modify the pressor effect of angiotensin II, although it impairs the secretion of aldosterone during stimulation by supraphysiological doses of angiotensin II.
Abstract: An experimental study was carried out in eight dogs to investigate whether the Cushing response (CR) during intracranial hypertension is due to pressure per se, tissue distortion, or ischemia in the brain stem. To minimize the effects of rostrocaudal displacement, intracranial pressure was raised by an expanding mass lesion located in the posterior fossa. Regional cerebral blood flow (rCBF) was measured with radioactive microspheres and compartmental cerebrospinal fluid (CSF) pressures were recorded during the CR which was induced by the continuous inflation at a constant rate of an infratentorial epidural rubber balloon in two groups of four dogs. In one group (A) rCBF was measured at the onset of the CR and in the other group (B) at the peak of the systemic blood pressure rise. In the animals of group A blood flow in the mesencephalon, pons and upper medulla oblongata was reduced from control values by 32%, 57% and 85% respectively. In group B blood flow in the same areas did not differ significantly from pre-inflation values. In contrast, the recorded balloon volume, which was assumed to be an index of mechanical distortion of the brain stem, varied considerably at the beginning of the blood pressure rise (from 2.5 to 4.7% of the calculated intracranial space). Similarly, CSF pressure in the posterior fossa at the onset of the CR also varied considerably (from 52 to 117 mmHg). Thus, the large quantitative variations meant that both absolute pressure and tissue distortion were poor predictors of the onset of the CR. The findings suggest that ischemia, rather than brain stem distortion per se or pressure by itself, is responsible for the initiation of the CR. The rise in blood pressure elicited during the CR seems capable of restoring blood flow in the brain stem back to control values.
Abstract: In 3 groups of 4 dogs with normotensive, induced-hypotensive and induced-hypertensive blood pressure respectively, continuous expansion of an extradural supratentorial balloon led to respiratory arrest at inflation volumes which increased with increasing blood pressure. This positive correlation between the volume tolerance to an expanding lesion and blood pressure was also found in similar experiments on 4 hypotensive and 4 hypertensive cats. Monitoring cerebrospinal fluid pressures in the cerebral lateral ventricles, in the posterior fossa and in the spinal subarachnoid space showed that absolute pressures in the various compartments as well as the intercompartmental pressure gradients at the moment of respiratory arrest were increased in proportion to the level of the systemic arterial pressure in each case. These observations do not support current concepts that brain-stem distortion alone or that stimulation of baroreceptors in the posterior fossa are responsible for eliciting the Cushing response. The fact that the supratentorial perfusion pressure was the only parameter which did not differ significantly under the different experimental conditions suggests that the mechanism responsible for the respiratory arrest is local brain tissue ischemia, probably near the tentorial incisure. The magnitude of gain in volume tolerance, when mean arterial pressure was varied from 60 mmHg to 190 mmHg, was 87% suggesting that the blood pressure may have a critical role in an intracranial lesion. These findings have clinical implications.
Abstract: The hemodynamic effects of three different infusion rates of epinephrine (25, 50, or 100 ng X kg-1 X min-1 for 14 min) were examined in 10 normal human subjects. Ejection fraction and changes in cardiac volumes were assessed by radionuclide ventriculography. Plasma epinephrine was increased to levels that spanned the normal physiological range (178 +/- 15, 259 +/- 24, and 484 +/- 69 pg/ml, respectively). Epinephrine infusions resulted in dose-dependent increases in heart rate (8 +/- 3, 12 +/- 2, and 17 +/- 1 beats/min, mean +/- SE) and systolic pressure (8 +/- 1, 18 +/- 2, and 30 +/- 6 mmHg). Although epinephrine infusions had minimal effects on end-diastolic volume, there were significant increases in stroke volume (+26 +/- 2, 31 +/- 4, and 40 +/- 4%), ejection fraction (+0.10 +/- 0.01, 0.14 +/- 0.02 and 0.16 +/- 0.03 ejection fraction units), and cardiac output (+41 +/- 4, 58 +/- 5, and 74 +/- 1%). These increases in left ventricular performance were associated with a decreased systemic vascular resistance (-31 +/- 3, -42 +/- 2, and -48 +/- 8%). Supine bicycle exercise resulted in similar plasma epinephrine levels (417 +/- 109 pg/ml) and similar changes in stroke volume, ejection fraction, and systemic vascular resistance but greater increases in heart rate and systolic blood pressure. Since infusion-associated hemodynamic changes occurred at plasma epinephrine levels commonly achieved during many types of physical and emotional stress, epinephrine release may have an important role in regulating systemic vascular resistance, stroke volume, and ejection fraction responses to stress in man.
Abstract: [3H]Ethylpropylamiloride is a useful radioactive label to identify the Na+/H+ exchange system (Vigne, P., Frelin, C., Audinot, M., Borsotto, M., Cragoe, E. J., and Lazdunski, M. (1984) EMBO J. 3, 2647-2651). This paper extends the analysis of the properties of interaction of [3H]ethylpropylamiloride with the exchanger and describes its use with hypertrophied kidneys. [3H]Ethylpropylamiloride-binding sites copurify with the luminal membrane marker alkaline phosphatase but not with the basolateral membrane marker (Na+,K+)ATPase, thus indicating an asymmetric distribution of the Na+/H+ exchanger. Specific [3H]ethylpropylamiloride binding is dependent on pH. The pH dependency indicates that an ionizable function with a pKapp of 7.0 is essential in the association of the amiloride derivative. H+ acts competitively on [3H]ethylpropylamiloride binding; Na+, Li+, or cholinium ions have no effect on the association. Compensatory adaptation of the kidney to chronic reduction of renal mass is accompanied by a 1.7-fold increase in the activity of the Na+/H+ exchange system. Properties of interaction of internal and external pH with the Na+/H+ exchanger of normal and hypertrophied kidneys are identical. Titration of [3H]ethylpropylamiloride-binding sites in normal and hypertrophied kidneys suggests that the increased activity of the Na+/H+ exchange system is not accompanied by an increased concentration of exchangers.
Abstract: Previous studies have shown that a normal LVEF is not a reliable index of LV function in MR. We hypothesized that the forward EF, which is the forward stroke volume (measured by Fick or thermodilution) divided by end-diastolic volume (measured by contrast ventriculography) may be a useful index of LV function, since it represents LV emptying into the aorta. This index was examined in 54 patients with chronic MR who had normal EF (greater than or equal to 50%). There were significant correlations between the forward EF and the end-diastolic volume index (r = -0.69, p less than 0.001), end-systolic volume index (r = -0.64, p less than 0.001), cardiac index (r = 0.43, p less than 0.01), and the ratio of systolic pressure-to-end-systolic volume (r = 0.65, p less than 0.001). Patients were divided into two groups according to the forward EF: group I (n = 34) had forward EF less than or equal to 35%; and group II (n = 20) had forward EF greater than 35%. Of the 32 patients who subsequently underwent mitral valve replacement, 24 patients were in group I and eight patients were in group II. At a mean follow-up of 35 months, four patients died; all of them were in group I. Improvement in functional class occurred in 75% of surgical survivors (80% in group I and 63% in group II, p = NS). These preliminary data suggest that forward EF may be a useful index of LV performance in patients with MR who have normal EF.
Abstract: Plasma concentrations of immunoreactive atrial natriuretic peptide (ANP) were low or undetectable in 8 healthy subjects and 9 control patients without cardiac disease, and raised in 17 patients with congestive heart failure (CHF). Highest concentrations were measured in patients with severe CHF. High plasma ANP levels were also found in 2 patients with paroxysmal supraventricular tachycardia and associated transient polyuria. Infusion of synthetic human alpha-ANP, 110-125 micrograms over 30 min, to 3 healthy males resulted in a 2.3-fold increase in natriuresis and diuresis but had no effect on kaliuresis. Plasma levels of renin activity, aldosterone, and antidiuretic hormone did not change significantly. ANP infusion gave plasma ANP levels of the same magnitude as those found in severe CHF; levels returned to baseline within 15 min of stopping the infusion. Thus ANP appears to be a circulating hormone in man, at least in severe CHF and supraventricular tachycardia.
Abstract: Patients with uncontrolled insulin-dependent diabetes mellitus have elevations in plasma vasopressin that cannot be accounted for totally by recognized osmotic or nonosmotic stimuli. To investigate the possibility that regulation of vasopressin secretion is abnormal in this disease, we characterized the vasopressin response to osmotic and hemodynamic stimuli in five uncomplicated, well-controlled insulin-dependent diabetics, and compared the results with those found in nondiabetic volunteers. During osmotic stimulation with hypertonic saline, plasma vasopressin increased in close linear correlation with plasma osmolality or sodium in both groups. However, in the diabetics, the lines describing the relationships between plasma sodium and vasopressin were shifted significantly to the left of normal, suggesting resetting of the osmostat. This shift was not due to abnormal stimulation by hyperglycemia, because increasing plasma glucose and osmolality by intravenous infusion of hypertonic dextrose produced no increase in plasma vasopressin in diabetics or normals. Tilt tests produced a slightly exaggerated increase in plasma vasopressin in diabetics, but their basal and upright pulse rate, blood pressure, plasma renin activity, norepinephrine, and hematocrit were all normal. The results indicate that in diabetic patients the osmoreceptor for osmotic regulation of vasopressin secretion is reset in such a way that higher plasma vasopressin levels are observed at comparable levels of plasma sodium. The exact cause and consequence of this abnormality remain to be determined.
Abstract: To assess the role of endogenous opioids in the secretion of pituitary and adrenal hormones, we injected intravenously the antagonist naloxone (1 mg/kg) into six dogs, euhydrated or dehydrated. Plasma renin activity (PRA), osmolality, and concentrations of adrenocorticotropic hormone (ACTH), cortisol, aldosterone, vasopressin, Na+, and K+ were measured. Dehydration elevated (P less than 0.05) PRA, vasopressin, osmolality, and Na+. Thirty minutes after injection of naloxone, osmolality, Na+, K+, hematocrit, and plasma protein were not altered. Naloxone-induced elevations of ACTH (25 +/- 10 and 22 +/- 4 pg/ml) and cortisol (4.8 +/- 1.0 and 5.1 +/- 1.0 micrograms/dl) were similar during euhydration and dehydration, respectively. The increase in aldosterone due to naloxone was greater after euhydration (7.7 +/- 3 ng/dl) than during dehydration (2.3 +/- 0.8 ng/dl). Naloxone increased vasopressin by (5.3 +/- 2.8 microU/ml) during dehydration but not during euhydration. Intravenous hypertonic saline infusions showed that naloxone potentiates the osmotic release of vasopressin. Our results indicated that dehydration did not alter the inhibitory role of opioids in regulation of ACTH and cortisol but suppressed the inhibition of aldosterone secretion. Our findings also showed that opioids inhibit secretion of vasopressin during dehydration by decreased responsiveness to osmotic stimulation.
Abstract: To investigate the relationships between oxygen consumption (VO2) and the rates of systemic lactate appearance (Ra) and disappearance (Rd), six healthy males were studied at rest and during continuous graded exercise using a primed continuous infusion of lactate tracer. Subjects exercised for 6 min at 300, 600, 900, and 1,200 kg . m . min-1. L-(+)-[1-14C]lactate was infused intravenously, and arterial samples were drawn at rest and every 2 min throughout the exercise period. Ra and Rd were calculated using nonsteady-state equations. At rest Ra and Rd were 14.4 +/- 1.8 and 15.1 +/- 2.2 mumol . kg-1 . min-1, respectively. Near steady-state values were observed toward the end of the first two work loads. Ra and Rd values were 32.8 +/- 2.3 and 37.4 +/- 1.3 mumol . kg-1 . min-1 during min 5 and 6 at 300 kg . m . min-1 and were 59.1 +/- 2.6 and 55.4 +/- 2.3 mumol . kg-1 . min-1 during min 5 and 6 at 600 kg . m . min-1. Ra was significantly greater than Rd at both 900 and 1,200 kg . m . min-1. Ra and Rd averaged 145.4 +/- 10.5 and 110.2 +/- 5.6 mumol . kg-1 . min-1, respectively, during the last 2 min at 900 kg . m . min-1, and 309.4 +/- 20.8 and 169.7 +/- 10.6 mumol . kg-1 . min-1, respectively, at 1,200 kg . m . min-1.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Dynamic computerized tomography (CT) was performed on 42 patients with acute head injury to evaluate the hemodynamics and to elucidate the nature of fatal diffuse brain bulk enlargement. Patients were divided into two groups according to the outcome: Group A included 17 nonfatally injured patients, eight with acute epidural hematomas and nine with acute subdural hematomas; Group B included 25 fatally injured patients, 16 with acute subdural hematomas and nine with bilateral brain bulk enlargement. Remarkable brain bulk enlargement could be seen in all fatally injured patients with acute subdural hematoma. In 29 (69%) of 42 patients, dynamic CT was performed within 2 hours after the impact. In the nonfatally injured patients with brain bulk enlargement, dynamic CT scans suggested a hyperemic state. On the other hand, in 17 (68%) of the 25 fatally injured patients, dynamic CT scans revealed a severely ischemic state. In the fatally injured patients with acute subdural hematoma, CT Hounsfield numbers in the enlarged hemisphere (hematoma side) were significantly lower than those of the opposite side (p less than 0.001). Severe diffuse brain damage confirmed by follow-up CT scans and uncontrollable high intracranial pressure were noted in the fatally injured patients. Brain bulk enlargement following head injury originates from acute brain edema and an increase of cerebral blood volume. In cases of fatal head injury, acute brain edema is the more common cause of brain bulk enlargement and occurs more rapidly than is usually thought.
Abstract: Thiopental was used in long-term infusion (3-4.5 mg . kg-1 . h-1 during 4-8 days) to protect the brain from injury following trauma. Thiopental plasma concentrations were measured during infusion (48 patients) and after infusion (14 patients) to determine the kinetics of the drug in continuous infusion. All mean values were mean +/- SD. Steady state concentrations (Css) were 31.8 +/- 10.7 mg/l for an infusion rate of 3.05 +/- 0.37 mg . kg-1 . h-1 and 48.9 +/- 14.6 mg/l for a rate of 4.2 +/- 0.3 mg . kg-1 . h-1. Corresponding steady state clearance decreased when Css increased, indicating possible saturation of the metabolic enzymatic system. Michaelis-Menten kinetics were confirmed by postinfusion data that give, for higher Css, a nonlinear decay of log C versus time. First-order kinetics were only obtained with Css below 30 mg/l. The maximum rate of elimination (Vm) was 1.76 +/- 1.15 mg . l-1 . h-1 (n = 11), and the Michaelis constant (Km) was 26.7 +/- 22.9 mg/l (n = 11). Hepatic enzyme saturation was between 35 and 85%. The volume of distribution at steady state was 4.35 +/- 1.83 l/kg (n = 11). Apparent half-lives of elimination were between 18 and 36 h at the end of infusion, and predicted terminal half-lives were 10.15 +/- 5.43 h (n = 11). Phases of burst-suppression were observed on electroencephalographic traces for concentrations greater than 40 mg/l. The authors’ results suggest that a continuous infusion at a dose of 4 mg . kg-1 . h-1 induces EEG changes consistent with a near-maximum reduction in cerebral metabolism. Because of the thiopental Michaelis-Menten kinetics at doses above 4 mg . kg-1 . h-1, the authors suggest that thiopental plasma concentrations be measured and/or the drug effect be measured with the EEG to prevent excessive thiopental overdosage, causing a prolonged recovery time.
Abstract: The amplitude of ventricular fibrillation found initially in 394 patients was compared to clinical and logistical findings at the time of cardiac arrest. Peak-to-peak amplitude averaged 0.55 +/- 0.25 mV; a very low amplitude (0.2 mV or less) or "fine" fibrillation was present in 66 patients (17%). The amplitude was not found to be related to clinical histories, but depended on the length of the period from collapse until start of basic life support (p = 0.004) and the delay until assessment by paramedics (p = 0.001). Survival rates were strongly associated with amplitude: only 4 patients (6%) with fine ventricular fibrillation survived, compared to 117 or 328 patients (36%) in whom the initial amplitude was higher (p less than 0.001). Patient outcome related to amplitude even after adjusting for clinical history and logistical delays (p less than 0.005). We conclude that fine ventricular fibrillation is in part the result of delay in initiation of treatment, and that fibrillation amplitude is a powerful indicator of outcome after cardiac arrest.
Abstract: Eighty-seven patients who had out-of-hospital cardiac arrests received defibrillating shocks delivered by minimally trained first responders before the arrival of paramedics in a city with short emergency response times. Their outcomes were compared with those of 370 other victims who received only basic life support by first responders until paramedics arrived. Survival was improved by early defibrillation in cases in which there was a delay in initiating cardiopulmonary resuscitation and in which paramedic response times exceeded 9 min; there was 62% survival after early defibrillation by first responders and 27% if first responders provided only basic life support (p less than .02). Neurologic recovery was also improved after early defibrillation. Eighteen of 46 resuscitated patients (39%) receiving early defibrillation were awake at 24 hr compared with 49 of 204 patients (24%) who received only basic life support while awaiting paramedics (p less than .02). Incorporating defibrillation as part of basic life support can reduce both mortality and morbidity from cardiac arrest, even in cities with established, rapidly responding emergency care systems.
Abstract: The goals of this study were to quantify the effects of epinephrine on myocardial and cerebral blood flow during conventional cardiopulmonary resuscitation (CPR) and CPR with simultaneous chest compression-ventilation and to test the hypothesis that epinephrine would improve myocardial and cerebral blood flow by preventing collapse of intrathoracic arteries and by vasoconstricting other vascular beds, thereby increasing perfusion pressures. Cerebral and myocardial blood flow were measured by the radiolabeled microsphere technique, which we have previously validated during CPR. We studied the effect of epinephrine on established arterial collapse during CPR with simultaneous chest compression-ventilation with the abdomen bound or unbound. Epinephrine reversed arterial collapse, thereby eliminating the systolic gradient between aortic and carotid pressures and increasing cerebral perfusion pressure and cerebral blood flow while decreasing blood flow to other cephalic tissues. Epinephrine produced higher cerebral and myocardial perfusion pressures during CPR with simultaneous chest compression-ventilation when the abdomen was unbound rather than bound because abdominal binding increased intracranial and venous pressures. In other experiments we compared the effect of epinephrine on blood flow during 1 hr of either conventional CPR or with simultaneous chest compression-ventilation with the abdomen unbound. Epinephrine infusion during conventional CPR produced an average cerebral blood flow of 15 ml/min . 100 g (41 +/- 15% of control) and an average myocardial blood flow of 18 ml/min . 100 g (15 +/- 8% of control). In our previous studies, cerebral and myocardial blood flow were less than 3 +/- 1% of control during conventional CPR without epinephrine. Although flows during CPR with simultaneous chest compression-ventilation without epinephrine were initially higher than those during conventional CPR, arterial collapse developed after 20 min, limiting cerebral and myocardial blood flow. The use of epinephrine throughout 50 min of CPR with simultaneous chest compression-ventilation maintained cerebral blood flow at 22 +/- 2 ml/min . 100 g (73 +/- 25% control) and left ventricular blood flow at 38 +/- 9 ml/min . 100 g (28 +/- 8% control). The improved blood flows with epinephrine correlated with improved electroencephalographic activity and restoration of spontaneous circulation.(ABSTRACT TRUNCATED AT 400 WORDS)
Abstract: Eighty-seven patients who had out-of-hospital cardiac arrests received defibrillating shocks delivered by minimally trained first responders before the arrival of paramedics in a city with short emergency response times. Their outcomes were compared with those of 370 other victims who received only basic life support by first responders until paramedics arrived. Survival was improved by early defibrillation in cases in which there was a delay in initiating cardiopulmonary resuscitation and in which paramedic response times exceeded 9 min; there was 62% survival after early defibrillation by first responders and 27% if first responders provided only basic life support (p less than .02). Neurologic recovery was also improved after early defibrillation. Eighteen of 46 resuscitated patients (39%) receiving early defibrillation were awake at 24 hr compared with 49 of 204 patients (24%) who received only basic life support while awaiting paramedics (p less than .02). Incorporating defibrillation as part of basic life support can reduce both mortality and morbidity from cardiac arrest, even in cities with established, rapidly responding emergency care systems.
Abstract: The effect of the duration of cardiopulmonary resuscitation (CPR) on capillary perfusion in selected organs was studied in two methods of CPR. Flows were measured during sinus rhythm and at two and ten minutes of CPR by injection of labeled microspheres. Cardiac output during CPR was redistributed, with a higher percentage directed cephalad. Brain blood flow during early CPR was preserved, but flow decreased significantly (P less than .05) by ten minutes. Flow to all other organs also decreased over time in CPR, but the differences were significant only for organs above the diaphragm and spleen. Although CPR with abdominal binding as compared to CPR without binding did not significantly increase flow to any organ (P less than .05), flow with binding (versus without binding) was higher to the organs above the diaphragm and lower to organs below the diaphragm.
Abstract: Blood pressure in patients with progressive autonomic failure falls during salt restriction or orthostasis. We contrasted the regulation of plasma volume in patients with progressive autonomic failure with that of controls to determine whether hypovolemia contributes to this hypotension. When sitting, the plasma volume (measured from distribution of human serum albumin) was normal. During 1 week of low Na+ intake, patients with progressive autonomic failure lost three times as much body weight as controls; however, changes in plasma volume were strictly comparable. Therefore, the extra fluid lost in the patients must have derived primarily from the interstitial space. During alteration in Na+ intake, mean blood pressure values were closely related to plasma volume in the patients (r = 0.80, p less than 0.01) but not in controls. Changes in plasma volume in the head-up tilt position were assessed from the hematocrit values. During tilting, the blood pressure in controls was unchanged, but their plasma volume fell by 10.3% +/- 1.8% (p less than 0.001). In contrast, the mean blood pressure of the patients with progressive autonomic failure fell by 40 +/- 6 mm Hg; yet, their plasma volume was unchanged. Thus, in progressive autonomic failure, plasma volume measured during sitting is normal, but dynamic regulation of plasma volume during salt restriction or orthostasis is abnormal and hypovolemia is offset by partitioning of interstitial fluid into the plasma. Also, because the blood pressure is unusually dependent on volume, this fluid redistribution could be an important defense against severe hypotension in patients lacking cardiovascular reflex control.
Abstract: The importance of aortic chemoreceptors in the circulatory and metabolic responses during acute anemia was studied in anesthetized dogs. Data were obtained from nine dogs in which the aortic chemoreceptors were surgically denervated prior to induction of anemia, and from seven sham-operated dogs. Cardiac output (QT), limb blood flow (QL), limb and whole body oxygen uptake (VO2) were determined at normal hematocrit (Hct) and at 30 min of anemia (Hct = 13%) produced by isovolemic dextran-for-blood exchange. At 30 min of anemia, QT was increased from 91 to 186 mL . kg-1 . min-1 (p less than 0.01) and from 99 to 153 mL . kg-1 . min-1 (p less than 0.01) in the sham and denervated groups, respectively. The increase in QT during anemia was less (p less than 0.05) in the aortic-denervated series. Limb flow was also increased during anemia in both groups (p less than 0.01); the mean value of 89 mL . kg-1 . min-1 in the denervated group was less than that of 130 mL . kg-1 . min-1 observed in the sham animals (p less than 0.05). Whole body VO2 decreased (p less than 0.05) in the denervated group at 30 min of anemia; limb VO2 was maintained at the preanemic control value in both groups. The data indicate that during acute anemia the aortic chemoreceptors contribute to the increase in QT.
Abstract: The maximal exercise capacity of patients with chronic heart failure is frequently reduced. To investigate whether this exercise intolerance is caused by inadequate nutritive flow to skeletal muscle, we compared cardiac outputs, leg blood flow, and leg metabolism during maximal bicycle exercise in seven patients with normal maximal oxygen uptake (VO2) (greater than 20 ml/min/kg; group A), eight patients with heart failure and moderately reduced maximal VO2 (15 to 18 ml/min/kg; group B), and eight patients with heart failure and markedly reduced maximal VO2 (less than 14 ml/min/kg; group C). As the severity of exercise intolerance increased from group A to group C there was a progressive decline in cardiac output and leg blood flow at any given workload accompanied by a progressive decline in maximal cardiac output (liters/min) (A, 12.4 +/- 1.0; B, 8.7 +/- 0.9; C, 5.5 +/- 0.7), maximal leg flow (liters/min) (A, 4.0 +/- 0.3; B, 2.6 +/- 0.4; C, 1.4 +/- 0.2), and maximal leg VO2 (ml/min) (A, 564 +/- 49; B, 403 +/- 41; C, 213 +/- 35 ml/min). All patients terminated exercise because of severe leg fatigue. At termination of exercise, all three groups exhibited similar marked levels of leg O2 extraction (%) (A, 80 +/- 2; B, 83 +/- 3; C, 89 +/- 1) and high femoral-arterial lactate gradients (mg/dl) (A, 15.4 +/- 2.6; B, 18.3 +/- 3.5; C, 19.2 +/- 3.6), suggesting that exercise was limited when a critical level of muscle underperfusion was reached. These data suggest that the reduced maximal exercise capacity of patients with chronic heart failure is primarily due to impaired nutritive flow to skeletal muscle and resultant muscular fatigue.
Abstract: Numerous previous studies have proposed a role for angiotensin II (AII) in the renal regulation of salt balance. At least one nephron site, the proximal convoluted segment, has been implicated in this role. We used in vitro microperfusion of rabbit proximal convoluted tubules to further examine this question. To insure use of appropriate in vivo concentrations as well as potency of the hormone in vitro, we measured plasma AII levels by radioimmunoassay in normal, sodium-depleted, and adrenalectomized rabbits, and measured AII activity by bioassay after incubation in various microperfusion baths. Plasma levels ranged from approximately 2 X 10(-11) to 5 X 10(-11) M. AII activity was stable in Ringer’s solution plus albumin, but not in rabbit serum or Ringer’s solution plus fetal calf serum. In Ringer’s solution plus albumin, physiologic concentrations of AII stimulated volume reabsorption (Jv). 10(-11) M AII increased Jv by 16% (P less than 0.01). 10(-10) M AII produced a lesser increase, 7.5% (P less than 0.05). At a frequently studied, but probably pharmacologic dose, 10(-7) M AII inhibited Jv by 24% (P less than 0.001). AII at 10(-11) M did not stimulate Jv in the presence of 10(-7) M saralasin. Though previous studies have suggested agonistic effects of saralasin alone in epithelia, we found no significant effect of 10(-7) M saralasin on Jv. None of the AII doses measurably changed transepithelial voltage. We conclude that AII in physiologic doses directly stimulates Jv in proximal convoluted tubules and this effect is probably receptor mediated and, within the limits of detection, electroneutral.
Abstract: We have examined the hypothesis that hypoxaemia contributes to breathlessness by a mechanism distinct from its action as a ventilatory stimulant. Five patients who developed arterial oxygen desaturation during incremental exercise were studied. Exercise tests were performed on a cycle-ergometer. Breathlessness was measured by using a visual analogue scale technique. All five patients had considerable previous experience of these procedures. Two identical exercise tests were performed by each patient, breathing either room air or 60% oxygen in a blind randomized study. Breathing air, arterial saturation at rest was 93% and fell by 7% during exercise. Breathing 60% oxygen, resting saturation was 98% and there was no fall during exercise. Breathing oxygen, ventilation for a given work load was reduced and exercise duration was increased when compared with air breathing. In each of the five patients the relationship between breathlessness and minute ventilation was the same whether breathing air or 60% oxygen, despite the reduction in ventilation for a given work rate.
Abstract: Tissue carbon monoxide (CO) content was investigated in rats severely intoxicated with CO under various exposure conditions: 1% CO for 4 min, 0.4% CO for 40 min and 0.12% CO for 12 h. Extravascular CO was determined in the heart and skeletal muscles immediately after termination of exposure, and carboxymyoglobin (MbCO) percent saturation was calculated. Total brain CO was estimated immediately after termination of exposure and after the time periods of restitution. After the same exposure conditions, MbCO percent saturation was higher in the heart than in skeletal muscle. In both types of muscle, saturation of myoglobin (Mb) with CO depended on blood carboxyhemoglobin (HbCO) level and not on the duration of exposure. The time course of CO elimination was the same for blood and brain, irrespective of CO exposure conditions. The results obtained showed that acute CO intoxication induced by long duration exposures did not involve CO accumulation in the tissues.
Abstract: Mouse and human atrial natriuretic factor (ANF) genes have been cloned and their nucleotide sequences determined. Each ANF gene consists of three coding blocks separated by two intervening sequences. The 5’ flanking sequences and those encoding proANF are highly conserved between the two species, while the intervening sequences and 3’ untranslated regions are not. The conserved sequences 5’ of the gene may play an important role in the regulation of ANF gene expression.
Abstract: The interaction of angiotensin II and plasma K concentration in stimulating aldosterone secretion was studied in a group of six dogs by determining the aldosterone response to three levels of angiotensin II while the dogs were maintained on three levels of K intake. The levels of angiotensin were 1) the endogenous level, 2) the concentration resulting from infusion of 5 ng X kg-1 X min-1, and 3) the concentration resulting from infusion of 10 ng X kg-1 X min-1. Each level was maintained for 5 days. The three rates of K intake were 10, 100, and 200 meq/day, each maintained for 3 wk. Data were analyzed from days 1, 2, and 5 of the angiotensin infusion periods. The regressions obtained from plotting plasma K (PK) versus aldosterone concentration on day 5 of each level of infusion were 1) for no infusion (endogenous PRA = 0.4 to 0.5 ng ANG I X ml-1 X h-1), aldosterone = 5.04 X PK - 16.56; 2) for 5 ng X kg-1 X min-1 infusion, aldosterone = 12.20 X PK - 39.09; and 3) for 10 ng X kg-1 X min-1 infusion, aldosterone = 35.50 X Pk - 119.31. Each regression was significantly different (P less than 0.001) from the other two. The plasma K axis intercepts, which are the points at which aldosterone secretion is zero, were 3.29, 3.20, and 3.36 for the regression from the 0, 5, and 10 ng X kg-1 X min-1 infusion rates, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: The effects of changes in sodium intake on the steady-state relationship between plasma potassium concentration and potassium excretion were studied in 15 chronically adrenalectomized dogs. Throughout the experiments the dogs received aldosterone at a rate of 50 micrograms/day and methylprednisolone at 1 mg/day. The relationship between plasma potassium and steady-state potassium excretion was obtained by changing potassium intake from 10 to 30 to 100 meq/day, each level being maintained for 7-10 days. At the conclusion of each period at a given level of potassium intake, plasma potassium and excretion were measured and plotted, plasma potassium being the independent variable. Such a relationship was obtained while the dogs were on three different levels of sodium intake: 10, 100, and 200 meq/day. The curves from the data obtained at 100 and 200 meq/day sodium intake both were shifted to the left of the curve obtained at 10 meq/day (P less than 0.05), although the 100 and 200 meq/day curves were not different from each other. On the basis of these data one could predict that, at a plasma potassium concentration of 4.0 meq/liter, the animals would excrete potassium at a rate of 17 meq/day on a 10 meq/day sodium intake, 37 meq/day on a 100 meq/day sodium intake, and 47 meq/day on a 200 meq/day sodium intake. Urine flow and electrolyte concentration data are consistent with the hypothesis that the sodium intake effect on potassium excretion was mediated through increases in distal nephron flow rate and decreases in distal nephron potassium concentration.
Abstract: Forty-six male Sprague-Dawley rats were divided in five groups: awake animals and those receiving ketamine, halothane, enflurane, or isoflurane anesthesia. Cannulae were inserted into the left femoral artery and vein and the left ventricle. Inspired concentrations of the volatile anesthetics were adjusted to achieve the minimal alveolar concentration (MAC) of each drug. Ketamine, 125 mg . kg-1, was injected intraperitoneally and then infused at a rate of 1 mg . kg-1 . min-1. All animals breathed spontaneously throughout the experiment (FIO2 = 0.3). Following a 2-h stabilization period, 30% of estimated blood volume was withdrawn gradually over 10 min. Immediately before and 20 min after hemorrhage, cardiac output and regional blood flows were measured by the microsphere method (85Sr, 141Ce-labeled 15-microns microspheres, respectively). Arterial blood samples were analyzed for PO2, PCO2, pH, lactate, and pyruvate at these times also. Prior to hemorrhage, cardiac output (CO) values were similar in awake rats and those receiving ketamine or isoflurane, but CO was reduced moderately by enflurane and to a greater extent by halothane. After hemorrhage, CO was greatest in awake animals and those receiving isoflurane, and awake rats tended to have the greatest organ blood flows. Values of lactate/pyruvate and excess lactate were least in awake animals. Overall results suggested that, in terms of cardiac output and regional blood flows, ketamine approximates the awake state most closely in normovolemic animals, whereas isoflurane anesthesia is most like the awake condition after hemorrhage.
Abstract: Immobilization in plaster, bed rest, and the weightless state all result in calcium loss which if continued for a few months will result in detectable demineralization of the lower extremities. The upper extremities are "different" bones (presumably differently programmed genetically), for they have not been seen to develop X-ray-detectable demineralization except after several months of severe paralysis. The substantial losses of calcium in inactivity are accompanied by sizeable losses of nitrogen, reflective of muscle atrophy. Hence, we do not know how much of the bone loss in disuse is mediated by diminished direct physical forces on bone, how much by decreased muscle pull on periosteum, and how much perhaps by circulatory or other changes.
Abstract: We have recently described rapid cardiac atrophy in response to decreased load. The present study was designed to determine whether this atrophy is solely a degenerative response of damaged myocardium or is, instead, an adaptive response of viable myocardium. A discrete portion of cat myocardium was unloaded by severing the chordae tendinae of a single right ventricular papillary muscle. One week later, the muscle was reloaded by attachment of its apex to the ventricular free wall. This allowed the load to be removed and restored without altering the blood supply, innervation, or frequency of contraction of the tissue. In myocardium unloaded for 1 week, the cardiocyte cross-sectional area and the volume densities of mitochondria and myofibrils decreased significantly. Large areas of cytoplasm were devoid of organelles, and the few remaining myofilaments were oriented in a variety of directions rather than longitudinally within the cell. Upon reloading for 1 week, the cardiocyte cross-sectional area, volume density of mitochondria, and ultrastructural organization all returned to normal. The volume density of the myofibrils increased toward control, and they reoriented with respect to the long axis of the cardiocyte. The contractile function of the papillary muscles, which was depressed as early as 1 day after unloading and almost absent at times later than 3 days after unloading, returned to normal after 2 weeks of reloading. This study demonstrates that adult mammalian myocardium responds to unloading with a marked loss of cellular differentiation, organization, and function which is fully reversible with reloading. This plasticity in response to load may well be the basic mechanism responsible for the development and maintenance of normal cardiac structure and function.
Abstract: The present study was undertaken to determine the plasma levels of somatostatin-like immunoreactivity (SLI) during constant infusion of graded concentrations of synthetic somatostatin-14 (S-14); to determine the half-life (t1/2) and metabolic clearance rate (MCR) of SLI; to correlate the plasma SLI levels with the degree of inhibition of pituitary and islet hormone secretion and to establish whether the plasma SLI levels capable of inhibiting pituitary and islet hormone secretion fall into the physiological range. Four normal subjects on separate occasions were each infused with saline or S-14 (25,50 and 75 micrograms/h) at a constant rate for 2 1/2 h. Thirty min following the infusions, TRH (200 micrograms) and arginine (0.5 g/kg) were given i.v. Blood samples were drawn every 15 min for measurement of GH, TSH, insulin, glucagon and SLI (by RIA of acid-ethanol extracted plasma) and at rapid intervals for 10 min after stopping the infusions for measurement of SLI disappearance. During S-14 infusions, plasma SLI rose rapidly, reached a plateau from 15-150 min and declined rapidly on cessation of the infusions with a mean t 1/2 of 2.72 +/- 0.45 min. Mean plateau SLI levels were: 149 +/- 3 pg/ml (25 micrograms/h), 465 +/- 35 pg/ml (50 micrograms/h), and 1244 +/- 71 pg/ml (75 micrograms/h). SLI was cleared rapidly but the MCR exhibited a dose-dependent decrease from 3225 +/- 699 ml/min for the 25 micrograms infusion to 1249 +/- 241 ml/min for the 75 micrograms/h infusion (P less than 0.05). The 25 micrograms/h infusion dose produced near-maximal suppression of GH secretion and inhibited insulin secretion but not TSH or glucagon secretion. The intermediate dose significantly inhibited GH, TSH, and insulin but not glucagon whereas the 75 micrograms/h infusion suppressed all four hormones. In six normal subjects endogenous plasma SLI rose from a basal value of 32.5 +/- 4.9 pg/ml to 75.5 +/- 9.0 pg/ml following ingestion of a mixed meal. This level was 50% of that resulting from the 25 micrograms/h infusion and which suppressed GH almost completely. We concluded that: Infused S-14 is cleared rapidly and decays with a short t 1/2; S-14 inhibits its own MCR; The somatotrophs are the most sensitive to S-14 inhibition, followed by the thyrotrophs and the B-cells (approximately equally) followed by the A-cells; Fluctuations in plasma SLI occurring physiologically may influence GH and possibly other S-14 sensitive cells by an endocrine mechanism.
Abstract: To examine the role of neural factors in the control of coronary vasoactivity in conscious animals, dogs were supplied with miniature pressure gauges in the aorta and left ventricle (to measure aortic and left ventricular pressures, respectively and with a flow probe on the left circumflex coronary artery (to measure coronary blood flow). The experiments were conducted several weeks after recovery from operation. Stimulation of the carotid chemoreceptor and pulmonary inflation elicited a biphasic reflex response. Initially, coronary vasodilation was observed; coronary blood flow tripled even after changes in metabolic factors were minimized by pretreatment with propranolol. A similar response occurred after a spontaneous deep breath. The coronary vasodilation could be blocked by alpha-adrenergic receptor blockade. The second phase of the response involved an increase in coronary vascular resistance, associated with elevated arterial pressure and an absolute reduction in coronary blood flow and coronary sinus oxygen content. The secondary coronary vasoconstriction was also abolished by alpha-adrenergic blockade. Paradoxically, alpha-adrenergic receptor blockade with phentolamine (at constant heart rate and after beta-adrenergic receptor blockade) did not increase coronary blood flow and reduced coronary vascular resistance only slightly. Selective alpha 1-adrenergic receptor blockade with prazosin and trimazosin on different days induced progressively greater reductions in coronary vascular resistance. Trimazosin was the only alpha-adrenergic receptor blocker to elevate coronary blood flow significantly. It is conceivable, but speculative, that withdrawal of alpha-adrenergic tone may involve activation of an intermediate agent, which is a potent coronary vasodilator. Alternatively, withdrawal of alpha-adrenergic tone may be an important mechanism for immediate control of the coronary circulation, but under more chronic conditions it plays a lesser role as a result of suppression by metabolic factors.
Abstract: The effects of physical training on skeletal muscle morphology and enzyme activities were compared in 10 male, type I diabetic subjects and 10 healthy, male, control subjects. The training program consisted of running for 45 min, three times per week for 8 wk. Muscle biopsies were obtained before and after the training period from the lateral portion of the gastrocnemius muscle. Pretraining maximal oxygen uptake was similar in the two groups (diabetic subjects 42 +/- 1 versus control subjects 43 +/- 2 ml X kg-1 X min-1), and the training resulted in an identical increase (+ 13%, P less than 0.01). Muscle capillarization (number of capillaries per muscle fiber) increased on the average in the control group (+ 14 +/- 4%, P less than 0.01), but was unchanged in the diabetic group (0 +/- 4%). Capillary density, expressed as number of capillaries per unit muscle cross sectional area, also increased on the average in controls (8 +/- 4%, P less than 0.05) but failed to do so in the diabetic patients (-8 +/- 6%, NS). The activities of the mitochondrial enzymes citrate synthase (+ 26-27%, P less than 0.01-0.05) and succinate dehydrogenase (+ 24-25%, P less than 0.05) increased significantly and similarly in the two groups, whereas training did not result in significant changes in the activities of the glycolytic enzymes 6-phosphofructokinase and glyceraldehyde-phosphate dehydrogenase. Glycemic control in the diabetic group did not improve with the training, as evaluated from hemoglobin A1 and home-monitored blood glucose.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: We have previously shown that certain aspects of internephron heterogeneity are reduced or absent in Brattleboro rats with hereditary diabetes insipidus (DI) lacking ADH and can be restored by long-term ADH administration started before complete kidney maturation. In the present study, the effects of long- and short-term availability of ADH in adulthood were studied in Brattleboro DI rats. Single nephron glomerular filtration rate (SNGFR), glomerular volume (GV), and proximal tubular length (PTL) were measured in superficial and juxtamedullary nephrons using the ferrocyanide and microdissection techniques. ADH administration for 6 wk in adult DI rats (group A) restored normal nephron heterogeneity of SNGFR, GV, and PTL by increasing the filtration and size of deep nephrons. Acute changes in ADH availability induced either by 1-h ADH infusion in DI rats (group C) or by ADH discontinuation for 2 days in treated DI rats (group D) did not significantly change the anatomical parameters and only moderately affected SNGFR compared with the preexisting states (groups B and A, respectively). These results suggest that the influence of ADH on internephron heterogeneity is initiated by an increase in deep nephron SNGFR. Based on recent findings concerning the effects of ADH on the medullary (M) part of the thick ascending limbs (TAL), we suggest that the increase in deep nephron SNGFR after ADH may be due to a change in the tubuloglomerular feedback signal at the macula densa resulting from ADH-induced stimulation of the solute reabsorption in the MTAL. Superficial nephrons would be less sensitive to this change due to their long cortical TAL, which removes the macula densa further from the MTAL and provides additional sites for solute reabsorption.
Abstract: The time courses of changes in levels of beta-hydroxybutyrate (BOHB), glucose (GLC), and glycogen (GLY) were measured hourly for 7 h after i.p. 2 g/kg ethanol (ETOH) in samples of liver, blood, and brain in 21 day old C57BL/6J mice. After acute ETOH, brain GLC remained at 2.1 mmol/kg for 2 h, fell to a low of 1.5 mmol/kg at 5 h, then rose slightly. Blood GLC remained near 8 mmol/kg until 3 h, then fell. Liver GLC fell steadily from 10.2 to 7.2 mmol/kg at 7 h. Brain GLY rose from 1.7 to 2.9 mmol/kg at 3 h, then fell steadily. Blood GLY increased from 2.7 to 4.6 mmol/kg at 2 h, then fell to 1.7 mmol/kg. Liver GLY decreased from 70 to 30 mmol/kg. BOHB changes were similar in all samples. BOHB in brain fell from 0.12 to 0.08 mmol/kg at 2 to 3 h; then rose steadily to 0.27 mmol/kg at 7 h. Blood and liver BOHB fell from 0.40 to 0.25 mmol/kg, then rose to 1.0 mmol/kg. In a previous study, susceptibility to audiogenic seizures after 2 g/kg ETOH was completely suppressed for up to 1 h, then susceptibility increased to a maximum at 5 1/2 h, when a period of potentiation was observed. In this study, brain GLY levels were increased during the period of protection, and brain GLC levels were decreased during the period of potentiation. Together, these data may lend support to an hypothesis of an indirect effect of ETOH on the brain, leading to changes in susceptibility to audiogenic seizures via changes in metabolite availability.
Abstract: The aim of this study was to evaluate the effect of acetazolamide on cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2). CBF, arterial and jugular venous partial O2 pressure, partial CO2 pressure, pH, and O2 saturation percentage were measured in six patients before and 3 and 20 minutes after intravenous administration of 1 g of acetazolamide. CBF was measured by the intracarotid 133xenon injection technique. In addition, changes in CBF were estimated from the arteriovenous oxygen content difference. CBF increased in all patients after acetazolamide, by approximately 55 and 70% after 3 and 20 min, respectively. The CBF changes were of the same order whether calculated from the 133Xe clearance or from the arteriovenous oxygen differences (A-V)O2. CMRO2, calculated from (A-V)O2 differences and CBF, remained constant. Except for an increase in the venous oxygen saturation, the blood gases remained constant. Acetazolamide, in a dose sufficient to inhibit the erythrocyte carbonic anhydrase (EC 4.2.1.1), thus induced a rapid and marked increase in CBF, leaving CMRO2 unchanged. This effect of acetazolamide on CBF is probably explained by a decrease in brain pH rather than by brain tissue hypoxia due to inhibition of oxygen unloading in the brain capillaries.
Abstract: Various hypertonic solutions were infused in healthy human volunteers to determine their effect on thirst and vasopressin secretion. Hypertonic saline and mannitol produced prompt and parallel increases in plasma osmolality and vasopressin concentration. For both of these solutes, there was a high degree of correlation between these measurements. The slope describing this relationship varied considerably between individuals, but the same subjects showed similar slopes with either saline or mannitol. Both solutions stimulated thirst. Hypertonic urea infusions produced a comparable rise in osmolality but produced a smaller increase in plasma vasopressin and stimulated thirst in only one of the subjects. With urea, the correlation between plasma osmolality and vasopressin was significantly lower. Within individuals, the slope describing this relationship was significantly correlated with that seen during hypertonic saline. Hypertonic glucose significantly increased plasma osmolality but decreased plasma vasopressin and had no detectable effect on thirst. We conclude that osmoregulation of vasopressin in humans is mediated by a selective osmoreceptor that is located primarily outside of the blood-brain barrier and that individual differences in osmoregulatory sensitivity are not solute specific.
Abstract: Mean arterial blood pressure, heart rate, and cardiac output were monitored at rest and during exercise of two grades of severity in conscious dogs under control conditions and after progressive interruption of the baroreflexes. Aortic arch denervation and vascular isolation and pressurization of the carotid sinuses were used to interrupt arterial baroreflexes. Subsequent interruption of cardiopulmonary afferents was produced by acute bilateral cervical vagotomy. The results indicate that 1) with the cardiopulmonary receptors alone operative, the arterial blood pressure response to exercise is abnormal, 2) cardiopulmonary receptors do not contribute to the moment-to-moment modulation of arterial pressure, and 3) the carotid sinuses, aortic arch, and cardiopulmonary receptors are all involved in determining the mean level of arterial blood pressure. It is concluded that vagally innervated cardiopulmonary receptors do not have a significant role in regulating arterial blood pressure during exercise but are involved in establishing the general level of arterial blood pressure.
Abstract: The two horizontal forces acting on a sprinter are ground reaction driving him forward and air resistance impeding him. The driving force starts off at a maximum value but decreases with increase in velocity, whereas the resisting force varies as the square of velocity. Mathematical models of these two forces have been incorporated in Newton’s Second Law to yield a second order nonlinear differential equation to describe the sprinter’s motion. This equation may be numerically integrated, and validation of the model has shown there is good agreement between theory and experimental data. The model may be used to characterise a runner’s performance (a so-called ’sprint profile’), to pinpoint his strengths and/or weaknesses, and to predict what his time might be for a particular distance if he were able to maintain maximum velocity.
Abstract: The effects of peripheral hypoxia on ventilation were investigated in 18 cats anaesthetized with chloralose urethane. The ponto-medullary region of the brain was artificially perfused via a cannulated vertebral artery, using an extracorporeal circuit fed from a femoral artery. In this way the carbon dioxide tension (PacCO2) and the oxygen tension in the blood supplying the brainstem could be imposed independently from the peripheral PCO2 (PapCO2) and PO2 (PapO2) in the systemic circulation. In all experiments the brainstem was kept hyperoxic. The steady-state ventilation VE could be described by (formula; see text) where Sp and Sc represent the peripheral and central sensitivity to carbon dioxide and K is a constant. Sc and K were independent of the PapO2. In general, peripheral hypoxia increased and peripheral hyperoxia decreased Sp, compared to normoxia. It is concluded that: (1) there is no interaction in the ventilatory response between peripheral O2-CO2 and central CO2 stimuli; and (2) a positive interaction in the ventilatory response between peripheral hypoxia and CO2 originates from the arterial chemoreceptors.
Abstract: The effects of sodium depletion on plasma norepinephrine (NE) kinetics were studied in 14 patients with essential hypertension using the steady state NE infusion technique on the theoretical basis of a two-compartmental open model. The calculated half time of rapid removal phase (t 1/2 alpha) of plasma NE was significantly delayed in the hypertensives (1.20 +/- 0.22 min, mean +/- SD) than in normal subjects (0.89 +/- 0.14) (p less than 0.01). The total clearance rates were comparable between the 2 groups (47 +/- 7 vs 48 +/- 11 ml/kg/min). The rates of the endogenous NE outflow into the circulation (RE-NE) were not significantly different between normal (5.29 +/- 1.68 ng/kg/min) and hypertensives (7.69 +/- 5.42), although 5 hypertensive patients (36%) showed an increased RE-NE above the normal range. The prolonged half time (t 1/2 alpha) in the hypertensives tended to be shortened after sodium depletion induced by either low sodium diet or diuretics (1.04 +/- 0.22, p less than 0.001). Both plasma NE and RE-NE were significantly increased after sodium depletion. A close correlation was observed between plasma NE and RE-NE (r = 0.907, p less than 0.001) in these subjects. These results suggest the slowed neuronal uptake of NE at the sympathetic nerve terminals in some patients with essential hypertension, occurring in part as a sodium-mediated consequence.
Abstract: 1. The effect of an intravenous infusion of insulin [2.5 units h-1 (m2 of body surface area)-1] on the rise in blood pressure and plasma aldosterone after intravenous angiotensin II (5, 10, and 20 ng min-1 kg-1) was investigated in six healthy, sodium-loaded men. 2. Serum insulin reached 96.8 +/- 18.1 mu-units/ml (control: 7.0 +/- 1.5 mu-units/ml) and serum potassium fell from 4.2 +/- 0.2 mmol/l to 3.6 +/- 0.2 mmol/l (P less than 0.005). 3. Hyperinsulinaemia increased (P less than 0.05) the secretion of aldosterone during the largest dose of angiotensin II (20 ng min-1 kg-1), but had no effect on the rise in blood pressure after angiotensin II.
Abstract: We studied the effects of physiological rates (0-4 Hz) of sympathetic stimulation on blood flow and oxygen consumption of extensor digitorum longus muscles isolated from anesthetized dogs. Observations were made with the preparation at rest and during isometric twitch exercise at 1 and 4 Hz produced by somatic nerve stimulation. Graded increases in sympathetic stimulation rate resulted in graded and sustained reductions in muscle blood flow in all cases. A given rate of sympathetic stimulation reduced muscle blood flow by nearly the same absolute amount regardless of muscle exercise rate. Consequently the curve relating muscle blood flow to muscle oxygen consumption was progressively shifted downward in a parallel fashion with graded increases in sympathetic stimulation rate. Sympathetic stimulation at 0.5 and 1 Hz reduced muscle oxygen consumption during 4-Hz exercise but failed to do so during rest or 1-Hz exercise. Thus even during heavy exercise, local metabolic mechanisms do not override sympathetic vasoconstriction sufficiently to prevent the latter from limiting muscle oxygen consumption. In addition, the functional consequences of sympathetic activation appear to be greater for heavily exercising muscle than resting muscle.
Abstract: Excessive doses of insulin cause unstable or "brittle" diabetes in many diabetic patients. Chronic insulin overtreatment can be very difficult to recognize because nocturnal hypoglycemia may be infrequent and asymptomatic. Recognition of subtle historical clues and informed interpretation of laboratory results facilitate diagnosis. Some insulin-treated diabetic patients fail to respond to severe nocturnal hypoglycemia with the acute secretion of counterregulatory hormones. "Rebound" morning hyperglycemia coincides with decreased plasma free insulin levels and the normal diurnal rise in plasma cortisol levels. Moreover, these patients show hyperresponsiveness to counterregulatory hormones (particularly cortisol and epinephrine), exaggerated hepatic glucose production, and prolonged impairment of peripheral and splanchnic glucose disposal. When chronic overtreatment is suspected, insulin therapy must be modified to better approximate physiologic needs for glucose disposal. Until fundamental problems of insulin replacement are solved, chronic insulin overtreatment should be considered as one cause of unstable diabetes.
Abstract: Dopamine (DA) normally circulates in plasma. The plasma concentration of the free form of DA is approximately equivalent to that of epinephrine (E) and 20% that of norepinephrine (NE). The free form constitutes less than 2% of total plasma DA, and the remainder exists predominantly as sulfate or glucuronide conjugates. DA is found in adrenal medulla and cortex, peripheral nerves, sympathetic ganglia, carotid body, and kidney, but quantitatively the origin of circulating DA remains poorly understood. Plasma concentrations of free DA increase in association with events that increase sympathetic tone, although to a much lesser degree than seen for NE or E. Thus, upright posture, bicycle exercise, a variety of emotional and physical stresses, and hypoglycemia may be associated with increases in plasma free DA. Plasma DA decreases during the course of dietary sodium depletion in humans, in contrast to the plasma NE response, and consistent with a physiological role for DA in the regulation of aldosterone secretion. Plasma DA increases after administration of its precursor L-dihydroxyphenylalanine, together with the decarboxylase inhibitor carbidopa. Plasma NE and (in some studies) plasma DA decrease after administration of the DA receptor agonist bromocriptine. In contrast, plasma DA and one of its major metabolites, homovanillic acid, increase after administration of the DA receptor antagonist haloperidol. Administration of the endogenous opioid peptide beta-endorphin into the brain increases central sympathetic outflow, thus increasing plasma DA concentration, although to a lesser extent than for NE or E. Disordered basal concentrations of DA in plasma or disordered responses of plasma DA have been reported in a number of disease states. Clear understanding of physiological roles of DA in plasma and of its pathophysiology awaits definition.
Abstract: The genetically obese (ob/ob) mouse exhibits defective thermoregulatory responses to cold exposure. Pathophysiological explanations for this phenomenon have focused on abnormalities in intracellular metabolism or insensitivity of peripheral tissues to the thermogenic effects of catecholamines. Because the sympathetic nervous system (SNS) is subject to feedback regulation, a peripheral impairment in thermogenesis should be associated with a compensatory increase in SNS activity. To examine SNS activity in the ob/ob mouse, norepinephrine (NE) turnover was measured in heart and interscapular brown adipose tissue (IBAT) of ob/ob and lean mice. The results from studies utilizing radiolabeled NE or inhibition of NE biosynthesis with alpha-methyl-p-tyrosine to measure NE turnover demonstrated reductions in SNS activity of 33-56% in heart and of 45-73% in IBAT in ob/ob mice at ambient temperature (22 degrees C) compared with measurements in lean controls. During cold exposure (4 degrees C) NE turnover increased in heart and IBAT to a similar extent in both ob/ob and lean mice, but NE turnover rates in heart, and probably in IBAT as well, remained lower in the obese mice than in the lean despite the gradual development of hypothermia in the ob/ob mice during this period. Administration of naltrexone, a long-acting opiate antagonist, failed to reverse the suppression of SNS activity observed in the ob/ob mice. These data indicate that diminished SNS activity in ob/ob mice may be an additional factor contributing to the defective thermogenesis characteristic of these animals.
Abstract: The interacting effects of aldosterone and plasma potassium concentration on steady-state renal potassium excretion were studied in two groups of chronically adrenalectomized dogs. In group I (six dogs, 22.9 kg) aldosterone was infused intravenously at 20 micrograms/day while potassium intake was changed in steps of 7-10 days duration from 10 to 30 to 100 meq/day. At the completion of each step, plasma potassium concentration, urinary potassium excretion, and other variables that potentially may affect renal function were measured. In group II (six dogs, 22.2 kg) a similar protocol was followed except that aldosterone was infused at 250 micrograms/day and the potassium intake levels were 30, 100, and 200 meq/day. Plasma potassium concentration and excretion data for the 20 micrograms/day group were: 3.22 +/- 0.26 meq/liter and 5 +/- 1 meq/day, 4.35 +/- 0.08 meq/liter and 21 +/- 2 meq/day, and 5.88 meq/liter and 82 +/- 3 meq/day at the 10, 30, and 100 meq/day intake levels, respectively. For the 250 micrograms/day group the values were: 2.72 +/- 0.18 meq/liter and 28 +/- 7 meq/day, 4.16 +/- 0.14 meq/liter and 71 +/- 8 meq/day, and 4.40 +/- 0.14 meq/liter and 172 +/- 26 meq/day at the 30, 100, and 200 meq/day intake levels. Therefore, the increase in aldosterone infusion rate shifted the relationship between plasma potassium concentration and potassium excretion to the left so that at a given level of plasma potassium a greater amount of potassium was excreted. In the normal range of plasma potassium concentration (4.00-4.40 meq/liter) the increase in aldosterone levels resulted in a four- to eightfold increase in daily potassium excretion.
Abstract: Quantitative analysis of ionic solutions in terms of physical and chemical principles has been effectively prohibited in the past by the overwhelming amount of calculation it required, but computers have suddenly eliminated that prohibition. The result is an approach to acid-base which revolutionizes our ability to understand, predict, and control what happens to hydrogen ions in living systems. This review outlines that approach and suggests some of its most useful implications. Quantitative understanding requires distinctions between independent variables (in body fluids: pCO2, net strong ion charge, and total weak acid, usually protein), and dependent variables [( HCO-3], [HA], [A-], [CO(2-)3], [OH-], and [H+] (or pH]. Dependent variables are determined by independent variables, and can be calculated from the defining equations for the specific system. Hydrogen ion movements between solutions can not affect hydrogen ion concentration; only changes in independent variables can. Many current models for ion movements through membranes will require modification on the basis of this quantitative analysis. Whole body acid-base balance can be understood quantitatively in terms of the three independent variables and their physiological regulation by the lungs, kidneys, gut, and liver. Quantitative analysis also shows that body fluids interact mainly by strong ion movements through the membranes separating them.
Abstract: Body fluid volumes and their relation to mean arterial pressure and plasma renin activity (PRA) were examined in heminephrectomized rats after 4 wk of treatment with deoxy-corticosterone acetate (DOCA) and placed on one of three levels of salt intake, either high (D-HS), normal (D-NS), or low (D-LS); sham-operated rats, which received heminephrectomy and no DOCA treatment, also received high (S-HS), normal (S-NS), or low (S-LS) intakes of salt. Body fluid volumes were measured as the distribution volumes of radioiodinated serum albumin, 35SO4, and tritiated water for plasma volume (PV), extracellular fluid volume (EFV), and total body water (TBW), respectively. Approximately the same degrees of hypertension occurred in the D-HS and D-NS rats, but the D-LS rats were normotensive. PV and EFV were increased only in the D-HS rats, with no prominent changes occurring in the D-NS rats. Intracellular fluid volume (ICF) was not changed in the D-NS rats when compared with the S-NS rats. The ratios of PV/EFV and EFV/TBW in the DOCA-treated groups on high or normal salt were not different from their controls. PRA was greatly suppressed in the D-HS and D-NS rats when compared with all other groups. In another group of D-HS rats, sodium was restricted for 2 wk; in this group the mean arterial pressure fell to control levels without significant changes in PV, but interstitial fluid volume was reduced to normal levels. These results demonstrated that 1) in DOCA-salt hypertensive rats there is expansion of body fluid volumes that are proportionally distributed among the PV, EFV, and ICF; 2) increases in body fluid volumes are not necessary for DOCA to maintain hypertension; 3) a certain minimal amount of dietary sodium is necessary for the development and maintenance of hypertension; and 4) following DOCA treatment the suppression of PRA is not due solely to expansion of body fluid volumes.
Abstract: 1. The initial heart rate (HR) response evoked by standing, 70 degrees head-up tilt, handgrip and contraction of abdominal and leg muscles was analysed in diabetic patients with autonomic neuropathy and in matched controls. 2. In healthy subjects standing induced an immediate, large, HR increase lasting 20s that far exceeded the small HR rise induced by tilt. The HR response with handgrip and to contraction of abdominal and leg muscles was strikingly similar for the first 5 s to the HR increase after standing. 3. In diabetic patients handgrip and standing induced a small HR increase starting after 2-3 s. Contraction of abdominal and leg muscles evoked little or no HR changes. The HR rise after tilt up was delayed by 10 s compared with healthy controls. 4. It is concluded that the circulatory response to active and passive changes of posture differs fundamentally. Standing and handgrip are superior to head-up tilt as a test for vagal HR control. An abrupt and large HR increase after standing excludes cardiac parasympathetic neuropathy. A modified response, however, may be due to afferent as well as to efferent lesions, e.g. in muscle afferents or in vagal afferents from cardiopulmonary receptors.
Abstract: The metabolic pathways involved in renal ammonia production have been considered and potential sites of regulatory control have been delineated. New information that acute acidosis stimulates renal ammonia production and that chronic respiratory acidosis does not result in an adaptive increase in the renal capacity to produce ammonia has been emphasized. The effect of potassium on renal ammonia production and the physiologic and pathophysiologic implication of this relationship have been detailed. Finally, the mechanism of urinary ammonium excretion and the impact of altered ammoniagenesis on urinary acidification, and the interpretation of clinical acidification tests have been discussed.
Abstract: Experiments were performed to determine the renal effects of acute hypoxia in conscious normovolemic dogs. Dogs were made hypoxic and also became hypocapnic through increased ventilation. Hypocapnic hypoxia was associated with increased urine flow, arterial blood pressure, cardiac output, PAH and inulin clearance, and electrolyte excretion. Urinary excretion of prostaglandin E2 (PGE2) also increased during hypocapnic hypoxia. To test whether the respiratory alkalosis accompanying hypoxic exposure was important in mediating the observed response, experiments were conducted in which the dogs were hypoxic but remained isocapnic via addition of CO2 to the inspired gas. Urine flow increased and was associated with changes in renal function and hemodynamics similar to those during hypocapnic hypoxia. Experiments were also conducted to determine whether the increased PGE2 release in hypoxia was functionally significant. Dogs were pretreated with meclofenamate and then made hypoxic. Prostaglandin synthesis inhibition did not alter the renal response to hypocapnic hypoxia. Dogs were also treated chronically with propranolol in an attempt to blunt the rise in blood pressure during hypoxia. In dogs with only a small transient increase in blood pressure, the diuresis was blocked. It is concluded that systemic hypoxia results in a mild diuresis in the conscious normovolemic dog. This response occurs independent of changes in arterial pH or renal prostaglandin release. The diuretic effect of hypoxia is probably due to increased renal perfusion pressure and resultant increased filtration.
Abstract: In anesthetized rats micropuncture and microcatheterization were used to collect tubular fluid from end proximal and distal tubules and from the outer medullary collecting duct. Urine was collected at the papilla tip. Samples were taken from the same sites before and after intravenous injection of atrial tissue extract; rats injected with ventricular extract served as controls. Sodium excretion increased 17-fold after atrial extract, a significantly greater rise than the 3-fold increase after ventricular extract. Clearances of inulin and single nephron filtration rates did not change significantly in either group. Tubular fluid collection results showed a similar reduction (16 to 20%) of proximal fluid and sodium reabsorption in both groups. In the experimental group only, NaCl reabsorption failed to rise in response to increased load in the medullary collecting duct. The resulting fall in fractional reabsorption in the medullary collecting duct accounted for 80% of the natriuresis. We conclude that atrial tissue from rat hearts contains a factor which causes increased renal NaCl excretion by inhibiting transport in the medullary collecting duct.
Abstract: To determine the relative importance of plasma and luminal pH changes as factors regulating potassium secretion by rat distal tubule, superficial tubules were continuously microperfused in vivo. The effects of changes in plasma pH were examined by producing acute systemic metabolic acidosis or alkalosis and holding luminal flow rate, solute composition, and pH constant by microperfusion. Alternatively, the effect of luminal solution pH was evaluated by microperfusing tubules with solutions buffered to either pH 6.5 or 8.0 at constant systemic acid-base balance. Net transport of Na and K and the pH of the luminal fluid were measured. Results showed that metabolic acidosis inhibited and metabolic alkalosis stimulated potassium secretion. Increased luminal fluid pH, in contrast, did not stimulate potassium transport. In experiments in which metabolic acidosis produced a diuresis, urinary potassium excretion was enhanced compared with hydropenic controls. Free-flow micropuncture studies revealed that the rate of fluid delivery to the distal tubule was 45% greater during acidosis compared with control and that potassium secretion increased in both the distal and collecting tubule. Since the rate of fluid delivery is a potent stimulus of potassium secretion in the distal tubule, it is concluded that the stimulus of increased delivery of fluid, observed in free-flow conditions, masked the inhibitory effect of acidosis on potassium transport. Potassium transport by the distal tubule, during acid-base disorders, is regulated by plasma pH and the rate of delivery of fluid but is not stimulated by alkalinization of the luminal fluid.
Abstract: The rate of renin secretion (product of renal plasma flow and the arteriovenous difference for plasma renin concentration) was measured by continuous collection of 2-min samples of arterial and left renal venous blood with continuous electromagnetic monitoring of left renal blood flow in 5 anesthetized male mongrel dogs. Measurements were made for 1 h before and at least 53 min after withdrawal of 16 ml blood/kg BW in 2 min. During the 1-h control period, there were no significant changes in measured variables. The hemorrhage was followed by a sustained reduction in average mean arterial blood pressure to 78.5 +/- 2.24% (SD) of average control values and by a sustained reduction in average renal blood flow to 87.3 +/- 4.47% (SD) of average control values. An increase in rate of secretion of renin began during the hemorrhage in every animal. The increase was transient, reaching a peak at 3-5 min and a nadir at 5-11 min after initiation of hemorrhage. At the peak, the mean value was 1996.9 +/- 977.6% (SE) of mean control, and at the nadir, it was 87.6 +/- 44.7% (SE) of mean control. After the initial treatment increase there was a gradual irregular mean increase in the rate of renin secretion. These data demonstrate that the immediate changes in rate of renin secretion in response to a brief hemorrhage sufficient to cause sustained hypotension are biphasic. This characteristic must be taken into account in modeling regulation of renin secretion and in planning experiments.
Abstract: Sympathetic vasoconstrictor impulses were recorded with microelectrodes in peroneal muscle nerve fascicles during vasovagal syncope in two subjects. After a preceding period of increased nerve activity, onset of syncope was associated with bradycardia and sudden cessation of sympathetic outflow. The findings provide direct evidence that neurally mediated muscular vasodilatation occurring during syncope is due to inhibition of vasoconstrictor impulses.
Abstract: To study the relationship between extracellular potassium concentration and renal excretion of potassium, seven chronically adrenalectomized dogs were maintained on a constant intravenous infusion of aldosterone (50 micrograms/day), and constant sodium intake (30 meq/day ) while they received four levels of potassium intake–10, 30, 100, and 200 meq/day–for 7-10 days each. At the conclusion of each level of intake, plasma potassium and renal excretion as well as other variables known to influence potassium excretion were measured. There were minimal changes in arterial pH, mean arterial pressure, extracellular fluid volume, or glomerular filtration rate at any level of potassium intake. The values for plasma potassium and renal potassium excretion attained at each level of intake were: 3.13 +/- 0.24 and 10 +/- 2; 4.18 +/- 0.18 and 21 +/- 6; 4.31 +/- 0.11 and 66 +/- 10; and 4.75 +/- 0.10 meq/liter and 170 +/- 16 meq/day, respectively. Under these experimental conditions in which the levels of aldosterone, sodium intake, arterial pH, arterial pressure, extracellular fluid volume, and glomerular filtration rate remain constant, plasma potassium concentration appears to have a week effect on renal potassium excretion below the normal level of plasma potassium (approx. 11 meq/day change in excretion for each milliequivalent per liter change in concentration). Above the normal level, however, plasma potassium concentration has a powerful effect, 260 meq/day per milliequivalent per liter. The characteristics of the relationship between plasma potassium and renal potassium excretion make it ideally suited for controlling potassium excretion in response to greater than normal potassium intake.
Abstract: Intralymphatic end pressure and Starling pressures (interstitial fluid pressure (Pif), plasma and interstitial fluid colloid osmotic pressures (COPpl and COPif)) were measured in leg subcutaneous tissue in 5 patients with local leg edema following femoropopliteal reconstruction for lower limb atherosclerosis. Superficial lymphatics were cannulated proximal to the ankle and the catheter was connected to either syringes for determination of lymph flow and colloid osmotic pressure (COPl), or to a pressure transducer for measurement of intralymphatic end pressure. Samples of interstitial fluid were collected by implantation of nylon wicks and Pif was measured by the "wick-in-needle" technique. In all patients normal end pressure waves with maximum values ranging between 30 and 40 mmHg were recorded, indicating that the ischemia prior to surgery had not significantly affected the intrinsic mechanism for lymph propulsion. COPif of the operated leg averaged 5.7 mmHg +/- 1.0 which was 0.9 mmHg +/- 0.7 higher than the corresponding COPl. This supports the theory of "preferential channels" between the capillaries and the lymphatics. There was a statistically significant correlation between lymph flow and estimated capillary pressure (reabsorption pressure), capillary filtration coefficient, calf blood flow and Pif. According to this study the capillary pressure should at least be 11 mmHg before production of lymph occurs.
Abstract: In the excised canine left ventricle, the end-systolic pressure-volume relationship (ESPVR) has been shown to be approximately linear over the working range of loading conditions when coronary arterial pressure (CAP) is maintained constant, independent of loading conditions. To investigate the ESPVR under the more intact physiological condition in which the CAP varies with loading on the left ventricle, we studied the effect of changes in CAP on the ESPVR in 10 excised cross-circulated canine ventricles which were contracting isovolumically. The ESPVR, determined from isovolumic contractions at four different volumes, was reasonably independent of CAP as long as CAP remained above a critical pressure (67.0 +/- 22.1 mm Hg). Below this pressure, the slope of ESPVR decreased although the volume axis intercept (V0) remained unaltered. These findings indicate that under physiological conditions, where there is a close coupling of CAP to systolic left ventricular pressure, the ESPVR should become nonlinear in the low preload or afterload regions. When CAP was varied with the left ventricular pressure in five ventricles, the ESPVR indeed became nonlinear in the low-load region. We conclude that the ESPVR in intact conditions is reasonably linear in the physiological load range, but it can be nonlinear in the low-load range.
Abstract: Changes in inulin space, plasma and blood volume, exchangeable and "noninulin" sodium were studied during the prehypertensive, early and late hypertensive stages of deoxycorticosterone (DOC)-salt administration in the rat. The effect of an acute water load in previously nephrectomized animals was also studied. Hypertension developed after 1 to 2 weeks of the DOC-salt regimen and was always preceded by enlargement of the inulin space and increased plasma and blood volume. Expansion of extracellular fluids receded when blood pressure started to rise but reappeared after 4 to 6 weeks of treatment. Plasma sodium was high only in the hypertensive groups. An acute water load increased blood pressure of normal rats and decreased blood pressure of DOC-salt early hypertensive rats. These findings suggest that extracellular volume expansion inhibits a vasopressor mechanism that involves vasopressin and could be stimulated by hypernatremia.
Abstract: To assess the effects of long-term changes in aldosterone on potassium distribution within the body, two groups of experiments were conducted. In the first, seven normal dogs received continuous infusion of aldosterone at a high physiological rate, 250 micrograms/day. Total exchangeable potassium (Ke) and plasma potassium concentration (KP) were measured before and 4 and 6 days after aldosterone infusion. KP fell by 20% while Ke decreased by 8% after 6 days of infusion; the ratio between extracellular and total body potassium had been altered by the aldosterone infusion. In the second study, 10 adrenalectomized dogs received aldosterone infusion first at 50 micrograms/day, then at 250 micrograms/day. While on each level of aldosterone infusion, three levels of potassium intake were given by iv infusion. When the animals were in electrolyte balance at each level of aldosterone and potassium (after at least 7 days on each level of infusion), Ke (expressed as meq/kg) and KP were measured. The two variables were plotted against each other, Ke being the independent variable. Data taken while the dogs received 50 micrograms/day aldosterone were described by the equation, KP = 0.100Ke + 0.055, while those obtained at 250 micrograms/day were fitted by the equation, KP = 0.057Ke + 1.30. The correlation coefficients for the two were 0.778 and 0.760, respectively. The regressions were significantly different at a level of P less than 0.02. Data from the two groups of experiments are consistent with the hypothesis that aldosterone alters the distribution of potassium between the intra- and extracellular spaces, a greater portion of total potassium being intracellular at higher levels of aldosterone.
Abstract: To define aspects common to different flow-dependent renal transport processes, four examples of such transport processes are considered: glomerular filtration, distal potassium secretion, ascending limb sodium absorption, and proximal fluid absorption. For each example the phenomenon of flow dependence is documented and the mechanism underlying this behavior is explored. Two general types of flow dependence are recognized: dissipative and generative. The first three processes are examples of dissipative flow dependence. In each a flow-sensitive component of the driving force for transport is generated upstream from the site of transport, the transport process tends to dissipate its driving force, and higher flow rates tend to maintain the driving force. The fourth process considered is an example of generative flow dependence. In this case the flow-sensitive component of the driving force is generated within the transporting segment. Flow affects the transport process by preventing dissipation of the driving force, as in the first three cases. Both types of processes can be expected to be more flow dependent in some lower range of flow rate and to be less flow dependent in some higher range of flow rate. This is because the proximate cause of a change in transport, a flow-dependent change in driving force is larger for a given change of flow rate when flow rates are relatively slow.
Abstract: Muscular work requires the integration of cardiopulmonary mechanisms for gas exchange and O2 delivery. In patients with chronic cardiac failure, the response of these mechanisms may be impaired, and the pattern of O2 utilization (VO2) and gas exchange during exercise would thus provide an objective assessment of the severity of heart failure. Accordingly, rates of air flow, O2 uptake, CO2 elimination and minute ventilation were determined during progressive treadmill exercise in 62 patients with stable heart failure. Exercise cardiac output, systemic O2 extraction and lactate production were measured directly in 40 patients with heart failure of varying severity. As the severity of heart failure increased from class A to D, there was a progressive decrease in exercise capacity (from 1157 +/- 154 to 373 +/- 157 seconds) and maximum VO2 (23 +/- 3.2 to 8.4 +/- 1.5 ml/min/kg). These decreases corresponded with the reduced maximum cardiac output and stroke volume during exercise. The appearance of anaerobic metabolism (580 +/- 17 to 157 +/- 7 seconds of exercise) and the corresponding anaerobic threshold (17 +/- 0.34 to 7.1 +/- 1.5 ml/min/kg), determined noninvasively, were reproducible and correlated with the rise in mixed venous lactate concentration. No apparent untoward effects were experienced during or after the progressive exercise test. We conclude that the measurement of respiratory gas exchange and air flow during exercise is an objective, reproducible and safe noninvasive method for characterizing cardiac reserve and functional status in patients with chronic cardiac failure.
Abstract: Volume expansion could inhibit renal nerve activity by stimulating cardiopulmonary baroreflexes or by increasing arterial pressure (i.e., stimulating the sinoaortic baroreflexes). Our study assessed the relative roles of these two reflexes in the renal nerve activity responses to volume expansion (15 ml/kg 6% dextran in normal saline). With cardiopulmonary and arterial baroreflexes intact, volume expansion resulted in increases in arterial pressure and pulmonary artery wedge pressure and in decreases in renal nerve activity. After sinoaortic denervation, volume expansion resulted in similar decreases in renal nerve activity for similar increases in pulmonary artery wedge pressure. In contrast, after selective vagotomy (sinoaortic baroreflexes intact) volume expansion resulted in increases in arterial pressure and pulmonary artery wedge pressure, but reductions in renal nerve activity were markedly attenuated. After sinoaortic denervation and vagotomy, volume expansion did not result in significant changes in renal nerve activity. We conclude that decreases in renal nerve activity during volume expansion are mediated mainly by cardiopulmonary receptors with afferent vagal fibers. Sinoaortic baroreceptors appear to play a minor role in mediating these responses.
Abstract: Fundamental physicochemical characteristics of the acid-base related constituents of extracellular and intracellular fluid spaces of vertebrates in relation to changes in temperature have been reviewed. Emphasis has been placed upon the dissociation constant of water, the solubility constant of CO2, the dissociation constant of histidine imidazole, the hydroxyl-hydrogen ion ratio, the protein charge state and the alpha-imidazole regulation concept. Because pN and pKIm change in parallel when temperature varies, the OH/H ratio and the alpha-imidazole value for any sample of blood or plasma held anaerobically in vitro are invariant with changing temperature, since a constant CO2 content is maintained. Thus, when blood or plasma cools, pH increases and PCO2 decreases, but relative alkalinity and the protein charge state remain constant. These responses are solely the consequence of physical constants, that is, equilibrium constants and gas solubility, changing with temperature. In vivo, the set of PCO2 is established in each poikilothermic species by its normal ventilatory pattern designed to maintain constant CO2 content. Regulation in vivo in poikilotherms consists of adjustments of ventilation per unit metabolism (VA/VCO2) appropriate to every temperature. When the ventilatory and renal mechanisms of human beings are suppressed by anesthesia and hypothermia, their extracellular and intracellular responses mimic those of poikilotherms. Clinical management of hypothermia in humans requires ventilatory control using oxygen-augmented room air without added CO2 monitored by pH measurements of arterial blood warmed anaerobically to 37 degrees C. Finally, the need for new techniques to measure intracellular pH as temperature is lowered and some areas for further investigation are suggested.
Abstract: Captopril was administered (50 mg orally) to 88 untreated hypertensive patients (70 with essential hypertension, eight with renal arterial disease, 10 with renal parenchymal disease) and to 25 hypertensive patients treated with sympatholytic or beta-blocking agent (20 with essential hypertension, five with renal arterial disease). In the former group, captopril caused a decrease in heart rate (HR) in 18 patients and an increase in only two. As a whole, captopril caused significant decreases in blood pressure without increase in HR. Significant negative correlation was observed between change in HR and plasma renin activity obtained before captopril administration (n = 79, r = -0.425, p less than 0.0001). Hypotensive and chronotropic effects of captopril were almost identical in untreated and treated patients. Hypotensive effects caused by captopril and nifedipine (20 mg orally) were almost identical. Nifedipine caused reflex tachycardia, while captopril caused slight bradycardia. Absence of compensatory tachycardia appears to be related to reduction of endogenous angiotensin II by captopril.U
Abstract: We compared the effects of initial electrical shocks using 175 and 320 J (joules) in 249 patients with ventricular fibrillation. Survival was unrelated to the energy level used for defibrillation. Reversion to an organized rhythm occurred in a similar proportion of both treatment groups after one or two shocks. The rhythm identified after the first shock was related to outcome (the survival rate was 42 per cent in patients with supraventricular rhythm, 30 per cent in persistent ventricular fibrillation, 26 per cent in idioventricular rhythm, and 14 per cent in asystole; P less than 0.02). Fibrillation recurred in 68 per cent of patients who had been initially defibrillated to an organized rhythm. Repeated shocks at the higher energy level resulted in a higher incidence of atrioventricular block after defibrillation (24 per cent of patients receiving 320 J and 9 per cent of those receiving shocks of lower energy; P less than 0.005). Patients who survived required fewer shocks than patients who later died in the hospital (2.6 shocks as compared with 3.6; P less than 0.005). We conclude that initial defibrillatory shocks using 175 J are as safe and effective as shocks of nearly twice that energy level.
Abstract: Total renal ammonia production and ammonia precursor utilization were evaluated in patients under normal acid-base balance and in patients with 24-h NH4Cl acidosis by measuring (a) ammonia excreted with urine and that added to renal venous blood, and (b) amino acid exchange across the kidney. In 24-h acidosis not only urinary ammonia excretion is increased, but also total ammonia production is augmented (P less than 0.005) in comparison with controls. By evaluating the individual role of acid-base parameters, urine pH and urine flow in influencing renal ammonia production, it was shown that the degree of acidosis and urine flow are likely major factors stimulating ammoniagenesis. Both urine pH and urine flow are determinant in the preferential shift of ammonia into urine. In 1-d acidosis, renal extraction of glutamine was not increased and the total ammonia produced/glutamine N extracted ratio was higher than in controls (P less than 0.005) and was inversely correlated with the log of arterial bicarbonate concentration (P less than 0.001). In the same condition, renal glycine and ornithine uptake took place; the more severe the acidosis, the greater was the renal extraction of these amino acids (P less than 0.001). These data indicate that at the early stages of metabolic acidosis, in spite of a brisk increase in ammonia production, the mechanisms responsible for the increased glutamine use, which are operative in chronic acidosis, are not activated and other ammonia precursors, besides glutamine, are probably used for ammonia production.
Abstract: To define precisely the effects of dopamine on hypoxic ventilatory drive, two sets of experiments were performed in five healthy subjects. End-tidal CO2 was held constant in all experiments. First, a dopamine infusion (3 microgram/kg/min) was started in subjects already rendered hypoxic, causing an average sustained decrease in ventilation to 60% of the preinfusion ventilation. In the second group of experiments, the ventilatory response of subjects made hypoxic during a dopamine infusion was compared with the hypoxic ventilatory response without the dopamine infusion. Without dopamine, a sudden decrease in end-tidal O2 from 100 to 53 torr caused ventilation to increase from 11.9 to 20.9 L/min (p less than 0.01). During the dopamine infusion, only a statistically insignificant increase in ventilation (9.8 to 12.8 L/min) was seen with the same hypoxic stimulus. Low dose dopamine is a potent depressant of hypoxic ventilatory response.
Abstract: Hyperventilation is one of the most important features of acclimatization to high altitude. Resting ventilation at extreme altitudes increases up to fourfold and exercise ventilation for a given work level increases to the same extent. Hypoxic stimulation of the peripheral chemoreceptors is the chief mechanism for the hyperventilation but there is also evidence that central sensitization of the respiratory centres occurs. Permanent residents of high altitude have a blunted hypoxic ventilatory response compared to acclimatized lowlanders. Cardiac output increases in responses to acute hypoxia but returns to normal in acclimatized lowlanders. Oxygen uptake at extreme altitudes is markedly limited by the diffusion properties of the blood gas barrier. As a consequence the maximal oxygen consumption of a climber near the summit of Mount Everest is near his basal oxygen requirements. Maximal oxygen consumption is so sensitive to barometric pressure that it may be that day-to-day variations will affect the chances of a climber reaching the summit without supplementary oxygen.
Abstract: A pituitary glycopeptide whose amino acid sequence was previously identified has now been recognized as the final portion of the precursor to arginine vasopressin and its associated neurophysin. Immunocytochemical techniques with antiserums against this 39 amino acid peptide and vasopressin were used to study their distribution in the rat central nervous system. The peptide is located in vasopressin-synthesizing cells in the neurosecretory magnocellular nuclei. Positively stained fibers project from the magnocellular nuclei through the median eminence to the posterior pituitary. Studies of the homozygous Brattleboro rat, which is known to be deficient in the production of vasopressin and its related neurophysin, also show the absence of immunoreactivity to this peptide. These immunocytochemical data strongly indicate that the peptide is synthesized with vasopressin.
Abstract: We studied the effects of the right ventricle (RV) and pericardium on left ventricular (LV) diastolic pressure-volume (P-V) relations in the normothermic isolated blood-perfused dog heart. Studies were performed at a constant heart rate (atrial pacing at 120 beats/min) with a coronary perfusion pressure of 100 mm Hg. LV volume was directly controlled by an intraventricular balloon, whereas RV filling pressure was increased stepwise from zero to 20 mm Hg. During progressive increases in RV filling pressure, with the pericardium intact, the LV diastolic P-V relations were shifted up and to the left; this leftward shift of the LV diastolic P-V relation was associated with an increase in the modulus of LV chamber stiffness. Closing the small pericardial incisions with sutures significantly increased this effect. In the absence of the pericardium, progressive filling of the RV resulted in minor changes in LV diastolic P-V relations. Only when the RV filling pressure was markedly elevated (20 mm Hg) was there a significant effect on LV diastolic pressure. The pericardium has a small but significant effect on LV diastolic P-V relations at physiological RV filling pressures, and this effect becomes considerable at high RV filling pressures. The RV influence on LV diastolic P-V relations is significantly modulated by the presence of tightness of the pericardium.
Abstract: We have assessed viscoelastic properties of pericardium within the physiological range of stresses and related mechanical behavior to fiber direction as defined by scanning electron microscopy. Stiffness, stress relaxation, and creep were measured in samples taken from the anterior surface of 14 canine pericardia. Stress-strain relations generally were not exponential; stiffness at a stress of 1 g/mm2 ranged from 12.9 to 239 g/mm2 during stretch and varied both from pericardium to pericardium and with the orientation of the strip within the sample (anisotropy). The strips exhibited hysteretic behavior which was not promotional to rate of strain. Following a rapid increase in stress, creep averaged less than 1% and stress relaxation, 34% in a 30-minute test period. The orientation of the strip with the greatest stiffness was consistent from pericardium to pericardium, and correlated with a layer of collagen fibers oriented along the major axis of te strip.
Abstract: The effect of postural changes upon fluid filtration rate in the calf was studied in 3 healthy subjects placed in supine position. Volume changes in the calf were measured by a water plethysmograph. Relative changes in blood flow in subcutaneous tissue and anterior tibial muscle were measured by the local 133Xe washout technique. Lowering the calf from 5-25 cm caused a linear increase in filtration rate whereas blood flow in subcutaneous tissue of the segment studied and anterior tibial muscle remained constant. Based on this average CFC was about 0.0012 ml X min-1 X 100 g-1 X mmHg-1. Further lowering of the calf caused a decrease in blood flow in subcutaneous tissue and skeletal muscle by about 50% corresponding to an increase in total vascular resistance by about 100%. During these circumstances the increase in infiltration rate was reduced by about 33%. The resulted indicate that the local veno-anterior reflex responsible for the observed vasoconstriction in the tissue under study together with intrinsic vascular mechanisms reduces transcapillary fluid filtration in the lower position. The mechanism appears to be mainly due to a reduction of the increase in mean capillary pressure whereas CFC seems to remain almost constant.
Abstract: To examine the relationship between tubular transport of potassium and cell structure in segments of the superficial distal nephron, we performed potassium transport and quantitative electron microscopic studies in rats after potassium adaptation and potassium depletion. In distal nephrons continuously microperfused in vivo, potassium adaptation stimulated potassium secretion by 200%. Microperfused distal convoluted tubules (earliest portion of accessible distal nephron) did not, however, secrete potassium in potassium adapted animals. Morphometric analysis of the distal convoluted tubule also revealed no detectable effect of potassium diet on the structure of the distal cell type. In contrast, examination of the connecting tubule and the initial collecting tubule of the distal nephron demonstrated a striking increase in basolateral membrane in potassium-adapted animals. This change was limited to the connecting tubule cell and the principal cell type. No structural change of the intercalated cell type in either segment was associated with altered potassium transport. We conclude that cells of the distal convoluted tubule do not secrete potassium. Functional and morphologic evidence suggests that potassium is secreted by the connecting tubule cell and the principal cell of the connecting tubule and the initial collecting tubule, respectively.
Abstract: To discover which factors contributed to recovery after surgical intracranial decompression, we reviewed the records of 82 consecutive comatose patients with traumatic acute subdural hematoma (ASDH) who were treated in a single center under a uniform protocol. The delay from injury to operation was the factor of greatest therapeutic importance. Patients who underwent surgery within the first four hours had a 30 per cent mortality rate, as compared with 90 percent in those who had surgery after four hours (P less than 0.0001). Other important prognostic variables included results of the initial neurologic examination, sex, multimodality-evoked potentials, and postoperative intracranial pressure (ICP). If all patients with traumatic ASDH were taken directly to hospitals equipped to diagnose and remove the hematoma within four hours of injury, mortality rates could be reduced considerably.
Abstract: Plasma angiotensin II concentrations were measured in 14 patients in diabetic ketoacidosis and in two patients with hyperosmolar non-ketotic hyperglycemia, before treatment and again when blood glucose control was restored. In the ketoacidosis group plasma angiotensin II before treatment was markedly raised in all patients with otherwise uncomplicated diabetes, but was within the normal range in some patients with long-term complications such as neuropathy, retinopathy and nephropathy. Mean angiotensin II before treatment was significantly higher in otherwise uncomplicated patients than in those with long-term complications. However, plasma angiotensin II decreased with improved control in all. Angiotensin II levels did not correlate with indices of rehydration such as changes in blood urea, packed cell volume and calculated changes in plasma volume. There was, however, a significant negative association between pre-treatment angiotensin II and pH. Two patients with hyperosmolar non-ketotic hyperglycemia were more dehydrated but less acidotic. Pre-treatment angiotensin II in each was well below the mean of the ketoacidosis group. These data are further evidence that the renin-angiotensin system may be imparied in diabetics with long-term complications. In addition, they suggest that factors other than fluid depletion are also important in activating the renin-angiotensin system in uncontrolled diabetes.
Abstract: The role of vasopressin in the regulation of blood pressure during nonhypotensive hemorrhage was assessed in conscious dogs. An antagonist of the vasoconstrictor activity of vasopressin was administered (10 microgram/kg) to four normal dogs five min prior to the commencement of a 15 min arterial hemorrhage (1 ml/kg/min). The withdrawn blood was reinfused 15 min after completion of the hemorrhage. In the absence of vasopressin blockade, blood pressure and heart rate did not change significantly, while plasma renin activity increased from 3.8 +/- 0.9 to 10.8 +/- 3.1 ng/ml/3h (P less than 0.005), and plasma corticosteroid concentration increased from 1.5 +/- 0.8 to 8.6 +/- 2.0 microgram/dl (P less than 0.001). Following vasopressin blockade, the same hemorrhage decreased mean arterial pressure from 96 +/- 264 +/- 7 mmHg (P less than 0.001), increased heart rate from 71 +/- 10 to 130 +/- 23 beats/min (P less than 0.05), increased plasma renin activity from 7.1 +/- 0.8 to 30.3 +/- 6.7 ng/ml/3h (P less than 0.005) and increased plasma corticosteroid concentration from 1.9 +/- 0.7 to 11.4 +/- 1.2 microgram/dl (P less than 0.001). These data indicate that vasopressin plays an important role in blood pressure regulation during mild hemorrhage in conscious dogs.
Abstract: We scrutinized the recently reported correlation between the canine left ventricular systolic pressure-volume area (PVA) and cardiac oxygen consumption rate per beat (Vo2) by use of an improved method of Vo2 assessment. PVA is the specific area in the pressure-volume (PV) plane bounded by the end-systolic and end-diastolic PV lines and the systolic segment of the PV loop. Different from the previous study in which Vo2-PVA data from isovolumic and ejecting contractions were pooled for analyses, we analyzed Vo2-PVA data from the two different modes separately to examine whether there was any difference of Vo2-PVA relationship between them. The results indicated that the linear regressions of Vo2 on PVA were virtually the same for isovolumic and ejecting contractions. The regression line was Vo2 (ml O2/beat) = a[PVA (mmHg x ml x beat-1)] + b, where a = 1.64 (+/- 0.12 SE) X 10(-5) (ml O2/beat)/(mmHg x ml x beat-1) and b = 0.015 +/- 0.002 ml O2/beat in 10 hearts. We conclude that PVA serves as a reliable predictor of Vo2 regardless of the mode of contraction in a given left ventricle with a stable inotropic background.
Abstract: Pulmonary edema fluid and serum samples were obtained from 20 patients with cardiac and noncardiac pulmonary edema, and total protein, albumin, and globulin concentrations were measured. The mean edema fluid to serum protein ratio in patients with pure cardiogenic pulmonary edema was 0.37 +/- 0.09. In contrast, the patients with pure noncardiogenic pulmonary edema had protein ratios of 0.84 +/- 0.12 (p less than 0.001). Another group of patients with both cardiac and noncardiac causes for edema demonstrated edema fluid to serum protein ratios that were significantly higher than those found in the cardiogenic patients and lower than the protein ratios in the noncardiogenic patients (0.60 +/- 0.07) (p less than 0.01) A cardiac or noncardiac causes of pulmonary edema could be determined in all patients, using edema fluid to serum total protein ratios in conjunction with globulin ratios. Cardiogenic and noncardiogenic pulmonary edema represent the extremes in the spectrum of pulmonary edema. A combination of increased permeability and hydrostatic pressure may account for an intermediate form of pulmonary edema.
Abstract: 1. Five males were studied on three occasions, after oral administration of CaCO3 (control), NH4Cl (acidosis) and NaHCO3 (alkalosis), in a dose of 0.3 g/kg, taken over a 3 h period at rest. The subjects then exercised on a cycle ergometer for 20 min at 33% maximal oxygen uptake (VO2 max.), followed by 20 min at 66% and at 95% VO2 max. until exhaustion. 2. Endurance at 95% VO2 max. was longest with alkalosis (5.44 +/- 1.05 min), shortest with acidosis (3.13 +/- 0.97 min) and intermediate in the control study (4.56 +/- 1.31 min); venous blood pH at exhaustion was 7.33 +/- 0.02 (mean +/- 1 SEM), 7.13 +/- 0.02 and 7.26 +/- 0.02 respectively. 3. Concentrations of plasma lactate at exhaustion were 7.10 +/- 0.8 mmol/1 4.0 +/- 0.5 and 7.9 +/- 0.9 mmol/l in the control, acidosis and alkalosis studies respectively. 4. Muscle lactate increased most from rest to exhaustion with alkalosis to 17.1 +/- 2.5 mumol/g and least with acidosis to 12.2 +/- 1.4 mumol/g. Muscle glycogen depletion was comparable in control and alkalosis studies. 5. The lower plasma lactate concentration during exercise in acidosis compared with control and alkalosis appears to be due to an inhibition of muscle glycolysis combined with a reduction in lactate efflux from muscle.
Abstract: A 16-month-old girl suffered low-voltage electrocution from a hairdryer while playing in the bathtub. At exploratory laparotomy about 18 hours postinjury because of distention and persistent, unexplained acidosis, a 1.5-cm diameter necrotic lesion in the terminal ileum surrounded by multiple superficial serosal burns and a 1.5 x 1.0 cm eschar in the mid-transverse colon were found. The lesion in the small intestine was resected with wide margins and the colon lesion exteriorized. The child ultimately expired 12 hours after surgery from recurrent cardiac arrest. Abdominal visceral injury associated with major electrical injury is reviewed. Although the colon is probably the most frequently injured, the esophagus, pancreas, gallbladder, and small intestine have also been reported as directly injured by electric current. The importance of meticulous examination of the abdominal contents at laparotomy is stressed. Lesions of the small intestine should be resected with wide margins when possible and lesions of the colon resected with a colostomy of the injured segment exteriorized.
Abstract: In anesthetized and deafferented rabbits, rhythmic and static contractions of the hindlimb muscles were elicited by stimulating the femoral nerve at 3 and 100 Hz with the intensity of 2.0-2.5 times threshold for the motor fibers. Rhythmic contractions caused a decrease in systemic blood pressure, heart rate, and vascular resistance of the resting hindlimb with hyperpnea. Tetanic contractions caused a rise in arterial pressure, in vascular resistance of the nonexercising hindlimb, and in pulmonary ventilation with small increases in heart rate. These responses were not obtained after sectioning the somatic nerves of the exercised limb or when the cut central end of the femoral nerve or the intact nerve in curarized animals was stimulated with the same intensity of 2.0-2.5 times the motor threshold. Both depressor and pressor responses were, therefore, reflexes initiated in the contracting limbs. Removal of the skin from the exercising limb did not change the typical patterns of response. The most likely source of the observed reflexes is that from receptors activated by metabolites released in the exercising muscles.
Abstract: Twenty-four hr glucose and hormonal monitoring was conducted in 34 randomly selected children with insulin dependent diabetes. Asymptomatic nocturnal hypoglycemia was present in 18% (6/34). The nocturnal plasma glucose decline of 20-25 mg/dl/hr reached a mean nadir of 50 mg/dl. The mean rebound hyperglycemia of 300 mg/dl over the subsequent 6.4 hrs. was significantly greater than any glucose excursion in diabetic children with daytime, symptomatic hypoglycemia (n = 5) or in those with non-hypoglycemic profiles (n = 23). Coincident with the nocturnal decline, but preceding the glucose nadir, was a marked release of growth hormone which was significantly greater (p less than .05) than that observed in the other diabetic groups. This release of growth hormone, and the nocturnal hypoglycemia, were reflected in the ratio of awake/sleep mean concentrations of glucose and growth hormone. These data support the speculation that growth hormone release contribute to the hyperglycemic rebound observed. Mean 24 hr growth hormone concentrations varied considerably from patient to patient such that a generalization for growth hormone concentrations in insulin dependent diabetes cannot be made. Asymptomatic nocturnal hypoglycemia is a frequent complication of the therapy of insulin dependent diabetes. Subsequent hyperglycemic rebound (the "Somogyi Effect") is associated with exuberant counterregulatory release of growth hormone. The precise pathophysiological role of this growth hormone release is unclear.
Abstract: The renal interstitial space analyzed as "inulin space" comprises about 13% in the rat. The Starling forces of this compartment are governed by the balance between tubular and capillary fluid transport and also by the leakage of plasma proteins from the blood side. Protein transport will occur in a large-pore system in the peritubular capillary membrane. During control antidiuresis, the interstitial hydrostatic pressure is 2-4 mmHg. The colloid osmotic pressure shows a larger variability but is generally about 5 mmHg. During conditions of depressed capillary reabsorption but unchanged tubular reabsorption, as in saline expansion, the interstitial hydrostatic pressure rises 3-4 times, whereas the colloid osmotic pressure will show a steep fall resulting from the increased fluid entry and unchanged protein transport. The interstitial volume increases only slightly, since it is compressed by the expanding tubules. The influence of interstitial physical forces on tubular transport remains unclear, mainly due to the inaccessibility of the lateral interspaces to direct measurement of relevant parameters.
Abstract: The morphological, functional, and biochemical properties of freshly isolated heart muscle cells were examined. A reproducible method for the separation and purification of such cells isolated from adult rat heart was developed. It yields an average of 5 X 10(6) striated rectangular cells which retain normal morphology (range 2.5 to 11 X 10(6) and 4 X 10(6) calcium-tolerant cells (range 2.5 to 5.5 X 10(6) per heart. After purification, 85 to 95% of the cells retain normal morphology in solutions of calcium ion activity equal to 10 microM, and 65 to 79% of the cells are rectangular in solutions of calcium ion activity equal to 1 mM. Under the light microscope we were able to identify functionally intact individual cells that are calcium-tolerant and contract only in response to electrical stimulations, as well as dying myocytes that beat spontaneously. The examination of such cells under the electron microscope permitted us to address the question: What is the sequence of structural changes in a dying cell? The sarcomere lengths measured both in the living state and after preparation for electron microscopy are in the physiological range. In steady states of oxygen tension, respiration of the intact cells is undiminished from 50 torr to 2 torr. The oxygen tension for half maximal respiration is 0.15 torr. Therefore, the limitation of oxygen diffusion to the mitochondria of isolated heart muscle cells must be remarkably small.
Abstract: The cardiovascular responses elicited by dobutamine are distinctly different from those produced by other adrenergic or dopaminergic agonists. To test the hypothesis that dobutamine could have differential affinities for adrenergic receptor subtypes, and that such subtype selectivity could be related to its relatively unique pharmacologic properties, we assessed the ability of dobutamine to displace adrenergic radioligands from membrane receptors in a number of tissues of previously characterized adrenergic receptor subtype. For beta adrenergic receptors identified by (-) [(3)H]dihydroalprenolol (DHA), dobutamine had significantly greater affinity for the beta(1) subtype (K(D) = 2.5 muM in rat heart and 2.6 muM in turkey erythrocyte) than for the beta(2) subtype (K(D) = 14.8 muM in frog heart and 25.4 muM in rat lung) (P \textless 0.001). For alpha adrenergic receptors, dobutamine had markedly greater affinity for the alpha(1)-subtype identified by [(3)H]prazosin (K(D) = 0.09 muM in rat heart and 0.14 muM in rabbit uterus) than for the alpha(2)-subtype identified by [(3)H]dihydroergocryptine (DHE) (K(D) = 9.3 muM in human platelet) or by [(3)H]yohimbine (K(D) = 5.7 muM in rabbit uterus) (P \textless 0.001). Like other beta(1)-agonists, in the absence of guanine nucleotide, dobutamine competition curves for DHA binding in rat heart demonstrated two classes of binding sites, with one site of significantly higher affinity (K(D) = 0.5 muM, P = 0.008) than the single class of binding sites (K(D) = 5.2 muM) identified in the presence of guanine nucleotide. However, unlike beta(2)- or alpha(2)-agonists, dobutamine displacement of DHA binding in rat lung or of DHE binding in human platelets demonstrated only a single class of binding sites, and guanine nucleotide had only minimal effects. We conclude that dobutamine is selective for beta(1) as opposed to beta(2), and for alpha(1) as opposed to alpha(2) adrenergic receptors. Furthermore, guanine nucleotide effects on dobutamine binding, and biochemical response data in vitro suggest that dobutamine is a beta(1)-agonist, but has little intrinsic activity at beta(2) and alpha(2)-receptors. This selectivity for adrenergic receptor subtypes may be part of the basis for dobutamine’s distinctive pharmacologic properties in vivo.
Abstract: Sodium absorption and K secretion were measured in isolated perfused rabbit cortical collecting tubules. To increase the range of transport rates some tubules were dissected from rabbit pretreated with DOcA. K secretin was unaffected by varying axial volume flow from 4 to 15 nl/min. K secretion was, however, correlated with transepithelial voltage and Na absorption. The Na:K transfer ratio was 1.35. In tubules dissected from normal rabbits, K secretion was almost eliminated by reducing Na concentration in the lumen to near 0 and was unaffected by varying luminal Na concentration from 30 to 145 mM. These data, together with other experimental results reported by several investigators, are consistent with a model for K secretion that places the rate-limiting step at the Na-K pump located on the basolateral membrane. The apical (luminal) membrane appears to be highly permeable to K.
Abstract: Recordings of multiunit sympathetic activity were made in muscle branches of the peroneal nerve in 22 healthy subjects at rest in recumbent position. Nerve activity was quantitated in terms of burst incidence (number of pulse synchronous sympathetic bursts per 100 heart beats or per min). In a separate session, 4-45 months later, blood was drawn from an antecubital vein for noradrenaline analysis. Both sympathetic activity and plasma concentrations of noradrenaline varied widely between subjects and both parameters increased with age. There was a significant positive correlation between a subject’s level of sympathetic activity and his plasma concentration of noradrenaline. It is suggested that overflow of transmitter from sympathetic terminals in muscles contributes significantly to plasma levels of noradrenaline at rest.
Abstract: The purpose of this study was to determine if there is an interaction between carotid baroreceptors (CBR) and cardiopulmonary receptors with vagal afferents (CPVA) in the control of plasma vasopressin (ADH). Changes in ADH (radioimmunoassay) in the superior vena cava were determined in 13 chloralose-anesthetized dogs with aortic nerves sectioned during concomitantly induced changes in CBR and CPVA input. CBR input was changed by altering pressure (CSP) in the isolated perfused sinuses. Carotid sinus pressure (CSP) was initially set at 50 mmHg. The CPVA input was reversibly interrupted by cooling the vagi to 0 degrees C while CSP was concomitantly increased to 135 or 200 mmHg or was held constant at 50 mmHg. Vagal cold block (VCB) with CSP held constant at 50 mmHg resulted in large increases in arterial pressure and plasma vasopressin. Increases in CSP to 200 mmHg resulted in significant decreases in arterial pressure and in plasma vasopressin despite concomitant VCB. VCB and concomitant increase in CSP to 135 mmHg resulted in a significant fall in arterial pressure, whereas plasma vasopressin tended to increase. Thus, the influence on arterial pressure of raising CSP to 135 mmHg exceeds that of VCB. In contrast, the influence of VCB on ADH equals or exceeds that of raising CSP to 135 mmHg. These differential responses of arterial pressure and plasma ADH suggest an interaction between CBR and CPVA in the control of ADH and arterial pressure.
Abstract: The diagnoses provided by a standard indirect test of vasopressin function were compared with those obtained by radioimmunoassay of plasma vasopressin in 24 patients with nonglucosuric polyuria. All seven cases of severe neurogenic diabetes insipidus diagnosed by the indirect tests were confirmed by the vasopressin assay. However, two of six patients with partial neurogenic diabetes insipidus by indirect criteria had normal vasopressin secretion by the direct assay; one was found to have primary polydipsia, and the other nephrogenic diabetes insipidus. Moreover, three of 10 patients diagnosed as having primary polydipsia by the indirect test had clear evidence of partial vasopressin deficiency by the direct assay. The inability of the indirect test to distinguish accurately between partial neurogenic diabetes insipidus and primary polydipsia may be explained by increased sensitivity to low concentrations of vasopressin in the former disorder and a reduction of maximal concentrating ability in both. We conclude that the incorporation of a vasopressin assay improves accuracy in the differential diagnosis of polyuria.
Abstract: The loss of 18O from labeled CO2 caused by the exchange of oxygen with water, a process catalyzed by carbonic anhydrase, has been measured in suspensions of rat erythrocytes at pH 7.4 and 25 percent C. The rate of loss of 18O from all CO2 and the rate of loss of 18O from doubly-labeled CO2 are shown to be related to the rate constant for the catalyzed hydration of CO2 inside the cell and a rate constant for the diffusion of CO2 out of the cell. The results show that the diffusion of CO2 out of the cell with a half-time near 2 msec is a slower process than the intracellular, catalytic conversion of CO2 to HCO3- which has a half-time near 0.3 msec. From this information we estimate the gradient of 18O content in CO2 in the red cell during an 18O-exchange experiment. The rate constant for the entry of CO2 into red cells, also obtained from 18O-exchange data, has a value of the same magnitude as that anticipated for the diffusion-controlled rate of encounter between CO2 and red cells. This indication of diffusion-controlled depletion of 18O from Co2 is supported by experiments with a carbonic anhydrase inhibitor which show that carbonic anhydrase does not have a rate-limiting role in the 18O exchange until greater than 80% of the enzyme is inhibited.
Abstract: The plasma potassium concentration is determined both by external potassium balance and by the distribution of potassium between extracellular and intracellular fluid compartments, i.e., "internal potassium balance." Whenever external potassium balance is altered, the resultant change in the plasma potassium concentration is strongly influenced by concomitant alterations in internal potassium balance. Several factors alter internal potassium balance independently of changes in external balance. Acid-base disturbances produce shifts of potassium into or out of cells, but attempts to quantify these effects are not likely to be clinically useful. Hypertonicity produces a shift of potassium out of cells. Several hormones (insulin, aldosterone, catecholamines, glucagon, and growth hormone) may have roles in internal potassium balance. Digitalis and succinylcholine, by producing efflux of potassium from cells, may cause hyperkalemia. Potassium is released from skeletal muscle during exercise, causing an increase in the plasma potassium concentration. The periodic paralyses are associated with well-defined transient alterations in internal potassium balance.
Abstract: Patients with high-normal or above-normal haematocrit were found to have impaired alertness when compared with a control group matched for age and occupation. On retesting the controls had improved alertness scores attributable to a practice effect; but the patients, when retested after reduction of haematocrit by venesection, had improved significantly more than the controls. Improvement in alertness correlated very well with the increase in cerebral blood flow which followed venesection. Levels of venous haematocrit that are generally accepted as normal may not necessarily be optimum.
Abstract: Cerebral blood flow was measured before and after venesection in 6 patients with chronic obstructive pulmonary disease and secondary polycythemia. The hematocrit was decreased from a mean of 59.6 to 43.9%, and whole blood viscosity was decreased by 35%. The supratentorial blood flow increased 78.2% (p \textless 0.005) after venesection; subtentorial flow also increased, but not significantly. The improvement in cerebral blood flow appeared to be related to a decrease in blood viscosity, because pulmonary function and arterial blood gases did not change significantly. There was subjective improvement in all patients, and this improvement might have been due to the increased supratentorial blood flow.
Abstract: An attempt was made to determine if emphysema and static lung recoil were related in a group of 65 excised human lungs. We studied 23 normal lungs, 24 lungs with an emphysema score of 5 or less, and 18 lungs with an emphysema score greater than 5. A comparison of the percentage of predicted elastic recoil revealed that both emphysema groups were significantly different from normal lungs. In addition, the total lung capacities were significantly different between the three groups. In the group with an emphysema score greater than 5 we found a linear negative correlation between the extent of emphysema and percent of predicted elastic recoil at 90% total lung capacity (r = -0.696, p \textless 0.01). We found a negative correlation between the percentage of predicted elastic recoil and the lung volume (r = -0.612, p \textless 0.01). We conclude that a significant loss of elastic recoil and a significant increase in total lung capacity occurs in the early stages of emphysema.
Abstract: We reported previously that chronic administration of hydrocortisone to normal developing mice increases the brain glucose content and cerebral energy reserve. The present report concerns possible mechanisms of this action. Increases in brain glucose (and glycogen) levels were not due to reduction of cerebral metabolic rate, and the effect of hydrocortisone in facilitating transport of hexose from blood to brain was not impressive. Chronic hydrocortisone treatment induced increases in the activities of brain glycerophosphate dehydrogenase and pyruvate carboxylase in vivo; there was no effect on eleven other enzymes of brain glucose and glycogen metabolism. In normal nursing mice, hydrocortisone produced consistent elevations in plasma beta-hydroxybutyrate (and glycerol) levels. Brain beta-hydroxybutyrate levels were also increased. Therefore, the brain glucose concentration may be elevated in these animals because of the availability of an increased supply of ketone bodies as alternative substrates for cerebral oxidative metabolism and biosynthesis. Ketonemia, elevated cerebral glucose and beta-hydroxybutyrate concentrations, and increased glycerophosphate dehydrogenase activity in brain suggest possible explanations for the beneficial action of adrenocorticotropic hormone and glucocorticoids in the treatment of infantile myoclonic epilepsy and other neurological disorders.
Abstract: Regional cerebral blood flow (rCBF) was measured by 133Xe inhalation in 17 patients with chronic spinal cord transection. This was done to investigate any effects such spinal cord deafferentation might have on resting rCBF and to test whether resulting chronic preganglionic sympathectomy influenced cerebral vasomotor CO2 responsiveness and autoregulation. Thirteen patients had complete cervical cord transection (CCT) at levels C4–C6 (age 37 +/- 15 years, time interval, 2 months–20 years). Four patients had complete thoracic cord transection at levels T3–4, T8 and T12 (TCT; age 49 +/- 22 years; time interval 2–5 months). CO2 responsiveness was tested by induced hypercapnia in 11 patients with CCT and 2 patients with TCT. Autoregulation was tested in 10 patients with CCT and 4 patients with TCT by decreasing cerebral perfusion pressure during postural tilting. Mean resting hemispheric Fg values (MHFg) were significantly reduced only in patients with CCT (MHFg = 69 +/- 12 ml/100 g brain/min), while brain stem-cerebellar Fg values (BSC Fg) were reduced significantly both in patients with CCT (BSC Fg = 85 +/- 10) and with TCT (BSC Fg = 88 +/- 12) compared to values measured in healthy normals (N = 21, MHFg = 81 +/- 10, BSC Fg = 98 +/- 10). Hemispheric CO2 responsiveness showed a trend toward reduction in patients with CCT but this was not statistically significant. Hemispheric autoregulation was significantly impaired in CCT compared to healthy normals but improved with time and rehabilitation.
Abstract: We present the results of our investigation of 220 electrocutions. The ratio of high voltage to low voltage electrocution is found to be nearly 1:1. Further, in low voltage electrocution deaths electrical burns were absent in over 40% of the cases. Our approach to the investigation of possible electrocution, including equipment analysis, is discussed.
Abstract: Plasma dopamine is present in free form in a concentration approximately equivalent to that of epinephrine and about 25% that of norepinephrine. It originates in a variety of tissues including sympathetic nerves and adrenal, and the percentage originating from the various sources remains unknown. Events that are associated with increases in sympathetic activity such as stress, exercise, standing, or hypovolemia are associated with increases in plasma dopamine concentration, although the responses may be of considerably smaller magnitude than those for plasma norepinephrine and epinephrine. The functional importance of dopamine in the periphery and of changes in circulating dopamine remain only poorly defined. These include possible roles in neurotransmission in sympathetic ganglia, altering renal vascular bed, modulation of aldosterone secretion and sodium excretion, mediation of certain stress responses, and others yet to be revealed.
Abstract: Individual pharmacokinetic par parameters quantify the pharmacokinetics of an individual, while population pharmacokinetic parameters quantify population mean kinetics, interindividual variability, and residual intraindividual variability plus measurement error. Individual pharmacokinetics are estimated by fitting individual data to a pharmacokinetic model. Population pharmacokinetic parameters are estimated either by fitting all individual’s data together as though there was no individual kinetic differences (the naive pooled data approach), or by fitting each individual’s data separately, and then combining the individual parameter estimates (the two-stage approach). A third approach, NONMEM, takes a middle course between these, and avoids shortcomings of each of them. A data set consisting of 124 steady-state phenytoin concentration-dosage pairs from 49 patients, obtained in the routine course of their therapy, was analyzed by each method. The resulting population parameter estimates differ considerably (population mean Km, for example, is estimated as 1.57, 5.36, and 4.44 micrograms/ml by the naive pooled data, two-stage, and NONMEN approaches, respectively). Simulations of the data were analyzed to investigate these differences. The simulations indicate that the pooled data approach fails to estimate variabilities and produces imprecise estimates of mean kinetics. The two-stage approach produces good estimates of mean kinetics, but biased and imprecise estimates of interindividual variability. NONMEN produces accurate and precise estimates of all parameters, and also reasonable confidence intervals for them. This performance is exactly what is expected from theoretical considerations and provides empirical support for the use of NONMEM when estimating population pharmacokinetics from routine type patient data.
Abstract: The effects of intravenous infusion of hypertonic NaCl, sucrose, glucose, urea, or isotonic NaCl solution on thirst and plasma arginine vasopressin concentration (AVP) were studied in five conscious dogs. The changes in osmolality and sodium concentration of plasma and cerebrospinal fluid (CSF) were measured at the threshold of drinking, or after 45 min if no drinking occurred. Hypertonic NaCl and sucrose stimulated drinking in all dogs and significantly elevated plasma AVP. Equally hypertonic glucose, urea, or isotonic NaCl failed to stimulate any drinking or vasopressin secretion. All hypertonic solutions caused significant and similar increases in the osmolality and sodium concentration of CSF. Plasma osmolality was increased by the hypertonic solutions. Plasma sodium was increased by hypertonic NaCl, decreased by sucrose and glucose, and not changed by urea. Isotonic NaCl had no effect on either plasma or CSF composition. These data are not consistent with either a sodium or an osmoreceptor mechanism located within the blood-brain barrier (BBB) or with a peripheral sodium receptor mechanism. An intracranial osmoreceptor located on the blood side of the BBB is proposed to explain these results.
Abstract: The primacy of angiotensin II as the mediator of the adrenal’s response to sodium restriction is controversial. We administered the oral converting enzyme inhibitor, captopril (SQ 14225), to test whether reduction of angiotension II generation for 26 h in sodium-restricted subjects would lower plasma aldosterone levels to values observed in subjects on a high sodium intake. Accordingly, plasma angiotensin II and aldosterone levels were measured in nine recumbent normal subjects on high (200 meq) and low (10 meq) sodium intakes and low sodium intake with captopril (12.5–25 mg four times a day for 26 h). Captopril reduced the sodium-restricted angiotensin II levels from 31 +/- 6 to 13 +/- 2 pg/ml, which was indistinguishable from that measured on the high sodium intake (11 +/- 2 pg/ml). Concomitantly, aldosterone levels were reduced from 25 +/- 4 to 7 +/- 1 ng/dl, which was similar to the high sodium value (8 +/- 1 ng/dl). There were no significant changes in serum sodium, cortisol, or potassium at the three sampling times. Thus, the complete suppression of the sodium-restricted levels of both angiotensin II and aldosterone into the high sodium range by captopril provides strong support for the hypothesis that the renin-angiotensin system is the prime mediator of the adrenal’s response to sodium restriction.
Abstract: The pressure-volume index (PVI) technique was used to measure neural axis compliance, cerebrospinal fluid (CSF) formation (If), and CSF absorption (Ro) in 23 children and 7 adults, all free from intracranial masses, who were undergoing diagnostic or therapeutic procedures. Using bolus manipulation of CSF, If was 0.36 +/- 0.08 ml/min and Ro was 2.8 +/- 0.8 mm Hg/ml/min in both adults and children. PVI, as a measure of neural axis compliance or volume buffering capacity, was 25.9 +/- 3.7 ml for the adults. Measured PVI in the children varied from 8.2 to 30.1 ml but correlated well (r = 0.93) with predicted PVI based on estimates of intracranial and spinal volumes obtained from external measurements. This study provides normal reference data in humans for assessing CSF hydrodynamics and neural axis compliance using the PVI technique in pathological settings.
Abstract: Freeze-fracture and thin-section electron microscopy and morphometry were used to characterize further the response of the rat medullary collecting duct to potassium depletion. In freeze-fracture replicas, principal cells and intercalated cells were identified based on the assumption that intercalated cells possess a high density of rod-shaped intramembrane particles in their luminal membranes. Potassium depletion caused an increase in the relative number of cells with a high density of rod-shaped particles from the control level of 22% to 31% after 2 weeks and to 36% after 4 weeks. The frequency of intercalated cells identified by thin-section criteria was, however, about 35% in controls and unchanged by potassium depletion. This suggests that intercalated cells can have two types of membrane morphology. In potassium depletion, all intercalated cells display a high density of rod-shaped particles in their luminal membranes. In addition, the luminal membrane area of intercalated cells increased more than threefold, and the density of their rod-shaped particles increased by 21%. These observations suggest that the intercalated cell and its rod-shaped particle may be involved with the potassium reabsorption that occurs in this nephron segment with potassium depletion.
Abstract: To determine the importance of the renin-angiotensin system in control of plasma potassium concentration and excretion, potassium control was studied in two groups of dogs in response to a 20-fold increase in sodium intake (from 10 to 200 meq/day). Group I was intact whereas group II lacked feedback control of the renin-angiotensin system, which was eliminated by continuous infusion of 10 ng . kg-1 . min-1 angiotensin II. This rate of infusion reduced endogenous plasma renin activity (PRA) to undetectable levels throughout the study. The sodium forcing did not result in measurable changes in plasma potassium concentration or excretion in group I, in which PRA fell to 40% and plasma aldosterone concentration (PAC) to 60% of the low sodium levels. In group II the same sodium forcing produced a 12% decrease in plasma potassium concentration and a 79% increase in urinary potassium excretion. PAC also fell to 60% of the low sodium level in group II. The results demonstrate the importance of the renin-angiotensin system as a link between the nephron and the zona glomerulosa that is essential in controlling plasma potassium concentration and excretion during changes in sodium balance.
Abstract: The effects of alterations of plasma osmolality on plasma arginine vasopressin (AVP) and renin activity (PRA) following graded hemorrhage were studied in conscious dogs who were either euhydrated, dehydrated, water loaded, or infused with hypertonic saline. Base-line plasma osmolality and AVP were significantly different in the four treatment groups; however, following hemorrhage the increases in log AVP did not significantly differ. An unexpected finding was that water loading resulted in significant elevations in PRA and plasma aldosterone concentrations, whereas plasma osmolality and AVP were reduced. Prior to hemorrhage, PRA was significantly greater in the water-loaded and dehydrated groups than in the euhydrated or saline-infused groups; following hemorrhage the increases in log PRA were not significantly different in all four treatment groups. The data suggest that, although alterations in osmolality influence base-line levels of AVP, they have no effect on relative (logarithmic) rises in AVP following hemorrhage. Similarly, alterations in AVP may influence base-line PRA, but do not influence relative rises in PRA following hemorrhage.
Abstract: Muscle triglycerides and glycogen were measured in biopsy specimens of the vastus lateralis muscle before and after 1 h of ergometric exercise at 50 to 60% of maximal capacity (i. e. at a pulse rate during exercise of 180 minus age) in 3 groups of 19 to 35 year old, non-obese male subjects: 10 normals, 10 insulin dependent diabetic patients in relatively good control and 10 poorly controlled insulin dependent diabetic patients in whom insulin was withdrawn 24 h prior to examination. At rest in all subjects muscle triglyceride content was positively correlated with serum triglycerides(p \textless 0.001) and blood glucose (p \textless 0.05), resulting in elevated muscle triglyceride stores in the insulin deficient diabetic patients (17.9 +/- 1.8 mumol/g protein vs. 13.4 +/- 1.3 and 9.4 +/- 1.2 in the normal subjects and the well controlled diabetic patients; p \textless 0.05 and \textless 0.001). During exercise, utilisation of muscle triglycerides and glycogen were directly related to content at rest (p \textless 0.001), including the insulin-deprived patients with decreased glycogen. The decrease of muscle fat was associated with a rise in serum glycerol (p \textless 0.001) and non-esterified fatty acids (p \textless 0.001) during exercise.
Abstract: Decreases in regional endocardial function (ultrasonic dimension technique) and blood flow (radioactive microsphere technique) were correlated in 14 conscious dogs with acute graded levels of coronary stenosis. Coronary stenosis affected overall ventricular function only slightly, but induced gradual reductions in regional blood flow (BF) and segment length (SL) shortening in the ischemic zone. The relationship was best fit by an exponential function relating % change in SL to % change in BF; i.e., SL(% delta) = -161.6 e -0.047BF(% delta) (r = 0.92). In 14 segments, where no change in function was observed, blood flow fell by 6 +/- 1%. However, 10–20% reductions of blood flow impaired function significantly. Severe reduction of blood flow was required to reduce function completely. In 12 segments exhibiting paradoxical motion, blood flow fell by 95 +/- 2%, a value greater (P \textless 0.01) than in four akinetic segments, i.e., those with no shortening or lengthening (-82 +/- 4%). These data, which show on one hand that only 10-20% reductions in blood flow impair function significantly and that, on the other hand, severe reductions in blood flow are required to abolish active shortening completely, indicate sensitive coupling between blood flow and function in the conscious dog with acute myocardial ischemia.
Abstract: 1. Captopril infused into sodium-loaded dogs produced a fall in both blood pressure [117 +/- 9.7 to 96.6 +/- 11.4 (SD) mmHg] and plasma angiotensin II [11.0 +/- 3.0 to 1.6 +/- 1.3 (SD) pmol/l]. Plasma aldosterone fell while both blood angiotensin I and renin concentration rose. 2. Angiotensin II was infused at 2, 6, 18 and 54 ng min-1 kg-1 into sodium-depleted dogs. Plasma angiotensin II and arterial pressure both rose and were related in a dose-response curve. 3. On a separate occasion the same dogs were given an intravenous infusion of captopril (6 mg h-1 kg-1) and the angiotensin II infusion was repeated. Again plasma angiotensin II and arterial pressure rose but the dose-response curve was displaced downwards; a higher concentration of angiotensin II being required to produce the same blood pressure as in the dogs not given captopril. 4. These finding suggest that the acute hypotensive effect of captopril is not wholly explained by a decrease in plasma angiotensin II concentration and the consequent reduction of its acute vasoconstrictor effect.
Abstract: 1. Forearm venous plasma noradrenaline, heart rate and intra-arterial blood pressure were measured sequentially during and after upright bicycle exercise in five normotensive and six hypertensive patients. 2. Plasma noradrenaline increased significantly between 4 and 8 min during exercise. 3. On stopping exercise blood pressure and heart rate decreased rapidly whilst plasma noradrenaline increased in each subject to reach a maximum at a median time of 108 s after exercise. 4. Plasma noradrenaline decreased in five of six normotensive patients between the end of exercise and 2 min after exercise performed in the supine position. 5. Evidence in favour of a reflex increase in sympathetic activity after upright exercise is discussed.
Abstract: After destruction, by pithing, of the central nervous system, the blood pressure (BP) of the spontaneously hypertensive (SHR) rat falls, but remains higher than in the pithed normotensive (WKY) rat. At all ages examined, stimulation of the sympathetic outflow evoked greater increases in BP of pithed SHR rats, but the increases in plasma catecholamines were similar in the two strains. The BP increase evoked by administered norepinephrine was greater in old SHR than in old WKY rats, but this increased response was not found in young animals. Both young and old SHR rats, however, were more sensitive than WKY rats to the pressor effects of epinephrine. Results of selective pharmacologic blockade of cardiac or vascular beta-adrenoceptors suggest that a smaller vasodilator response in young SHR rats to the beta-adrenergic effects of epinephrine is responsible for the greater pressor response than in WKY rats. This factor diminishes in older SHR rats in which, as suggested by Folkow, structural changes in the resistance blood vessel diameter may account for the enhanced pressor responsivity of SHR rats.
Abstract: Asystole can be the presenting ECG finding of accidental hypothermia when the core temperature is less than 28 degrees C. Even two hours of persistent asystole does not represent irreversible cardiac compromise. With cardiopulmonary support and active rewarming, resuscitation and survival without serious sequelae can be achieved. Case reports and electrophysiology studies suggest that asystole is a primary manifestation of hypothermia potentiated by carbon dioxide retention. However, ventricular fibrillation in this setting is probably a secondary complication of resuscitation efforts, being precipitated by hypocapnic alkalosis, physical manipulation of the heart, and rewarming.
Abstract: The cerebral blood flow is low in primary polycythaemia, and it has been suggested that this is due to the increase in viscosity which accompanies the elevated haematocrit. In the present study cerebral blood flow has been measured by a non-invasive 133Xenon technique in six subjects with an elevated haematocrit secondary to a haemoglobin variant with increased oxygen affinity. Flow was significantly higher than normal and 81% higher than in 11 subjects of comparable age, matched for haematocrit and viscosity, but without the haemoglobin variant. In patients with this unusual type of polycythaemia, cerebral blood flow is high despite the elevated blood viscosity and the implications of these results are discussed.
Abstract: Plasma vasopressin concentration (PAVP), renal function, and effectors of vasopressin release were evaluated in male volunteers during running at heart rates of 0, 35, 70, and 100% of maximum after 10 h abstinence from water (normal hydration) and at 100% after ingestion of 300 ml water. Plasma renin activity (PRA) and PAVP were linearly correlated and correlated to work intensity over all observations. Changes in PAVP were not correlated with changes in plasma osmolality (POSMOL) and plasma volume (PV) over all observations. Furthermore, despite similar changes in POSMOL, PV, PRA, body weight, mean arterial pressure, and plasma lactate concentration, the increase in PAVP after maximal exercise was greater during normal hydration than the water-supplemented state. Decreased urine flow observed in association with exercise was characterized by increased free water and decreased osmotic and creatinine clearances. Thus increased PAVP associated with exercise appears not to play a role in the concomitant antidiuresis. Vasopressin stimuli are probably variable at different times during exercise and may include factors other than those measured.
Abstract: The purpose of this study was to determine the mechanism of the decrease in left ventricular stroke volume during spontaneous inspiration. We determined the transmural pressures of the left heart by measuring left atrial and diastolic left ventricular pressures relative to esophageal pressure. We estimated the directional changes in end-systolic and end-diastolic volumes of the left ventricle by determining the transit time of sound transmission between two ultrasonic crystals facing each other across the minor axis of the left ventricle. Left ventricular stroke volume decreased with spontaneous inspiratory effort as pleural pressure fell, regardless of whether lung volume increased or remained constant. The stroke volume was decreased during the fall in pleural pressure because of an increase in end-systolic volume with an essentially unchanged diastolic volume. Thus, the decrease in stroke volume was due to a decrease in ejection, rather than a decrease in filling of the left ventricle. We believe that left ventricular ejection was impeded by the fall in pressure around the heart relative to the pressure in the aorta. In spite of the essentially constant diastolic volume, diastolic left ventricular transmural pressure rose, suggesting that spontaneous inspiration decreases the diastolic compliance of the left ventricle. The change in diastolic compliance contributed to the decrease in stroke volume but was not the primary cause.
Abstract: A little bit of RISA (0.01–0.02 ML) was injected into a lymphatic at the back of a human foot in supine and/or sitting position, and the radioactivity curves were obtained at the inguinal and/or at the middle of the thigh. Radioactivity curves at the inguinal region showed stepwise rise with the frequency of about 1/min. in subjects without edema and steep rise without staircase in patients with cardiac edema. Radioactivity curves at the middle of the thigh showed many spiky waves with the frequency of about 1/min. in supine subjects without edema, which were increased in frequency, duration and/or height in sitting subjects without edema and also in supine and sitting patients with cardiac edema. Therefore, it may be said that there are rhythmic lymph flows in lower leg of subjects without edema and of patients with cardiac edema not only in supine but also in sitting position, and also that lymphatic contractility plays some role in propelling lymph in human leg.
Abstract: Concentrations of the antidiuretic hormone, arginine vasopressin, were measured in 28 patients with severe hyperglycemia to determine if abnormalities in hormonal regulation of water excretion could contribute to the extreme dehydration of uncontrolled diabetes mellitus. Vasopressin levels were markedly elevated in both nonketotic and ketotic patients, indicating that vasopressin deficiency plays no role in the polyuria that accompanies hyperglycemia. Instead, the observed increases in vasopressin represent an ineffective effort to conserve water in the face of an overwhelming solute diuresis caused by the glucosuria. The reasons for such marked elevations in plasma vasopressin in these diabetic patients are multifactorial. Both groups of diabetic patients had evidence of hypovolemia, which was sufficient in magnitude to stimulate vasopressin release. Furthermore, nausea provided an independent stimulus to vasopressin secretion in many patients. Osmotic stimulation might have resulted from the large fraction of unidentified plasma solutes, but this factor alone was not sufficient to explain the markedly increased concentrations of vasopressin. Whether such elevations in vasopressin could have metabolic and/or hemodynamic effects in uncrontrolled diabetes remains to be established.
Abstract: Pulmonary edema is common cause of acute respiratory failure and can be seen in not only cardiac but also noncardiac diseases. The pathophysiologic mechanism for the development of acute pulmonary edema in any clinical situation can usually be explained alterations in the forces governing the transvascular flux of fluid in the pulmonary microvasculature, according to the Starling equation. "Cardiac" pulmonary edema is primarily due to an increase in the capillary hydrostatic pressure of sufficient magnitude to overcome the forces maintaining fluid within the vessel and the ability of the lymphatics to drain the transudated fluid. On the other hand, pulmonary edema occurring in association with noncardiac disease (e.g., sepsis, aspiration or shock) is secondary to an increase in the permeability of the pulmonary microvasculature and is referred to as noncardiogenic pulmonary edema or the adult respiratory distress syndrome. This article examines the mechanisms for the development of pulmonary edema and discusses the differences between the cardiac and noncardiac types.
Abstract: Several aspects of lipid metabolism in the soleus and diaphragm muscles of streptozotocin-diabetic and control rats were investigated. The triglyceride content of both muscles was elevated in the diabetic state and the presence of increased intracellular lipid was confirmed by electron microscopy. In vitro glucose and palmitate oxidation studies showed that both types of muscle from the diabetic animals metabolized more fat than did the soleus and diaphragm from control rats. While isoproterenol alone produced a significant lipolytic response in both the soleus and diaphragm from control and diabetic animals, there was no difference in the percent increase in fatty acids released from muscles of diabetic rats compared to controls. However, the absolute difference was greater when the diaphragms were compared. Muscles from experimental and control animals showed a marked reduction in the amount of free fatty acids released in response to insulin. In addition, in the presence of the hormone, both the absolute and percent isoproterenol-stimulated increases in fatty acids were significantly greater for both diaphragm and soleus muscles from diabetic rats. The effects of insulin, isoproterenol, and the combination of these two hormones on the amount of glycerol released into the incubation medium were similar to those found on free fatty acid release. The results of these experiments show that there is an apparent increase in fat utilization in skeletal muscle of diabetic rats. Furthermore, measurements of triglyceride concentration and the enhanced response to isoproterenol stimulation in the muscles from these animals suggests that they may have an increased capacity for mobilization of intracellular lipids. Finally, in the diabetic state, both the soleus and diaphragm appear to demonstrate an increased response to the antilipolytic effect of insulin as measured by the decreased amount of fatty acid released into the incubation medium, the percent change also being significant for the soleus muscle.-Stearns, S. B., H. M. Tepperman, and J. Tepperman. Studies on the utilization and mobilization of lipid in skeletal muscles from streptozotocin-diabetic and control rats.
Abstract: A 15 year old girl presented with excessive thirst and hypertension (170/110 mm Hg). Biochemical investigations revealed serum sodium 118 meq/liter, serum osmolality 238 mosmol/liter, urine sodium 90 meq/liter, urine osmolality 700 mosmol/liter, persistenly elevated serum antidiuretic hormone (ADH) levels (5.8 to 11.9 pg/ml) and no obvious cause for the hypertension. The hypertension is, at least in part, volume-related, diminishing with fluid restriction. Features of gross water intoxication (e.g., confusion, coma) have not occurred. The etiology of the inappropriate secretion of ADH is not obvious but is not thought to be due to "resetting of osmoreceptors" as evidenced by failure to maximally dilute urine following a water load test and persistently elevated serum ADH levels. A similar patient described by Epstein and associates in 1962 is presently well with persistent features of inappropriate secretion of ADH.
Abstract: Hill’s equation can be slightly modified to fit the standard human blood O2 dissociation curve to within plus or minus 0.0055 fractional saturation (S) from O less than S less than 1. Other modifications of Hill’s equation may be used to compute Po2 (Torr) from S (Eq. 2), and the temperature coefficient of Po2 (Eq. 3). Variations of the Bohr coefficient with Po2 are given by Eq. 4. S = (((Po2(3) + 150 Po2)(-1) x 23,400) + 1)(-1) (1) In Po2 = 0.385 In (S-1 - 1)(-1) + 3.32 - (72 S)(-1) - 0.17(S6) (2) DELTA In Po2/delta T = 0.058 ((0.243 X Po2/100)(3.88) + 1)(-1) + 0.013 (3) delta In Po2/delta pH = (Po2/26.6)(0.184) - 2.2 (4) Procedures are described to determine Po2 and S of blood iteratively after extraction or addition of a defined amount of O2 and to compute P50 of blood from a single sample after measuring Po2, pH, and S.
Abstract: Physiological levels of arginine vasopressin (AVP) were continuously infused 24 h/day into six dogs for periods ranging from 7 to 34 days. The acute and chronic responses of the mean arterial pressure (MAP), body fluid volumes, renal function indices, plasma electrolyte concentrations, plasma renin activity, and urinary electrolyte and water excretion rates were measured. MAP was unaffected acutely but rose significantly to a peak on day 9 before declining toward control. MAP was significantly and positively correlated with the plasma volume, but had a diphasic correlation with the plasma sodium concentration and the change in total body sodium. The plasma sodium concentration reached a relatively stable plateau that was maintained in spite of large changes in total body water. We conclude that AVP produces only a transient hypervolemic hypertension; that AVP is a natriuretic agent, either directly or indirectly, both acutely and chronically; and that chronically it is a more potent controller of the plasma sodium concentration than of the total body water except in extreme cases.
Abstract: Tubuloglomerular feedback has been defined as a mechanism in which changes in distal tubular sodium chloride delivery induce changes in glomerular arteriolar resistance. Experiments were performed in rats to test the hypothesis that the alterations in vasomotor activity are controlled by local hormonal mechanisms. Early proximal flow rate (EPFR), used as an index of filtration rate, was assessed at loop perfusion rates of 10 and 40 nl/min and during zero loop flow before and during intravenous administration of agents which interfere with the reninangiotensin or adrenergic systems. During infusion of the angiotensin (A) antagonists [Sar1,Ile8-]-AII or [Me2,Gly1,Ile8]-AII at doses ranging from 4.8 to 30.6 micrograms/kg . min, feedback response, expressed as percent change of EPFR during loop flow elevation from 3 to 40 nl/min, fell from a mean of 47.6 +/- 3.3% to 33.2 +/- 2.9% (P less than 0.05). Likewise, after administration of the converting enzyme inhibitor SQ 20881 in a dose ranging between 5.5 and 34.0 mg/kg, feedback response decreased from 48.5 +/- 2.1% to 25.9 +/- 1.9% (P less than 0.001) and returned to 43.1 +/- 5.1% after the inhibitory effect of SQ 20881 on the pressure response to angiotensin I had disappeared. Luminal application of [Sar1,Thr2]-AII (5mM) or of SQ 20881 (5 or 10 mM) had no effect on the feedback response. A significant reduction in the feedback response was noted also during intravenous infusion of propranolol (46.4 +/- 3.2% vs. 29.0 +/- 2.8%, P less than 0.001), whereas 6-OH-dopamine, reserpine, or phenoxybenzamine had no detectable effect. Our results are in agreement with the concept that the renin-angiotensin system may mediate feedback-induced resistance changes. In addition, circulating catecholamines may, in some unknown manner, act as modulators of the feedback response.
Abstract: The pharmacokinetics and pharmacodynamics of intravenous furosemide, 40 mg, were studied in four normal males in a crossover fashion with and without indomethacin pretreatment. In each study 16 plasma and 10 urine samples were collected over 24 hr. Fluid and electrolyte urinary losses were replaced orally throughout the study. Unchanged furosemide and indomethacin were measured using HPLC; urinary sodium was measured by flame photometry. Pretreatment with indomethacin resulted in increased and prolonged fourosemide plasma levels, increased area under the curve, decreased plasma clearance, decreased renal clearance, increased half-life, no change in volume of distribution, and decreased sodium excretion and urine volume. Analysis of sodium excretion rate with time shows that the inhibiting effect of indomethacin was greater during the first 2 hr than at later times.
Abstract: We studied the effect of alpha-adrenergic stimulation, using phenylephrine, on basal and isoproterenol-provoked renin secretion in the isolated perfused rat kidney. Infusion of phenylephrine increased renal perfusion pressure and prevented the response in renin secretion to isoproterenol. No suppression of basal secretion was observed. Renal vasoconstriction was abolished, and the response in renin secretion to isoproterenol was restored by alpha-adrenoceptor blockade with phenoxybenzamine. In contrast, when renal vasoconstriction was prevented by dihydralazine, suppression of renin release by phenylephrine still occurred. These observations support an inhibitory effect of a nonvascular alpha-adrenergic mechanism on renin release. We suggest that the alpha receptor mediating this effect is related directly to the juxtaglomerular cell.
Abstract: There is considerable evidence that the level of afferent cardiopulmonary receptor activity modulates sinus node responses to arterial baroreflex stimulation in experimental animals. We tested the hypothesis that this reflex interaction occurs also in man by measuring sinus node responses to arterial baroreceptor stimulation with phenylephrine injection or neck suction, before and during changes of central venous pressure provoked by lower body negative pressure or leg and lower trunk elevation. Variations of central venous pressure between 1.1 and 9.0 mmHg did not influence arterial baroreflex mediated bradycardia. Baroreflex sinus node responses were augmented by intravenous propranolol, but the level of responses after propranolol was comparable during the control state, lower body negative pressure, and leg and trunk elevation. Sinus node responses to very brief baroreceptor stimuli applied during the transitions of central venous pressure also were comparable in the three states. We conclude that physiological variations of central venous pressure do not influence sinus node responses to arterial baroreceptor stimulation in man.
Abstract: Mechanical energy (ENG) required by a time-varying elastance model of the ventricle was compared with oxygen consumption per beat (VO2) of the canine left ventricle contracting under a variety of loading conditions. ENG needed for this model to increase its elastance during systole is shown to be equal to the sum of the potential energy built in the elastance during systole plus the external mechanical stroke work. This ENG is equivalent to the area (PVA) bounded by the end-systolic and end-diastolic P-V curves and the systolic limb of the P-V loop trajectory in the P-V plane. There was a high correlation (r = 0.89) between VO2s documented in the literature and PVAs assessed by the author from the accompanying P-V data from both isovolumic and ejecting contractions in 11 hearts. A linear regression analysis yielded an empirical equation: VO2 (ml O2/beat) = a . PVA (mmHg . ml/beat) + b, where a = 1.37 X 10(-5) and b = 0.027, which can be used to predict VO2 from PVA. A preliminary experimental study in my laboratory confirmed the validity of this empirical equation.
Abstract: Sympathetic stimulation in pithed rats elicits increases in blood pressure (BP) and plasma levels of catecholamines. The BP is proportional to the logarithm of the plasma norepinephrine (NE) concentration. Adrenal medullectomy diminishes slightly only the initial phase of the BP responses, whereas bretylium blocks completely the BP response and diminishes by about 70% the increase in plasma NE. Adrenal medullectomy completely prevents the increase in plasma epinephrine (Epi) and diminishes by 30% plasma NE. Plasma levels of NE appear to reflect sympathetic neuronal activity, but the NE at sympathetic nerve endings is responsible for the increase in BP. Epi released from the adrenal medulla may enhance and accelerate the initial BP response, but plays only a minor role after the first 15 s.
Abstract: While the existence of an osmotic control for vasopressin (AVP) release has been long recognized, development of a sensitive immunoassay has allowed for better understanding of factors affecting the threshold and sensitivity of AVP release. Individual variation, genetic, environmental, and species differences, and the nature of the solute providing the osmotic stimuli can significantly affect the release of the hormone by altering the threshold and/or the sensitivity of the osmoreceptor. In addition to the hypothalamic osmoreceptor, AVP secretion is also controlled by an anatomically separate pathway which is responsive to nonosmotic stimuli. It appears that both low-pressure (left atrial) and high-pressure (carotid and aortic) receptors via the parasympathetic pathways provide the major nonosmotic pathway for vasopressin release. Such pathways are activated in response to acute systemic hemodynamic changes, stress, and hypoxia. The precise interaction between osmotic and nonosmotic AVP release remains to be clarified. A model of osmotic and nonosmotic interactions, based on available electrophysiologic studies, is presented and its clinical implications are discussed.
Abstract: Earlier reports indicated that arterial hypoxia not only dilated intestinal resistance vessels but also increased capillary filtration coefficients. The latter finding was interpreted as reflecting an increased number of perfused capillaries. Because both increased blood flow and increased capillary density would tend to maintain tissue oxygenation in spite of arterial hypoxia, the main purpose of this paper was to determine how effectively intestinal O2 utilization is maintained during arterial hypoxia. Therefore, I perfused isolated loops of canine small bowel at constant arterial pressure. Under this condition, reducing arterial PO2 to a mean value of 46 +/- 2.4 mmHg caused blood flow to increase to 146% of control, and O2 consumption was kept within 26% of control. In gut loops perfused at constant blood flow, arterial hypoxia depressed O2 uptake still further, but measurements of 86Rb extraction confirmed that the density of the perfused capillary bed increased. Thus, the responses of both resistance and exchange vessels tend to maintain O2 delivery to intestinal tissue during arterial hypoxia.
Abstract: Severe abnormalities of potassium balance constitute medical emergencies. Symptoms of hypokalemia are vague between 3.5 and 3.0 mEq/liter. Clinical problems can occur with the plasma potassium value lower than 2.7 mEq/liter. Hypokalemia and digitalis glycosides share electrophysiologic actions. Hypokalemia is both synergistic and potentiating for digitalis. In the presence of a normal amount of digitalis, toxicity may be prompted by coexisting hypokalemia. Hyperkalemia does not threaten life until plasma potassium values are greater than 7.0 mEq/liter. The immediate suspicion and recognition of hypokalemia or hyperkalemia in various clinical situations is imperative. Once suspected, confirmation of the diagnosis should follow immediately. Probably the single most useful diagnostic aid is the electrocardiogram, especially in critical situations with hyperkalemia. Prompt intravenous infusion of a calcium preparation, sodium bicarbonate, glucose, and insulin will provide rapid relief from serious hyperkalemia. The appropriate administration of these readily available drugs may obviate an otherwise critical situation.
Abstract: 1. Recordings of multi-unit sympathetic activity were made from median or peroneal muscle nerve fascicles in thirty-three healthy subjects, resting in recumbent position. Simultaneous recordings of intra-arterial blood pressure were made in seventeen subjects. The neural activity, quantified by counting the number of pulse synchronous sympathetic bursts in the mean voltage neurogram (burst incidence), was plotted against the arterial blood pressure level and the age of the subjects. The effects of spontaneous temporary blood pressure fluctuations were studied by correlating different pressure parameters of individual heart beats to the probability of occurrence of a sympathetic burst and to the amplitude of the occurring burst.2. Between different subjects there were marked differences in burst incidence, from less than 10 to more than 90 bursts/100 heart beats. No correlation was found to interindividual differences in the arterial blood pressure level but there was a slight tendency for increasing burst incidence with increasing age.3. Irrespective of the magnitude of the burst incidence, the bursts always occurred more frequently during spontaneous transient blood pressure reductions than during transient increases in blood pressure. When, for each heart cycle, the occurrence of a sympathetic burst was correlated with different blood pressure parameters there was regularly a close negative correlation to diastolic pressure, a low correlation to systolic and an intermediary negative correlation to mean blood pressure. There was a positive correlation to pulse pressure and to pulse interval.4. When measured for individual heart beats, not only the occurrence but also the mean voltage amplitude of the sympathetic bursts tended to increase with decreasing diastolic pressure.5. In a given subject when comparing heart beats with the same diastolic pressure, the occurrence as well as the amplitude of the sympathetic bursts was higher for heart beats occurring during falling than for heart beats occurring during rising blood pressure. For a given change in diastolic blood pressure, sympathetic activity changed more if pressure was falling than if it was rising.6. The findings suggest that the sympathetic outflow is modulated by arterial baroreflex mechanisms and that transient variations in the strength of the activity are, to a large extent, determined by diastolic blood pressure fluctuations. The intimate correlation with ;dynamic’ variations in blood pressure and the absence of correlation to the ;static’ blood pressure level suggests that the sympathetic outflow to skeletal muscles is of importance for buffering acute blood pressure changes but has little influence on the long term blood pressure level. The difference in reflex sensitivity between falling and rising pressure indicates that acute blood pressure decreases may be buffered more efficiently than acute blood pressure increases.7. In twenty-seven subjects baroreflex latency was calculated from the QRS-complexes in the e.c.g. to the appropriate systolic inhibition in the sympathetic activity. When recording in the peroneal nerve, the latency ranged between 1.16 and 1.49 sec and there was a positive correlation with the height of the subjects. It is suggested that such latency measurements may be used clinically to evaluate conduction in sympathetic fibres.
Abstract: Left ventricular pressure and segment length were measured in seven conscious chronically instrumented dogs with the pericardium intact and 3-9 days after pericardiectomy. Diastolic pressure-length plots were obtained under control conditions and after acute volume loading followed by sodium nitroprusside infusion. In all dogs with intact pericardium, volume loading displaced the entire diastolic pressure-length curve upwards and sodium nitroprusside shifted it toward control. After pericardiectomy the pressure-segment length data during control, volume loading and sodium nitroprusside fell on a single curve (intercepts and slopes not statistically different); After dextran infusion, intrapericardial pressure rose from control 1.5 +/- 0.7 mm Hg to 8.2 +/- 0.5 mm Hg, and it fell to 4.8 +/- 0.1 mm Hg after nitroprusside. Therefore, in acute cardiac dilatation the pericardium contributed significantly to the increased left ventricular diastolic pressure and to the fall during sodium nitroprusside infusion and appeared responsible for shifts in the diastolic pressure-segment length relation.
Abstract: A patient presenting with apparent pulmonary edema in whom transient, large increases in systemic arterial, pulmonary arterial, and pulmonary capillary wedge pressures occurred and spontaneously resolved within a few minutes is presented. This appears to lend support to the pressure and volume overload theory of the pathogenesis of neurogenic pulmonary edema that previously has not been demonstrated in humans.
Abstract: Nineteen patients, aged 58-80 years, with severe isolated aortic valve stenosis, severely reduced ejection fraction and clinical heart failure underwent aortic valve replacement between January 1970 and April 1977. Ten had concomitant coronary artery disease (all underwent additional coronary bypass surgery), 17 had angina pectoris and four had syncope. Aortic valve area index was 0.32 +/- 0.03 cm2/m2 (mean +/- SEM); left ventricular (LV) end-diastolic volume index was 117 +/- 9 ml/m2 and LV ejection fraction was 0.37 +/- 0.02. There were four operative deaths and one late death. The follow-up time ranged from six to 74 months (38 +/- 6 months). Actuarially determined three-year survival is 74 +/- 10%; the expected five-year survival is the same. One patient had a serious cerebrovascular accident. Of the remaining survivors, seven were initially Functional Class IV and six Class III; currently, six are Class I and seven Class II (New York Heart Association classifications). The cardiothoracic ratio has decreased from 0.54 +/- 0.03 to 0.49 +/- 0.03. Repeat hemodynamic evaluation has been performed in 10 patients, 22 +/- 6 months after surgery. In these 10 patients, the aortic valve gradient decreased from 55 +/- 7 11 +/- 1.3 mm Hg; LV end-diastolic pressure from 22 +/- 2.4 to 9 +/- 1.9 mm Hg; LV end-diastolic volume index from 119 +/- 16 ml/m2 to 107 +/- 11 ml/m2. LV ejection fraction has increased dramatically from 0.34 +/- 0.03 to 0.63 +/- 0.05 and mean velocity of circumferential fiber shortening from 0.57 +/- 0.08 to 1.3 +/- 0.18 circ/sec. The encouraging long-term survival, improved functional class and the marked improvement in left ventricular function that occurred in our patients indicate that all patients with severe aortic stenosis in clinical heart failure should be offered aortic valve replacement.
Abstract: Anesthetic indices for methoxyflurane, enflurane, and isoflurane in oxygen and halothane in nitrous oxide and oxygen (50:50), were determined in rats using measurements of heart and brain concentrations of the volatile agents at the endpoints of anesthesia, respiratory arrest and cardiac failure. The indices related respiratory arrest to anesthesia (respiratory index-A1r), cardiac failure to anesthesia (cardiac index-AIc) and respiratory arrest to cardiac failure (cardiorespiratory index-AIcr). Isoflurane had a significantly higher AIr (3.1) and AIc (5.7) than enflurane (AIr 1.8, AIc 3.3), methoxyflurane (AIr 2.2, AIc 3.7) and halothane in nitrous oxide and oxygen (AIr 2.4, AIc 3.7). These indices were also higher than those previously determined for halothane (AIr 2.3, AIc 3.0). Isoflurane had a higher AIcr (1.9) than halothane (1.6). Enflurane had a significantly lower AIr (1.8) than any of the other agents studied. These findings suggested a greater margin of safety for isoflurane, especially with respect to the heart, and a greater potential for respiratory depression for enflurane than for the other agents. Nitrous oxide decreased the amount of halothane necessary to produce anesthesia, but also that needed to produce respiratory arrest or cardiac failure. The addition of nitrous oxide, therefore, did not significantly enhance the overall safety of halothane anesthesia with respect to potential respiratory or cardiac depression.
Abstract: Impaired excretion of a water load is known to occur in adrenal insufficiency and to be corrected by administration of glucocorticoid. Such impairment has been related to either a loss of a permissive effect of glucocorticoids on the diluting segments of the nephron or to an alteration of release, turnover, or action of antidiuretic hormone. Specific and sensitive RIAs for arginine vasopressin and neurophysin were utilized to measure plasma and pituitary levels of neurohypophyseal peptides at baseline and after an intragastrically administered water load. Conscious, unanesthetized, and nonstressed sham-operated, adrenalectomized, and adrenalectomized prednisone-treated rats were studied. The results demonstrate a significant elevation in vasopressin and neurophysin in plasma in adrenalectomized rats maintained in a normal state of hydration. After water loading, the adrenalectomized rats diluted their plasma osmolality but had a decreased urinary volume, increased urinary osmolality, and elevated vasopressin and neurophysin in their plasma. In the pituitary, vasopressin and neurophysin were depleted in adrenalectomized rats, indicating increased secretion of these peptides. It is concluded that elevated vasopressin in plasma may be an important factor in the incomplete water diuresis in adrenal insufficiency.
Abstract: We determined the mechanical and metabolic effects of graded myocardial ischemia in 23 open-chest, anesthetized pigs. By connecting the midportion of the left anterior descending artery (LAD) to the carotid artery via a constant volume, calibrated pump, we reduced the flow in the LAD to 0, 25, 50, and 75% of control rates for periods of 1 h. Flows of 100% and 150% were also examined. Using pairs of ultrasonic crystals to measure segment dimensions, we calculated segment shortening and thickening, and total and systolic stroke work in the ischemic and normally perfused segments. Blood gases, pH, and lactate and inosine balances were determined from the regional coronary venous blood. At coronary blood flows of 0, 25, 50, and 75% of normal resting flow, total segment work was 8 +/- 8, 25 +/- 4, 51 +/- 5, and 80 +/- 6% of control, respectively, while systolic segment work was -2 +/- 5, -10 +/- 5, 40 +/- 5, and 86 +/- 7% of control, respectively (means +/- SE). Thus, the decrease in total segment stroke work is proportional to the decrease in flow over the range 0-100%. However, no useful work (i.e., systolic work) is done until flow exceeds 25%. Segment shortening and thickening are significantly depressed with flows diminished by only 25%. Segmental inosine production correlates with lactate production and parallels decreased mechanical performance.
Abstract: Basic physical principles and concepts plus computer-implemented numberical techniques now make possible a thorough quantitative analysis of acid-base systems. Some important conclusions from that analysis are presented: 1. Acid-base balance for physiological solutions hould be defined as the value of [OH-]/[H+]. 2. pH is a dangerously misleading indirect representation of [H+]. 3. Strong electrolytes affect [H+] and other deendent acid-base variables primarily through their resultant, the strong ion difference. 4 Hydrogen ion concentration in biological solutions is determined by the strong ion difference, the carbon dioxide partial pressure, and the total weak acid present. Changes in hydrogen ion concentration can be broght about only by changing one or more of these three independent variables. The same statements apply to all the other dependent variables, notably bicarbonate ion concentration. None of the dependent variables determines any other dependent variable, although their quantitative behaviors are necessarily correlected. 5. Solutions separated by membranes can interact in acid-base terms only by processes which alter the values of their independent variables. Interaction of intra- and extracellular acid-base balance can only occur by the cell membrane altering these independent variables in the extracellular fluid and in the cytosol.
Abstract: To determine whether norepinephrine could subserve a hormonal as well as a neurotransmitter function, norepinephrine was infused for 60 min into each of five normal young men in doses of 0.1, 0.5, 1.0, 2.5, and 5.0 microgram/min. After infusion, the plasma norepinephrine concentration fell with a mean (+/-SD) half-time of 2.4 +/- 0.7 min. The mean (+/-SD) norepinephrine metabolic clearance rate was 3,070 +/- 200 ml/min. The calculated basal plasma norepinephrine production rate was 0.7 microgram/min. The blood pressure and circulating glycerol, acetoacetate, beta-hydroxybutyrate, and glucose (increased) and the heart rate and circulating insulin, lactate, pyruvate, and alanine (decreased) exhibited highly significant parabolic relationships with the steady-state plasma norepinephrine concentrations. However, norepinephrine levels in excess of 1,800 pg/ml were required to produce hemodynamic and/or metabolic effects. Thus, under usual conditions, the biologic actions of norepinephrine can be attributed only to its sympathetic neurotransmitter function. Plasma norepinephrine concentrations do at times exceed 1,800 pg/ml during exercise and during major acute illness. Thus, under conditions of stress, norepinephrine may subserve a hormonal, as well as a neurotransmitter, function.
Abstract: The relationship between birth weight, postnatal age and acidosis-induced urinary sodium excretion was studied in 43 one-week-old newborn infants with birth weights of 1000-4300 g and gestational age of 28-41 weeks; and in 13 premature infants with birth weights of 1000-1970 g (mean 1620 g) and gestational age of 29-35 weeks (mean, 31.4 weeks) during the first six weeks of life. Developmental changes were found in acidosis-induced urinary sodium excretion. Newborns with higher birth weight and postnatal age excreted significantly more sodium in response to acidosis than their lighter and younger matches. It is suggested that the degree of acidosis must be taken into account when estimating the sodium requirement of newborn infants different in birth weight and postnatal age.
Abstract: 1. Using the mouth occlusion pressure technique, we have studied the control of breathing in seven hypercapnic and eight non-hypercapnic patients with chronic obstructive lung disease. 2. When breathing room air, pulmonary ventilation, mean inspiratory flow and P0.1 (mouth occlusion pressure developed 0.1 s after the onset of occluded inspiration at functional residual capacity) were not significantly different between the two groups of patients. Tidal volume, however, was significantly lower in the hypercapnic than in the non-hypercapnic patients, as a result of a significantly lower duration of inspiration. 3. The lower tidal volume in the hypercapnic patients leads to decreased alveolar ventilation, and appears to be the main cause of retention of carbon dioxide.
Abstract: The first aim of this study was to determine whether the plasma glucose level can regulate hepatic glucose balance in vivo independent of its effects on insulin and glucagon secretion. To accomplish this, glucose was infused into conscious dogs whose basal insulin and glucagon secretion had been replaced by exogenous intraportal insulin and glucagon infusion after somatostatin inhibition of endogenous pancreatic hormone release. The acute induction of hyperglycemia (mean increment of 121 mg/dl) in the presence of basal levels of insulin (7+/-1 muU/ml) and glucagon (76+/-3 pg/ml) resulted in a 56% decrease in net hepatic glucose production but did not cause net hepatic glucose uptake. The second aim of the study was to determine whether a decrease in the plasma glucagon level would modify the effect of glucose on the liver. The above protocol was repeated with the exception that glucagon was withdrawn (83% decrease in plasma glucagon) coincident with the induction of hyperglycemia. Under this circumstance, with the insulin level basal (7+/-1 muU/ml) and the glucagon levels reduced (16+/-2 pg/ml), hyperglycemia (mean increment of 130 mg/dl) promoted marked net hepatic glucose uptake (1.5+/-0.2 mg/kg per min) and glycogen deposition. In conclusion, (a) physiological increments in the plasma glucose concentration, independent of their effects on insulin and glucagon secretion, can significantly reduce net hepatic glucose production in vivo but at levels as high as 230 mg/dl cannot induce net hepatic glucose storage and (b) in the presence of basal insulin the ability of hyperglycemia to stimulate net hepatic glucose storage is influenced by the plasma glucagon concentration.
Abstract: The relationship between cerebral oxygen consumption (CMRO2) and anesthetic concentration has been assumed (based upon isolated measurements) to be approximately linear at concentrations less than 1 MAC. The shapes of the anesthetic dose-response curves for both CMRO2 and cerebral blood flow (CBF) were examined by multiple measurements made at small, progressive concentration increments from 0 to 2 MAC halothane (six dogs), enflurane (six dogs), and isoflurane (six dogs), and during a constant 23 mg/kg/hr infusion of thiopental (six dogs). The EEG was continuously recorded and changes in EEG patterns from "awake" to "anesthetic" were correlated with changes in anesthetic concentration, CBF, and CMRO2. The significance of changes in the slopes of regression lines for CMRO2 before, during and after changes in EEG patterns from "awake" to "anesthetic" were then determined. Contrary to previous inferences, CMRO2 dose-response curves were found to be nonlinear at anesthetic concentrations less than 1 MAC for all anesthetics studied. CMRO2 decreased precipitously until a stable "anesthetic" pattern was observed on the EEG; thereafter, CMRO2 decreased at a markedly reduced rate. The onset of this change occurred at concentrations well below MAC for the inhalational anesthetics. With the thiopental infusion, CMRO2 decreased most rapidly during the first 25 minutes. With halothane and enflurane, CBF was maximal during the period of transition in the EEG from an "awake" to an "anesthetic" pattern. CBF was elevated at all concentrations of isoflurane studied. CBF decreased rapidly during thiopental infusion until the EEG pattern changed from "awake" to "anesthetic" and then more slowly. The results demonstrate that the change in the EEG to an "anesthetic" pattern, which occurs at concentrations well below MAC, is accompanied by an abrupt metabolic depression. It is speculated that these events coincide with the onset of functional depression.
Abstract: The relationship between the force in the left ventricular wall during systole and myocardial O2 consumption (MVO2) was determined. In addition, the relative influence of the load imposed during shortening and fiber shortening on MVO2 was assessed. For this purpose, 14 servo-regulated, paced, isolated canine hearts were used and the steady-state response in total coronary flow and arteriovenous oxygen difference was measured. For both the isovolumetrically beating and the ejecting ventricle, statistically significant linear relations were observed between MVO2 and the integral of systolic force. These relations were not significantly different from one another, indicating that shortening was not a determinant of MVO2. Moreover, when ejecting an isolumetric beats of equivalent developed force were compared, a difference in MVO2 (deltaMVO2) was found. deltaMVO2 was a function of the force integral difference between these contractions and not fiber shortening. Thus, under the conditions of this experiment, the integral of systolic force that includes developed force and shortening load is the predominant factor regulating MVO2 for any given contractile state, whereas the influence of fiber shortening is negligible.
Abstract: To determine the sequence of changes in segmental myocardial function, regional lactate metabolism and global left ventricular function induced by mild regional ischemia, blood flow in the left anterior descending coronary artery of 10 dogs was reduced by 10 percent decrements with use of a screw clamp. At each level of flow, segmental mechanical function and regional metabolism were assessed, the former with use of a mercury-in-Silastic length gauge and the latter with transmyocardial lactate balance measurements obtained with sampling from the anterior interventricular vein. Coronary arterial flow at the onset of regional lactate production was 48 +/- 4 percent (mean +/- standard error of the mean) of the control value. The onset of segmental mechanical dysfunction coincided with the onset of lactate production. Epicardial S-T segment abnormalities over the ischemic zone usually could not be detected until coronary flow was further reduced. After the onset of regional ischemia there was a linear correlation between coronary arterial flow and regional lactate production. At the onset of mild regional ischemia, defined as the onset of regional lactate production, no significant or directionally consistent changes were noted in standard measurements of global left ventricular performance, including heart rate, mean aortic pressure, left ventricular end-diastolic pressure, cardiac output, stroke volume, stroke work and peak positive dP/dt (maximal rate of rise of pressure). However, peak negative dP/dt (maximal rate of pressure decrease) decreased from 99 +/- 2 to 89 +/- 3 percent of the control value (P less than 0.0005) coincident with the onset of ischemia. It is hypothesized that dyssynchronous wall motion in the ischemic zone during isometric relaxation accounts for this decrease in peak negative dP/dt.
Abstract: There is considerable evidence that fluids are removed from the peritoneal cavity by drainage into lymphatics lining the surface of the diaphragm, but there is little quantitative information on the rate of reabsorption as affected by conditions which exist in cirrhotic ascites. In the present study a plethysmographic technique was utilized to record the rate of absorption of fluid from the peritoneal cavity of anesthetized cats. The results of studies in 33 cats showed that the rate of fluid absorption from the peritoneal cavity was directly proportional to the intraperitoneal pressure regardless of whether the intraperitoneal fluid was free from protein or contained a protein concentration equivalent to that of plasma. Fluid was absorbed with a protein concentration equivalent to that present in the peritoneal cavity. Thus it is apparent that the intraperitoneal pressure is an important factor controlling the accumulation of ascitic fluid but the protein concentration of the intraperitoneal fluid does not affect the rate of reabsorption. In addition, marked diuresis induced by intravenous furosemide does not appear to mobilize ascites by an effect on the reabsorption process.
Abstract: We assessed vascular and hormonal responses to inhibition of peptidyldipeptide hydrolase, which converts angiotensin I to angiotensin II (converting enzyme) and degrades bradykinin (kininase II), in subjects given 10 meq of sodium to activate both systems. In nine normal subjects a threshold dose of 30 MICROgram per kilogram of the inhibitor, SQ 20881, modestly influenced mean blood pressure (-5 +/- 1 mm Hg, P less than 0.05), and renal blood flow (+50+/-8 ml per 100 g per minute), plasma renin activity (+ 2.3 +/- 0.6 ng per milliliter per hour), and angiotensin II (-11 +/- 3 pg per milliliter) more strikingly (P less than 0.01). In six patients with essential hypertension the threshold inhibitor dose was reduced to 10 microgram per kilogram; 30 kilogram per kilogram had an enhanced (P less than 0.01) effect on mean blood pressure (-11 +/- 2 mm Hg), renal blood flow (137 +/- 20 ml per 100 g per minute), and angiotensin II concentration (-29 +/- 12 pg per milliliter). SQ 20881 elevated plasma bradykinin concentration (7.4 +/- 2.6 ng per milliliter, P less than 0.02) only in the hypertensive patients. Because both renin-angiotensin and kallikrein-bradykinin systems are influenced, vascular responses to SQ 20881 must be interpreted cautiously, but this agent has excellent antihypertensive characteristics.
Abstract: These experiments were designed to investigate the effects of O2 breathing on limb blood flow and metabolism during exercise. Six subjects took part in the study. Four subjects breathed air or 100% O2 while pedaling a Krogh bicycle at 150 W (55-70% of maximal aerobic capacity). Two subjects breathed either 60% or 100% O2 while working at a power output at or slightly in excess of their maximal aerobic capacities. The major findings of the study were 1) leg blood flow is reduced during exercise when comparing hyperoxia with normoxia; 2) VO2 of the exercising limb is not different during hyperoxia; 3) O2 delivery to the leg (the product of blood flow and arteriovenous O2 difference) is not significantly different in the two conditions; and 4) blood pressure is not markedly affected in the experiments at 150 W. Since BP was not different during hyperoxia, at a time when flow was reduced by 11%, this suggests an increased resistance to flow in the exercising limb. In general, these findings are consistent with those reported for the in situ dog muscle but are at variance with results of experiments with humans, especially the reports indicating substantial increases in O2 uptake during hypertoxic conditions.
Abstract: Administering D-aldosterone, 7 microgram 100 g-1, to rats results in a marked rise in ammonium excretion and metabolic alkalosis. Increased ammonium excretion is not related to either a significant elevation in potassium excretion nor to hypokalemia. Consequently, potassium depletion does not appear to be the causative factor in the aldosterone-stimulated ammonium excretion. Isolated kidneys from aldosterone-treated rats, perfused with 1 mM L-glutamine, produced twice as much ammonia from glutamine as did controls. Ammonia production per glutamine extracted increased from 1.33 +/- 0.07 in control to 1.79 +/- 0.08 in kidneys from hormone-treated rats, suggesting stimulation of the mitochondrial glutaminase I-glutamate dehydrogenase pathway; this was supported by a proportional rise in production of glucose and CO2, end products of glutamine’s carbon skeleton. Consequently, aldosterone-stimulated renal ammonia production, by specifically activating the mitochondrial pathway, leads to the elimination of hydrogen ions in the form of urinary ammonium excretion and an ensuing metabolic alkalosis.
Abstract: The effect of phenoxybenzamine (PBA), desmethylimipramine (DMI), clonidine (CLND), sotalol (STL), and isoproterenol (ISPR) on the release of endogenous norepinephrine (NE) from the heart on right cardioaccelerator nerve stimulation was studied in anesthetized dogs. Under control conditions, the catecholamine levels in coronary sinus blood increased linearly with increasing frequencies of stimulation up to 10 Hz and did not increase further at 30 Hz. The release of NE was markedly enhanced after PBA (1 mg/kg, iv) and DMI (1 mg/kg, iv). The enhanced release of NE after DMI, but not after PBA, was associated with a prolonged response in heart rate. In contrast, NE release was reduced after CLND (15 microgram/kg, iv) at stimulation frequencies of 1 and 2 Hz and this was associated with reduced responses in heart rate and left ventricular dtp/dt. STL (5 mg/kg, iv) reduced significantly the release of NE at stimulation frequencies of 1-5 Hz, whereas ISPR enhanced NE outflow at frequencies of 1-4 Hz. These results support the existence of both negative and positive feedback mechanisms on the release of norepinephrine by cardiac sympathetic fibers mediated through presynaptic alpha- and beta-adrenoreceptors, respectively. The functional significance of these mechanisms is also suggested by the correlation found between changes in NE release and variations in cardiac responses under the various drug treatements.
Abstract: Cerebral blood-flow (C.B.F.) was measured in 38 patients with haematocrit values (Hct) in the range 0-47–0-53 and was found to be significantly lower than in 43 patients with Hct in a lower range (0-36–0-46). After reduction of Hct in the higher Hct group by venesection, flow increased by a mean of 50%. This improvement in flow was largely due to a reduction in viscosity. Hct around the generally accepted upper limit of normal may be an important factor in the causation of occlusive vascular disease.
Abstract: The natural history of electrical injury, exclusive of electrical flash burns, was determined in 64 patients. These patients sustained relatively small burns (x=11%); only nine patients (14%) had burns greater than 25%. Forty-six patients suffered 114 major complications. EKG abnormalities occurred in 36%, including major cardiac arrhythmias in ten patients. One-fourth of the patients developed neurologic sequelae (CNS-8, peripheral-8). Electrical vascular injury with subsequent arterial occlusion was responsible for many of the major amputations. Nineteen patients required 32 amputations (digits-17, hand-1, foot-2, leg-3, arm-9). Early patient referral and vigorous fluid resuscitation minimized renal failure (1.5%) and mortality (3.1%). Early fasciotomy and vigorous debridement appeared to decrease wound sepsis (8%), but apparently had little if any effect on major limb salvage. The unsolved problems of electrical injury, namely neurological and vascular sequelae, are major contributors to the high morbidity of electrical injury.
Abstract: 1. Intracellular pH (pH(i)), Cl(-) and Na(+) levels were recorded in snail neurones using ion-sensitive micro-electrodes, and the mechanism of the pH(i) recovery from internal acidification investigated.2. Reducing the external HCO(3) (-) concentration greatly inhibited the rate of pH(i) recovery from HCl injection.3. Reducing external Cl(-) did not inhibit pH(i) recovery, but reducing internal Cl(-), by exposing the cell to sulphate Ringer, inhibited pH(i) recovery from CO(2) application.4. During pH(i) recovery from CO(2) application the internal Cl(-) concentration decreased. The measured fall in internal Cl(-) concentration averaged about 25% of the calculated increase in internal HCO(3) (-).5. Removal of external Na inhibited the pH(i) recovery from either CO(2) application or HCl injection.6. During the pH(i) recovery from acidification there was an increase in the internal Na(+) concentration ([Na(+)](i)). The increase was larger than that occurring when the Na pump was inhibited by K-free Ringer.7. The increase in [Na(+)](i) that occurred during pH(i) recovery from an injection of HCl was about half of that produced by a similar injection of NaCl.8. The inhibitory effects of Na-free Ringer and of the anion exchange inhibitor SITS on pH(i) recovery after HCl injection were not additive.9. It is concluded that the pH(i) regulating system involves tightly linked Cl(-)-HCO(3) (-) and Na(+)-H(+) exchange, with Na entry down its concentration gradient probably providing the energy to drive the movement inwards of HCO(3) (-) and the movement outward of Cl(-) and H(+) ions.
Abstract: Clinically isolated aortic stenosis is most commonly caused by a congenitally malformed aortic valve. Many elderly patients with isolated aortic stenosis have a tricuspid aortic valve. It has been suggested in the past that inequalities in individual cusp size could be a factor leading to the development of the stenoses in these cases. In this study the width and height of individual aortic valve cusps were measured at necropsy in 200 hearts of patients without clinical signs of aortic stenosis, though the majority of valves obtained from elderly persons showed some ageing changes. The results were compared with similar measurements in 16 hearts of patients with clinically diagnosed and necropsy proven isolated aortic stenosis. The results show that inequality in cusp size is the rule rather than the exception. Indeed, only 5 of the 200 ’normal’ tricuspid aortic valves had 3 cusps of identical height and width, and each of the 16 cases with isolated aortic stenosis has cusps of differing size. The results seem to contradict the aforementioned hypothesis. However, the striking similarities between isolated aortic stenosis and the ageing aortic valve, suggest that isolated tricuspid aortic stenosis is an extreme with a spectrum of ageing alterations. Inequality in cusp size, with differences in mechanical tissue stress as a consequence, could then play a role in the pathogenesis of the stenosis by accelerating the ageing process.
Abstract: What mathematical or physiological principles govern the radii of blood vessels in the cardiovascular system and by what mechanisms are those principles implemented? This question is studied in the contexts of fluid dynamics and physiology of the cardiovascular system, and a possible answer is examined in the light of empirical data.
Abstract: 1. Pulse synchronous bursts of multi-unit sympathetic activity was recorded from median or peroneal muscle nerve fascicles in fourteen subjects resting in the recumbent position. The neural activity was quantitated in terms of burst incidence, i.e. the number of bursts in the mean voltage neurogram/100 heart beats, during successive rest periods of 2-4 min.2. For each individual the burst incidence was fairly constant between different rest periods but the mean burst incidence varied widely between individuals, the range being from less than 10 to more than 90 bursts/100 heart beats.3. Simultaneous double nerve recordings were made on one subject from median and peroneal nerves and on eight subjects from the two peroneal nerves. There was always close similarity between the two records in such experiments regardless of which muscles the nerve fascicles innervated. When analysed separately the difference in burst incidence between the two sides ranged from 0.7 to 5.1 bursts/100 heart beats. The findings suggest that sympathetic neurones destined to skeletal muscles are subjected to a homogenous central drive and that contributions to the activity from ganglionic or segmental sources are of lesser importance.4. On seven subjects repeated recordings at rest were made with intervals of 3 weeks-21 months between recordings. In each subject mean burst incidences were similar in all recordings (range of differences 0.5-11.2 bursts/100 heart beats) suggesting an individually constant level of sympathetic activity in muscle nerves.5. For each individual the variability of burst amplitudes in the mean voltage neurogram was described by burst amplitude spectra. Most subjects had a relatively larger proportion of small than high amplitude bursts, but there was a tendency for more even amplitude distributions in subjects with high burst incidence. The finding may be an indication of interindividual differences in the average number of impulses/burst.6. It is concluded that the multi-unit recording technique can be used for comparisons of the level of muscle nerve ;sympathetic tone’ between different subjects.
Abstract: Excessive reactivity of blood platelets may contribute to atherosclerotic vascular disease. Hence drugs which alter platelet function may be protective. Prompted by findings that propranolol therapy normalized hyperactive platelet aggregation in patients with coronary artery disease, we studied propranolol in vitro to assess its action on platelets. At concentrations similar to those achieved in vivo (0.1-1 muM), propranolol raised the thresholds for aggregation of some normal paltelets by adenosine diphosphate (ADP). At higher concentrations (10-50 muM), propranolol abolished the second wave of platelet aggregation induced by ADP and epinephrine, and inhibited aggregation induced by collagen, thrombin, and the ionophore A23187. Propanolol blocked the release of 14C-serotonin from platelets, inhibited platelet adhesion to collagen, and interfered with clot retraction. Propranolol blocked ionophore-induced uptake of 45Ca by platelets. Inhibition appeared unrelated to beta-adrenergic blockage, as d(+) propranolol (which lacks beta-blocking activity) was equipotent with 1(-) propranolol. Moreover, practolol, a beta-blockading drug which is nonlipophilic, did not inhibit platelet function. These studies suggested that propranolol, like local anesthetics, decreased platelet responsiveness by a direct action on the platelet membrane, possibly by interfering with calcium availability. Modulation of platelet function by propranolol may occur at concentrations achieved at usual clinical doses of the drug.
Abstract: The rate of ascites formation or reabsorption was recorded in anesthetized cats using the technique of intraperitoneal plethysmography. Hepatic venous pressure was increased using an extracorporeal circuit to drain effluent blood from the liver. When the intraperitoneal pressure was set to zero, elevation of hepatic venous pressure increased portal pressure and produced a constant rate of ascites formation. However, equivalent increments of portal pressure without elevation of hepatic venous pressure did not cause ascites formation, indicating that the liver was the source of ascites when hepatic venous pressure was increased. The rate of ascites formation was proportional to hepatic venous pressure, but elevation of the intraperitoneal pressure reduced the transsinusoidal pressure gradient responsible for fluid filtration from the liver. Although this reduced the rate of ascites formation, a secondary effect partly opposed this reduction in filtration rate. From this study and from previous work, there are now quantitative data showing that the intraperitoneal pressure is an important factor which accelerates the rate of reabsorption and decreases the rate of formation of ascites to bring these processes into equilibrium.
Abstract: This study was conducted to determine the quantitative importance of the aldosterone feedback mechanism in controlling each one of three major factors that have often been associated with aldosterone, namely, extracellular fluid sodium concentration, extracellular fluid potassium concentration, and extracellular fluid volume. To do this, the ability of the body to control these three factors in the face of marked changes in daily sodium or potassium intake was studied under two conditions: 1) in the normal dog, and 2) in the dog in which the aldosterone feedback mechanism was prevented from functioning by removing the adrenal glands and then providing a continuous fixed level of supportive aldosterone and glucocorticoids during the low and high electrolyte intake periods. Under these conditions, removal of feedback control of aldosterone secretion decreased the effectiveness of plasma potassium control by nearly fivefold (39% vs. 8% change in plasma potassium concentration), fluid volume by sixfold (12% vs. 2% change in sodium space) and had no effect on control of plasma sodium concentration (2% change with and without feedback control of aldosterone secretion.)
Abstract: The chronic effects of potassium loading on sodium balance and related variables were studied in two groups of dogs. The first group was intact except for the presence of indwelling arterial and venous cannulas. On the 1st day, increasing daily potassium intake from a normal level (30 mEq/day) to 200 mEq/day produced a 0.47-mEq increase in plasma potassium with a 56% increase (P greater than 0.01) in sodium excretion in spite of a 58% increase in plasma aldosterone concentration. After 6 days of potassium loading the cumulative negative sodium balance averaged 44 mEq while 22Na space decreased 6.7% (P less than 0.025). In this group arterial pressure did not change measurably. The same experimental protocol was repeated in a second group of dogs that were chronically adrenalectomized and maintained on fixed levels of aldosterone (50 mug/day) and hydrocortisone (1 mg/day). With aldosterone levels held constant the same increase in potassium intake produced a 1st day increase in potassium concentration of 1.20 mEq/liter and 217% (P less than 0.001) increase in sodium excretion. After 5 days of high potassium intake, the cumulative negative sodium balance totaled 84 mEq. Sodium space decreased 7.5% (P less than .005) during the course of the 5-day high potassium intake period. Potassium loading caused a fall in mean arterial pressure in this group; pressure fell from the control level of 110 +/- mm Hg to 87 +/- 4 mm Hg (P less than .001) after 3 days of high intake. By the 5th day of the experiment, pressure stabilized at 96 +/- 3 mm Hg, 13% less than (P less than 0.01) the control level. The results suggest that changes in plasma potassium concentration within physiological limits may have long term effects on sodium balance.
Abstract: The effects of 60-min intraarterial infusion of vasopressin (0.005 U per kg-min) and epinephrine (0.05 mu per kg-min) on gastric hemodynamics were studied in anesthetized baboons. Total gastric blood flow was measured electromagnetically and radioactive microspheres (15 +/- 5 mu) with three labels were used to determine regional distribution of gastric blood flow and arteriovenous shunting. Control flow was 55 +/- 8 ml per min, with 77.4 +/- 2.7% of flow going to the gastric mucosa and 1.7 +/- 0.4% of injected spheres appearing in the liver. Epinephrine infusion resulted in a sustained vasoconstriction to 18 +/- 5 ml per min with no autoregulatory escape and no changes in arterial pressure or cardiac output. Vasopressin resulted in a decrease in flow to 14 +/- 3 ml per min with no excape. Whereas cardiac output did not change, there was a singificant hypertensive effect during the vasopressin infusion. There was neither redistribution of flow nor change in arteriovenous shunting with either epinephrine or vasopressin. Transmucosal electrical potential difference was 62 +/- 8 mv and did not change significantly with either infusion.
Abstract: In isolated gastrocnemius muscles from 19 dogs the interstitial H+ activity ([H+]int) was measured with bulb-type buffer-filled glass minielectrodes. The muscles were working isotonically and perfused with blood. In addition arterial and venous pH, venous O2 saturation, muscle temperature, and blood flow were meausred continuously at rest, during 12 min of sustained exercise, and in the recovery period. Lactate (LA-) release and O2 consumption were calculated by the Fick principle. The experiments were performed under normal acid-base conditions and during artificially induced metabolic acidosis and alkalosis. 1. In normal acid-base balance [H+]int at rest was 54 +/- 3.3 neq/l (= pH 7.24), while venous H+ ([H+]ven) was 45 +/- 4.7 neq/l (= pH 7.34) A[H+] gradient was always observed between interstitial fluid and venous blood. 2. Immediately after onset of exercise [H+]int decreased transiently. After about 15 s [H+]int increased rapidly up to values of 105 +/- 7 neq/l (= pH 6.98). In the recovery period [H+]int diminished and reached control values after about 20-30 min. [H+]ven increased up to 74.4 +/- 8.4 neq/l (= pH 7.13). Maximal gradients between [H+]int and [H+]ven were 36 neq/l (= pH 0.2). 3. During repeated exercise the decrease in [H+]int at the onset of exercise was more extensive, while the subsequent increase was lowered. These changes correspond to a smaller LA- release. 4. During metabolic alkalosis at the onset of exercise [h+]int decreased less, during metabolic acidosis more than under normal acid-base conditions. Thereafter during metabolic alkalosis maximal values of 95.4 +/ 2 neq/l (= pH 7.03), during metabolic acidosis of 180 +/- 8.6 neq/l (= pH 6.74) were reached. This led to [H+] gradients between interstitial fluid and venous blood which were much higher in metabolic acidosis than in normal acid-base balance or in metabolic alkalosis. In metabolic acidosis [H+]int decreased very sle rapidly than during metabolic alkalosis or during normal acid-base conditions. It is concluded that the H+ activity measured is that within the interstitial space. Exercise hyperemia is not caused by changes of [H+]int. Mechanisms are discussed which may explain H+ gradients between interstitial fluid and venous blood and rapid changes of [H+]int at the onset of exercise.
Abstract: Results of estimation of infarct size with a selected biochemical marker in blood, creatine phosphokinase (CPK), have suggested that infarct size is an important determinant of prognosis, impaired ventricular function, early ventricular dysrhythmia, and the severity of clinical manifestations. Estimates based on serial changes in serum CPK activity have correlated with morphological estimates and have been employed to evaluate therapeutic interventions. Improved estimates with any biochemical marker require exclusion of noncardiac sources of the marker and characterization of the influence of physiological alterations on parameters in empirical or physiologically based mathematical models utilized. Use of MB CPK instead of total CPK therefore improves enzymatic estimates when infarction is accompanied by release of noncardiac CPK into the circulation. Preliminary results with physiologically based models of CPK release from the infarct and its disappearance from the circulation suggest that release may be diffusion-limited and that the CPK disappearance rate is relatively uninfluenced by profound hemodynamic derangements or myocardial infarctions per se. The substantial inactivation of CPK in lymph in vitro and in situ underscores the importance of defining factors influencing the proportion of a biochemical marker depleted from necrotic myocardium appearing in blood, since the proportion is one parameter used in models employed to quantitatively estimate irreversible ischemic injury.
Abstract: Twelve patients with congestive heart failure receiving maintenance therapy with digoxin and potent diuretics were followed closely during development of hypokalemia and potassium loss. Cardiac arrhythmias compatible with digoxtin toxicity developed in 6 patients in the presence of stable, normal serum digoxin concentrations. The mechanisms involved in the development of the rhythm disturbances are discussed with regard to hypokalaemia, intracellular potassium loss, intra-/extracellular potassium gradients and digoxin, and the significance of maintaining a normal potassium balance in this setting is stressed.
Abstract: Ehrlich ascites-tumour cells were investigated with regard to their stability to transport L-lactate by measuring either the distribution of [14C]lactate or concomitant H+ ion movements. The movement of lactate was dependent on the pH difference across the cell membrane and was electroneutral, as evidenced by an observed 1:1 antiport for OH- ions or 1:1 symport with H+ ions. 2. Kinetic experiments showed that lactate transport was saturable, with an apparent Km of approx. 4.68 mM and a Vmax. as high as 680 nmol/min per mg of protein at pH 6.2 and 37 degrees C. 3. Lactate transport exhibited a high temperature dependence (activation energy = 139 kJ/mol). 4. Lactate transport was inhibited competitively by (a) a variety of other substituted monocarboxylic acids (e.g. pyruvate, Ki = 6.3 mM), which were themselves transported, (b) the non-transportable analogues alpha-cyano-4-hydroxycinnamate (Ki = 0.5 mM), alpha-cyano-3-hydroxycinnamate (Ki = 2mM) and DL-p-hydroxyphenyl-lactate (Ki = 3.6 mM) and (c) the thiol-group reagent mersalyl (Ki = 125 muM). 5. Transport of simple monocarboxylic acids, including acetate and propionate, was insensitive to these inhibitors; they presumably cross the membrane by means of a different mechanism. 6. Experiments using saturating amounts of mersalyl as an "inhibitor stop" allowed measurements of the initial rates of net influx and of net efflux of [14C]lactate. Influx and efflux of lactate were judged to be symmetrical reactions in that they exhibited similar concentration dependence. 7. It is concluded that lactate transport in Ehrlich ascites-tumour cells is mediated by a carrier capable of transporting a number of other substituted monocarboxylic acids, but not unsubstituted short-chain aliphatic acids.
Abstract: The influence of isoflurane on haemodynamics and myocardial oxygen consumption was examined in seven geriatric patients under conditions of controlled ventilation and a normal arterial carbon dioxide tension. During isoflurane/nitrous oxide in oxygen anaesthesia (0.75 and 1.5 vol% inspired isoflurane) no significant changes occurred in cardiac output, stroke volume, heart rate, central venous and pulmonary artery pressure. Arterial pressure decreased, as did total peripheral resistance. A reduction in left ventricular maximum dp/dt (18-39%) was, at least in part, a result of changes in loading conditions. Total body (CaO2–CVO2) and base excess values remained within the normal range. We consider that the oxygen supply was adequate to meet the metabolic demands of the body as a whole. Myocardial oxygen consumption decreased by 25% during 0.75 vol% inspired isoflurane and by 43.5% with deepening of anaesthesia (1.5 vol% isoflurane).
Abstract: It is usually assumed that the concentration of glucose in the brain reflects that in the blood, so that measuring the latter provides an accurate index of the former. However, in two experimental situations analogous to anoxia and salicylate poisoning, brain glucose was found to be dangerously low in the presence of normal or even elevated blood glucose levels, and in these experiments administering glucose prolonged survival.
Abstract: Patients suffering from pheochromocytoma characterized by an exclusive or almost exclusive excess of norepinephrine showed no (one patient) or only a moderate increase (two patients) in renin and aldosterone secretion. In those three patients with concomitant distinct hypersecretion of epinephrine, renin release (and aldosterone secretion except in one patient) was markedly enhanced. Similar results were obtained in a patient with excess norepinephrine and dopamine secretion. Renin release was markedly reduced in all patients during preoperative long-term alpha-adrenergic receptor blockade. With the exception of one patient, increased renin and aldosterone secretion was abolished. The results indicate that augmentation in renin release depends on the ratio of the different catecholamines secreted by the pheochromocytoma and their different effe-tiveness in stimulating beta-adrenergic receptors. Even in the presence of excess catecholamine secretion, there is evidence that renin secretion is predominantly mediated by beta receptors rather than by renal vascular alpha-adrenergic receptors. Normalization of catecholamine-induced enhanced renin release in patients with pheochromocytoma during chronic alpha-adrenergic receptor blockade supports the assumption that (alpha-) adrenergic blocking agents inhibit renin secretion distal to their blockade of specific adrenergic receptors. However, contrary to beta-adrenergic blockade, circadian rhythm of renin release seems to remain intact during alpha-adrenergic blockade.
Abstract: Evidence suggests the following pathogenesis for neurogenic pulmonary edema. The initial phase results from a centrally mediated, massive, sympathetic discharge. This produces intense, generalized, but transient, vasoconstriction with a resultant shift of blood from the high-resistance systemic circulation to the lowresistance pulmonary circulation. Marked increases in pulmonary vascular pressures and marked increases in pulmonary blood volume then produce pulmonary edema because of the hydrostatic effect of increased pulmonary capillary pressure. In addition, pulmonary hypertension and hypervolemia injure pulmonary blood vessels, altering pulmonary capillary permeability and producing lung hemorrhage. After the transient systemic and pulmonary vascular hypertension subside, the patient is left with abnormal pulmonary capillary permeability, so that pulmonary edema persists in the face of normal hemodynamics and normal cardia function.
Abstract: 1. Rabbit antisera against arginine-vasopressin (AVP) were evaluated for sensitivity and specificity in a radioimmunoassay based on the extraction of AVP from plasma and urine on to Florisil. 2. Comparison of the immunoreactivity of AVP with analogues showed that one antiserum (R2) reacted principally with the hexapeptide ring and another (R4) bound to the tripeptide tail and was reactive with some reduction and hydrolytic products of the native peptide. 3. The minimum amount of AVP measurable in the radioimmunoassay was 1 pg. The extraction of AVP from plasma and urine gave a recovery of 93 per cent (sd 5 per cent). A plasma sample repeatedly assayed with R2 gave a value of 1.4 ng/1 (sd 0.2, n=12). 4. The antiserum specific for the hexapeptide ring (R2) showed that in normal subjects AVP concentration ranged from 3.2 +/- 2.52 ng/1 after dehydration to 0.16 +/- 0.1 ng/1 after water loading.
Abstract: Although a diminished fractional excretion of sodium (FENa) is the hallmark of acute proliferative glomerulonephritis (APGN), an enhanced natriuresis per glomerular filtration rate (GFR) in the chronic phases of this disease has been reported. We studied this adaptive response utilizing two different split-bladder dog models with unilateral, and a third group of dogs with bilateral Masugi’s nephritis. Group I. Six dogs with unilateral nonaccelerated APGN studied a mean of 6 days after induction had a mean base-line APGN/intact kidney GFR of 31/50 ml/min (P less than 0.005) and FENa of 0.2/0.75% (P less than 0.005). Acute volume expansion caused a smaller absolute increase in FENa from the APGN kidney, 1.6%, than from the intact kidney, 4.0%, (P less than 0.01). Maximum tubular secretion of rho-aminohippuric acid/GFR (TmPAH/GFR) measured in three dogs was higher in the APGN kidney than intact kidney, 13.1 vs. 9.3 mg/dl. Subsequent studies on three of the six dogs when the disease had become chronic demonstrated a reversal in the pattern of sodium excretion in response to volume expansion. Group II. Six dogs with accelerated unilateral APGN (dogs presensitized to antibody source) studied a mean of 5 days after induction had a mean base-line APGN/intact kidney GFR of 16/57 ml/min and FENa of 0.22/0.12% (P less than 0.1). Contrary to group I, volume expansion caused a greater absolute increase in FENa from the APGN kidney, 5.8%, than from the intact kidney, 2.9% (P less than 0.05). TmPAH/GFR studied in four dogs was similar for both kidneys, 17.9 and 18.5 mg/dl for the APGN kidney and intact kidney, respectively. Group III. Sequential studies were performed on seven dogs with bilateral nonaccelerated APGN. Initially each demonstrated sodium retention and a smaller absolute increase in FENa in response to volume expansion compared to a predisease control study. With disease progression, volume expansion induced a greater absolute increase in FENa than in the control study. We concluded that (a) the fractional excretion of sodium from the APGN kidney will be less or greater than the contralateral intact kidney or control study depending on the severity and/or chronicity of the disease, possibly as the result of morphologic alterations; (b) the degree of extracellular fluid volume expansion is an important variable influencing similarity of glomerulotubular balance between the APGN and contralateral intact kidney; and (c) the "intact nephron hypothesis" applies in a limited fashion to kidneys with APGN in the absence of volume expansion just as it does for kidneys with chronic glomerulonephritis or pyelonephritis.
Abstract: 1. Intracellular pH (pHi) was measured using pH-sensitive glass micro-electrodes. The effects on pHi of CO2 applied externally and HCO3-, H+ and NH4+ injected iontophoretically, were investigated. 2. The transport numbers for iontophoretic injection into aqueous micro-droples were found by potentiometric titration to be 0-3 for HCO3- and 0-94 for H+. 3. Exposure to Ringer, pH 7-5, equilibrated with 2-2% CO2 caused a rapid, but only transient, fall in pHi. Within 1 or 2 min pHi began to return exponentially to normal, with a time constant of about 5 min. 4. When external CO2 was removed, pHi rapidly increased, and then slowly returned to normal. The pHi changes with CO2 application or removal gave a calculated intracellular buffer value of about 30 m-equiv H+/pH unit per litre. 5. Injection of HCO3- caused a rise in pHi very similar to that seen on removal of external CO2. 6. The pHi responses to CO2 application, CO2 removal and HCO3- injection were slowed by the carbonic anhydrase inhibitor acetazolamide. 7. H+ injection caused a transient fall in pHi. In CO2 Ringer pHi fell less and recovered faster than in CO2-free Ringer. Calculation of the internal buffer value from the pHi responses to H+ and HCO3- injection gave very similar values. 8. The internal buffer value (measured by H+ injection) was greatly increased by exposure to CO2 Ringer. Acetazolamide reduced this effect of CO2, suggesting that the function of intracellular carbonic anhydrase may be to maximize the internal buffering power in CO2. 9. It was concluded that the internal HCO3- was determined primarily by the CO2 level and pHi, that internal HCO3- made a large contribution to the buffering power, and that after internal acidfication pHi was restored to normal by active transport of H+, OH- or HCO3- across the cell membrane. The active transport was much faster in CO2 than in CO2-free Ringer.
Abstract: Experiments were performed on cats to explore the integrated cardiovascular responses when excitatory (chemoreceptor) and inhibitory (baroreceptor or cardiac receptor) influences are simultaneously presented to the medullary cardiovascular areas. At a given sinus pressure in the low or medium pressure range, the systemic blood pressure and the vascular resistance were higher when the chemoreceptors were stimulated, while a high, pulsating sinus pressure, i.e.a strong baroreceptor stimulation, could suppress completely even an intense chemoreceptor activation. Thus, the set point and the gain of the baroreflex were increased by a concomitant chemoreceptor activation. These effects are compatible with a simple, mutual ’summation’ of excitatory and inhibitory influences on a common population of central vasomotor neurons. The reflex vasodilator effects elicited via vagal cardiac afferents were found to be more effectively suppressed by a concomitant chemoreceptor stimulation than were the baroreceptor effects, provided a primary chemoreceptor response (bradycardia) was at hand, while the heart rate responses were essentially uninfluenced by the prevailing chemoreceptor activity. This chemoreceptor suppression of the reflex vasodilatation from cardiac receptors, which may be of great importance in hypoxic situations, e.g. during a dive, suggests a more complex, neuronal interaction between the two reflex mechanisms in the CNS.
Abstract: Ammonia production by rat renal cortical mitochondria was studied with both in vivo and in vitro manipulation of potassium to further elucidate the mechanisms relating potassium homeostasis and renal ammonia production. Mitochondria from potassium-depleted animals demonstrated an increase in ammonia production at all glutamine concentrations studied, which ranged from 0.5 to 10 mM. This increase in ammoniagenesis compared favorably in degree of change with and was of sufficient absolute magnitude to entirely account for the findings observed both in renal cortical slices studied in vitro and in the intact animal. When rotenone is added to the medium, increased ammoniagenesis is still detected, indicating that either glutamine entry into the mitochondria and/or the activity of phosphate-dependent glutaminase are critical rate-controlling steps. In contrast to studies with renal slices, a decrease in ammonia production was not apparent with cortical mitochondria from chronically potassium-loaded animals. In vitro alterations of the potassium homeostasis. Therefore, these experimental manipulations either do not activate an effector mechanism which takes place in vivo, or the alteration in ammoniagenesis requires an adaptation over time that is not achieved with this in vitro approach.
Abstract: In order to examine the mechanism underlying incomplete suppression of TSH secretion by thyroid hormones, we measured serum TSH and T3 levels (radioimmunoassay) in 3,5,3’-triiodothyromine (T3)-injected groups of euthyroid and hypothyroid rats. In 2 experiments, euthyroid rats received a single injection of 10 mug T3 and 25 mug T3/100 g body weight (BW). After T3 injection, the TSH levels fell rapidly to the undetectable range of the assay (1-5 ng/ml) within 3 h. TSH concentration returned to control levels following reduction of plasma T3 to pre-injection values as a result of hormone metabolism. Hypothyroid rats were used in the remaining experiments. They were injected with T3, 25 mug/100 g BW in 2 studies and 1000 mug/100 g BW in one. TSH levels in vehicle-injected groups were relatively constant for 9 days. In T3-injected groups, TSH decreased rapidly to about 10% of pre-injection concentrations within 5 hours. In the 3 studies, TSH remained at 100 ng/ml, 40 ng/ml and 30 ng/ml for 3-6 days despite markedly elevated T3 values. TSH then increased toward pre-injection values when T3 concentrations decreased to the euthyroid range. In an additional study, the daily injection of T3, 1 mug/100 g BW, resulted in a further decrease in plasma TSH to undetectable values only after 15-25 days. These studies show 2 components of TSH suppression in hypothyroid rats. Ninety per cent suppression occurs rapidly (hours) after a large dose of T3 Suppression of the residual TSH to the undetectable assay range occurs slowly, requiring prolonged (15-25 days) T3 administration. Further studies showed that TSH isolated from plasma of hypothyroid rats after T3 injection had an apparent molecular weight of 29,000 Daltons and exhibited an immunoassay curve parallel to rat TSH RP-1. Persistent secretion of TSH in the face of very high plasma T3 concentrations may reflect partial autonomy of thyrotrophs in TSH secretion or a nonspecific leak of TSH which is related in amount to the number of thyrotrophs present and/or their secretory activity in different thyroid states.
Abstract: Pyridine, isonicotinoylhydrazide and 1-methylamidazole have been used to investigate carotenoid biosynthesis in V. agaricinum. The results suggest that both torulin (C40) and neurosporaxanthin (C35) are formed from the precursors phytoene and phytofluene. These was no evidence of lycopene accumulation under these conditions. After 4 days’ growth in the presence of isocotinolyhydrazine the fungus contained torulin and neurosporaxanthin only, whereas after 7 days, seven other carotenoids appeared as well, some of which were at the early stages of carotenoid biosynthesis. There results cannot be explained on the basis of a system consisting of free enzymes but of an enzyme aggregate already proposed for Phycomyces.
Abstract: The present study on canine left ventricles showed that Emax which we previously proposed as a good index of both ventricular contractility and its pumping capability, decreased from 2.06 to 1.38 kPa/ml (15.5 to 10.4 mmHg/ml) via the sino-aortic baroreceptor reflex. Cerebral ischaemic response increased Emax to 3.83 kPa/ml (28.8 mmHg/ml). Emax decreased to 1.17 kPa/ml (8.8 mmHg/ml) after cardiac denervation.
Abstract: To evaluate the role of hyperketonemia in the hypoalaninemia and decreased protein catabolism of prolonged starvation, Na dl-beta-hydroxybutyrate was administered as a primed continuous 3-6-h infusion in nonobese subjects and in obese subjects in the postabsorptive state and after 3 days and 3-5 1/2 wk of starvation. An additional obese group received 12-h ketone infusions on 2 consecutive days after 5-10 wk of fasting. The ketone infusion in nonobese and obese subjects studied in the postabsorptive state resulted in total blood ketone acid levels of 1.1-1.2 mM, a 5-15 mg/100 ml decrease in plasma glucose, and unchanged levels of insulin, glucagon, lactate, and pyruvate. Plasma alanine fell by 21% (P smaller than 0.001) in 3 h. In contrast, other amino acids were stable or varied by less than 10%. Infusions lasting 6 h reduced plasma alanine by 37%, reaching levels comparable to those observed in prolonged starvation. Equimolar infusions of NaC1 and/or administration of NaHCO3 failed to alter plasma alanine levels. During prolonged fasting, plasma alanine, which had fallen by 40% below prefast levels, fell an additional 30% in response to the ketone infusion. In association with repeated prolonged (12 h) infusions in subjects fasted 5-10 wk, urinary nitrogen excretion fell by 30%, returning to base line after cessation of theinfusions and paralleling the changes in plasma alanine. Ketone infusins resulted in two- to fourfold greater increments in blood ketone acids in fasted as compared to postabsorptive subjects. It is concluded that increased blood ketone acid levels induced by infusions of Na DL-beta-hydroxybutyrate result in hypoalaninemia and in nitrogen conservation in starvation. These data suggest that hyperketonemia may be a contributory factor in the decreased availability or circulating alanine and reduction in protein catabolism characteristic of prolonged fastings9
Abstract: Evidence suggests that the initial phase of neurogenic pulmonary oedema results from a centrally mediated, massive, sympathetic discharge. It is postulated that this produces intense, generlised, but transient, vasoconstriction with a resultant shift of blood from the high-resistance systemic circulation to the low-resistance pulmonary circulation. Pronounced increases in pulmonary vascular pressures and blood-volume then produce pulmonary oedema because of the hydrostatic effect of increased pulmonary capillary pressure. In addition, pulmonary hypertension and hypervolaemia injure pulmonary blood-vessels, altering pulmonary capillary permeability and producing lung haemorrhage. After the transient systemic and pulmonary vascular hypertension subside, the patient is left with abnormal pulmonary capillary permeability, so that pulmonary oedema persists in the face of normal haemodynamic and cardiac function.
Abstract: The present study was designed to determine whether there were differebnces between the effects of isoflurane and halothane on canine whole-body Vo2 and myocardial, splanchnic, renal, and skelatal muscle Vo2’s were determined at isoflurane concentrations equivilent to those used in a previous study with holothane. With increases in isoflurane, whole-body Vo2 decreased progressively. As with halothane, the major comdial Vo2 that was related to a reduction in cardiac output and arterial blood pressure; contributions from other organs were minor. No significant difference between the effects of isoflurane and halothane on whole-body or individual organ Vo2’s was found. These finding support the view that anesthetic agents are no general metabolic depressants and that observed changed in whole-body Vo2 reflect the su-mated changes in individual argan Vo2’s occasioned by an anesthetic-induced change in organ function and metabolic requirements.
Abstract: 1. The renal response to a low-sodium diet alone and a low-sodium diet plus the daily oral administration of chlorothiazide was examined in rats. Sodium restriction resulted in a decrease in sodium excretion until day 4, after which it remained constant. The administration of chlorothiazide resulted in an initial natriuresis. By day 6, however, the natriuresis had abated and thereafter sodium excretion remained the same as that of the low sodium group. 2. After the animals were in balance on their respective regimens, clearance and micropuncture studies were performed. The glomerular filtration rate was lower in the chlorothiazide-treated rats than in control rats and/or in the low-sodium group. End proximal tubule TF/Pinulin ratios were higher in the diuretic-treated animals than in control rats. TF/Pinulin ratios in low-sodium animals were lower than in the diuretic-animals but higher than in control rats. 3. These studies demonstrate that the escape from the chronic effects of chlorothiazide is due to a decrease in the glomerular filtration rate and to an increase in fractional reabsorption in the proximal tubule, resulting in a reduction in delivery of filtrate to the cortical diluting segment where chlorothiazide exerts its major inhibitory effect.
Abstract: Controversy exists regarding the mechanism by which catecholamines stimulate renin secretion in vivo. A sensitive rat kidney slice system was utilized to study the direct effects of adrenergic agonists and antagonists on renin release in vitro. Catecholamines were protected from degradation by the addition of ascorbic acid to the incubation medium. Significant dose-related stimulation of renin release was observed with epinephrine and norepinephrine in concentrations from 1.5 times 10(-9) to 1.5 times 10(-7)M and with isoproterenol in concentrations from 2 times 10(-9) to 2 times 10(-7)M. No significant stimulation was seen with 10(-10)M concentrations of the three agents. Methoxamine (10(-6)M) stimulated renin release significantly (P less than 0.01). The stimulation observed with epinephrine, norepinephrine, or isoproterenol was blocked by d,l- and l-propranolol (2 times 10(-4)M) but not by d-ropranolol (2 times 10(-4)M) or phentolamine (9 times 10(-4)M). Methoxamine-induced stimulation was abolished by d,l-propranolol but not by phentolamine. These data that the in vitro kidney slice system is responsive to physiological concentrations of catecholamines when they are protected from degradation. The results further demonstrate a direct stimulatory role for beta-adrenergic agents on renin release and suggest that alpha-adrenergic effects seen in vivo are mediated indirectly by hemodynamic, vascular, or functional changes in the kidney.
Abstract: Blood drawn from Apollo crew member; to the mission, at recovery, and postmission was used to examine the effect Apollo mission activities have on tyroid hormone levels. At recovery, statistically significant increases in thyroxine and the free thyroxine index were found. Serum cholesterol and triglycerides were decreased. No change of statistical significance was found in the T3 binding percentage, total serum proteins, and albumin. We conclude that apollo activities and environment caused the postmission increase in serum cholesterol may be one result of the increased thyroxine activity.
Abstract: Subjects exercised for 30 min on a bicycle ergometer at 30, 50, and 70% of maximal aerobic power in ambient temperatures of 15, 25, and 35 degrees C and vapor pressures of less than 18 Torr. Exercise was used to vary internal temperature during an experiment, and different ambient temperatures were used to vary skin temperatures independently of internal temperature. Forearm skin temperature was fixed at about 36.5 degrees C. Esophageal temperature (Tes) was measured with a thermocouple at the level of the left atrium, and mean skin temperature (Tsk) was calculated from a weighted mean of thermocouple temperatures at eight skin sites. Forearm blood flow (BF) was measured by electrocapacitance plethysmography. Our data are well accounted for by an equation of the form BF = a1Tes + q2Tsk + b, independent of exercise intensity, although some subjects showed an equivocal vasodilator effect of exercise. The ratios a1/a2 (7.5, 9.6, 11.7) are quite similar to the ratios (8.6, 10.4) of the corresponding coefficients in two recent models of thermoregulatory sweating.
Abstract: Myocardial damage resulting from transthoracic administration of direct current with cardiac defilbrillators present in clinical use was studied in 66 dogs. Electrodes were applied to the thoracic skin. All direct current discharges were delivered via a commercially available defilbrillator. Most of the animals received ten consecutive discharges with a dial setting of 400 watt-seconds. Animals were killed from 3 to 14 days after receiving the discharges. Myocarial necrosis was produced in most of the animals. The lesions were characterized by sharply localized areas of muscle necrosis that progressed to fibrous scars. Mineralization of damaged muscle and florid proliferation of large mononuclear cells were striking features of the lesions.
Abstract: This study was designed to determine the effects of enflurane on canine whole-body and individual organ oxygen consumption (Vo2). Whole-body, myocardial, splanchnic, renal, and skeletal muscle Vo2 were determined at enflurane concentrations equivalent to those used in previous studies with halothane and isoflurane. With increasing enflurane concentrations, whole-body Vo2 decreased progressively. The major component of the decrease was a reduction in myocardial Vo2 resulting from a decrease in myocardial external work as a result of a decrease in cardiac output and arterial pressure. Other organs contributed to a lesser extent to the overall decrease in whole-body Vo2. In each respect the findings with enflurance were not significantly different from those with halothane and isoflurane. These findings did support to the view that anaesthetic agents are not general metabolic depressants and that observed changes in whole-body Vo2 reflect the summated changes in individual organ Vo2 occasioned by an anaesthetic-induced change in organ function and metabolic requirements.
Abstract: An increased venous capacity and a decreased myocardial contractility can be expected in patients with an acute spinal cord lesion at or above T6. Both factors may contribute to a high incidence of arterial hypotension and pulmonary oedema in these patients especially during anaesthesia. We feel that the Swan-Ganz catheter provides valuable information concerning prevention, diagnosis and treatment of arterial hypotension and pulmonary oedema. Although there may be occasional difficulty in interpretation of measurements from the Swan-Ganz catheter if high airway pressures are used, it is a more sensitive monitor than C.V.P. measurement and is particularly useful in patients with a sympathectomy secondary to spinal cord trauma.
Abstract: The cariac response to anesthetic doses of ketamine hydrochloride was studied in dogs, initially in the absence of other drugs and subsequently during beta adrenergic block with propranolol and combined beta adrenergic and cholinergic blockade with propranolol and atropine. Ketamine (4 mg/kg) was injected into the left atrium or the jugular vein. Administration of ketamine alone resulted in increases in heart rate (61 beats/min, P smaller than .001), cardiac output and left ventricular systolic pressure, but left ventricular end-diastolic pressure and dP/dt max (maximum rate of change of left ventricular isovolumic pressure development) were unchanged. After propranolol, the increase in heart rate produced by ketamine was attenuated, and a transient fall in dP/dt max occurred. After propranolol and atropine, heart rate was not changed by ketamine, but dP/dt max fell and left ventricular end-diastolic pressure rose. Systemic vascular resistance was not altered by ketamine. It is concluded that administration of ketamine increases sympathetic discharge and reduces vagal discharge to the heart. In the absence of sympathetic and vegal control over the heart, the drug depresses myocardial contractility.
Abstract: A review of the available information about fatty acid binding to plasma albumin is presented. Albumin is composed of a single polypeptide chain, folded so as to form three or four spherical units. The strong fatty acid binding sites probably are located in crevices between these spherical regions. The anionic form of the fatty acid binds to albumin. Most of the binding energy comes from nonpolar interactions between the fatty acid hydrocarbon chain and uncharged amino acid side chains that line the binding sites. The binding sites are somewhat pliable, and their configuration can adapt to fit the incoming fatty acid. Stepwise association constants for binding to human albumin of fatty acids containing 6-18 carbon atoms are presented. These data indicate that each mole of fatty acid binds with a different affinity and that the association constants for multiple binding diminish sequentially, i.e., kappa 1 greater than kappa 2 greater than kappa 3 greater ... greater kappan. Because of uncertainties concerning fatty acid association in aqueous solutions, the constants for the 14-18 carbon acids probably are not definitive. In the usual physiological concentration range, free fatty acids do not displace appreciable amounts of a second organic compound from albumin. Sensitive spectrophotometric analyses revealed, however, that even small increases in free fatty acid concentration alter the molecular interaction between human albumin and another organic compound.
Abstract: The contribution of nyoglobin to the oxygen uptake of red skeletal muscle was estimated from the difference in oxygen uptake with and without functional myoglobin. The oxygen uptake of bundles (25 mm long, 0.5 mm mean diameter) of muscle fibers teased from pigeon breast muscle was measured in families of steady states of oxygen pressure from 0 to 250 mm Hg. The oxygen-binding function of myoglobin, in situ in muscle fiber bundles, was abolished by treatment with nitrite of hydroxylamine, which convert oxymyoglobin in situ to high spin ferric myoglobin, or with phenylhydrazine, which converts oxymyoglobin to denatured products, or with 2-hydroxyethylhydrazine, which appears to remove myoglobin from the muslce. The oxygen uptake was again measured. At higher oxygen pressure, where oxygen availability does not limit the respiration of the fiber bundles, oxygen uptake is not affected by any of the four reagents, which is evidence that mitochondrial oxygen uptake is not impaired. At lower oxygen pressure, where oxygen uptake is one-half maximal, the steady state oxygen consumption is roughly halved by abolishing functional myoglobin. Under the steady state conditions studied, the storage function of myoglobin, being static, vanishes and the transport function stands revealed. We conclude from these experiments that myoglobin may transport a significant fraction of the oxygen consumed by muscle mitochondria.
Abstract: We systematically modified isoproterenol’s chemical structure to reduce chronotropic, arrhythmogenic, and vascular side effects. Experiments on dogs showed that the resulting drug, dobutamine, had an inotropic efficacy as great as that of epinephrine due to a direct action on beta1 cardiac receptors. However, unlike epinephrine, dobutamine’s effect on alpha and beta2 vascular receptors was slight. At equivalent inotropic doses, dobutamine had less than a fourth of the chronotropic effect of isoproterenol. Desmethylimipramine (DMI), which blocks the sympathetic nerve fiber uptake mechanism, had no effect on dobutamine’s actions. In contrast, DMI antagonized dopamine’s inotropic effect, and marked chronotropic and pressor responses occurred when we used doses of dopamine large enough to elicit a direct inotropic effect. Dobutamine increased the contractility of isolated cat papillary muscles more but the automaticity less than did isoproterenol. In ischemic dog hearts, dobutamine lacked significant arrhythmic activity, whereas dopamine, norepinephrine, and isoproterenol caused severe ectopic activity. In dogs with experimentally induced low cardiac contractility, low cardiac output, and hypotension, dobutamine produced dose-related increases in cardiac contractility and output, restored arterial blood pressure, and reduced total peripheral resistance slightly. In contrast, isoproterenol failed to restore blood pressure, had only a meager effect on cardiac contractility and output, cuased extreme tachycardia, and lowered peripheral resistance more than did dobutamine. Norepinephrine, which did not increase cardiac contractility or output as much as dobutamine, excessively elevated peripheral resistance and arterial blood pressure.
Abstract: Despite continuing advances in understanding of the basic pharmacology of the cardiac glycosides, digitalis intoxication remains a common clinical problem. Physician education programs and increasing use of serum or plasma concentration data have, however, been shown to be capable of substantially reducing the incidence of digitalis toxicity. Methodologic progress and availability of commercial radioimmunoassay kits have placed measurement of clinically relevant serum or plasma cardiac glycoside concentrations within the capability of most well equipped clinical laboratories. Extensive experience with serum digitalis levels now provides a basis for ongoing examination of the role of these measurements in clinical practice. Results of studies to date demonstrate that mean serum digoxin and digitoxin levels are significantly higher in patients with electrocardiographic evidence of toxicity compared with patients without such evidence. It must be emphasized, however, that because of overlap in serum digitalis levels between these two groups, sole dependence on these levels for established of a diagnosis of digitalis toxicity is not warranted. Multiple factors influence individual responses to cardiac glycosides, and serum concentration data must be interpreted in the over-all clinical context. Type and extent of underlying heart disease are important determinants of the clinical response to any given dose or concentration of cardiac glycoside. Knowledge of the serum digitalis concentration is likely to be helpful in the setting of suspected digitalis intoxication in the absence of an adequate history, or in the presence of fluctuating renal function, overt or suspected malabsorption, or uncertain bioavailability. More generally, such measurements may prove useful whenever an unanticipated response to digitalis is encountered, whether it be suspected toxicity or the absence of an expected therapeutic effect.
Abstract: 1. The effect of antidiuretic hormone (ADH) on isoprenaline-stimulated renin secretion was examined in the isolated rat kidney perfused with modified Krebs-Ringer saline. 2. Intrarenal infusion OF ADH effectively prevented stimulation of renin secretion by isoprenaline whilst increasing renal perfusion pressure. 3. The exclusion of calcium ions from the perfusion medium abolished the vasoconstrictor effect of ADH and attenuated the inhibitory effect of ADH on isoprenaline-stimulated renin secretion. However, significant suppression of renin secretion was still apparent compared with experiments where isoprenaline was infused alone. 4. These observations indicate that ADH inhibits renin secretion and that this is effected by a direct action on the kidney. Although this may be partly mediated by the rise in renal perfusion pressure, an additional direct effect of ADH on the renin-producing cell, which is dependent on the availability of calcium ions, is proposed.
Abstract: The effects of hemorrhage on arterial pressure, blood flows, and resistances in the coronary, mesenteric, renal, and iliac beds of healthy, conscious dogs and intact, tranquilized baboons were studied. Mild nonhypotensive hemorrhage (14+/-2 ml/kg) increased heart rate and mesenteric and iliac resistances slightly but significantly, and decreased renal resistance (-13+/-2%). Moderate hypotensive hemorrhage, 26+/-2 ml/kg, reduced mean arterial pressure (-23+/-2 mm Hg) and blood flows to the mesenteric (-56+/-3%), iliac (-58+/-5%), and coronary (-39+/-4%) vascular beds, and increased heart rate (+89+/-9 beats/min) and resistances in the mesenteric (+73+/-15%), iliac (+102+/-19%), and coronary (+27+/-5%) beds. In contrast to the other beds, renal flow rose 11+/-6% above control and renal resistance fell 31+/-2% below control. Renal vasodilatation with hemorrhage was also observed in five baboons. The increases in mesenteric and iliac resistances were blocked almost completely by phentolamine, while the increase in coronary resistance was only partially blocked by phentolamine. The renal dilatation was not blocked by phentolamine, propranolol, atropine, or tripelennamine, but was prevented by indomethacin, suggesting that this dilatation was mediated by a prostaglandin-like compound. Thus the peripheral vascular responses to hemorrhage involve intense vasoconstriction in the mesenteric and iliac beds. In the normal conscious dog and the intact, tranquilized primate, the renal bed does not share in the augmentation of total peripheral resistance with nonhypotensive and moderate hypotensive hemorrhage, but does with more severe hemorrhage. In fact, renal vasodilatation occurs with nonhypotensive or moderate hypotensive hemorrhage, which can be prevented by blockade of prostaglandin synthetase with indomethacin.
Abstract: Microperfusion experiments have shown that increases in flow rate of tubule fluid through the loop of Henle are followed by reductions in single nephron glomerular filtration rate (SNGFR) and stop-flow pressure (SFP) measured in the proximal tubule of the same nephron. Because changes in luminal sodium concentration are not consistently related to changes in SNGFR and SFP, we explored the possibility that a transport step at a flow-dependent distal-sensing site might be involved in feedback control of SNGFR. Because the macula densa cells of the distal tubule are adjacent to the glomerular vessels of the same nephrons, they could be the distal-sensing mechanism. We perfused superficial loops of Henle from late proximal to early distal segments in three groups of rats while measuring SFP in the proximal tubule of the same nephron, SNGFR in the proximal tubule of the same nephron, or flow rates of fluid, Na, K, and Cl emerging from the perfused loops. Perfusion solutions used were 0.15 NaCl, Ringer or Ringer with one of several inhibitors of electrolyte transport. Perfusion rates were 10 or 40 nl/min (also, zero during measurements of SFP and SNGFR). With Ringer alone the loop-flow rate increased from 10 to 40 nl/min, caused a decrease in SFP from 37.6 to 32.1 mm Hg, and a decrease in SNGFR from 29.9 to 18.7 nl/min. Concentrations of Na, K, and Cl in early distal fluid and absorption of Na and Cl along the loop segment were also increased when loop perfusion rate was increased. Decreasing the perfusion rate to zero had little effect on SFP or SNGFR. The SFP response to increased flow rate did not occur when the perfusion solution contained furosemide (10(-4) M). No reduction of the SFP response was seen with other diuretics tested (amiloride, acetazolamide, ethacrynic acid, mercaptomerin) or with 0.15 M NaCl alone. The SNGFR response to increased perfusion rate was reduced by furosemide, triflocin, and cyanide but not by amiloride. Na and Cl absorption by the perfused segment were inhibited by furosemide, triflocin, cyanide, and amiloride. Amiloride and acetazolamide, probably do not act in the ascending limb. Ethacrynic acid and mercaptomerin are known to be ineffective in rat nephrons. Thus, agents that could have inhibited NaCl absorption by macula densa cells interfered with the feedback mechanism.
Abstract: A clinical scale has been evolved for assessing the depth and duration of impaired consciousness and coma. Three aspects of behaviour are independently measured—motor responsiveness, verbal performance, and eye opening. These can be evaluated consistently by doctors and nurses and recorded on a simple chart which has proved practical both in a neurosurgical unit and in a general hospital. The scale facilitates consultations between general and special units in cases of recent brain damage, and is useful also in defining the duration of prolonged coma.
Abstract: The effects of dobutamine ([+/-]-4-[2-[[3-(p-hydroxyphenyl)-1-methyl propyl] amino] ethyl] pyrocatechol hydrochloride), a new synthetic cardioactive sympathomimetic amine, were examined on direct and continuous measurements of left ventricular (LV) diameter (D), pressures (P), velocity of shortening (V), dP/dt, dP/dt/P, arterial pressure, cardiac output, and regional blood flows in the left circumflex coronary, mesenteric, renal, and iliac beds in healthy, conscious dogs. At the highest dose of dobutamine examined, 40 mug/kg/min, the drug increased dP/dt/P from 65+/-3 to 128+/-4 s(-1) and isolength velocity from 72+/-4 to 120+/-7 mm/s without affecting LV end diastolic D significantly. Mean arterial P rose from 92+/-2 to 104+/-3 mm Hg and heart rate from 78+/-3 to 111+/-7 beats/min, while LV end systolic D fell from 24.1+/-1.4 to 19.9+/-1.8 mm, reflecting a rise in stroke volume from 30+/-4 to 42+/-3 ml. Cardiac output rose from 2.41+/-0.23 to 4.35+/-0.28 liter/min, while calculated total peripheral resistance declined from 0.042+/-0.005 to 0.028+/-0.003 mm Hg/ml/min. The greatest increases in flow and decreases in calculated resistance occurred in the iliac and coronary beds, and the least occurred in the renal bed. Propranolol blocked the inotropic and beta(2) dilator responses while vasoconstricting effects mediated by alpha adrenergic stimulation remained in each of the beds studied. When dobutamine was infused after a combination of practolol and phentolamine, dilatation occurred in each of the beds studied. These observations indicate that dobutamine is a potent positive inotropic agent with relatively slight effects on preload, afterload, or heart rate, and thus may be a potentially useful clinical agent. The one property of this drug which is not ideal is its tendency to cause a redistribution of cardiac output favoring the muscular beds at the expense of the kidney and visceral beds.
Abstract: 1. The construction and properties of a new design of pH-sensitive micro-electrode are described. The electrodes are very durable, and have a recessed configuration so that only the extreme tip, which can be as small as 1 mum in diameter, needs to enter the cell.2. The average intracellular pH in thirty-two snail neurones was 7.4. This was not in accord with a passive distribution of H(+) ions across the cell membrane.3. Changing membrane potential or external pH had only slow effects on internal pH.4. Removing external K had no effect, and removing external Na had only slow and variable effects on intracellular pH.5. Anoxia, azide and DNP all caused a slow fall in internal pH.6. External CO(2) caused large and rapid decreases in internal pH, which external bicarbonate appeared to offset slowly. Injected bicarbonate increased internal pH.7. The size of the pH changes caused by CO(2) suggested a minimum intracellular buffering power of 25 m-equiv H(+)/unit pH per l., equivalent to that of 150 mM Tris maleate, pH 7.4.8. External ammonia caused a large and rapid increase in internal pH, while the injection of ammonium ions had the opposite effect.
Abstract: Proximal and distal tubular function was compared with urinary excretion in rats after chronic administration of salt and deoxycorticosterone acetate (DOCA) or during salt deprivation. DOCA rats excreted significantly more sodium than did salt-deprived rats. Measurements of tubular fluid to plasma (TF/P) inulin ratios and concentrations of sodium and potassium in quantitative, timed collections, related to measured tubular length, allowed calculation of absolute reabsorption of fluid and ions in the different nephron segments. Proximal transport was not reduced in DOCA-treated rats compared with salt-deprived animals; in distal tubule the former group reabsorbed more sodium and secreted less potassium than the latter. Calculation of sodium transport in loop of Henle as the difference in flow between the end of the proximal convolution and the beginnings of the distal tubule indicated no inhibition of reabsorption in DOCA animals. Comparison of end-distal tubular flow with simultaneous urinary excretion suggested that sodium load was not the determining factor of enhanced natriuresis in DOCA-treated animals. The data are interpreted as indicating that DOCA-escape in the rat is associated with specific alteration of sodium transport in the collecting duct system.
Abstract: The influence on urinary acidification of prolonged ingestion of a high potassium diet was explored in normal men and dogs. In men, the response to acute ingestion of ammonium chloride was assessed in a paired fashion after 5 days of ingesting a formula diet of normal or high potassium content; whereas in animals chronically ingesting a small amount of hydrochloric acid, the response to an increase in daily potassium intake was assessed. Urine pH was lower in the potassium-loaded state with both these models, and the effect persisted in the dog studies as long as a high potassium intake was continued. The decrease in urine pH could not be accounted for by changes in plasma acid-base status, net acid excretion, rate of urine flow, urine ionic strength, or fixed buffer excretion, i.e., phosphate, creatinine, or organic acids. Studies of men with administration of exogenous aldosterone and studies of adrenalectomized dogs with constant, maintenance steroid replacement indicated that the decrease in urine pH does not result from altered aldosterone secretion.In the human studies the largest decreases in urine pH were associated with a concomitant diminution in both ammonium and net acid excretion, suggesting a primary decrease of ammonia diffusion into the urine. These events during potassium loading, which are the mirror image of changes during potassium depletion, suggest that the relation between potassium, urine acidification, and ammonia metabolism may play an important role in the maintenance of hydrogen ion and possibly potassium homeostasis during alterations in potassium intake.
Abstract: Three groups of dogs were run under different experimental conditions characterized by varying the work load or the running time. Lipid and glycogen analyses were carried out on biopsy specimens from the biceps femoris muscle before and after exercise. In addition, arterial and venous triglycerides and free fatty acids were determined on plasma samples from one group of dogs that had been previously catheterized. Under the conditions of these experiments, results revealed: (1) plasma triglycerides did not contribute significantly to the energy supply for muscle contraction; (2) plasma free fatty acid efflux into muscle was increased during mild exercise but significantly lowered during heavy exercise; (3) exercise did not affect the phospholipid level or its composition in the muscle; and (4) muscle triglyceride levels may increase, decrease, or remain unchanged, depending upon the work load imposed by the exercise.
Abstract: Studies were performed on 11 healthy men to evaluate the role of low pressure baroreceptors in the reflex forearm vasoconstrictor responses (plethysmography) to venous pooling produced by lower body negative pressure. Lower body negative pressure (LBNP) at - 5, - 10, - 20, and - 40 mm Hg lowered central venous pressure by 42, 59, 74, and 93%, respectively, and decreased forearm vascular conductance by 24, 29, 34, and 40%, respectively. The decreases in forearm blood flow and conductance during the low levels of venous pooling (LBNP - 5 and - 10 mm Hg) occurred without significant changes in arterial pressure, arterial dP/dt. and heart rate. These results with the low levels indicate that maneuvers which decrease venous return and central venous pressure in man can influence forearm vascular tone without significant changes in the determinants of carotid and aortic baroreceptor activity. During high levels of venous pooling (LBNP - 20 and - 40 mm Hg), significant decreases in arterial pressure and dP/dt and significant increases in heart rate accompanied the further reductions in central venous pressure, forearm blood flow, and forearm vascular conductance. About 73% of the decrease in conductance during venous pooling at LBNP - 40 mm Hg, which was sufficient to decrease arterial pressure and activate high pressure baroreceptor reflexes, occurred during low levels of venous pooling at LBNP - 10 mm Hg without changes in arterial pressure. This suggests that much of the forearm vasoconstriction with the high levels of venous pooling, which were sufficient to decrease arterial pressure, may be accounted for by reflexes originating in areas other than high pressure baroreceptors. The results of these studies suggest that low pressure baroreceptors exert an important influence on forearm vascular tone during decreases in venous return and central venous pressure in man.
Abstract: The peripheral plasma levels of aldosterone, renin activity, potassium, sodium, corticosterone, and cortisol were measured in six normal subjects four times daily-10 a.m., 2 p.m., 5 p.m., 11 p.m.-on 3 consecutive days. A constant daytime activity program was maintained throughout the study. After 5 days on a 10 mEq sodium/100 mEq potassium isocaloric intake, the mean upright 10 a.m. plasma renin activity was 1773+/-186 ng/100 ml per 3 hr and the mean plasma aldosterone, 81+/-14 ng/100 ml. These two parameters fell continuously throughout the day parallel to the fall in plasma cortisol and corticosterone. In response to 2 liters of normal saline infused from 10 a.m. to 2 p.m. on 2 consecutive days, plasma aldosterone levels fell significantly to 13+/-5 ng/100 ml at 2 p.m. after the 1st day’s infusion and to 6+/-1 ng/100 ml at 2 p.m. after the 2nd. Plasma renin activity demonstrated a parallel fall to 368+/-63 ng/100 ml per 3 hr and 189+/-27 ng/100 ml per 3 hr at 2 p.m. on the 1st and 2nd days, respectively. There was no significant alteration in plasma levels of cortisol, corticosterone, potassium, or sodium on the 2 days of sodium loading in comparison with the control day. In an additional study, five normal supine subjects received 500 ml saline/hr for 6 hr. As in the 2 day study, plasma aldosterone and renin activity had parallel decrements at 1, 2, 4, and 6 hr after the start of the saline infusion. From these studies, it is concluded that plasma renin activity is the dominant factor controlling plasma aldosterone when sodium-depleted normal subjects are acutely repleted.
Abstract: In order to investigate the syndrome of postobstructive diuresis, clearance and micropuncture studies were carried out in rats after relief of 24 hr of bilateral (BUL) or unilateral (UUL) ureteral ligation. In rats with BUL, a striking diuresis and natriuresis occurred when the obstruction to one kidney (the experimental kidney) was relieved. The results were not influenced by administration of vasopressin or d-aldosterone. Whole kidney clearances of inulin and p-aminohippuric acid (PAH) in the experimental kidney were reduced to 10% and 20% of normal, respectively. Superficial nephron inulin and PAH clearances were also reduced, but only to 40% and 45%, respectively. These findings suggest a heterogeneity of nephron function in which deep nephrons were functioning poorly or not at all. To investigate the site of impaired tubular reabsorption in the surface nephrons, absolute and fractional water reabsorption was measured. Absolute reabsorption was found to be decreased all along the nephron. Fractional reabsorption in proximal tubules was normal, as indicated by an average endproximal tubular fluid per plasma inulin (TF/P(In)) of 2.16 vs. 2.30 in controls. TF/P(In) was markedly decreased in distal tubules (2.91 vs. 8.02) and final urine (5.56 vs. 263). These observations indicate that the major sites of impaired sodium reabsorption leading to the diuresis were beyond the proximal tubule.Rats with 24 hr of UUL did not demonstrate a comparable natriuresis or diuresis either spontaneously when the obstruction was relieved or after i.v. infusion of urea. A major difference between the BUL and UUL rats was that prerelease intrarenal hydrostatic pressure was markedly elevated (30.1 mm Hg) in the former but was below normal free-flow values (9.2 mm Hg) in the latter. Thus, elevation of intrarenal pressure during the period of obstruction may be causally related to the natriuresis and diuresis which occurs after the obstruction is relieved.
Abstract: The peripheral plasma levels of aldosterone, renin activity (PRA), potassium, corticosterone, cortisol, and in some cases angiotensin II, were measured in normal subjects undergoing postural changes, acute diuretic-induced volume depletion, and alterations in dietary sodium. On a 10 mEq sodium/100 mEq potassium intake, subjects supine for 3 consecutive days had identical diurnal patterns of PRA, angiotensin II, aldosterone, cortisol, and corticosterone, with peaks at 8 a.m. and nadirs at 11 p.m. With an increase in sodium intake to 200 mEq, plasma levels of aldosterone and PRA fell to one-third their previous levels but the diurnal pattern in supine subjects was unchanged and again parallel to that of cortisol and corticosterone. There was no diurnal variation of plasma potassium on either sodium intake in the supine subjects. On a 10 mEq sodium/100 mEq potassium intake, supine 8 a.m. plasma aldosterone (55+/-7 ng/100 ml) and PRA (886+/-121 ng/100 ml per 3 hr) increased by 150-200% after subjects were upright for 3 hr. However, even though the patients maintained an upright activity pattern, there was a significant fall in plasma aldosterone to 33+/-5 ng/100 ml at 11 p.m. Potassium levels varied in a fashion parallel to aldosterone and PRA. Plasma cortisol and corticosterone had a diurnal pattern similar to that found in supine subjects. In response to acute diuretic-induced volume depletion, the nocturnal fall in aldosterone levels did not occur. The 11 p.m. value (102+/-20 ng/100 ml) and the 8 a.m. value postdiuresis (86+/-15 ng/100 ml) were both significantly greater than the prediuresis levels. PRA showed a similar altered pattern while potassium levels fell throughout the day. In some but not all studies, changes in plasma aldosterone coincided with changes in plasma cortisol, corticosterone, and/or potassium. However, in all studies, changes in plasma aldosterone were invariably associated with parallel changes in plasma renin activity and/or angiotensin II levels. These findings support the concept that PRA is the dominant factor in the control of aldosterone when volume and/or dietary sodium is altered in normal man.
Abstract: Splanchnic and leg exchange of glucose, lactate, pyruvate, and individual plasma amino acids was studied in diabetics 24 hr after withdrawal of insulin and in healthy controls. Measurements were made in the basal postabsorptive state and during the administration of glucose at a rate of 2 mg/kg per min for 45 min. In the basal state, net splanchnic glucose production did not differ significantly between diabetics and controls. However, splanchnic uptake of alanine and other glycogenic amino acids was 1(1/2)-2 times greater in the diabetics, while lactate and pyruvate uptake was increased by 65-115%. Splanchnic uptake of these glucose precursors could account for 32% of hepatic glucose output in the diabetics, as compared to 20% in the controls. This increase in precursor uptake was a consequence of a two- to threefold increment in fractional extraction of these substrates inasmuch as arterial levels of alanine, glycine, and threonine were reduced in the diabetics, while the levels of the remaining substrates were similar in the two groups. Peripheral output of alanine and other glycogenic amino acids as reflected in arterio-femoral venous differences was similar in both groups. An elevation in arterial valine, leucine, and isoleucine was observed in the diabetics, but could not be accounted for on the basis of alterations in splanchnic or peripheral exchange of these amino acids. Administration of glucose (2 mg/kg per min) for 45 min resulted in an 80% reduction in splanchnic glucose output in controls, but failed to inhibit hepatic glucose release in the diabetics despite a twofold greater increment in arterial glucose levels. In both groups no consistent changes in arterial glucagon were observed during the infusion. It is concluded that in nonketotic diabetics (a) total splanchnic output of glucose is comparable to controls, but the relative contribution of gluconeogenesis may be increased by more than 50%; (b) accelerated splanchnic uptake of glucose precursors is a consequence of increased hepatic extraction of available substrates rather than a result of augmented substrate supply; and (c) the failure of glucose infusion to inhibit hepatic glucose output suggests that the exquisite sensitivity of the liver to the infusion of glucose in normal man is a consequence of glucose-induced insulin secretion.
Abstract: 1. The mechanism of fatigue has been studied in maintained maximal voluntary contractions of the first dorsal interosseous muscle of the hand.2. Fatigue occurs in two phases. In the first, lasting 1 min, force falls to about 50%. The smoothed rectified e.m.g. (s.r.e.) falls with the same time course and the normal linear relation between s.r.e. and force of unfatigued muscle is preserved.3. In the second phase, force falls relatively faster than s.r.e.4. Arterial occlusion does not affect the first phase, but in the second phase causes force to fall to zero, whereas without occlusion it tends to stabilize at about 25%.5. The size of the synchronous muscle action potential evoked by ulnar nerve stimulation falls to about 65% of normal, most of this fall occurring in the first phase.6. During recovery after prolonged fatigue, the relation between force and s.r.e. is changed for weak voluntary contractions much more than for strong ones, such that force is less for a given s.r.e. than normal.7. These results are interpreted as evidence that, in a maximal voluntary contraction, neuromuscular junction fatigue is most important at first, but later, contractile element fatigue increases, particularly when the blood supply is obstructed.8. Neuromuscular junction fatigue is believed to be most marked in high threshold motor units, while contractile element fatigue more especially affects low threshold units.
Abstract: Arterial concentrations and net substrate exchange across the leg and splanchnic vascular bed were determined for glucose, lactate, pyruvate, and glycerol in healthy postabsorptive subjects at rest and during 40 min of exercise on a bicycle ergometer at work intensities of 400, 800, and 1200 kg-m/min. Rising arterial glucose levels and small decreases in plasma insulin concentrations were found during heavy exercise. Significant arterial-femoral venous differences for glucose were demonstrated both at rest and during exercise, their magnitude increasing with work intensity as well as duration of the exercise performed. Estimated glucose uptake by the leg increased 7-fold after 40 min of light exercise and 10- to 20-fold at moderate to heavy exercise. Blood glucose uptake could at this time account for 28-37% of total substrate oxidation by leg muscle and 75-89% of the estimated carbohydrate oxidation. Splanchnic glucose production increased progressively during exercise reaching levels 3 to 5-fold above resting values at the heavy work loads. Close agreement was observed between estimates of total glucose turnover during exercise based on leg glucose uptake and splanchnic glucose production. Hepatic gluconeogenesis-estimated from splanchnic removal of lactate, pyruvate, glycerol, and glycogenic amino acids-could supply a maximum of 25% of the resting hepatic glucose production but could account for only 6-11% of splanchnic glucose production after 40 min of moderate to heavy exercise. IT IS CONCLUDED THAT: (a) blood glucose becomes an increasingly important substrate for muscle oxidation during prolonged exercise of this type: (b) peripheral glucose utilization increases in exercise despite a reduction in circulating insulin levels: (c) increased hepatic output of glucose, primarily by means of augmented glycogenolysis, contributes to blood glucose homeostasis in exercise and provides an important source of substrate for exercising muscle.
Abstract: To determine whether chronic exposure to hypoxia during adulthood produces alterations in the control of ventilation, measurements of the resting ventilatory response to hypoxia and hypercapnia, as well as ventilatory response to hypoxia during exercise, were carried out in a group of 10 long-term (3-39 yr) non-native residents of Leadville, Colo. (elevation 3100 m). A group of 8 subjects native to Leadville was also studied and 10 low altitude subjects of Denver, Colo. (elevation 1600 m) served as controls. Hypoxic ventilatory drive was measured as the shape parameter A of isocapnic VE-PA(o2) curves. In the non-native high altitude resident this parameter averaged 43% of the value for low altitude controls (P\textless0.05) denoting a diminished ventilatory response to hypoxia. The degree of attenuation was related to the length of time spent at high altitude. In the high altitude natives the parameter A averaged 9.6% of control (P\textless0.01). Similarly hypercapnic ventilatory drive as measured by the slope of the isoxic VE-PA(co2) lines was reduced in the non-native residents to 65% of control (P\textless0.05) and in the natives averaged 54% of control (P\textless0.01).In contrast with these findings at rest induction of hypoxia during exercise produced an increase in ventilation comparable to that in the controls in both groups of highlanders.Hence chronic exposure to hypoxia during adulthood in man results in marked attenuation of the ventilatory response to hypoxia at rest and this is a function of the length of exposure to hypoxia. This attenuation of the ventilatory response to hypoxia was associated with a decrease in hypercapnic ventilatory drive. The fact that hypoxic ventilatory drive was almost completely absent while hypercapnic drive was only partially reduced parallels closely the more important role of the peripheral chemoreceptors in mediating ventilatory responses to hypoxia than to hypercapnia. This suggests that the alterations in ventilatory control at altitude are due to failure of peripheral chemoreceptor function.
Abstract: Alterations in human cerebral blood flow and related blood constituents were studied during exposure to acute hypoxia. Observations were made during serial inhalation of decreasing O(2) concentrations with and without maintenance of normocarbia, during 8 min inhalation of 10% O(2), and after hyperventilation at an arterial P(O2) of about 40 mm Hg. In the range of hypoxemia studied, from normal down to arterial P(O2) of about 40 mm Hg, the magnitude of the cerebral vasodilator response to hypoxia appeared to be largely dependent upon the coexisting arterial CO(2) tension. The mean slope of the increase in cerebral blood flow with decreasing arterial O(2) tension rose more quickly (P \textless 0.05) when eucapnia was maintained when compared with the slope derived under similar hypoxic conditions without maintenance of eucapnia. When 12 subjects inhaled 10% oxygen, cerebral blood flow rose to more than 135% of control in four whose mean decrease in arterial CO(2) tension was - 2.0 mm Hg. The remaining eight had flows ranging from 97 to 120% of control, and their mean decrease in CO(2) tension was - 5.1 mm Hg. When mean arterial P(O2) was 37 mm Hg, hyperventilation was carried out in 10 subjects. Arterial P(O2) increased insignificantly, arterial P(CO2) declined from 34 to 27 mm Hg (P \textless 0.05), and cerebral blood flow which had been 143% of control decreased to 109%, a figure not significantly different from control.These data demonstrate the powerful counterbalancing constrictor effects of modest reductions in CO(2) tension on the vasodilator influence of hypoxia represented by arterial P(O2) reductions to about 40 mm Hg. Indeed, mild hyperventilation completely overcame the vasodilator effect provided by an arterial O(2) tension as low as 40 mm Hg. The effects of hypoxia on the control of the cerebral circulation must be analyzed in terms of the effects of any associated changes in CO(2) tension.
Abstract: A technique is described which permits the inscription of the ventilatory response to isocapnic hypoxia in man as a continuous curve relating alveolar oxygen tension and minute ventilation. The adjustment of ventilation to changes in alveolar oxygen tension is complete in 18-23 sec and this is sufficiently rapid to justify the use of a non-steady-state method. Changes in alveolar carbon dioxide tension are prevented by addition of carbon dioxide to the inspired gas. The resulting [unk]V(E)-P(Ao2) curves are hyperbolic such that falling P(Ao2) produces only slight rises in [unk]V(E) until a critical P(Ao2) range of 50-60 mm Hg is reached. With further fall in P(Ao2), [unk]V(E) increases steeply and the slope of the curve approaches infinity at a tension of 30-40 mm Hg. For purposes of quantitation these curves are approximated by a simple hyperbolic function, the parameters of which are evaluated by a least squares fit of the data. The parameter A denotes curve shape such that the higher the value of A. the greater the increase in ventilation for a given decrease in P(Ao2) and hence the greater the hypoxic drive. Curves are highly reproducible for each subject and curves from different subjects are similar. In 10 normal subjects at resting P(ACo2), A = 180.2 +/-14.5 (SEM). When P(ACo2) is adjusted to levels 5 mm Hg above and below control in six subjects A = 453.4 +/-103 and 30.2 +/-6.8 respectively. These latter values differed significantly from control (P \textless 0.05). These changes in curve shape provide a clear graphic description of interaction between hypercapnic and hypoxic ventilatory stimuli. At normal P(ACo2) the [unk]V(E)-P(Ao2) curve has an inflection zone located over the same P(o2) range as the inflection in the oxygen-hemoglobin dissociation curve. This indicated that ventilation might be a linear function of arterial oxygen saturation or content. Studies in four subjects have demonstrated that ventilation is indeed related to arterial oxygen content in a linear fashion. These data suggest, but do not prove, that oxygen tension in chemoreceptor tissue as in part determined by circulatory oxygen delivery may be an important factor in controlling the ventilatory response to hypoxia.
Abstract: The development of a glucagon radioimmunoassay with a relatively high degree of specificity for pancreatic glucagon made possible studies of alpha cell function in healthy nondiabetic subjects and in patients with diabetes mellitus. In the former group mean fasting plasma glucagon averaged 108 mumug/ml (SEM +/-10). In 12 juvenile-type diabetics fasting glucagon averaged 110 (+/-9) and in 33 adult-type diabetics the average was 114 (+/-8). The diabetic averages did not differ significantly from the nondiabetic subjects; however, when hyperglycemia was induced by glucose infusion in the nondiabetic subjects so as to simulate the fasting hyperglycemia of the diabetics, mean glucagon fell to 57 mumug (+/-8), which was significantly below the diabetic mean. In 28 healthy subjects the infusion of arginine elicited a rise in glucagon of at least 100 mumug/ml with a peak level averaging 331 mumug/ml (+/-22) at 40 min. This response to arginine was diminished but not abolished during hyperglycemia induced by simultaneous glucose infusion. In everyone of 45 diabetic subjects tested the infusion of arginine elicited a rise in glucagon of at least 140 mumug/ml to levels significantly greater than in nondiabetics. The peak glucagon level in juvenile-type diabetics averaged 458 mumug/ml (SEM +/-36) and in adult-type diabetics averaged 452 mumug/ml (SEM +/-38). The glucagon response to arginine was unrelated to duration of diabetes, to body weight, type of diabetic treatment, or to other known factors. Marked hyperresponsiveness of glucagon to arginine infusion was observed in two patients with advanced Kimmelsteil-Wilson disease. Glucagon levels were markedly elevated in certain patients with severe diabetic ketoacidosis before treatment with insulin. The findings suggest that alpha cell function is inappropriately increased in diabetes mellitus and could play a significant role in the diabetic syndrome.
Abstract: The effects of hematocrit on renal hemodynamics and sodium excretion were studied in anesthetized dogs during both hydropenia and volume expansion. The hematocrit was decreased by isovolemic exchange with the animal’s own previously harvested plasma and increased by isovolemic exchange with fresh, washed red blood cells. Renal perfusion pressure was maintained constant throughout the experiments by the adjustment of a suprarenal aortic clamp. During hydropenia, a decrease in hematocrit was associated with an increase in sodium and potassium excretion and solutefree water reabsorption. These changes were accompained by an increase in renal plasma flow and renal blood flow and a decrease in renal vascular resistance. Glomerular filtration rate was unchanged and filtration fraction was significantly decreased as hematocrit was lowered. Increasing hematocrit during hydropenia had the opposite effects on electrolyte excretion, solute-free water reabsorption, and renal hemodynamics. In another group of animals, hematocrit was lowered during volume expansion with either saline or plasma, then returned to the control level by isovolemic exchange with washed red blood cells. This increase in hematocrit during volume expansion had a similar effect on electrolyte excretion, solute-free water reabsorption, and renal hemodynamics as during hydropenia. These results therefore suggest that acute changes in hematocrit may significantly affect sodium excretion and renal hemodynamics during both hydropenia and volume expansion. The changes in solute-free water reabsorption and potassium excretion suggest that the alterations in hematocrit may affect primarily the reabsorption of sodium in the proximal tubule. The concommitant effects of hematocrit on renal vascular resistance and filtration fraction may mediate this change in sodium reabsorption by altering hydrostatic and oncotic pressures in the peritubular circulation.
Abstract: After the intraperitoneal injection into young mice of 700-800 mg/kg of salicylate, brain glucose fell to one-third or less of control values despite normal plasma glucose levels; brain lactate was nearly doubled and there were small decreases in phosphocreatine (18%) and in glycogen (17%). ATP, pyruvate, alpha-ketoglutarate, and glutamate were unchanged. In liver, glycogen was reduced 79% and lactate was five times higher than in control animals; glucose, glucose-6-phosphate, and ATP were unchanged.Since salicylate uncouples oxidative phosphorylation, it is postulated that high energy phosphate in the brain is maintained near normal levels by a compensatory increase in cerebral glycolysis. Apparently the brain glucose level falls because the rate of utilization exceeds the rate at which glucose can be supplied from the blood. Concurrent administration of glucose with salicylate elevated brain glucose concentration and was associated with striking improvement in the condition and the increased survival of the animals. These findings stress the fact that in salicylate poisoning the supply of glucose to the brain may be inadequate even when blood glucose levels are normal.
Abstract: Plasma renin activity and renin substrate were measured in nine groups of rats which were maintained for 7 wk on diets in which the proportions of sodium and potassium were varied. Balance data indicated that the highest dietary intake of potassium employed (92 mEq K(+)/100 g food) consistently induced sodium depletion. With less consistency, the highest sodium intake employed (52 mEq Na(+)/100 g food) tended to induce potassium depletion.In accordance with previous reports, sodium deprivation induced significant increases in plasma renin activity. But the present results indicated that changes in potassium intake exerted a highly significant modulating influence on this characteristic response. The results describe an inverse relationship between potassium administration and the concurrent level of plasma renin activity. The highest serum renin levels of all occurred in the potassium-depleted animals and the usual renin response to sodium deprivation was virtually abolished in the presence of a high potassium diet. Neither the suppressing effect of K(+) administration nor the stimulating effect of K(+) depletion on plasma renin activity could be explained in terms of any predicted changes in aldosterone secretion or observed changes in sodium balance. Therefore, the effect seems to be mediated by a direct influence of potassium ions on renal renin secretion, perhaps via induced changes in sodium load to the macula densa.These studies point to an important role for potassium in the regulation of renin secretion. The results in turn raise the possibility that renin secretion per se may be importantly involved in effecting potassium conservation and potassium elimination. The means by which these interactions are finally mediated remain to be clarified.
Abstract: The present study was designed to examine the question of whether or not there is a natriuretic hormonal substance involved in the renal regulation of sodium balance.For this purpose, procedures for concentration and fractionation of plasma and urine samples and a sensitive bioassay for demonstrating changes in renal sodium excretion were developed. The natriuretic assay utilized rats with mild diabetes insipidus which were maintained in salt and water balance.Using these approaches a natriuretic humoral substance was demonstrated in plasma and urine from normal man and sheep, and in patients with primary aldosteronism or essential hypertension.It seems likely that this substance participates in day to day regulation of sodium balance because it was not detectable in sodium-depleted subjects and it consistently appeared in the sodium-loaded subjects.The hormonal agent may not act immediately and its activity can be apparent for up to 3 hr. Full expression of its activity requires that the assay animals be appropriately volume expanded. This suggests that the increases in sodium excretion mediated by this hormonal substance depend in part on the coparticipation of other physical and perhaps humoral factors.This natriuretic substance appears to be of large molecular weight or carried by a large molecule. The data suggest that it acts, at least in part, to block sodium reabsorption in a more distal portion of the tubule.
Abstract: Fractional reabsorption of water, sodium, and potassium at proximal and distal tubular sites within the nephron was studied by recollection-micropuncture experiments on dogs undergoing hypertonic mannitol diuresis. After an initial control hydropenic phase, 16% mannitol in modified Ringer’s solution was administered intravenously, resulting in marked increases in fractional excretion of water (28.7%), sodium (12.6%), and potassium (63.9%). Inulin clearance decreased significantly from 35.1 to 25.2 ml/min. Analysis of paired micropuncture data revealed a significant decrease in tubule fluid to plasma (TF:P) inulin ratios in both the proximal tubule (1.63-1.45) and distal tubule (5.38-1.94). There was also a significant decrease in proximal TF:P sodium ratios (0.99-0.93) and potassium ratios (1.05-0.98). Distal TF:P sodium ratios, in contrast, rose significantly (0.38-0.59), while TF:P potassium ratios tended towards unity whether initially greater or less than one. Fractional reabsorption of sodium and water decreased by 5% and 10% respectively in the proximal tubule, but to a lesser extent than the resulting increases in fractional urinary excretion. The nonreabsorbed fraction, however, had increased sharply at the point of distal puncture for water (32%), sodium (26%), and potassium (26%), indicating a large inhibitory effect within the loop of Henle in addition to the smaller proximal effects.
Abstract: The objective of this investigation was to characterize the mechanism of peripheral vasoconstriction observed in heart failure and to determine whether it can be attributed to the augmented sympathetic nervous activity, characteristic of this state. The response of the resistance bed in the forearm after release of inflow occlusion (reactive hyperemia), to hand exercise, and to local heating and the response of the calf resistance vessels to arterial occlusion and intra-arterial sodium nitrite and phentolamine were studied in 23 patients with congestive heart failure and 21 normal subjects. In the normal subjects, reactive hyperemia blood flow after varying periods of arterial occlusion greatly exceeded the values observed in patients with heart failure. Local anesthetic blockade and intra-arterial phentolamine did not significantly alter the reactive hyperemia response in heart failure patients, militating against the possibility that increased sympathetic vasoconstrictor activity is responsible for the reduction of this response. Following compensation, the reactive hyperemia response returned toward normal. The striking elevations of the forearm blood flow observed after hand exercise and heating of the forearm in normal subjects were also markedly attenuated in patients with heart failure. Following intra-arterial phentolamine and/or sodium nitrite, peak calf blood flow was still significantly reduced in heart failure. These observations indicate that (1) heart failure is characterized by a striking reduction in the response to a variety of endogenous and exogenous vasodilator stimuli; (2) circulating catecholamines and sympathetic vasoconstrictor activity are not solely responsible for the elevation of peripheral vascular resistance and the reduced response to vasodilator stimuli in heart failure; and (3) heart failure may increase systemic vascular resistance directly by altering the mechanical properties and reducing the dilating ability of the resistance vessels.
Abstract: It has been postulated that alterations in the intravascular distribution of blood affect antidiuretic hormone (ADH) secretion in man. The studies reported here were designed to alter blood distribution by thermal and by positional change to test this thesis.HUMAN BLOOD ADH LEVELS HAVE BEEN SHOWN TO VARY WITH POSITION: a mean value of 0.4 +/- 0.6 (SD) muU/ml was obtained while the subject was supine, a value of 1.4 +/- 0.7 muU/ml while sitting, and 3.1 +/- 1.5 muU/ml while standing. In 79 control subjects, sitting comfortably for 30 min in a normal environment, a blood ADH level of 1.65 +/- 0.63 muU/ml was found. It is suggested that subjects assume this position during experiments in which blood is drawn for measurement of ADH levels.In eight seated subjects the ADH level rose from 1.6 +/- 0.4 to 5.2 +/- 0.8 muU/ml after a 2 hr exposure at 50 degrees C and fell to 1.0 +/- 0.26 muU/ml within 15 min at 26 degrees C.Six subjects with a mean ADH level of 2.2 +/- 0.58 muU/ml sat quietly in the cold (13 degrees C) for 1 hr, and the ADH level fell to 1.2 +/- 0.36 muU/ml. After 15 min at 26 degrees C, the level rose to 3.1 +/- 0.78 muU/ml. The serum sodium and osmolal concentrations remained constant during all studies.Water, sodium, and total solute excretion decreased during exposure to the heat, whereas the urine to plasma (U/P) osmolal ratio increased. During cold exposure, water, sodium, and total solute excretion increased, and there was a decrease in the U/P osmolal ratio.These data are interpreted as indicating that changes in activity of intrathoracic stretch receptors, in response to redistribution of blood, alter ADH secretion independently of changes in serum osmolality. The rapidity of change of blood ADH concentration indicates a great sensitivity and a prime functional role for the "volume receptors" in the regulation of ADH secretion.
Abstract: 1. The contractile responses of helically cut vascular strips of chickens to vasoactive agents were studied.2. Large pulmonary arteries were contracted by neurohypophysial peptides, but not by angiotensin, acetylcholine, histamine, 5-hydroxytryptamine, bradykinin or eledoisin. The activity of oxytocin was greater than that of arginine vasopressin.3. Vasodilator effects of oxytocin upon small (200-500 mu diameter) mesenteric and muscular arteries were demonstrable, but inconsistent.4. Magnesium potentiated in a parallel fashion the vasoconstrictor effects of oxytocin and of arginine vasopressin.5. Deamino-oxytocin was potentiated by magnesium. This finding suggests a difference between the peptide-protein interactions of tissue receptors and those of neurophysin.
