Abstract: Through oxygen-dependent release of the vasodilator ATP, the mobile erythrocyte plays a fundamental role in matching microvascular oxygen supply with local tissue oxygen demand. Signal transduction within the erythrocyte and microvessels as well as feedback mechanisms controlling ATP release have been described. Our understanding of the impact of this novel control mechanism will rely on the integration of in vivo experiments and computational models.
Abstract: It has been difficult to establish whether we are limited to the heart muscle cells we are born with or if cardiomyocytes are generated also later in life. We have taken advantage of the integration of carbon-14, generated by nuclear bomb tests during the Cold War, into DNA to establish the age of cardiomyocytes in humans. We report that cardiomyocytes renew, with a gradual decrease from 1% turning over annually at the age of 25 to 0.45% at the age of 75. Fewer than 50% of cardiomyocytes are exchanged during a normal life span. The capacity to generate cardiomyocytes in the adult human heart suggests that it may be rational to work toward the development of therapeutic strategies aimed at stimulating this process in cardiac pathologies.
Abstract: Chronic hyperglycemia contributes to the development of diabetes-associated complications. Increases in the concentration of circulating glucose activate the hexosamine biosynthetic pathway (HBP) and promote the O-glycosylation of proteins by O-glycosyl transferase (OGT). We show that OGT triggered hepatic gluconeogenesis through the O-glycosylation of the transducer of regulated cyclic adenosine monophosphate response element-binding protein (CREB) 2 (TORC2 or CRTC2). CRTC2 was O-glycosylated at sites that normally sequester CRTC2 in the cytoplasm through a phosphorylation-dependent mechanism. Decreasing amounts of O-glycosylated CRTC2 by expression of the deglycosylating enzyme O-GlcNAcase blocked effects of glucose on gluconeogenesis, demonstrating the importance of the HBP in the development of glucose intolerance.
Abstract: The renin-angiotensin system in the brain acts to regulate a number of physiological processes. Evidence suggests that angiotensin peptides may act as neurotransmitters, although their biosynthetic pathways are poorly understood. We review evidence for neuronal production of angiotensin peptides and hypothesize that angiotensin may be synthesized intracellularly in neurons.
Abstract: Myogenic constriction is a vasoconstriction of blood vessels to increases in perfusion pressure. In renal preglomerular vasculature, it is an established mechanism of renal blood flow autoregulation. Recently, myogenic constriction has been identified as an important protective mechanism, preventing the transmission of systemic pressure to the fragile glomerular vasculature. Although the signal transduction pathways mediating vasoconstriction are well known, how the increases in pressure trigger vasoconstriction is unclear. The response is initiated by pressure-induced stretch of the vessel wall and thus is dependent on mechanical signaling. The identity of the sensor detecting VSMC stretch is unknown. Previous studies have considered the role of extracellular matrix-integrin interactions, ion conduction units (channels and/or transporters), and the cytoskeleton as pressure detectors. Whether, and how, these structures fit together in VSMCs is poorly understood. However, a model of mechanotransduction in the nematode Caenorhadbditis elegans (C. elegans) has been established that ties together extracellular matrix, ion channels, and cytoskeletal proteins into a large mechanosensing complex. In the C. elegans mechanotransducer model, a family of evolutionarily conserved proteins, referred to as the DEG/ENaC/ASIC family, form the ion-conducting pore of the mechanotransducer. Members of this protein family are expressed in VSMC where they may participate in pressure detection. This review will address how the C. elegans mechanotransducer model can be used to model pressure detection in mammalian VSMCs and provide a new perspective to pressure detection in VSMCs.
Abstract: OBJECTIVE: To determine the size of the baboon corpus luteum (CL) and levels of plasma P, 17alpha-hydroxyprogesterone (17-OHP), and E2 in the ovarian vein draining it, the contralateral ovarian vein, and peripheral blood throughout the luteal phase of the menstrual cycle. DESIGN: Prospective study. SETTING: Academic department of obstetrics and gynecology in a US medical school. ANIMAL(S): Corpora lutea from a cohort of 27 adult cycling baboons (Papio anubis). INTERVENTION(S): Timed luteectomy. MAIN OUTCOME MEASURE(S): The authors weighed 166 CL and measured plasma P, 17-OHP, and E(2) in the blood samples obtained at luteectomy. RESULT(S): Early luteal phase corpora lutea weighed 189.1 +/- 12.3 mg (mean +/- SEM); their weight significantly increased to 239.4 +/- 8.4 mg at mid luteal phase and significantly declined to 188.3 +/- 14.0 mg in late luteal phase. Plasma P draining the CL (134.4 +/- 20.5 ng/mL in early, 167.4 +/- 18.7 ng/mL in mid, and 126.4 +/- 23.4 ng/mL in late luteal phase) was significantly higher than that in contralateral ovarian (11.0 +/- 1.4 ng/mL) and peripheral plasma (7.1 +/- 0.9 ng/mL). Similarly, levels of both plasma 17-OHP (10.9 +/- 1.5 to 15.9 +/- 2.4 ng/mL) and E2 (1.6 +/- 0.2 to 2.6 +/- 0.6 ng/mL) draining the CL were significantly higher than those from the contralateral ovary and peripheral blood (17-OHP, 1.1 +/- 0.2 ng/mL; E2, 0.2 +/- 0.05 ng/mL). CONCLUSION(S): Largest in mid luteal phase, the baboon CL secretes P, 17-OHP, and E2 throughout the luteal phase, with the highest levels seen in the ovarian vein draining the CL in the mid compared with the early and late luteal phases.
Abstract: Several studies have shown that healthy individuals with fasting plasma glucose (FPG) levels at the high end of the normal range have an increased risk of mortality. To identify genetic determinants that contribute to interindividual variation in FPG, we tested 392,935 single-nucleotide polymorphisms (SNPs) in 654 normoglycemic participants for association with FPG, and we replicated the most strongly associated SNP (rs560887, P = 4 x 10(-7)) in 9353 participants. SNP rs560887 maps to intron 3 of the G6PC2 gene, which encodes glucose-6-phosphatase catalytic subunit-related protein (also known as IGRP), a protein selectively expressed in pancreatic islets. This SNP was associated with FPG (linear regression coefficient beta = -0.06 millimoles per liter per A allele, combined P = 4 x 10(-23)) and with pancreatic beta cell function (Homa-B model, combined P = 3 x 10(-13)) in three populations; however, it was not associated with type 2 diabetes risk. We speculate that G6PC2 regulates FPG by modulating the set point for glucose-stimulated insulin secretion in pancreatic beta cells.
Abstract: A significant fraction of astronauts experience postflight orthostatic intolerance (POI) during 10-min stand tests conducted on landing day. The average time that nonfinishers can stand is about 7 min. This phenomenon, including the delay in occurrence of presyncope, was studied with a five-compartment model of the cardiovascular system incorporating compartments for the heart/lungs, systemic arteries and cephalic, central, and caudal veins. The model included 28 independent parameters, including factors characterizing cardiac performance, vascular resistance, intrathoracic pressure, nonlinear venous compliance and circulating blood volume, and 13 dependent parameters, including cardiac output and cardiac and vascular compartment pressures and volumes. First, a sensitivity analysis of hemodynamic indicators of presyncope to independent parameters was performed. Results demonstrated that both cardiac output and arterial pressure were most sensitive to volume-related parameters, particularly total blood volume, and less sensitive to peripheral resistance. Next, a simulated postflight stand test confirmed that fluid loss due to capillary filtration, particularly from the caudal region where transmural pressure is high during standing, is a plausible mechanism of POI that also explains the delayed onset of symptoms in most astronauts. An accumulated drop in arterial pressure sufficient to compromise cerebral perfusion and, therefore, cause syncope was reached in about 7 min with a fluid loss of 280 mL. Finally, additional simulations showed that a 75% increase in peripheral resistance, similar to finishers of stand tests, was insufficient to overcome the loss of circulating fluid associated with capillary filtration, and extended the time that the modeled astronaut could stand by only about 1 min. It is therefore concluded that capillary filtration may play a key role in producing POI and that development of countermeasures should perhaps focus on reducing postflight capillary permeability or on stimulating volume-compensating mechanisms.
Abstract: New strategies for prevention and treatment of type 2 diabetes (T2D) require improved insight into disease etiology. We analyzed 386,731 common single-nucleotide polymorphisms (SNPs) in 1464 patients with T2D and 1467 matched controls, each characterized for measures of glucose metabolism, lipids, obesity, and blood pressure. With collaborators (FUSION and WTCCC/UKT2D), we identified and confirmed three loci associated with T2D-in a noncoding region near CDKN2A and CDKN2B, in an intron of IGF2BP2, and an intron of CDKAL1-and replicated associations near HHEX and in SLC30A8 found by a recent whole-genome association study. We identified and confirmed association of a SNP in an intron of glucokinase regulatory protein (GCKR) with serum triglycerides. The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues to the pathogenesis of common diseases.
Abstract: Studies of the fat-derived hormone leptin have provided key insights into the molecular and neural components of feeding behavior and body weight regulation. An important challenge lies in understanding how the rewarding properties of food interact with, and can override, physiological satiety signals and promote overeating. We used functional magnetic resonance imaging to measure brain responses in two human patients with congenital leptin deficiency who were shown images of food before and after 7 days of leptin replacement therapy. Leptin was found to modulate neural activation in key striatal regions, suggesting that the hormone acts on neural circuits governing food intake to diminish the perception of food reward while enhancing the response to satiety signals generated during food consumption.
Abstract: During spaceflight the normal head-to-foot hydrostatic pressure gradients are eliminated and body fluids shift toward the head, resulting in a diminished fluid volume in the legs and an increased fluid volume in the head, neck, and upper extremities. Lymphatic function is important in the maintenance of normal tissue fluid volume, but it is not clear how microgravity influences lymphatic pumping. We performed a detailed evaluation of the influence of simulated microgravity on lymphatic diameter, wall thickness, elastance, tone, and other measures of phasic contractility in isolated lymphatics. Head-down tail suspension (HDT) rats were used to simulate the effects of microgravity. Animals were exposed to HDT for 2 wk, after which data were collected and compared with the control non-HDT group. Lymphatics from four regional lymphatic beds (thoracic duct, cervical, mesenteric, and femoral lymphatics) were isolated, cannulated, and pressurized. Input and output pressures were adjusted to apply a range of transmural pressures and flows to the lymphatics. Simulated microgravity caused a potent inhibition of pressure/stretch-stimulated pumping in all four groups of lymphatics. The greatest inhibition was found in cervical lymphatics. These findings presumably are correlated to the cephalic fluid shifts that occur in HDT rats as well as those observed during spaceflight. Flow-dependent pump inhibition was increased after HDT, especially in the thoracic duct. Mesenteric lymphatics were less strongly influenced by HDT, which may support the idea that lymph hydrodynamic conditions in the mesenteric lymphatic during HDT are not dramatically altered.
Abstract: Muscle atrophy results from a variety of conditions such as disease states, neuromuscular injuries, disuse, and aging. Absence of gravitational loading during spaceflight or long-term bed rest predisposes humans to undergo substantial loss of muscle mass and, consequently, become unfit and/or unhealthy. Disuse- or inactivity-induced skeletal muscle protein loss takes place by differential modulation of proteolytic and synthetic systems. Transcriptional, translational, and posttranslational events are involved in the regulation of protein synthesis and degradation in myofibers, and these regulatory events are known to be responsive to contractile activity. However, regardless of the numerous studies which have been performed, the intracellular signals that mediate skeletal muscle wasting due to muscular disuse are not completely comprehended. Understanding the triggers of atrophy and the mechanisms that regulate protein loss in unloaded muscles may lead to the development of effective countermeasures such as exercise and dietary intervention. The objective of the present review is to provide a window into the molecular processes that underlie skeletal muscle remodeling and to examine what we know about exercise and nutrition countermeasures designed to minimize muscle atrophy.
Abstract: RATIONALE: The intimate mechanisms of early onset anemia observed in critically ill patients with septic shock remain unclear. OBJECTIVES: We investigated erythropoiesis abnormalities in this setting by studying morphologic, functional, and biochemical patterns of erythroid lineage. METHODS: Erythroid lineage in the bone marrow from patients with septic shock who developed early-onset anemia was compared with that of healthy control subjects. Survival and proliferation capacities were quantified in both groups. Biochemical and flow cytometry patterns of apoptosis were dissected by exploring antiapoptotic (erythropoietin [Epo] receptor-dependent) and proapoptotic (death receptor-dependent) pathways. MEASUREMENTS AND MAIN RESULTS: Erythroid lineage was morphologically similar in both groups. Apoptosis of glycophorin-A-positive erythroid precursors was increased in patients versus control subjects as assessed by labeling with annexin V (26.1 +/- 8.8 vs. 3.1 +/- 2.9%, p \textbackslashtextless 0.05) or 3-3’-dihexyloxacarbocyanine iodide (55.9 +/- 10.5 vs. 19.1 +/- 5.4%, p \textbackslashtextless 0.05), respectively. This was associated with significant overexpression of Fas on erythroid precursors and higher tumor necrosis factor-alpha plasma levels in patients with septic shock vs. control subjects. Moreover, growth capacities of late erythroid progenitors of burst-forming unit erythroids (BFU-Es) at Day 10 were impaired in the presence of serum from patients with septic shock as compared with the effect of serum from control subjects (27 +/- 12 vs. 109 +/- 27 per 10(5) seeded cells, respectively; p \textbackslashtextless 0.001). Saturating concentrations of recombinant human Epo (rHuEpo) restored growth capacity of patients’ BFU-Es (72 +/- 14 per 10(5) seeded cells) in autologous conditions of serum. CONCLUSIONS: Early-onset anemia that may be observed in patients with septic shock is associated with defective erythropoiesis related to an excess of apoptosis that can be counterbalanced in vitro by rHuEpo.
Abstract: The mammalian Target of Rapamycin (mTOR) protein is a serine-threonine kinase that regulates cell-cycle progression and growth by sensing changes in energy status. We demonstrated that mTOR signaling plays a role in the brain mechanisms that respond to nutrient availability, regulating energy balance. In the rat, mTOR signaling is controlled by energy status in specific regions of the hypothalamus and colocalizes with neuropeptide Y and proopiomelanocortin neurons in the arcuate nucleus. Central administration of leucine increases hypothalamic mTOR signaling and decreases food intake and body weight. The hormone leptin increases hypothalamic mTOR activity, and the inhibition of mTOR signaling blunts leptin’s anorectic effect. Thus, mTOR is a cellular fuel sensor whose hypothalamic activity is directly tied to the regulation of energy intake.
Abstract: Little is known about the acute regulation of adiponectin in humans. In animal studies, adiponectin increases the clearance of free fatty acids (FFA) from the circulation by increasing skeletal uptake and oxidation of lipid, thereby regulating the FFA concentration. However, it is unknown if FFA regulate adiponectin. The aim of the present study was to investigate the effect of an acute reduction in free fatty acids on adiponectin concentration in healthy subjects. Ten normal male subjects were admitted for 2 inpatient visits and randomized to receive either acipimox (500 mg orally at 2 am and again at 6 am) or placebo on the first visit and vice versa on the second visit. Adiponectin, FFA, insulin and glucose were measured at 7:45 am. FFA concentrations were significantly lower after acipimox than placebo administration (0.08 +/- 0.02 mEq/L v 0.35 +/- 0.53 mEq/L, P \textbackslashtextless.05). Adiponectin concentrations were also significantly lower after acipimox than placebo administration (7.4 +/- 1.2 microg/mL v 10.3 +/- 1.7 microg/mL, P \textbackslashtextless.05). The change in FFA between acipimox and placebo correlated significantly with the change in adiponectin (r = 0.66, P \textbackslashtextless.05), eg, the larger the reduction in FFA in response to acipimox, the larger the reduction in adiponectin. These results suggest that acute lowering of FFA is associated with decreased adiponectin concentrations.
Abstract: That obesity is associated with insulin resistance and type II diabetes mellitus is well accepted. Overloading of white adipose tissue beyond its storage capacity leads to lipid disorders in non-adipose tissues, namely skeletal and cardiac muscles, pancreas, and liver, effects that are often mediated through increased non-esterified fatty acid fluxes. This in turn leads to a tissue-specific disordered insulin response and increased lipid deposition and lipotoxicity, coupled to abnormal plasma metabolic and (or) lipoprotein profiles. Thus, the importance of functional adipocytes is crucial, as highlighted by the disorders seen in both "too much" (obesity) and "too little" (lipodystrophy) white adipose tissue. However, beyond its capacity for fat storage, white adipose tissue is now well recognised as an endocrine tissue producing multiple hormones whose plasma levels are altered in obese, insulin-resistant, and diabetic subjects. The consequence of these hormonal alterations with respect to both glucose and lipid metabolism in insulin target tissues is just beginning to be understood. The present review will focus on a number of these hormones: acylation-stimulating protein, leptin, adiponectin, tumour necrosis factor alpha, interleukin-6, and resistin, defining their changes induced in obesity and diabetes mellitus and highlighting their functional properties that may protect or worsen lipid metabolism.
Abstract: Resistin is an adipose-derived hormone that has been proposed as a link among obesity, insulin resistance, and diabetes. In agreement with a role of resistin in insulin resistance, the administration of recombinant resistin led to glucose intolerance in mice and impaired insulin action in rat liver. However, the regulation of resistin expression by physiological conditions, hormones, or agents known to modulate insulin sensitivity does not always support the association between resistin and obesity-induced insulin resistance. In the present study we investigated the effects of leptin administration on adipose resistin expression in insulin-resistant and obese ob/ob mice. We show that the expression of resistin mRNA and protein in adipose tissue is lower in ob/ob than in wild-type control mice, in agreement with the reduced adipocyte resistin mRNA level reported in several models of obesity. Leptin administration in ob/ob mice resulted in improvement of insulin sensitivity concomitant with a decrease in resistin gene expression. The lack of effect of leptin on resistin in db/db mice indicated that the leptin inhibitory action on resistin expression requires the long leptin receptor isoform. In addition, we demonstrated that the effect of leptin on resistin expression was centrally mediated. High-fat feeding in C57BL/6J wild-type mice, which is known to induce the development of obesity and insulin resistance, produced an increase in resistin expression. Interestingly, in both ob/ob and high fat-fed mice we obtained a striking positive correlation between glycemia and resistin gene expression. In conclusion, our results demonstrate that leptin decreases resistin expression and suggest that resistin may influence glucose homeostasis.
Abstract: Inherited defects in signaling pathways downstream of the insulin receptor have long been suggested to contribute to human type 2 diabetes mellitus. Here we describe a mutation in the gene encoding the protein kinase AKT2/PKBbeta in a family that shows autosomal dominant inheritance of severe insulin resistance and diabetes mellitus. Expression of the mutant kinase in cultured cells disrupted insulin signaling to metabolic end points and inhibited the function of coexpressed, wild-type AKT. These findings demonstrate the central importance of AKT signaling to insulin sensitivity in humans.
Abstract: The G protein alpha-subunit Gsalpha is required for hormone-stimulated cAMP generation. The Gsalpha gene Gnas is a complex gene with multiple imprinted gene products. Mice with heterozygous disruption of the Gnas paternal allele (+/p-) are partially Gsalpha deficient and totally deficient in XLalphas, a neuroendocrine-specific Gsalpha isoform that is expressed only from the paternal Gnas allele. We previously showed that these mice are hypermetabolic and lean and have increased insulin sensitivity. We now performed hyperinsulinemic-euglycemic clamp studies, which confirmed the markedly increased whole body insulin sensitivity in +/p- mice. +/p- mice had 1.4-, 7- and 3.8-fold increases in insulin-stimulated glucose uptake in muscle and white and brown adipose tissue, respectively, and markedly suppressed endogenous glucose production from the liver. This was associated with increased phosphorylation of insulin receptor and a downstream effector (Akt kinase) in both liver and muscle in response to insulin. Triglycerides cleared more rapidly in +/p- mice after a bolus administered by gavage. This was associated with decreased liver and muscle triglyceride content and increased muscle acyl-CoA oxidase mRNA expression. Resistin and adiponectin were overexpressed in white adipose tissue of +/p- mice, although there was no difference in serum adiponectin levels. The lean phenotype and increased insulin sensitivity observed in +/p- mice is likely a consequence of increased lipid oxidation in muscle and possibly other tissues. Further studies will clarify whether XLalphas deficiency is responsible for these effects and if so, the mechanism by which XLalphas deficiency leads to this metabolic phenotype.
Abstract: We investigated the capacity for torque development and muscle activation at the onset of fast voluntary isometric knee extensions at 30, 60, and 90 degrees knee angle. Experiments were performed in subjects (n = 7) who had high levels (\textbackslashtextgreater90%) of activation at the plateau of maximal voluntary contractions. During maximal electrical nerve stimulation (8 pulses at 300 Hz), the maximal rate of torque development (MRTD) and torque time integral over the first 40 ms (TTI40) changed in proportion with torque at the different knee angles (highest values at 60 degrees ). At each knee angle, voluntary MRTD and stimulated MRTD were similar (P \textbackslashtextless 0.05), but time to voluntary MRTD was significantly longer. Voluntary TTI40 was independent (P \textbackslashtextgreater 0.05) of knee angle and on average (all subjects and angles) only 40% of stimulated TTI40. However, among subjects, the averaged (across knee angles) values ranged from 10.3 +/- 3.1 to 83.3 +/- 3.2% and were positively related (r2 = 0.75, P \textbackslashtextless 0.05) to the knee-extensor surface EMG at the start of torque development. It was concluded that, although all subjects had high levels of voluntary activation at the plateau of maximal voluntary contraction, among subjects and independent of knee angle, the capacity for fast muscle activation varied substantially. Moreover, in all subjects, torque developed considerably faster during maximal electrical stimulation than during maximal voluntary effort. At different knee angles, stimulated MRTD and TTI40 changed in proportion with stimulated torque, but voluntary MRTD and TTI40 changed less than maximal voluntary torque.
Abstract: The loss of normal weight-bearing activity, which occurs during bed rest, limb immobilization, and spaceflight, stimulates a catabolic response within the musculoskeletal system, which results in a loss of skeletal muscle mass and bone mineral. The mechanism by which loading of muscle and bone is sensed and translated into signals controlling tissue formation remains a major question in the field of musculoskeletal research. In this investigation, we have examined the ability of two potentially anti-atrophic proteins, IGF-I and Shh, to inhibit disuse atrophy within muscle and bone, when electroporated into skeletal muscle. We have found that electroporation and ectopic expression of IGF-I and/or Shh within the gastrocnemius/soleus muscle significantly stimulated muscle fiber hypertrophy and increases in muscle size. In addition, we report that electroporation and ectopic expression of IGF-I and/or Shh within the gastrocnemius/soleus muscle attenuated the lost of muscle fiber area, muscle mass, and muscle mass density that normally occurs during disuse muscle atrophy. Finally, we found that ectopic expression of IGF-I and Shh within the gastrocnemius/soleus muscle inhibits parameters of osteopenia within the tibia and fibula associated with hindlimb unloading. These results support the theory that skeletal muscle can regulate bone maintenance and could offer potentially novel and efficient therapeutic options for attenuating muscle and bone atrophy during aging, illness and spaceflight.
Abstract: The discovery of leptin in 1994 has led to astonishing advances in understanding the regulation of energy balance in rodents and humans. The demonstration of leptin receptors in hypothalamic regions known to play critical roles in regulating energy intake and body weight has produced considerable excitement in the field. Most attention has focused on the central actions of leptin. The receptor is present in several populations of neurons that express specific appetite-regulating neuropeptides for which both expression and release are regulated by leptin. Recent advances show that central leptin action is not limited to influencing energy balance. Leptin regulates a broad variety of processes and behaviors, such as blood pressure, neuroendocrine axes, bone mass, and immune function. The cloning of leptin receptors also led to parallel studies examining their signaling capacities in mammalian cell lines. The long-form receptor regulates multiple intracellular signaling cascades, including the classic janus activating kinase-signal transducer and activator of transcription (JAK-STAT) pathway, consistent with belonging to the cytokine-receptor superfamily and the phosphoinositol-3 kinase and adenosine monophosphate kinase pathways. Progress has been made in understanding the role of individual signaling pathways in vivo and the mechanisms by which specific neuropeptides are regulated. Regulation of the pro-opiomelanocortin (pomc) and the thyrotropin-releasing hormone (trh) genes by leptin is particularly well understood. Novel players in negative regulation of central leptin receptor signaling have been identified and open the possibility that these may be important in the development of leptin resistance and obesity. While initial focus was on the central effects of leptin, important actions have been discovered in peripheral tissues. These include roles of leptin to directly regulate immune cells, pancreatic beta cells, adipocytes, and muscle cells. Recent elucidation of a new signaling pathway in skeletal muscle affecting fatty acid metabolism has implications for regulation of insulin sensitivity and glucose metabolism. Recent progress in understanding central and peripheral leptin receptor signaling provides potential new targets for anti-obesity and anti-diabetes drug development.
Abstract: The aim of this study was to establish a diabetic model of primary human adipocytes for investigating potential defects in early insulin signalling. Specimens of human subcutaneous adipose tissue were obtained during orthopaedic surgical procedures. Preadipocytes were isolated and differentiated to adipocytes. Western blot analysis and immunoprecipitation were performed to determine protein content of IRS-1, IRS-2, p85, phosphorylation of IRS-1, IRS-2, Akt and MAPK as well as association between p85 and IRS-1/IRS-2. In addition to short-term insulin stimulation, the effect of hyperinsulinaemia was investigated by treating cells with insulin over a period of 36 hours. We found a significantly reduced basal expression of IRS-1 (54 +/- 15%) in adipocytes from type 2 diabetic subjects compared to controls with a further significant reduction in expression after long-term treatment (30 +/- 12%) compared to short-term treatment. IRS-2 expression also showed a significant reduction under hyperinsulinaemic conditions (20 +/- 2%) in diabetics vs. controls. Furthermore, long-term treatment with insulin in diabetic adipocytes led to a significant reduction in the phosphorylation of IRS-1(68 +/- 11%), IRS-2 (82 +/- 11%), Akt (42 +/- 2%), and MAPK (92 +/- 12%) and in the subsequent association between p85 to IRS-1 and IRS-2 (100 +/- 16% and 96 +/- 12%) in comparison to controls. Investigating glucose uptake diabetic adipocytes revealed a significant reduction of 90 +/- 2%. In this study, we were able to establish a new diabetic model of primary human adipocytes. A defect in early insulin signalling in type 2 diabetic patients under hyperinsulinaemic conditions was determined. These results might help to give further insights in early insulin action; additionally, this human model represents a useful target for the study of new therapeutic approaches.
Abstract: This study examined the importance of aldosterone (ALDO) in mediating changes in renal function and increased mean arterial pressure (MAP) during the development of dietary-induced obesity in chronically instrumented dogs. Mean arterial pressure, heart rate (HR), and cardiac output (CO) were recorded 24 hours per day in lean dogs (n=7) before and after administration of an ALDO antagonist, eplerenone (EP) (10 mg/kg twice daily), for 10 days. After 10 days of EP treatment, the dogs (n=7) were given a supplement of cooked beef fat for 5 weeks while EP was continued. An untreated group (n=6) was fed a high fat diet for 5 weeks and used as control (C). In lean dogs, EP decreased MAP from 89+/-4 to 84+/-4 mm Hg and glomerular filtration rate from 67.4+/-6.8 to 53.2+/-4.9 mL/min while inducing a small negative Na+ balance (-42+/-12 mEq). Plasma renin activity increased from 0.4+/-0.1 to 2.7+/-0.7 ng AI/mL per hour and plasma K+ increased from 4.8+/-0.1 to 6.1+/-0.3 mEq/L. After 5 weeks of a high fat diet, body weight increased 45% to 53% in EP and C obese dogs. In C dogs, MAP increased by 16+/-3 mm Hg, compared with only 7+/-1 mm Hg in EPLE dogs. Compared with untreated dogs, the EP dogs had smaller increases in CO (18+/-4.6% versus 43+/-1.5%), HR (33+/-5% versus 60+/-3%), glomerular filtration rate (19+/-5% versus 38+/-6%), and cumulative Na+ balance (138+/-35 mEq versus 472+/-110 mEq) after 5 weeks of a high fat diet. Thus, EP markedly attenuated glomerular hyperfiltration, sodium retention, and hypertension associated with chronic dietary-induced obesity. These observations indicate that ALDO plays an important role in the pathogenesis of obesity hypertension.
Abstract: Ghrelin is a recently discovered gastric peptide that increases appetite, glucose oxidation, and lipogenesis and stimulates the secretion of GH. In contrast to ghrelin, GH promotes lipolysis, glucose production, and insulin secretion. Both ghrelin and GH are suppressed by intake of nutrients, especially glucose. The role of GH in the regulation of ghrelin has not yet been established. We investigated the effect of GH on circulating levels of ghrelin in relation to its effects on glucose, insulin, body composition, and the adipocyte-derived peptides leptin and adiponectin. Thirty-six patients with adult-onset GH deficiency received recombinant human GH for 9 months in a placebo-controlled study. Body composition and fasting serum analytes were assessed at baseline and at the end of the study. The GH treatment was accompanied by increased serum levels of IGF-I, reduced body weight (-2%) and body fat (-27%), and increased serum concentrations of glucose (+10%) and insulin (+48%). Ghrelin levels decreased in 30 of 36 subjects by a mean of -29%, and leptin decreased by a mean of -24%. Adiponectin increased in the women only. The decreases in ghrelin and leptin correlated with changes in fat mass, fat-free mass, and IGF-I. The reductions in ghrelin were predicted independently of the changes in IGF-I and fat mass. It is likely that the reductions in ghrelin and leptin reflect the metabolic effects of GH on lipid mobilization and glucose production. Possibly, a suppression of ghrelin promotes loss of body fat in GH-deficient patients receiving treatment. The observed correlation between the changes in ghrelin and IGF-I may suggest that the GH/IGF-I axis has a negative feedback on ghrelin secretion.
Abstract: BACKGROUND: Simple obesity and Cushing’s syndrome (CS) are two clinical models of leptin hypersecretion coupled with GH hyposecretion. Fasting inhibits leptin while stimulating GH secretion in normal human subjects. OBJECTIVES: To clarify the effect of fasting on leptin and GH secretion in obesity and CS. PATIENTS AND PROTOCOL: We studied six women with CS [age 17-66 years; body mass index (BMI) 28.6 kg/m2], seven women with visceral obesity (OB; 20-41 years; BMI 42.9 kg/m2) and seven normal women (NS; 25-31 years; BMI 19.3 kg/m2). The effects of 36-h fasting on 8-h diurnal mean leptin, GH, insulin and glucose concentrations (mLEPTc, mGHc, mINSc and mGLUc) as well as on the IGF/IGFBP system were studied. RESULTS: Before fasting, mLEPTc in OB and in CS were similar and both were higher (P \textbackslashtextless 0.01) than in NS. OB and CS showed similar mGHc, which were lower (P \textbackslashtextless 0.05) than in NS. Fasting induced a reduction in mLEPTc that was significant in NS and CS (P \textbackslashtextless 0.04) but not in OB. The mLEPTc in OB and CS after fasting remained higher (P \textbackslashtextless 0.05) than in NS. After fasting, OB and CS showed no increase in mGHc, although this clearly increased (P \textbackslashtextless 0.02) in NS. IGF-I but not IGFBP-3 levels decreased in all groups (P \textbackslashtextless 0.05). Fasting reduced mINSc and mGLUc while increasing IGFBP-1 in all groups. After fasting, mINSc in OB and CS remained higher (P \textbackslashtextless 0.03) than in NS. CONCLUSIONS: Short-term fasting has less inhibitory effect on leptin and no stimulatory effect on GH secretion in patients with Cushing’s syndrome as well as simple obesity. After fasting, insulin levels in hypercortisolaemic and also in obese patients remained higher than in normal subjects suggesting that hyperinsulinism could play a role in the altered response of leptin and GH to starvation in these conditions.
Abstract: Obesity has become an epidemic problem in western societies, contributing to metabolic diseases, hypertension, and cardiovascular disease. Overweight and obesity are frequently associated with increased plasma levels of aldosterone. Recent evidence suggests that human fat is a highly active endocrine tissue. Therefore, we tested the hypothesis that adipocyte secretory products directly stimulate adrenocortical aldosterone secretion. Secretory products from isolated human adipocytes strongly stimulated steroidogenesis in human adrenocortical cells (NCI-H295R) with a predominant effect on mineralocorticoid secretion. Aldosterone secretion increased 7-fold during 24 h of incubation. This stimulation was comparable to maximal stimulation of these cells with forskolin (2 x 10(-5) M). On the molecular level, there was a 10-fold increase in the expression of steroid acute regulatory peptide mRNA. This effect was independent of adipose angiotensin II as revealed by the stimulatory effect of fat cell-conditioned medium even in the presence of the angiotensin type 1 receptor antagonist, valsartan. None of the recently defined adipocytokines accounted for the effect. Mineralocorticoid-stimulating activity was heat sensitive and could be blunted by heating fat cell-conditioned medium to 99 degrees C. Centrifugal filtration based on molecular mass revealed at least two releasing factors: a heat sensitive fraction (molecular mass \textbackslashtextgreater50 kDa) representing 60% of total activity, and an inactive fraction (molecular mass \textbackslashtextless50 kDa). However, the recovery rate increased to 92% when combining these two fractions, indicating the interaction of at least two factors. In conclusion, human adipocytes secrete potent mineralocorticoid-releasing factors, suggesting a direct link between obesity and hypertension.
Abstract: A new framework for understanding the control of feeding behavior, with special emphasis on the evolution of hunger, the initiation of feeding, and its dependence on patterns of blood glucose, is the subject of this review. A perspective on the current status and future directions of this search for a more complete understanding of the regulation of feeding behavior in laboratory rats and humans is presented including theoretical and experimental components. First, a historical perspective on the role of blood glucose in the control of feeding is presented. Next, the theoretical approaches that have been applied to the control of feeding and had a strong influence on experimental feeding research are summarized. This is followed by a statement and overview of a current theory that has emerged from studies of the role of transient declines in blood glucose in the control of meal initiation. The current working hypothesis that transient declines in blood glucose are endogenous metabolic patterns that are detected and recognized by the central nervous system and are mapped into meal initiation in rats and are correlated with meal requests in humans are then presented. Then, the experimental studies on meal initiation and its dependence on patterns of blood glucose, first in rats and then in humans, are reviewed in detail. Finally, the future directions of the work, limitations, and the implications for the understanding of the control of feeding behavior and the regulation of energy balance are discussed.
Abstract: Immune-mediated renal diseases can be classified by the clinical syndromes they produce, by the attendant renal pathology, or by the dominant immune effector mechanism of renal injury. The major clinical syndromes produced by immune-mediated renal injury include the nephrotic syndrome, the nephritic syndrome, rapidly progressive glomerulonephritis, and acute renal failure. The notion of clinical syndromes facilitates diagnosis and treatment, but does not accurately define disease pathogenesis. In this summary, we discuss pathologically defined immune-mediated renal diseases under the clinical syndrome with which they are most frequently associated. There is overlap between the clinical syndromes, but the syndromes provide a useful framework. Relevant information regarding the proposed pathogenesis of disease entities is included under specific disease entities.
Abstract: BACKGROUND: Obesity, a multifactorial disease caused by the interaction of genetic factors with the environment, is largely polygenic. A few mutations in these genes, such as in the leptin receptor (LEPR) gene and melanocortin 4 receptor (MC4R) gene, have been identified as causes of monogenic obesity. METHODS: We sequenced the complete MC4R coding region, the region of the proopiomelanocortin gene (POMC) encoding the alpha melanocyte-stimulating hormone, and the leptin-binding domain of LEPR in 469 severely obese white subjects (370 women and 99 men; mean [+/-SE] age, 41.0+/-0.5 years; body-mass index [the weight in kilograms divided by the square of the height in meters], 44.1+/-2.0). Fifteen women and 10 men without a history of dieting or a family history of obesity served as normal-weight controls (age, 47.7+/-2.0 years; body-mass index, 21.6+/-0.4). Detailed phenotypic data, including information on body fat, resting energy expenditure, diet-induced thermogenesis, serum concentrations of leptin, and eating behavior, were collected. RESULTS: Twenty-four obese subjects (5.1 percent) and one control subject (4 percent) had MC4R mutations, including five novel variants. Twenty of the 24 obese subjects with an MC4R mutation were matched for age, sex, and body-mass index with 120 of the 445 obese subjects without an MC4R mutation. All mutation carriers reported binge eating, as compared with 14.2 percent of obese subjects without mutations (P\textbackslashtextless0.001) and 0 percent of the normal-weight subjects without mutations. The prevalence of binge eating was similar among carriers of mutations in the leptin-binding domain of LEPR and noncarriers. No mutations were found in the region of POMC encoding alpha melanocyte-stimulating hormone. CONCLUSIONS: Binge eating is a major phenotypic characteristic of subjects with a mutation in MC4R, a candidate gene for the control of eating behavior.
Abstract: The brain contains a significant amount of glycogen that is an order of magnitude smaller than that in muscle, but several-fold higher than the cerebral glucose content. Although the precise role of brain glycogen to date is unknown, it seems affected by focal activation, neurotransmitters, and overall electrical activity and hormones. Based on its relatively low concentration, the role of brain glycogen as a significant energy store has been discounted. This work reviews recent experimental evidence that brain glycogen is an important reserve of glucose equivalents: (1) glial glycogen can provide the majority of the glucose supply deficit during hypoglycemia for more than 100 min, consistent with the proposal that glial lactate is a fuel for neurons; (2) glycogen concentrations may be as high as 10 micromol/g, substantially higher than was thought previously; (3) glucose cycling in and out of glycogen amounts to approximately 1% of the cerebral metabolic rate of glucose (CMRglc) in human and rat brain, amounting to an effective stability of glycogen in the resting awake brain during euglycemia and hyperglycemia, (4) brain glycogen metabolism/concentrations are insulin/glucose sensitive; and (5) after a single episode of hypoglycemia, brain glycogen levels rebound to levels that exceed the pre-hypoglycemic concentrations (supercompensation). This experimental evidence supports the proposal that brain glycogen may be involved in the development of diabetes complications, specifically impaired glucose sensing (hypoglycemia unawareness) observed clinically in some diabetes patients under insulin treatment. It is proposed further that brain glycogen becomes important in any metabolic state where supply transiently cannot meet demand, such conditions that could occur during prolonged focal activation, sleep deprivation, seizures, and mild hypoxia.
Abstract: This study tested the hypotheses that differences in the adrenergic, central venous pressure (CVP), cardiovascular, or baroreflex responses to lower body negative pressure (LBNP) or differences in body size would be associated with gender differences in orthostatic tolerance. Subjects (24 females, 22 males) underwent graded LBNP to -100 mmHg or presyncope. At rest, the males had higher SV (+ 21 ml x beat(-1)), cardiac output (+ 1.65 L x min(-1)), systolic blood pressure (+ 29 mmHg) and mean arterial pressure (+ 8 mmHg; all P \textbackslashtextless 0.05). Neither the CVP responses to LBNP to -60 mmHg, the deltaforearm vascular conductance/deltaCVP with LBNP to -20 mmHg nor the deltaheart rate/deltaCVP with LBNP of -30 to -60 mmHg differed between genders. LBNP tolerance was lower for the females than males (276 +/- 12 vs 337 +/- 14 mmHg x min; LBNP tolerance index; P \textbackslashtextless 0.01) and, of the resting data, only gender was associated with LBNP tolerance (R(2) = 20 %). Use of gender, the maximal change in HR with LBNP and the change in HR from 0 to -40 mmHg in a regression equation could explain 75 % of the variability in orthostatic tolerance. No cardiovascular parameter differed between genders in the two minutes preceding presyncope. In the last completed stage and at test termination, [epinephrine] and [norepinephrine] were higher in the men. These data suggest that the CVP, cardiovascular and baroreflex responses to graded LBNP are similar in men and women despite marked differences in LBNP tolerance. Differences in body size do not explain the gender difference although differences in the adrenergic responses at maximal LBNP may play a role.
Abstract: Astronauts returning from space have reduced red blood cell masses, hypovolaemia and orthostatic intolerance, marked by greater cardio-acceleration during standing than before spaceflight, and in some, orthostatic hypotension and presyncope. Adaptation of the sympathetic nervous system occurring during spaceflight may be responsible for these postflight alterations. We tested the hypotheses that exposure to microgravity reduces sympathetic neural outflow and impairs sympathetic neural responses to orthostatic stress. We measured heart rate, photoplethysmographic finger arterial pressure, peroneal nerve muscle sympathetic activity and plasma noradrenaline spillover and clearance, in male astronauts before, during (flight day 12 or 13) and after the 16 day Neurolab space shuttle mission. Measurements were made during supine rest and orthostatic stress, as simulated on Earth and in space by 7 min periods of 15 and 30 mmHg lower body suction. Mean (+/- S.E.M.) heart rates before lower body suction were similar pre-flight and in flight. Heart rate responses to -30 mmHg were greater in flight (from 56 +/- 4 to 72 +/- 4 beats min(-1)) than pre-flight (from 56 +/- 4 at rest to 62 +/- 4 beats min(-1), P \textbackslashtextless 0.05). Noradrenaline spillover and clearance were increased from pre-flight levels during baseline periods and during lower body suction, both in flight (n = 3) and on post-flight days 1 or 2 (n = 5, P \textbackslashtextless 0.05). In-flight baseline sympathetic nerve activity was increased above pre-flight levels (by 10-33 %) in the same three subjects in whom noradrenaline spillover and clearance were increased. The sympathetic response to 30 mmHg lower body suction was at pre-flight levels or higher in each subject (35 pre-flight vs. 40 bursts min(-1) in flight). No astronaut experienced presyncope during lower body suction in space (or during upright tilt following the Neurolab mission). We conclude that in space, baseline sympathetic neural outflow is increased moderately and sympathetic responses to lower body suction are exaggerated. Therefore, notwithstanding hypovolaemia, astronauts respond normally to simulated orthostatic stress and are able to maintain their arterial pressures at normal levels.
Abstract: BACKGROUND: Carbonic anhydrase inhibition with benzolamide reduces proximal reabsorption and activates tubuloglomerular feedback (TGF). In rats, TGF activation for 30 to 60 minutes locally suppresses renin secretion and resets TGF rightward to accommodate increased late proximal flow. After 24 hours of TGF activation, there is upward resetting of GFR and increased activity of macula densa nitric oxide synthase I (NOS I). METHODS: We studied renal hemodynamics during early TGF resetting with attention to the importance of renin suppression and NOS I activation. Left kidney blood flow (RBF, pulse Doppler) and glomerular filtration rate (GFR; inulin clearance or Fick method) were measured before and during benzolamide infusion (5 mg/kg bolus followed by 5 mg/kg/h IV) in Wistar rats concurrently receiving the converting enzyme inhibitor, enalaprilat (0.3 mg/kg/h IV) or NOS-I blocker S-methyl-thiocitrulline (SMTC; 2.7 mg/kg/h IV). RESULTS: Activating TGF initially reduced RBF and GFR in all groups as expected. During continuous benzolamide, RBF gradually increased toward baseline in control and enalaprilat-treated rats, but not in NOS I-blocked rats. After the initial decline, GFR did not change further during one hour of benzolamide in any group. CONCLUSIONS: During one hour of persistent TGF stimulation, RBF increases toward normal, but GFR does not. This requires an overall decrease in renal vascular resistance and a decrease in the ratio of efferent/afferent arteriolar resistance (RE/RA), implying a major decrease in RE. NOS I, but not angiotensin-converting enzyme (ACE), is required for RBF to increase during TGF resetting. Although the hemodynamic changes during TGF resetting resemble the response to blocking the renin-angiotensin system, these data fail to show that the increase in RBF during early TGF resetting is mediated by renin suppression.
Abstract: The power function of basal metabolic rate scaling is expressed as aM(b), where a corresponds to a scaling constant (intercept), M is body mass, and b is the scaling exponent. The 3/4 power law (the best-fit b value for mammals) was developed from Kleiber’s original analysis and, since then, most workers have searched for a single cause to explain the observed allometry. Here we present a multiple-causes model of allometry, where the exponent b is the sum of the influences of multiple contributors to metabolism and control. The relative strength of each contributor, with its own characteristic exponent value, is determined by the control contribution. To illustrate its use, we apply this model to maximum versus basal metabolic rates to explain the differing scaling behaviour of these two biological states in mammals. The main difference in scaling is that, for the basal metabolic rate, the O(2) delivery steps contribute almost nothing to the global b scaling exponent, whereas for the maximum metabolic rate, the O(2) delivery steps significantly increase the global b value.
Abstract: Insulin resistance occurs in obesity and Type II (non-insulin-dependent) diabetes mellitus, but it is also a prominent feature of lipodystrophy. Adipose tissue could play a crucial part in buffering the flux of fatty acids in the circulation in the postprandial period, analogous to the roles of the liver and skeletal muscle in buffering postprandial glucose fluxes. Adipose tissue provides its buffering action by suppressing the release of non-esterified fatty acids into the circulation and by increasing triacylglycerol clearance. In particular, the pathway of ’fatty acid trapping’ (adipocyte uptake of fatty acids liberated from plasma triacylglycerol by lipoprotein lipase) could play a key part in the buffering process. If this buffering action is impaired, then extra-adipose tissues are exposed to excessive fluxes of lipid fuels and could accumulate these in the form of triacylglycerol, leading to insulin resistance. These tissues will include liver, skeletal muscle and the pancreatic beta cell, where the long term effect is to impair insulin secretion. Adipose tissue buffering of lipid fluxes is impaired in obesity through defects in the ability of adipose tissue to respond rapidly to the dynamic situation that occurs after meals. It is also impaired in lipodystrophy because there is not sufficient adipose tissue to provide the necessary buffering capacity. Thus, the phenotype, at least with regard to insulin resistance, is similar with both excess and deficiency of adipose tissue. Furthermore, this concept could provide a framework for understanding the action of the thiazolidinedione insulin-sensitizing agents.
Abstract: We hypothesized that contractions of the expiratory muscles carried out to the point of task failure would cause an increase in muscle sympathetic nerve activity (MSNA). We measured MSNA directly in six healthy men during resisted expiration (60% maximal expiratory pressure) leading to task failure with long [breathing frequency (f(b)) = 15 breaths/min; expiratory time (TE)/total respiratory cycle duration (TT) = 0.7] and short (f(b) = 30 breaths/min; TE/TT = 0.4) TE. Both of these types of expiratory muscle contractions elicited time-dependent increases in MSNA burst frequency that averaged +139 and +239%, respectively, above baseline at end exercise. The increased MSNA coincided with increases in mean arterial pressure (MAP) for both the long-TE (+28 +/- 6 mmHg) and short-TE (+22 +/- 14 mmHg) trials. Neither MSNA nor MAP changed when the breathing patterns and increased tidal volume of the task failure trials were mimicked without resistance or task failure. Furthermore, very high levels of expiratory motor output (95% maximal expiratory pressure; f(b) = 12 breaths/min; TE/TT = 0.35) and high rates of expiratory flow and expiratory muscle shortening without task failure (no resistance; f(b) = 45 breaths/min; TE/TT = 0.4; tidal volume = 1.9 x eupnea) had no effect on MSNA or MAP. Within-breath analysis of the short-expiration trials showed augmented MSNA at the onset of and throughout expiration that was consistent with an influence of high levels of central expiratory motor output. Thus high-intensity contractions of expiratory muscles to the point of task failure caused a time-dependent sympathoexcitation; these effects on MSNA were similar in their time dependency to those caused by high-intensity rhythmic contractions of the diaphragm and forearm muscles taken to the point of task failure. The evidence suggests that these effects are mediated primarily via a muscle metaboreflex with a minor, variable contribution from augmented central expiratory motor output.
Abstract: The renin-angiotensin-aldosterone system (RAAS) plays a well-recognized role in the regulation of BP and in salt and water balance. Since hypertension affects a considerable proportion of obese patients, circulating RAAS has been studied in obese subjects with and without hypertension, albeit with conflicting results. Furthermore, attention has recently focused on the expression of the components of the Renin-angiotensin system (RAS) in some organs, including adipose tissue where it seems to be involved in the regulation of growth and differentiation. The aim of our study was to investigate circulating RAAS and adipose tissue RAS in obese patients with and without hypertension and in matched controls. PRA, and plasma and urinary aldosterone levels were measured in 35 obese, 30 hypertensive obese patients and in 20 controls. In addition, the expression of angiotensinogen (AGT) and angiotensin II type 1 receptor (AT1) genes was studied in sc adipose tissue from 8 obese, 6 hypertensive obese and 6 healthy subjects. As previously demonstrated in other studies, there were no significant differences in the levels of circulating RAAS components in the 3 groups. As regards local RAS, interestingly, we found that AT1 gene was significantly more expressed in sc adipose tissue from obese patients with hypertension than in those without hypertension and controls. By contrast, AGT levels were similar in the 3 groups. Our data do not support the hypothesis of an involvement of circulating RAAS in the development of obesity-related hypertension. On the other hand, local RAS seems to be differently regulated in sc adipose tissue from obese patients with hypertension with respect to normotensive obese patients and controls.
Abstract: OBJECTIVE:To investigate the effects of some acid-base abnormalities on blood capacity of transporting CO(2).DESIGN: Prospective study.SETTING: General and Cardiosurgical ICUs of a University hospital.PATIENTS: Six groups of ten patients characterized by: metabolic alkalosis; respiratory alkalosis; absence of acid-base abnormalities; metabolic acidosis; uncompensated respiratory acidosis; and compensated respiratory acidosis.MEASUREMENTS AND RESULTS: The CO(2) dissociation curve, Haldane effect, and the ratio Ra-v between Ca-vCO(2) and Pa-vCO(2) were calculated from arterial and mixed-venous blood gas analyses. The CO(2) dissociation curve was shifted upwards by metabolic alkalosis and compensated respiratory acidosis and downwards by metabolic acidosis. The slope of the curve was unaffected, but CO(2) transport not due to Haldane effect was significantly lower in respiratory acidosis since the slope was less steep at higher PCO(2) values. In comparison with controls, patients affected by metabolic acidosis showed lower Haldane effect values (0.18+/-0.15 vs 0.59+/-0.26 ml of CO(2) per ml of arterial-mixed venous O(2) content difference; P \textbackslashtextless.05) and Ra-v values (0.43+/-0.10 vs 0.84+/-0.17 ml of CO(2) transported by 100 ml of blood per Torr of arterial-mixed venous PCO(2) gradient; P \textbackslashtextless.05).CONCLUSIONS: Our findings suggest that acid-base abnormalities, particularly metabolic acidosis, markedly affect blood capacity of transporting CO(2) and may worsen tissue hypercarbia associated with hypoperfusion. However, because of possible errors due to small measurements and the assumptions of the method, in the future definitive clarification will require the construction of original CO(2) dissociation curves for each acid-base abnormality.
Abstract: When astronauts return to Earth and stand, their heart rates may speed inordinately, their blood pressures may fall, and some may experience frank syncope. We studied brief autonomic and haemodynamic transients provoked by graded Valsalva manoeuvres in astronauts on Earth and in space, and tested the hypothesis that exposure to microgravity impairs sympathetic as well as vagal baroreflex responses. We recorded the electrocardiogram, finger photoplethysmographic arterial pressure, respiration and peroneal nerve muscle sympathetic activity in four healthy male astronauts (aged 38-44 years) before, during and after the 16 day Neurolab space shuttle mission. Astronauts performed two 15 s Valsalva manoeuvres at each pressure, 15 and 30 mmHg, in random order. Although no astronaut experienced presyncope after the mission, microgravity provoked major changes. For example, the average systolic pressure reduction during 30 mmHg straining was 27 mmHg pre-flight and 49 mmHg in flight. Increases in muscle sympathetic nerve activity during straining were also much greater in space than on Earth. For example, mean normalized sympathetic activity increased 445% during 30 mmHg straining on earth and 792% in space. However, sympathetic baroreflex gain, taken as the integrated sympathetic response divided by the maximum diastolic pressure reduction during straining, was the same in space and on Earth. In contrast, vagal baroreflex gain, particularly during arterial pressure reductions, was diminished in space. This and earlier research suggest that exposure of healthy humans to microgravity augments arterial pressure and sympathetic responses to Valsalva straining and differentially reduces vagal, but not sympathetic baroreflex gain.
Abstract: Insulin resistance is one of the key factors responsible for hyperglycaemia in type 2 diabetes and can result in a number of metabolic abnormalities associated with cardiovascular disease (insulin resistance syndrome), even in the absence of overt diabetes. The mechanisms involved in the development of insulin resistance are multifactorial and are only partly understood, but increased availability of free fatty acids (FFAs) is of particular importance for the liver and skeletal muscle. The role of FFAs in type 2 diabetes is most evident in obese patients who have several abnormalities in FFA metabolism. Because of a mass effect, the release of FFAs from the total adipose tissue depot to the blood stream is increased and the high concentration of circulating FFAs impairs muscle uptake of glucose by competitive inhibition. In upper-body obesity, which predisposes individuals to type 2 diabetes, the rate of lipolysis is accelerated in visceral adipose tissue. This results in a selective increase in FFA mobilisation to the portal vein, which connects visceral fat to the liver. A high ’portal’ FFA concentration has undesirable effects on the liver, resulting in dyslipidaemia, hyperinsulinaemia, hyperglycaemia and hepatic insulin resistance. Recently, a new class of antidiabetic agents, the thiazolidinediones (TZDs) or ’glitazones’ has been developed. A prominent effect of these agents is the lowering of circulating FFA levels and it is believed, but not yet proven, that this interaction with FFAs constitutes a major mechanism behind the glucose-lowering effect of the TZDs.
Abstract: Congestive heart failure is the most common cause of mortality in patients with end-stage renal disease (ESRD). Ultrasonic tissue characterization with integrated backscatter offers a promising method for the noninvasive assessment of regional myocardial contractile performance and fibrosis. The aim of this study was to investigate the effect of hemodialysis (HD) on myocardial tissue characterization and left ventricular function in ESRD patients. We examined 26 patients with ESRD undergoing routine HD (age 63 +/- 12 years, duration of HD 9.2 +/- 3.2 years) and 30 patients with essential hypertension (HT; 60 +/- 10 years). Routine echocardiographic parameters and the cyclic variation of ultrasonic integrated backscatter of the ventricular septum (CV-IBS) were measured. Left ventricular mass index was significantly larger in patients with ESRD than in those with HT (217 +/- 56 vs 146 +/- 45 g/m(2), P \textbackslashtextless 0.05). The indices for left ventricular diastolic function (E/A, the ratio of left ventricular peak early to late diastolic filling velocity; DT, the deceleration time of the early diastolic filling) and CV-IBS had deteriorated significantly in patients with ESRD before HD compared with those with HT (E/A, 0.6 +/- 0.2 vs 0.9 +/- 0.3, P \textbackslashtextless 0.05; DT, 228 +/- 23 vs 184 +/- 19 ms, P \textbackslashtextless 0.05; CV-IBS, 9.0 +/- 1.3 vs 12.4 +/- 0.9 dB, P \textbackslashtextless 0.05), possibly reflecting interstitial fibrosis. In patients with ESRD, HD reduced calculated left ventricular mass index by 19% (before HD, 217 +/- 56 vs immediately after HD, 176 +/- 45 g/m(2), P \textbackslashtextless 0.05) and CV-IBS by 19% (9.0 +/- 1.3 vs 7.3 +/- 1.1 dB, P \textbackslashtextless 0.05), that possibly reflected improvement of interstitial edema. HD also significantly improved indices for left ventricular diastolic function (E/A, 0.6 +/- 0.2 vs 0.9 +/- 0.2, P \textbackslashtextless 0.05; DT, 228 +/- 23 vs 188 +/- 21 ms, P \textbackslashtextless 0.05). HD improves myocardial interstitial edema and left ventricular diastolic function in patients with ESRD. Noninvasive assessment of ultrasonic tissue characterization is useful in defining the pathophysiological changes of ventricular myocardium in patients with ESRD.
Abstract: The wide range of phenotypic abnormalities seen in the leptin-deficient ob/ob mouse and their reversibility by leptin administration provide compelling evidence for the existence of multiple physiological functions of this hormone in rodents. In contrast, information regarding the roles of this hormone in humans is limited. Three morbidly obese children, who were congenitally deficient in leptin, were treated with daily subcutaneous injections of recombinant human leptin for up to 4 years with sustained, beneficial effects on appetite, fat mass, hyperinsulinemia, and hyperlipidemia. Leptin therapy resulted in a rapid and sustained increase in plasma thyroid hormone levels and, through its age-dependent effects on gonadotropin secretion, facilitated appropriately timed pubertal development. Leptin deficiency was associated with reduced numbers of circulating CD4⊕ T cells and impaired T cell proliferation and cytokine release, all of which were reversed by recombinant human leptin administration. The subcutaneous administration of recombinant human leptin has major and sustained beneficial effects on the multiple phenotypic abnormalities associated with congenital human leptin deficiency.
Abstract: Aldosterone plays a pivotal role in electrolyte and fluid homeostasis and thus control of blood pressure. The "classical" view of aldosterone action is that it targets epithelia of the distal colon and renal nephron to stimulate Na⊕ (re)absorption and K⊕ secretion. In these cells, aldosterone binds steroid receptors, promoting translocation to the nucleus, where they modulate gene expression with the induced proteins stimulating transport. This "genomic" action is dependent on transcription and translation and has a latency of 0.5-1.0 h. Recently, more rapid actions of aldosterone that are independent of transcription and translation have been described. These "nongenomic" actions are mediated by a distinct receptor that is insensitive to inhibitors of the classical mineralocorticoid receptor, such as spironolactone. The present review describes advances in our understanding of the classical model of aldosterone action as well as those that broaden this model to encompass nongenomic actions, nonepithelial targets, production of aldosterone outside of the adrenal gland, novel mechanisms of specificity, and novel mechanisms for mediating genomic actions.
Abstract: Glucose, the major fuel in the brain, is transported across the cell membranes by facilitated diffusion mediated by glucose transporter proteins. Essentially two types of glucose transporters are localized in the membranes of brain endothelial cells, astrocytes, and neurons. Their densities are well adjusted to changes in local energy demand.
Abstract: OBJECTIVE: To evaluate the relationship between insulin, the renin-aldosterone system and blood pressure in obese subjects. DESIGN AND METHODS: A cross sectional study of a group of severely obese normotensive subjects who were surgical candidates (n=39; mean BMI: 47.8+/-1.4) and a group of hypertensive patients (n=57; mean BMI: 28.0+/-0.7) twenty-nine of whom had BMI\textbackslashtextgreater27. All subjects were studied after 15 days on a balanced diet. Insulin, plasma renin activity and aldosterone were measured. RESULTS: Fasting insulin, plasma renin activity and aldosterone were higher in severely obese normotensive subjects than in hypertensive subjects (respectively 32.3+/-3.0 vs 13.1+/-1.0 mU/l, P=0.0001; 1.34+/-0.22 vs 0.88+/-0.12 ng/ml/h, P=0.04; 137.2+/-16.2 vs 87.9+/-12.1 pg/ml, P=0.015). Insulin was related to BMI and to aldosterone both in normotensive and in hypertensive patients. CONCLUSION: Hyperinsulinemia itself does not determine hypertension; in some people it could play a vasodilator role in opposition to the renin-aldosterone system.
Abstract: OBJECTIVES: Central adiposity, insulin resistance and hypertension are clearly interrelated but the mechanisms underlying this association have not been thoroughly elucidated. As renal sodium handling plays a central role in salt-sensitive forms of hypertension, we investigated the relation of renal tubular sodium handling to abdominal adiposity, blood pressure and insulin sensitivity. DESIGN: Population-based study. PARTICIPANTS: Five hundred and fifty-five untreated Olivetti male workers, aged 25-75 years. SETTING: Olivetti factory medical centers in Pozzuoli and Marcianise (Naples, Italy) MAIN OUTCOME MEASURES: Anthropometric indices, serum insulin, homeostatic model assessment index of insulin sensitivity, blood pressure, fractional excretions of uric acid and exogenous lithium (as markers of renal tubular sodium handling). RESULTS: In univariate analysis, measures of central adiposity (i.e. sagittal abdominal diameter and umbilical circumference) were directly correlated with serum insulin (P \textbackslashtextless 0.001) and blood pressure levels (P \textbackslashtextless 0.001) and inversely associated with the fractional excretions of uric acid and lithium (P = 0.01-0.001). In multiple linear regression analysis, the same anthropometric indices but not the measures of peripheral adiposity (arm circumference and tricipital skinfold thickness), were significant predictors of the fractional excretion of uric acid and lithium, independently of age, blood pressure and serum insulin levels (P = 0.01-0.001). CONCLUSIONS: Abdominal adiposity was associated with altered renal tubular sodium handling apart from insulin resistance and high blood pressure. The data indicate that men with prevalent abdominal adiposity have an enhanced rate of tubular sodium reabsorption, mainly at proximal sites. These findings provide a possible mechanistic link between central adiposity and salt-dependent hypertension.
Abstract: Our purpose is to summarize the major effects of space travel on skeletal muscle with particular emphasis on factors that alter function. The primary deleterious changes are muscle atrophy and the associated decline in peak force and power. Studies on both rats and humans demonstrate a rapid loss of cell mass with microgravity. In rats, a reduction in muscle mass of up to 37% was observed within 1 week. For both species, the antigravity soleus muscle showed greater atrophy than the fast-twitch gastrocnemius. However, in the rat, the slow type I fibers atrophied more than the fast type II fibers, while in humans, the fast type II fibers were at least as susceptible to space-induced atrophy as the slow fiber type. Space flight also resulted in a significant decline in peak force. For example, the maximal voluntary contraction of the human plantar flexor muscles declined by 20-48% following 6 months in space, while a 21% decline in the peak force of the soleus type I fibers was observed after a 17-day shuttle flight. The reduced force can be attributed both to muscle atrophy and to a selective loss of contractile protein. The former was the primary cause because, when force was expressed per cross-sectional area (kNm(-2)), the human fast type II and slow type I fibers of the soleus showed no change and a 4% decrease in force, respectively. Microgravity has been shown to increase the shortening velocity of the plantar flexors. This increase can be attributed both to an elevated maximal shortening velocity (V(0)) of the individual slow and fast fibers and to an increased expression of fibers containing fast myosin. Although the cause of the former is unknown, it might result from the selective loss of the thin filament actin and an associated decline in the internal drag during cross-bridge cycling. Despite the increase in fiber V(0), peak power of the slow type I fiber was reduced following space flight. The decreased power was a direct result of the reduced force caused by the fiber atrophy. In addition to fiber atrophy and the loss of force and power, weightlessness reduces the ability of the slow soleus to oxidize fats and increases the utilization of muscle glycogen, at least in rats. This substrate change leads to an increased rate of fatigue. Finally, with return to the 1g environment of earth, rat studies have shown an increased occurrence of eccentric contraction-induced fiber damage. The damage occurs with re-loading and not in-flight, but the etiology has not been established.
Abstract: Body fluid homeostasis was investigated during chronic bed rest (BR) and compared with that of acute supine conditions. The hypothesis was tested that 6 degrees head-down BR leads to hypovolemia, which activates antinatriuretic mechanisms so that the renal responses to standardized saline loading are attenuated. Isotonic (20 ml/kg body wt) and hypertonic (2.5%, 7.2 ml/kg body wt) infusions were performed in eight subjects over 20 min following 7 and 10 days, respectively, of BR during constant sodium intake (200 meq/day). BR decreased body weight (83.0 +/- 4.8 to 81.8 +/- 4.4 kg) and increased plasma osmolality (285.9 +/- 0.6 to 288.5 +/- 0.9 mosmol/kgH(2)O, P \textbackslashtextless 0.05). Plasma ANG II doubled (4.2 +/- 1.2 to 8.8 +/- 1.8 pg/ml), whereas other endocrine variables decreased: plasma atrial natriuretic peptide (42 +/- 3 to 24 +/- 3 pg/ml), urinary urodilatin excretion rate (4.5 +/- 0.3 to 3.2 +/- 0.1 pg/min), and plasma vasopressin (1.7 +/- 0.3 to 0.8 +/- 0.2 pg/ml, P \textbackslashtextless 0.05). During BR, the natriuretic response to the isotonic saline infusion was augmented (39 +/- 8 vs. 18 +/- 6 meq sodium/350 min), whereas the response to hypertonic saline was unaltered (32 +/- 8 vs. 29 +/- 5 meq/350 min, P \textbackslashtextless 0.05). In conclusion, BR elicits antinatriuretic endocrine signals, but it does not attenuate the renal natriuretic response to saline stimuli in men; on the contrary, the response to isotonic saline is augmented.
Abstract: BACKGROUND: Although it is known that the skin acts as a water reservoir and participates in the fluid content of the whole body, no method has been established to quantify the fluid shifts in superficial tissue. OBJECTIVES: The aim of this study was to investigate changes in dermal and subcutis thickness and echodensity at the forehead and lower leg by high-frequency (20 MHz) ultrasound under various physiological conditions influencing water balance. METHODS: These parameters were measured in the skin of 20 healthy male volunteers at baseline and successively at 30 min after lying down, in a head-down position, after physical activity and after infusion of 10 mL kg-1 body weight of Ringer’s solution. RESULTS: Dermal thickness at the forehead showed a significant increase from baseline to a horizontal position and a further increase in the head-down position. Physical activity did not lead to further changes, whereas after fluid infusion the dermal thickness also increased markedly. The echodensity showed inverse changes, with decreasing values. The thickness of the subcutis increased slightly from baseline to a lying position and decreased in the head-down position and after fluid infusion. At the lower leg, skin thickness decreased slightly in the head-down position with elevated legs, and increased after fluid infusion. CONCLUSIONS: Our results show that slight changes in the water distribution of the body influence the thickness and the echodensity of the dermis. Changes are more pronounced at the forehead than on the lower legs. Further, the fluid storage takes place mainly in the dermis and not in the subcutis. High-frequency ultrasound is able to quantify these effects and is a sensitive method for measuring fluid intake and balance during anaesthesia and therapy.
Abstract: Acute renal failure (ARF) with overhydration and edematous state may follow Acute endocapillary proliferative glomerulonephritis and extracapillary glomerulonephritis, because of reduction of the glomerular capillary area available for filtration. But ARF may also be observed in edematous patients with minimal change nephrotic syndrome; it may require dialysis until recovery and is attributable to some of the following factors: (1) ischemic renal injury, (2) hypovolemia, (3) interstitial edema with tubular collapse, (4) redistribution of renal blood flow (RBF) from cortical to juxtaglomerular nephrons, (5) decrease of capillary filtration coefficient (Kf), (6) use of nonsteroidal antiinflammatory drugs. Congestive heart failure also leads to prerenal azotemia and edema formation secondary to salt retention. Multiple organ dysfunction syndrome (MODS) is frequently associated with ARF; but edema occurs even without ARF in septic patients with severe inflammatory response syndrome (SIRS). ARF may follow severe burns; burned patients are frequently edematous because of a rapid leak of fluid from the vascular bed into the wound; edema in undamaged areas occurs in the ’flow phase’, because of a fall of oncotic pressure because of massive loss of plasma proteins into the wound. Edema must be treated with diuretics or by dialysis.
Abstract: OBJECTIVES: To evaluate spontaneous blood pressure and heart rate variability and spontaneous baroreflex sensitivity before and after brain death. METHODS: Spontaneous variability of arterial blood pressure and heart rate-estimated by power spectra of systolic (SBP) and diastolic blood pressure (DBP) and pulse interval (PI)-and spontaneous baroreflex sensitivity (BRS)-estimated by the alpha index and the sequence technique-were evaluated in 11 patients twice: shortly before and 1 hour after the onset of brain death. RESULTS: Significant spectral changes occurred after brain death: a general power reduction in PI spectra; a shift of SBP, DBP and PI powers toward the lower frequencies, resulting in a greater slope of the "1/f" spectral trends; and a marked reduction of SBP and DBP powers (-93%) and of SBP-PI coherence (-63%) at 0.1 Hz. The estimated average BRS was relatively high before brain death (around 11 ms/mm Hg), and fell close to 0 or even was not detectable at all after brain death. CONCLUSIONS: Parameters describing spontaneous blood pressure and heart rate variability and indexes reflecting the baroreflex function, which were relatively normal up to a few hours before brain death, underwent marked changes with the onset of brain death. All the changes found are likely to reflect the cessation of activity of the cardiovascular brain stem centres. These findings indicate that techniques of blood pressure and heart rate spectral analysis and of dynamic assessment of baroreflex sensitivity may be useful to complement the diagnosis of brain stem death.
Abstract: Microgravity is associated with an impaired stroke volume and, therefore, cardiac output response to orthostatic stress. We hypothesized that a decreased venous filling pressure due to increased venous compliance may be an important contributing factor in this response. We used a constant flow, constant right atrial pressure cardiopulmonary bypass procedure to measure total systemic vascular compliance (C(T)), arterial compliance (C(A)), and venous compliance (C(V)) in seven control and seven 21-day hindlimb unweighted (HLU) rats. These compliance values were calculated under baseline conditions and during an infusion of 0.2 microg*kg(-1)*min(-1) norepinephrine (NE). The change in reservoir volume, which reflects changes in unstressed vascular volume (DeltaV(0)) that occurred upon infusion of NE, was also measured. C(T) and C(V) were larger in HLU rats both at baseline and during the NE infusion (P \textbackslashtextless 0.05). Infusion of NE decreased C(T) and C(V) by \textbackslashtextasciitilde20% in both HLU and control rats (P \textbackslashtextless 0.01). C(A) was also significantly decreased in both groups of rats by NE (P \textbackslashtextless 0.01), but values of C(A) were similar between HLU and control rats both at baseline and during the NE infusion. Additionally, the NE-induced DeltaV(0) was attenuated by 53% in HLU rats compared with control rats (P \textbackslashtextless 0.05). The larger C(V) and attenuated DeltaV(0) in HLU rats could contribute to a decreased filling pressure during orthostasis and thus may partially underlie the mechanism leading to the exaggerated fall in stroke volume and cardiac output seen in astronauts during an orthostatic stress after exposure to microgravity.
Abstract: The objectives of the present study were: (1) to develop a risk assessment methodology for chemical mixtures that accounts for pharmacokinetic interactions among components, and (2) to apply this methodology to assess the health risk associated with occupational inhalation exposure to airborne mixtures of dichloromethane, benzene, toluene, ethylbenzene, and m-xylene. The basis of the proposed risk assessment methodology relates to the characterization of the change in tissue dose metrics (e.g., area under the concentration-time curve for parent chemical in tissues [AUCtissue], maximal concentration of parent chemical or metabolite [Cmax], quantity metabolized over a period of time) in humans, during mixed exposures using PBPK models. For systemic toxicants, an interaction-based hazard index was calculated using data on tissue dose of mixture constituents. Initially, the AUCtarget tissue (AUCtt) corresponding to guideline values (e.g., threshold limit value [TLV]) of individual chemicals were obtained. Then, the AUCtt for each chemical during mixed exposure was obtained using a mixture PBPK model that accounted for the binary and higher order interactions occurring within the mixture. An interaction-based hazard index was then calculated for each toxic effect by summing the ratio of AUCtt obtained during mixed exposure (predefined mixture) and single exposure (TLV). For the carcinogenic constituents of the mixture, an interaction-based response additivity approach was applied. This method consisted of adding the cancer risk for each constituent, calculated as the product of q*tissue dose and AUCtt. The AUCtt during mixture exposures was obtained using an interaction-based PBPK model. The approaches developed in the present study permit, for the first time, the consideration of the impact of multichemical pharmacokinetic interactions at a quantitative level in mixture risk assessments.
Abstract: Food intake (eating) is a form of behavior that is subject to conscious control. In practice, many obese and weight-gaining individuals claim that their eating is out of (their) control. Mechanistic models describe the interplay of biological and environmental forces that control food intake. However, because human food intake is characterized by individuals intervening to adjust their own patterns of behavior, food intake should reflect interactions among biology, environment, and attempted self-imposed control of behavior. In general, humans display a system of weight regulation that is asymmetrical–a reduction in body weight is strongly defended but weight gain is not. The body seems to tolerate a positive energy balance. There is no mechanism that can detect a positive energy balance per se or that can implement a sufficiently strong correction to behavior to maintain body weight in an environment that promotes consumption. The evolutionary process has favored biological traits associated with preferences for high energy density (sweet and/or fatty) energy-yielding foods. The control of food intake in obese or weight-gaining individuals may display various risk factors that favor an increase in energy. These include the preference for high energy-dense over low energy-dense foods, weak postprandial inhibitory signaling, strong hunger traits associated with low leptin levels after weight loss, and the consumption of fatty foods. In addition, many individuals (up to 47% of some samples) display binge eating patterns, whereas approximately 16% show either night eating or nocturnal eating. Because energy expenditure is only loosely coupled to energy intake, sedentariness does not down-regulate food intake.
Abstract: The treatment of hypertension with high-dose thiazide diuretics results in potassium depletion and a limited benefit for preventing coronary events. The clinical relevance of hypokalemia associated with low-dose diuretics has not been assessed. To determine whether hypokalemia that occurs with low-dose diuretics is associated with a reduced benefit on cardiovascular events, we analyzed data of 4126 participants in the Systolic Hypertension in the Elderly Program (SHEP), a 5-year randomized, placebo-controlled clinical trial of chlorthalidone-based treatment of isolated systolic hypertension in older persons. After 1 year of treatment, 7.2% of the participants randomized to active treatment had a serum potassium \textbackslashtextless3.5 mmol/L compared with 1% of the participants randomized to placebo (P\textbackslashtextless0.001). During the 4 years after the first annual visit, 451 participants experienced a cardiovascular event, 215 experienced a coronary event, 177 experienced stroke, and 323 died. After adjustment for known risk factors and study drug dose, the participants who received active treatment and who experienced hypokalemia had a similar risk of cardiovascular events, coronary events, and stroke as those randomized to placebo. Within the active treatment group, the risk of these events was 51%, 55%, and 72% lower, respectively, among those who had normal serum potassium levels compared with those who experienced hypokalemia (P\textbackslashtextless0.05). The participants who had hypokalemia after 1 year of treatment with a low-dose diuretic did not experience the reduction in cardiovascular events achieved among those who did not have hypokalemia.
Abstract: CO(2) produced within skeletal muscle has to leave the body finally via ventilation by the lung. To get there, CO(2) diffuses from the intracellular space into the convective transport medium blood with the two compartments, plasma and erythrocytes. Within the body, CO(2) is transported in three different forms: physically dissolved, as HCO(3)⊖, or as carbamate. The relative contribution of these three forms to overall transport is changing along this elimination pathway. Thus the kinetics of the interchange have to be considered. Carbonic anhydrase accelerates the hydration/dehydration reaction between CO(2), HCO(3)⊖, and H⊕. In skeletal muscle, various isozymes of carbonic anhydrase are localized within erythrocytes but are also bound to the capillary wall, thus accessible to plasma; bound to the sarcolemma, thus producing catalytic activity within the interstitial space; and associated with the sarcoplasmic reticulum. In some fiber types, carbonic anhydrase is also present in the sarcoplasm. In exercising skeletal muscle, lactic acid contributes huge amounts of H⊕ and by these affects the relative contribution of the three forms of CO(2). With a theoretical model, the complex interdependence of reactions and transport processes involved in CO(2) exchange was analyzed.
Abstract: BACKGROUND: Noncardiogenic pulmonary edema is often associated with increased intracranial pressure and can be the initial manifestation of hyponatremic encephalopathy. Marathon runners tend to develop conditions that lead to hyponatremia. OBJECTIVE: To describe the development and treatment of noncardiogenic pulmonary edema in marathon runners that was associated with hyponatremic encephalopathy. DESIGN: Case series. SETTING: One university hospital and two community hospitals. PATIENTS: Seven healthy marathon runners who had a history of nonsteroidal anti-inflammatory drug use. The runners collapsed after competing in a marathon and were hospitalized with pulmonary edema. MEASUREMENTS: Plasma sodium levels, chest radiograph, electrocardiogram, cardiac enzyme levels, and magnetic resonance imaging or computed tomographic scans of the brain. RESULTS: Patients had nausea, emesis, and obtundation. The mean (+/-SD) plasma sodium level was 121 +/- 3 mmol/L, and oxygen saturation was less than 70%. Electrocardiograms and echocardiograms were normal. Chest radiographs showed pulmonary edema with a normal heart. Creatine phosphokinase-MB bands, troponin levels, and pulmonary wedge pressure were not elevated. Scanning of the brain showed cerebral edema. All patients were intubated and mechanically ventilated. Treatment with intravenous NaCl, 514 mmol/L, increased plasma sodium levels by 10 mmol/L in 12 hours. Pulmonary and cerebral edema resolved as the sodium level increased. One patient had unsuspected hyponatremic encephalopathy and died of cardiopulmonary arrest caused by brainstem herniation. All six treated patients recovered and were well after 1 year of follow-up. CONCLUSIONS: In healthy marathon runners, noncardiogenic pulmonary edema can be associated with hyponatremic encephalopathy. The condition may be fatal if undiagnosed and can be successfully treated with hypertonic NaCl.
Abstract: Cerebral oedema remains the leading cause of death and morbidity in children with Type 1 diabetes mellitus. Around seven per thousand episodes of diabetic ketoacidosis (DKA) are complicated by cerebral oedema, and one-quarter of those children will die from it. The cause or causes of cerebral oedema are still very poorly understood, but lawyers are already keen to implicate various aspects of the management of DKA. There have been many theories as to the pathophysiology of cerebral oedema, and possible contributing factors may be excessive rate of rehydration, falling plasma osmolality (particularly that due to a reduction in plasma sodium concentration), hypoxia and insulin dosage. There is some supportive evidence for all of these factors in some cases, but there have been no sizeable case-control studies, in part because of the rarity of the condition. Furthermore, cerebral oedema can still occur even when the management of DKA follows current ’best practice’ guidelines. As the mechanisms of cell volume regulation within the brain are increasingly understood, different questions may provide greater insights. For example, what is it about children that makes them so much more susceptible to cerebral oedema than adults? And why does one child treated in a certain way develop cerebral oedema whereas another does not? The anxiety over causing cerebral oedema has driven most of the changes in the management of DKA over recent decades, yet there is no evidence that the incidence has reduced. Until the causes are understood, we cannot be dogmatic about treatment recommendations.
Abstract: We reviewed the ventilatory responses obtained from rebreathing experiments on a population of 22 subjects. Our aim was to derive parameter estimates for an ’average subject’ so as to model the respiratory chemoreflex control system. The rebreathing technique used was modified to include a prior hyperventilation, so that rebreathing started at a hypocapnic P(CO2) and ended at a hypercapnic P(CO2). In addition, oxygen was added to the rebreathing bag in a controlled manner to maintain iso-oxia during rebreathing, which allowed determination of the response at several iso-oxic P(O2) levels. The breath-by-breath responses were analysed in terms of tidal volume, breathing frequency and ventilation. As P(CO2) rose, ventilation was first steady at a basal value, then increased as P(CO2) exceeded a breakpoint. We interpreted this first breakpoint as the threshold of the combined central and peripheral chemoreflex responses. Above, ventilation increased linearly with P(CO2), with tidal volume usually contributing more than frequency to the increase. When breathing was driven strongly, such as in hypoxia, a second breakpoint P(CO2) was often observed. Beyond the second breakpoint, ventilation continued to increase linearly with P(CO2) at a different slope, with frequency usually contributing more than tidal volume to the increase. We defined the parameters of the variation of tidal volume, frequency and ventilation with P(O2) and P(CO2) for an average subject based on a three-segment linear fit of the individual responses. These were incorporated into a model of the respiratory chemoreflex control system based on the general scheme of the ’Oxford’ model. However, instead of considering ventilatory responses alone, the model also incorporates tidal volume and frequency responses.
Abstract: A pulse ([(14)C]palmitate)-chase ([(3)H]palmitate) approach was used to study intramuscular triglyceride (imTG) fatty acid and plasma free fatty acid (FFA) kinetics during exercise at approximately 45% peak O(2) consumption in 12 adults. Vastus lateralis muscle was biopsied before and after 90 min of bicycle exercise; (3)H(2)O production, breath (14)CO(2) excretion and lipid oxidation (indirect calorimetry) rates were measured during exercise. Results: during exercise, 8.2+/-1.2 and 8.4+/-0.7 micromol x kg(-1) x min(-1) of imTG fatty acids and plasma FFA, respectively, were oxidized according to isotopic measurements. The sum of these two values was not different (P = 0.6) from lipid oxidation by indirect calorimetry (15.4 +/-1.6 micromol x kg(-1) x min(-1)); the isotopic and indirect calorimetry values were correlated (r = 0.79, P\textbackslashtextless0.005). During exercise, imTG turnover rate was 0.32+/-0.07%/min (6.0+/-2.0 micromol of imTG x kg wet muscle(-1) x min(-1)) and plasma FFA were incorporated into imTG at a rate of 0.7+/-0.1 micromol x kg wet muscle(-1) x min(-1). The imTG pool size did not change during exercise. This pulse-chase, dual tracer appears to be a reasonable approach to measure oxidation and synthesis kinetics of imTG.
Abstract: To better understand the regulation of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) during liver transplantation, we used a computer model of the human circulatory system to simultaneously evaluate the effect of t-PA secretion, t-PA inhibition by PAI-1, hepatic clearance of t-PA, blood loss, transfusion and hemodynamics on t-PA and PAI-1 levels during liver transplantation in three patients that differed in severity of liver disease, blood loss and anhepatic changes in t-PA. Higher preoperative t-PA levels were primarily related to underlying liver disease and reduced hepatic clearance. During the anhepatic stage, when hepatic t-PA clearance was eliminated: (1) the expected rise in t-PA was modulated by the extent of bleeding, which acted as an alternate t-PA clearance mechanism; and (2) the ratio of t-PA:PAI-1 was increased due both to lower t-PA clearance and reduced PAI-1 secretion. Recirculation of the new liver was associated with renewed clearance of t-PA, an acute phase increase in PAI-1 and a drop in the t-PA:PAI-1 ratio. Understanding fibrinolytic regulation required simultaneous analysis of t-PA secretion, inhibition and clearance. Anhepatic t-PA levels could be predicted based on preoperative liver function and surgical blood loss, which acted as an alternate t-PA clearance mechanism.
Abstract: We evaluated the changes of tissue layer thickness in circumscribed superficial tissue areas with a 10-MHz A-mode and a 20-MHz B-mode ultrasound device under alterations in body posture and plasma volume to detect fluid shifts between the different compartments. In 20 male volunteers, we measured tissue thickness by A mode and corium and subcutis thickness by B mode at the forehead before and 30 min after three procedures: change from upright to supine position (P1); change from upright to 30 degrees head-down-tilt position (P2); infusion of 10 ml/kg body wt of Ringer solution (P3). We found a significant correlation between baseline tissue thickness and the sum of corium and subcutis thicknesses (r = 0.75, P \textbackslashtextless 0.01). The changes of body posture and plasma volume resulted in significant increases of tissue thickness (P1, 2.9%; P2, 11.6%; P3, 5.8%) and corium thickness (P1, 4.7%; P2, 8.1%; P3, 9.1%) but not of the sum of chorium and subcutis thicknesses. We conclude that fluid shifts from the intravascular to the extravascular compartment are detectable by evaluating corium thickness with a B-mode, or more easily tissue thickness with an A-mode, ultrasound device.
Abstract: Lactate traverses the cell membranes of many tissues, including the heart and skeletal muscle via a facilitated monocarboxylate transport system that functions as a proton symport and is stereoselective for L-lactate. In the past few years, seven monocarboxylate transporters have been cloned. Monocarboxylate transporters are ubiquitously distributed among many tissues, and the transcripts of several monocarboxylate transporters are present within many of the same tissues. This complicates the identification of their metabolic function. There is also evidence that that there is some species specificity, with differences in MCT tissue distributions in hamsters, rats, and humans. MCT1 and MCT3-M/MCT4 are present in rat and human muscles, and MCT1 expression is highly correlated with the oxidative capacity of skeletal muscles and with their capacity to take up lactate from the circulation. MCT1 is also present in heart and is located on the plasma membrane (in subdomains), T-tubules, and in caveolae. With training, MCT1 is increased in rat and human muscle, and in rat hearts, resulting in an increased uptake of lactate from the buffers perfused through these tissues and an increase in lactate efflux out of purified vesicles. In humans, the training-induced increases in MCT1 are associated with an increased lactate efflux out of muscle. MCT3-M/MCT4 is not correlated with the muscles’ oxidative capacities but is equally abundant in Type IIa and IIb muscles, whereas it is markedly lower in slow-twitch (Type I) muscles. Clearly, we are at the threshold of a new era in understanding the regulation of lactate movement into and out of skeletal muscle and cardiac cells.
Abstract: Increased total fat mass (FM) and visceral fat (VF) may account in part for age-associated decrease in hepatic insulin action. This study determined whether preventing the changes in body fat distribution abolished this defect throughout aging. We studied the F(1) hybrid of Brown Norway-Fischer 344 rats (n = 29), which we assigned to caloric restriction (CR) or fed ad libitum (AL). CR (55% of the calories consumed by AL) was initiated and used at 2 mo to prevent age-dependent increases in FM and VF. AL rats were studied at 2, 8, and 20 mo; CR rats were studied at 8 and 20 mo. VF and FM remained unchanged throughout aging in CR rats. AL-fed rats at 8 and 20 mo had over fourfold higher FM and VF compared with both CR groups. Insulin clamp studies (3 mU. kg(-1). min(-1) with somatostatin) were performed to assess hepatic insulin sensitivity. Prevention of fat accretion resulted in a marked improvement in insulin action in the suppression of hepatic glucose production (HGP) (6.3 +/- 0.3 and 7.2 +/- 1.2 mg. kg(-1). min(-1) in 8- and 20-mo CR rats vs. 8.3 +/- 0.5 and 10.8 +/- 0.9 mg. kg(-1). min(-1) in 8- and 20-mo AL rats, respectively). The rate of gluconeogenesis (by enrichment of hepatic uridine diphosphate glucose and phosphoenolpyruvate pools by [(14)C]lactate) was unchanged in all groups. The improvement in hepatic insulin action in the CR group was mostly due to effective suppression of glycogenolysis (4.4 +/- 0.3 and 4.9 +/- 0.3 mg. kg(-1). min(-1) in 8- and 20-mo CR rats vs. 5.8 +/- 0.6 and 8.2 +/- 1.0 mg. kg(-1). min(-1) in 8- and 20-mo AL rats, respectively). The results demonstrated the preservation of hepatic insulin action in aging CR rats. Therefore, body fat and its distribution are major determinants of age-associated hepatic insulin resistance.
Abstract: The "lactate shuttle hypothesis" holds that lactate plays a key role in the distribution of carbohydrate potential energy that occurs among various tissue and cellular compartments such as between: cytosol and mitochondria, muscle and blood, blood and muscle, active and inactive muscles, white and red muscles, blood and heart, arterial blood and liver, liver and other tissues such as exercising muscle, intestine and portal blood, portal blood and liver, zones of the liver, and skin and blood. Studies on resting and exercising humans indicate that most lactate (75-80%) is disposed of through oxidation, with much of the remainder converted to glucose and glycogen. Lactate transport across cellular membranes occurs by means of facilitated exchange along pH and concentration gradients involving a family of lactate transport proteins, now called monocarboxylate transporters (MCTs). Current evidence is that muscle and other cell membrane lactate transporters are abundant with characteristics of high Km and Vmax. There appears to be long-term plasticity in the number of cell membrane transporters, but short-term regulation by allosteric modulation or phosphorylation is not known. In addition to cell membranes, mitochondria also contain monocarboxylate transporters (mMCT) and lactic dehydrogenase (mLDH). Therefore, mitochondrial monocarboxylate uptake and oxidation, rather than translocation of transporters to the cell surfaces, probably regulate lactate flux in vivo. Accordingly, the "lactate shuttle" hypothesis has been modified to include a new, intracellular component involving cytosolic to mitochondrial exchange. The intracellular lactate shuttle emphasizes the role of mitochondrial redox in the oxidation and disposal of lactate during exercise and other conditions.
Abstract: Similar to the response to central hypervolemic conditions on Earth, the shift of blood volume from the legs to the upper part of the body in astronauts entering micro-gravity should, in accordance with the Henry-Gauer mechanism, mediate diuresis and natriuresis. However, fluid balance and kidney function experiments during various space missions resulted in the surprising observation that the responses qualitatively differ from those observed during simulations of hypervolemia on Earth. There is some evidence that the attenuated responses of the kidney while entering weightlessness, and also later during space flight, may be caused by augmented fluid distribution to extravascular compartments compared to conditions on Earth. A functional decoupling of the kidney may also contribute to the observation that renal responses during exposure to micro-gravity are consistently weaker than those during simulation experiments before space flight. Deficits in body mass after landing have always been interpreted as an indication of absolute fluid loss early during space missions. However, recent data suggest that body mass changes during space flight are rather the consequences of hypocaloric nutrition and can be overcome by improved nutrition schemes. Finally, sodium-retaining humoral systems are activated during space flight and may contribute to a new steady-state of metabolic balances with a pronounced increase in body sodium compared to respective conditions on Earth. A revision of the classical "micro-gravity fluid shift" scheme is required.
Abstract: Orthostatic stress causes, in addition to venous pooling, a loss of plasma fluid from capillaries to the dependent tissues. The rate of this loss may be one of the factors determining orthostatic tolerance. In this study we assessed the use of a multichannel impedance plethysmograph for determining changes in volume in the calf, thigh, and abdominal segments, in asymptomatic volunteers and in patients shown to have poor tolerance to orthostatic stress. Impedance plethysmography showed, for leg segments, that following head-up tilt there was an initial rapid change in volume followed after 2 to 4 minutes by an almost linear change. Results from the abdominal segment were more variable. The rate of change of leg (thigh + calf) volume was significantly correlated with the estimated loss of plasma volume derived from the changes in the concentration of plasma protein, using Evans Blue dye as the marker. Comparison of results of leg filtration rates between patients and volunteers indicated that some of the patients had abnormally high filtration rates and suggests that impedance plethysmography may have a role in assessing the possible reasons for orthostatic intolerance.
Abstract: BACKGROUND: Body-mass index (the weight in kilograms divided by the square of the height in meters) is known to be associated with overall mortality. We investigated the effects of age, race, sex, smoking status, and history of disease on the relation between body-mass index and mortality. METHODS: In a prospective study of more than 1 million adults in the United States (457,785 men and 588,369 women), 201,622 deaths occurred during 14 years of follow-up. We examined the relation between body-mass index and the risk of death from all causes in four subgroups categorized according to smoking status and history of disease. In healthy people who had never smoked, we further examined whether the relation varied according to race, cause of death, or age. The relative risk was used to assess the relation between mortality and body-mass index. RESULTS: The association between body-mass index and the risk of death was substantially modified by smoking status and the presence of disease. In healthy people who had never smoked, the nadir of the curve for body-mass index and mortality was found at a body-mass index of 23.5 to 24.9 in men and 22.0 to 23.4 in women. Among subjects with the highest body-mass indexes, white men and women had a relative risk of death of 2.58 and 2.00, respectively, as compared with those with a body-mass index of 23.5 to 24.9. Black men and women with the highest body-mass indexes had much lower risks of death (1.35 and 1.21), which did not differ significantly from 1.00. A high body-mass index was most predictive of death from cardiovascular disease, especially in men (relative risk, 2.90; 95 percent confidence interval, 2.37 to 3.56). Heavier men and women in all age groups had an increased risk of death. CONCLUSIONS: The risk of death from all causes, cardiovascular disease, cancer, or other diseases increases throughout the range of moderate and severe overweight for both men and women in all age groups. The risk associated with a high body-mass index is greater for whites than for blacks.
Abstract: Although transport of long-chain free fatty acids (FFAs) into cells is often analyzed in the same way as glucose transport, we argue that the transport of the lipid-soluble amphipathic FFA molecule must be viewed differently. The partitioning of FFAs into phospholipid bilayers and their interfacial ionization are particularly relevant to transport. We summarize new data supporting the diffusion hypothesis in simple lipid bilayers and in plasma membranes of cells. Along with previous supporting data, the new data indicate that transport of FFAs through membranes could occur rapidly by flip-flop of the un-ionized form of the FFA. It appears that, at least for the adipocyte, passive diffusion guarantees fast entry and exit of FFAs at both low and high concentrations. Although there are several candidate proteins for the membrane transport of FFAs, most of these proteins have other established functions. Thus, unlike the glucose transporters, these proteins would not be single-function proteins. Definitive proof of their function as FFA transporters awaits their reconstitution into simple model systems.
Abstract: The diagnosis, treatment and prevention of high altitude cerebral edema (HACE) are fairly well established. The major unresolved issues are 1) the pathophysiology, 2) the individual susceptibility, and 3) the relationship of HACE to acute mountain sickness (AMS) and to high altitude pulmonary edema (HAPE). In the context of the two types of cerebral edema, cytotoxic (intracellular) and vasogenic, a leaking of proteins and water through the blood-brain barrier (BBB), a recent MRI study in persons ill with HACE (16) suggested a predominantly vasogenic mechanism. Causes of increased BBB permeability might include mechanical factors (loss of autoregulation and increased capillary pressure), ischemia, neurogenic influences (adrenergic and cholinergic activation), and a host of permeability mediators. Once vasogenic edema develops, cytotoxic edema generally follows, and although likely in HACE, this is still unproven. Symptoms of HACE are related to increased intracranial pressure (ICP), and death is from brain herniation. Treatment is directed both to lowering ICP by reducing the volume of intracranial contents, and to stopping the vasogenic leak. Evidence is accumulating that established moderate to severe AMS is due to cerebral edema, but whether this is true for early AMS (headache) is unclear. New work suggests that the brain swells on ascent to altitude, but that this is unrelated to AMS. Preliminary data showing that those with less cerebrospinal fluid volume (a tighter fit of the brain in the cranium) were more likely to develop AMS supports the hypothesis of Ross that those with less ability to accommodate the increased brain volume are the ones that suffer AMS. The blood-brain barrier and intracranial hemodynamics are the two key elements in the pathophysiology of HACE and AMS.
Abstract: There is a high prevalence of type 2 diabetes mellitus and coronary artery disease among urban and migrant Asian Indians despite the absence of traditional risk factors. Evidence exists that Asian Indians are more hyperinsulinemic than Caucasians and that hyperinsulinemia may be important in the development of these diseases. To test whether insulin action was related to total or regional adiposity and to explore the potential role of plasma leptin and lipids, we measured insulin-mediated glucose disposal by the euglycemic insulin clamp, adipose distribution and muscle volume using computed axial tomography, and fasting serum leptin and lipid levels in 20 healthy Asian Indian male volunteers (age, 36 +/- 10 yr). A mean body mass index of 24.5 +/- 2.5 kg/m2 was associated with an unusually high percentage of body fat (33 +/- 7%). The majority of the fat was sc, and 16% was visceral (intraabdominal) adipose tissue. The majority (66%) of these nonobese men were insulin resistant. The mean fasting serum leptin level was 7.6 +/- 3.3 ng/mL. Insulin action was inversely correlated with visceral adipose tissue, not total or abdominal sc adipose tissue. In contrast, leptin levels correlated with sc and total (not visceral) adipose tissue. Serum triglyceride and high density lipoprotein cholesterol levels were inversely correlated with each other and were directly related to insulin resistance and visceral (not subcutaneous) fat. Increased visceral fat in Asian Indians is associated with increased generalized obesity, which is not apparent from their nonobese body mass index. Increased visceral fat is related to dyslipidemia and increased frequency of insulin resistance and may account for the increased prevalence of diabetes mellitus and cardiovascular disease in Asian Indians.
Abstract: The effects of a 37-day period of bed rest on myosin heavy chain (MHC) expression on both mRNA and protein level in human skeletal muscle fibers were studied. Muscle biopsies from vastus lateralis muscle were obtained from seven healthy young male subjects before and after the bed-rest period. Combined in situ hybridization, immunocytochemistry, and ATPase histochemistry analysis of serial sections of the muscle biopsies demonstrated that fibers showing a mismatch between MHC isoforms at the mRNA and protein level increased significantly after the bed-rest period, suggesting an increase in the amount of muscle fibers in a transitional state. Accordingly, fibers showing a match in expression of MHC-1 and of MHC-2A at the mRNA and protein level decreased, whereas fibers showing a match between MHC-2X mRNA and protein increased after bed rest. Overall, there was an increase in fibers in a transitional state from phenotypic type 1 –\textbackslashtextgreater 2A and 2A –\textbackslashtextgreater 2X. Furthermore, a number of fibers with unusual MHC mRNA and isoprotein combinations were observed after bed rest (e.g., type 1 fibers with only mRNA for 2X and type 1 fibers negative for mRNA for MHC-betâ„Âlow, 2A, and 2X). In contrast, no changes were revealed after an examination at the protein level alone. These data suggest that the reduced load-bearing activity imposed on the skeletal muscles through bed rest will alter MHC gene expression, resulting in combinations of mRNA and MHC isoforms normally not (or only rarely) observed in muscles subjected to load-bearing activity. On the other hand, the present data also show that 37 days of bed rest are not a sufficient stimulus to induce a similar change at the protein level, as was observed at the gene level.
Abstract: After birth, new blood vessel formation proceeds via angiogenesis or arteriogenesis. Angiogenesis (capillary sprouting) results in higher capillary density. Arteriogenesis (rapid proliferation of collateral arteries) is potentially able to significantly alter the outcome of coronary and peripheral artery disease. The processes share some growth features but differ in many aspects.
Abstract: Angiotensin II (AngII) enhances tubuloglomerular feedback responses and is considered to be a specific modulator of feedback activity. The sites at which AngII interacts with the signal transmission process remain unknown. In certain renal epithelia, AngII stimulates Na/H exchange activities. Evidence for the regulation of macula densa apical Na/H exchange by AngII was recently reported. Because macula densa cells also express a basolateral Na/H exchanger, the possibility that AngII stimulates this exchanger activity was investigated. In preparations of isolated perfused thick ascending limb with attached glomerulus dissected from rabbit kidney, the intracellular pH (pHi) of macula densa cells was measured with fluorescence microscopy using 2’,7’-bis(2-carboxyethyl)-5-(and -6)carboxyfluorescein. Perfusion and bathing solutions were iso-osmotic Cl-free Ringer’s solutions modified using N-methyl-D-glucamine and cyclamate as the Na and Cl substitutes, respectively. Control pHi, during perfusion with 0 mM Na and 150 mM Na in the bath, averaged 7.21+/-0.07 (n=10). Removal of Na from the bath (i.e., basolateral solution) decreased pHi by 0.39+/-0.06 units (n=5, P \textbackslashtextless 0.01). Addition of 10(-9) M AngII to the bath resulted in a significant increase in the Na-dependent acid load. This increase in Na-dependent cell acidification was completely blocked by coadministration of the AngII type 1 (AT1) receptor blocker candesartan (10(-8) M). In addition, AngII increased the rate of pHi recovery from the acid load induced by readdition of bath Na. This stimulatory effect of AngII was also completely reversed by coadministration of the AT1 receptor blocker candesartan. These results indicate that AngII stimulates macula densa basolateral Na/H exchange via AT1 receptors and therefore may affect tubuloglomerular feedback signal transmission, at least in part, through direct effects on macula densa transport processes.
Abstract: Previous studies have shown that a metabolic alkalosis develops in the muscle during early exercise. This has been linked to phosphocreatine hydrolysis. Over a similar time frame, the femoral vein blood pH and plasma K⊕ and HCO⊖(3) concentrations increase without an increase in PCO(2). Thus CO(2) from aerobic metabolism is converted to HCO⊖(3) rather than being eliminated by the lungs. The purpose of this study was to quantify the increase in early CO(2) stores and the component due to the exercise-induced metabolic alkalosis (E-I Alk). To avoid masking the increase in CO(2) stores by CO(2) released as HCO⊖(3) buffers lactic acid, the transient increase in CO(2) stores was measured only for work rates (WRs) below the lactic acidosis threshold (LAT). The increase in CO(2) stores was evident at the airway starting at approximately 15 s; the increase reached a peak at approximately 60 s and was complete by approximately 3 min of exercise. The increase in CO(2) stores was greater, but the kinetics were unaffected at the higher WR. Three components of the change in aerobically generated CO(2) stores were considered relevant: the carbamate component of the Haldane effect, the increase in CO(2) stores due to increase in tissue PCO(2), and the E-I Alk. The Haldane effect was calculated to be approximately 5%. Physically dissolved CO(2) in the tissues was approximately 30% of the store increase. The remaining E-I Alk CO(2) stores averaged 61 and 68% for 60 and 80% LAT WRs, respectively. The kinetics of O(2) uptake correlated with the time course of the increase in CO(2) stores; the size of the O(2) deficit correlated with the size of the E-I Alk component of the CO(2) stores. We conclude that a major component of the aerobically generated increase in CO(2) stores is the new HCO⊖(3) generated as phosphocreatine is converted to creatine.
Abstract: The study of the underlying mechanisms by which cells respond to mechanical stimuli, i.e. the link between the mechanical stimulus and gene expression, represents a new and important area in the morphological sciences. Several cell types (’mechanocytes’), e.g. osteoblasts and fibroblasts as well as smooth, cardiac and skeletal muscle cells are activated by mechanical strain and there is now mounting evidence that this involves the cytoskeleton. Muscle offers one of the best opportunities for studying this type of mechanotransduction as the mechanical activity generated by and imposed upon muscle tissue can be accurately controlled and measured in both in vitro and in vivo systems. Muscle is highly responsive to changes in functional demands. Overload leads to hypertrophy, whilst decreased load force generation and immobilisation with the muscle in the shortened position leads to atrophy. For instance it has been shown that stretch is an important mechanical signal for the production of more actin and myosin filaments and the addition of new sarcomeres in series and in parallel. This is preceded by upregulation of transcription of the appropriate genes some of which such as the myosin isoforms markedly change the muscle phenotype. Indeed, the switch in the expression induced by mechanical activity of myosin heavy chain genes which encode different molecular motors is a means via which the tissue adapts to a given type of physical activity. As far as increase in mass is concerned, our group have cloned the cDNA of a splice variant of IGF-1 that is produced by active muscle that appears to be the factor that controls local tissue repair, maintenance and remodelling. From its sequence it can be seen that it is derived from the IGF-1 gene by alternative splicing but it has different exons to the liver isoforms. It has a 52 base insert in the E domain which alters the reading frame of the 3’ end. Therefore, this splice variant of IGF-1 is likely to bind to a different binding protein which exists in the interstitial tissue spaces of muscle, neuronal tissue and bone. This would be expected to localise its action as it would be unstable in the unbound form which is important as its production would not disturb the glucose homeostasis unduly. This new growth factor has been called mechano growth factor (MGF) to distinguish it from the liver IGFs which have a systemic mode of action. Although the liver is usually thought of as the source of circulating IGF-1, it has recently been shown that during exercise skeletal muscle not only produces much of the circulating IGF-1 but active musculature also utilises most of the IGF-I produced. We have cloned both an autocrine and endocrine IGF-1, both of which are upregulated in cardiac as well as skeletal muscle when subjected to overload. It has been shown that, in contrast to normal muscle, MGF is not detectable in dystrophic mdx muscles even when subjected to stretch and stretch combined with electrical stimulation. This is true for muscular dystrophies that are due to the lack of dystrophin (X-linked) and due to a laminin deficiency (autosomal), thus indicating that the dystrophin cytoskeletal complex may be involved in the mechanotransduction mechanism. When this complex is defective the necessary systemic as well as autocrine IGF-1 growth factors required for local repair are not produced and the ensuing cell death results in progressive loss of muscle mass. The discovery of the locally produced IGF-1 appears to provide the link between the mechanical stimulus and the activation of gene expression.
Abstract: This study investigated the effect of age on pulse pressure and its underlying mechanisms in unmedicated hypertensive men with the same level of mean arterial pressure. We included 77 men 17 to 76 years old with daytime mean arterial pressure between 95 and 114 mm Hg. In the supine position, pulse pressure showed a significant widening in young (\textbackslashtextless30 years) and older (\textbackslashtextgreater≠60 years) patients. Pulse pressure decreased in parallel with stroke index from age \textbackslashtextgreater30 to 40 to 49 years. Upright posture, however, eliminated this difference through a larger orthostatic fall in stroke index and pulse pressure in the youngest patients. After age 50 years, pulse pressure exhibited a progressive widening despite the further age-related decrease in stroke index. Supine, upright, and 24-hour pulse pressure fitted a curvilinear correlation with age (r=0.55, 0.56, and 0.68, respectively, P\textbackslashtextless0.001), with a transition at age 50 years. Before age 50 years, 24-hour pulse pressure correlated positively with stroke volume (r=0.5, P\textbackslashtextless0.001) and negatively with arterial compliance (SV/PP ratio, r=-0.37, P\textbackslashtextless0.01). In contrast, in men \textbackslashtextgreater≠50 years old, 24-hour pulse pressure correlated negatively with the SV/PP ratio (r=-0.5; P\textbackslashtextless0.01), without significant influence of stroke volume. Thus, in hypertensive men, the age-related change in stroke volume significantly accounted for the change in clinic and ambulatory pulse pressure during young adulthood, but its contribution decreased after the fifth decade.
Abstract: Cannulation of the canine major prenodal cardiac lymphatic (MPCL) is the most common approach for the investigation of myocardial lymphatic function. However, the assumption that the MPCL drains pure cardiac lymph has been questioned. We studied variations of MPCL anatomy and investigated whether noncardiac lymph is drained by this lymphatic. After dye was injected into the lungs and left ventricular myocardium in 21 dogs, dissection of the cardiac lymphatic system yielded 3 anatomic variations. In variations 1 and 2 (81% of dogs), a mixture of cardiac and pulmonary lymph was drained via the MPCL. In variation 3 (19% of dogs) no connection was found between MPCL and pulmonary lymphatics. In variations 1 and 2, alteration of tidal volume resulted in significant changes of lymph flow rate. The pulmonary contribution to MPCL lymph flow was estimated as 34% in variation 2. We conclude that MPCL lymph may contain not only cardiac lymph but also significant pulmonary contamination. This finding should be considered in the interpretation of lymph data from cannulation of the canine MPCL.
Abstract: OBJECTIVE: To investigate whether leptin interferes directly with glycogenolysis and gluconeogenesis in isolated rat hepatocytes and also in in situ rat perfused livers. ANIMALS: Male albino rats (200-250 g) were used in all experiments. MEASUREMENTS: D-glucose, L-lactate and pyruvate production. RESULTS: In the present study, no differences were found for the rates of glycolysis, as expressed by the areas under the curves, among control (24.2+5.0 mmol¿g), leptin (32.0+4.5 mmol¿g), glucagon (24.7+3.0 mmol¿g), and the leptin + glucagon (23.8+3.4 mmol¿g) groups. No difference was found for the rates of glycogenolysis between the control and the leptin perfused livers (15.2+3.9 and 15.0+3.2 mmol¿g, respectively). In the presence of glucagon, the areas under the curves for the rate of glycogenolysis rose to 108.6+3.8 mmol¿g. When leptin was combined with glucagon, the area under the curve for glycogenolysis was 43. 7+4.3 mmol¿g. In fact, leptin caused a reduction of almost 60% (P\textbackslashtextless0. 001) in the rate of glucagon-stimulated glycogenolysis. Under basal conditions, the addition of leptin (100 ng¿ml) to the incubation medium did not elicit any alteration in glucose production by isolated hepatocytes. However, in the presence of leptin, the production of glucose from glycerol (2 mM), L-lactate (2 mM). L-alanine (5 mM) and L-glutamine (5 mM) by the isolated hepatocytes was significantly reduced (30%, 30%, 23% and 25%, respectively). The rate of glucose production (glycogenolysis) by isolated hepatocytes was not different between the control and the leptin incubated groups (445.0+/-91.0 and 428.0+/-72.0 nmol¿106 cells¿h, respectively). CONCLUSION: We conclude that leptin per se does not directly affect either liver glycolysis or its glucose production, but a physiological leptin concentration is capable of acutely inducing a direct marked reduction on the rate of glucagon-stimulated glucose production in in situ rat perfused liver. Leptin is also capable of reducing glucose production from different gluconeogenic precursors in isolated hepatocytes.
Abstract: A decrease in intracellular ionic strength appears involved in the activation of swelling-elicited 3H-taurine efflux in cortical cultured astrocytes. Hyposmotic (50%) or isosmotic urea-induced swelling leading to a decrease of intracellular ionic strength, activated 3H-taurine efflux from a rate constant of about 0.008 min(-1) to 0.33 min(-1) (hyposmotic) and 0.59 min(-1) (urea). This efflux rate was markedly lower (maximal 0.03 min(-1)) in isosmotic swelling caused by K+ accumulation, where there is no decrease in ionic strength, or in cold (10 degrees C) hyposmotic medium (maximal 0.18 min(-1)), where swelling is reduced and consequently intracellular ionic strength is less affected. Also, astrocytes pretreated with hyperosmotic medium, which recover cell volume by ion accumulation, did not release 3H-taurine when they swelled by switching to isosmotic medium, but when volume was recovered by accumulation of urea, taurine release was restored. These results point to a key role of ionic strength in the activation of osmosensitive 3H-taurine efflux. In contrast, its inactivation was independent of the change in ionic strength but appears related to the reduction in cell volume after swelling, since despite the extent or direction of the change in ionic strength, the 3H-taurine efflux did not inactivate in isosmotic KCl-elicited swelling when cell volume did not recover nor in hyposmotic swelling when RVD was impaired by replacing NaCl in the medium by permeant osmolytes.
Abstract: This study examined the influence of spinal cord injury (SCI) on affected skeletal muscle. The right vastus lateralis muscle was biopsied in 12 patients as soon as they were clinically stable (average 6 wk after SCI), and 11 and 24 wk after injury. Samples were also taken from nine able-bodied controls at two time points 18 wk apart. Surface electrical stimulation (ES) was applied to the left quadriceps femoris muscle to assess fatigue at these same time intervals. Biopsies were analyzed for fiber type percent and cross-sectional area (CSA), fiber type-specific succinic dehydrogenase (SDH) and alpha-glycerophosphate dehydrogenase (GPDH) activities, and myosin heavy chain percent. Controls showed no change in any variable over time. Patients showed 27-56% atrophy (P = 0.000) of type I, IIa, and IIax+IIx fibers from 6 to 24 wk after injury, resulting in fiber CSA approximately one-third that of controls. Their fiber type specific SDH and GPDH activities increased (P \textbackslashtextless≠0.001) from 32 to 90% over the 18 wk, thereby approaching or surpassing control values. The relative CSA of type I fibers and percentage of myosin heavy chain type I did not change. There was apparent conversion among type II fiber subtypes; type IIa decreased and type IIax+IIx increased (P \textbackslashtextless≠0.012). Force loss during ES did not change over time for either group but was greater (P = 0.000) for SCI patients than for controls overall (27 vs. 9%). The results indicate that vastus lateralis muscle shows marked fiber atrophy, no change in the proportion of type I fibers, and a relative independence of metabolic enzyme levels from activation during the first 24 wk after clinically complete SCI. Over this time, quadriceps femoris muscle showed moderately greater force loss during ES in patients than in controls. It is suggested that the predominant response of mixed human skeletal muscle within 6 mo of SCI is loss of contractile protein. Therapeutic interventions could take advantage of this to increase muscle mass.
Abstract: Leptin decreases visceral fat (VF) and increases peripheral and hepatic insulin action. Here, we generated similar decreases in VF using leptin (Lep), beta(3)-adrenoreceptor agonism (beta3), or food restriction (FR) and asked whether insulin action would be equally improved. For 8 days before the in vivo study, Sprague-Dawley rats (n = 24) were either fed ad libitum [control (Con)], treated with Lep or beta3 (CL-316,243) by implanted osmotic mini-pumps, or treated with FR. Total VF was similarly decreased in the latter three groups (Lep, 3.11 +/- 0.96 g; beta3, 2.87 +/- 0.48 g; and FR, 3.54 +/- 0.77 g compared with 6.91 +/- 1.41 g in Con; P \textbackslashtextless 0.001) independent of total fat mass (by (3)H(2)O) and food intake. Insulin (3 mU. kg(-1). min(-1)) clamp studies were performed to assess hepatic and peripheral insulin sensitivity. Decreased VF resulted in similar and marked improvements in insulin action on glucose production (GP) (Lep, 1.19 +/- 0.51; beta3, 1.46 +/- 0.68; FR, 2.27 +/-0.71 compared with 6.06 +/- 0.70 mg. kg(-1). min(-1) in Con; P \textbackslashtextless 0.001). By contrast, reduction in VF by beta3 and FR failed to reproduce the stimulation of insulin-mediated glucose uptake ( approximately 60%), glycogen synthesis ( approximately 80%), and glycolysis ( approximately 25%) observed with Lep. We conclude that 1) a moderate decrease in VF uniformly leads to a marked increase in hepatic insulin action, but 2) the effects of leptin on peripheral insulin action are not due to the associated changes in VF or beta3 activation.
Abstract: Cerebral venous blood gas values have been used to indicate brain tissue oxygenation. However, it is not clear how cerebral tissue and venous measures may vary under physiologic conditions caused by arteriovenous shunt. The purpose of this study was to measure brain tissue and local cerebral venous oxygen (PO2) and carbon dioxide (P(CO2)) partial pressure during changes in ventilation and to calculate shunt fraction. Eight dogs were anesthetized with isoflurane. After a craniotomy, a Neurotrend probe (Diametrics Inc., St. Paul, MN) that measures P(O2), P(CO2), pH, and temperature was inserted into brain tissue, and a small vein that drained the same tissue was catheterized. Arterial, cerebral venous, and brain tissue P(O2) and Pco2 were measured during random changes in ventilation to produce five different levels of inspired oxygen (room air, 40%, 60%, 80%, 95%) at each of three different end-tidal Pco2 (20 mm Hg, 40 mm Hg, 60 mm Hg). Arteriovenous shunt was calculated from oxygen and C(O2) content in artery, vein, and tissue, representing capillary. Tissue P(CO2) was 8 mm Hg greater than vein Pco2 during hypocapnia and this difference increased to 20 mm Hg during hypercapnia. Vein P(O2) was 8 mm Hg higher than tissue P(O2) during hypocapnia, and this difference increased to 40 mm Hg during hypercapnia. Shunt fraction increased from 10%-20% during hypocapnia to 50%-60% during hypercapnia. These results show that brain vein and tissue P(O2) and P(CO2) differ because of arteriovenous shunting and this difference is increased as end-tidal P(CO2) increases. IMPLICATIONS: We found, in dogs, that the gradient between brain venous and tissue P(O2) and PCO2 is increased with increased arterial P(CO2). The divergence between tissue and venous gases can be described by arterial to venous shunting.
Abstract: Obesity often leads to symptoms of cardiopulmonary congestion associated with normal systolic but abnormal diastolic function. This study analyzed alterations in passive diastolic compliance in obesity using the rabbit model. New Zealand White rabbits were fed a normal (n=8) or 10% added fat diet (n=8). After 12 weeks, rabbits fed the high fat diet developed obesity (5.34+/-0.11 versus 3.68+/-0. 04 kg, P\textbackslashtextless≠0.05) and left ventricular hypertrophy (1.37+/-0.07 versus 0.98+/-0.03 g dry weight, P\textbackslashtextless≠0.05). Compliance was assessed with the isolated heart preparation by analyzing the passive end-diastolic left ventricular pressure-volume relationship. The pressure-volume relation was fit to an exponential function by regression analysis; results showed that the modulus of stiffness was greater in obese than in lean rabbits (1.21+/-0.16 versus 0. 83+/-0.05, P\textbackslashtextless≠0.05), indicating that diastolic compliance was reduced. Computer simulation analyses suggested that an isolated reduction in diastolic compliance may contribute to elevated cardiac filling pressures and exercise intolerance. These data suggest that diastolic compliance is reduced early in the development of obesity and may be an important component in the reduction of cardiac reserve in obesity.
Abstract: The mouse ob gene encodes leptin, an adipocyte hormone that regulates body weight and energy expenditure. Leptin has potent metabolic effects on fat and glucose metabolism. A mutation of the ob gene results in mice with severe hereditary obesity and diabetes that can be corrected by treatment with the hormone. In lean mice, leptin acutely increases glucose metabolism in an insulin-independent manner, which could account, at least in part, for some of the antidiabetic effect of the hormone. To investigate further the acute effect of leptin on glucose metabolism in insulin-resistant obese diabetic mice, leptin (40 ng x g(-1) x h(-1)) was administered intravenously for 6 h in C57Bl/6J ob/ob mice. Leptin increased glucose turnover and stimulated glucose uptake in brown adipose tissue (BAT), brain, and heart with no increase in heart rate. A slight increase in all splanchnic tissues was also noticed. Conversely, no increase in skeletal muscle or white adipose tissue (WAT) glucose uptake was observed. Plasma insulin concentration increased moderately but neither glucose, glucagon, thyroid hormones, growth hormone, nor IGF-1 levels were different from phosphate-buffered saline-infused C57Bl/6J ob/ob mice. In addition, leptin stimulated hepatic glucose production, which was associated with increased glucose-6-phosphatase activity. Conversely, PEPCK activity was rather diminished. Interestingly, hepatic insulin receptor substrate (IRS)1-associated phosphatidylinositol 3-kinase activity was slightly elevated, but neither the content of glucose transporter GLUT2 nor the phosphorylation state of the insulin receptor and IRS-1 were changed by acute leptin treatment. Hepatic lipid metabolism was not stimulated during the acute leptin infusion, since the content of triglycerides, glycerol, and citrate was unchanged. These findings suggest that in ob/ob mice, the antidiabetic antiobesity effect of leptin could be the result of a profound alteration of glucose metabolism in liver, BAT, heart, and consequently, glucose turnover. Insulin resistance of skeletal muscle and WAT, while not affected by acute leptin treatment, could also be corrected in the long term and account for some of leptin’s antidiabetic effects.
Abstract: Alterations in arteriolar reactivity to dilator agonists were assessed in the skeletal muscle microcirculation of normotensive male Sprague-Dawley rats fed either high- (4% NaCl; HS) or low- (0. 4% NaCl; LS) salt diets and in reduced renal mass hypertensive rats (RRM-HT) on a high-salt diet for 3 days. An in situ cremaster muscle preparation was superfused with physiological salt solution, transilluminated, and viewed via television microscopy. A videomicrometer was used to measure changes in diameter of distal arterioles in response to increasing concentrations of acetylcholine (ACH), iloprost (ILO), cholera toxin (CT), forskolin (FOR), and sodium nitroprusside (SNP). Arteriolar dilation in response to ACH, ILO, and CT was significantly reduced in both HS and RRM-HT rats, while responses to FOR and SNP were decreased in RRM-HT rats only. The maximum dilation of the arterioles (determined during superfusion of the muscle with Ca2+-free solution containing 10(-4) M adenosine) was similar in the normotensive control animals on LS and HS diets, but was reduced in the RRM-HT rats, suggesting that early anatomic remodeling of the vessel wall may be occurring with RRM-HT. We conclude that arteriolar reactivity to endothelium-dependent and -independent vasodilator agonists is impaired as early as 3 days after the development of RRM hypertension or commencement of a high-salt diet in normotensive rats. Structural remodeling of the arteriolar wall, although becoming evident in the hypertensive rats, takes longer to develop than the impaired vasodilator reactivity.
Abstract: 1. The source and physiological significance of dopamine (DA) sulphate, which exists in plasma at much higher concentrations than free DA, have long been a puzzle. The present article reviews how the convergence of modern molecular and traditional clinical approaches is shedding new light on the origins and meaning of DA sulphate. 2. The sulphotransferase isoenzyme responsible for production of DA sulphate in humans (SULT1A3) has been cloned and shown to be expressed in large quantities in the gastro-intestinal tract, but not in liver. No orthologue of SULT1A3 has yet been identified in other species, consistent with the greater importance of sulphate conjugation of DA in humans than in most animals. 3. Diet has a major impact on plasma DA sulphate, with dramatic increases after ingestion of meals and foods rich in biogenic amines; however, substantial amounts of DA sulphate remaining after prolonged fasting indicate the presence of a mainly endogenous source. The lack of influence of acute or chronic changes in sympathetic outflow or of sympathoneural degeneration on plasma DA sulphate indicates that DA sulphate does not derive from sympathetic nerve. Relatively low rates of production from intravenously infused DA indicate that very little DA sulphate (\textbackslashtextless 2%) derives from metabolism of circulating DA, such as in red cells or platelets. 4. Consistent increments in DA sulphate from arterial to the outflowing venous plasma draining mesenteric organs, without increments across other organs or tissues (e.g., heart, lungs, liver), indicate that the gastrointestinal tract is a major source of more than 75% of DA sulphate produced in the body. The gastro-intestinal tract is also the site of a novel DA autocrine/paracrine system that produces nearly 50% of the DA in the body. Therefore, production of DA sulphate appears to reflect an enzymatic ’gut-blood’ barrier for detoxifying dietary biogenic amines and delimiting autocrine/paracrine effects of endogenous DA generated in a novel ’third catecholamine system’.
Abstract: To provide a framework for quantitative analysis of metabolic and transport processes associated with ATP production during exercise, we adapted a recently developed model that links cellular metabolism and its control to whole body responses at rest. The enhanced model is based on dynamic mass balances for glycogen, glucose, pyruvate (PY), lactate (LA), O(2), and CO(2) and is solved numerically to simulate responses to acute (\textbackslashtextless20 min), moderate exercise (i.e., below the LA threshold, less than approximately 60% maximal rate of O(2) uptake). Simulations of responses to a step change in muscle ATP turnover predict substrate changes in muscle, splanchnic, and other tissues compartments, as well as changes in other metabolites (e.g., NADH, ADP) whose reactions are coupled to the main reactions. Even a significant (64%) decrease in muscle O(2) concentration (C(m, O(2))) did not affect muscle O(2) consumption. Model simulations of moderate exercise show that 1) muscle oxygenation is sufficient (C(m, O(2)) \textbackslashtextgreater2 mM) even during the transient state; 2) transient increases in concentration of muscle LA and arterial concentration of LA are associated with increases in glycolysis from increases in ADP/ATP and in LA production associated with a rise in NADH/NAD; 3) muscle ADP/ATP reaches a higher steady state that stimulates glycolysis, glycogenolysis, and oxidative phosphorylation to match the ATP demand; and 4) muscle NADH/NAD reaches a lower steady state that stimulates LA oxidation. It is suggested that the continuous stimulation of ATP synthesis processes during moderate exercise is mainly due to a higher ADP/ATP, not to a higher NADH/NAD. Critical measurements needed to quantify metabolic control mechanisms are identified.
Abstract: At the onset of exercise there is a rapid increase in skeletal muscle vascular conductance and blood flow. Several mechanisms involved in the regulation of muscle perfusion have been proposed to initiate this hyperemic response, including neural, metabolic, endothelial, myogenic, and muscle pump mechanisms. Investigators utilizing pharmacological blockade of cholinergic muscarinic receptors and sympathectomy have concluded that neither sympathetic cholinergic nor adrenergic neural mechanisms are involved in the initial hyperemia. Studies have also shown that the time course for vasoactive metabolite release, diffusion, accumulation, and action is too long to account for the rapid increase in vascular conductance at the initiation of exercise. Furthermore, there is little or no evidence to support an endothelium or myogenic mechanism as the initiating factor in the muscle hyperemia. Thus, the rise in muscle blood flow does not appear to be explained by known neural, metabolic, endothelial, or myogenic influences. However, the initial hyperemia is consistent with the mechanical effects of the muscle pump to increase the arteriovenous pressure gradient across muscle. Because skeletal muscle blood flow is regulated by multiple and redundant mechanisms, it is likely that neural, metabolic, and possibly endothelial factors become important modulators of mechanically induced exercise hyperemia following the first 5-10 s of exercise.
Abstract: Body water and electrolyte balance are essential to optimal physiological function and health. During exercise, work, or high temperatures, a significant level of dehydration can develop, and the ratio of extracellular to intracellular fluid can change, despite an ample supply of water. Physical and cognitive performance are impaired at 1-2% dehydration, and the body can collapse when water loss approaches 7%. Because fluid needs and intakes vary, formulating one general guideline for fluid replacement is difficult. Knowing the amount of water lost in sweat may enable predicting fluid needs via mathematical models for industrial, athletic, and military scenarios. Sodium imbalance might result from excessive Na+ loss or from gross overhydration. In most work or exercise lasting \textbackslashtextless 3-4 hr, the major concern is that fluid be available to prevent heat-related illnesses, which can be prevented if fluid and electrolyte losses are balanced with intake, using the recommendations presented.
Abstract: Cardiac complications are frequent in patients with subarachnoid hemorrhage (SAH). They include ECG abnormalities, cardiac arrhythmias, myocardial damage, and neurogenic pulmonary edema. The pathophysiology of these abnormalities is related to an imbalance of the autonomic cardiovascular control and to increased circulating and local myocardial tissue catecholamines. Cardiac involvement is more common in patients with severe neurological deficits and it may increase the morbidity associated with SAH because of the occurrence of life-threatening arrhythmias or pulmonary edema. Monitoring of cardiac events in patients with SAH might result in a better understanding of their clinical outcome, as well as providing a basis for specific treatment capable of preventing myocardial necrosis and cardiac arrhythmias.
Abstract: BACKGROUND: Although myocardial edema is known to impair diastolic filling of the left ventricle, the interrelation of edema, histologic condition, and function has not been quantitated sufficiently for extrapolation to studies of multifactorial influences on diastolic properties. METHODS: Accordingly, ACI rat hearts arrested at 4 degrees C underwent coronary artery perfusion with a cardioplegia solution that was either unaltered (288 mOsm/L, P288 group, n = 6), diluted (144 mOsm/L, P144 group, n = 6), or concentrated (380 mOsm/L, P380 group, n = 6). Postmortem left ventricular pressure-volume curves and myocardial water content were measured. Myocardial samples were fixed in varying dilutions of glutaraldehyde. After dehydration and paraffin embedding, edema was graded subjectively (0 to 5), and myocardial interstitial spaces were determined by use of a semiquantitative method. RESULTS: Mean normalized left ventricular filling volume at 20 mm Hg filling pressure in the P144 group, 189 +/- 16 microliters (SEM), was reduced versus both the P288 (278 +/- 26 microliters) and the P380 (332 +/- 18 microliters) groups (p \textbackslashtextless 0.05, ANOVA). Mean myocardial water content in the P144 group, 80.7% +/- 1%, was increased versus the P380 (76.7% +/- 0.4%, p \textbackslashtextless 0.05) but not versus the P288 group (78.4% +/- 0.8%). In hearts preserved with 2.5% glutaraldehyde, mean edema grade and interstitial space in the P144 group (4.0 +/- 0.3) were increased versus the P380 (1.8 +/- 0.3, p \textbackslashtextless 0.05) but not the P288 group (2.7 +/- 0.5). Derived linear regressions relate water content to filling volume and histologic condition. CONCLUSIONS: Coronary perfusate osmolarity is thus associated with predictable changes in myocardial water content, left ventricular filling volume, and edema. These correlations allow definition of new hypotheses for the study of cardiac allograft rejection in patients and experimental animals.
Abstract: The age-related reduction in exercise capacity is associated with a reduction in cardiac output and maximal oxygen consumption (VO2max). The loss of muscle mass explains a large portion of the age-related decline in VO2max. The capillary supply to a muscle fibre is primarily determined by its size, but also by its metabolic profile and the metabolic profile of surrounding fibres. Thus the age-related fibre atrophy and changes in the fibre type composition are expected to be accompanied by changes in the capillarisation. The exchange of oxygen, blood-borne energy sources, metabolites and heat between the blood and muscle tissue takes place in the microcirculation. Changes in the microcirculation may thus affect the functioning and viability of the muscle. The resting blood flow is minimally affected by age, but blood flow during or following exercise is generally reduced. This may in part be due to a reduced vasodilatory capacity and a decreased capillarisation. However, the coupling between capillary supply to a fibre and its metabolic profile or the profile of the surrounding fibres is maintained. There are some changes in ultrastructure of the endothelium. The age-related changes in the microcirculation are associated with a reduced VO2max and exercise capacity. The adaptability of the microcirculation is maintained at old age.
Abstract: The first objective of this study was to confirm that 4 days of head-down tilt (HDT) were sufficient to induce orthostatic intolerance, and to check if 4 days of physical confinement may also induce orthostatic intolerance. Evidence of orthostatic intolerance during tilt-up tests was obtained from blood pressure and clinical criteria. The second objective was to quantify the arterial and venous changes associated with orthostatic intolerance and to check whether abnormal responses to the tilt test and lower body negative pressure (LBNP) may occur in the absence of blood pressure or clinical signs of orthostatic intolerance. The cerebral and lower limb arterial blood flow and vascular resistance, the flow redistribution between these two areas, and the femoral vein distension were assessed during tilt-up and LBNP by ultrasound. Eight subjects were given 4 days of HDT and, 1 month later, 4 days of physical confinement. Tilt and LBNP test were performed pre- and post-HDT and confinement. Orthostatic intolerance was significantly more frequent after HDT (63%) than after confinement (25%, P \textbackslashtextless 0.001). Cerebral haemodynamic responses to tilt-up and LBNP tests were similar pre- and post-HDT or confinement. Conversely, during both tilt and LBNP tests the femoral vascular resistances increased less (P \textbackslashtextless 0.002), and the femoral blood flow reduced less (P \textbackslashtextless 0.001) after HDT than before HDT or after confinement. The cerebral to femoral blood flow ratio increased less after HDT than before (P \textbackslashtextless 0.002) but remained unchanged before and after confinement. This ratio was significantly more disturbed in the subjects who did not complete the tilt test. The femoral superficial vein was more distended during post-HDT LBNP than pre-HDT or after confinement (P \textbackslashtextless 0.01). In conclusion, 4 days of HDT were enough to alter the lower limb arterial vasoconstriction and venous distensibility during tilt-up and LBNP, which reduced the flow redistribution in favour of the brain in all HDT subjects. Confinement did not alter significantly the haemodynamic responses to orthostatic tests. The cerebral to femoral blood flow ratio measured during LBNP was the best predictor of orthostatic intolerance.
Abstract: The anatomical and functional status of the epifascial and subfascial lymphatic compartments was analyzed using two compartment lymphoscintigraphy in five groups of patients (total 55) with various forms of edema of the lower extremities. Digital whole body scintigraphy enabled semiquantitative estimation of radiotracer transport with comparison of lymphatic drainage between those individuals without (normal) and those with leg edema by calculating the uptake of the radiopharmaceutical transported to regional lymph nodes. A visual assessment of the lymphatic drainage pathways of the legs was also performed. In patients with cyclic idiopathic edema, an accelerated rate of lymphatic transport was detected (high lymph volume overload or dynamic insufficiency). In those with venous (phlebo) edemas, high volume lymphatic overload (dynamic insufficiency) of the epifascial compartment was scintigraphically detected by increased tracer uptake in regional nodes. In patients with deep femoral venous occlusion (post-thrombotic syndrome). subfascial lymphatic transport was uniformly markedly reduced (safety valve lymphatic insufficiency). On the other hand, in the epifascial compartment, lymph transport was accelerated. In those patients with recurrent or extensive skin ulceration, lymph transport was reduced. Patients with lipedema (obesity) scintigraphically showed no alteration in lymphatic transport. This study demonstrates that lymphatic drainage is notably affected (except in obesity termed lipedema) in various edemas of the leg. Lymphatic drainage varied depending on the specific compartment and the pathophysiologic mechanism accounting for the edema. Two compartment lymphoscintigraphy is a valuable diagnostic tool for accurate assessment of leg edema of known and unknown origin.
Abstract: Atrial natriuretic factor (ANF) and nitric oxide (NO) stimulate production of guanosine 3’,5’-cyclic monophosphate (cGMP) and are natriuretic. Split-drop micropuncture was performed on anesthetized rats to determine the effects of ANF and the NO donor sodium nitroprusside (SNP) on proximal tubular fluid absorption rate (Jva). Compared with control solutions, SNP (10(-4) M) decreased Jva by 23% when administered luminally and by 35% when added to the peritubular perfusate. Stimulation of fluid uptake by luminal angiotensin II (ANG II; 10(-9) M) was abolished by SNP (10(-4) and 10(-6) M). In proximal tubule suspensions, ANF (10(-6) M) increased cGMP concentration to 143%, whereas SNP (10(-6), 10(-5), 10(-4), 10(-3) M) raised cGMP to 231, 594, 687, and 880%, respectively. S-nitroso-N-acetylpenicillamine (SNAP) also raised cGMP concentrations with similar dose-response relations. These studies demonstrate inhibition by luminal and peritubular NO of basal and ANG II-stimulated proximal fluid absorption in vivo. The ability of SNP to inhibit basal fluid uptake whereas ANF only affected ANG II-stimulated transport may be because of production of higher concentrations of cGMP by SNP.
Abstract: Cell swelling activates an outwardly rectifying anion channel termed VSOAC (volume-sensitive organic osmolyte/anion channel). Regulation of VSOAC by intracellular electrolytes was characterized in Chinese hamster ovary cells by whole cell patch clamp. Elevation of intracellular CsCl concentration from 40 to 180 mM resulted in a concentration-dependent decrease in channel activation. Activation of VSOAC was insensitive to the salt gradient across the plasma membrane, the intracellular concentration of specific anions or cations, and the total intracellular concentration of cations, anions, or electrolytes. Comparison of cells dialyzed with either CsCl or Na2SO4 solutions demonstrated directly that VSOAC activation is modulated by intracellular ionic strength (microi). The relative cell volume at which VSOAC current activation was triggered, termed the channel volume set point, decreased with decreasing ionic strength. At microi = 0.04, VSOAC activation occurred spontaneously in shrunken cells. The rate of VSOAC activation was nearly 50-fold higher in cells with microi = 0.04 vs. those with microi = 0.18. We propose that microi modulates the volume sensor responsible for channel activation.
Abstract: Functions of carotid and aortic baroreflex control of heart rate (HR), cardiopulmonary baroreflex control of vascular resistance, adrenoreceptor responsiveness, indexes of baseline vagal and sympathetic tone, circulating blood volume, and venous compliance were compared in men and women to test the hypothesis that lower orthostatic tolerance in women would be associated with lower responsiveness of specific mechanisms of blood pressure regulation. HR, stroke volume (SV), cardiac output (Q), mean arterial blood pressure (MAP), central venous pressure, forearm (FVR) and leg (LVR) vascular resistance, catecholamines, and changes in leg volume (%DeltaLV) were measured during various protocols of lower body negative pressure (LBNP), carotid stimulation, and infusions of adrenoreceptor agonists in 7 females and 10 males matched for age and fitness. LBNP tolerance for the women (797 +/- 63 mmHg/min) was 35% lower (P = 0.002) than 1,235 +/- 101 mmHg/min for the men. At presyncope, SV, Q, MAP, and %DeltaLV were lower (P \textbackslashtextless 0.05) in females compared with males, whereas HR, FVR, and total peripheral resistance were similar in both groups. Lower LBNP tolerance in females was associated with reduced HR response to carotid baroreceptor stimulation, lower baseline cardiac vagal activity, greater decline in Q induced by LBNP, increased beta1-adrenoreceptor responsiveness, greater vasoconstriction under equal LBNP, lower levels of circulating NE at presyncope, and lower relative blood volume. The results of this investigation support the hypothesis that women have less responsiveness in mechanisms that underlie blood pressure regulation under orthostatic challenge.
Abstract: Aging is associated with diminished cold-induced thermoregulation (CIT). The mechanisms accounting for this phenomenon have yet to be clearly elucidated but most likely reflect a combination of increased heat loss and decreased metabolic heat production. The inability of the aged subject to reduce heat loss during cold exposure is associated with diminished reactive tone of the cutaneous vasculature and, to a lesser degree, alterations in the insulative properties of body fat. Cold-induced metabolic heat production via skeletal muscle shivering thermogenesis and brown adipose tissue nonshivering thermogenesis appears to decline with age. Few investigations have directly linked diminished skeletal muscle shivering thermogenesis with the age-related reduction in cold-induced thermoregulatory capacity. Rather, age-related declines in skeletal muscle mass and metabolic activity are cited as evidence for decreased heat production via shivering. Reduced mass, GDP binding to brown fat mitochondria, and uncoupling protein (UCP) levels are cited as evidence for attenuated brown adipose tissue cold-induced nonshivering thermogenic capacity during aging. The age-related reduction in brown fat nonshivering thermogenic capacity most likely reflects altered cellular signal transduction rather than changes in neural and hormonal signaling. The discussion in this review focuses on how alterations in CIT during the life span may offer insight into possible mechanisms of biological aging. Although the preponderance of evidence presented here demonstrates that CIT declines with chronological time, the mechanism reflecting this attenuated function remains to be elucidated. The inability to draw definitive conclusions regarding biological aging and CIT reflects the lack of a clear definition of aging. It is unlikely that the mechanisms accounting for the decline in cold-induced thermoregulation during aging will be determined until biological aging is more precisely defined.
Abstract: 1. We tested the hypothesis that the cytoplasmic control mechanism for glycolysis is affected by the presence of oxygen during exercise. We used a comparison of maximal twitch stimulation under ischaemic and intact circulation in human wrist flexor and ankle dorsiflexor muscles. 31P magnetic resonance spectroscopy followed the phosphocreatine (PCr), Pi and pH dynamics at 6-9 s intervals. Glycolytic PCr synthesis was determined during stimulation from pH and tissue buffer capacity, as well as the oxidative phosphorylation rate. 2. Ischaemic vs. aerobic stimulation resulted in similar glycolytic fluxes in the two muscles. The onset of glycolysis occured after fifty to seventy stimulations and the extent of glycolytic PCr synthesis was directly proportional to the number of stimulations thereafter. 3. Two-fold differences in the putative feedback regulators of glycolysis, [Pi] and [ADP], were found between aerobic and ischaemic stimulation. The similar glycolytic fluxes in the face of these differences in metabolite levels eliminates feedback as a control mechanism in glycolysis. 4. These results demonstrate that glycolytic flux is independent of oxygenation state and metabolic feedback, but proportional to muscle activation. These results show a key role for muscle stimulation in the activation and maintenance of glycolysis. Further, this glycolytic control mechanism is independent of the feedback control mechanism that governs oxidative phosphorylation.
Abstract: Inhibition of the renin-angiotensin system has been shown to improve symptoms and prognosis in heart failure. We compared the effects of inhibition of angiotensin-converting enzyme or blockade of angiotensin II type 1 (AT1) receptors in a model with renin-induced hypertension that is known to exhibit similar changes in sympathetic activation and beta-adrenergic desensitization, as observed in heart failure. Treatment with captopril (100 mg/kg of feed) or the AT1-antagonist Bay 10-6734 (100 mg/kg of feed) was performed in transgenic rats harboring the mouse renin 2d gene [TG(mREN2)27]. Neuropeptide Y and angiotensin II levels, adenylyl cyclase activity, beta-adrenergic receptors, G(salpha), and G(ialpha) were investigated. TG(mREN2)27 showed a depletion of myocardial neuropeptide Y stores and an increase in myocardial angiotensin II concentrations. Isoprenaline- and guanylylimidodiphosphate-stimulated adenylyl cyclase activities and beta-adrenergic receptor density were reduced, whereas the catalyst and G(salpha)-function were unchanged. G(ialpha) protein and mRNA concentrations were increased. All alterations were normalized by both treatments. Systolic left ventricular pressures, plasma atrial natriuretic peptide, and myocardial steady state atrial natriuretic peptide mRNA concentrations and heart weights were similarly reduced by both treatments. Sympathetic neuroeffector defects are similarly reversed by angiotensin-converting enzyme inhibition or AT1 antagonism. The data support the concept that pharmacological interventions in the myocardial renin-angiotensin system significantly reverse local sympathetic neuroeffector defects. This could be important for the beneficial effects of these agents.
Abstract: Purpose: The purpose of this study was to investigate the relationship between myosin heavy chain (MHC) composition and maximal contraction strength of the human quadriceps femoris muscle. Methods: Muscle biopsies were obtained from m. vastus lateralis in your highly physical active males (N = 7). The MHC composition of muscle homogenates was determined by electrophoresis techniques (SDS-PAGE). Isokinetic peak torque and constant-angle torque (50 degrees knee flexion) were obtained during slow (30 degrees.s-1), medium (120 degrees.s-1), and fast (240 degrees.s-1) maximal concentric and eccentric quadriceps contractions and expressed relative to muscle volume. Results: The percentage of MHC II in the quadriceps muscle was positively correlated (rs = 0.61-0.93; P \textbackslashtextless 0.05-0.01) to maximal concentric quadriceps strength obtained at medium to high knee angular velocity. In contrast, no consistent pattern of correlation was observed for maximal eccentric quadriceps strength. Conclusions: The relationship observed between muscular MHC composition and maximal contractile strength is suggested to appear as a consequence of MHC -related differences in contractile force-velocity characteristics and/or contractile Rate of Force Development (RFD).
Abstract: The insulin-responsive glucose transporter, GLUT-4, is found primarily in adipocytes and skeletal muscle cells, where it is sequestered in a specialized recycling compartment, from which it can be recruited to the cell surface following insulin stimulation. Lower levels of GLUT-4 are also expressed in other tissues, including the kidney, where it is present particularly in cells of the afferent arteriole and juxtaglomerular apparatus (JGA). The exact nature of GLUT-4-containing compartments and their relationship to other regulated trafficking pathways in different cells are not yet well defined. The trafficking of GLUT-4 has been studied in different cells with regulated secretory pathways, and a recent study shows that, in cardiomyocytes, GLUT-4 is sorted and packaged into multiple regulated pathways (J. W. Slot, G. Garruti, S. Martin, V. Oorschot, G. Pshuma, E. W. Kraegen, R. Laybutt, G. Thibault, and D. E. James. J. Cell Biol. 137: 1243-1254, 1997). In the kidney, cells of the JGA synthesize and secrete their major product, renin, via a well-established, regulated, secretory pathway. These cells also express GLUT-4 and thus offer the potential to directly compare the localization and trafficking of GLUT-4 and renin in a unique cell type. The present study was undertaken to investigate the intracellular distribution of GLUT-4 in mouse kidney cortex and to determine whether GLUT-4 and renin are trafficked in the same or in separate regulated pathways. Ultrathin cryosections of mouse kidney were labeled by the immunogold technique and viewed by electron microscopy, demonstrating the distribution of GLUT-4 in cells of the JGA, afferent arteriole, and distal tubule. In granular cells of the JGA, renin was localized in secretory granules of the regulated secretory pathway, whereas GLUT-4 labeling in the same cells was found in a distinct tubulovesicular compartment located adjacent to the trans-Golgi network. We show that granular cells have separate, morphologically distinct compartments for the sequestration of renin and GLUT-4, providing evidence that there may be distinct pathways for the sorting and trafficking of these two proteins.
Abstract: The present study was undertaken in order to establish the possible involvement of melatonin in the mechanisms underlying the arginine-vasopressin (AVP) responses to physical exercise and angiotensin II (ANG II). On two mornings at least 1 week apart, normal male subjects were tested with exercise on a bicycle ergometer (the workload was gradually increased at 3-min intervals until exhaustion and lasted about 15 min in all subjects) or ANG II (60-min infusion of ANG II (Asp 1, IIe 5 angiotensin II) dissolved in 5% glucose in successively increasing doses of 4, 8, 16 ng/kg/min; each dose for 20 min). Tests were carried out with the administration of either 6 mg melatonin or placebo. Melatonin treatment neither modified the basal concentrations of AVP nor changed the AVP response to ANG II. In contrast, plasma AVP levels rose 3.6 times during exercise in the absence of melatonin, but only 2.3 times in the presence of melatonin. These data indicate an involvement of melatonin in the mechanism underlying the AVP response to physical exercise, but not ANG II, in normal men.
Abstract: Alterations in ventilation and the chemoreceptor response to CO2 during 23 d of 1.2% inspired CO2 were studied in four male subjects. Resting ventilation (VE), tidal volume (VT), respiratory frequency (fR), inspired and end tidal O2 and CO2 and the hypercapnic ventilatory response (HCVR) measured by CO2 rebreathing were measured once before entering the chamber, on days 2, 5, 11, and 22 of CO2 exposure, and one day after. Resting VE slightly increased (5%) on day 2 of exposure and significantly increased (22%) by day 5 followed by a progressive decrease to pre-chamber levels by day 22 and on the first day of recovery. Tidal volume and fR were not statistically different. During the exposure PetCO2 was significantly elevated with day 2 having the largest increase (19.6%). PetCO2 returned to normal within 24 h post exposure. The HCVR was characterized by the slope (SHCVR), intercept at zero ventilation (B), and the ventilation at a PCO2 = 60 mmHg (VE60). The SHCVR decreased (14%) on day 2, but was not significant; the SHCVR on the other exposure days were also not different. The SHCVR on the first recovery day significantly increased (37%). The HCVR B was shifted to the right on day 2 by 5.2 mmHg, then progressively returned to the pre-exposure position. On recovery the B significantly shifted 6.9 mmHg to the right of pre-exposure B. The VE60 decreased by approximately 32% and 16% on day 2 and 5, respectively, then returned within pre-exposure range for the remainder of the exposure and during recovery. During the early phase and one day after the exposure the HCVR was right shifted. One day after exposure chemoreceptor sensitivity to elevated CO2 was increased but, the B was right shifted resulting in a reduced HCVR below PCO2 of 60 mmHg and a greater HCVR above 60 mmHg.
Abstract: The effects of the acute administration of arterial vasoconstrictors on renal plasma flow (RPF) and urinary sodium excretion (UNaV) in cirrhotic patients with ascites with or without hepatorenal syndrome (HRS) are still controversial. As a consequence, vasoconstrictors are not actually used in the treatment of renal sodium retention or HRS in these patients, regardless of the several lines of evidence suggesting that these renal functional abnormalities are related to a marked arterial vasodilation. The lack of an orally available effective arterial vasoconstrictor probably represents a further reason for this omission. Consequently, the present study was made to evaluate the acute effects of the oral administration of midodrine, an orally available -mimetic drug, on systemic and renal hemodynamics and on UNaV in cirrhotic patients with ascites. Mean arterial pressure (MAP), heart rate (HR), cardiac index (CI), systemic vascular resistance (SVR), left forearm blood flow (LFBF), left leg blood flow (LLBF), RPF, glomerular filtration rate (GFR), UNaV, plasma renin activity (PRA), plasma concentration of antidiuretic hormone (ADH), and the serum levels of nitrite and nitrate (NOx) were evaluated in 25 cirrhotic patients with ascites (17 without HRS and 8 with type 2 HRS) before and during the 6 hours following the oral administration of 15 mg of midodrine. During the first 3 hours after the drug administration, a significant increase in MAP (89.6 +/- 1.7 vs. 81.80 +/- 1.3 mm Hg; P \textbackslashtextless .0001) and SVR (1, 313.9 +/- 44.4 vs. 1,121.2 +/- 60.1 dyn . sec . cm-5; P \textbackslashtextless .0001) accompanied by a decrease in HR (69 +/- 2 vs. 77 +/- 3 bpm; P \textbackslashtextless .005) and CI (2,932.7 +/- 131.4 vs. 3,152.5 +/- 131.4 mL . min-1 . m2 BSA; P \textbackslashtextless .0025) was observed in patients without HRS. No change was observed in LFBF and LLBF. The improvement in systemic hemodynamics, which was also maintained during the the 3- to 6-hour period after midodrine administration, was accompanied by a significant increase in RPF (541.5 +/- 43.1 vs. 385.7 +/- 39.9 mL . min-1; P \textbackslashtextless .005), GFR (93.1 +/- 6.5 vs. 77.0 +/- 6.7 mL . min-1; P \textbackslashtextless .025), and UNaV (92.7 +/- 16.4 vs. 72.2 +/- 10.7 microEq . min-1; P \textbackslashtextless .025). In addition, a decrease in PRA (5.33 +/- 1.47 vs. 7.74 +/- 2.17 ng . mL-1 . h; P \textbackslashtextless .05), ADH (1.4 +/- 0.2 vs. 1.7 +/- 0.2 pg . mL-1; P \textbackslashtextless .05), and NOx (33.4 +/- 5.0 vs. 49.3 +/- 7.3 micromol-1; P \textbackslashtextless .05) was found. In patients with HRS, the effects of the drug on the systemic hemodynamics was smaller and shorter. Accordingly, regardless of a significant decrease in PRA (15.87 +/- 3.70 vs. 20.70 +/- 4.82 ng . mL-1 . h; P \textbackslashtextless .0025) in patients with HRS, no significant improvement was observed in RPF, GFR, or UNaV. In conclusion, the acute oral administration of midodrine is associated with a significant improvement in systemic hemodynamics in nonazotemic cirrhotic patients with ascites. As a result, renal perfusion and UNaV also improve in these patients. By contrast, midodrine only slightly improves systemic hemodynamics in patients with type 2 HRS, with no effect on renal hemodynamics and renal function.
Abstract: The essential cardiac response to a fixed increase in hemodynamic load is an increase in cardiac mass. If the load increase is neither too severe initially nor indefinitely progressive, cardiac stress is renormalized, and compensated hypertrophy ensues. But hypertrophic compensation is often abrogated by progressively abnormal contractile performance per unit mass of myocardium, even when function at the organ level is maintained by the mass increase itself. That is, even when hypertrophy is appropriate to the load imposed, and in a manner analogous to dystrophic growth of skeletal muscle, specific phenotypic changes occurring during this growth response render compensation imperfect such that congestive heart failure ensues. This fact, and the fact that the presence of deleterious phenotypic changes in hypertrophied myocardium is critically dependent on the type of hemodynamic load imposed, mandates that cardiac hypertrophy be understood on the most basic level as a growth process if early, definitive interventions to prevent congestive heart failure following pathological hemodynamic overloads are to be realized.
Abstract: This in vivo study investigated whether adenosine (ADO) plays a role in oxygen-dependent production of erythropoietin (EPO). Exposure of rats to 0.075% carbon monoxide (CO) for four hours was used as a stimulus for EPO production. To inhibit potential effects of ADO, rats were treated with the non-specific ADO antagonist theophylline, the selective ADO A1 receptor blockers DPCPX and KW-3902, the selective ADO A2 receptor blocker DMPX, and AOPCP, an inhibitor of 5’-ectonucleotidase, an ADO generating enzyme that is expressed on the surface of EPO producing cells. To stimulate ADO receptor activity, animals were treated with the selective ADO A1 and A2 receptor agonists CHA and CGS 21680, the ADO reuptake inhibitors dipyridamole and soluflazine and the ADO desaminase inhibitor EHNA. At doses known to interfere with ADO signal transmission in vivo, none of these substances either influenced EPO serum levels in normoxic rats or affected the approximately 30-fold rise in EPO serum levels and the increase in renal EPO mRNA after exposure to carbon monoxide. Continuous administration of theophylline to normoxic rats for seven days did not alter hematocrit, hemoglobin or EPO serum levels. Taken together, these experiments do not support the hypothesis that ADO plays an important role in the regulation of EPO production.
Abstract: Putative endothelial cell (EC) progenitors or angioblasts were isolated from human peripheral blood by magnetic bead selection on the basis of cell surface antigen expression. In vitro, these cells differentiated into ECs. In animal models of ischemia, heterologous, homologous, and autologous EC progenitors incorporated into sites of active angiogenesis. These findings suggest that EC progenitors may be useful for augmenting collateral vessel growth to ischemic tissues (therapeutic angiogenesis) and for delivering anti- or pro-angiogenic agents, respectively, to sites of pathologic or utilitarian angiogenesis.
Abstract: 1. The correction of metabolic acidosis with sodium bicarbonate remains controversial. Experiments in vitro have suggested possible deleterious effects after alkalinization of the extracellular fluid. Disequilibrium of carbon dioxide and bicarbonate across cell membranes after alkali administration, leading to the phenomenon of ’paradoxical’ intracellular acidosis, has been held responsible for some of these adverse effects. 2. Changes in intracellular pH in suspensions of leucocytes from healthy volunteers were monitored using a fluorescent intracellular dye. The effect in vitro of increasing extracellular pH with sodium bicarbonate was studied at different sodium bicarbonate concentrations. Lactic acid and propionic acid were added to the extracellular buffer to mimic conditions of metabolic acidosis. 3. The addition of a large bolus of sodium bicarbonate caused intracellular acidification as has been observed previously. The extent of the intracellular acidosis was dependent on several factors, being most evident at higher starting intracellular pH. When sodium bicarbonate was added as a series of small boluses the reduction in intracellular pH was small. Under conditions of initial acidosis this was rapidly followed by intracellular alkalinization. 4. Although intracellular acidification occurs after addition of sodium bicarbonate to a suspension of human leucocytes in vitro, the effect is minimal when the conditions approximate those seen in clinical practice. We suggest that the observed small and transient lowering of intracellular pH is insufficient grounds in itself to abandon the use of sodium bicarbonate in human acidosis.
Abstract: Congestive heart failure is a major public health problem in Western countries. Despite current treatment including angiotensin converting enzyme inhibitors, mortality and morbidity remain high. The sympathetic nervous system is markedly activated in heart failure, and inhibition of this system with the beta-adrenergic blocking agents may provide further benefit. Several clinical trials involving over 3,000 patients have shown that beta-blocker therapy improves left ventricular function in patients with heart failure. However, the effects of such therapy on symptoms and exercise tolerance have been variable. Recent reports have suggested that survival is improved with the beta-blocker carvedilol. Large-scale, long-term clinical trials are required to confirm these findings and to clearly define the role of this promising therapy for patients with heart failure.
Abstract: Experimental studies in animals have suggested that brain death (BD) – related endocrinological dysregulations lead to a significant depression of cardiac pump and muscle function, however, the discussion about the relative extent of this influence remains controversal. The aim of the present study was to assess in an open chest animal model the short time course (5 hours) of hormonal (epinephrine, norepinephrine, T3, T4, ACTH, cortisol, insuline) and metabolic (glucose, lactate) changes in 10 brain dead dogs with special respect to the hemodynamic stability and myocardial pump function. After the onset of BD the concentrations of all hormonal parameters showed a significant decrease. Despite these changes, and in contrast to other studies, an adequate pump function (filling pressures, cardiac output) and muscle function (LVdp/dt) could be maintained by exclusive volume substitution without the use of hormonal or pressor agents. We conclude that in the present model a sufficient pump and muscle function can be maintained by adequate volume substitution, exclusively. The significant fall in adrenal and thyroid hormones had no direct effects on heart functional parameters in the first 5 hours after experimental BD induction.
Abstract: Recognition that non-insulin-dependent diabetes mellitus (NIDDM) is a leading cause of end-stage renal disease (ESRD), and a focus of recent therapeutic and genetic studies on the renin system have rekindled interest in mechanisms by which angiotensin converting enzyme (ACE) inhibitors influence the diabetic kidney. We evaluated the renal hemodynamic status of 19 hypertensive patients with NIDDM under controlled sodium balance, low (10 mmol/day for 5 to 7 days) or high (200 mmol/day for 5 to 7 days). The renal plasma flow (RPF) response to ACE inhibition and to angiotensin II (Ang II) infusion was measured as para-aminohippurate (PAH) clearance before and during enalapril administration (10 mg b.i.d. for 3 days). Our premise was that if renal vasodilation induced by ACEI involves kinins, prostaglandins, and/or nitric oxide, vasoconstrictor responses to Ang II would be blunted. Conversely, if the dominant ACE inhibitor action were a reduction in Ang II formation, the consequence would be up-regulation and an enhanced vasoconstrictor response to exogenous Ang II. RPF in NIDDM on a high-salt diet was lower than in age-matched controls (477 +/- 25 vs. 551 +/- 25 ml/min/1.73 m2; P = 0.02). Enalapril increased RPF in NIDDM to 511 +/- 29 ml/min/1.73 m2 (P \textbackslashtextless 0.05) and enhanced renal vasoconstrictor responses to Ang II infusion, from -68 +/- 9 to -106 +/- 18 ml/min/1.73 m2 (P = 0.03). Baseline plasma renin activity (PRA) and plasma aldosterone significantly exceeded matched normotensive controls (1.1 +/- 0.5 vs. 0.3 +/- 0.1 ng AI/ml/hr and 10 +/- 0.9 vs. 4.1 +/- 0.5 ng/dl, P \textbackslashtextless 0.01, respectively). Conversely all measures in studies on a low-salt diet were normal. Our findings indicate that: (1) NIDDM with hypertension is associated with reduced RPF when dietary salt intake is high, (2) reduced Ang II formation is the dominant mechanism of ACEI-induced renal vasodilation in hypertensives with NIDDM; and (3) the sustained renal hemodynamic responses to ACE inhibition despite high-salt balance, and the increased PRA suggest an autonomous renin-angiotensin system suppressed subnormally by a high salt diet in patients with NIDDM despite greater volume expansion.
Abstract: The Henderson-Hasselbalch equation and Stewart’s strong ion model are currently used to describe mammalian acid-base equilibria. Anomalies exist when the Henderson-Hasselbalch equation is applied to plasma, whereas the strong ion model does not provide a practical method for determining the total plasma concentration of nonvolatile weak acids ([Atot]) and the effective dissociation constant for plasma weak acids (Ka). A simplified strong ion model, which was developed from the assumption that plasma ions act as strong ions, volatile buffer ions (HCO-3), or nonvolatile buffer ions, indicates that plasma pH is determined by five independent variables: PCO2, strong ion difference, concentration of individual nonvolatile plasma buffers (albumin, globulin, and phosphate), ionic strength, and temperature. The simplified strong ion model conveys on a fundamental level the mechanism for change in acid-base status, explains many of the anomalies when the Henderson-Hasselbalch equation is applied to plasma, is conceptually and algebraically simpler than Stewart’s strong ion model, and provides a practical in vitro method for determining [Atot] and Ka of plasma. Application of the simplified strong ion model to CO2-tonometered horse plasma produced values for [Atot] (15.0 +/- 3.1 meq/l) and Ka (2.22 +/- 0.32 x 10(-7) eq/l) that were significantly different from the values commonly assumed for human plasma ([Atot] = 20.0 meq/l, Ka = 3.0 x 10(-7) eq/l). Moreover, application of the experimentally determined values for [Atot] and Ka to published data for the horse (known PCO2, strong ion difference, and plasma protein concentration) predicted plasma pH more accurately than the values for [Atot] and Ka commonly assumed for human plasma. Species-specific values for [Atot] and Ka should be experimentally determined when the simplified strong ion model (or strong ion model) is used to describe acid-base equilibria.
Abstract: Hypoglycemia elicits a characteristic sequence of responses in healthy humans. These responses (and their arterialized venous glycemic thresholds) include: 1) Decreased insulin secretion (approximately 4.5 mmol/L). 2) Increased glucose counterregulatory hormone (glucagon, epinephrine, growth hormone and cortisol) secretion (approximately 3.6-3.8 mmol/L). 3) Symptoms of hypoglycemia (approximately 3.0 mmol/L). 4) Cognitive dysfunction (approximately 2.6 mmol/L). Thus, insulin secretion decreases as plasma glucose levels fall within the physiological range, and counterregulatory hormone secretion increases as plasma glucose levels fall just below the physiological range at substantially higher glucose levels than those required to produce symptoms and impair cognitive function. These data are entirely consistent with the body of evidence that insulin, glucagon and epinephrine stand high in the hierarchy of redundant glucoregulatory factors that prevent, as well as correct, hypoglycemia. When the same methods are used, these thresholds are remarkably reproducible from laboratory to laboratory. Nonetheless, the glycemic thresholds are dynamic rather than static. They vary in relation to recent antecedent glycemia. For example, lower plasma glucose concentrations are required to elicit autonomic, including epinephrine, and symptomatic responses in patients with well controlled IDDM, a phenomenon best attributed to recent antecedent iatrogenic hypoglycemia. This is the basis of the clinical syndrome of hypoglycemia unawareness, which is now known to be reversible with scrupulous avoidance of iatrogenic hypoglycemia. The latter also at least partially reverses reduced epinephrine responses to hypoglycemia, a key component (in the setting of absent glucagon responses) of the syndrome of defective glucose counterregulation. While perhaps seemingly adaptive, these threshold shifts appear to be maladaptive since both defective glucose counterregulation and hypoglycemia unawareness are associated with substantially increased rates of severe iatrogenic hypoglycemia in people with IDDM.
Abstract: In hamster cremaster muscle, capillary networks consist of anatomically invariant subunits termed modules [Berg, B. R., and I. H. Sarelius, Am. J. Physiol. 268 (Heart Circ. Physiol. 37): H1215-H1222, 1995]. To explore local coupling between blood flow and metabolism, we used micropipettes to stimulate five to six muscle fibers running underneath specified capillary modules. Capillary erythrocyte flow increased significantly at all stimulation frequencies because of increased erythrocyte content at 2 Hz and increased erythrocyte velocity at 4 and 8 Hz. Erythrocyte flow did not increase when the fibers underlying the module were mechanically tugged but did not actively contract at these frequencies. Increased capillary flow was accommodated by dilation of three upstream arteriolar generations: the module inflow arteriole dilated significantly at all frequencies, and further upstream, dilations were significant at higher frequencies. Other module inflow arterioles in the same capillary network as the stimulated module did not dilate. Dilations in the module inflow arteriole were abolished by 600 mosM sucrose but were unaffected by 10(-6) M tetrodotoxin. These data suggest that local coupling between capillary flow and muscle contraction includes a conducted vasodilation that is responsible for the remote upstream dilations.
Abstract: Six normal untrained men were studied during the intravenous infusion of a balanced amino acid mixture (approximately 0.15 g.kg-1.h-1 for 3 h) at rest and after a leg resistance exercise routine to test the influence of exercise on the regulation of muscle protein kinetics by hyperaminoacidemia. Leg muscle protein kinetics and transport of selected amino acids (alanine, phenylalanine, leucine, and lysine) were isotopically determined using a model based on arteriovenous blood samples and muscle biopsy. The intravenous amino acid infusion resulted in comparable increases in arterial amino acid concentrations at rest and after exercise, whereas leg blood flow was 64 +/- 5% greater after exercise than at rest. During hyperaminoacidemia, the increases in amino acid transport above basal were 30-100% greater after exercise than at rest. Increases in muscle protein synthesis were also greater after exercise than at rest (291 +/- 42% vs. 141 +/- 45%). Muscle protein breakdown was not significantly affected by hyperminoacidemia either at rest or after exercise. We conclude that the stimulatory effect of exogenous amino acids on muscle protein synthesis is enhanced by prior exercise, perhaps in part because of enhanced blood flow. Our results imply that protein intake immediately after exercise may be more anabolic than when ingested at some later time.
Abstract: 1. Transport of lactate, H+ and fluid across muscle sarcolemma was studied in contracting muscles under varying blood acid-base conditions. 2. Subjects performed two-legged submaximal knee-extensor exercise for 29-35 min consisting of warming up for 5 min followed by 10 min of leg exercise (L1), leg and arm exercise for 6-10 min (L2 + A) and leg exercise for 10 min (L3). The experimental protocol was performed on two occasions; inspiring air (normoxia, N) or breathing 14% O2 in N2 (hypoxia, H). Leg blood flow was measured and femoral arterial and venous blood was sampled before and during each phase of exercise. 3. Arterial blood lactate concentration increased progressively during exercise to 5.9 +/- 0.8 (N) and 8.2 +/- 0.8 mmol l-1 (H) (P \textbackslashtextless 0.05) after 5.5 min of L2 + A. Arterial blood pH was higher (P \textbackslashtextless 0.05) in H than in N, whereas arterial blood HCO3- concentrations were the same. Leg lactate release was higher in H than in N (3.1 +/- 0.7 vs. 2.0 mmol l-1 (P \textbackslashtextless 0.05) during L1. In L2 + A a net uptake of lactate was observed in both N and H. The concentration of lactate in the red blood cells increased during exercise to 2.3 +/- 0.4 (N) and 4.3 +/- 0.7 mmol l-1 (H) (P \textbackslashtextless 0.05) after 5.5 min of L2 + A, but no red blood cell femoral arterial-venous lactate difference was observed. 4. Net proton release, estimated from actual base excess (ABE) adjusted for changes in reduced haemoglobin, was significant (P \textbackslashtextless 0.05) both at rest and during each phase of exercise. Furthermore, the difference between net proton and lactate release was positive throughout exercise and of similar magnitude in N and H. 5. The present data suggest that (1) H+ exchange in muscle during submaximal exercise can to a large extent occur through mechanisms other than via coupling to lactate; (2) muscle transport of H+ is insensitive to changes in blood pH in the range of 0.02-0.08 pH units; (3) transport of lactate across the membrane of red blood cells appears to be of minor importance for lactate release from active muscles.
Abstract: The bone mineral density and the biochemical parameters exploring bone cell activities were analyzed in two cosmonauts who spent 1 and 6 months, respectively, in the Russian MIR station. Measurements were performed before the flight, after the flight, and after a recovery period. At the end of the first month, peripheral QCT measurements indicated a slight decrease of trabecular bone mass in the distal tibial metaphysis. However, after 6 months of spaceflight, a more marked loss of trabecular and cortical bones was observed in the tibia, and was still significant after 6 month recovery in the trabecular compartment, whereas a decrease was no longer observed in the cortical envelope. No change was observed in either compartment of the distal radius at any time. Ultrasound BUA of the calcaneus was greatly reduced by the first month, followed by a more dramatic decrease after month 6. Ultrasound SOS detected no change. Parameters reflecting bone formation activity appeared to be depressed after both missions. In contrast, no dramatic change in resorption parameters was observed, except for a trend toward an increase in pyridinoline. In conclusion, the lower weight-bearing bones appeared more sensitive than the upper ones in terms of spaceflight-induced bone loss. This probably explained the absence of marked systemic biochemical data changes. This study further suggests that recovery in the tibial trabecular compartment 6 months after landing was not completed after a 6 month mission.
Abstract: Many patients fail to achieve target heart rate during dobutamine stress echocardiography (DSE). We evaluated the pharmacokinetics of dobutamine during DSE to determine whether patients with an impaired chronotropic response have higher rates of dobutamine clearance and consequently relatively lower plasma dobutamine levels. Plasma dobutamine levels, heart rate, and left ventricular (LV) ejection fraction (EF) were measured in 13 male patients referred for DSE at baseline and at the end of stepped 3-minute dobutamine infusions of 5, 10, 20, and 30 microg/kg/min. Dobutamine levels increased with doses: 27 +/- 10, 111 +/- 17, 275 +/- 17, and 403 +/- 28 ng/ml (mean +/- SEM). There was no relation observed between the plasma dobutamine level achieved at the 30-microg infusion dose and the increase in heart rate from baseline (r = 0.066; p = 0.83). Baseline LVEF and a measure of chronotropic beta responsivity were identified as independent predictors of dobutamine clearance, together accounting for 73% of the variance in dobutamine clearance. In conclusion, (1) there is a dose-dependent increase in plasma dobutamine levels during DSE, (2) dobutamine clearance is positively related to baseline LVEF and is partially mediated by a beta-receptor mechanism, and (3) an impaired chronotropic response during DSE is not due to failure to achieve a sufficiently high dobutamine level. We conclude that in patients who lack an adequate heart rate response during the early stages of DSE (e.g., up to 20 microg/kg/min infusion), administration of atropine rather than progressively higher amounts of dobutamine may provide a more effective strategy to achieve target heart rate.
Abstract: We tested the postulate that the renal density of the thiazide-inhibitable Na-Cl cotransporter or thiazide receptor (TZR) is modulated as part of the renal homeostatic response to changes in dietary intake of NaCl or KCl. Renal excretion of NaCl or KCl varied \textbackslashtextgreater 10-fold in response to alterations in oral intake. Renal TZR density was quantitated by binding of [3H]metolazone to renal membranes. Renal TZR density was not altered by sodium deficit (with increased plasma aldosterone concentration), by sodium surfeit (8% NaCl content of diet), by potassium deficit (with hypokalemia), or by potassium surfeit (drinking 1% KCl solution). Unexpectedly, we conclude that regulation of the renal density of TZR is not part of the renal homeostatic responses that adjust excretion of NaCl and KCl to changes in dietary intake of NaCl or KCl.
Abstract: Right ventricular (RV) failure, which is a leading cause of early morbidity and mortality following cardiac transplantation, is attributed to the inability of the donor RV to acutely compensate for the recipient’s elevated pulmonary vascular resistance (PVR). Furthermore, the effect of donor brain death (BD) on RV function is unclear. The purpose of this study was to investigate the effects of donor BD on RV function in the setting of elevated PVR. The interactions of the RV and its afterload, the pulmonary vasculature, and left atrial pressure were assessed by measurements of pulmonary vascular energetics and their oscillatory nature using proximal ultrasonic pulmonary artery (PA) flow probe and micromanometers in the proximal and distal PA in 20 mongrel dogs (25.8 +/- 0.4 kg, five control animals). A band was placed around the distal PA (PA-systolic gradient \textbackslashtextgreater 15 mm Hg). BD was induced by rising intracranial pressure and was validated neuropathologically. Data were collected at 0, 2, 4, and 6 h after BD in both banded and control animals. Fourier analysis was used to calculate RV oscillatory power, mean power, and total power (TP). Comparison of changes due to banding were made to baseline measurements using multivariate analysis and paired Student’s t test (p \textbackslashtextless 0.05). A significant twofold to fourfold increase in pulmonary impedance and PVR occurred with an acute rise in PA gradient. Control animals tolerated acute increases in PVR without significant changes in TP. There was a significant increase of RV TP from 73 (+/-11) to 98 (+/-10) mW at baseline after the acute rise in PVR and impedance. After BD, the response to increased PVR and impedance was abolished significantly compared with baseline and control animals, suggesting a significant loss of compensatory TP to sustain pulmonary vascular blood flow. The data indicate that BD is detrimental to RV mechanical function.
Abstract: Methylglucose can be used to assay brain glucose levels because the equilibrium brain-to-plasma distribution ratio for methylglucose (Ce*/Cp*) is quantitatively related to brain (Ce) and plasma (Cp) glucose contents. The relationship between Ce and Ce*/Cp* predicted by Michaelis-Menten kinetics has been experimentally confirmed when glucose utilization rate (CMRGlc) is maintained at normal, resting levels and Cp is varied in conscious rats. Theoretically, however, Ce and Ce*/Cp* should change when CMRGlc is altered and Cp is held constant; their relationship in such conditions was, therefore, examined experimentally. Drugs were applied topically to brains of conscious rats with fixed levels of Cp to produce focal alterations in CMRGlc, and Ce and Ce*/Cp* were measured. Plots of Ce as a function of Ce*/Cp* for each Cp produced straight lines; their slopes decreased as Cp increased. The results confirm that a single theoretical framework describes the relationship between Ce and Ce*/Cp* as either glucose supply or demand is altered over a wide range; they also validate the use of methylglucose to estimate local Ce under abnormal conditions.
Abstract: Regulation of the volume sensitivity of the swelling-activated organic osmolyte/anion channel VSOAC by intracellular electrolytes was examined in intact and patch-clamped C6 glioma cells. In intact cells, VSOAC activation was monitored by [3H]taurine efflux measurements, and intracellular electrolyte concentrations were manipulated by acclimation to hypertonic medium for varying periods of time. Hypertonic shrinkage was followed by a rapid and complete regulatory volume increase mediated by electrolyte accumulation that elevated intracellular Na+, K+, and Cl- concentrations. During prolonged (4-48 h) exposure to hypertonicity, electrolyte concentrations decreased gradually as cells accumulated the organic osmolyte myo-inositol. VSOAC activation induced by cell swelling of 35-40% increased as a function of the time of exposure to hypertonicity and was inversely correlated with measured intracellular Na+, K+ and Cl- levels. In patch-clamped cells, swelling-induced Cl- current activation was unaffected by acclimation conditions but was inhibited by increasing the concentration of electrolytes in the patch pipette solution. Quantification of the relationship between VSOAC activation and cell swelling demonstrated that increases in intracellular electrolyte levels increase VSOAC volume set point. Regulation of VSOAC volume sensitivity by electrolytes allows cells to selectively utilize electrolytes or a combination of electrolytes and organic osmolytes for regulatory volume decrease (RVD). Control over the type of solute used for volume regulation is advantageous, allowing cells to control intracellular ionic composition and prevent increases in cytoplasmic ionic strength during RVD.
Abstract: We tested the cytoplasmic control mechanisms for glycolytic ATP synthesis in human wrist flexor muscles. The forearm was made ischemic and activated by maximal twitch stimulation of the median and ulnar nerves in 10 subjects. Kinetic changes in phosphocreatine, Pi, ADP, ATP, sugar phosphates, and pH were measured by 31P magnetic resonance spectroscopy at 7.1-s intervals. Proton production was determined from pH and tissue buffer capacity during stimulation. Glycolysis was activated between 30 and 50 stimulations, and the rate did not significantly change through the stimulation period. The independence of glycolytic rate on [Pi], [ADP], or [AMP] indicates that feedback regulation by these metabolites could not account for this activation of glycolysis. However, glycolytic H+ and ATP production increased sixfold from 0.5 to 3 Hz, indicating that glycolytic rate reflected muscle activation frequency. This dependence of glycolytic rate on muscle stimulation frequency and independence on metabolite levels is consistent with control of glycolysis by Ca2+.
Abstract: Cardiac hypertrophy in essential and experimental (genetic) hypertension have been initially attributed to increased pressure load. However, the level of blood pressure does not parallel the degree of cardiac hypertrophy, i.e., a complex relationship rather than a simple dose-response effect has to be suggested. Several non-haemodynamic factors which influence LV mass have been identified with genetic and neuro-hormonal influences playing a major role. The experimental strategies which have been used to highlight one or more of these influences include pharmacological studies of regression or prevention of LVH and studies designed to produce LVH de-novo in normotensive strains. All these studies while confirming an important role of haemodynamic factors also stress the major influence of the renin-angiotensin system and the inter-relationship between angiotensin II and nitric oxide. In contrast, genetic strategies, from simple co-segregation analysis to most complex genome scan studies, suggest the existence of "susceptibility genes" for LV hypertrophy, a finding which deserves further study in large collections of siblings and family groups with essential hypertension.
Abstract: BACKGROUND: Diastolic ventricular interaction describes a situation in which the volume of one ventricle is directly influenced by the volume of the other ventricle. Such interaction is normally negligible, but it is accentuated in circumstances associated with pulmonary hypertension and volume overload. When this interaction occurs, acute volume unloading results in a reduction in right ventricular end-diastolic volume, as expected, but left ventricular end-diastolic volume paradoxically increases. Since chronic heart failure is a volume-overloaded state associated with pulmonary hypertension, we hypothesised that this interaction may be clinically important in patients with heart failure. METHODS: A radionuclide technique incorporating cardiac scintigraphy was used to measure the effect of acute volume unloading, achieved by 30 mm Hg lower-body suction, on right and left ventricular end-diastolic volumes in 21 patients with chronic heart failure and 12 healthy individuals (controls). FINDINGS: In nine heart-failure patients, there was a paradoxical increase in left ventricular end-diastolic volume in association with an expected decrease in right ventricular end-diastolic volume during lower-body suction. This response was not seen in the control group. The mean change in left ventricular end-diastolic volume differed significantly between the heart-failure patients and controls (6 [SD 19] vs -19 [12] mL, p = 0.0003). However, the change in right ventricular end-diastolic volume was similar in the two groups (-18 [11] vs -20 [8]%. p = 0.70). Patients who increased left ventricular end-diastolic volume during lower-body suction had higher resting pulmonary arterial and pulmonary capillary wedge pressures than the remaining heart-failure patients. INTERPRETATION: The response of nine patients in our study suggests diastolic ventricular interaction, which we believe could be common in patients with chronic heart failure. This finding is relevant to their management, since it emphasises the importance of venodilator therapy. The relation between stroke volume and left ventricular end-diastolic volume, by the Frank-Starting law of the heart, may explain why some patients with chronic heart failure paradoxically increase stroke volume when pulmonary capillary wedge pressure is lowered with vasodilators.
Abstract: To investigate the effect of acute graded increases in plasma volume (PV) on fluid and regulatory hormone levels, eight untrained men (peak aerobic power 45.2 +/- 2.2 ml.kg-1.min-1) performed prolonged cycle exercise (46 +/- 4% maximal aerobic power on three occasions, namely, with no PV expansion (Con) and after 14% (Low) and 21% (High) expansions, respectively. The exercise plasma levels of aldosterone (Aldo), arginine vasopressin (AVP), and atrial natriuretic peptide (ANP) were all altered by acute PV increases. A pronounced blunting (P \textbackslashtextless 0.05) of the Aldo response during exercise was observed, the magnitude of which was directly related to the amount of hypervolemia (Con \textbackslashtextless Low \textbackslashtextless High). At 120 min of exercise, Aldo concentrations were 660 +/- 71, 490 +/- 85, and 365 +/- 78 pg/ml for Con, Low, and High conditions, respectively. In contrast, the lower AVP and the higher ANP observed during exercise appeared to be due to the effect of PV expansion on resting concentrations. Because osmolality did not vary among conditions, the results indicate that PV represents an important primary stimulus in the response of Aldo to exercise. The lower exercise blood concentrations of both epinephrine and norepinephrine observed with PV expansion would suggest that a lower sympathetic drive may be implicated at least in the lower Aldo responses.
Abstract: The pH has marked effects on the blood flow in several vascular beds but the underlying mechanisms remain incompletely understood. It is still not agreed, for example, whether it is the fall in extracellular pH or intracellular pH that is responsible for changes in tone resulting from hypercapnic acidosis. The issue has been further complicated by the recent discovery that nitric oxide (NO) may also be involved in vasodilator responses to hypercapnia with the result that, in some laboratories, attention has been focused away from vascular smooth muscle. The recent availability of fluorescent dyes sensitive to pH has enabled some of the uncertainties in this field to be addressed. In light of these new observations, we have attempted to put older viewpoints in perspective. We conclude that, whilst a fall in smooth muscle intracellular pH is likely to be responsible for immediate responses to acidosis, the extracellular pH probably plays the predominant role in the steady state. The role of NO is best investigated in the cerebral circulation where it plays an important modulating role in the response to acidosis, and is probably of extravascular origin.
Abstract: Gravity affects cardiac filling pressure and intravascular fluid distribution significantly. A major central fluid shift occurs when all hydrostatic gradients are abolished on entry into microgravity (microG). Understanding the dynamics of this shift requires continuous monitoring of cardiac filling pressure; central venous pressure (CVP) measurement is the only feasible means of accomplishing this. We directly measured CVP in three subjects: one aboard the Spacelab Life Sciences-1 space shuttle flight and two aboard the Spacelab Life Sciences-2 space shuttle flight. Continuous CVP measurements, with a 4-Fr catheter, began 4 h before launch and continued into microG. Mean CVP was 8.4 cmH2O seated before flight, 15.0 cmH2O in the supine legs-elevated posture in the shuttle, and 2.5 cmH2O after 10 min in microG. Although CVP decreased, the left ventricular end-diastolic dimension measured by echocardiography increased from a mean of 4.60 cm supine preflight to 4.97 cm within 48 h in microG. These data are consistent with increased cardiac filling early in microG despite a fall in CVP, suggesting that the relationship between CVP and actual transmural left ventricular filling pressure is altered in microG.
Abstract: The causative factors in muscle fatigue are multiple, and vary depending on the intensity and duration of the exercise, the fibre type composition of the muscle, and the individual’s degree of fitness. Regardless of the aetiology, fatigue is characterized by the inability to maintain the required power output and the decline in power can be attributed to a reduced force and velocity. Following high-intensity exercise, peak force has been shown to recover biphasically with an initial rapid (2 min) recovery followed by a slower (50 min) return to the pre-fatigued condition. The resting membrane potential depolarizes by 10-15 mV, while the action potential overshoot declines by a similar magnitude. Following high-frequency stimulation of the frog semitendinous muscle, we observed intracellular potassium [K+]1 decrease from 142 +/- 5 to 97 +/- 8 mM, while sodium [Na+]i rose from 16 +/- 1 to 49 +/- 6 mM. The [K+]i loss was similar to that observed in fatigued mouse and human skeletal muscle, which suggests that there may be a limit to which [K+]i can decrease before the associated depolarization begins to limit the action potential frequency. Fibre depolarization to- 60 mV (a value observed in some cells) caused a significant reduction in the t-tubular charge movement, and the extent of the decline was inversely related to the concentration of extracellular Ca2+. A decrease in intracellular pH (pHi) to 6.0 was observed, and it has been suggested by some that low pH may disrupt E-C coupling by directly inhibiting the SR Ca2+ release channel. However, Lamb at al. (1992) observed that low pH had no effect on Ca2+ release, and we found low pHi to have no effect on t-tubular charge movement (Q) or the Q vs. Vm relationship. The Ca2+ released from the SR plays three important roles in the regulation of E-C coupling. As Ca2+ rises, it binds to the inner surface of the t-tubular charge sensor to increase charge (Q gamma) and thus Ca2+ release, it opens SR Ca2+ channels that are not voltage-regulated, and as [Ca2+]i increases further it feeds back to close the same channels. The late stages of fatigue have been shown to be in part caused by a reduced SR Ca2+ release. The exact cause of the reduced release is unknown, but the mechanism appears to involve a direct inhibition of the SR Ca2+ channel.
Abstract: In 64 apparently healthy adult humans (ages 17-74 yr) ingesting controlled diets, we investigated the separate and combined effects of age, glomerular filtration rate (GFR, index of age-related renal functional decline), renal net acid excretion [NAE, index of endogenous acid production (EAP)], and blood PCO2 (PbCO2, index of respiratory set point) on steady-state blood hydrogen ion ([H+]b) and plasma bicarbonate concentration ([HCO3-]p). Independent predictors of [H+]b and [HCO3-]p were PbCO2, NAE, and either age or GFR, but not both, because the two were highly correlated (inversely). [H+]b increased with increasing PbCO2, NAE, and age and with decreasing GFR. [HCO3-]p decreased with increasing NAE and age but increased with increasing PbCO2 and GFR. Age (or GFR) at constant NAE had greater effect on both [H+]b and [HCO3-]p than did NAE at constant age (or GFR). Neither PbCO2 nor NAE correlated with age or GFR. Thus two metabolic factors, diet-dependent EAP and age (or GFR), operate independently to determine blood acid-base composition in adult humans. Otherwise healthy adults manifest a low-grade diet-dependent metabolic acidosis, the severity of which increases with age at constant EAP, apparently due in part to the normal age-related decline of renal function.
Abstract: Traditional explanations for the hyperaemia which accompanies exercise have invoked the ’metabolic theory’ of vasodilation, whereby contractile activity in the active muscle gives rise to metabolic by-products which dilate vessels bathed in interstitial fluid. Whilst metabolites with vasodilator properties have been identified, this theory does not adequately explain the magnitude of hyperaemia observed in active skeletal muscle, principally because large increases in flow are dependent on dilation of ’feed’ arteries which lie outside the tissue parenchyma and are not subjected to changes in the interstitial milieu. Coordinated resistance vessel dilation during exercise is therefore dependent on a signal which ’ascends’ from the microvessels to the feed arteries located upstream. Recent studies of ascending vasodilation have concentrated on the possible contribution of the endothelium, a monolayer of flattened squamous cells which lie at the interface between the circulating blood and vascular wall. These cells are uniquely positioned to respond to changes in rheological and humoral conditions within the cardiovascular system, and to transduce these changes into vasoactive signals which regulate blood flow, vascular tone and arterial pressure. Endothelial cells produce nitric oxide (NO), a rapidly diffusing labile substance which relaxes adjacent vascular smooth muscle. NO is released basally and contributes to the regulation of vascular tone by acting as a functional antagonist to sympathetic neural constriction. In addition, NO is spontaneously released in response to deformation of the endothelial cell membrane, indicating that changes in pulsatile flow and wall shear stress are likely physiological stimuli. Since the dilation of microvessels in response to exercise increases blood flow through the upstream feed arteries, which subsequently dilate, one explanation for ascending vasodilation is that NO release is stimulated by flow-induced shear stress. Evidence that NO contributes to ascending vasodilation is reviewed, along with studies which indicate that NO mediates exercise hyperaemia, that physical conditioning upregulates NO production and that NO controls blood flow by modifying other physiological mechanisms.
Abstract: The aim of this study was to analyze the time course of erythropoietin (EPO) during Earth-bound microgravity simulations such as bed rest, isolation and confinement (IC), head-down tilt (HDT; -6 degrees), and immersion to evaluate which factors could contribute to alterations in EPO under real microgravity conditions during and after short- (\textbackslashtextless 10 days) and long-term (\textbackslashtextgreater 6 mo) spaceflights. During bed rest (24h), no significant changes in EPO could be observed. Subjects confined in a diving chamber facility for 60 days showed a decrease in EPO. In the recovery period a slight increase was observed, but EPO concentrations did not reach the pre-IC control level. In the control period before HDT, subjects showed normal resting values for EPO, but on day 2 of HDT the EPO concentrations were decreased (P \textbackslashtextless 0.01). Later the EPO levels remained below the control value and were increased after HDT (P \textbackslashtextless 0.05). After immersion (24 h) increased EPO concentrations could be determined (P \textbackslashtextless 0.05). During a short-term spaceflight the astronauts showed in-flight (day 4) decreased and unchanged EPO concentrations. During a long-term spaceflight, 24 h after recovery, the cosmonaut showed slightly elevated EPO concentration, which increased markedly during the following days. It is concluded that 1) HDT (-6 degrees) causes a rapid decrease in EPO in humans, 2) IC per se leads to diminished EPO concentrations, 3) EPO regulation in humans during short- and long-term spaceflights might be different, 4) changes in central blood volume, i.e., central venous pressure, seem to be involved in the modulation of EPO production and release under simulated and real microgravity conditions, and 5) the HDT (-6 degrees) Earth-bound simulation reflects mostly the changes in EPO production and release observed under real microgravity conditions in humans.
Abstract: We studied the effects of unilateral tension pneumothorax and its release on bronchial and pulmonary arterial blood flow and gas exchange in 10 adult anesthetized and mechanically ventilated sheep with chronically implanted ultrasonic flow probes. Right pleural pressure (Ppl) was increased in two steps from -5 to 10 and 25 cmH2O and then decreased to 10 and -5 cmH2O. Each level of Ppl was maintained for 5 min. Bronchial blood flow, right and left pulmonary arterial flows, cardiac output (QT), hemodynamic measurements, and arterial blood gases were obtained at the end of each period. Pneumothorax resulted in a 66% decrease in QT, bronchial blood flow decreased by 84%, and right pulmonary arterial flow decreased by 80% at Ppl of 25 cmH2O (P \textbackslashtextless 0.001). At peak Ppl, the majority of QT was due to blood flow through the left pulmonary artery. With resolution of pneumothorax, hemodynamic parameters normalized, although abnormalities in gas exchange persisted for 60-90 min after recovery and were associated with a decrease in total respiratory compliance.
Abstract: The effect of spaceflight on red blood cell mass (RBCM), plasma volume (PV), erythron iron turnover, serum erythropoietin, and red blood cell (RBC) production and survival and indexes were determined for six astronauts on two shuttle missions, 9 and 14 days in duration, respectively. PV decreased within the first day. RBCM decreased because of destruction of RBCs either newly released or scheduled to be released from the bone marrow. Older RBCs survived normally. On return to Earth, plasma volume increased, hemoglobin concentration and RBC count declined, and serum erythropoietin increased. We propose that entry into microgravity results in acute plethora as a result of a decrease in vascular space. PV decreases, causing an increase in hemoglobin concentration that effects a decrease in erythropoietin or other growth factors or cytokines. The RBCM decreases by destruction of recently formed RBCs to a level appropriate for the microgravity environment. Return to Earth results sequentially in acute hypovolemia as vascular space dependent on gravity is refilled, an increase in plasma volume, a decrease in hemoglobin concentration (anemia), and an increase in serum erythropoietin.
Abstract: OBJECTIVES: To study sequential changes in heart rate, respiratory rate, blood pressure, heart rate power spectra, and plasma catecholamine concentrations in patients with acute brain injury and correlate these variables with the severity of neurologic dysfunction and patient outcome. DESIGN: Prospective, clinical study. SETTING: Pediatric intensive care unit. PATIENTS: Thirty-seven pediatric patients with acute brain injury caused by trauma, anoxia/ischemia, hemorrhage, or infection. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We found significant associations between low-frequency (0.01 to 0.15 Hz) heart rate power and severity of neurologic dysfunction (as assessed by the admission Glasgow Coma Scale) (p \textbackslashtextless .001) and patient outcome (as assessed by the Glasgow Outcome Scale) (p = .05). The admission (p = .05) and maximum (p \textbackslashtextless .001) values for low-frequency heart rate power and the minimum value for high-frequency (0.15 to 0.50 Hz) heart rate power obtained during hospitalization (p = .001) predicted an increased likelihood of survival. Ten brain-dead patients had significantly decreased low-frequency heart rate power (p = .008) and plasma norepinephrine (p = .015), epinephrine (p = .03), and dopamine (p = .04) concentrations when compared with six non-brain-dead patients with a Glasgow Coma Scale score of 3. CONCLUSIONS: Our results imply that autonomic nervous system control of heart rate is disrupted in proportion to the degree of neurologic insult in children after acute brain injury. Thus, heart rate power spectral analysis and plasma catecholamine concentrations may prove to be useful adjuncts in determining severity of neurologic injury and prognosis for recovery in children suffering from brain injury. In addition, these techniques may aid in the determination of brain death.
Abstract: The adaptive responses of the cardiovascular system to regular physical activity appear to include a reduction in sympathetic (SNS) activity and an increase in parasympathetic (PNS) activity during rest and at different absolute intensities of exercise. In a cross-sectional design, trained individuals who exercised at least 5 days/week for 45 min/day or more were compared with age- and gender-matched untrained controls. There was a relative bradycardia in the trained groups at rest and at the same absolute intensity of exercise in both young and middle-aged subjects. There were no differences in indicators of PNS and SNS activity at rest in young subjects. There was a reduced SNS activity and increased PNS activity in middle-aged trained subjects versus their age-matched controls. Spectral analysis was capable of showing changes in autonomic control of heart rate at rest and across intensities of exercise. These data showed significant shifts to increased PNS and reduced SNS indicators at rest in trained versus untrained middle-aged subjects and in females in both age groups versus males.
Abstract: Our previous work has shown that chronic metabolic acidosis can induce changes in protein and amino acid metabolism in muscle. The relationship of these metabolic responses to changes in muscle pH is unknown. To examine the role that acute acidosis might have on intracellular pH in rats, we evaluated the influence an acute infusion of HCl had on intracellular pH using 31P-NMR. Male rats fed 22% protein and weighing between 150 and 170 g were infused with 150 mM HCl (4 mmol/kg) over a 2- or 4-hour period. Baseline blood pH was 7.36 and dropped to 7.04 at the end of the infusion. Despite this, no changes in intracellular pH were seen. In contrast, we found that chronic acid loading (4 mmol NH4Cl/100 g/day for 5 days) produces a small change in muscle pH (0.05 pH units, p \textbackslashtextless 0.05). Chronic uremia did not change resting muscle pH despite a decrease in extracellular pH to 7.23 even though metabolic changes are well documented. Conclusions: (1) An acute acid load does not alter intracellular pH while chronic metabolic acidosis does reduce intracellular pH. (2) The lack of an acute change in intracellular pH suggests that intracellular buffering capacity changes over time.
Abstract: Increases in blood pressure during the period of emotional arousal attendant to impending exertion are well documented, yet the etiologic significance of these elevations is unknown. Research suggests that exaggerated cardiovascular responses to psychological stress may be importantly related to hypertension. We examined blood pressure reactivity in anticipation of an exercise stress test in relation to future hypertension in the Kuopio Ischemic Heart Disease Risk Factor Study, a population-based study of middle-aged men from Eastern Finland. Subjects were 508 unmedicated men with resting blood pressure less than 165/95 mm Hg who completed a bicycle ergometer stress test at baseline and whose hypertensive status was assessed at 4 years of follow-up. Systolic and diastolic reactivity were calculated as the difference between blood pressure measured after seated rest on the bicycle ergometer before initiation of exercise and mean seated resting blood pressure measured 1 week earlier. Logistic regression models adjusted for age and resting blood pressure revealed a graded association between quartiles of reactivity and risk of subsequent hypertension ( \textbackslashtextgreater or = 165/95 mm Hg), with men showing systolic responses greater than or equal to 30 mm Hg or diastolic responses greater than 15 mm Hg at nearly four times the risk of becoming hypertensive (odds ratios, 3.80 [95% confidence interval, 1.90 to 7.63] and 3.65 [95% confidence interval, 1.86 to 7.17], respectively) relative to the least-reactive groups (systolic response, \textbackslashtextless 10 mm Hg; diastolic response, \textbackslashtextless 5 mm Hg). Adjustments for traditional risk factors for hypertension did not alter these associations. Results demonstrate the clinical significance of the pressor response in anticipation of exercise and support the hypothesis that cardiovascular reactivity to psychological challenge plays a role in the etiology of hypertension.
Abstract: OBJECTIVE: To examine the hormonal and hemodynamic changes in a validated animal model of brain death. DESIGN: Prospective, controlled study. SETTING: Experimental research laboratory. SUBJECTS: Adult male mongrel dogs (n = 10). INTERVENTIONS: Brain death was induced by inflation of a subdural balloon in ten mongrel dogs weighing 23 to 30 kg and validated neuropathologically. The hearts were instrumented with micromanometers and ultrasonic flow probes to measure cardiovascular changes. No inotropic or vasoactive support was given. Hemodynamic stability was maintained with intravenous fluids. Blood samples and hemodynamic readings were collected before and after the induction of brain death. MEASUREMENTS AND MAIN RESULTS: A Cushing reflex, followed by a hyperdynamic response and diabetes insipidus, occurred in every animal following brain death. Mean arterial pressure, heart rate, contractility, and cardiac output increased to \textbackslashtextgreater 350 mm Hg, 230 beats/min, 4200 mm Hg/sec, and 2.8 L/min, respectively, at the peak of this phenomenon before returning to baseline. A plasma catecholamine surge was observed in every animal 15 mins after brain death, while the circulating concentrations of the pituitary gland hormones vasopressin and adrenocorticotrophic hormone decreased significantly after 15 and 45 mins of brain death, respectively, and continued to decrease throughout the experiments. Circulating triiodothyronine, thyroxine, and glucagon concentrations decreased significantly (p \textbackslashtextless .01) from 0.58 +/- 0.05 ng/mL, 2.20 +/- 0.15 micrograms/dL, and 49.7 +/- 9.1 pg/mL, respectively, to 0.34 +/- 0.03 ng/mL, 1.14 +/- 1.14 micrograms/dL, and 6.9 +/- 1.4 pg/mL, respectively, 420 mins after brain death. The hematocrit increased significantly 15 mins after brain death and then gradually decreased throughout the duration of the experiments. CONCLUSIONS: In a validated animal model of brain death, significant decreases in the circulating concentrations of stress hormones, as well as hemodynamic instability, occurred after brain death. Measurements of plasma adrenocorticotrophic hormone and vasopressin values may be useful as diagnostic predictors of brain death. Furthermore, the observed changes may contribute to organ dysfunction after brain death and may necessitate hormonal as well as inotropic and vasoactive support to maintain donor organ function in the clinical setting.
Abstract: We tested the hypothesis that the amplitude of the additional slow component of O2 uptake (VO2) during heavy exercise is correlated with the percentage of type II (fast-twitch) fibers in the contracting muscles. Ten subjects performed transitions to a work rate calculated to require a VO2 equal to 50% between the estimated lactate (Lac) threshold and maximal VO2 (50% delta). Nine subjects consented to a muscle biopsy of the vastus lateralis. To enhance the influence of differences in fiber type among subjects, transitions were made while subjects were pedaling at 45, 60, 75, and 90 rpm in different trials. Baseline VO2 was designed to be similar at the different pedal rates by adjusting baseline work rate while the absolute increase in work rate above the baseline was the same. The VO2 response after the onset of exercise was described by a three-exponential model. The relative magnitude of the slow component at the end of 8-min exercise was significantly negatively correlated with % type I fibers at every pedal rate (r = 0.64 to 0.83, P \textbackslashtextless 0.05-0.01). Furthermore, the gain of the fast component for VO2 (as ml.min-1.W-1) was positively correlated with the % type I fibers across pedal rates (r = 0.69-0.83). Increase in pedal rate was associated with decreased relative stress of the exercise but did not affect the relationships between % fiber type and VO2 parameters. The relative contribution of the slow component was also significantly negatively correlated with maximal VO2 (r = -0.65), whereas the gain for the fast component was positively associated (r = 0.68-0.71 across rpm). The amplitude of the slow component was significantly correlated with net end-exercise Lac at all four pedal rates (r = 0.64-0.84), but Lac was not correlated with % type I (P \textbackslashtextgreater 0.05). We conclude that fiber type distribution significantly affects both the fast and slow components of VO2 during heavy exercise and that fiber type and fitness may have both codependent and independent influences on the metabolic and gas-exchange responses to heavy exercise.
Abstract: Acute blood loss is a common, but often challenging, problem facing emergency physicians. Inadequate or delay in treatment can lead to morbidity or mortality. Standard classifications to quantify blood loss, as well as vital signs alone, are inadequate for guiding therapy. Mechanism of injury, base deficit and blood lactate, central venous oxygen saturation, and oxygen transport parameters should all play a role in deciding the need for further diagnostic studies and resuscitation. Extreme care must be taken to evaluate and resuscitate those with decreased physiologic reserve adequately, such as the elderly. Once bleeding has been identified, expeditious control of bleeding should be accomplished, either operatively or angiographically. Care must be individualized, but adherence to these general guidelines will improve outcome.
Abstract: To investigate whether systemic acid-base equilibrium changes with aging in normal adult humans, we reviewed published articles reporting the acid-base composition of arterial, arterialized venous, or capillary blood in age-identified healthy subjects. We extracted or calculated blood hydrogen ion concentration ([H+]), plasma bicarbonate concentration ([HCO3⊖]), blood PCO2, and age, and computed a total of 61 age-group means, distributed among eight 10-year intervals from age 20 to 100 years. Using linear regression analysis, we found that with increasing age, there is a significant increase in the steady-state blood [H+] (p \textbackslashtextless .001), and reduction in steady-state plasma [HCO3⊖] (p \textbackslashtextless .001), indicative of a progressively worsening low-level metabolic acidosis. Blood PCO2 decreased with age (p \textbackslashtextless .05), in keeping with the expected respiratory adaptation to metabolic acidosis. Such age-related increasing metabolic acidosis may reflect in part the normal decline of renal function with increasing age. The role of age-related metabolic acidosis in the pathogenesis of the degenerative diseases of aging warrants consideration.
Abstract: OBJECTIVE: This study was performed to determine the pharmakocinetics of recombinant leptin in lean rats and to test the hypothesis that the kidneys play an important role in the clearance of leptin from the circulation. DESIGN: 126I-leptin was administered by bolus intravenous injection. Blood samples were taken at various time points ranging from 1-180 min after administration and assayed for leptin. Pharmacokinetic parameters were determined in normal animals and after either bilateral nephrectomy or bilateral ureteral ligation. RESULTS: Leptin was eliminated from the circulation following a three compartment model. The importance of the kidneys to the systemic clearance of leptin was studied by administrating leptin to binephrectomized rats. The systemic clearance of leptin in anephric rats was only 19% of that calculated for control animals. In order to assess the role of glomerular filtration, both ureters were ligated 5 h before leptin administration. Ureteral ligation reduced the systemic clearance of leptin by 30%. CONCLUSION: These findings demonstrate that the short half life of leptin in the circulation is mainly determined by efficient renal clearance which is mediated in part by glomerular filtration.
Abstract: Skeletal muscles are important reflexogenic areas of the cardiovascular system. The afferent pathways of the reflex loops involve slow-conducting group III and group IV fibers that are excited by mechanical and chemical events in the muscle. The present paper reviews a series of experiments dealing with the question of whether those afferents are also influenced by gravitational forces. The results of these studies suggest the following answers: 1) gravitational forces can modulate cardiovascular reflexes from exercising skeletal muscles. 2) This effect is primarily due to changes in the interstitial fluid volume rather than to a direct mechanical influence, venous pressure, or venous volume. 3) The amplitudes of heart rate and blood pressure responses during exercise are inversely related to the local interstitial volume. Measurements during post-exercise circulatory arrest indicate that this sensitivity is mainly mediated by muscle chemoreceptors. These receptors, which also contribute to the spinal control of movement, generally appear to be sensitized by regional fluid losses and desensitized by overhydration of their environment.
Abstract: BACKGROUND. In patients with insulin-dependent diabetes mellitus (IDDM) whose treatment results in nearly normal mean plasma glucose concentrations, an unawareness of hypoglycemia can develop, and such patients are at increased risk for seizures and coma. We tested the hypothesis that during hypoglycemia, these patients would have normal glucose uptake in the brain and that consequently no sympathoadrenal activation would begin, resulting in an unawareness of hypoglycemia. METHODS. We measured glucose uptake in the brain at plasma glucose concentrations of 105 and 54 mg per deciliter (5.8 and 3.0 mmol per liter) in 24 patients with IDDM, stratified into three groups according to their glycosylated hemoglobin values (mean [+/- SD] values, 7.2 +/- 0.5, 8.5 +/- 0.4, and 10.2 +/- 1.3 percent) and compared the values for brain glucose uptake with those measured in 15 normal subjects at plasma glucose concentrations of 85 and 55 mg per deciliter (4.2 and 3.1 mmol per liter). We also recorded the subjects’ hypoglycemic-symptom scores and measured their plasma concentrations of counterregulatory hormones. RESULTS. There was no significant change in the uptake of glucose in the brain (calculated as the uptake during hypoglycemia minus the uptake during normoglycemia) among the patients with IDDM who had the lowest glycosylated hemoglobin values (+0.6 +/- 2.0 mg [3.3 +/- 11.1 mumol] per 100 g of brain tissue per minute, P = 0.39). Conversely, glucose uptake in the brain fell in both the group with intermediate values (a decrease of 1.3 +/- 1.0 mg [7.2 +/- 5.6 mumol] per 100 g per minute, P = 0.009) and the group with the highest values (a decrease of 1.8 +/- 1.6 mg [10.0 +/- 9.0 mumol] per 100 g per minute, P = 0.01), as it did in the normal subjects (a decrease of 1.6 +/- 1.8 mg [9.0 +/- 10.1 mumol] per 100 g per minute, P = 0.003). The responses of plasma epinephrine and pancreatic polypeptide and the frequency of symptoms of hypoglycemia were lowest in the group with the lowest glycosylated hemoglobin values. CONCLUSIONS. During hypoglycemia, patients with IDDM who have nearly normal glycosylated hemoglobin values have normal glucose uptake in the brain, which preserves cerebral metabolism, reduces the responses of counterregulatory hormones, and causes an unawareness of hypoglycemia.
Abstract: It was the aim of this study to determine whether FFA inhibit insulin-stimulated whole body glucose uptake and utilization in patients with non-insulin-dependent diabetes. We performed five types of isoglycemic (approximately 11mM) clamps: (a) with insulin; (b) with insulin plus fat/heparin; (c) with insulin plus glycerol; (d) with saline; (e) with saline plus fat/heparin and two types of euglycemic (approximately 5mM) clamps: (a) with insulin; (b) with insulin plus fat/heparin. During these studies, we determined rates of glucose uptake, glycolysis (both with 3[3H] glucose), glycogen synthesis (determined as glucose uptake minus glycolysis), carbohydrate oxidation (by indirect calorimetry) and nonoxidative glycolysis (determined as glycolysis minus carbohydrate oxidation). Fat/heparin infusion did not affect basal glucose uptake, but inhibited total stimulated (insulin stimulated plus basal) glucose uptake by 40-50% in isoglycemic and in euglycemic patients at plasma FFA concentration of approximately 950 and approximately 550 microM, respectively. In isoglycemic patients, the 40-50% inhibition of total stimulated glucose uptake was due to near complete inhibition of the insulin-stimulated part of glucose uptake. Proportional inhibition of glucose uptake, glycogen synthesis, and glycolysis suggested a major FFA-mediated defect involving glucose transport and/or phosphorylation. In summary, fat produced proportional inhibitions of insulin-stimulated glucose uptake and of intracellular glucose utilization. We conclude, that physiologically elevated levels of FFa could potentially be responsible for a large part of the peripheral insulin resistance in patients with non-insulin-dependent diabetes mellitus.
Abstract: A mathematical model of the blood coagulation system intrinsic pathway is developed based on a reaction cascade scheme with two positive feedbacks. The model describes quantitatively well-known experimental data on blood plasma coagulation kinetics for various levels of activation and varying calcium concentrations. In the limit of experimental variety of the values of the rate for individual stages of coagulation cascade, obtained in [5-12], a good agreement with experimental data was shown for two discrete sets of the constants. The model relates unambiguously the threshold properties in coagulation activation by calcium with existence of the activation threshold. The model allows numerical estimates of the threshold activation values for various calcium concentrations. At calcium concentration of 0.2 mM, corresponding to normal calcium content in blood, the activation threshold is equal to 0.00016 nM and 0.0019 nM of Factor XIa for the first and the second sets of the system parameters, respectively.
Abstract: The discovery of glycogenin as a self-glucosylating protein that primes glycogen synthesis has significantly increased our understanding of the structure and metabolism of this storage polysaccharide. The amount of glycogenin will influence how much glycogen the cell can store. Therefore, the production of active glycogenin primer in the cell has the potential to be the overall rate-limiting process in glycogen formation, capable of overriding the better understood hormonally controlled mechanisms of protein phosphorylation/dephosphorylation that regulate the activities of glycogen synthase and phosphorylase. There are indications that a similar covalent modification control is also being exerted on glycogenin. Glycogenin has the ability to glucosylate molecules other than itself and to hydrolyze UDPglucose. These are independent of self-glucosylation, so that glycogenin, even when it has completed its priming role and become part of the glycogen molecule, retains its catalytic potential. Another new component of glycogen metabolism has been discovered that may have even greater influence on total glycogen stores than does glycogenin. This is proglycogen, a low molecular mass (approximately 400 kDa) form of glycogen that serves as a stable intermediate on the pathways to and from depot glycogen (macroglycogen, mass 10(7) Da, in muscle). It is suggested that glycogen oscillates, according to glucose supply and energy demand, between the macroglycogen and proglycogen, but not usually the glycogenin, forms. The proportion of proglycogen to macroglycogen varies widely between liver, skeletal muscle, and heart, from 3 to 15% to 50% by weight, respectively. On a molar basis, proglycogen is greatly in excess over macroglycogen in muscle and heart, meaning that if the proglycogen in these tissues could be converted into macroglycogen, they could store much more total glycogen. Discovering the factors that regulate the balance between glycogenin, proglycogen, and macroglycogen may have important implications for the understanding and management of noninsulin-dependent diabetes and for exercise physiology.
Abstract: BACKGROUND: This study was designed to establish a validated canine brain death model. Ten consecutive dogs were studied to investigate the effects of brain death on hemodynamic, metabolic, and hormonal function. METHODS: Brain death was induced by inflation of a subdurally placed balloon and was validated neuropathologically. Functional data and blood samples were collected before and 15, 45, 90, 240, 360, and 420 minutes after the induction of brain death. No inotropic or vasoactive support was given. The results are expressed as mean +/- standard error of the mean. RESULTS: The Cushing reflex occurred in all animals and lasted 13.3 +/- 1.5 minutes. Raised catecholamine levels were documented at 15 minutes, whereas the pituitary gland hormones vasopressin and adrenocorticotrophic hormone decreased significantly after 15 and 45 minutes, respectively. Triiodothyronine, thyroxine, and glucagon decreased significantly from 0.58 +/- 0.05 ng/ml, 2.20 +/- 0.15 micrograms/dl, and 49.7 +/- 9.1 pg/ml to 0.34 +/- 0.03 ng/ml (p \textbackslashtextless 0.05 versus baseline; paired two-tailed t-test), 1.14 +/- 1.14 micrograms/dl (p \textbackslashtextless 0.05), and 6.9 +/- 1.4 pg/ml (p \textbackslashtextless 0.05). Insulin and lactate dehydrogenase showed a moderate increase after brain death. Diabetes insipidus occurred after 45 minutes in nine animals (urine output 13.5 +/- 1.8 ml/kg/hour). Left and right ventricular end-diastolic pressure increased significantly toward the end of all experiments. Cardiac output increased and systemic and pulmonary vascular resistance decreased, but heart rate remained unchanged. CONCLUSION: This simple, reproducible, moderately invasive, and reliable model of brain death in animals assesses donor organ function and preservation. Cushing reflex, hyperdynamic state, catecholamine storm, vasopressin and adrenocorticotropic hormone cessation, total cerebral necrosis, and diabetes insipidus were consistent findings.
Abstract: The ob gene product, leptin, is an important circulating signal for the regulation of body weight. To identify high affinity leptin-binding sites, we generated a series of leptin-alkaline phosphatase (AP) fusion proteins as well as [125I]leptin. After a binding survey of cell lines and tissues, we identified leptin-binding sites in the mouse choroid plexus. A cDNA expression library was prepared from mouse choroid plexus and screened with a leptin-AP fusion protein to identify a leptin receptor (OB-R). OB-R is a single membrane-spanning receptor most related to the gp130 signal-transducing component of the IL-6 receptor, the G-CSF receptor, and the LIF receptor. OB-R mRNA is expressed not only in choroid plexus, but also in several other tissues, including hypothalamus. Genetic mapping of the gene encoding OB-R shows that it is within the 5.1 cM interval of mouse chromosome 4 that contains the db locus.
Abstract: Patients with COPD usually are limited in their exercise tolerance by a limited ventilatory capacity. Lactic acidosis induced by exercise increases the stress on the ventilatory system due to CO2 generated by bicarbonate buffering and hydrogen ion stimulation. Patients with COPD are often observed to increase blood lactate levels at low levels of exercise. We wished to determine whether patients with COPD who experience lactic acidosis do so because of respiratory muscle production of lactate. Eight patients with moderate to severe COPD (FEV1 = 43.5 +/- 11.6% predicted) and 5 healthy subjects performed 10 min of moderate constant work rate exercise either breathing spontaneously or volitionally increasing their ventilation for 5 min to approximate the peak minute ventilation seen during incremental exercise. During volitional increased ventilation, 3% CO2 was added to the inspirate to prevent alkalosis and hypocapnia. In neither the healthy subjects nor the COPD group was the end-exercise lactate level significantly higher during volitional ventilation increase than during spontaneous ventilation. Further, in the COPD patients, the blood lactate levels during volitional ventilation increase were much lower than during maximal exercise (averaging 2.4 vs 5.3 mmol/L) despite similar ventilation levels (averaging 50 and 53 L/min). We conclude that it is unlikely that the respiratory muscles have an important influence on the blood lactate level elevation seen during maximal exercise in COPD patients.
Abstract: PURPOSE: Endocrinologic and metabolic changes after brain death (BD) have not yet been investigated in a validated animal model. Therefore, the effects of BD on hormonal and metabolic function were studied in 10 dogs (23 to 31 kg). METHODS: BD was induced by intracranial pressure increase and validated neuropathologically. Plasma concentrations of pituitary, thyroid, adrenal, and pancreatic hormones were measured pre/post BD. The results are expressed as mean (+/- SEM). RESULTS: A Cushing reflex and diabetes insipidus occurred after BD. Elevated catecholamine levels were documented after 15 minutes whereas the pituitary gland hormones vasopressin and adrenocorticotrophic hormone (ACTH) decreased significantly after 15 and 45 minutes of BD respectively. Thyroxine, triiodothyronine, and glucagon decreased significantly (P \textbackslashtextless .01) from 0.58 ng/mL (+/- 0.05), 2.20 micrograms/dL (+/- 0.15), and 49.7 pg/mL (+/- 9.1) respectively to 0.34 ng/mL (+/- 0.03), 1.14 micrograms/dL (+/- 1.14), and 6.9 pg/mL (+/- 1.4) respectively 420 minutes after BD. The hematocrit increased significantly after BD and declined toward the end of all experiments. Metabolic acidosis occurred immediately after BD and at the end of the experiments. CONCLUSIONS: In a simple, reproducible, and reliable animal model of BD, a catecholamine storm, vasopressin and ACTH cessation, and diabetes insipidus were consistent findings. The decrease in cortisol and vasopressin levels warrant consideration of hormonal therapy.
Abstract: It has been suggested that airway obstruction may be mediated in part by airway vascular engorgement or airway wall edema. However, there are few data that support this conjecture. In this study we examined the effects of increased bronchial blood flow (Qba) on airway wall dimensions, conducting airway resistance, peripheral airway resistance, and airway reactivity assessed by methacholine aerosol challenge. The bronchial artery was perfused with autologous blood (control Qba = 0.6 ml.min-1.kg-1) in anesthetized ventilated sheep. The artery was perfused at either control (C) Qba or at high (H) Qba (300% of C Qba) for 3 h. Morphometry showed a doubling of the vascular area in airways exposed to H Qba (n = 4) compared with C Qba (n = 4). However, the significant increase in wall area could be accounted for only partially by the vascular changes, with edema fluid accumulation accounting for the major increase. Despite these changes, baseline airway resistance (n = 16) and peripheral airway resistance were both unaltered. Airway reactivity to methacholine before and after H Qba was also examined (n = 12). The 3 h of H Qba had no effect on airway reactivity regardless of whether challenge occurred with C or H Qba. The lack of effect of vascular engorgement on airway resistance or reactivity does not support a primary role for these factors in mediating airway obstruction.
Abstract: This study examined whether high physiological concentrations of epinephrine (EPI) would enhance muscle glycogenolysis during intense muscular contractions. Muscles of the rat hindlimb were perfused for 12 min at rest and 45 s of tetanic stimulation (1.0-Hz train rate, 100-ms train duration at 80 Hz) without EPI (control) or with 15 or 35 nM EPI. In the EPI groups the muscles were perfused with EPI for the last 2 min of rest perfusion and throughout stimulation. Glycogenolysis in the white gastrocnemius, red gastrocnemius, plantaris, and soleus muscles during stimulation was unaffected by the presence of EPI in the perfusion medium. In addition, muscle lactate and hindlimb lactate efflux were similar in EPI and control groups. It is concluded that EPI is not important for enhancing glycogenolysis in rat muscles composed predominantly of fast-twitch fibers during intense short-term tetanic stimulation.
Abstract: Inhibin has been suggested to play a role in gonadal feedback regulation of follicle-stimulating hormone (FSH) secretion; however, neither the half-life nor the time course of action of recombinant inhibin has been reported in any primate species. We sought to determine the disappearance half-life of circulating endogenous inhibin following castration in adult male monkeys, Macaca fascicularis, and to determine the half-life of administered recombinant human inhibin A and its effect on bioactive FSH and luteinizing hormone (LH) levels in castrate monkeys. Endogenous inhibin fell from 8,122 +/- 2,077 U/L (mean +/- SEM, n = 5) prior to castration to 383 +/- 84 U/L at 24 hours and 269 +/- 44 U/L at day 21 (P \textbackslashtextless 0.05 at 24 hours vs. day 21) (detection limit of assay 234 U/L). The early phase half-life of endogenous inhibin was 34 minutes (between 8 and 60 minutes) and a later phase half-life of 75 minutes was observed between 1 and 4 hours following castration. Recombinant inhibin exhibited a 14-minute early phase half-life between 8 and 60 minutes following the 5 micrograms intravenous (i.v.) recombinant inhibin dose, and a later phase half-life of 70 minutes between 1 and 4 hours in castrate monkeys (n = 3). Serum inhibin levels were maintained within or above the precastration range for 15 minutes. Single dose recombinant inhibin, 100 micrograms subcutaneous (SC) or intramuscular (IM) administered to castrate monkeys (n = 3), achieved and maintained normal serum inhibin levels for 6 hours.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Systemic glucose utilization declines during sleep in man. We tested the hypothesis that this decline in utilization is largely accounted for by reduced brain glucose metabolism. 10 normal subjects underwent internal jugular and radial artery cannulation to determine cerebral blood flow by N2O equilibrium technique and to quantitate cross-brain glucose and oxygen differences before and every 3 h during sleep. Sleep stage was graded by continuous electroencephalogram, and systemic glucose turnover was estimated by isotope dilution. Brain glucose metabolism fell from 33.6 +/- 2.2 mumol/100 g per min (mean +/- SE) before sleep (2300 h) to a mean nadir of 24.3 +/- 1.1 mumol/100 g per min at 0300 h during sleep (P = 0.001). Corresponding rates of systemic glucose utilization fell from 13.2 +/- 0.8 to 11.0 +/- 0.5 mumol/kg per min (P = 0.003). Diminished brain glucose metabolism was the product of a reduced arteriovenous glucose difference, 0.643 +/- 0.024 to 0.546 +/- 0.020 mmol/liter (P = 0.002), and cerebral blood flow, 50.3 +/- 2.8 to 44.6 +/- 1.4 cc/100 g per min (P = 0.021). Brain oxygen metabolism fell commensurately from 153.4 +/- 11.8 to 128.0 +/- 8.4 mumol/100 g per min (P = 0.045). The observed reduction in brain metabolism occurred independent of stage of central nervous system electrical activity (electroencephalographic data), and was more closely linked to duration of sleep. We conclude that a decline in brain glucose metabolism is a significant determinant of falling rates of systemic glucose utilization during sleep.
Abstract: OBJECTIVES. The purpose of this study was to determine the feasibility, relation to other methods and significance of the effective regurgitant orifice area measurement. BACKGROUND. Assessment of the severity of valvular regurgitation (effective regurgitant orifice area) has not been implemented in clinical practice but can be made by Doppler echocardiography. METHODS. Effective regurgitant orifice area was calculated by Doppler echocardiography as the ratio of regurgitant volume/regurgitant jet time-velocity integral and compared with color flow Doppler mapping, angiography, surgical classification, regurgitant fraction and variables of volume overload. RESULTS. In 210 consecutive patients examined prospectively, feasibility improved from the early to the late experience (65% to 95%). Effective regurgitant orifice area was 28 +/- 23 mm2 (mean +/- SD) for aortic regurgitation (32 patients), 22 +/- 13 mm2 for ischemic/functional mitral regurgitation (50 patients) and 41 +/- 32 mm2 for organic mitral regurgitation (82 patients). Significant correlations were found between effective regurgitant orifice and mitral jet area by color flow Doppler mapping (r = 0.68 and r = 0.63, p \textbackslashtextless 0.0001, respectively) and angiographic grade (r = 0.77, p = 0.0004). Effective regurgitant orifice area in surgically determined moderate and severe lesions was markedly different in mitral regurgitation (35 +/- 12 and 75 +/- 33 mm2, respectively, p = 0.009) and in aortic regurgitation (21 +/- 8 and 38 +/- 5 mm2, respectively, p = 0.08). Strong correlations were found between effective regurgitant orifice area and variables reflecting volume overload. A logarithmic regression was found between effective regurgitant orifice area and regurgitant fraction, underlining the complementarity of these indexes. CONCLUSIONS. Calculation of effective regurgitant orifice area is a noninvasive Doppler development of an old hemodynamic concept, allowing assessment of the lesion severity of valvular regurgitation. Feasibility is excellent with experience. Effective regurgitant orifice area is an important and clinically significant index of regurgitation severity. It brings additive information to other quantitative indexes and its measurement should be implemented in the comprehensive assessment of valvular regurgitation.
Abstract: This study addressed two questions: 1) Does net lactate uptake (L) by muscle approach a saturation limit with increasing blood lactate concentration ([La])? 2) Is the muscle net L response to increasing blood [La] affected by metabolic rate (VO2)? The gastrocnemius plantaris muscle group (GP) was isolated in situ in 20 anesthetized dogs. In three series of experiments, a lactate-lactic acid solution was infused into the arterial inflow of the GP to produce five different plasma [La] values: approximately 3, 9, 16, 22, and 30 mM, each of them maintained for 30 min. In one series, the GP remained at rest, whereas in the second series it contracted at 1 Hz and in the third series at 4 Hz. VO2 averaged approximately 3, 43, and 100 ml.kg-1.min-1 at rest and at 1 and 4 Hz, respectively. Within each of the three metabolic rates, increasing plasma [La] resulted in an increase in net L, which was well described (R \textbackslashtextgreater 0.98) by exponential equations. These equations predicted net L asymptotic values of 0.80, 0.72, and 1.09 mmol.kg-1.min-1 for rest and for 1 and 4 Hz, respectively. The corresponding plasma [La]s for half-maximal net L from the exponential equations were 16, 10, and 12 mM. Glucose uptake, pyruvate uptake/output, and alanine output by the muscles were not affected by the increasing [La] (and concomitant increases in net L) at any of the metabolic rates. Neither net glycogen synthesis nor depletion was changed by increasing [La].(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: We tested the hypothesis that when fat is ingested in combination with carbohydrate, direct release of fatty acids into the plasma may occur. Eight normal subjects ingested two meals: high-fat (80 g fat, 80 g carbohydrate, and 18 g protein) and low-fat (\textbackslashtextless 1 g fat, otherwise closely matched). Over the subsequent 6 h, net fat oxidation was greater after the high-fat meal (20.7 vs 10.6 g, P \textbackslashtextless 0.01). Plasma nonesterified fatty acid (NEFA) concentrations were markedly suppressed after the low-fat meal, but relatively maintained after the high-fat meal (P \textbackslashtextless 0.01). The profile of plasma NEFAs changed after the high-fat meal, consistent with entry of meal-derived fatty acids into the NEFA pool. We suggest that after ingestion of combinations of carbohydrate and fat, the action of lipoprotein lipase on chylomicron-triacylglycerol leads to direct release of fatty acids into the plasma and increased fat oxidation.
Abstract: We tested the hypothesis that increased lymph flow from the abdominal organs would increase the pressure within the thoracic duct at the thoracic duct-lung lymphatic junction. Cannulas were placed into the thoracic duct via the caudal mediastinal (lung) node efferent lymphatics in 4 sheep. After the sheep recovered from the surgery, we monitored the thoracic duct pressure with pressure transducers. To increase lymph flow from the lower body, we infused Ringers solution (59 +/- 19 [mean +/- SD] ml/kg body weight in 30 min.) intravenously into the sheep and we inflated a balloon in the inferior vena cava. This technique causes substantial increases in lymph flow from the lower body (mainly from the liver and intestines) through the thoracic duct. During the infusions, the thoracic duct pressure increased significantly from 4.1 +/- 2.9 cm H2O (baseline) to 6.8 +/- 1.7 cm H2O. The neck vein pressure (pressure at the outflow of the thoracic duct) did not increase from baseline (3.0 +/- 2.6 cm H2O). Thus our results support the hypotheses that increased flow through the thoracic duct causes increased thoracic duct pressure.
Abstract: We tested the hypothesis that chronic reduction in perfusion pressure and flow in the coronary circulation induces a state of myocardial "hibernation" characterized not only by a steady-state reduction in myocardial O2 consumption (MVO2) but also by evidence of persistent dilator reserve of the distal vasculature. Biochemical and morphological changes in the coronary vasculature were also assessed. Experiments were conducted in swine with an extraluminal coronary stenosis placed 4-32 wk before study. Stenosis reduced lumen diameter by approximately 80% at the time of final experimentation. Baseline, regional myocardial blood flow distal to the stenosis in both endocardial and epicardial layers was reduced vs. that of the normal zone. Vasodilator reserve persisted in both endocardial and epicardial layers of the stenosis zone. Flow increased in each layer in response to adenosine plus phenylephrine and failed to decline despite a marked reduction in perfusion pressure in response to adenosine alone. Regional MVO2 at baseline was reduced vs. historical controls without coronary stenosis. Protein synthesis rate in coronary vessels of the stenosis zone was reduced vs. that of the normal zone. Morphological responses of stenosis zone vessel walls were heterogeneous. Smaller microvessels exhibited mild hypertrophy of their walls, whereas walls of larger microvessels tended to atrophy. Thus chronic reduction in perfusion pressure and flow induces a state of myocardial hibernation characterized by a steady-state reduction in MVO2 in association with persistent dilator capacity. Biochemical and morphological changes occur in microvessel walls and may contribute to observed physiological responses.
Abstract: We evaluated the effect of frequent, early bolus administration of low-dose sodium bicarbonate (NaHCO3) on blood gas values during ventricular fibrillation and cardiopulmonary resuscitation (CPR) compared with normal saline and standard bolus doses of NaHCO3. This was a randomized laboratory investigation involving 13 mongrel dogs and 18 experiments (5 dogs were used in a crossover manner). Each dog underwent 3 minutes of ventricular fibrillation, followed by 15 minutes of CPR. Animals were randomly assigned to one of three treatments administered early in the resuscitation effort: NaHCO3 0.5 mEq/kg at 5, 10, and 15 minutes of ventricular fibrillation (SB); NaHCO3 1 mEq/kg at 5 minutes and 0.5 mEq/kg at 15 minutes of fibrillation (SB); or 0.9% NaCl 1 ml/kg at 5 minutes and 0.5 ml/kg at 15 minutes of fibrillation (P). A total of 15 experiments were included for analysis. Arterial and venous blood gases were sampled at 4, 8, 13, and 18 minutes of fibrillation. The SB group demonstrated the highest arterial partial pressures of carbon dioxide (pCO2) at each sampling point after NaHCO3, including the 18-minute sample: 42 +/- 12, 29 +/- 11, and 35 +/- 10 torr for SB, P, and B, respectively. In addition, SB produced arterial alkalemia (pH \textbackslashtextgreater 7.45) after NaHCO3 administration. The arterial pH at 18 minutes of fibrillation for SB, P, and B was 7.46 +/- 0.14, 7.29 +/- 0.07, and 7.41 +/- 0.1, respectively. Similar trends for pCO2 and pH were observed for venous samples.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: This article focuses on the links between insulin and blood pressure at the level of the renin-angiotensin-aldosterone system (RAAS). The effects of insulin on plasma potassium levels and whole-body potassium content and the effect of potassium on glucose-induced insulin release identify a physiological glucose-potassium cycle. The normal interactions of insulin and hyperglycemia with the hormones of the RAAS are reviewed, and their changes in patients with diabetes mellitus are discussed. Some key findings on the interrelationships of insulin and the RAAS with regard to sodium metabolism are also brought into focus. A role for changes in the RAAS secondary to insulin resistance, hyperinsulinemia, and hyperglycemia is delineated in relation to the excess hypertension of diabetes. The effects of angiotensin-converting enzyme inhibition on insulin sensitivity and glucose tolerance are reviewed in the context of the glucose-potassium cycle.
Abstract: We examined the effects of angiotensin II (Ang II) and Ang-(1-7) on the release of [3H]norepinephrine elicited by nerve stimulation (2 Hz, 0.5 millisecond, for 2 minutes) in rat atria isolated with their cardioaccelerans nerves. The stimulation-induced release of [3H]norepinephrine was increased 50% by 3 x 10(-8) mol/L of either peptide. No further increase in [3H]norepinephrine release was observed with peptide concentrations up to 3 x 10(-7) mol/L. This effect was completely blocked by the nonselective angiotensin receptor antagonist saralasin (1 x 10(-7) mol/L). The type 1 angiotensin receptor antagonist DuP 753 (1 x 10(-6) mol/L) entirely prevented the increases in [3H]norepinephrine caused by Ang II and Ang-(1-7). On the other hand, the type 2 angiotensin receptor antagonist PD 123319 (1 x 10(-6) mol/L) prevented the increase in [3H]norepinephrine release elicited by Ang-(1-7) but not by Ang II. These results suggest that Ang-(1-7), like Ang II, could have a neuromodulatory function in rat atria via activation of specific angiotensin receptor subtypes, which could be the subtype 1 angiotensin receptor for Ang II and subtypes 1 and 2 for Ang-(1-7).
Abstract: The aim of these studies was to investigate the mechanism underlying the haemodynamic changes associated with brain death. The initial series of studies were to assess whether these changes involved some blood-borne factor. When control rats (n = 6) were exsanguinated whilst being simultaneously transfused with blood from rats that had been brain-dead for 60 min, their haemodynamic function did not deteriorate. Likewise, when brain-dead rats (n = 6) were exsanguinated and transfused with blood from control rats there was no improvement of haemodynamic function. The absence of any blood-borne factor was further confirmed in studies in which isolated hearts from control rats were perfused with blood from a support rat which had been brain-dead for 15 min (n = 6/group). The brain-death-induced haemodynamic changes in the support rat (mean arterial pressure increased from 98 +/- 6 to 176 +/- 9 mm Hg after 30 s and then fell to 44 +/- 5 mm Hg after 5 min) were not associated with changes in cardiac function of the perfused heart (left ventricular developed pressure was 146 +/- 4 mmHg before the induction of brain death and 147 +/- 4 and 151 +/- 7 mm Hg at 30 s and 5 min, respectively, after the induction). In further in vivo studies, we assessed the involvement of the autonomic nervous system in brain-death-induced haemodynamic instability. We achieved this by employing beta-adrenoreceptor blockade or bilateral vagotomy (n = 6/group); propranolol (1 mg/kg given as a bolus 6 min before brain death followed by 0.5 mg/kg/h continuous infusion) abolished the early transient tachycardia and positive inotropic response to brain death but did not alter the subsequent deterioration of function (mean arterial pressure fell from 75 +/- 7 mmHg before brain death to 49 +/- 5 mmHg after 30 min). Bilateral vagotomy had no effect on the functional changes induced by brain death. The effect of catecholamine depletion was then investigated; 6-hydroxydopamine (given over 15 days) depleted myocardial norepinephrine content by approximately 90% (from 2.3 +/- 0.1 to 0.3 +/- 0.1 nmol/g wet wt; P \textbackslashtextless 0.05). Depletion of cardiac catecholamines reduced brain-death-induced mortality to zero but did not affect cardiac dysfunction. Finally, we used L-NAME and naloxone in an attempt to identify roles for nitric oxide and endogenous opioid peptides but were again unable to influence the cardiac events. In conclusion, the initial transient hyperdynamic response induced by brain death appears to be mediated through cardiac innervation and can be inhibited by beta-adrenoreceptor blockade. However, the autonomic nervous system, nitric oxide, endogenous opioid peptides and blood-borne factors do not appear to be involved in the subsequent deterioration of cardiac function.
Abstract: OBJECTIVE: To determine whether early invasive monitoring is necessary in young trauma patients. DESIGN: A prospective study. SETTING: Surgical intensive care unit (ICU) at an inner-city, Level I trauma center. PATIENTS: Thirty-nine patients \textbackslashtextless 40 yrs of age, who required operative therapy for penetrating trauma and who received \textbackslashtextgreater 6 units of intraoperative blood. INTERVENTIONS: Invasive hemodynamic monitoring, with percutaneous insertion of arterial and pulmonary artery catheters. Vital signs, hemodynamic and oxygen transport values, and laboratory tests were obtained at 1, 8, and 24 hrs postoperatively. Oxygen delivery was increased until a normal serum lactate concentration and a state of nonflow-dependent oxygen consumption were achieved. MEASUREMENTS AND MAIN RESULTS: Despite normal heart rate, blood pressure, and urine output, only five (15%) patients achieved an optimized state at 1 hr postoperatively. Of the other 34 patients, two patients achieved an optimized state with volume infusion alone and 32 (82%) patients required inotropes. Five (12%) patients never achieved an optimized state and died within hours of their arrival to the ICU. Two other patients achieved an optimized state but died of sepsis and organ failure. The other 32 (82%) patients achieved an optimized state within 24 hrs and survived. The hemodynamic values of survivors at 1 hr postoperatively showed a significantly lower pulmonary vascular resistance and serum lactate concentration, and a significantly higher oxygen delivery and mixed venous oxygen saturation, when compared with the values of nonsurvivors. At 24 hrs postoperatively, survivors also had a significantly lower pulmonary vascular resistance and serum lactate concentration, and significantly higher oxygen delivery than nonsurvivors. Survivors’ oxygen consumption was also higher than the oxygen consumption of nonsurvivors. CONCLUSIONS: Our data demonstrate that young trauma patients have substantial but clinically occult myocardial depression after shock, and most of these patients require inotropes to optimize and clear circulating lactate. Early invasive monitoring is necessary to precisely define the adequacy of the cardiac response and to individually tailor therapy. Patients who do not optimize and clear their lactate within 24 hrs may not survive.
Abstract: Brain death is a pathophysiological condition associated with major hemodynamic changes, temporary myocardial ischemia, and histological damage of the heart. These modifications could be related to a major local release of norepinephrine from myocardial sympathetic nerve endings leading to norepinephrine cardiotoxicity. This study was designed to evaluate the utility of cardiac microdialysis to measure interstitial myocardial norepinephrine release resulting from brain death. The dialysis probe consisted in a 10 x 0.20-mm dialysis fiber with a 18,000 mol wt cutoff. Dialysis probes were implanted into the right and left ventricular walls of the beating heart in anesthetized pigs and perfused with Ringer solution at 2 microliters/min. Dialysate norepinephrine concentration was measured using HPLC with electrochemical detection. The relative recovery rate of norepinephrine in vivo was 34 +/- 4%. Interstitial fluid concentrations were obtained using the following formula: [C]interstitium = [C]dialysate/Recovery in vivo. After brain death, a transient increase in interstitial norepinephrine concentration was observed (from 0.74 +/- 0.20 to 4.50 +/- 0.60 ng/ml and 0.76 +/- 0.20 to 6.2 +/- 0.9 ng/ml in left and right ventricle, respectively, P \textbackslashtextless 0.01) which far exceeded plasma level increase (from 0.50 +/- 0.10 ng/ml to 0.91 +/- 0.20 ng/ml, P \textbackslashtextless 0.05). This increase in myocardial norepinephrine was, moreover, biphasic, with a second peak occurring 40 min after brain death. The present study confirms the onset of a dramatic increase in cardiac norepinephrine release from myocardial nerve endings following brain death, and demonstrate the utility of the new cardiac microdialysis technique to assess changes in interstitial fluid content.
Abstract: Early experience with continuous monitoring of jugular venous oxygen saturation (SjvO2) suggested that this technology might allow early identification of global cerebral ischaemia in patients with severe head injury. The purpose of the present study was to examine the relationship between episodes of jugular venous desaturation and neurological outcome. One hundred and sixteen severely head-injured patients had continuous monitoring of SjvO2 during days 1-5 after injury. Episodes of jugular venous desaturation (SjvO2 \textbackslashtextless 50% for more than 10 minutes) were prospectively identified, and the incidence of desaturation was correlated with neurological outcome: 77 episodes of desaturation occurred in 46 of the 116 patients; 27 had one episode and 19 had multiple episodes of desaturation. The causes of these episodes were systemic (n = 36), cerebral (n = 35), or both (n = 6). Most of the episodes were less than 1 hour in duration, and it is probable that many of them would not have been detected without continuous measurement of SjvO2. Episodes of desaturation were most common on day 1 after injury, and were twice as common in patients with a reduced cerebral blood flow as in patients with a normal or elevated cerebral blood flow. The occurrence of jugular venous desaturation was strongly associated with a poor neurological outcome. The percentage of patients with a poor neurological outcome was 90% with multiple episodes of desaturation and 74% in patients with one desaturation, compared to 55% in patients with no episodes of desaturation. When adjusted for all co-variates that were found to be significant, including age, Glasgow coma score, papillary reactivity, type of injury, lowest recorded cerebral perfusion pressure, and highest recorded temperature, the incidence of desaturation remained significantly associated with a poor outcome. Although a cause and effect relationship with outcome cannot be established in this study, the data suggest that monitoring SvO2 might allow early identification and therefore treatment of many types of secondary injury to the brain.
Abstract: Although epinephrine is widely used clinically, its effect on myocardial energy substrate preference in the intact heart has yet to be clearly defined. We determined the effects of epinephrine on glucose and fatty acid metabolism in isolated working rat hearts perfused with 11 mM glucose, 0.4 mM palmitate, and 100 muU/ml insulin at an 11.5-mmHg left atrial preload and a 60-mmHg aortic afterload. Glycolysis and glucose oxidation were measured in hearts perfused with [5-3H]glucose and [U-14C]glucose, whereas fatty acid oxidation was measured in hearts perfused with [1-14C]palmitate. Addition of 1 microM epinephrine resulted in a 53% increase in the heart rate-developed pressure product. Glycolysis increased dramatically following addition of epinephrine (a 272% increase), as did glucose oxidation (a 410% increase). In contrast, fatty acid oxidation increased by only 10%. Epinephrine treatment did not increase the amount of oxygen required to produce an equivalent amount of ATP; however, epinephrine did increase the uncoupling between glycolysis and glucose oxidation in these fatty acid-perfused hearts, resulting in a significant increase in H+ production from glucose metabolism. Overall ATP production in epinephrine-treated hearts increased 59%. The contribution of glucose (glycolysis and glucose oxidation) to ATP production increased from 13 to 36%, which was accompanied by a reciprocal decrease in the contribution of fatty acid oxidation to ATP production from 83 to 63%. The increase in glucose oxidation was accompanied by a significant increase in pyruvate dehydrogenase complex activity in the active form. We conclude that the increase in ATP required for contractile function following epinephrine treatment occurs through a preferential increase in glucose use.
Abstract: We evaluated plasma osmolality (pOsm), thirst, and vasopressin response to hypertonic saline infusion in 14 patients with multiple system atrophy (MSA). This disease is characterized by the degeneration of noradrenergic neurons in the central nervous system and severe orthostatic hypotension. Seven patients were also characterized by the lack of vasopressin response to hypotension (group B) and seven by a preserved response (group A). In group A pOsm rose from 290 +/- 2 to 312 +/- 6 mosmol/kgH2O, vasopressin from 0.9 +/- 0.3 to 5.7 +/- 0.5 pmol/l, and thirst from 1.1 +/- 0.1 to 8.7 +/- 1.1 cm on the visual analog scale. After saline, patients drank 1,215 +/- 150 ml of water (no different from healthy controls). In group B patients’ pOsm rose from 296 +/- 3 to 325 +/- 6 mosmol/kgH2O and vasopressin from 1.2 +/- 0.1 to 19.6 +/- 0.4 pmol/l (P \textbackslashtextless 0.01 vs. group A and controls). Group B patients had no thirst during saline and drank little after the challenge (175 +/- 50 ml; P \textbackslashtextless 0.01 vs. group A and control). Forced drinking decreased vasopressin in patients before changes in pOsm, showing that inhibitory afferents from oropharyngeal mucosa were intact. In MSA patients with altered afferent control of vasopressin there is a dissociation between the osmotic control of thirst and the osmotic control of vasopressin.
Abstract: According to the Rosenblueth-Simeone model, the heart rate (HR) is proportional to the sympathovagal balance. The individual proportionality constant is the intrinsic heart rate, which can only be determined invasively. The normalized low-frequency heart rate variability power (LF) has been raised as a calibrated noninvasive alternative. To concrete this assumption, we studied the individual LF-HR relation during incremental head-up tilt (0, 10, 20, 30, 40, 45, 50, 55, 60, 65, 70, 75, and 80 degrees) in 21 young, healthy males. HR (means +/- SD) increased from 61.0 +/- 9.1 beats/min at 0 degree to 85.9 +/- 18.3 beats/min at 80 degrees. LF increased from 45.8 +/- 16.7 nu at 0 degrees to 79.8 +/- 13.8 nu at 80 degrees (nu meaning normalized units). Individual regressions of LF on HR yielded correlation coefficients of 0.80 +/- 0.13 (means +/- SD). The demonstrated linear relation between LF and HR confirms the potential significance of heart rate variability as a noninvasive means of assessing the sympathovagal balance.
Abstract: Circulating atrial natriuretic factor (ANF) is regulated by clearance receptors (ANFR-C). C-ANF-(4-23) is a ring-deleted analogue of ANF, which binds specifically to ANFR-C. The present studies were undertaken to determine total metabolic (TMCR), pulmonary (PCR), and renal clearance rates (RCR) of ANF in a group of seven mongrel dogs in chronic congestive heart failure (CHF) in comparison with a control group (n = 6). TMCR was not altered in CHF [1,534 +/- 319 vs. control: 1,735 +/- 208 ml/min; P = not significant (NS)] in association with an elevation of circulating endogenous ANF (206 +/- 44 vs. control: 36 +/- 10 pg/ml; P \textbackslashtextless 0.01). Infusion of C-ANF-(4-23) reduced TMCR in both groups similarly (CHF: 753 +/- 134 vs. control: 972 +/- 156 ml/min; P = NS). PCR was lower in CHF (286 +/- 431 vs. 1,672 +/- 407 ml/min; P \textbackslashtextless 0.05), whereas RCR was not different (10 +/- 24 vs. control: 15 +/- 25 ml/min; P = NS). ANFR-C blockade did not facilitate urinary sodium excretion in CHF. These studies demonstrate that 1) TMCR does not contribute to elevated endogenous ANF in CHF; 2) total functional activity of the clearance receptor pathway is preserved in CHF; and 3) renal ANF metabolism and the clearance receptor pathway are not linked to the avid sodium retention and renal ANF resistance observed in chronic CHF.
Abstract: We used the rapid ventricular pacing model to examine myocardial norepinephrine (NE) uptake kinetics in congestive heart failure. Dogs subjected to pacing at 225 beats/min for 8 wk developed heart failure as evidenced by elevated left atrial pressure, depressed first derivative of left ventricular pressure with respect to time, and depressed cardiac output compared with dogs paced at 100 beats/min for 8 wk. Fast-paced dogs also exhibited an elevated plasma NE and reduced myocardial NE content. Myocardial NE uptake kinetics and interstitial NE concentration were measured in vivo using a triple-isotope intracoronary tracer technique. The rate constant of neuronal uptake of NE was significantly depressed in the fast-paced animals (0.224 +/- 0.027 vs. 0.725 +/- 0.097 s-1, P \textbackslashtextless 0.001), while the interstitial NE concentration was significantly increased in the heart (1.12 +/- 0.15 vs. 0.17 +/- 0.07 ng/ml, P \textbackslashtextless 0.001). Myocardial beta-adrenoceptor density was significantly reduced in the fast-paced animals (49 +/- 7 vs. 86 +/- 6 fmol/mg, P \textbackslashtextless 0.001), and there was a significant inverse correlation between beta-adrenoceptor density and interstitial NE concentration. Thus we conclude that excess myocardial interstitial NE content contributes to the abnormalities in the beta-adrenoceptor system.
Abstract: Lymphatic vessels have the ability to contract and transport liquid and protein from tissue spaces to the intravascular space. The purpose of this investigation was to test whether this lymph pump is stimulated following a fixed volume hemorrhage in awake sheep. To quantitate lymphatic pumping in vivo, a mesenteric lymphatic was isolated from all lymph input and provided with Krebs solution at a fixed transmural pressure. A branch of the mesenteric duct was cannulated to provide a measure of lymph flow rate. Each animal was either bled 25% of blood volume over 5 min or was observed. Systemic arterial blood pressure declined in all bled sheep (P \textbackslashtextless 0.05). Hemorrhage had no effect on lymph flow from mesenteric ducts. However, hemorrhage significantly enhanced lymphatic pumping, approximately 200% of control values 3 hr after hemorrhage (P \textbackslashtextless 0.01). Increased lymphatic pumping after hemorrhage may play an important role in blood volume and protein restitution.
Abstract: This study determined the variation among individuals in ATP use during contraction and ATP synthesis after stimulation in a human limb muscle. Muscle energetics were evaluated using a metabolic stress test that separates ATP utilization from synthesis by 31P NMR spectroscopy. Epicutaneous supramaximal twitch stimulation (1 Hz) of the median and ulnar nerves was applied in combination with ischemia of the finger and wrist flexors in eight normal subjects. The linear creatine phosphate (PCr) breakdown during ischemic stimulation defined ATP use (delta PCr per twitch or approximately P/twitch) and was highly reproducible as shown by the relative standard deviation [(standard deviation/mean) x 100] of 11% in three repeated measures. The time constant of the monoexponential PCr change during aerobic recovery represented ATP synthesis rate and also showed a low relative standard deviation (9%). Individuals were found to differ significantly in both mean approximately P/twitch (PCr breakdown rates, 0.29-0.45% PCr per sec or % PCr per twitch; ANOVA, p \textbackslashtextless 0.001) and in mean recovery time constants (41-74 sec; ANOVA, P \textbackslashtextless 0.001). This range of approximately P/twitch corresponded with the range of fiber types reported for a flexor muscle. In addition, approximately P/twitch was negatively correlated with a metabolite marker of slow-twitch fiber composition (Pi/ATP). The nearly 2-fold range of recovery time constants agreed with the range of mitochondrial volume densities found in human muscle biopsies. These results indicate that both components involved in the muscle energy balance–oxidative capacity and contractile costs–vary among individuals in human muscle and can be measured noninvasively by 31 P NMR.
Abstract: Active pumping in postnodal lymphatic vessels is an important factor influencing lymph flow. However, the output of the lymphatic pump also depends on the rate of flow into the pump. This arrangement is similar to the blood circulation where cardiac output depends on the rate of blood flow through the veins into the heart (venous return) and on the pumping characteristics of the heart itself (cardiac function curves). One common way to analyze the blood circulation rate is to interrelate venous return and cardiac function curves. In this study, we used a similar technique to analyze lymph flow. We used lymphatic flow vs. outflow pressure (passive flow) relationships for nonpumping lymphatics to represent the inflow of lymph to the lymphatic pump. We used data on the pumping characteristics of postnodal lymphatic vessels to generate relationships between lymphatic pump outflow and pump inflow pressure (pump function curves), and then interrelated these curves. The results were not only similar to previously measured lymph flow data obtained from experimental animals, but also support the observation that under normal circumstances lymph flow is periodic and in surges (active pumping) but in edematogenic states lymph flows more continuously (i.e., passively).
Abstract: Virtually every part of the body can be injured by electric current. The extent of injury to any given tissue will depend on many factors, including the nature of the tissue and the amount and duration of the electric current. In addition, cardiac and respiratory arrest can be induced by a number of mechanisms with little or no immediate tissue damage. Burns can be caused by the heating of tissue by electric current and by other mechanisms. Secondary trauma may result from falls, explosions, and other events initiated by electric forces. Nervous tissue has the least resistance to current flow and is thus more easily damaged. Part II in this 3-part series will discuss nervous tissue damage first, followed by discussions of damage to tissues of increasingly greater electric resistance. These are blood vessels, muscle, skin, and bone. Less common injuries are discussed last.
Abstract: The Effective Blood Concentration (EC) of propofol required to prevent response to surgical incision was determined in 65 ASA I or II female patients breathing either 100% oxygen or 67% N2O in oxygen. Propofol was administered via a microcomputer-controlled infusion system programmed to maintain the blood propofol concentration at predetermined target values. The blood propofol concentrations predicted by the micro-computer were validated by measurement of whole blood propofol concentration. Predicted and measured concentrations differed during infusion of propofol, but became similar after discontinuing the infusion for at least 90 s, suggesting that equilibration within the central compartment was incomplete during infusion. The response to the initial incision was observed and probit analysis used to determine the predicted blood concentration at which 50% of patients responded. The predicted EC50 for propofol/N2O/O2 and propofol/O2 was 4.5 micrograms ml-1 and 6.0 micrograms ml-1 respectively, and the measured EC50 propofol/N2O/O2 and propofol/O2 was 5.36 micrograms ml-1 and 8.1 micrograms ml-1, 67% nitrous oxide in oxygen reducing the predicted EC50 by 25% and the measured EC50 of propofol by 33%. The predicted EC may be more representative of the equilibrated concentration in the central compartment and thus reflective of tissue propofol concentrations.
Abstract: The purpose of this study was to examine the sequential changes in renal and cardiovascular function produced by chronic Benazepril administration at different stages of heart failure in dogs. Heart failure was produced by rapid ventricular pacing in five dogs with a normally functioning renin-angiotensin system (angiotensin normal, AN) and six dogs chronically administered the angiotensin-converting-enzyme inhibitor (ACEI) Benazepril. After 7 days of pacing, cardiac output was significantly higher and total peripheral resistance (TPR) lower in the ACEI compared with the AN dogs. Cumulative sodium and water balance increased significantly in both groups, but after 7 days of pacing there were no significant differences between groups. However, the rate of increase in sodium and water balance was significantly less in the ACEI group. Effective renal plasma flow decreased in the AN and ACEI groups during pacing, but there were no between-group differences, and no significant changes in glomerular filtration rate (GFR) occurred in either group. In the AN dogs, pacing was continued for 7-21 days until the onset of decompensated heart failure. Urinary sodium excretion increased on the first day of ACEI infusion during this stage but returned to pre-ACEI levels during the next 2-3 days. No significant improvement in cardiac output was measured during ACEI in decompensated heart failure. These data suggest that chronic ACEI administration can improve renal and cardiac function in early heart failure without impairing GFR but is less chronic ACEI administration can improve renal and cardiac function in early heart failure without impairing GFR but is less effective in later, decompensated stages.
Abstract: Hypokalemic metabolic alkalosis is one of the most common complications of chronic furosemide administration. In this study we examined acid-base composition and ATPase enzyme activities in medullary thick ascending limb of Henle’s loop (MTAL) and collecting tubule (CCT and MCT) after seven days of chronic furosemide therapy. All of the studies were conducted in adrenal intact (AI) rats or in adrenalectomized (ADX) glucocorticoid replete rats replaced with a physiological dose of aldosterone (Aldo). Furosemide (F) was administered to each rat by mini-osmotic pump. In the AI+F group, plasma Aldo was high and obvious metabolic alkalosis occurred (HCO3- = 37 +/- 2 mEq/liter vs. 22 +/- 2 mEq/liter in controls, P \textbackslashtextless 0.005); activities of H-K-ATPase, H-ATPase, and Na-K-ATPase were increased approximately twofold in both CCT and MCT. In the ADX+F group (HCO3- = 28 +/- 2 mEq/liter, P \textbackslashtextless 0.05 from control), H-ATPase activity was normal in CCT and it was slightly increased in MCT. CCT and MCT H-K-ATPase activities were markedly increased (approximately twofold). Na-K-ATPase activity was the same as control in CCT but it was increased in MCT. In ADX+F+Vanadate (V) group which also had normal Aldo levels, acid-base changes were modest (20 +/- 2 mEq/liter, NS from control); in CCT and MCT H-K-ATPase and Na-K-ATPase activities were markedly reduced, but H-ATPase activity in MCT was increased. In all three experimental groups Na-K-ATPase activity in MTAL was reduced fivefold. Hypokalemia developed in both intact and ADX animals receiving furosemide.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: OBJECTIVE: To study and compare the autonomic cardiovascular state of children after severe brain injury and brain death. DESIGN: Prospective clinical study. SETTING: Pediatric ICU. PATIENTS: Pediatric patients suffering severe brain injury caused by trauma, anoxia, or hemorrhage. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: We analyzed cardiorespiratory parameters, heart rate power spectra, plasma catecholamine concentrations, and the response to the cold pressor test in nine brain-dead patients and compared the results with the test findings of 11 patients with severe brain injury. Low-frequency total heart rate power (p \textbackslashtextless .03), peak amplitude (p \textbackslashtextless .02), and plasma catecholamine concentrations (p \textbackslashtextless .001) were different with no overlap of values between groups. Cold pressor testing in patients with severe brain injury showed changes in respiratory rate and low-frequency heart rate power that were +/- 20% to 100% from baseline values; however, there were no measurable changes in brain-dead patients. CONCLUSIONS: Our results support the concept of a damaged sympathetic cardiovascular system in severe brain injury and complete interruption of the autonomic cardiovascular pathways in brain death. Since determination of brain death may be difficult, our findings have implications for corroborating brain death using autonomic cardiovascular testing.
Abstract: The pathogenesis of renal sodium and water retention in cardiac failure, cirrhosis, and the nephrotic syndrome may be explained by the unifying hypothesis of body fluid volume regulation. According to this hypothesis, underfilling of the arterial vascular compartment initiates a sequence of events, including activation of various neurohormonal vasoconstrictor systems, which results in enhanced renal sodium and water reabsorption, the failure to escape from the sodium-retaining effect of aldosterone, and renal resistance to atrial natriuretic peptide. In patients with low-output cardiac failure, a decrease in cardiac output results in arterial underfilling. Peripheral arterial vasodilation diminishes the fullness of the arterial vascular compartment in patients with high-output cardiac failure and cirrhosis. In the nephrotic syndrome, the decrease in plasma oncotic pressure due to hypoalbuminemia initiates arterial underfilling. The factors that are responsible for the peripheral arterial vasodilation in patients with cirrhosis remain obscure. Diuretics are initially effective in reducing the excess of total-body sodium and water in edematous patients. Loop diuretics, with or without metolazone or a thiazide diuretic, are quite useful in patients with heart failure. In cirrhosis and the nephrotic syndrome, the specific aldosterone antagonist spironolactone, alone or in combination with other diuretics, has proven to be highly efficacious. However, in all instances, the emergence of diuretic resistance represents a major limitation of diuretic therapy for the edematous patient. This diuretic resistance may be mediated by further activation of vasoconstrictor, antinatriuretic neurohormones.
Abstract: Sympathetic mechanisms play an important role in the acute regulation of renin release in humans. On the other hand, the effect of chronic sympathetic deprivation on the renin-aldosterone system has not been fully evaluated. We, therefore, studied 24 patients with severe autonomic failure due to pure autonomic failure (n = 14) or to multiple system atrophy (n = 10). Supine plasma renin activity (PRA) was low (0.09 +/- 0.01 ng/(L*s)) and remained virtually unchanged in the upright posture (0.10 +/- 0.01 ng/(L*s)) despite profound orthostatic hypotension to levels that should activate renal baroreceptors. Isoproterenol, at doses that produced significant tachycardia and hypotension, also failed to stimulate PRA. Furthermore, renin-producing cells were absent in the kidneys of two autopsy cases. Norepinephrine depletion alone could not explain these findings because no correlation was found between plasma norepinephrine and PRA, and because PRA was normal in patients with intact sympathetic innervation but congenital absence of norepinephrine. In contrast, supine and upright plasma aldosterone were normal in autonomic failure patients (220 +/- 20 and 440 +/- 70 pmol/L). We speculate that direct sympathetic innervation is essential for the maintenance of renin, perhaps by providing trophic stimuli.
Abstract: The prevention or correction of hypoglycemia in humans is the result of both dissipation of insulin and activation of glucose counterregulatory (glucose-raising) systems. Whereas insulin is the dominant glucose-lowering factor, there are redundant glucose counterregulatory factors. Furthermore, there is a hierarchy among the glucoregulatory factors. The first defense against a decrement in plasma glucose is decreased insulin secretion; this occurs with glucose decrements within the physiological range at a glycemic threshold of 4.6 +/- 0.2 mmol/l. However, biological glucose recovery from hypoglycemia can occur despite mild (approximately 2-fold) peripheral hyperinsulinemia and can occur in the absence of portal hypoinsulinemia. Thus additional (glucose counterregulatory) factors must be involved. Critical glucose counterregulatory systems are activated at glycemic thresholds of approximately 3.8 mmol/l (the level at which brain glucose uptake is first measurably reduced), well above the thresholds for symptoms of hypoglycemia (approximately 3.0 mmol/l) and those for cognitive dysfunction resulting from neuroglycopenia (approximately 2.7 mmol/l). Among the glucose counterregulatory factors, glucagon plays a primary role. Indeed, it may be that hypoglycemia does not occur if the secretion and actions of both glucagon and insulin, among the glucoregulatory hormones, are normal. Epinephrine is not normally critical, but it becomes critical to glucose counterregulation when glucagon is deficient. Because hypoglycemia develops or progresses when both glucagon and epinephrine are deficient and insulin is present, these three hormones stand high in the hierarchy of redundant glucoregulatory factors.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: BACKGROUND. Prompt initiation of bystander cardiopulmonary resuscitation (CPR) improves survival. Basic life support with mouth-to-mouth ventilation and chest compressions is intimidating, difficult to remember, and difficult to perform. Chest compressions alone can be easily taught, easily remembered, easily performed, adequately taught by dispatcher-delivered telephone instruction, and more readily accepted by the public. The principal objective of this study was to evaluate the need for ventilation during CPR in a clinically relevant swine model of prehospital witnessed cardiac arrest. METHODS AND RESULTS. Thirty seconds after ventricular fibrillation, swine were randomly assigned to 12 minutes of chest compressions plus mechanical ventilation (group A), chest compressions only (group B), or no CPR (group C). Standard advanced cardiac life support was then provided. Animals successfully resuscitated were supported for 2 hours in an intensive care setting, and then observed for 24 hours. All 16 swine in groups A and B were successfully resuscitated and neurologically normal at 24 hours, whereas only 2 of 8 group C animals survived for 24 hours (P \textbackslashtextless .001, Fisher’s exact test). One of the 2 group C survivors was comatose and unresponsive. CONCLUSIONS. In this swine model of witnessed prehospital cardiac arrest, the survival and neurological outcome data establish that prompt initiation of chest compressions alone appears to be as effective as chest compressions plus ventilation and that both techniques of bystander CPR markedly improve outcome compared with no bystander CPR.
Abstract: The brain is particularly vulnerable to disturbances of body fluid osmolality. Studies in animals indicate that brain adaptation to osmotic stresses is a very complex process involving transient changes in water content and sustained changes in electrolyte and organic osmolyte contents. Appreciation of the nature of the adaptation process enables a better understanding of the marked variations in neurological sequelae that characterize hyper- and hypoosmolar states and provides a basis for more rational therapy.
Abstract: We investigated whether a glycolytic burst contributes to the initial adaptation of ATP synthesis to increased cardiac metabolic demand. Six isolated rabbit hearts were perfused with glucose-containing Tyrode solution at 28 degrees C. In venous and arterial samples the lactate concentration was determined with a sensitive enzymatic cycling method. After the heart rate was doubled from 60 to 120 beats/min, lactate efflux increased from 0.23 +/- 0.10 (SE) to 0.45 +/- 0.12 mumol.min-1.g-1 dry weight with a mean response time of 21.3 s but without an overshoot. The transport time for lactate is longer than 15.7 s, suggesting that lactate production adapts with a mean response time of less than 6 s. Because no overshoot in lactate efflux was found, it is unlikely that a glycolytic burst after a step in heart rate contributes to the fast adaptation of ATP synthesis to demand in the isolated rabbit heart, although it might be possible that a change in cytosolic lactate production is not reflected in an increase in lactate efflux. Extrapolation of the results of this study to the in vivo situation should be done with caution.
Abstract: BACKGROUND. Epidemiologic studies have implicated the ingestion of cow’s milk in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). Moreover, in a recent study, 100 percent of patients with new-onset IDDM had antibodies against bovine serum albumin (BSA), with a majority directed against a 17-amino-acid BSA peptide (ABBOS). Cellular immune mechanisms are thought to be the principal mediators of pancreatic beta-cell destruction in IDDM. METHODS. We measured the responses of peripheral-blood mononuclear cells to BSA and ABBOS or serum IgG anti-BSA antibodies (by particle-concentration fluorescence immunoassay) in 71 patients with IDDM, 55 subjects at various degrees of risk for IDDM, 36 patients with other autoimmune disorders (chronic autoimmune thyroiditis, rheumatoid arthritis, and systemic lupus erythematosus), and 48 normal subjects. RESULTS. The responses of peripheral-blood mononuclear cells to BSA or ABBOS were positive in 2 of 24 patients with new-onset IDDM, 1 of 25 first-degree relatives of patients with IDDM who were negative for islet-cell antibodies, 2 of 30 first-degree relatives of patients with IDDM who were positive for islet-cell antibodies, 1 of 28 patients with established IDDM, and 1 of 29 normal subjects. Similarly, anti-BSA antibodies were not detected significantly more often in patients with new-onset IDDM (3 of 31, 10 percent) than in normal subjects (1 of 37, 3 percent; P = 0.32). However, many patients with autoimmune disease and subjects at increased risk for IDDM had anti-BSA antibodies (frequency, 10 to 31 percent). CONCLUSIONS. Anti-BSA antibodies may reflect a general defect in the process of immunologic tolerance associated with a predisposition to autoimmunity rather than immunity specific to beta cells. The absence of cellular immunity to BSA and ABBOS in IDDM does not support a role for this antigen in the pathogenesis of the disorder.
Abstract: Biochemical mechanisms underlying impaired myocardial glucose utilization in diabetes mellitus have not been elucidated. We studied sarcolemmal vesicles (SL) in control, streptozotocin-induced diabetic (D), and insulin-treated diabetic (Tx) rats and found that 3-O-methylglucose transport rates were decreased 53% in D rats and were normalized by insulin therapy. Immunoblot analyses of SL revealed that GLUT4 glucose transporters were decreased 56% in D and were normal in Tx rats. Thus diminished transport rates could be fully explained by reduced numbers of SL GLUT4 with normal functional activity. To determine whether SL GLUT4 were decreased due to tissue depletion or abnormal subcellular distribution, we measured GLUT4 in total membranes (SL plus intracellular fractions). Total GLUT4 (per mg membrane protein or per DNA) was decreased 45-51% in D [half time = 3.5 days after streptozotocin], and these values were restored to normal in Tx rats. Also, diabetes decreased GLUT4 mRNA levels by 43%, and this effect was reversed by insulin therapy. We conclude that, in diabetes, 1) impaired myocardial glucose utilization is the result of a decrease in glucose transport activity, and 2) transport rates are reduced due to pretranslational suppression of GLUT4 gene expression and can be corrected by insulin therapy. GLUT4 depletion could limit glucose availability under conditions of increased workload and anoxia and could cause myocardial dysfunction.
Abstract: Though spinal reflexes have been described in experimental brain-death animals, no documentation has been previously provided for human. The hemodynamic responses to surgical stimuli have been investigated here in eight brain-death organ donors. Baseline systolic blood pressure, diastolic blood pressure, and heart rate in observed patients were 99 +/- 15 mmHg, 61 +/- 13 mmHg, and 105 +/- 22 beats/min respectively. After skin incision, these parameters elevated maximally to 130 +/- 23 mmHg, 74 +/- 17 mmHg, and 119 +/- 18 beats/min (p \textbackslashtextless 0.05). Either spinal reflex arcs or adrenal medullary stimulation, or both, have been speculated to possibly play the role in these hemodynamic responses. However, the existence of such responses should not invalidate the diagnosis of brain death.
Abstract: While the study of the physiochemical composition and structure of the interstitium on a molecular level is a large and important field in itself, the present review centered mainly on the functional consequences for the control of extracellular fluid volume. As pointed out in section I, a biological monitoring system for the total extracellular volume seems very unlikely because a major part of that volume is made up of multiple, separate, and functionally heterogeneous interstitial compartments. Even less likely is a selective volume control of each of these compartments by the nervous system. Instead, as shown by many studies cited in this review, a local autoregulation of interstitial volume is provided by automatic adjustment of the transcapillary Starling forces and lymph flow. Local vascular control of capillary pressure and surface area, of special importance in orthostasis, has been discussed in several recent reviews and was mentioned only briefly in this article. The gel-like consistency of the interstitium is attributed to glycosaminoglycans, in soft connective tissues mainly hyaluronan. However, the concept of a gel phase and a free fluid phase now seems to be replaced by the quantitatively more well-defined distribution spaces for glycosaminoglycans and plasma protein, apparently in osmotic equilibrium with each other. The protein-excluded space, determined mainly by the content of glycosaminoglycans and collagen, has been measured in vivo in many tissues, and the effect of exclusion on the oncotic buffering has been clarified. The effect of protein charge on its excluded volume and on interstitial hydraulic conductivity has been studied only in lungs and is only partly clarified. Of unknown functional importance is also the recent finding of a free interstitial hyaluronan pool with relatively rapid removal by lymph. The postulated preferential channels from capillaries to lymphatics have received little direct support. Thus the variation of plasma-to-lymph passage times for proteins may probably be ascribed to heterogeneity with respect to path length, linear velocity, and distribution volumes. Techniques for measuring interstitial fluid pressure have been refined and reevaluated, approaching some concensus on slightly negative control pressures in soft connective tissues (0 to -4 mmHg), zero, or slightly positive pressure in other tissues. Interstitial pressure-volume curves have been recorded in several tissues, and progress has been made in clarifying the dependency of interstitial compliance on glycosaminoglycan-osmotic pressure, collagen, and microfibrils.(ABSTRACT TRUNCATED AT 400 WORDS)
Abstract: Cardiac arrest from electrical shock or lightning strike is associated with significant mortality and requires modification and extension of standard advanced life support measures to achieve successful resuscitation. Patients who experience electrical shock or lightning strike may sustain cardiac and respiratory arrest secondary to the direct effects of current. However, the majority of victims have associated multisystem involvement, including neurologic complications, cutaneous burns, and associated blunt trauma. As a result, a combination of advanced cardiac life support measures and advanced trauma life support techniques is indicated. Victims with cardiac arrest from electrical shock or lightning strike require prompt, aggressive resuscitation using standard methods for airway control, ventilation, and chest compressions, as well as usual measures for defibrillation and cardiac pharmacotherapy. Unique considerations include vigorous fluid resuscitation and spinal immobilization for victims of electrical shock and reversal of normal multiple casualty triage priorities when managing several lightning strike victims. Because the majority of victims are relatively young and seldom have significant underlying cardiac disease, the chance for successful resuscitation may be greater for patients who experience sudden death from electrical shock or lightning strike than for those with other causes of cardiac arrest, even among patients with initial rhythms traditionally unresponsive to therapy. Although numerous specialized aspects are required for the successful management of victims of electrical shock and lightning strike, the following article focuses on the unique considerations necessary for immediate care of cardiac arrest victims, with emphasis on the underlying mechanisms of sudden death and currently recommended guidelines for resuscitation.
Abstract: Intravenous fluid infusions cause increased venous pressure and increased lymph flow throughout the body. Together the increased lymph flow and increased venous pressure (the outflow pressure to the lymphatic system) should increase the pressure within the postnodal intestinal lymphatics. To test this, we measured the pressure in postnodal intestinal lymphatics and the neck vein pressure in five awake sheep. At baseline, the neck vein pressure was 1.2 +/- 1.5 (SD) cmH2O and the lymphatic pressure was 12.5 +/- 1.7 cmH2O. When we infused Ringer solution intravenously (10% body weight in approximately 50 min), the neck vein pressure increased to 17.3 +/- 0.9 cmH2O and the lymphatic pressure increased to 24.6 +/- 3.8 cmH2O (both P \textbackslashtextless 0.05). In two additional sheep, the thoracic duct lymph flow rate increased from 0.8 +/- 0.4 ml/min at baseline to 5.5 +/- 2.0 ml/min during the infusions. Our results show that postnodal intestinal lymphatic pressure may increase substantially during intravenous fluid infusions. This is important because increases in postnodal lymphatic pressure may slow lymph flow from the intestine.
Abstract: In cross-sectional comparisons, several investigators have reported highly trained endurance athletes to have a prevalence toward orthostatic hypotension and intolerance compared with average fit individuals. These observations have raised concern that regular exercise designed to increase aerobic capacity may impair regulatory mechanisms of blood pressure control and that perhaps certain populations of individuals with a predisposition for fainting exhibit an inability to elevate heart rate, vasoactive hormones, and peripheral resistance during an orthostatic challenge. In longitudinal experiments, when exercise training was performed by subjects who increased their aerobic capacity by 20% but maintained VO2max below 50 ml.kg-1.min-1, tolerance to lower body negative pressure (LBNP) was increased by 28%. Exercise training did not compromise baroreflex functions despite evidence of increased resting vagal cardiac tone and reduced sympathetic tone. In contrast to fainters, increased orthostatic tolerance in the exercised-trained subjects was associated with no alteration in their ability to elevate heart rate, vasoactive hormones, and peripheral resistance at peak LBNP. However, cardiac output and mean arterial blood pressure were maintained during higher submaximal LBNP levels by a 20% increase in stroke volume. The elevation in stroke volume during LBNP after training was associated with blood volume expansion.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Emergency physicians need to be alert to the potential effects of electric shock in pregnancy. A review of all case reports in the English language literature of pregnant women exposed to electric shock was performed. Information on voltage, gestation, injury-to-delivery interval, and outcome was collected. There were 15 victims of electric shock in pregnancy. Fetal mortality (N = 11) was 73% and there was only one normal pregnancy following electric shock. The fetus is much less resistant to electric shock than the mother. Any woman who suffers from an electric shock in pregnancy, however minor, requires prompt fetal monitoring and careful obstetric supervision.
Abstract: It has been suggested that muscle contraction causes prejunctional inhibition of transmitter release from sympathetic nerves. In accordance with this, we found that second-order (50 microns ID) arterioles of the cat sartorius muscle dilate 40-80% more with muscle contraction during 2-, 4-, or 8-Hz sympathetic nerve stimulation than during equivalent constriction produced by intravenous norepinephrine injection. However, when constriction was to the selective alpha 1-agonist phenylephrine, the magnitude of dilation induced by muscle contraction was similar to that seen with sympathetic nerve stimulation, suggesting that prejunctional inhibition is not involved. Alternatively, different receptor subtypes may be activated by sympathetic nerve stimulation and exogenous norepinephrine. In support of this explanation, we found that approximately 50% of the vasoconstrictor effect of sympathetic nerve stimulation (8 Hz) was blocked by prazosin, an alpha 1-adrenergic antagonist, but no further diminution of tone was seen with addiction of yohimbine, an alpha 2-adrenergic antagonist. In contrast, the vasoconstrictor response to exogenous norepinephrine was not affected by prazosin, while addition of yohimbine almost completely blocked the response. These findings suggest that muscle contraction selectively attenuates vasoconstriction mediated by junctional receptors in second-order arterioles.
Abstract: Lactic acidosis decreases left ventricular contractility, but whether bicarbonate increases left ventricular contractility during lactic acidosis in vivo is controversial. Therefore, we measured hemodynamics and left ventricular mechanics before and after bicarbonate administration during L-lactic acid infusion in 15 anesthetized pigs. The pigs were beta-blocked and atrially paced to minimize indirect effects of acidosis on contractility. We measured mean arterial pressure, left ventricular end-diastolic pressure, thermodilution cardiac output, left ventricular pressure (Miller catheter), and left ventricular volume (three orthogonal pairs of ultrasonic crystals). Left ventricular contractility was assessed primarily using the slope (Emax) of the end-systolic pressure-volume relationship. While PCO2 was kept constant, 0.2 M L-lactic acid was infused, which reduced arterial pH to 7.05 +/- 0.06. Animals were then randomized to receive either 1 M NaHCO3 (n = 8), which increased pH to 7.45 +/- 0.11, or an equivalent amount of 1 M NaCl (n = 7). Bicarbonate decreased mean arterial pressure (105 +/- 20 to 95 +/- 39 mm Hg, p \textbackslashtextless 0.05) but did not increase cardiac output. These effects were not significantly different from the effects of saline. Bicarbonate did not significantly increase Emax (4.2 +/- 0.8 to 4.9 +/- 0.8 mm Hg/ml) and was indistinguishable from saline (5.0 +/- 0.7 to 5.2 +/- 0.7 mm Hg/ml). We conclude that bicarbonate infusion does not directly increase left ventricular contractility during lactic acidemia in pigs within this pH range.
Abstract: OBJECTIVES: Epinephrine administered during cardiopulmonary resuscitation (CPR) is known to increase aortic diastolic and myocardial perfusion pressures, while enhancing myocardial blood flow. Optimal dosing of epinephrine during CPR is less certain. Interest in high-dose epinephrine use under such circumstances is increasing. The effect of different doses of epinephrine on simultaneously measured perfusion pressures, myocardial blood flow, cardiac output, and end-tidal CO2 (PCO2) (used as an indirect measure of cardiac output during CPR) is unknown. DESIGN: Prospective, sequential evaluation of no epinephrine, standard dose epinephrine, and high-dose epinephrine. SETTING: An experimental resuscitation laboratory. SUBJECTS: Twelve domestic swine. INTERVENTIONS: Myocardial perfusion pressure, myocardial blood flow, cardiac output, and end-tidal PCO2 were studied after various doses of epinephrine were administered during prolonged CPR. After 3 mins of untreated ventricular fibrillation, each animal received 5 mins of CPR without epinephrine, 5 mins of CPR after standard dose epinephrine (0.02 mg/kg), and 5 mins of CPR after high-dose epinephrine (0.2 mg/kg). Cardiac output and regional myocardial blood flow values were measured with nonradioactive, colored microspheres. MEASUREMENTS AND MAIN RESULTS: Myocardial perfusion pressure (aortic diastolic minus right atrial diastolic) was significantly (p \textbackslashtextless .05) increased over baseline with high-dose epinephrine (35 +/- 8 vs. 14 +/- 4 mm Hg), but not with standard dose epinephrine (20 +/- 5 vs. 14 +/- 4 mm Hg). Epinephrine’s effect on myocardial blood flow was similar, increasing after the high dose (71 +/- 21 vs. 20 +/- 5 mL/min/100 g; p \textbackslashtextgreater .05), but not with the standard dose (23 +/- 6 vs. 20 +/- 5 mL/min/100 g). Cardiac output decreased significantly (p \textbackslashtextless .05) after high-dose epinephrine (7 +/- 1 vs. 13 +/- 1 mL/min/kg). Mean end-tidal PCO2 levels were lower after high-dose epinephrine (15 +/- 2 vs. 20 +/- 2 mm Hg; p \textbackslashtextless .05) but not after standard dose epinephrine (19 +/- 2 vs. 20 +/- 2 mm Hg). CONCLUSIONS: Standard dose epinephrine had minimal effect on myocardial perfusion pressure, myocardial blood flow, cardiac output, or end-tidal PCO2. High-dose epinephrine enhanced myocardial perfusion pressure and myocardial blood flow despite significantly decreasing cardiac output.
Abstract: Electric shock causes injury and death through a variety of mechanisms. The proper treatment of a patient with electric shock depends upon the nature of the injuries sustained. The primary electric injuries to be expected depend in large part on the type of electric energy source, the amount and duration of current flow, and the parts of the body affected. Secondary injury can be caused by trauma associated with the electric accident such as falls and explosions.
Abstract: To define the precise neuroendocrine characteristics of the luteal-follicular transition, 11 normal women underwent 12 frequent sampling studies at 10-min intervals for 48 h at various points during the transition from one cycle to the next. Daily blood samples captured both the preceding and subsequent LH surges, so that studies could be characterized in relation to the preceding LH peak (LH+), the subsequent LH peak (LH-), and menses (M). In the frequent sampling study, LH and FSH were measured in all samples, and estradiol (E2) and progesterone (P) were measured in 2-h pools. The frequency of pulsatile LH secretion increased 4.5-fold over an 8-day period spanning the luteal-follicular transition. This increase in LH pulse frequency was strongly related to the preceding LH peak (r = 0.82; P less than 0.00001), but was not at all related to the onset of menses. When the temporal markers (i.e. LH+, LH-, and M) were removed from the analysis, LH pulse frequency was inversely related to the log of serum P (r = 0.50; P less than 0.005), but not E2. FSH levels increased both within the individual studies (P less than 0.005) and in the group as a whole over the duration of the luteal-follicular transition. Mean FSH rose 3.5-fold compared to less than a 2-fold increase in mean LH. As with LH pulse frequency, the increase in FSH was most strongly related to the preceding LH peak, but was also significantly associated with the subsequent LH peak and the onset of menses. The relationship between FSH and the number of days from the preceding LH peak is even better fit by a second degree polynomial, which revealed an abrupt increase in LH beginning at LH+11. With the temporal markers excluded, the increase in FSH related only to LH pulse frequency (r = 0.62; P less than 0.001). FSH was not statistically related to the decreases in P or E2, which are also key variables at this stage of the menstrual cycle. We reached the following conclusions. 1) A dramatic increase in LH pulse frequency, and by inference GnRH pulse frequency, accompanies the selective rise in FSH levels during the luteal-follicular transition of the normal menstrual cycle. 2) Both the increase in GnRH pulse frequency and the rise in FSH levels during this transition are strongly related to the preceding LH peak, while the clinical marker of menses is a relatively poor indicator of these events.(ABSTRACT TRUNCATED AT 400 WORDS)
Abstract: OBJECTIVE: To evaluate the pharmacokinetics and pharmacodynamics of dobutamine in critically ill children. DESIGN: A prospective study of pediatric patients receiving continuous infusions of dobutamine in a stepwise format from 2.5 to 10.0 micrograms/kg/min. SETTING: A pediatric critical care unit. PATIENTS: Twelve children ranging in age from 1 month to 17 yrs with primary medical conditions. MEASUREMENTS: Plasma dobutamine concentrations and hemodynamic responses were measured at each infusion rate at steady state. Dose response data were analyzed to determine the threshold or minimum plasma dobutamine concentration necessary for discernible hemodynamic effects. MAIN RESULTS: Dobutamine plasma clearance rates ranged from 40 to 130 mL/kg/min. Each patient presented a linear increase in the plasma dobutamine concentration at each infusion rate (r2 = .97, p less than .001). Plasma clearance rate vs. actual dobutamine concentration did not vary. Cardiac output, BP, and heart rate increased 30%, 17%, and 7%, respectively, at maximal dose. The dobutamine concentration thresholds for changes in cardiac output, BP, and heart rate were 13 +/- 6, 23 +/- 14, and 65 +/- 30 ng/mL, respectively. CONCLUSIONS: There was no effect of plasma dobutamine concentration or infusion rate on plasma clearance rate. For this group of patients, over the range of the intravenous doses studied, dobutamine pharmacokinetics followed a first-order kinetic model. Threshold values for dobutamine usually show increases in cardiac output before changes in heart rate. These data demonstrate that dobutamine is an effective inotropic agent in critically ill pediatric patients and has minimal chronotropic action.
Abstract: Skeletal muscle is a dynamic organ that adapts to alterations in weight bearing. This brief review examines changes in muscle gene expression resulting from the removal of weight bearing by hindlimb suspension and from increased weight bearing due to eccentric exercise. Acute (less than or equal to 2 days) non-weight bearing of adult rat soleus muscle alters only the translational control of muscle gene expression, while chronic (greater than or equal to 7 days) removal of weight bearing appears to influence pretranslational, translational, and posttranslational mechanisms of control. Acute and chronic eccentric exercise are associated with alterations of translational and posttranslational control, while chronic eccentric training also alters the pretranslational control of muscle gene expression. Thus alterations in weight bearing influence multiple sites of gene regulation.
Abstract: Ischemic injury to the renal allograft, prior to implantation, is an important cause of delayed graft function. With improved understanding of the pathophysiological mechanisms involved, strategies have been devised to minimize ischemic injury during preservation ex vivo. It is clear that reducing the warm ischemic time, flushing the kidney with hypothermic solution containing cell-impermeant compounds, and maintaining the organ at low temperature ex vivo have increased the duration that the kidney can be preserved. The effectiveness of a number of other components of preservation solutions, as well as the relative merits of continuous perfusion of the organ ex vivo, is more controversial. In this chapter, we review the mechanistic features of ischemic acute renal failure and discuss various preservation strategies and their success in the context of these basic principles of ischemic pathophysiology.
Abstract: To determine the role of growth hormone in overnight insulin requirements and lipolysis, five patients with chronic growth hormone deficiency and Type 1 (insulin-dependent) diabetes mellitus and six control patients with diabetes were each studied on two separate nights. Insulin was infused at a variable rate throughout one night to maintain euglycaemia and fixed at 04.00 hours on another. During the variable infusion, euglycaemia was maintained in control patients by a 36% increase in insulin infusion rate between 03.00 and 08.00 hours while a 46% decrease in the rate was required in growth hormone deficient patients (p less than 0.02). Despite this difference, mean free insulin values were equivalent. This finding is suggestive of increased insulin clearance in growth hormone sufficient patients. Glucose levels rose in control and fell in growth hormone deficient patients when insulin infusion rates were fixed at 04.00 hours. Glycerol production and non-esterified fatty acid concentrations were significantly lower in the growth hormone deficient diabetic patients, p less than 0.001, and when normalized with a heparin infusion, had no effect on insulin requirements. We conclude that: (1) growth hormone contributes to the development of the "dawn phenomenon," possibly by increasing insulin clearance (2) growth hormone helps sustain nocturnal lipolysis in Type 1 diabetes and (3) non-esterified fatty acids are not involved in the dawn phenomenon.
Abstract: We investigated the effects of clinically administered volatile anesthetics and of adenosine on the microvasculature of the in situ beating canine heart. Thirteen dogs were studied during general anesthesia with an opioid (piritramide), which was infused throughout the experiments. Measurements were obtained in each animal at control (piritramide only) and during hypotension (mean arterial pressure 60 mmHg) induced by halothane, enflurane, isoflurane, and adenosine. Using epiillumination and fluorescence microscopy, 354 arterial microvessels with diameters from 20 to 450 microns were examined through all experimental periods. Hypotension by halothane, enflurane, isoflurane, and adenosine reduced coronary vascular resistance by 13%, 23%, 40%, and 85%, respectively. Coronary venous PO2 was unchanged from control with halothane (+/- 0%) and enflurane (+7%) and significantly increased with isoflurane (+16%) and adenosine (+65%). Left ventricular blood flow decreased significantly during halothane (-35%) and enflurane (-23%); was unchanged from control during isoflurane (-9%); but significantly increased during adenosine (+397%). Coronary arterial and arteriolar diameters increased with all hypotensive agents. Vasodilation was least with halothane, intermediate with enflurane and isoflurane, and most pronounced with adenosine. Diameters increased considerably more in vessels with initial diameters below 100 microns as opposed to larger vessels. Calculation of microvascular segmental resistances revealed that the maximum conductance changes during volatile anesthetics were located in the vessel segments visualized by microscopy, i.e., in vessels larger than 20 microns. However, this was not the case with adenosine. We conclude that volatile anesthetics induce coronary vasodilation by preferentially acting on vessels with diameters from 20 microns to approximately 200 microns, whereas adenosine, in addition, has a pronounced impact on the small precapillary arterioles.
Abstract: BACKGROUND. At end diastole, the position and shape of the ventricular septum depend on the transseptal pressure gradient. It is not clear, however, how the septal radius of curvature changes in response to the gradual change in transseptal pressure gradient during progressive pulmonary arterial constriction (PAC) and aortic constriction (AC). METHODS AND RESULTS. In 11 anesthetized open-chest dogs, the septal radius of curvature was measured from the short-axis two-dimensional echocardiogram, and the transseptal pressure gradient (left ventricular [LV] pressure minus right ventricular [RV] pressure) was calculated from ventricular pressures measured with micromanometers. Seven dogs were studied with both PAC and AC (group 1) and four dogs only with PAC, which was initiated before and after volume loading (group 2). The transseptal pressure gradient decreased during PAC. As the transseptal pressure gradient decreased, the septum shifted continuously leftward with decreases in the LV septum-free wall diameter and in LV cross-sectional area. The septal radius of curvature (Rs) increased until the septum became flat. The flat septum (i.e., Rs = infinity) occurred at a relatively constant value of transseptal pressure gradient (-4.6 +/- 1.4 mm Hg) independently of the absolute values of LV pressures when between 2 and 9 mm Hg, although necessarily a greater RV pressure was needed to make the septum flat when LV pressure was higher. After inversion, the septum again became curved, with a decrease in the absolute value of septal radius of curvature as the transseptal pressure gradient became increasingly negative. The septum was still concave to the LV cavity at zero transseptal pressure gradient, and its curvature decreased (i.e., its radius of curvature increased) with increases in ventricular pressures. During AC, the septal radius of curvature also increased, but with an increase in transseptal pressure gradient accompanied by increases in LV septum-free wall diameter and in LV area. In group 2 animals, at zero transseptal pressure gradient, the normalized septal radius of curvature was greater (p less than 0.005) at high LV pressure than at low LV pressure. The transseptal pressure gradient required to make the septum flat was not significantly different between low and high LV pressure, which confirmed the results of group 1. CONCLUSIONS. The results of the present study show that the shape and position of the ventricular septum are determined by the transseptal pressure gradient but that the shape of the septum is also affected by the ventricular pressures. The septum was not flat but rather still concave to the LV cavity at zero transseptal pressure gradient. Approximately 5 mm Hg of negative transseptal pressure gradient was required to displace the septum farther leftward and make it flat. The septal radius of curvature increased during both PAC (which decreased transseptal pressure gradient) and AC (which increased transseptal pressure gradient), indicating that the mechanisms involved in changing septal radius of curvature are different during PAC and AC.
Abstract: We determined that the variability in the oxygen cost and thus the caloric expenditure of cycling at a given work rate (i.e., cycling economy) observed among highly endurance-trained cyclists (N = 19; mean +/- SE; VO2max, 4.9 +/- 0.1 l.min-1; body weight, 71 +/- 1 kg) is related to differences in their % Type I muscle fibers. The percentage of Type I and II muscle fibers was determined from biopsies of the vastus lateralis muscle that were histochemically stained for ATPase activity. When cycling a Monark ergometer at 80 RPM at work rates eliciting 52 +/- 1, 61 +/- 1, and 71 +/- 1% VO2max, efficiency was determined from the caloric expenditure responses (VO2 and RER using open circuit spirometry) to steady-state exercise. Gross efficiency (GE) was calculated as the ratio of work accomplished.min-1 to caloric expenditure.min-1, whereas delta efficiency (DE) was calculated as the slope of this relationship between approximately 50 and 70% VO2max. The % Type I fibers ranged from 32 to 76%, and DE when cycling ranged from 18.3 to 25.6% in these subjects. The % Type I fibers was positively correlated with both DE (r = 0.85; P less than 0.001; N = 19) and GE (r = 0.75; P less than 0.001; N = 19) during cycling. Additionally, % Type I fibers was positively correlated with GE (r = 0.74; P less than 0.001; N = 13) measured during the novel task of two-legged knee extension; performed at a velocity of 177 +/- 6 degrees.s-1 and intensity of 50 and 70% of peak VO2 for that activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: 1. In published studies of the effects of acute blood loss in conscious rabbits, the rates of haemorrhage have ranged for 3-9% of blood volume/min. This is potentially a confounding factor when it comes to comparing the results of different studies. We have therefore tested whether the haemodynamic response to acute central hypovolaemia depends on the rate of fall of cardiac output. 2. Cardiac output in six conscious rabbits was reduced by 4, 8 and 12% of baseline levels per min by gradual inflation of a cuff around the thoracic inferior vena cava. These rates correspond approximately to blood loss at rates of 3, 6 and 9% of blood volume/min. 3. The haemodynamic responses were biphasic. In Phase I (compensatory) there was progressive systemic vasoconstriction and tachycardia, and only a small fall in blood pressure. In Phase II (decompensatory), systemic vasoconstriction failed abruptly, arterial pressure plummeted and heart rate declined. 4. We could detect no effect of rate of fall of cardiac output on the pattern of the haemodynamic responses in either Phase I or Phase II. 5. We conclude that the rate of blood loss in different studies of haemorrhage in conscious rabbits, within the range 3 to 9 per cent of blood volume per minute, need not be regarded as a confounding factor when it comes to interpreting the results. It is likely that this conclusion can be generalized to studies of haemorrhage in other mammalian species.
Abstract: A 22-year-old man eventually had a good neurologic recovery following prolonged coma after extracorporeal rewarming from profound hypothermia (24 degrees C) due to exposure. The patient was in full arrest for 60 minutes prior to institution of cardiopulmonary bypass (CPB). Total bypass time was 50 minutes. Cardiopulmonary bypass is the current rewarming method of choice for severe hypothermia associated with a persistent nonperfusing cardiac rhythm. CPB provides the most rapid core rewarming with the additional benefit of circulatory support during the period of cardiac instability.
Abstract: Glucose is the main fuel for energy metabolism in the normal human brain. It is generally assumed that glucose transport into the brain is not rate-limiting for metabolism. Since brain glucose concentrations cannot be determined directly by radiotracer techniques, we used 13C NMR spectroscopy after infusing enriched D-[1-13C]glucose to measure brain glucose concentrations at euglycemia and at hyperglycemia (range, 4.5-12.1 mM) in six healthy children (13-16 years old). Brain glucose concentrations averaged 1.0 +/- 0.1 mumol/ml at euglycemia (4.7 +/- 0.3 mM plasma) and 1.8-2.7 mumol/ml at hyperglycemia (7.3-12.1 mM plasma). Michaelis-Menten parameters of transport were calculated to be Kt = 6.2 +/- 1.7 mM and Tmax = 1.2 +/- 0.1 mumol/g.min from the relationship between plasma and brain glucose concentrations. The brain glucose concentrations and transport constants are consistent with transport not being rate-limiting for resting brain metabolism at plasma levels greater than 3 mM.
Abstract: To evaluate the therapeutic value of various antihypotensive agents we investigated amezinium (AMZ; CAS 30578-37-1), dihydroergotamine (DHE; CAS 511-12-6), midodrine (MDD; CAS 42794-76-3), and oxilofrine (OXF; CAS 365-26-4) in volunteers during passive orthostasis in a randomized double-blind study against placebo (PCB). Blood pressure, heart rate, and circulating catecholamines were determined before and after i.v. injections of the mentioned agents before and during 10 min of passive orthostasis. Echocardiographic and venous plethysmographic data were obtained during resting before and after the administration of the drugs. Resting heart rate decreased after injection of PCB, AMZ, DHE, and MDD. During tilting no significant changes in heart rate could be observed. Blood pressure remained unchanged at rest and during orthostasis after all agents injected. DHE and MDD lowered circulating noradrenaline. Echocardiographic parameters were changed after administration of AMZ (increase in stroke volume index (SVI) and ejection fraction (EF)), MDD (increase in enddiastolic volume index and SVI), and OXF (increase in SVI, EF, and cardiac index). The venous capacity of the lower left leg was only significantly decreased after injection of DHE, indicating an increased venous tone of the leg veins. The observed changes in sympathetic and cardiovascular parameters are in agreement with their sympathomimetic actions and allow a differential therapeutic classification: DHE and MDD are suitable agents for patients with sympathotonic orthostatic reaction; if asympathotonic orthostatic reaction occurs MDD, AMX and OXF should be recommended to those patients.
Abstract: It has been shown that with increased carboxyhemoglobin (COHb) and associated decrease in blood oxygen-carrying capacity, a compensatory increase in brain-blood flow (BBF) develops. The BBF response in humans has been shown to be quite variable. Two experiments were conducted in which humans were exposed to sufficient carbon monoxide (CO) to produce COHb levels up to 18.4%. BBF was measured by the method of impedance plethysmography. The first was a pilot study in which BBF in 14 men was studied after transient exposure to various concentrations of CO in air. BBF increased as a function of COHb but not to the same extent (or at all) in some subjects. In a confirmatory experiment with 12 men, BBF was measured once per h during a 4-h experiment. All 12 subjects received CO. The variation of the BBF response among subjects was large and statistically significant whereas the variation over time was not significant. Thus it appears that the magnitude of the BBF response is unique for a given subject and differs across subjects. These results may help predict CO-induced behavioral decrements in future studies if subjects whose BBF response to COHb is small or absent are also more susceptible to impairment by acute CO exposure.
Abstract: The purpose of this study was to determine the effect of blood flow on net lactate uptake (L) at constant elevated blood lactate concentration and metabolic rate in the in situ dog gastrocnemius-plantaris (GP) muscle. In all experiments, an infusion of lactate/lactic acid at a pH of 3.8 established a blood lactate concentration of 10-13 mM while maintaining normal blood gas/pH status as the GP was stimulated to contract with twitches at 1 Hz. In series 1 (n = 14), blood flow (ml.kg-1.min-1) was controlled by a pump at either 1) the spontaneous level for 1-Hz contractions (control flow = 332 +/- 23) or 2) a level estimated to be approximately 65% greater (high flow = 543 +/- 42). In series 2 (n = 7), perfusion pressure was varied during 1-Hz contractions. Four different perfusion pressures (80, 120, 155, and 180 Torr) were presented to each GP preparation, resulting in mean flow rates of 308 +/- 34, 419 +/- 30, 492 +/- 37, and 646 +/- 30 ml.kg-1.min-1. Increasing blood flow had no significant effect on net L in series 1. Similarly, there was no significant change in net L across the first three perfusion pressures/flow rates in series 2. However, net L (mmol.kg-1.min-1) was significantly increased in the highest perfusion pressure/flow rate period (from 0.335 +/- 0.029 at 80 Torr to 0.431 +/- 0.034 at 180 Torr). This study suggests that blood flow may have an independent effect on net L at the upper extreme of the normal blood flow range during contractions but very little effect over a fairly wide low-to-middle range of flow rates.
Abstract: To study the mechanism whereby positive end-expiratory pressure (PEEP) decreases venous return, we used a closed-chest canine venous bypass preparation to study the effects of 10 mm Hg PEEP on the systemic venous pressure-flow curves from the superior and inferior vena cava (SVC and IVC). These curves were characterized by three variables: the critical downstream pressure below which venous return was maximal (PCRIT), the conductance to venous return (GVR), and the effective upstream pressure driving venous return. PEEP reduced venous return by decreasing the maximal venous return even when the pressures at the outflow of the IVC and SVC were maintained below zero. PEEP increased PCRIT in the SVC and IVC (SVC: -0.31 +/- 0.53 to 3.21 +/- 0.84; IVC: -0.41 +/- 0.64 to 5.23 +/- 1.02 (SE) mm Hg; p less than 0.005). GVR in the SVC was reduced (52.5 +/- 26 to 37.8 +/- 5.3 (SE) ml/min/mm Hg; p less than 0.005), but changes in the IVC did not reach statistical significance. These changes were partially offset by increases in the upstream pressure driving venous return (SVC: 9.44 +/- 0.54 to 12.25 +/- 0.71; IVC: 9.42 +/- 0.69 to 12.51 +/- 1.02 (SE) mm Hg; p less than 0.01). Analysis of these findings suggests that PEEP may alter venous return through effects on the peripheral circulation, independent of its effects on the heart.
Abstract: Cardiac arrest causes a rapid loss of cerebral adenosine triphosphate [corrected] (ATP) and a decrease in cerebral intracellular pH (pHi). Depending on the efficacy of cardiopulmonary resuscitation (CPR), cerebral blood flow levels (CBF) ranging from near zero to near normal have been reported experimentally. Using 31P magnetic resonance spectroscopy, the authors tested whether experimental CPR with normal levels of cerebral blood flow can rapidly restore cerebral ATP and pHi despite the progressive systemic acidemia associated with CPR. After 6 min of ventricular fibrillation in six dogs anesthetized with fentanyl and pentobarbital, ATP was reduced to undetectable concentrations and pHi decreased from 7.11 +/- 0.02 to 6.28 +/- 0.09 (+/- SE) as measured by 31P magnetic resonance spectroscopy. Application of cyclic chest compression by an inflatable vest placed around the thorax and infusion of epinephrine (40 micrograms/kg bolus plus 8 micrograms/kg/min, intravenously) maintained cerebral perfusion pressure greater than 70 mmHg for 50 min with the dog remaining in the magnet. Prearrest cerebral blood flows were generated. Cerebral pHi recovered to 7.03 +/- 0.03 by 35 min of CPR, whereas arterial pH decreased from 7.41 +/- 0.4 to 7.08 +/- 0.04 and cerebral venous pH decreased from 7.29 +/- 0.03 to 7.01 +/- 0.04. Cerebral ATP levels recovered to 86 +/- 7% (+/- SE) of prearrest concentration by 6 min of CPR. There was no further recovery of ATP, which remained significantly less than control. Therefore, in contrast to hyperemic reperfusion with spontaneous circulation and full ATP recovery, experimental CPR may not be able to restore ATP completely after 6 min of global ischemia despite restoration of CBF and brain pHi to prearrest levels.
Abstract: 31P nuclear magnetic resonance spectroscopy (31P-NMRS) was performed on brain cross sections of four human subjects before and after 7 days in a hypobaric chamber at 447 Torr to test the hypothesis that brain intracellular acidosis develops during acclimatization to high altitude and accounts for the progressively increasing ventilation that develops (ventilatory acclimatization). Arterial blood gas measurements confirmed increased ventilation. At the end of 1 wk of hypobaria, brain intracellular pH was 7.023 +/- 0.046 (SD), unchanged from preexposure pH of 6.998 +/- 0.029. After return to sea level, however, it decreased to 6.918 +/- 0.032 at 15 min (P less than 0.01) and 6.920 +/- 0.046 at 12 h (P less than 0.01). The ventilatory response to hypoxia increased [from 0.35 +/- 0.11 (l/min)/(-%O2 saturation) before exposure to 0.69 +/- 0.19 after, P = 0.06]. Brain intracellular acidosis is probably not a supplemental stimulus to ventilatory acclimatization to high altitude. However, brain intracellular acidosis develops on return to normoxia from chronic hypoxia, suggesting that brain pH may follow changes in blood and cerebrospinal fluid pH as they are altered by changes in ventilation.
Abstract: To understand the potential early responses of human bone and the calcium endocrine system to spaceflight, we studied 8 healthy men, aged 35-44 years before, during, and after bed rest in a -6 degrees head-down tilt model for microgravity. Based on a novel single-dose labeling schedule, average rates of bone formation in the iliac crest were reduced in 6, unchanged in 1, and increased in 1 following the bed rest period. The decrease was greatest for subjects whose daily walking miles were highest (r = -0.762, p less than 0.05, n = 7). Before a measurable increase in ionized serum calcium the sixth bed rest day, there was increased excretion of urinary calcium and sodium, evident the first 2 bed-rest days and parallel for the entire week (r = 0.92, p less than 0.001). Reduced excretion of phosphorus and 3’, 5’ cyclic adenosine monophosphate on the first and second bed rest days was followed by an increase in serum phosphorus by the sixth bed rest day. Depressed serum concentrations of parathyroid hormone and 1,25-dihydroxyvitamin D were manifest by the sixth and seventh bed rest days. The similarity of the response of bone and the calcium endocrine system of healthy men after only 7 days to results of longer term bed rest studies emphasizes the responsiveness of the adult human skeleton to biomechanical stimuli induced by changes in activity and/or position.
Abstract: Systemic acidosis occurs during cardiac arrest and cardiopulmonary resuscitation (CPR). The present study investigated the effect of different modes of sodium bicarbonate administration on blood gas parameters during CPR. Arterial and venous blood gases were obtained during 10 minutes of CPR which was preceded by 3 minutes of unassisted ventricular fibrillation in 36 dogs. Following 1 minute of CPR, the animals received one of four treatments in a randomized and blinded manner: normal saline (NS), sodium bicarbonate bolus dose 1 mEq/kg (B), sodium bicarbonate continuous infusion 0.1 mEq/kg/min (I), and sodium bicarbonate bolus dose (0.5 mEq/kg) plus continuous infusion 0.1 mEq/kg/min (L+I). Eleven dogs completed NS, 8 B, 8 I, and 9 L+I protocol. Following NS infusion, both arterial and venous pH declined consistently over time. Significant differences compared with NS treatment in venous pH were observed at 12 minutes of ventricular fibrillation (L+I, 7.27 +/- 0.05; NS, 7.15 +/- 0.05; B, 7.20 +/- 0.05; I, 7.24 +/- 0.04, each bicarbonate treatment versus NS, and L+I versus B, (P \textbackslashtextless .05). The B group had an elevated venous PCO2 (mm Hg) concentration following 6 minutes of ventricular fibrillation compared with NS, L+I, and I groups (81 +/- 14 versus 69 +/- 10 versus 68 +/- 10 versus 71 +/- 8, respectively, (P = .07). Arterial pH and PCO2 values showed a similar trend as the venous data with the L+I group demonstrating arterial alkalosis (pH \textbackslashtextgreater 7.45) at 12 minutes of ventricular fibrillation.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Increased brain tissue stiffness following severe traumatic brain injury is an important factor in the development of raised intracranial pressure (ICP). However, the mechanisms involved in brain tissue stiffness are not well understood, particularly the effect of changes in systemic blood pressure. Thus, controversy exists as to the optimum management of blood pressure in severe head injury, and diverging treatment strategies have been proposed. In the present study, the effect of induced alterations in blood pressure on ICP and brain stiffness as indicated by the pressure-volume index (PVI) was studied during 58 tests of autoregulation of cerebral blood flow in 47 comatose head-injured patients. In patients with intact autoregulation mechanisms, lowering the blood pressure caused a steep increase in ICP (from 20 +/- 3 to 30 +/- 2 mm Hg, mean +/- standard error of the mean), while raising blood pressure did not change the ICP. When autoregulation was defective, ICP varied directly with blood pressure. Accordingly, with intact autoregulation, a weak positive correlation between PVI and cerebral perfusion pressure was found; however, with defective autoregulation, the PVI was inversely related to cerebral perfusion pressure. The various blood pressure manipulations did not significantly alter the cerebral metabolic rate of oxygen, irrespective of the status of autoregulation. It is concluded that the changes in ICP can be explained by changes in cerebral blood volume due to cerebral vasoconstriction or dilatation, while the changes in PVI can be largely attributed to alterations in transmural pressure, which may or may not be attenuated by cerebral arteriolar vasoconstriction, depending on the autoregulatory status. The data indicate that a decline in blood pressure should be avoided in head-injured patients, even when baseline blood pressure is high. On the other hand, induced hypertension did not consistently reduce ICP in patients with intact autoregulation and should only be attempted after thorough assessment of the cerebrovascular status and under careful monitoring of its effects.
Abstract: The case report presents evidence for the spinal origin of the marked hypertensive responses to noxious stimuli that may occur in organ donors who fulfill the commonly accepted criteria of brain death. Cardiovascular spinal reflex activity does not invalidate these criteria. For the first time, the catecholamine plasma concentrations have been determined during spinal pressor reflex activity. Circulating epinephrine increased more markedly than norepinephrine in both cases, rising to 4.7 and 44 times the baseline concentration respectively. The relation between plasma norepinephrine and epinephrine suggests involvement of the adrenal medulla in the reflex arc. The literature on spinal hemodynamic reflexes is reviewed.
Abstract: The glycogen content of astroglia-rich primary cultures derived from the brains of newborn rats depends on the concentration of glucose in the culture medium. After administration of culture medium lacking glucose, the glycogen content decreases with a half-time of 7 min. Readdition of glucose results in replenishment of the glycogen stores within 2-3 h, but fully only if glucose is present in a concentration of at least 4 mM. Insulin, or the more potent insulin-like growth factor I, increases the content of glycogen approximately 1.7-fold, with the half-maximal effects being attained at concentrations of 10 and 0.5 nM, respectively. These results suggest that (a) glucose or a metabolite of it and (b) insulin-like growth factor I or a closely related peptide, but not insulin, are likely to be physiological regulators of the level of glycogen in astrocytes.
Abstract: In quiescent rabbit papillary muscle at 20 degrees C, the formation of ATP in nitrogen, estimated from the production of lactate, is 21% of that in oxygen. Stimulating the anoxic muscles at 0.2 Hz causes a threefold increase in ATP formation. In this study we want to determine 1) whether glycolytic ATP formation can be increased to a rate that would meet the aerobic ATP demand at rest and 2) what the maximum glycolytic rate attainable through stimulation is. Glycolytic rate is estimated from the amount of lactate produced at various times over 40 min of anoxia. Nucleotides and creatine compounds are also determined. Lactate formation at the onset of anoxia is proportional to stimulus frequency. The amount of lactate formed is correlated to the breakdown of glycogen; glucose is not used. Therefore the amount of glycogen present in the muscle at the onset of anoxia is the main determinant of the amount of ATP formed when oxidative phosphorylation is inhibited. The rate of lactate formation at the onset of anoxia increases from 1.22 mumol.g dry wt-1.min-1 in resting muscles to 18.5 mumol.g dry wt-1.min-1 in 1-Hz-stimulated muscles. This implies that in anoxic myocardium, glycolysis can provide ATP at more than three times the rate found in the muscle at rest in ample oxygen.
Abstract: BACKGROUND AND METHODS: Previous studies have shown that Paco2 and end-tidal CO2 reflect coronary artery perfusion pressures during cardiac arrest. We investigated the relationship of coronary artery perfusion pressure to central arterial pH and Paco2 values during resuscitation from cardiac arrest in a canine model. Twenty-four mongrel dogs were block randomized to three different resuscitation groups after induction of ventricular fibrillation and cardiac arrest: a) standard cardiopulmonary resuscitation (CPR) and advanced life support (n = 8); b) cardiopulmonary bypass (n = 8); or c) open-chest CPR (n = 8). Central arterial blood gases and perfusion pressures were monitored during cardiac arrest and during resuscitation. RESULTS: Prearrest blood gases and hemodynamic values were similar between groups. Sixteen dogs from all three groups were successfully resuscitated. Survivors had significantly higher coronary artery perfusion pressure (p = .03), Paco2 (p = .015), and lower pH (p = .01) values than nonsurvivors. There was no correlation of pH and Paco2 during mechanical external CPR. However, after institution of the different resuscitation techniques, pH and Paco2 each showed a statistically significant correlation (r2 = .50 and .33, respectively) with coronary artery perfusion pressure. CONCLUSIONS: Central arterial pH and Paco2 monitoring during cardiac arrest may reflect the adequacy of tissue perfusion during resuscitation and may predict resuscitation outcome from ventricular fibrillation.
Abstract: Brief low-dose infusions of atrial natriuretic peptide (ANP) that emulate physiological plasma concentrations in humans have little if any effect on renal excretory function. This study explored the possibility that ANP-mediated reductions in cardiac filling pressures (through ANP’s rapid effect on capillary dynamics) could attenuate its purported renal effects. Protocol A consisted of 16 healthy subjects (ages 19-27 yr old) who underwent three consecutive 45-min experimental sequences: 1) placebo, 2) ANP (10 ng.kg-1 x min-1), and 3) ANP alone (n = 8) or ANP with simultaneous lower body positive pressure (LBPP, n = 8). Electrocardiogram and direct measures of arterial and central venous pressures were continuously monitored. Blood was sampled at the end of each 45-min sequence before subjects stood to void. Compared with control (placebo), ANP produced a hemoconcentration and increased plasma norepinephrine, but did not change heart rate, blood pressure, plasma levels of renin, aldosterone, or vasopressin, or renal excretion of volume or sodium. In subjects receiving LBPP to maintain central venous pressure during the last 45 min of ANP infusion, norepinephrine did not increase and urine volume and sodium excretion increased (P \textbackslashtextless 0.05). In a second study (protocol B), five healthy subjects received a placebo infusion for 45 min followed by two consecutive 45-min infusions of ANP (10 ng.kg-1 x min-1). Central venous pressure was maintained (LBPP) at placebo baseline throughout the two ANP infusion periods. Urine volume and sodium excretion rates increased progressively and significantly during both ANP infusion periods (P \textbackslashtextless 0.05) without significant changes in creatinine clearance, blood pressure, or heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Difficulties in studying myocardial metabolism with adequate time resolution have led to contradictory conclusions regarding the mechanisms causing contractile abnormalities during the early stages of ischemia. In acutely instrumented swine, we investigated whether abnormalities in subendocardial ATP, phosphocreatine, or lactate content develop rapidly enough during the first few heart beats after onset of partial myocardial ischemia to contribute to contractile failure. Within the first 15 beats of a 40-50% reduction in left anterior descending coronary artery blood flow, regional myocardial function was significantly reduced but continuing to deteriorate. Rapidly frozen transmural left ventricular biopsies obtained on the 15th heart beat (+/- 1.5 beats) after the onset of ischemia revealed significant decrements in subendocardial phosphocreatine and ATP levels to 77% (p less than 0.05) and 84% (p less than 0.005) of control values, respectively, but minimal change in lactate content. Metabolic effects as assessed by transmural averages took longer to become detectable; thus, there was a tendency to underestimate the importance of subendocardial metabolic effects on myocardial function. When left ventricular preload was assessed during this early time period, left ventricular end-diastolic wall thickness only decreased by 3%, and left ventricular end-diastolic pressure did not change significantly despite a large fall in coronary perfusion pressure. Thus, in an in vivo pig model with techniques optimized to detect subendocardial metabolic changes within the period of very early moderate myocardial ischemia, abnormalities in high energy phosphate compounds occurred rapidly enough to contribute to developing myocardial dysfunction, whereas preload-mediated mechanisms related to vascular distending pressure could not explain the functional deterioration under these conditions.
Abstract: PRESSURE-NATRIURESIS EFFECTS IN HYPERTENSION: Considerable advances have been made in our understanding of pressure-natriuresis and the effects of this mechanism in hypertension. We have shown that in the absence of changes in neural and endocrine factors, sodium and water excretion doubled when arterial pressure was increased by only 10 mmHg. These responses were greatly blunted or obscured by elevations in renal sympathetic tone, infusion of the vasoconstrictors angiotensin and vasopressin or by inhibition of paracrine factors such as eicosanoids and nitric oxide. EFFECT OF CHANGES ON MEDULLARY BLOOD FLOW: The pressure-natriuresis response is closely associated with changes in papillary blood flow as determined by laser-Doppler flowmetry. In volume-expanded rats, papillary blood flow is not well autoregulated, which results in elevations of vasa recta capillary pressure and renal interstitial fluid pressure. The increased interstitial fluid pressure is transmitted from the medulla to the cortex in the encapsulated organ and is associated with inhibition of sodium transport in the proximal tubule and/or the thin descending loop of Henle of deep nephrons. Selective reductions in medullary blood flow by infusion of the nitric oxide inhibitor N6-nitro-L-arginine methylester (L-NAME) into the renal medullary interstitial space resulted in decreased interstitial fluid pressure and reduced sodium excretion. The mechanisms by which small elevations in renal interstitial fluid pressure alter tubular sodium reabsorption remain to be determined. PRESSURE-NATRIURESIS EFFECTS IN HYPERTENSIVE RATS: Our studies have also shown that the pressure-natriuresis response is blunted in spontaneously hypertensive rats (SHR) compared to normotensive Wistar-Kyoto (WKY) rats. This abnormality is associated with shifts in the relationships among papillary flow, renal interstitial pressure and renal perfusion pressure towards higher pressures. The calcium antagonist nisoldipine corrected the defect in vasa recta hemodynamics in SHR and normalized relationships among sodium excretion, renal interstitial pressure and renal perfusion pressure. CONCLUSIONS: These studies indicate that sodium and water excretion is very sensitive to small changes in renal perfusion pressure due to associated changes in papillary blood flow, and that alterations in medullary hemodynamics can have an important effect on the relationship between arterial pressure and sodium and water excretion.
Abstract: This study tested the hypothesis that cerebral blood flow (CBF) is maintained by vasodilation, which manifests itself as a progressive increase in mean transit time (MTT) and cerebral blood volume (CBV) when cerebral perfusion pressure is reduced. Cerebral perfusion pressure was decreased in 10 pentobarbital-anesthetized dogs by controlled hemorrhage. Microsphere-determined CBF was autoregulated in all tested cerebral regions over the 40- to 130-mmHg cerebral perfusion pressure range but decreased by 50% at approximately 30 mmHg. MTT and CBV progressively and proportionately increased in the right parietal cerebral cortex over the 40- to 130-mmHg cerebral perfusion pressure range. Total hemoglobin content (Hb1), measured in the same area by an optical method, increased in parallel with the increases in CBV computed as the (CBF.MTT) product. At 30 mmHg cerebral perfusion pressure, CBV and Hb were still increased and MTT was disproportionately lengthened (690% of control). We conclude that within the autoregulatory range, CBF constancy is maintained by both increased CBV and MTT. Outside the autoregulatory range, substantial prolongation of the MTT occurs. When CBV is maximal, further reductions in cerebral perfusion pressure produce disproportionate increases in MTT that signal the loss of cerebral vascular dilatory hemodynamic reserve.
Abstract: The first human studies using relatively high-doses of ANF revealed similar effects as observed in the preceding animal reports, including effects on systemic vasculature (blood pressure fall, decrease in intravascular volume), renal vasculature (rise in GFR, fall in renal blood flow), renal electrolyte excretion (rises in many electrolytes), and changes in release of a number of different hormones. Whether all these changes are the result of direct ANF effects or secondary to a (single) primary event of the hormone remains to be determined. Certainly, it has been proven that more physiological doses of ANF fail to induce short-term changes in many of these parameters leaving only a rise in hematocrit, natriuresis and an inhibition of the RAAS as important detectable ANF effects in humans. This leads us to hypothesize that ANF is a "natriuretic" hormone with physiological significance. The primary function in humans is to regulate sodium homeostasis in response to changes in intravascular volume (cardiac atrial stretch). Induction of excess renal sodium excretion and extracellular volume shift appear to be the effector mechanisms. The exact mechanism of the natriuresis in humans still needs to be resolved. It appears however, that possibly a small rise in GFR, a reduction in proximal and distal tubular sodium reabsorption, as well as an ensuing medullary washout, are of importance. The pathophysiological role of ANF in human disease is unclear. One may find elevated plasma irANF levels and/or decreased responses to exogenous ANF in some disease states. Whether these findings are secondary to the disease state rather than the cause of the disease remains to be resolved. Therapeutic applications for ANF, or drugs that intervene in its production or receptor-binding, seem to be multiple. Most important could be the antihypertensive effect, although areas such as congestive heart failure, renal failure, liver cirrhosis and the nephrotic syndrome cannot be excluded. Although the data that have been gathered to date allowed us to draw some careful conclusions as to the (patho)physiological role of ANF, the exact place of ANF in sodium homeostatic control must still be better defined. To achieve this, we will need more carefully designed low-dose ANF infusion, as well as ANF-breakdown inhibitor studies. Even more promising, however, is the potential area of studies open to us when ANF-receptor (ant)agonists become available for human use.
Abstract: Breathing, diaphragmatic and transversus abdominis electromyograms (EMGdi and EMGta, respectively), and arterial blood gases were studied during normoxia (arterial PO2 = 95 Torr) and 48 h of hypoxia (arterial PO2 = 40-50 Torr) in intact (n = 11) and carotid body-denervated (CBD, n = 9) awake ponies. In intact ponies, arterial PCO2 was 7, 5, 9, and 11 Torr below control (P less than 0.01) at 1 and 10 min and 5 and 24-48 h of hypoxia, respectively. In CBD ponies, arterial PCO2 was 3-4 Torr below control (P less than 0.01) at 4, 5, 6, and 24 h of hypoxia. In intact ponies, pulmonary ventilation, mean inspiratory flow rate, and rate of rise of EMGdi and EMGta changed in a multi-phasic fashion during hypoxia; each reached a maximum during the 1st h (P less than 0.05), declined between 1 and 5 h (P less than 0.05), and increased between 5 and 24-48 h of hypoxia. As a result of the increased drive to the diaphragm, the mean EMGdi was above control throughout hypoxia (P less than 0.05). In contrast, as a result of a sustained reduction in duration of the EMGta, the mean EMGta was below control for most of the hypoxic period. In CBD ponies, pulmonary ventilation and mean inspiratory flow rate did not change during chronic hypoxia (P greater than 0.10). In these ponies, the rate of rise of the EMGdi was less than control (P less than 0.05) for most of the hypoxic period, which resulted in the mean EMGdi to also be less than control (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Lymphatic vessels from the intestines drain into the thoracic duct, and the thoracic duct empties into veins in the neck. Thus increases in neck vein pressure (PNV) might slow intestinal lymph flow, provided the increased pressure is reflected upstream through the lymphatic vessels. To test the effect of increases in PNV on lymphatic pressure, we cannulated intestinal lymphatics in the direction of flow in six sheep. After the sheep recovered from surgery, we measured the pressure in the lymphatics (Px) as we increased PNV in steps. Px increased only slightly (but significantly) from 7.4 +/- 2.0 to 11.4 +/- 5.2 (SD) cmH2O when we increased PNV from baseline (0.8 +/- 2.4 cmH2O) to 37.4 +/- 4.1 cmH2O. However, when we simulated an increased lymph flow by infusing Ringer solution into the lymphatics at 1,000 microliters/min, Px increased to 24.6 +/- 7.0 cmH2O at PNV equal to 37.1 +/- 5.3 cmH2O. These results indicate that, at normal lymph flow rates, increases in neck vein pressure cause only small increases in intestinal lymphatic pressure. On the other hand, when lymph flow is elevated, increases in neck vein pressure may substantially increase lymphatic pressure and thus slow intestinal lymph flow.
Abstract: A computer simulation was developed to study the regulation of active tissue plasminogen activator (t-PA) levels in plasma by kinetically modeling t-PA secretion, t-PA inhibition by plasminogen activator inhibitor type 1 (PAI-1), and hepatic clearance of t-PA, PAI-1 and t-PA/PAI-1 complex throughout a simplified human circulatory system. The model indicates that as the active PAI-1 concentration increases, the percent of t-PA in the active form decreases exponentially. Further, the reaction between t-PA and PAI-1 substantially reduces the half-lives of both active factors. By adjusting the t-PA and PAI-1 secretion rates to provide the best fit between simulated and measured circadian variations in t-PA, PAI-1 and complex, the model predicts that the diurnal rhythm in active t-PA levels is principally due to changes in the rate of PAI-1 secretion and not to variations in the t-PA secretion rate. In conclusion, the model predicts that PAI-1 is an important regulator of the concentration, half-life and circadian variation of active t-PA.
Abstract: Peak tetanic tension was measured during acidosis resulting from either hypercapnia or repetitive tetanic stimulation in isolated, arterially perfused cat biceps brachii (predominantly fast twitch) or soleus (slow twitch) muscles. Phosphocreatine (PCr), Pi, intracellular pH (pHi), and extracellular pH (pHo) were monitored by 31P-nuclear magnetic resonance spectroscopy. During repetitive stimulation under normocapnic conditions (5% CO2, pHo 7.4) Pi increased, pHi decreased from 7.1 to 6.3, and there were significant correlations between both pHi and calculated [H2PO4-] vs. peak tetanic force in both muscle types. However, hypercapnic perfusion (70% CO2, pHo, 6.7, pHi 6.4-6.5) had no effect on peak tetanic force, and there was no significant correlation between pHi or [H2PO4-] during hypercapnia in either muscle. The results indicate that decreased peak tetanic force during repetitive stimulation is not directly due to changes in pHi or diprotonated phosphate.
Abstract: Orthostatic dysfunction occurs after exposure to microgravity, and is not completely understood. The authors developed a device for stimulating carotid baroreceptors to test the hypothesis that exposure to microgravity leads to impairment of arterial baroreflex mechanisms. Data obtained before and after two head-down bedrest studies and before and after brief Space Shuttle missions indicate that baroreceptor-cardiac reflex control is impaired by simulated or actual weightlessness. The authors speculate that arterial baroreflex derangements combine with blood volume reductions and increased venous compliance to provoke orthostatic hypotension after microgravity exposure. Altered baroreflex function after missions may result from autonomic neuronal plasticity that develops during missions secondary to changes of cardiopulmonary and arterial dimensions and consequent changes of autonomic sensory input profiles.
Abstract: Although experimental and pathological studies suggest an important role for ischemia in the majority of fatal cases of traumatic brain injury, ischemia has been a rare finding in most clinical studies of cerebral blood flow (CBF) in head-injured patients. The hypothesis of the present study was that cerebral ischemia occurs in the first few hours after injury, but that CBF measurements have not been performed early enough. Early measurements of CBF (by the 133Xe intravenous method) and arteriovenous oxygen difference (AVDO2) were obtained in 186 adult head-injured patients with a Glasgow Coma Scale score of 8 or less, and were correlated with neurological status and outcome. During the first 6 hours after injury, CBF was low (22.5 +/- 5.2 ml/100 gm/min) but increased significantly during the first 24 hours. The AVDO2 followed the opposite course; the decline of AVDO2 was most profound in patients with low motor scores, suggesting relative hyperemia after 24 hours. A significant correlation between motor score and CBF was found in the first 8 hours after injury (Spearman coefficient = 0.69, p less than 0.001), but as early as 12 hours postinjury this correlation was lost. A similar pattern was found for the relationship between CBF and outcome. Cerebral blood flow below the threshold for infarction (CBF less than or equal to 18 ml/100 gm/min) was found in one-third of the studies obtained within 6 hours, the incidence rapidly decreasing thereafter. A low CBF after 24 hours was not generally associated with a high AVDO2, and was probably a reflection of low oxidative metabolism rather than frank ischemia. In 24 patients, a CBF of 18 ml/100 gm/min or less was found at some point after injury; the mortality rate was significantly higher in this subgroup, and survivors did worse. In some cases, ischemia was successfully treated by reducing hyperventilation or inducing arterial hypertension. These results support the above hypothesis, and suggest that early ischemia after traumatic brain injury may be an important factor determining neurological outcome. Moreover, these data indicate that early hyperventilation or lowering of blood pressure to prevent brain edema may be harmful.
Abstract: Two groups of patients who developed orthostatic hypotension (OH) after spinal cord injury (SCI) were studied. In the first group all patients (4 females and 6 males) were asymptomatic, whereas in the second group (1 female and 9 males) all had clinical manifestations of hypotension. All but 3 patients were tetraplegic, and these patients were paraplegic above the T6 level. For this study blood pressure (BP), heart rate and cerebral blood flow (CBF) velocity were measured simultaneously on a tilt table at 0, 30, 60, and 80 degrees. Cerebral blood flow in the middle cerebral artery was measured bilaterally utilising the transcranial Doppler technique. In asymptomatic patients the mean baseline (0 degrees) BP (110 +/- 16/70 +/- 77 mm Hg systolic/diastolic) was not significantly different from the BP (106 +/- 16/68 +/- 11 mm Hg) of symptomatic patients. The mean maximal change in BP during tilting in the asymptomatic group (-23 +/- 10/10 +/- 7 mm Hg) was also not significantly different when compared to the symptomatic group (-29 +/- 13/11 +/- 6 mm Hg). CBF in the symptomatic group during the hypotensive reaction at 80 degrees was 32.5 +/- 5 cm/sec, while at the same body position in the asymptomatic group it was 40.9 +/- 8 cm/sec (significant at the p less than 0.02). In addition, CBF decreased in the symptomatic group at 80 degrees to 55.5 +/- 9.6% of baseline, while in the asymptomatic group the fall was 69.3 +/- 7.2% (p less than 0.001). Our data suggest that autoregulation of CBF rather than systemic BP plays a dominant role in the adaptation to OH in patients with SCI.
Abstract: CVP increasing observed in OS "Mir" flights lets to consider it as one of the chief factors in stateman state disturbance. It is necessary to use prophylactic means to prevent pathological changes in long flights. The received data confirm physical training and clamping cuffs application efficiency as a blood volume decentring and CVP decreasing.
Abstract: The goal of this study was to determine whether the endothelium played a role in the myogenic response of skeletal muscle arterioles. First-order arterioles (n = 15) were isolated from the rat cremaster muscle and cannulated for in vitro study. The development of spontaneous tone reduced the diameter of the isolated arterioles from 166.7 +/- 7.6 microns to 89.2 +/- 7.2 microns. The arterioles were exposed to step changes in intraluminal pressure over a range of 10-170 cmH2O and had no flow through their lumen. The vessels exhibited active constriction to step increases or active dilation to step decreases in pressure (50-150 cmH2O). At 90 cmH2O, arterioles dilated by 89.2 +/- 6.0% in response to the endothelium-dependent vasodilator acetylcholine (10(-6) M; ACh) and 89.6 +/- 10.9% in response to endothelium-independent dilator adenosine (10(-4) M; Ado). The endothelium was physically denuded by rubbing the vessel lumen. After denudation, the arteriolar dilation to ACh was abolished, whereas the dilation to Ado was unaltered. The absence of endothelium was verified by electron microscopy. Basal tone and the response to changes in pressure were not significantly different from endothelium-intact vessels. These studies indicate that the endothelium is not responsible for myogenic activity or development of spontaneous tone in skeletal muscle arterioles.
Abstract: Incubation of a nontransformed rat liver cell line, Clone 9, at pH 8.5 resulted in an approximately 16-fold stimulation of cytochalasin B-inhibitable 3-O-methylglucose (3-OMG) transport, an effect that was independent of the presence of serum. Exposure to 100 ng/ml 12-O-tetradecanoylphorbol 13-acetate (TPA) stimulated 3-OMG uptake, and the enhancement was not additive to that produced by incubation at pH 8.5. In cells "depleted" of protein kinase C activity by a 20-hr exposure to TPA, however, the stimulation of 3-OMG transport in response to incubation at alkaline pH was still fully demonstrable. In control and alkaline pH-exposed cells, the inhibition of 3-OMG uptake by cytochalasin B was consistent with a single-site ligand binding model (K1 approximately 10(-7) M). Northern blot analysis demonstrated the presence of only the human erythrocyte/rat brain/HepG2 cell glucose transporter-mRNA isoform (EGT), and the abundance of this mRNA was unchanged following exposure to alkaline pH. Immunoblot analysis, using polyclonal antibodies directed against the carboxy-terminal dodecapeptide of EGT, demonstrated an approximately 2.0-fold increase in the abundance of transporters in partially purified plasma membrane fractions following incubation at pH 8.5, while EGT abundance was unchanged in whole-cell extracts. It is concluded that the stimulation of glucose transport in response to incubation of Clone 9 cells at alkaline pH does not require the presence of serum or activation of protein kinase C, and that the response is at least in part mediated by an increase in the number of glucose transporters in the plasma membrane.
Abstract: Twenty obese women aged 45-65 years with borderline hypertension were allocated randomly to either a group with an energy-restricted diet or to a control group. Body weight, blood pressure, urinary sodium, and urinary excretion of norepinephrine and plasma volume were recorded. Resting muscle sympathetic nerve activity was measured in the peroneal nerve by tungsten microelectrodes and expressed as bursts per minute. These measurements were repeated after 3 days of semistarvation and after a body weight reduction of 7% while each patient’s weight was in a steady state. After 3 days of semistarvation, only body weight was reduced, whereas after the long-term energy intake restriction, there were reductions of body weight (79.9 +/- 3.4 versus 74.1 +/- 3.4 kg; p less than 0.001), diastolic blood pressure (93 +/- 3 versus 86 +/- 4 mm Hg; p = 0.01), and muscle sympathetic nerve activity (49 +/- 2 versus 42 +/- 3 bursts/min; p less than 0.05). Other variables were unchanged. There were no changes in body weight, blood pressure, or muscle sympathetic nerve activity in the control group. We conclude that body weight decrease in obesity results in a reduction of blood pressure that is at least partially caused by a reduction of sympathetic vasoconstrictor activity.
Abstract: To assess the counterregulatory role of glucagon and to test the hypothesis that catecholamines can largely compensate for an impaired glucagon response, four studies were performed in seven normal volunteers. In all studies, insulin was infused subcutaneously (15 mU.m-2.min-1) and increased circulating insulin approximately twofold to levels (26 +/- 1 microU/ml) observed with intensive insulin therapy. In study 1, plasma glucose fluxes (D-[3-3H]glucose) and plasma substrate and counterregulatory hormone concentrations were simply monitored; plasma glucose decreased from 87 +/- 2 mg/dl and plateaued at 51 +/- 2 mg/dl for 3 h. In study 2 [pituitary-adrenal-pancreatic (PAP) clamp], secretion of insulin and counterregulatory hormones (except for catecholamines) was prevented by somatostatin (0.5 mg/h i.v.) and metyrapone (0.5 g/4 h per os), and glucagon, cortisol, and growth hormone were reinfused to reproduce the concentrations of study 1. In study 3 (lack of glucagon response), the PAP clamp was performed with maintenance of plasma glucagon at basal levels, and glucose was infused whenever needed to reproduce plasma glucose concentration of study 2. Study 4 was identical to study 3, but exogenous glucose was not infused. The PAP clamp (study 2) reproduced glucose concentrations and fluxes observed in study 1. In studies 3 and 4, isolated lack of glucagon response did not affect glucose utilization but caused an early and persistent decrease in hepatic glucose production (approximately 60%) that caused plasma glucose to decrease to 38 +/- 2 mg/dl (P less than 0.01 vs. control 62 +/- 2 mg/dl), despite compensatory increases in plasma epinephrine. We conclude that, in a model of clinical hypoglycemia, glucagon’s effect on hepatic glucose production is a dominant counterregulatory factor in humans and that its absence cannot be compensated for by increased epinephrine secretion.
Abstract: The role of C-atrial natriuretic factor (ANF) receptors and neutral endopeptidase (NEP) in the pharmacokinetics and hydrolysis of 125I-labeled ANF was evaluated in rats by using C-ANF and SCH 39370 to block the nonenzymatic and enzymatic pathways, respectively. After a bolus injection of 125I-ANF, the resulting area under the plasma concentration curve (AUC) with C-ANF treatment was seven times the control value with regard to trichloroacetic acid-precipitable (TCA-ppt) radioactivity (intact ANF). SCH 39370 tended to increase AUC, but the changes were not significant. Nevertheless, SCH 39370 suppressed the appearance of TCA-soluble radioactivity (hydrolytic products), indicating that in vivo inhibition of ANF degradation had occurred. SCH 39370 plus C-ANF produced a 15-fold increase in AUC for TCA-ppt radioactivity and a reduction in plasma TCA-soluble radioactivity. High-performance liquid chromatography (HPLC) analysis confirmed that combination treatment increased intact ANF and reduced hydrolytic products in the plasma. SCH 39370 reduced clearance (C) without altering volume of distribution in steady state (Vss) and half-life (t1/2). C-ANF decreased both C and Vss leading to a fourfold increase in t1/2, which was further prolonged by SCH 39370 (7.5 times control). Bilateral nephrectomy caused a proportionally similar decrease in Vss and C without changing t1/2, suggesting significant extrarenal metabolism of ANF. SCH 39370 systemically inhibits ANF hydrolysis; the resulting increase in ANF, however, is masked by the great capacity of ANF clearance receptors but can be revealed with excess C-ANF, suggesting that the plasma ANF concentrations are determined by the interplay of the C-ANF receptor and NEP systems.
Abstract: Contributions of carbohydrate and fat metabolism to the removal of a lactate (Lac-) load were quantified in inactive soleus (SL), plantaris (PL), and white gastrocnemius (WG) rat hindlimb muscle. Male Sprague-Dawley rats were perfused for 60 min with normal perfusate (NP, n = 8) or a high-lactate perfusate (LP, n = 8), simulating ionic conditions found in arterial blood and plasma after intense exercise: Lac- = 11.0 mM, K+ = 7.88 mM, and pH = 7.15. Metabolite fluxes across the hindlimb were calculated from blood flow and arteriovenous differences. In NP, Lac- was continuously released (2.9 +/- 0.2 mumol.min-1 x 100 g-1). However, in LP, a rapid and significant uptake of Lac- increased muscle Lac- fivefold to 39.6 +/- 1.1, 33.1 +/- 2.2, and 28.8 +/- 1.7 mumol/g dry wt in SL, PL, and WG, respectively. Glucose and O2 uptakes were similar during LP and NP perfusion. Glycerol release increased eightfold to 3.3 +/- 0.7 mumol.min-1 x 100 g-1 in response to LP. Muscle ATP, creatine phosphate, glycogen, glycolytic intermediate, and triacylglycerol concentrations did not change. However, muscle lactate-to-pyruvate ratios were elevated in all muscles of the LP group postperfusion, indicating changes in the mass action ratio at the pyruvate dehydrogenase reaction. In LP, of 80 mumol of Lac- taken up, 11% was accounted for by increased muscle Lac-, 12-24% was oxidized, and 5% may have been involved in glycerol release. The remaining Lac- may have been involved in metabolic cycling along the glyconeogenic-glycolytic pathway and/or in triacylglycerol-free fatty acid substrate cycling.
Abstract: To analyze the role of SV40 genome in the phenotypic alterations previously observed in SV40-transformed cell lines, we infected rabbit renal cortical cells with a temperature-sensitive SV40 mutant strain (tsA58) and compared the cell phenotypes at temperatures permissive (33 degrees C) and restrictive (39.5 degrees C) for SV40 genome expression. At both temperatures, the resulting cell line (RC.SVtsA58) expresses cytokeratin and uvomorulin, but epithelial differentiation is more elaborate at 39.5 degrees C as shown by the formation of a well-organized cuboidal monolayer with numerous tight junctions and desmosomes. Functional characteristics are also markedly influenced by the culture temperature: cells grown at 33 degrees C respond only to isoproterenol (ISO, 10(-6) M) by a sevenfold increase in cAMP cell content above basal values; in contrast, when transferred to 39.5 degrees C, they exhibit increased sensitivity to ISO (ISO/basal: 19.1) and a dramatic response to 10(-7) M dDarginine vasopressin (dDAVP/basal: 18.2, apparent Ka: 5 X 10(-9) M) which peaks 48 h after the temperature shift. The latter is associated with membrane expression of V2-type AVP receptors (approximately 50 fmol/10(6) cells) which are undetectable when SV40 genome is activated (33 degrees C). Clonal analysis, additivity studies, and desensitization experiments argue for the presence of a single cell type responsive to both AVP and ISO. The characteristics of the RC. SVtsA58 cell line at 39.5 degrees C (effector-stimulated cAMP profile, lack of expression of brush-border hydrolases and Tamm-Horsfall protein) suggest that it originates from the cortical collecting tubule, and probably from principal cells.
Abstract: The present study examined whether changes in plasma oncotic pressure or hematocrit play a role in the redistribution of renal blood flow and the natriuretic response to extracellular fluid volume (ECFV) expansion with saline. Intravenous infusion of saline produced a 46% increase in the flow of red blood cells (RBCs) in the papilla of Inactin-anesthetized euvolemic Munich-Wistar rats (n = 6). This was primarily due to an increase in the number of functional capillaries perfused with moving RBCs, as indicated both by laser-Doppler flowmetry and videomicroscopy. The velocity of RBCs in ascending or descending vasa recta was not significantly altered by the infusion of saline. Plasma volume expansion with a 6% solution of albumin (n = 6) did not increase papillary RBC flow, whereas volume expansion with whole blood produced a 17% increase in the flow of RBCs in the papilla. Sodium excretion after ECFV expansion with saline (n = 6) was greater than that seen after plasma volume expansion with a 6% solution of albumin (n = 5). The results indicate that the rise in papillary RBC flow after ECFV expansion with saline is due to an increase in the number of perfused vasa recta capillaries. The failure of plasma volume expansion to alter papillary RBC flow suggests that changes in plasma oncotic pressure and/or renal interstitial pressure may signal the rise in papillary RBC flow after intravenous infusion of saline. The present study also indicates that laser-Doppler flowmetry is a useful technique to monitor changes in the flow, velocity, and concentration of moving RBCs in tissue.
Abstract: We assessed the linearity of oxygen uptake (VO2) kinetics for several work intensities in four trained cyclists. VO2 was measured breath by breath during transitions from 33 W (baseline) to work rates requiring 38, 54, 85, and 100% of maximal aerobic capacity (VO2max). Each subject repeated each work rate four times over 8 test days. In every case, three phases (phases 1, 2, and 3) of the VO2 response could be identified. VO2 during phase 2 was fit by one of two models: model 1, a double exponential where both terms begin together close to the start of phase 2, and model 2, a double exponential where each of the exponential terms begins independently with separate time delays. VO2 rose linearly for the two lower work rates (slope 11 ml.min-1 W-1) but increased to a greater asymptote for the two heavier work rates. In all four subjects, for the two lighter work rates the double-exponential regression reduced to a single value for the time constant (average across subjects 16.1 +/- 7.7 s), indicating a truly monoexponential response. In addition, one of the responses to the heaviest work rate was monoexponential. For the remaining seven biexponential responses to the two heaviest work rates, model 2 produced a significantly better fit to the responses (P less than 0.05), with a mean time delay for the slow component of 105 +/- 46 s.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: The present study was undertaken to assess the effects of acute metabolic acidosis on the activity of the renin-angiotensin-aldosterone system in 12 children with a mean age of 8.9 years who underwent NH4Cl loading test. Ammonium chloride was given in a dose of 0.15 g/kg per day for 3 consecutive days to evaluate renal acidification. Prior to and following NH4Cl administration blood acid-base parameters, plasma and urine electrolytes, creatinine and aldosterone concentrations as well as plasma renin activity (PRA), urine flow rate and net H+ excretion were measured. Ammonium chloride administration significantly depressed blood pH (P less than 0.05), bicarbonate (P less than 0.01) and base excess (P less than 0.01) and resulted in a slight, but significant elevation of plasma potassium concentration (P less than 0.05). Furthermore, NH4Cl ingestion induced a marked increase in urine flow rate (P less than 0.01) and urinary sodium, potassium and chloride excretion (P less than 0.01). In response to NH4Cl metabolic acidosis, PRA doubled (4.72 +/- 1.18 vs 8.13 +/- 1.02 ng/ml per hour, P less than or equal to 0.05) and there was a nearly four-fold increase in plasma aldosterone level (0.49 +/- 0.12 vs 1.52 +/- 0.24 ng/ml, P less than 0.01) and in urinary aldosterone excretion (19.2 +/- 4.3 vs 71.8 +/- 13.8 micrograms/day, P less than 0.01). The elevated aldosterone production observed in this study is assumed to be mediated by the combined effect of sodium and water diuresis-related increased PRA, hyperkalaemia and the direct stimulation of adrenal steroidogenesis by metabolic acidosis.
Abstract: The effects of hyperglycemia on muscle glycogen use and carbohydrate metabolism were evaluated in eight well-trained cyclists (average maximal O2 consumption 4.5 +/- 0.1 l/min) during 2 h of exercise at 73 +/- 2% of maximal O2 consumption. During the control trial (CT), plasma glucose concentration averaged 4.2 +/- 0.2 mM and plasma insulin remained between 6 and 9 microU/ml. During the hyperglycemic trial (HT), 20 g of glucose were infused intravenously after 8 min of exercise, after which a variable-rate infusion of 18% glucose was used to maintain plasma glucose at 10.8 +/- 0.4 mM throughout exercise. Plasma insulin remained low during the 1st h of HT, yet it increased significantly (to 16-24 microU/ml; P less than 0.05) during the 2nd h. The amount of muscle glycogen utilized in the vastus lateralis during exercise was similar during HT and CT (75 +/- 8 and 76 +/- 7 mmol/kg, respectively). As exercise duration increased, carbohydrate oxidation declined during CT but increased during HT. Consequently, after 2 h of exercise, carbohydrate oxidation was 40% higher during HT than during CT (P less than 0.01). The rate of glucose infusion required to maintain hyperglycemia (10 mM) remained very stable at 1.6 +/- 0.1 g/min during the 1st h. However, during the 2nd h of exercise, the rate of glucose infusion increased (P less than 0.01) to 2.6 +/- 0.1 g/min (37 mg.kg body wt-1.min-1) during the final 20 min of exercise. We conclude that hyperglycemia (i.e., 10 mM) in humans does not alter muscle glycogen use during 2 h of intense cycling.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: This article is based on a Basic Science Symposium presented at the 23rd Annual Meeting of the American Society of Nephrology. New information on the segmental transport of ammonium by the proximal tubule, the thick ascending limb of Henle’s loop, and the collecting duct is integrated into a thesis that NH4+ excretion is controlled by the rate of production, by diffusion of NH3 along gradients established by proton secretion, and by active transport of NH4+. These new concepts are applied to a novel explanation of the pathogenesis of distal renal tubular acidosis.
Abstract: The purpose of this study was to determine the intensity threshold needed to elicit increases in plasma aldosterone and cortisol during graded exercise in humans. Seven male volunteers performed a maximal oxygen uptake (VO2max) test on a cycle ergometer. Plasma levels of aldosterone, cortisol, angiotensin II, ACTH, and potassium were measured at rest and at each 50 W workload of the exercise test. The results showed that aldosterone significantly (p less than or equal to 0.05) increased from a mean (+/- SE) of 231 +/- 22 pmol/L at rest to 464 +/- 22 pmol/L at exhaustion. Cortisol significantly (p less than or equal to 0.05) increased from 284 +/- 38 nmol/L at rest to 311 +/- 39 nmol/L at exhaustion. More importantly, however, was the fact that aldosterone was significantly increased above the resting level at exercise intensities greater than or equal to 60% VO2max. Cortisol, on the other hand, was only significantly increased at exhaustion (i.e. 100% VO2max). These results clearly show that increases in aldosterone precede those of cortisol during graded exercise in humans. Interestingly, potassium (r = 0.79), ACTH (r = 0.55), and angiotensin II (r = 0.54) were all significantly correlated with aldosterone during exercise. Such a finding seems to suggest that all 3 variables may be important stimuli for aldosterone secretion during graded exercise.
Abstract: This study examined the long-term actions of atrial natriuretic factor (ANF), at physiological levels, on renal function and mean arterial pressure (MAP) and the importance of Na intake and the renin-angiotensin-aldosterone system in modulating those effects. After a control period, ANF was infused intravenously at a rate of 10 ng.kg-1.min-1 for 7 days, followed by 7 days of 20 ng.kg-1.min-1 and 7 days of recovery. After 7 days of ANF at 10 ng.kg-1.min-1, MAP decreased from 87 +/- 3 to 80 +/- 2 mmHg in normal dogs on low sodium intake (LS, 7 meq Na/day) and from 89 +/- 2 to 79 +/- 2 mmHg in adrenalectomized dogs (ADX, 7 meq Na/day) given constant mineralocorticoid replacement. In both groups, no significant change in glomerular filtration rate (GFR) was observed, although sodium excretion increased transiently. ANF failed to cause significant changes in MAP, GFR, or sodium excretion in normal dogs on high sodium intake (HS, 269 meq Na/day). In LS and HS no long-term effects of ANF on plasma renin activity (PRA) and aldosterone were observed. In ADX, as expected, no change in aldosterone was observed. Thus, in normal and adrenalectomized dogs on LS, chronic ANF infusion caused sustained reductions in MAP. HS markedly attenuated the hypotensive effect of ANF. Our data suggest that the long-term effect of ANF is salt sensitive but that decreases in PRA and aldosterone are not essential for the long-term hypotensive effect of ANF.
Abstract: The purpose of this study was to compare measurements of static knee extension torque obtained using a hand-held dynamometer (HHD) and an isokinetic dynamometer (IKD). Twenty young healthy women performed two maximum knee extension efforts against each device. The two HHD measurements did not differ significantly and were highly reliable (intraclass correlation coefficient (ICC) = 0.945). The two IKD measurements did not differ significantly and were highly reliable (ICC = 0.932). The mean of the two HHD and two IKD measurements did not differ significantly. The inter-instrument reliability was fair (ICC = 0.797). Thus, under limited circumstances the instruments may be interchangeable. The less expensive and more portable HHD may be a practical alternative for the clinical measurement of muscle strength.
Abstract: Average capillary pressure (Pc) close to the venous end (fluid equilibrium point) of the exchange vessels (denoted Pc,v), arterial (PA) and venous pressure, and the rate of net transcapillary fluid flux were continuously recorded in sympathectomized muscle during 30 min of graded exercise and for 30 min in the post-exercise period. Regional changes in colloid osmotic pressure (pi pl) and total osmolality in plasma, the latter reflecting work-induced interstitial hyperosmolality, were measured at intervals. In the control state at rest with a Starling fluid equilibrium, Pc,v averaged 17.6 +/- 0.8 mmHg. Exercise caused a rapid transcapillary plasma fluid loss, the net driving pressure for which in the initial phase of heavy work was 58 mmHg (transcapillary fluid flux divided by the capillary filtration coefficient). This comprised an increase in Pc,v of 16 mmHg, a nonprotein osmotic force (Posm) related to exercise-induced tissue hyperosmolality corresponding to 46 mmHg and an opposing force established by a raised pi pl of 4 mmHg. A theoretical analysis indicated that the main fraction of the osmotic fluid loss passed through transcellular ultrapores and only a minor part through conventional small pores. In spite of the fact that Pc remained high throughout the exercise period, the outward fluid flux gradually declined and a Starling equilibrium was re-established 23 min after the commencement of heavy exercise. This was explained by a gradual decline of Posm and apparently also by a secondary increase in tissue pressure (Pif) and/or a decrease in interstitial colloid osmotic pressure (pi if). Net fluid absorption occurred in the post-exercise period as a result of a gradual decrease in Pc, reversed transcapillary Posm and also maintained high Pif and/or low pi if. Exercise (even light) abolished normal Pc autoregulation, implying that the filtration component of net transcapillary fluid flux becomes distinctly modulated if PA is altered.
Abstract: Myocardial damage after high voltage electrical body injury is a serious and often life-threatening situation. The purpose of this pilot study was to identify early clinical predictors of myocardial damage in patients with high voltage electrical injury. Twenty-four patients with high voltage electrical injuries and no evidence of arc burns were evaluated. In 13/24 patients the diagnosis of myocardial damage was confirmed by total creatine kinase (CK) and creatine kinase MB (CK-MB) isoenzyme elevation (group A). In these patients the total CK range was 1373 to 52,544 mU/ml. In 11/24 patients CK-MB was negative (group B) indicating absence of myocardial damage. ECG changes occurred in 10/13 group A and 4/11 group B patients (p less than .095). No patient in either group gave a history suggestive of myocardial ischemia after the electrical injury. The pathways of electricity through the body, as mapped by a line drawn between the wound(s) of entrance and exit, were vertical in all group A patients, i.e., from upper to lower body segment, vs. 5/11 group B patients with evidence of a vertical pathway (p less than .003). Group A patients also had greater body surface burns (16.0 +/- 2.7%) vs. group B patients (4.0 +/- 1.6%, p less than .001). The presence of a vertical pathway and the magnitude of percent surface burns were found to be the most significant clinical predictors of myocardial damage in multiple logistic regression analysis (p less than .0001).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: The remarkable capacity of the bone marrow to compensate for blood loss and for reduced atmospheric oxygen tension has been found to be mediated by a renal hormone, named erythropoietin. It is produced by peritubular interstitial cells in response to renal hypoxia, but molecular engineering has permitted large scale production of an identical recombinant erythropoietin in vitro. When used as a replacement hormone in patients with impaired endogenous production it has been found to be capable of improving or eliminating the anemia of chronic kidney disease and the anemia of prematurity. In the future it may also be used as a pharmacologic agent and possibly be able to control the anemia of patients with bone marrow failure and make them transfusion-independent.
Abstract: Congestive heart failure is a complex clinical syndrome that has its basis in an abnormality of myocardial cell function resulting in impaired ventricular performance, exercise intolerance, and ventricular arrhythmias. The functional defect in myocardial performance may be related to alterations in receptor function, in regulatory proteins, or in biochemical mechanisms. Remodeling of the left ventricle has been observed to play an important role in the natural course of heart failure. The complex interplay between cellular elongation, reactive hypertrophy, and the influence of the change from ellipsoid to spheroidal shape of the left ventricle after acute myocardial infarction are just beginning to be understood. Prevention of this remodeling effect by pharmacologic intervention is being widely explored, although the mechanisms are poorly defined. Impedance to left ventricular ejection is also an important determinant of cardiac performance in heart failure. Constriction of arteriolar resistance vessels and reduction in compliance of arterial conductance vessels is a common manifestation of heart failure and may be under the influence of neural, hormonal, endothelial, and local regulatory factors. Increased tone of venous capacitance vessels contributes to a shift of blood centrally and to an increase in ventricular preload. Vasodilator drugs by relaxing the arterial, arteriolar, and venous vasculature result in a reduction in impedance and left ventricular afterload and a decrease in cardiac filling pressure and preload. Structural changes of hypertrophy and remodeling apparently contribute to the changes in resistance, compliance, and capacitance in the vasculature. Treatment of heart failure is aimed at relieving symptoms and prolonging life. Interventions to improve left ventricular function are critical to symptom relief. Vasodilators have been most effective for this purpose, and new positive inotropic drugs are being tested for efficacy. Long-term benefit may require interference with the myocardial and peripheral vascular remodeling processes that lead to progressive depression of ventricular performance. New insights into the cellular and subcellular mechanisms of this progression are critical to the development of innovative therapeutic strategies.
Abstract: Tubuloglomerular feedback (TGF) function and autoregulation (renal blood flow RBF; glomerular filtration rate, GFR; single-nephron glomerular filtration rate, SNGFR) were examined in rats chronically treated with deoxycorticosterone acetate (DOCA) and given isotonic saline to drink. DOCA treatment depressed arterial plasma renin activity, expanded plasma volume by 25% and increased arterial blood pressure. Autoregulation of RBF and GFR was maintained in the DOCA animals above 90 mm Hg and 110 mm Hg respectively, whereby both GFR and RBF were lower than in controls. Micropuncture experiments demonstrated the absence of TGF in the DOCA animals. There was no difference between SNGFR values measured in the distal and proximal tubules, nor was there a significant response of SNGFR when loops of Henle were perfused with Ringer’s solution at 20 nl/min. Loop perfusion in control rats with tubular fluid collected in DOCA rats elicited a normal TGF response, showing that TGF inhibition in the DOCA animals is due to changes in the function of the juxtaglomerular apparatus. In contrast to control rats, proximal SNGFR was perfectly autoregulated. These results suggest that TGF is not primarily responsible for autoregulation and that the vasodilatation normally resulting from acute TGF interruption is therefore compensated by some other mechanism such that RBF and GFR are lower than in controls.
Abstract: Lightning kills or injures thousands of people in the United States each year. Injuries are caused by the effects of electrical, thermal and mechanical energy, and a wide range of clinical results, involving multiple body systems, is possible. Important differences exist between lightning victims and patients injured by fire or by other forms of electricity. In lightning victims, successful resuscitation is highly likely, even among patients with conventional signs of brain death. With proper management, long-term physical and psychologic sequelae of lightning injury are rare.
Abstract: Videometric measurements of changes in vessel lumen diameters were made to investigate autoregulatory and tubuloglomerular feedback (TGF) responses of early efferent arterioles (EA), mid-to-late afferent arterioles (MAA), and terminal, juxtaglomerular afferent arterioles (JAA) in rat juxtamedullary nephrons in vitro. High-contrast shadow-cast images of blood-perfused arterioles at the glomerular vascular pole were obtained with incident illumination and long-working-distance objectives fitted to a compound microscope. In response to an increase in blood perfusion pressure from 60 to 140 mmHg, strong autoregulatory vasoconstriction was observed in the MAA and JAA, with respective reductions in mean luminal diameter of 23 +/- 4 and 40 +/- 4% (mean +/- SE); EA diameter was unchanged. In response to TGF excitation by direct microinjection of Ringer solution into the cortical thick ascending limb segment near the macula densa, JAA luminal diameter decreased by 34 +/- 5%. The TGF responses were completely inhibited by the addition of 0.1 mM furosemide to the tubular injectate. Calcium channel blockade achieved by adding 1 microM nimodipine to the superfusate had no effect on early EA diameter but produced a blood pressure-dependent JAA and MAA vasodilation and complete inhibition of autoregulatory responses. These results provide direct evidence that the distal afferent arteriole in juxtamedullary nephrons is a major effector site for both renal autoregulation and tubuloglomerular feedback.
Abstract: [U-11-C]-glucose and positron emission tomography was used to evaluate transport and oxidative metabolism of glucose in the brain of non-diabetic and insulin dependent diabetic (IDDM) subjects. These results were compared with results obtained by the Fick principle. Blood glucose was regulated by a Biostator controlled glucose infusion during a constant insulin infusion. [U-11-C]-glucose was injected during normoglycemia as well as during moderate hypoglycemia. The tracer data were analysed using a three compartment model with a fixed correction for [11-C]-CO2 egress. During normoglycemia the influx rate constant (k1) and blood brain glucose flux of the two groups were similar. During hypoglycemia k1 increased significantly and to the same extent in both groups. During normoglycemia the tracer calculated metabolism of glucose was higher in the brain of non-diabetic than of diabetic subjects. When measured by the Fick principle the net uptake of glucose was broadly the same for the groups. During normoglycemia the molar ratio of O2 to glucose uptake was, however, lower in IDDM than in non-diabetic subjects (4.67 vs 5.50, P less than 0.05, Wilcoxon test). A significant release of lactate and pyruvate was seen in IDDM but not in non-diabetic subjects. The results imply that a larger fraction of glucose is non-oxidatively metabolized in IDDM than in non-diabetic subjects.
Abstract: We examined the relationship between the duration of hypoxic exposure and serum erythropoietin (EPO) production. Adult male Long-Evans rats were exposed to hypobaric hypoxia (HH = 0.5 atm) for a period of 15 min to 20 days. Serum for EPO by radioimmunoassay was collected immediately, 1 or 2 h after HH exposure. A significant rise in EPO levels occurred 1 h after a 30-min HH exposure that was not sustained 2 h after termination. One hour of HH exposure resulted in increased EPO levels 1 h after termination of exposure and further increased levels 2 h after termination of exposure. With prolonged exposure, serum levels remained elevated at 6 and 20 days, despite the development of polycythemia. We concluded that the hypoxic stimulus for elevation of serum EPO could be as short as 30 min and that EPO levels remained elevated after chronic HH. The experimental data were consistent with a mathematical model in which stimulated EPO production was proportional to the time of HH stimulus.
Abstract: Cases of lightning-related deaths and injuries that occurred in Florida in 1978-87 were reviewed to determine the factors involved, to quantify the morbidity and mortality related to lightning strikes, and to describe epidemiologically the injuries and circumstances involved. Statewide information on deaths was obtained from death certificates, autopsy reports, and investigative reports. Information about morbidity was obtained from the Florida Hospital Cost Containment Board data base and the National Climatic Data Center data base for all Florida counties, as well as from hospitals in selected counties. Lightning-related deaths totaled 101 in Florida during the period 1978-87, an annual average of 10.1. Eight percent of the victims were from other States. The overall yearly death rate for State residents was 0.09 per 100,000 population, with the highest rate being that for men aged 15-19 years, 0.38 per 100,000. Thirteen percent of victims were females. The ratio of lightning-related injuries to deaths in Florida was estimated at about four to one. Thirty percent of all deaths were occupationally related. The first strikes of lightning from a thunderstorm may be the most dangerous, not in terms of impact, but because of the element of surprise. During thunderstorms, people may seek shelter under isolated trees because they believe erroneously that a tree offers protection from lightning, or perhaps because their top priority is to escape from rain rather than lightning. People may not seek adequate shelter during thunderstorms because they do not know the dangers of remaining outdoors or their judgment is impaired by drugs or alcohol.
Abstract: After voluntary hyperventilation, normal humans do not develop a significant ventilatory depression despite low arterial CO2 tension, a phenomenon attributed to activation of a brain stem mechanism referred to as the "afterdischarge." Afterdischarge is one of the factors that promote ventilatory stability. It is not known whether physiological stimuli, such as hypoxia, are able to activate the afterdischarge in humans. To test this, breath-by-breath ventilation (VI) was measured in nine young adults during and immediately after a brief period (35-51 s) of acute hypoxia (end-tidal O2 tension 55 Torr). Hypoxia was terminated by switching to 100% O2 (end-tidal O2 tension of first posthypoxic breath greater than 100 Torr). Brief hypoxia increased VI and decreased end-tidal CO2 tension. In all subjects, termination of hypoxia was followed by a gradual ventilatory decay; hyperoxic VI remained higher than the normoxic baseline for several breaths and, despite the negative chemical stimulus of hyperoxia and hypocapnia, reached a new steady state without an apparent undershoot. We conclude that brief hypoxia is able to activate the afterdischarge mechanism in conscious humans. This contrasts sharply with the ventilatory undershoot that follows relief of sustained hypoxia, thereby suggesting that sustained hypoxia inactivates the afterdischarge mechanism. The present findings are of relevance to the pathogenesis of periodic breathing in a hypoxic environment. Furthermore, brief exposure to hypoxia might be useful for evaluation of the role of afterdischarge in other disorders associated with unstable breathing.
Abstract: To ascertain whether the dawn phenomenon occurs in normal adolescents and, if so, to determine its mechanism, we measured nocturnal plasma glucose, insulin, glucagon, growth hormone, cortisol, and adrenocorticotropic hormone (ACTH) levels between 01.00 and 08.00 h in 10 healthy adolescents. The prehepatic insulin secretion rate was calculated based on C peptide levels. The metabolic clearance rate of insulin (MCRI) was calculated as the ratio of mean insulin secretion rate to mean insulin concentration. There was no change in plasma glucose, insulin, and glucagon between 01.00-04.00 and 05.00-08.00 h (paired t test). The MCRI was higher at 05.00-08.00 h compared to 01.00-04.00 h (9.30 +/- 1.50 vs. 4.87 +/- 1.11 ml.kg-1.min-1; p = 0.008). The prehepatic insulin secretion increased at 05.00-08.00 h relative to 01.00-04.00 h (1.1 +/- 0.2 vs. 0.6 +/- 0.1 pmol.kg-1.min-1; p = 0.013). Similarly, cortisol and ACTH levels were higher at 05.00-08.00 versus 01.00-04.00 h (323 +/- 33 vs. 102 +/- 22 nmol/l, p less than 0.001; 3.6 +/- 0.5 vs. 1.8 +/- 0.4 pmol/l, p = 0.006, respectively). Growth hormone was higher at 01.00-04.00 versus 05.00-08.00 h (7.6 +/- 1.2 and 3.0 +/- 0.9 microgram/l; p = 0.019). ACTH correlated with MCRI (r = 0.66; p = 0.002) and prehepatic insulin secretion (r = 0.75; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: To better quantify and update the health impact of lightning and to compare potential sources of information, we reviewed data from the National Centre for Health Statistics (NCHS) database for 1968 through 1985 and from the North Carolina Medical Examiner (NCME) computerized database for 1972 through 1984. We epidemiologically characterized all lightning-related deaths identified in these databases. Results of our analysis are presented together with previously published information from the National Oceanic and Atmospheric Administration and from the National Institute for Occupational Safety and Health. In the US, Wyoming has the highest average annual lightning-related death rate (0.196/100,000), whereas Florida has the largest cumulative incidence of deaths (200) for this 18-year period. Death rates are the highest for males and for people 10-19 years old. There is a tendency toward a slight, but steady, decrease in the yearly incidence of lightning-related deaths. One-third of the fatalities are job-related. Both the NCHS and NCME databases are limited in describing the circumstances and aetiologies of these deaths.
Abstract: 1. In order to evaluate the importance of afferent neural feedback from the working muscles for cardiovascular and ventilatory responses to dynamic exercise, epidural anaesthesia was induced at L3-L4. Six healthy males cycled for 20 min at 57% of maximum oxygen uptake and for 8-12 min at increasing work intensities until exhaustion at 238 +/- 30 W without as well as with epidural anaesthesia. 2. Presence of afferent neural blockade was verified by cutaneous sensory analgesia below T10-T11 and attenuated post-exercise ischaemic pressor response (45 +/- 8-24 +/- 6 mmHg). Efferent sympathetic nerves appear to be intact since basal heart rate and blood pressure as well as the cardiovascular responses to a Valsalva manoeuvre and to a cold pressor test were unchanged. 3. During dynamic exercise with epidural anaesthesia, blood pressure was lower than in control experiments; however, ventilation and heart rate were not affected. 4. The results indicate that afferent neural activity from the working muscles is important for blood pressure regulation during dynamic exercise in man but may not be necessary for eliciting the ventilatory and heart rate responses.
Abstract: 1. An improved Doppler ultrasound technique was used to measure stroke volume (SV) and cardiac output (CO) on a beat-to-beat basis in a group of supine humans before, during and after periods of standardized, rhythmic exercise, involving the quadriceps muscle groups on both sides. The development of CO on such bouts of exercise was compared to Doppler ultrasound records of the simultaneous femoral arterial flow (FF) response. 2. Records of CO at rest revealed spontaneous fluctuations around a mean level, with differences between the minimal and maximal values of the order of 1 l min-1. The mean CO level at rest again varied considerably from one day to another and from test run to test run. 3. Upon start of exercise an immediate and rapid increase in heart rate (HR) and CO took place. The entire increase, the size of which varied appreciably from test run to test run, was completed within 10-15 s. No or only minor changes were seen in the mean SV level during the exercise periods. 4. The time course of the increase in FF was indistinguishable from that of the increase in CO, which occurred without any detectable delay relative to the changes in FF. These closely parallel developments indicate a tight regulatory coupling between the two types of flow changes. 5. In the majority of tests the total and two-sided increase in FF seen in the steady-state situation in the last part of an exercise period was significantly larger than the recorded increase in CO. This discrepancy implies that some redistribution of flow from tissues other than the working muscles might take place, even at this moderate level of work. 6. Upon the end of exercise a striking but transient increase in CO occurred, resulting from an increase in SV concomitant with a maintained HR. In the course of five to eight post-exercise cardiac cycles about 100 extra milliliters of blood were expelled from the heart. This cardiac outflow overshoot was found to occur during a post-exercise fall in mean arterial blood pressure (MAP).
Abstract: The metabolism of a typical North American diet yields a net acid load. Hydrogen ions are removed from the body after combining with bicarbonate to form CO2. This leaves the body with a deficit of bicarbonate. The role of the kidney is to add ʼnew’ bicarbonate to the body. It does so primarily by synthesizing NH4+ plus bicarbonate while making NH4+ an end-product of metabolism (excreting it in the urine). Production of NH4+ occurs primarily in proximal convoluted tubule cells. Although several possible pathways can do this, the primary one stimulated by chronic metabolic acidosis is the glutaminase/glutamate dehydrogenase one. The upper limit on this pathway is set by energy turnover considerations. This, in effect, means control by renal work (sodium reabsorption) and fuel competitions (availability of fat-derived fuels).
Abstract: Among the many classes of diuretics available, thiazides have emerged as the most appropriate category for the treatment of uncomplicated hypertension. Potassium-sparing agents may be added according to need or in fixed-combination therapy. Thiazides act on the cortical diluting segment of the renal tubule. The potassium-sparing agents interfere with the Na⊕-K+ exchange process in the terminal part of the distal tubule. Thiazides have been the cornerstone of therapy in nearly all prospective therapeutic, mild and moderate hypertension trials conducted to date. They have, therefore, proved their value in the prevention of hypertensive cardiovascular complications such as stroke and congestive heart failure. The physiologic changes occurring during antihypertensive treatment with thiazides have been extensively studied. The initial response to a thiazide is characterized by a mildly negative change in sodium and fluid balance. The resulting slight contraction in plasma volume is followed by reductions in cardiac output and blood pressure. Because these reductions are disproportionate, vascular resistance rises initially. In the longer term, plasma volume is partly restored, and cardiac output re-attains the baseline level. Thus, the reduction in blood pressure ultimately appears to be based on vasodilation. The mechanisms of this biphasic vascular response are not completely understood. This lack of insight, however, does not detract from the proven value of thiazides in treating hypertensive subjects.
Abstract: Several lines of evidence support the view that corticosteroids stimulate Na+, K+, HCO3-, and H+ transport by the TAL and that modulation of transport contributes to homeostasis of these ions. Although some details of the cellular and molecular mechanisms of corticosteroid action in the amphibian diluting segment are known, little is known about these pathways in TAL cells. In addition, the issue of mineralocorticoid versus glucocorticoid specificity and receptor localization in the TAL is not resolved. We anticipate that these intriguing issues will be addressed using TAL cells in culture and isolated TAL in conjunction with patch clamp, fluorescent probes and molecular biological approaches.
Abstract: In adult humans the ventilatory response to sustained hypoxia is biphasic, characterized by an early increase followed by a decline to an intermediate plateau. Recently, we have shown that this decrease in hypoxic sensitivity is long lasting, because up to 1 h of room air breathing is required for complete recovery of the initial hypoxic response (J. Appl. Physiol. 64: 521-528, 1988). It is not known whether this posthypoxia decrease in ventilatory response is general or specific only to hypoxic stimuli. We therefore examined responses to CO2 before and after hypoxia. The ventilatory response to 5 min of normoxic CO2 breathing was evaluated in eight normal adults on 2 days: 5 min before and after 25 min of normocapnic hypoxia (arterial O2 saturation +/- 80%) and 5 min before and after 25 min of room air breathing (control day). During hypoxia, ventilation (VI), after an initial increase, declined significantly. At the end of hypoxia, abrupt exposure to room air transiently dropped VI to values that were significantly below base line. On each experimental day, the first and second exposure to CO2 increased ventilation by a similar amount, averaging, respectively, 8.46 +/- 0.9 and 8.84 +/- 0.92 (SE) l/min on the hypoxic day and 8.24 +/- 0.96 and 7.65 +/- 0.94 l/min on the control day. All the hypercapnic increases of VI were accomplished through similar changes of breathing pattern with similar time courses. We conclude that sustained hypoxia does not affect the ventilatory response to CO2, but it selectively depresses hypoxic sensitivity.
Abstract: To determine how survival and clinical status were related to left ventricular (LV) size and systolic function after mitral valve replacement, 104 patients (48 mitral regurgitation [MR], 33 mitral stenosis [MS], and 23 MS/MR) with isolated mitral valve replacement were evaluated before and after surgery. Preoperative hemodynamic abnormalities by cardiac catheterization were improved 6 months after surgery in all three patient groups. The patients with MR exhibited reductions in LV end-diastolic volume index (EDVI) (117 +/- 51 to 89 +/- 27 ml/m2, p less than 0.001) and ejection fraction (EF) (0.56 +/- 0.15 to 0.45 +/- 0.13, p less than 0.001); however, the ratio of forward stroke volume to end-diastolic volume increased (0.32 +/- 0.21 to 0.45 +/- 0.17, p less than 0.001) because of the elimination of regurgitant volume. Survival analysis revealed that mortality was significantly higher in MS or MS/MR patients with postoperative EDVI more than 101 ml/m2 (p less than 0.001 and p less than 0.042, respectively) and in MR patients with postoperative EF less than or equal to 0.50 (p less than 0.031). Also, the majority of patients with MR or MS/MR and postoperative EDVI more than 101 ml/m2 and EF less than or equal to 0.50 were in New York Heart Association class III or IV. Multivariate logistic regression analysis in the patients with MR revealed that the strongest predictor of postoperative EF was preoperative EF (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Recent studies have demonstrated an increase in carbon dioxide (CO2) tension (PCO2) in both mixed venous and coronary vein blood early in the course of cardiac arrest and cardiopulmonary resuscitation. Because increased PCO2 in the myocardium correlates with both ischemic injury and depression of contractile function, the effects of hypertonic solutions of either the CO2-"generating" sodium bicarbonate (NaHCO3) buffer, a mixture of sodium carbonate (Na2CO3) and sodium bicarbonate (carbicarb) acting as a CO2-"consuming" buffer, or saline placebo (NaCl) were compared during cardiopulmonary resuscitation in 25 healthy minipigs. Both buffer agents significantly increased the pH and HCO3- of arterial, mixed venous and coronary vein blood. Bicarbonate increased whereas carbicarb reduced blood PCO2 in the systemic circuit as anticipated. However, neither the PCO2 nor the lactate content of coronary vein blood was favorably altered by buffer therapy. Four of eight animals treated with bicarbonate, five of eight treated with carbicarb and six of nine placebo-treated animals were successfully resuscitated and had a comparable 24 h survival rate. Coronary perfusion pressure during precordial compression, a critical determinant of resuscitability, was transiently decreased by each of the hypertonic solutions. Accordingly, neither CO2-generating nor CO2-consuming buffers mitigated increases in coronary vein PCO2 or improved the outcome of cardiopulmonary resuscitation under these experimental conditions.
Abstract: The tolerance of totally curarized subjects for prolonged breath hold is viewed by many as evidence that respiratory muscle contraction is essential to generate the sensation of breathlessness. Although conflicting evidence exists, none of it was obtained during total neuromuscular block. We completely paralyzed four normal, unsedated subjects with vecuronium (a non-depolarizing neuromuscular blocker). Subjects were mechanically ventilated with hyperoxic gas mixtures at fixed rate and tidal volume. End-expiratory PCO2 (PETCO2) was varied surreptitiously by changing inspired PCO2. Subjects rated their respiratory discomfort or ’air hunger’ every 45 sec. At low PETCO2 (median 35 Torr) they felt little or no air hunger. When PETCO2 was raised (median 44 Torr) all subjects reported severe air hunger. They had reported the same degree of air hunger at essentially the same PETCO2 before paralysis. When questioned afterwards all subjects said the sensation could be described by the terms ’air hunger’, ’urge to breathe’, and ’shortness of breath’, and that is was like breath holding. They reported no fundamental difference in the sensation before and after paralysis. We conclude that respiratory muscle contraction is not important in the genesis of air hunger evoked by hypercapnia.
Abstract: The glucose counterregulatory system is one of the most important homeostatic systems in physiology, since it normally prevents hypoglycaemia or, should it occur for any reason such as insulin administration, limits the severity of hypoglycaemia and ultimately may restore normoglycaemia. In normal nondiabetic subjects, activation of counterregulation does not result in overt hyperglycaemia in the post-absorptive state, because the pancreatic beta-cell increases insulin secretion. On the contrary, in subjects with insulin-dependent diabetes mellitus (IDDM) whose pancreatic B-cell cannot respond to an increase in plasma glucose, activated counterregulation may easily result in overt hyperglycaemia. There are two different circumstances under which counterregulation may contribute to excessive hyperglycaemia in IDDM, namely nonhypoglycaemic nocturnal activation of counterregulation (dawn phenomenon), and hypoglycaemic activation of counterregulation (Somogyi phenomenon). The dawn phenomenon is an increase in insulin requirements which occurs between 04.00 and 08.00 h in the absence of preceding hypoglycaemia and concomitant hypoinsulinemia. It is caused by a decrease in hepatic and extrahepatic sensitivity to insulin induced by the nocturnal secretion of growth hormone. The dawn phenomenon may contribute importantly to fasting hyperglycaemia in IDDM, because usually plasma insulin concentration following the pre-supper insulin injection decreases after 04.00 h, i.e. a time at which plasma insulin concentration should instead increase to maintain normoglycaemia. The Somogyi phenomenon is best defined as hyperglycaemia following hypoglycaemia and is caused by the insulin resistance induced by hypoglycaemic-activation of counterregulation. Although insulin resistance following hypoglycaemia is a constant event in IDDM, post-hypoglycaemic hyperglycaemia is not the rule. For example, if the responses of counterregulatory hormones to nocturnal hypoglycaemia are blunted, or plasma insulin concentration following hypoglycaemia is inappropriately high, post-hypoglycaemic insulin resistance is not powerful enough to result in overt hyperglycaemia in the fasting state. However, post-breakfast plasma glucose may be exaggerately elevated following nocturnal hypoglycaemia even in the case that fasting plasma glucose is only modestly increased. It is important to prevent nocturnal hypoglycaemia, not only to protect brain function, but also to prevent insulin resistance which may easily result in exaggerated hyperglycaemia and initiate the vicious circle "hypoglycaemia-hyperglycaemia-increase in insulin dose-risk for subsequent hypoglycaemia", and so on.
Abstract: Two cases of homicidal electrocutions are reported. A woman and her young son were killed in 1980 by her ex-husband. The criminal used electrical force as a method of killing. He wound flexible conducting wires around the limbs of the victims and switched on the current. He deliberately deceived his ex-wife by telling her that the circuits were incomplete and hence harmless. Thus, he persuaded her to be part of the circuits, so that a bulb could be lit when placed on her bare skin. The circumstances associated with these cases are given and the scene of the crime is described. Some important pathological aspects of electrical injuries are reviewed. The significance of pathological findings in the forensic investigations of electrocution is discussed.
Abstract: The effect of posture on plasma atrial natriuretic hormone (ANH) and renal function was studied in subjects with idiopathic edema. Sixty-five subjects with edema but with no clinical evidence for cardiac, renal, or pulmonary diseases were studied after they had been off all medication for 1 week or more. They had nothing by mouth after midnight and were admitted to the Clinical Research Center at 0800 h. They voided, were weighed, and had their blood pressure and pulse measured in the recumbent and upright positions. A needle was inserted, and subjects were recumbent for 0.5 h, after which blood was drawn for measurement of plasma ANH, serum sodium, potassium, and (in 35 subjects) creatinine. They were then given 150 mL 0.14% sodium chloride solution to drink every 0.5 h for the next 6 h. Urine was collected every 0.5 h for measurement of sodium, potassium, and creatinine. After 4 h of recumbency repeat blood samples were drawn, subjects ambulated for 2 h, after which final repeat blood samples were drawn. Subjects were considered to have postural edema if their upright urinary sodium/previous 2-h urinary sodium was less than 33%, and to have a normal response if it was 33% or more. The clinical characteristics of the 34 patients with postural edema and 31 patients with a normal response were similar. Plasma ANH levels (initial, after oral saline, and after standing) were similar in the two groups, and there was no relationship between changes in ANH and urinary sodium with standing. In conclusion, under conditions of mild oral sodium chloride loading, changes in plasma ANH do not cause the abnormal sodium retention found in patients with postural edema.
Abstract: This review examines the studies which have been undertaken to test the hypothesis that minimal change nephrotic syndrome of childhood (MCNS) is a primary immune disorder and that there is altered T-cell function which results in release of a circulating factor. This factor alters glomerular permeability, perhaps by modifying charge sites in the glomerular capillary bed, and results in selective proteinuria. The abnormalities in immune function observed in MCNS are summarized, as are the studies of circulating factors which have been identified. Although some agents have been shown to alter capillary permeability, the unequivocal demonstration of such a factor causing selective proteinuria in vivo, either directly or indirectly, is lacking. The question is raised whether intrarenal release or activation of mediators of altered permeability, rather than the systemic release of such factors, may be important in the pathogenesis of MCNS.
Abstract: The overwhelming majority of atrial natriuretic factor (ANF) receptors in kidney and vascular tissues do not mediate any of the known functional effects of the hormone. To test whether these receptors (C-ANF receptors) function as clearance receptors for circulating ANF-(1-28), we determined the effects of C-ANF-(4-23) [des[Gln18Ser19Gly20Leu21Gly22]rANF-(3-23)-NH2], a specific ligand of C-ANF receptors, on the pharmacokinetics and hydrolysis of 125I-labeled ANF-(1-28) in anesthetized rats. Radioactivity in plasma was characterized by trichloroacetic acid solubility and high-pressure liquid chromatography. C-ANF-(4-23) (1 and 10 micrograms.min-1.kg body wt-1) led to marked dose-dependent increases in initial plasma concentration of administered 125I-ANF-(1-28) and decreases in its volume of distribution at steady state (Vss), metabolic clearance rate (MCR), and appearance of hydrolytic products ([125I]monoiodotyrosine and free 125I) in plasma (Pm). At the highest dose, C-ANF-(4-23) decreased Vss from 97 +/- 12 to 36 +/- 2 ml/100 g body wt, MCR from 50 +/- 4 to 12 +/- 1 ml.min-1.100 g body wt-1, and Pm from 54 +/- 8 to 11 +/- 2% of initial plasma 125I-ANF-(1-28). The data demonstrate that C-ANF receptors are mainly responsible for the very large volume of distribution and fast MCR of ANF in the rat. In this manner, C-ANF receptors are likely to play an important role in the homeostasis of circulating ANF.
Abstract: The biologic function of the newly recognized binding proteins (BP) for human growth hormone (hGH) in human plasma is largely unknown; hGH circulates in part in complexed form in association with the BP. In a previous study we showed that the in vivo kinetics of hGH were altered in the presence of the BP. However, that study gave only qualitative information because the BP was present in excess and the complex was subject to dissociation in vivo. To gain more quantitative information about the in vivo behavior of complexed hGH, metabolic clearance (MCR), distribution volume (Vd), and degradation rate of a covalently crosslinked, stoichiometrically correct, chemically stable hGH-BP complex were measured. The MCR and the degradation rate of complexed hGH were tenfold lower than those of free hGH (P less than .001), and its Vd was significantly smaller than that for free hGH (P less than .001). The covalent complex was fully immunoreactive with polyclonal anti-hGH antibodies. We conclude that complexed hGH is protected from clearance and degradation by being restricted from access to degradation sites, including the proximal renal tubule and receptor-mediated delivery to intracellular proteolygic organelles. The data developed also yield preliminary information about the in vivo distribution of the BP itself. These data provide important guidelines for future studies regarding the in vivo effects of the BP. In addition, the results indicate that the principal epitope(s) of hGH remain(s) exposed on the outer surface of the complex.
Abstract: We have shown in surgical animal models that increased and decreased cardiac loading results in myocardial hypertrophy and atrophy, respectively. These changes, which are readily reversible upon the restoration of a normal cardiac load, occur without any requirement for neural or circulating intermediary factors. In our current studies we have focused first on an unequivocal demonstration of these same phenomena in a much simpler model consisting of isolated quiescent cardiocytes maintained in serum-free medium and second on an elucidation in isolated papillary muscles of the means by which a change in cardiac load is transduced into a change in cardiac mass. Adherent isolated adult cardiocytes held at their rest length exhibit only a very gradual loss of their differentiated features. In contrast, unloaded cardiocytes in suspension culture immediately cease nuclear RNA synthesis and rapidly come to resemble unloaded cardiac muscle–a cardiocyte cellular analog of cardiac tissue atrophy, while loaded adherent cardiocytes stretched past their rest length respond in terms of synthetic activity characteristic of growth initiation–a cardiocyte cellular analog of cardiac tissue hypertrophy. Both quiescent and contracting papillary muscles exhibit increased synthesis of cardiocyte structural proteins in direct relation to active and/or passive muscle tension. This load-dependent protein synthesis appears to require initial sodium influx through deformation-dependent sarcolemmal cation channels, in a manner analogous to the dependence of mitogen-stimulated growth initiation in a variety of other cell types on initial sodium entry, albeit by a different mechanism. Thus, load variation functions as an independent regulator of cardiac growth in the adult, and sarcolemmal deformation with consequent sodium entry may be an initial direct link between load and growth in the heart.
Abstract: The optimal dose of epinephrine during CPR in human beings is unknown. We studied ten prehospital cardiac arrest patients (six men and four women; mean age, 54 +/- 5 years) to determine the vasopressor response and change in the end-tidal carbon dioxide concentration (PetCO2) after incremental (1-, 3-, and 5-mg) doses of IV epinephrine given five minutes apart during closed-chest CPR. All patients were in ventricular fibrillation on arrival of the paramedics and did not respond to standard advanced cardiac life support. CPR was performed with a computerized Thumper; all patients were intubated and ventilated at 12 times a minute at an FiO2 of 0.8. Radial artery pressure was measured with a 20 angiocath inserted by radial artery cutdown. Paramedic response time was 4.3 +/- 0.5 minutes; elapsed time to emergency department arrival was 40.0 +/- 9.5 minutes. Initial blood gases were paO2, 241 +/- 50 mm Hg; pH, 7.23 +/- 0.08; paCO2, 27 +/- 5 mm Hg; and HCO3, 11 +/- 2 mEq/L. Baseline systolic and diastolic blood pressures were 47 +/- 5 mm Hg and 18 +/- 2 mm Hg, respectively. Systolic blood pressure was directly related to the dose of epinephrine (P less than .0001), rising to 69 +/- 7 mm Hg, 74 +/- 8 mm Hg, and 85 +/- 8 mm Hg after 1-, 3-, and 5-mg doses of epinephrine, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Hormonal regulation of renal ammonium production and handling has undergone recent intensive investigation. The relationship between hormone action and ammonium metabolism has been known since the beginning of this century. Hormones may directly affect production or excretion of ammonium. Second messengers have also been shown to effect changes in renal ammonium metabolism. Hormonal control of renal ammonium production and handling may play a role in regulation of acute acid-base metabolism, but its role in chronic acid-base pathophysiological states has yet to be determined.
Abstract: The half-life (t1/2) of disappearance of endogenous GH from serum was studied using physiological effectors to stimulate and then suppress GH release. GH secretion was stimulated by a single iv injection of GHRH, followed 45 min later by an iv bolus dose and then a 2.5-h infusion of somatostatin (SRIH) to suppress further release. The in vivo t1/2 of GH in seven men was calculated from serum GH concentrations measured at frequent intervals after beginning the SRIH infusion. The mean t1/2 of endogenous GH was 18.9 +/- 0.8 (+/- SE) min by monoexponential analysis and 3.5 +/- 0.7 and 20.7 +/- 0.7 min by biexponential fitting. In these normal men, the decline in GH concentrations after GHRH and SRIH administration was similar to that after the administration of GHRH alone, which yielded a t1/2 of 20.3 +/- 1.9 min. We conclude that the physiological kinetics of endogenous GH removal/disappearance can be estimated in vivo in man using GHRH with or without SRIH infusion.
Abstract: We have used an immunoradiometric assay for intact PTH in conjunction with calcium and citrate infusions to study whether levels of intact PTH are responsive to reversal of the direction of change in ionized calcium in normal humans. Eleven normal subjects received graded infusions of citrate or calcium on separate days to produce linear rates of decrease or increase in calcium. After discontinuation of the infusions, the return of calcium toward baseline was followed. Six subjects were given an infusion of citrate after the calcium infusion to speed the recovery of calcium toward baseline. Citrate-induced hypocalcemia produced a rise in serum PTH levels from 28.1 +/- 3.6 to 69.4 +/- 4.8 ng/L as calcium fell from 1.26 +/- 0.01 to 1.06 +/- 0.02 mmol/L. As calcium returned toward baseline, PTH levels fell dramatically, reaching levels indistinguishable from baseline despite persistent hypocalcemia. Slopes of regression lines defining the PTH-calcium relationships during decreasing and increasing calcium levels were significantly different. Those subjects receiving a calcium infusion alone showed a prompt suppression of PTH levels. As calcium returned toward baseline after the infusion, a modest decline in calcium produced no significant change in the PTH-calcium relationship. When citrate was used to return calcium to baseline, PTH levels rose from 7.8 +/- 2.0 to 55.0 +/- 6.8 ng/L as calcium fell from 1.42 +/- 0.02 to 1.26 +/- 0.02 mmol/L and defined a regression relationship significantly different from the period of increasing calcium. Thus, a hysteretic relationship between ionized calcium and levels of intact PTH can be induced in normal humans by reversing the direction of change in calcium. Therefore, the role played by calcium concentration per se in controlling PTH secretion may be part of more complex and dynamic regulatory mechanisms.
Abstract: Simultaneous arterial (aortic), mixed venous (pulmonary artery), and myocardial venous (great cardiac vein) blood gas and lactate concentrations were obtained in 12 dogs before and during cardiac arrest and CPR. We observed marked mixed venous and myocardial venous acidosis and increased PaCO2 but normal pHa and reduced PaCO2. Furthermore, the pH was significantly lower and the PCO2 significantly higher at the myocardial venous site compared to the mixed venous site, and marked myocardial lactate production occurred during CPR. Calculated bicarbonate and CO2 content (CCO2) did not increase during CPR from any site compared to control values and actually decreased significantly in arterial and myocardial venous samples. Changes in hydrogen ion concentration in both mixed venous and myocardial venous blood correlated with changes in lactate concentration but not total CCO2. Our results during CPR demonstrate a) a significant discrepancy between arterial and mixed venous blood gases but also a large and significant discrepancy between mixed venous and myocardial venous blood gases, b) significant anaerobic systemic and myocardial metabolism, and c) that mixed venous and myocardial venous acidosis is possibly a result of lactic acidosis.
Abstract: We analyzed the kinetics of the clotting system by a chromogenic substrate method in plasma with isolated factor deficiency. The sigmoidal extinction curve obtained was mathematically described by an equation with four constants K(i) relating to the activity of clotting factors and to the concentration of fibrinogen. The analysis of constants obtained from dilution series of factor-deficient plasma revealed a distribution pattern differing from one factor to another both for the extrinsic and the intrinsic system. The observations indicated that isolated factor deficiency may be identified through the analysis of 2 of the 4 constants, K(1) being the time value of the point of inflection of the extinction curve and K(2) a measure for the slope of the curve at the point of inflection. The observation was confirmed by a reclassification through nearest-neighbor discriminant analysis of K(1) and K(2) which revealed a correct classification in the pathological range for all factor deficiencies investigated with the exception of factors VIII and IX, the distribution patterns of which were superposed within the limits of distribution.
Abstract: 1. DOCA and 9 alpha-fludrocortisone were given to mice on a high-sodium diet for periods of up to 20 weeks, resulting in decreases in plasma renin concentration, renal renin concentration and renal renin mRNA with both treatments. 2. Plasma renin concentration was suppressed prior to suppression of renin mRNA and renal renin levels, indicating that suppression of synthesis and secretion of renin occur separately. 3. The decrease in renal renin concentration that occurred with DOCA was greater and more rapid than the decrease that occurred with 9 alpha-fludrocortisone, suggesting that DOCA caused intra-renal breakdown of renin. 4. When DOCA was given to mice on a low-sodium diet, plasma renin concentration and renal renin concentration increased, indicating that the effects of DOCA on renin levels were dependent on dietary sodium. 5. Renin secretion and synthesis appeared to be controlled by different mechanisms and sodium balance has an important effect on both processes.
Abstract: 1. Anterior tibial muscle protein synthesis in seven healthy postabsorptive men was determined from increases in muscle protein bound leucine enrichment during a primed continuous infusion of L-[1-13C]leucine. Biopsies were taken 30 min after the beginning of leucine infusion (when plasma 13C enrichment was steady), 240 min later during continued fasting and again after 240 min of infusion of a mixed amino acid solution which increased plasma total amino acid concentrations by 37%. The mean enrichment of 13C in plasma alpha-ketoisocaproate was used as an index of the enrichment of the precursor pool for leucine metabolism. 2. Anterior tibial muscle mixed protein synthetic rate during fasting was 0.055 (SD 0.008)%/h and this increased by an average of 35% during infusion of mixed amino acid to 0.074 (SD 0.021)%/h (P less than 0.05). 3. Whole-body protein breakdown (expressed as the rate of endogenous leucine appearance in plasma) was 121 (SD 8) mumol h-1 kg-1 during fasting and decreased (P less than 0.01) by an average of 12% during amino acid infusion. Leucine oxidation was 18 (SD 3) mumol h-1 kg-1 during fasting and increased (P less than 0.001) by 89% during amino acid infusion. Whole-body protein synthesis (non-oxidative leucine disappearance) was 104 (SD 6) mumol h-1 kg-1 during fasting and rose by 13% (P less than 0.001) during mixed amino acid infusion. 4. 13C enrichment of muscle free leucine was only 61 (SD 19)% of that in plasma alpha-ketoisocaproate and this increased to 74 (SD 16)% (P less than 0.02) during mixed amino acid infusion. 5. The results suggest that increased availability of amino acids reverses whole-body protein balance from negative to positive and a major component of this is the increase in muscle protein synthesis.
Abstract: To evaluate further the role of adenosine in the transmission of tubuloglomerular feedback signals, we studied the effects of an adenosine receptor antagonist and an adenosine A1-receptor agonist on feedback-mediated changes in stop-flow pressure (SFP). In orthograde perfusion experiments conducted in anesthetized rats, systemic administration of the adenosine receptor blocker 1,3-dipropyl-8-sulfophenylxanthine (PSPX) did not inhibit feedback responses. Control SFP feedback responses averaged 9.7 +/- 0.65 before and 8.6 +/- 0.55 mmHg during systemic infusion of the receptor blocker. In retrograde perfusion experiments, intratubular administration of the A1 agonist (360 nM) N6-cyclopentyladenosine (CPA), added to a hypotonic solution, markedly enhanced feedback responses. This effect was completely prevented by coinfusion of PSPX. Addition of 10 mM of the antagonist to the CPA-containing solution attenuated SFP feedback responses to less than 1 mmHg (delta = 0.44 +/- 0.50). Furthermore, PSPX also inhibited feedback responses obtained with an isotonic solution alone. Furosemide, which has been shown to block normal SFP responses obtained with isotonic solutions, failed to block CPA-induced decreases in SFP. These data demonstrate that intraluminal administration of an adenosine A1 analogue causes feedback-mediated decreases in SFP and therefore support a role for adenosine receptors in the signal transmission pathway.
Abstract: Cardiopulmonary function was measured in 6 conscious dogs with progressive degrees of induced pneumothorax. Minute volume, respiratory rate, central venous pressure, systemic arterial pressure, pulmonary arterial pressure, pulmonary arterial occlusion pressure, heart rate, cardiac output, and arterial and mixed venous blood gases were determined before pneumothorax and at progressive volumes of pneumothorax equivalent to 50, 100, and 150% of the calculated lung volume. Tidal volume, pulmonary vascular resistance, alveolar to arterial O2 tension difference, physiologic dead space fraction, and pulmonary venous admixture also were calculated. Linear increases in respiratory rate, central venous pressure, alveolar to arterial O2 tension difference, and pulmonary venous admixture differed significantly (P less than 0.05). Linear decreases in tidal volume, pHv, pHa, PvO2, and PaO2 were also significantly different. Quadratic increases were significantly different for pulmonary arterial pressure and pulmonary vascular resistance. Trends were not significantly different for other values.
Abstract: Studies were performed to characterize the determinants of proximal tubule ammonia entry (and retention) in vivo. Rat proximal tubules were studied in vivo using in situ microperfusion. In both normal animals and animals with metabolic acidosis, increasing luminal flow rate significantly enhanced luminal ammonia entry. In contrast, luminal pH was not as important in determining ammonia entry. Analysis of the levels of luminal NH3 in these studies was not consistent with simple diffusion equilibrium of NH3. In animals with chronic metabolic acidosis, additional studies demonstrated that inhibition of the Na+-H+ exchanger had no direct effect on luminal ammonia entry. However, studies of ammonia efflux from tubules perfused with 10 mmol/L ammonia demonstrated significant transport of both NH3 and NH4+. Studies of luminal glutamine deamidation via gamma-glutamyltransferase in control conditions did not indicate a significant role for luminal ammoniagenesis in the superficial proximal tubule in vivo. These and other recent studies of proximal tubule ammonia transport significantly modify the traditional diffusion equilibrium (of NH3) model of ammonia transport. Luminal flow rate is an important determinant of luminal ammonia entry. Transport of NH4+, both into and out of the tubule lumen, represents a major component of total ammonia transport.
Abstract: The mechanisms responsible for the elevated levels of circulating GH observed in diabetes mellitus (DM) remain incompletely defined. To assess the episodic fluctuations in serum GH as a reflection of hypothalamic-pituitary activity, we accumulated GH concentration-time series in a total of 48 adult men and women with and without insulin-dependent DM by obtaining serum samples at 10-min intervals over 24 h. Significant pulses of GH release were subsequently identified and characterized by an objective, statistically based pulse detection algorithm (Cluster) and fixed circadian (24-h) periodicities of secretory activity, resolved using Fourier expansion time-series analysis. Compared to those in age-matched controls, integrated 24-h concentrations of GH were 2- to 3.5-fold higher in diabetic men (P = 0.002) and women (P = 0.0005). Both men and women with DM had over 50% more GH pulses per 24 h than their non-DM counterparts. In addition, maximal GH pulse amplitude was markedly elevated in the men and women with DM (P = 0.0019 and 0.0189, respectively). That the increase in maximal pulse amplitude was accounted for by greater baseline levels was documented by a higher interpulse valley mean GH concentration in the diabetics compared to the controls (P = 0.0437 and 0.0056, men and women, respectively) and the absence of any difference in incremental pulse amplitude for either sex (P greater than 0.05). DM men had larger GH pulse areas (P = 0.039) than control men, apparently accounted for by greater pulse width (P = 0.0037). Pulse areas in DM and non-DM women were indistinguishable. Time-series analysis revealed that the 24-h (circadian) rhythms of serum GH concentrations exhibited significantly increased amplitudes in the diabetic group as a whole (compared to the controls, P = 0.011). However, the times of maximal GH concentrations (acrophases) were not significantly different. As a group, serum insulin-like growth factor-I was lower in DM vs. non-DM individuals (P = 0.0014), although when separated by sex this difference did not reach statistical significance in women (P = 0.317). The present data confirm the higher circulating levels of GH previously reported to occur in individuals with poorly controlled DM. The altered frequency of GH pulses together with enhanced interpulse GH concentrations and an amplified circadian GH rhythm are compatible with hypothalamic dysfunction associated with dysregulation of somatostatin and/or GHRH secretion.(ABSTRACT TRUNCATED AT 400 WORDS)
Abstract: A number of investigators have proposed that the sense of respiratory discomfort accompanying hypercapnia depends on respiratory mechanoreceptors which inform the sensory cortex of reflex increases in breathing. To test this hypothesis, we studied subjects whose respiratory muscles were paralyzed, and who were thus unable to increase breathing in response to hypercapnia. We gradually elevated inspired PCO2 in four tracheostomized quadriplegic subjects supported by constant mechanical ventilation. These subjects reported sensations of ’air hunger’ (e.g., "short of breath", "air-starved") when end-tidal PCO2 increased 10 Torr (mean) above their resting levels. In a second experiment we used the forced-choice technique to determine the ability of three of these subjects to detect repeated changes of end-tidal PCO2. Two detected 7 Torr changes, the third detected 11 Torr changes. These data suggest that changes in breathing are not necessary to evoke the sense of ’air hunger’. We conclude that the likely mechanisms are (1) projection of chemoreceptor afferent traffic to the sensory cortex, and (2) projection of corollary discharge from brainstem respiratory centers to the sensory cortex.
Abstract: Seven dehydrated volunteers received three hour infusions of 0.8 pmol kg-1 min-1 of human alpha-atrial natriuretic peptide (h-alpha ANP) or vehicle alone (Ve) in a single-blind, randomized cross-over design. H-alpha ANP infusion increased plasma h-alpha ANP from 4.2 +/- 0.4 to 20.3 +/- 6.4 pm. H-alpha ANP suppressed plasma renin activity from 3.30 +/- 0.48 to 1.37 +/- 0.35 ng ml-1 hr-1 (P less than 0.001 vs. Ve). Plasma aldosterone was unaltered by h-alpha ANP. Fractional excretion of filtered sodium (FENa) changed from 0.92 +/- 0.09 to 1.13 +/- 0.16% with h-alpha ANP, and from 1.02 +/- 0.09 to 0.69 +/- 0.11% with Ve (P less than 0.01 h-alpha ANP vs. Ve). FEK was unchanged. FEpo4 increased from 7.2 +/- 1.2 to 9.2 +/- 1.2% and FELi from 22.1 +/- 1.4 to 24.9 +/- 3.0% with h-alpha ANP (both P less than 0.05 vs. Ve). H-alpha ANP decreased mean urinary osmolality by approximately 150 mOsmol kg-1 compared to Ve (P less than 0.01). GFR, RPF and filtration fraction were unchanged by h-alpha ANP, H-alpha ANP was associated with a significant tachycardia (P less than 0.01 vs. Ve) but with no significant change in arterial pressure. These results suggest that small increments of plasma h-alpha ANP, mimicking physiological changes, are natriuretic at least partly by reducing proximal tubular reabsorption of sodium, and also impair urinary concentration.
Abstract: We studied the effects of dietary NaCl intake on the renal distal tubule by feeding rats high or low NaCl chow or by chronically infusing furosemide. Furosemide-treated animals were offered saline as drinking fluid to replace urinary losses. Effects of naCl intake were evaluated using free-flow micropuncture, in vivo microperfusion, and morphometric techniques. Dietary NaCl restriction did not affect NaCl delivery to the early distal tubule but markedly increased the capacity of the distal convoluted tubule to transport Na and Cl. Chronic furosemide infusion increased NaCl delivery to the early distal tubule and also increased the rates of Na and Cl transport above the rates observed in low NaCl diet rats. When compared with high NaCl intake alone, chronic furosemide infusion with saline ingestion increased the fractional volume of distal convoluted tubule cells by nearly 100%, whereas dietary NaCl restriction had no effect. The results are consistent with the hypotheses that (a) chronic NaCl restriction increases the transport ability of the distal convoluted tubule independent of changes in tubule structure, (b) high rates of ion delivery to the distal nephron cause tubule hypertrophy, and (c) tubule hypertrophy is associated with increases in ion transport capacity. They indicate that the distal tubule adapts functionally and structurally to perturbations in dietary Na and Cl intake.
Abstract: The excitability of proprio- and exteroceptive spinal reflexes was monitored electrophysiologically and clinically during the occurrence of brain death (BD) in 8 patients. After a period of total reflex unresponsiveness, the soleus H reflex attained a steady-state excitability level in 2-6 h. The recovery cycle of this response regained its normal shape at 10-20 h. The threshold of the cutaneous reflex evoked in the biceps femoris by electrical stimulation of the sural nerve had become normal in 4-13 h, although the response displayed an abnormal multi-component pattern. Digital responses to mechanical stimulation of the foot sole were evident after 6-8 h. Knee and ankle jerks were never evoked during the time of monitoring. The time-courses of the changes in excitability were not directly correlated with the fall in the blood pressure which may occur during BD. It is concluded that the human spinal cord reacts to BD with a spinal shock, characterized by sequential recovery of reflex transmission. The overall timing of this process appears to be much shorter than that previously described for the spinal shock following traumatic transection of the cord, but the latter was never studied in the earliest phases.
Abstract: In recent years, transplantation has assumed an important role in the treatment of patients with end-stage diseases of most major organ systems. However, the greatest limitation in organ transplantation today is organ supply. Among factors that can affect the organ supply favorably, donor management has received the least attention. This review addresses management of the multi-organ donor within the intensive care unit. With an increased awareness of donor management issues and the application of a rational physiological approach, the supply of functional organs for transplantation can be increased.
Abstract: The beta-adrenergic receptor kinase (beta-ARK), which specifically phosphorylates only the agonist-occupied form of the beta-adrenergic and closely related receptors, appears to be important in mediating rapid agonist-specific (homologous) desensitization. The structure of this enzyme was elucidated by isolating clones from a bovine brain complementary DNA library through the use of oligonucleotide probes derived from partial amino acid sequence. The beta-ARK cDNA codes for a protein of 689 amino acids (79.7 kilodaltons) with a protein kinase catalytic domain that bears greatest sequence similarity to protein kinase C and the cyclic adenosine monophosphate (cyclic AMP)–dependent protein kinase. When this clone was inserted into a mammalian expression vector and transfected into COS-7 cells, a protein that specifically phosphorylated the agonist-occupied form of the beta 2-adrenergic receptor and phosphorylated, much more weakly, the light-bleached form of rhodopsin was expressed. RNA blot analysis revealed a messenger RNA of four kilobases with highest amounts in brain and spleen. Genomic DNA blot analysis also suggests that beta-ARK may be the first sequenced member of a multigene family of receptor kinases.
Abstract: To assess arteriovenous differences in acid-base status, we measured the pH and partial pressure of carbon dioxide (PCO2) in blood drawn simultaneously from the arterial and central venous circulations in 26 patients with normal cardiac output, 36 patients with moderate and 5 patients with severe circulatory failure, and 38 patients with cardiac or cardiorespiratory arrest. The patients with normal cardiac output had the expected arteriovenous differences: venous pH was lower by 0.03 unit, and venous PCO2 was higher by 0.8 kPa (5.7 mm Hg). These differences widened only slightly in those with moderate cardiac failure. Additional simultaneous determinations in mixed venous blood from pulmonary arterial catheters were nearly identical to those in central venous blood. In the five hypotensive patients with severe circulatory failure there were substantial differences between the mean arterial and central venous pH (7.31 vs. 7.21) and PCO2 (5.8 vs. 9.0 kPa [44 vs. 68 mm Hg]). Large arteriovenous differences were present during cardiac arrest in patients whose ventilation was mechanically sustained, whether sodium bicarbonate had been administered (pH, 7.27 vs. 7.07; PCO2, 5.8 vs. 8.6 kPa [44 vs. 65 mm Hg]) or not (pH, 7.36 vs. 7.01; PCO2, 3.7 vs. 10.2 kPa [28 vs. 76 mm Hg]). By contrast, in patients with cardiorespiratory arrest, large arteriovenous differences were noted only when sodium bicarbonate had been given (pH, 7.24 vs. 7.01; PCO2, 9.5 vs. 16.9 kPa [71 vs. 127 mm Hg]). We conclude that both arterial and central venous blood samples are needed to assess acid-base status in patients with critical hemodynamic compromise. Although information about arterial blood gases is needed to assess pulmonary gas exchange, in the presence of severe hypoperfusion, the hypercapnia and acidemia at the level of the tissues are detected better in central venous blood.
Abstract: The normal relationship between arterial and venous acid-base composition is altered in hemodynamic compromise. Because the mechanism of this phenomenon remains conjectural, we have studied the acid-base profile and the end-tidal PCO2 of dogs with normal or depressed hemodynamic status in association with either normal ventilation or respiratory arrest. Reductions in cardiac output widened the arteriovenous difference in PCO2 and pH, largely due to arterial hypocapnia but also to venous hypercapnia, and decreased end-tidal PCO2. The arteriovenous gradients for PCO2 and pH of -5.1 +/- 0.4 mmHg and 0.02 +/- 0.01, respectively, during normal hemodynamics widened progressively with graded circulatory compromise reaching values of -30 +/- 5 mmHg for PCO2 (P less than 0.01) and 0.35 +/- 0.05 for pH (P less than 0.01) during cardiac arrest. Development of this disparity, however, required the presence of substantial pulmonary ventilation, since respiratory arrest obliterated the arteriovenous gradients. We propose that arterial hypocapnia, which occurs in association with reduced CO2 excretion, is secondary to an increased ventilation-to-perfusion ratio that reflects a disproportionate decrement in cardiac output. Venous hypercapnia, on the other hand, results from a greater than normal addition of CO2 per unit of blood traversing the capillaries of the hypoperfused peripheral tissues and a diminished CO2 excretion because of pulmonary hypoperfusion. Titration of bicarbonate stores by ongoing production of organic acids might also contribute to venous hypercapnia.
Abstract: Arterial blood gases were measured in 52 unanesthetized Sprague-Dawley rats following six weeks exposure to either room air at ambient altitude (950 m), room air containing 100 ppm CO at ambient altitude, room air at 4575 m simulated high altitude, or room air containing 100 ppm CO at 4575 m simulated high altitude. PaCO2 was significantly higher in animals exposed to CO both at ambient altitude (38.2 vs 34.5 Torr) and simulated high altitude (28.3 vs 23.6 Torr). The data show that chronic exposure to low concentrations of CO depresses ventilatory drive at both ambient and simulated high altitude. This depression could be related to changes in brain blood flow and the acidity of the central medullary chemosensitive area or to changes in peripheral chemoreceptor activity.
Abstract: It seems clear from the studies reviewed here that there is adequate evidence to support the concept of a biphasic response of the thyroid gland to cold as first postulated by Moll et al. (1972). The initial response to acute exposure to cold begins at the level of the hypothalamus as a result of either neural stimuli from skin and other areas and/or blood of somewhat lower than normal temperature reaching the hypothalamus (Andersson et al., 1963). As a result, the secretion of norepinephrine and/or dopamine may increase, and serotonin and/or somatostatin may decrease. The net result of these is an increase in the release of TRH from the hypothalamus. This, in turn, stimulates the cascade for the release of TSH from the anterior pituitary gland and thyroid hormone from the thyroid gland. Moll et al. (1972) postulated the lack of a feedback limb in this acute phase, and, indeed, this may be the case. It is possible, however, that certain hormones, such as somatostatin, norepinephrine, T3, and T4 could act in the capacity of feedback inhibitors. Additional experiments will be required to assess this possibility. The transitional link between the acute (less than 1 day) and chronic (greater than 1 day) phases of the response of the thyroid gland to cold could be T4 itself. An increase in the concentration of T4 in plasma has been reported to increase peripheral deiodination of T4 to T3 by kidneys and liver of rats. There are no studies at present to indicate that hepatic conjugation can be increased by elevation of plasma levels of T4 and T3. If it can, these responses would provide adequate reasons as to why peripheral metabolism of thyroid hormones increases during chronic exposure to cold. The time-course for these changes to occur needs to be studied in greater detail to establish the sequence of events following acute exposure to cold. The latter may also increase urinary excretion of T4 and T3 in man, but not the rat. This suggests that another aspect of exposure to cold needing additional study is measurement of the binding affinities of T4 and T3 for their transport proteins during exposure to cold as compared to affinities prior to exposure to cold. If binding affinities are reduced, the amount of free hormones would increase and, consequently the likelihood of being excreted into urine and conjugated by the liver would also increase.(ABSTRACT TRUNCATED AT 400 WORDS)
Abstract: Increased leg venous compliance may contribute to postflight orthostatic intolerance in astronauts. We reported that leg compliance was inversely related to the size of the muscle compartment. The purpose of this study was to test the hypothesis that reduced muscle compartment after long-duration exposure to microgravity would cause increased leg compliance. Eight men, 31-45 yr old, were measured for vascular compliance of the calf and serial circumferences of the calf before and after 30 days of continuous 6 degrees head-down bed rest. Cross-sectional areas (CSA) of muscle, fat, and bone compartments in the calf were determined before and after bed rest by computed tomography. From before to after bed rest, calculated calf volume (cm3) decreased (P less than 0.05) from 1,682 +/- 83 to 1,516 +/- 76. Calf muscle compartment CSA (cm2) also decreased (P less than 0.05) from 74.2 +/- 3.6 to 70.6 +/- 3.4; calf compliance (ml.100 ml-1.mmHg-1.100) increased (P less than 0.05) from 3.9 +/- .7 to 4.9 +/- .5. The percent change in calf compliance after bed rest was significantly correlated with changes in calf muscle compartment CSA (r = 0.72, P less than 0.05). The increased leg compliance observed after exposure to simulated microgravity can be partially explained by reduced muscle compartment. Countermeasures designed to minimize muscle atrophy in the lower extremities may be effective in ameliorating increased venous compliance and orthostatic intolerance after spaceflight.
Abstract: 1. In order to examine the handling of sodium by the nephrotic kidney when separated from the immediate influences of renal nerves and humoral factors, kidneys were taken from nephrotic rats (puromycin aminonucleoside) and studied over a range of perfusion pressures using the isolated perfused kidney technique. 2. When perfused with medium containing 6.7 g/dl albumin, the nephrotic kidneys performed differently from controls with a reduction in sodium excretion at all pressures [(mean +/- SEM) 1.14 +/- 0.43 vs 4.20 +/- 0.69 mumol/min at 105 mmHg (14 kPa); 6.32 +/- 1.56 vs 44.60 +/- 5.30 mumol/min at 150 mmHg (20 kPa)]. Renal vascular resistance, inulin clearance, fractional sodium excretion and fractional lithium excretion were also reduced. 3. When kidneys were perfused without oncotic agent these differences between nephrotic and control kidneys remained. Perfusion with medium containing 10 g/dl albumin, designed to prevent glomerular filtration, abolished the difference in vascular resistance between the two groups. Captopril had no effect on the sodium retention or vascular resistance of nephrotic kidneys. 4. It was concluded that (a) the isolated nephrotic kidney demonstrates increased avidity for sodium, (b) the abnormality of sodium handling is not dependent on the presence of altered oncotic forces, and (c) the alteration in vascular resistance is conditional upon glomerular filtration.
Abstract: We have reviewed carbohydrate metabolism in skeletal muscle with an emphasis on recent information. In this review a significant number of points have been made. These are summarized below. 1. CP and glycogen are concomitantly metabolized during short-term (less than or equal to 10 s) intense exercise. 2. Both epinephrine and contractile activity regulate glycogen use in muscle. 3. Glycogen sparing during exercise is promoted by fatty acids and probably glucose. 4. Glycogenesis increases during exercise in exercising muscle. 5. Ingested glucose is easily metabolized during exercise. 6. The heterogeneity in glucose uptake among muscles at rest and during exercise is likely not caused by blood flow differences per se. 7. Insulin binding, glucose transporters, glucose uptake, and glycogenesis are greater in ST than in FT muscles. 8. Acute changes in glucose metabolism are not always attributable to concomitant changes in insulin binding to its receptor. 9. Contractile activity alone will increase glucose uptake in muscle, and insulin is not required. 10. Insulin and contractile effects on glucose uptake are additive, suggesting that these stimuli mobilize different pools of glucose transporters. 11. Glycogen loss occurs in exercising and non-exercising muscle; therefore this substrate is not an appropriate index of muscle contractile activity. 12. Carbohydrate mobilization does not appear to be strictly determined by need for this substrate nor by the rate of muscle metabolism. 13. Glyconeogenesis from lactate occurs in ST and FT muscles and is regulated by pH.
Abstract: In this article we summarize studies of the hemodynamic and endocrine effects of desoxycorticosterone (DOC)-induced hypertension in dogs and also review new data of the action of this steroid on baroreceptors. The hemodynamic effect of subcutaneous injections of DOC to dogs, without supplementation of salt in their diet, consisted of increases in arterial pressure that were sustained for a 28-day observation period and associated with augmented cardiac output. At the early stage of the hypertensive response there was a rise in plasma Na+ concentration accompanied by increases in the plasma and cerebrospinal fluid (CSF) levels of vasopressin. The activity of the peripheral renin angiotensin system, as evaluated by the longitudinal changes in plasma renin activity and plasma immunoreactive angiotensin II (irAng-II), was markedly depressed in the hypertensive dogs. In contrast, the concentration of irAngII in the CSF did not change. Additional studies of the carotid occlusion reflex in anesthetized dogs revealed an enhanced buffering baroreceptor capacity in the early (less than day 10), but not the late (greater than day 28), stages of the hypertension. The abnormality in baroreflex function may be mediated by an effect of the steroid on an activity of brain angiotensin II that influences the inhibitory interaction between high and low pressure baroreceptors. The data acquired in these studies agree with the notion that excess mineralocorticoid production causes hypertension by mechanisms that influence the neurohormonal control of blood pressure by the central nervous system.
Abstract: In a five-center study, 73 patients with severe head injury and elevated intracranial pressure (ICP) were randomly assigned to receive either a regimen that included high-dose pentobarbital or one that was otherwise similar but did not include pentobarbital. The results indicated a 2:1 benefit for those treated with the drug with regard to ICP control. When patients were stratified by prerandomization cardiac complications, the advantage increased to 4:1. A multiple logistic model considering treatment and selected baseline variables indicated a significant positive treatment effect of barbiturates, a significant effect of time from injury to randomization, and an interaction of treatment with cardiovascular complications. However, of 925 patients potentially eligible for randomization, only 12% met ICP randomization criteria. The results support the hypothesis that high-dose pentobarbital is an effective adjunctive therapy, but that it is indicated in only a small subset of patients with severe head injury.
Abstract: The base deficit (BD), is a potentially useful indicator of volume deficit in trauma patients. To evaluate BD as an index for fluid resuscitation, the records of 209 trauma patients with serial arterial blood gases (ABG’s) were reviewed. The patients were grouped according to initial BD: mild, 2 to -5; moderate, -6 to -14; and severe, less than -15. The volume of resuscitative fluid administered, change in BD, mean arterial pressure (MAP), and presence of ongoing hemorrhage were analyzed for differences between the BD groups. The MAP decreased significantly and the volume of fluid required for resuscitation increased with increasing severity of BD group. A BD that increased (became more negative) with resuscitation was associated with ongoing hemorrhage in 65%. The data suggest that the BD is a useful guide to volume replacement in the resuscitation of trauma patients.
Abstract: 1. The subjective changes accompanying alterations in inspired oxygen concentration during heavy exercise have been investigated single blind, in normal subjects. 2. In particular, the intensity of the sensation of breathlessness was quantified using a visual analogue scale and changes were compared with those in objective ventilatory measures. 3. Eleven subjects performed three steady-state work-load exercise tests on different days and 100% O2, 15% O2 or air were randomly administered for a fixed interval during each test. 4. Compared with air breathing, all subjects felt less breathless during 100% O2 breathing, and ten of them felt more breathless when inspiring 15% O2; these changes were reversed on return to air breathing. 5. During and after 100% O2, the time course of changes in breathlessness was similar to those for ear arterial oxygen saturation and minute ventilation such that it could be a secondary response to either. However, during and after inspiration of 15% O2, changes in breathlessness occurred relatively more quickly than those in ventilation, more closely reflecting changes in oxygen saturation; this suggests that hypoxia, per se, could contribute to the genesis of this sensation. 6. Individual variability in breathlessness responses to exercise and changes in inspired oxygen concentration did not correlate with objective ventilatory changes; neither were changes in breathlessness in the group particularly associated with changes in respiratory frequency or tidal volume.
Abstract: We examined the interrelation between CO2 and the ventilatory response to moderate (80% arterial saturation) sustained hypoxia in normal young adults. On a background of continuous CO2-stimulated hyperventilation, hypoxia was introduced and sustained for 25 min. Initially, with the introduction of hypoxia onto hypercapnia, there was a brisk additional increase in inspiratory minute ventilation (VI) to 284% of resting VI, but the response was not sustained and hypoxic VI declined by 36% to a level intermediate between the initial increase and the preexisting hypercapnic hyperventilation. Through the continuous hypercapnia, the changes in hypoxic ventilation resulted from significant alterations in tidal volume (VT) and mean inspiratory flow (VT/TI) without changes in respiratory timing. In another experiment, sustained hypoxia was introduced on the usual background of room air, either with isocapnia or without maintenance of end-tidal CO2 (ETCO2) (poikilocapnic hypoxia). Regardless of the degree of maintenance of ETCO2, during 25 min of sustained hypoxia, VI showed an initial brisk increase and then declined by 35-40% of resting VI to a level intermediate between the initial response and resting room air VI. For both isocapnia and poikilocapnic conditions, the attenuation of VI was an expression of a diminished VT. Thus the decline in ventilation with sustained hypoxia occurred regardless of the background ETCO2, suggesting that the mechanism underlying the hypoxic decline is independent of CO2.
Abstract: We have investigated (a) effects of varying proton concentration on force and shortening velocity of glycerinated muscle fibers, (b) differences between these effects on fibers from psoas (fast) and soleus (slow) muscles, possibly due to differences in the actomyosin ATPase kinetic cycles, and (c) whether changes in intracellular pH explain altered contractility typically associated with prolonged excitation of fast, glycolytic muscle. The pH range was chosen to cover the physiological pH range (6.0-7.5) as well as pH 8.0, which has often been used for in vitro measurements of myosin ATPase activity. Steady-state isometric force increased monotonically (by about threefold) as pH was increased from pH 6.0; force in soleus (slow) fibers was less affected by pH than in psoas (fast) fibers. For both fiber types, the velocity of unloaded shortening was maximum near resting intracellular pH in vivo and was decreased at acid pH (by about one-half). At pH 6.0, force increased when the pH buffer concentration was decreased from 100 mM, as predicted by inadequate pH buffering and pH heterogeneity in the fiber. This heterogeneity was modeled by net proton consumption within the fiber, due to production by the actomyosin ATPase coupled to consumption by the creatine kinase reaction, with replenishment by diffusion of protons in equilibrium with a mobile buffer. Lactate anion had little mechanical effect. Inorganic phosphate (15 mM total) had an additive effect of depressing force that was similar at pH 7.1 and 6.0. By directly affecting the actomyosin interaction, decreased pH is at least partly responsible for the observed decreases in force and velocity in stimulated muscle with sufficient glycolytic capacity to decrease pH.
Abstract: Renal vasodilation has a marked effect on the pressure-natriuresis relationship. The purpose of this study was to determine the role of renal interstitial hydrostatic pressure (RIHP) in mediating the effect of renal perfusion pressure (RPP) on urinary sodium excretion rate (UNaV) in control and vasodilated kidneys. The effects of RPP on UNaV and RIHP were determined in dogs under control conditions and during renal vasodilation with acetylcholine (Ach, 2.0 micrograms.kg-1.min-1) or secretin (SEC, 0.025 micrograms.kg-1.min-1). Decreases in RPP in control kidneys from 130 to 60 mmHg decreased UNaV from 2.9 +/- 0.1 to 0.6 +/- 0.3 microeq/min and fractional excretion of Na (FENa) from 0.15 +/- 0.08 to 0.06 +/- 0.04%. These changes were associated with significant reductions in RIHP (8.9 +/- 0.6 to 5.6 +/- 1.2 mmHg). In Ach-vasodilated kidneys, reductions in RPP from 130 to 60 mmHg decreased UNaV from 149.8 +/- 52.4 to 0.2 +/- 0.1 microeq/min and FENa from 3.42 +/- 1.18 to 0.012 +/- 0.01%. RIHP decreased from 17.8 +/- 3.4 to 8.4 +/- 1.3 mmHg, despite autoregulation of RBF. Renal vasodilation with SEC, which did not affect RIHP, had only a small effect on the relationship between RPP and UNaV. These data suggest that RIHP may be playing an important role in mediating the effect of RPP on UNaV.
Abstract: To evaluate radiographic criteria recently proposed for determining causes of pulmonary edema, the authors studied 45 patients with severe pulmonary edema. Hydrostatic and increased permeability edemas were distinguished by means of the ratio of pulmonary edema fluid protein to plasma protein concentration and clinical and hemodynamic data. Chest radiographs were classified as showing hydrostatic, increased permeability, or mixed edema by three independent readers without knowledge of the clinical diagnosis. Overall, 87% of patients with hydrostatic edema but only 60% of patients with increased permeability edema were correctly identified. A patchy, peripheral distribution of edema was the single most discriminating criterion and was relatively specific for increased permeability edema, occurring in 13% of patients with hydrostatic and 50% with increased permeability edema (P less than .05). Some features considered more typical of hydrostatic edema were commonly found in patients with increased permeability, including a widened vascular pedicle (56%), pleural effusions (36%), peribronchial cuffs (72%), and septal lines (40%). The authors conclude that chest radiography is limited in the differentiation of type of pulmonary edema in severe cases.
Abstract: The bronchial vascular response to chemoreceptor stimulation was studied in sheep anesthetized with alpha-chloralose, paralyzed with pancuronium, and artificially ventilated with room air. Blood flow through the common bronchial artery was measured with an electromagnetic flow-meter. Pressures were measured in the left atrium and aorta using appropriately placed catheters connected to pressure transducers. The carotid body was vascularly isolated and perfused at aortic pressure with blood of varied PO2 and PCO2. The viability of our preparation was assessed by the occurrence of a bradycardia in response to carotid body stimulation, and only data from animals demonstrating a bradycardia were analyzed. During hypoxic perfusion of the carotid body, heart rate decreased 6% (P less than 0.05). Bronchial blood flow increased by 46% and bronchial vascular resistance decreased by 23%, both of which were significant changes (P less than 0.05). During control experiments in which the carotid body was perfused with normoxic blood, there were no significant (P greater than 0.05) changes in any of the parameters. These data suggest that carotid body stimulation results in a reflex bronchial vasodilation.
Abstract: Chronic hyperglycemia has been reported to decrease the maximum velocity of glucose transport across the blood-brain barrier by 30 to 40%. However, available measurements of brain glucose content during chronic hyperglycemia are consistent with an unaltered transport system. Because of this discrepancy the brain capillary permeability-surface area product (PA) was measured in awake-restrained rats during acute and chronic hyperglycemia. Acute hyperglycemia was produced by intraperitoneal injection of glucose, and chronic hyperglycemia was produced by treatment with streptozotocin. PA was measured using an intravenous tracer method. PA decreased during hyperglycemia, consistent with saturation kinetics for transfer. However, PA was similar in acutely and chronically hyperglycemic rats. These data suggest that down-regulation of facilitated glucose transport into the brain does not occur during chronic hyperglycemia.
Abstract: The objective of the present study was to examine the effect of direct expansion of the renal interstitial volume on sodium reabsorption by proximal tubules of superficial and deep nephrons in the absence of systemic extracellular volume expansion. Renal interstitial volume expansion was achieved by injection of 50 microliter of 2.5% albumin in 0.9% saline into the renal interstitium via a polyethylene matrix that was chronically implanted in the interstitium of the rat kidney. Renal interstitial volume expansion increased renal interstitial hydrostatic pressure from 3.8 +/- 0.5 to 6.8 +/- 1.1 mmHg, P less than 0.05 (n = 5 rats). Fractional reabsorption of sodium by the superficial late proximal tubule decreased from 45.7 +/- 5.6 to 34.2 +/- 5.4%, P less than 0.05, and by the proximal tubule and descending limb of Henle’s loop of deep nephrons it decreased from 73.9 +/- 2.9 to 57.2 +/- 6.3%, P less than 0.05 (n = 8 rats). Thus expansion of the renal interstitial volume increased renal interstitial hydrostatic pressure and decreased sodium reabsorption by the proximal tubules of superficial and deep nephrons.
Abstract: The rates of creatine/creatinine inter-conversions and their equilibrium were studied under controlled conditions of temperature and pH that simulate urine storage conditions. The concentrations and ratios of creatine to creatinine in urine obtained from subjects with various pathophysiological conditions were determined, both before and after storage. The observed changes occurring during storage were compared with predicted changes based on observations of standard solutions. The initial reaction rate was found to increase with temperature, occurring maximally at about pH 3.7 for the conversion of creatine to creatinine, and at about pH 5.0 for the conversion of creatinine to creatine. At low pHs the equilibrium position was displaced towards creatinine. Above about pH 6.0 the equilibrium was associated with approximately equimolar quantities of creatine and creatinine. The creatine content of urine ranged from virtually nil to about double that of creatinine and changed predictably during storage. These findings have implications for the use of creatinine as an index of muscle mass and nutritional status, and as a marker for the completeness of urine collections.
Abstract: The effect of alteration in renal perfusion pressure on the response of the isolated perfused rat kidney to concentrations of alpha-human atrial natriuretic peptide (ANP) within the pathophysiological range has been examined. At a perfusion pressure of 90 mmHg ANP concentrations of 50, 200, and 1,000 pmol/l were without effect on any parameter tested. At a perfusion pressure of 130 mmHg 50 pmol/l ANP produced an increase of 3.13 +/- 0.68 mumol/min in sodium excretion (UNa V), compared with a fall of 0.33 +/- 1.04 mumol/min in controls (P less than 0.02); fractional excretion of sodium (FENa) rose by 1.45 +/- 0.36% vs. -0.12 +/- 0.47% (P less than 0.05); glomerular filtration rate (GFR) was unchanged. At 200 and 1,000 pmol/l larger changes in UNa V and FENa were seen; only at 1,000 pmol/l was a significant effect on GFR observed. In contrast, frusemide (furosemide) at concentrations of 10 and 100 mumol/l was natriuretic at both 90 and 130 mmHg, with lesser absolute but greater proportional changes being seen at the lower pressure. It was concluded 1) the response of the isolated kidney to ANP is critically dependent on perfusion pressure, 2) at elevated levels of perfusion pressure the isolated kidney can respond to levels of ANP within the upper physiological and pathophysiological range.
Abstract: The influence of endogenous and exogenous atrial natriuretic factor (ANF) on pulmonary hemodynamics was investigated in anesthetized pigs during both normoxia and hypoxia. Continuous hypoxic ventilation with 11% O2 was associated with a uniform but transient increase of plasma immunoreactive (ir) ANF that peaked at 15 min. Plasma irANF was inversely related to pulmonary arterial pressure (Ppa; r = -0.66, P less than 0.01) and pulmonary vascular resistance (PVR; r = -0.56, P less than 0.05) at 30 min of hypoxia in 14 animals; no such relationship was found during normoxia. ANF infusion after 60 min of hypoxia in seven pigs reduced the 156 +/- 20% increase in PVR to 124 +/- 18% (P less than 0.01) at 0.01 microgram.kg-1.min-1 and to 101 +/- 15% (P less than 0.001) at 0.05 microgram.kg-1.min-1. Cardiac output (CO) and systemic arterial pressure (Psa) remained unchanged, whereas mean Ppa decreased from 25.5 +/- 1.5 to 20.5 +/- 15 mmHg (P less than 0.001) and plasma irANF increased two- to nine-fold. ANF infused at 0.1 microgram.kg-1.min-1 (resulting in a 50-fold plasma irANF increase) decreased Psa (-14%) and reduced CO (-10%); systemic vascular resistance (SVR) was not changed, nor was a further decrease in PVR induced. No change in PVR or SVR occurred in normoxic animals at any ANF infusion rate. These results suggest that ANF may act as an endogenous pulmonary vasodilator that could modulate the pulmonary pressor response to hypoxia.
Abstract: The causes of orthostatic intolerance following prolonged bed rest, head-down tilt or exposure to zero gravity are not completely understood. One possible contributing mechanism is increased venous compliance and peripheral venous pooling. The present study attempted to determine what proportion of the increased calf volume during progressive venous occlusion is due to deep venous filling. Deep veins in the leg have little sympathetic innervation and scant vascular smooth muscle, so their compliance may be determined primarily by the surrounding skeletal muscle. If deep veins make a large contribution to total leg venous compliance, then disuse-related changes in skeletal muscle mass and tone could increase leg compliance and lead to decreased orthostatic tolerance. The increase in deep venous volume during progressive venous occlusion at the knee was measured in 6 normal subjects using calf cross-sectional images obtained with magnetic resonance imaging. Conventional plethysmography was used simultaneously to give an independent second measurement of leg volume and monitor the time course of the volume changes. Most of the volume change at all occlusion levels (20, 40, 60, 80 and 100 mm Hg) could be attributed to deep venous filling (90.2% at 40 mm Hg and 50.6% at 100 mm Hg). It is concluded that a large fraction of the calf volume change during venous occlusion is attributable to filling of the deep venous spaces. This finding supports theories postulating an important role for physiological mechanisms controlling skeletal muscle tone during orthostatic stress.
Abstract: Leg compliance is "causally related with greater susceptibility" to orthostatic stress. Since peak O2 uptake (peak VO2) and muscle strength may be related to leg compliance, we examined the relationships between leg compliance and factors related to muscle size and physical fitness. Ten healthy men, 25-52 yr, underwent tests for determination of vascular compliance of the calf (Whitney mercury strain gauge), peak VO2 (Bruce treadmill), calf muscle strength (Cybex isokinetic dynamometer), body composition (densitometry), and anthropometric measurements of the calf. Cross-sectional areas (CSA) of muscle, fat, and bone in the calf were determined by computed tomography scans. Leg compliance was not significantly correlated with any variables associated with physical fitness per se (peak VO2, calf strength, age, body weight, or composition). Leg compliance correlated with calf CSA (r = -0.72, P less than 0.02) and calculated calf volume (r = -0.67, P less than 0.03). The most dominant contributing factor to the determination of leg compliance was CSA of calf muscle (r = -0.60, P less than 0.06), whereas fat and bone were poor predictors (r = -0.11 and 0.07, respectively). We suggest that leg compliance is less when there is a large muscle mass providing structural support to limit expansion of the veins. This relationship is independent of aerobic and/or strength fitness level of the individual.
Abstract: This study examined the effect of increases in renal interstitial hydrostatic pressure (PI) on sodium excretion (UNaV) utilizing a direct technique for increasing renal interstitial volume. PI was increased by renal interstitial volume expansion (RIVE) via injection of 50 microliters of a 2% albumin in saline solution into the renal interstitium through a chronically implanted interstitial catheter. RIVE resulted in a stable increase in PI (4.6 +/- 0.4 to 9.4 +/- 0.8 mmHg) that was sustained over a 30- to 40-min period without significant changes in renal blood flow or glomerular filtration rate. Increases in PI were associated with significant increases in urine flow (13.8 +/- 3.4 to 31.7 +/- 5.0 microliters/min) and UNaV (2.3 +/- 0.6 to 6.2 +/- 1.1 micro eq/min) and fractional excretion of Na (2.6 +/- 0.8 to 6.9 +/- 1.5%). To determine the importance of albumin in maintaining an elevated PI, the effects of renal interstitial injections of saline were compared with albumin in saline solution. Injection of 50 microliters of saline into the renal interstitium had no sustained effect on PI. Injection of 2% albumin in saline solution in the same group of rats resulted in significant elevations in PI and UNaV. These data indicate that direct increases in PI via renal interstitial volume expansion result in significant increases in UNaV, thus supporting a role for PI in controlling UNaV.
Abstract: The microcirculatory anatomy of the hamster tibialis anterior muscle is based on modules (units) consisting of groups of 12-20 capillaries which run parallel to muscle fibers. The units are supplied by a common terminal arteriole and drained by a common terminal venule; a single terminal arteriole commonly supplies two microvascular units or a "unit pair." Regulation of the tibialis muscle microcirculation was investigated in pentobarbital-anesthetized hamsters using epifluorescence microscopy. We examined the patterns of capillary control in response to physiological and pharmacological stimuli including elevation of superfusate oxygen content, direct muscle stimulation, and topical application of phenylephrine. Changes in capillary perfusion were rarely manifested as responses of individual capillaries. The predominant response consisted of a coordinated change in virtually all the capillaries of a unit pair. For example, gradual elevation of superfusate PO2 resulted in simultaneous arrest or "derecruitment" of capillary flow in all capillaries of a unit pair in 37 of 43 such elements studied. In the 6 unit pairs showing atypical behavior, no more than four individual capillaries showed atypical behavior. Capillaries in 28 of 29 unit pairs were also recruited during muscle stimulation as members of a unit pair. In 18 of 21 unit pairs, exposure to topical phenylephrine resulted in simultaneous arrest of capillary flow in all capillaries of a unit pair. These data suggest that in this striated muscle, regulation of capillary perfusion is accomplished by control of capillary unit pairs. Accordingly, the patterns of interdigitation of units will ultimately determine the precision of control of tissue diffusion distance as well as oxygenation.
Abstract: Angiotensin II has been implicated in the regulation of medullary blood flow and is known to interact with prostaglandins at sites within the kidney. Therefore the role of angiotensin in control of vasa recta blood flow was studied in antidiuretic, Munich-Wistar rats. We also tested the hypothesis that prostaglandins act to modulate the effect of angiotensin. Total renal blood flow was measured by an electromagnetic flow probe, vasa recta blood flow by a dual-slit method. Captopril was used to confirm that angiotensin blockade increased renal blood flow (by 15 +/- 4%). Captopril and saralasin were used to show that angiotensin blockade increased vasa recta blood flow (by 23 +/- 9 and 14 +/- 7%, respectively). The results demonstrate a tonic constrictor effect of angiotensin in the renal medulla. Exogenous angiotensin II, delivered intravenously, failed to mimic the effect of endogenous angiotensin. Indomethacin did not alter blood pressure or renal blood flow but did reduce vasa recta blood flow by 20 +/- 3%, suggesting that prostaglandins act preferentially on the medullary circulation. Nor did it alter the response of blood pressure, of renal blood flow, or of vasa recta blood flow to captopril. Moreover, prior angiotensin blockade with either captopril or saralasin enhanced the medullary vasoconstrictor effect of indomethacin (P less than 0.05). These results are not consistent with the hypothesis that prostaglandins act primarily as angiotensin modulators. They suggest that the medullary interaction between angiotensin and prostaglandins differs from that in the cortex.
Abstract: Calcitonin gene-related peptide (CGRP) was found to stimulate renin secretion in vivo in normal human volunteers. Moreover, CGRP stimulated the release of renin in vitro from isolated rat renal juxtaglomerular cells (half-maximal effective concentration [EC50] 100 nM) concomitant with stimulation of cAMP production (EC50 60 nM). Immunoreactive CGRP was recognized in rat renal cortical nerve fibers, and intact rat CGRP was identified in extracts of the rat renal cortex. Because CGRP containing sensory nerve fibers are seen in the region of the juxtaglomerular apparatus, it would seem that the release of CGRP from these afferent nerves may be involved in the physiological control of renin secretion.
Abstract: We have studied some of the effects of DNA sequence and negative superhelicity on the rate of cruciform formation. Replacing the sequence AATT at the center of a perfect 68 base-pair palindromic sequence with the sequence CCCGGG decreases the rate of cruciform formation by a factor of at least 100. The logarithm of the rate constant of cruciform formation was found to increase linearly with linking difference. For the 68 base-pair perfect palindrome in a 4400 base-pair plasmid, each additional negative superhelical turn increased the rate of cruciform formation by a factor of 1.6. These results are consistent with a mechanism in which cruciform formation is initiated by the formation of a single-stranded bubble, 10 base-pairs in length, near the center of the palindromic sequence. In addition, we have examined the effect of introducing an asymmetric insertion into the palindromic sequence.
Abstract: Previous reports have advocated the use of mixed venous blood gases to estimate arterial pH and as a reflection of tissue acid-based balance. However, true mixed venous samples are difficult to obtain during cardiac arrest as they require a pulmonary artery catheter. The purpose of this study was to determine whether central or femoral venous samples could be used in place of pulmonary artery samples. Blood gases from these sites were drawn at intervals during experimental cardiac arrest in dogs. The PO2, PCO2, and pH from the pulmonary artery samples were strongly correlated with those from the central venous (r = .93, .99, and .99, respectively) and from the femoral venous samples (r = .73, .93, and .97, respectively). There were no significant differences in the pulmonary artery, central, or femoral venous gases. This animal model suggests that femoral and central venous samples mirror true mixed venous blood gases from the pulmonary artery and could be used in their place.
Abstract: This study examines the effect of different behavioral conditions on patterns of correlation between regional cerebral metabolic rates for glucose. Cerebral glucose metabolism was determined with positron emission tomography and (11C)-deoxyglucose in 29 normal subjects between the ages of 23 and 55. Seventeen subjects were studied in an unstimulated (resting) condition and 12 subjects during a phoneme monitoring language stimulation. Partial correlation coefficients, controlling for whole brain glucose metabolism, were calculated for pairs of metabolic rates in 14 cortical and 2 subcortical regions. Both stimulated and unstimulated subjects showed statistically significant correlations between left and right hemisphere homologs. The stimulated subjects also showed significant within-hemisphere correlations between left but not right hemisphere regions. These included left perisylvian regions classically associated with language functions (left inferior frontal, left superior temporal and left transverse temporal cortical regions) as well as other regions. Significant correlations between left regions and a right superior temporal region were also found. In general, these findings show a pattern of cross-hemisphere symmetry at rest and of hemisphere asymmetry during stimulation. Moreover, the asymmetry observed during stimulation appears to be superimposed upon a pattern of cross-hemisphere symmetry similar to that observed in the unstimulated state.
Abstract: In vivo glucose uptake (Rd) occurs via two mechanisms: 1) insulin-mediated glucose uptake (IMGU), which occurs in insulin-sensitive tissues, and 2) noninsulin-mediated glucose uptake (NIMGU), which occurs in both insulin-sensitive and insulin-insensitive tissues. Thus, in the postabsorptive (basal) state Rd = IMGU + NIMGU. To determine whether these two pathways for in vivo glucose disposal are regulated independently, we studied the effect of stress levels of epinephrine (EPI) on IMGU and NIMGU in seven normal men after an overnight fast. To study NIMGU, somatostatin (600 micrograms/hr) was infused to suppress endogenous insulin secretion, and glucose turnover was measured isotopically while the serum glucose level was clamped at about 200 mg/dL for 240 min. Separate studies were done during the infusion of saline or EPI (0.2 microgram/kg X min). The final 120 min of each study were used for data analysis. Under these conditions insulin action is absent and Rd = NIMGU. NIMGU was 210 +/- 15 (+/- SEM) and 200 +/- 17 mg/min during saline and EPI treatment, respectively (P = NS). Therefore, EPI has no ability to modulate NIMGU. To measure the effect of EPI on Rd, hyperglycemic (200 mg/dL) hyperinsulinemic clamp (30 mU/M2 X min) studies were performed during the infusion of saline and EPI. EPI decreased Rd by 46 +/- 6% (751 +/- 85 to 405 +/- 43 mg/min; P less than 0.01). When the effect of EPI on IMGU (Rd - NIMGU) was considered separately, the inhibitory effect of EPI was more potent, as indicated by a 61 +/- 12% decrease in IMGU. In conclusion, 1) EPI inhibits IMGU, but has no effect on NIMGU; 2) when NIMGU is taken into account, EPI has a more potent ability to inhibit IMGU than previously found; and 3) the systems responsible for NIMGU and IMGU are independently regulated.
Abstract: A comprehensive model that describes the interaction between the cardiovascular system (CVS) and the intrathoracic pressure (ITP) based on a lumped parameter vascular representation and a time-varying elastance concept for the four cardiac chambers is presented. Special attention is given to two possible mechanisms of interventricular interaction; the constraining effects of the pericardium and direct interventricular interaction that results from the fact that the two ventricles share a common interventricular septum. The response of the CVS to positive and negative perturbations in the ITP and to injection of fluid into the pericardium was simulated and compared with experimental literature data. The results show that 1) the total heart volume is relatively constant throughout the cycle both for ITP of 0 and +15 mmHg, which is consistent with experimental data in dogs, thus suggesting that intrinsic properties of the cardiac chambers rather than a restricting pericardium is the mechanism for that observation. 2) The pericardium has a major role in modifying the transient and steady-state response to a step decrease in the ITP with a transient decrease in left ventricle (LV) end-diastolic volume followed by gradual increase afterwards. 3) The response to sudden injection of fluid into the pericardial space is a larger transient decrease in right ventricle than LV volume, which is consistent with experimental data. 4) Transmission across the septum has a relatively minor role in modifying the response of the CVS to negative pressure. Thus the model reasonably predicts the effects of intrathoracic and pericardial pressures on the circulation in a reflex-blocked animal and provides a means for placing multiple potential mechanisms in proper hierarchial order with regard to contributions to LV and overall CVS function.
Abstract: The purpose of this study was to determine how the distribution of blood flow within and among the skeletal muscles of miniature swine (22 +/- 1 kg body wt) varies as a function of treadmill speed. Radiolabeled microspheres were used to measure cardiac output (Q) and tissue blood flows in preexercise and at 3-5 min of treadmill exercise at 4.8, 8.0, 11.3, 14.5, and 17.7 km/h. All pigs (n = 8) attained maximal O2 consumption (VO2max) (60 +/- 4 ml X min-1 X kg-1) by the time they ran at 17.7 km/h. At VO2max, 87% of Q (9.9 +/- 0.5 l/min) was to skeletal muscle, which constituted 36 +/- 1% of body mass. Average total muscle blood flow at VO2max was 127 +/- 14 ml X min-1 X 100 g-1; average limb muscle flow was 135 +/- 17 ml X min-1 X 100 g-1. Within the limb muscles, blood flow was distributed so that the deep red parts of extensor muscles had flows about two times higher than the more superficial white portions of the same muscles; the highest muscle blood flows occurred in the elbow flexors (brachialis: 290 +/- 44 ml X min-1 X 100 g-1). Peak exercise blood flows in the limb muscles were proportional (P less than 0.05) to the succinate dehydrogenase activities (r = 0.84), capillary densities (r = 0.78), and populations of oxidative (slow-twitch oxidative + fast-twitch oxidative-glycolytic) fiber types (r = 0.93) in the muscles. Total muscle blood flow plotted as a function of exercise intensity did not peak until the pigs attained VO2max, although flows in some individual muscles showed a plateau in this relationship at submaximal exercise intensities. The data demonstrate that blood flow in skeletal muscles of miniature swine is distributed heterogeneously and varies in relation to fiber type composition and exercise intensity.
Abstract: Experimental work over the past decade has revealed three distinct mechanisms for generating artificial circulation during cardiac arrest and resuscitation. To isolate these mechanisms and study them in pure form, and in particular to characterize circulation during open vs. closed chest cardiopulmonary resuscitation (CPR), we developed an electrical model of the human circulatory system. Heart and blood vessels were modeled as resistive-capacitive networks, pressures in the chest, abdomen, and vascular compartments as voltages, blood flow as electric current, blood inertia as inductance, and the cardiac and venous valves as diodes. External pressurization of thoracic and abdominal vessels, as would occur in CPR, was simulated by application of half-sinusoidal voltage pulses. Simulations included two modes of creating artificial circulation: the cardiac pump mechanism, in which the atria and ventricles of the model were pressurized simultaneously, as occurs during open chest cardiac massage, and the thoracic pump mechanism, in which all intrathoracic elements of the model were pressurized simultaneously, as is likely to occur in closed chest CPR. The two mechanisms were compared for the same peak applied pressure (80 mmHg). Pure cardiac pump CPR generated near normal systemic perfusion pressures throughout the compression cycle. Pure thoracic pump CPR generated much lower systemic perfusion pressure only during the diastolic phase of the compression cycle. Simulation of cardiac compression at rates from 40 to 100/min produced total flows of 2500-3300, myocardial flows of 150-250 and cranial flows of 600-800 ml/min, depending on the compression rate. In contrast, thoracic pump CPR produced a total flow of approx. 1200, myocardial flow of 70, and cranial flow of 450 ml/min, independently of the compression rate. Direct cardiac compression is an inherently superior hemodynamic mechanism, because it can generate greater perfusion pressure throughout the compression cycle. If one presumes that improved blood flow during CPR is the key to more successful resuscitation, then it is reasonable to conclude that direct heart massage is the most effective available way to achieve this end.
Abstract: We administered recombinant human erythropoietin to 25 anemic patients with end-stage renal disease who were undergoing hemodialysis. The recombinant human erythropoietin was given intravenously three times weekly after dialysis, and transfusion requirements, hematocrit, ferrokinetics, and reticulocyte responses were monitored. Over a range of doses between 15 and 500 units per kilogram of body weight, dose-dependent increases in effective erythropoiesis were noted. At 500 units per kilogram, changes in the hematocrit of as much as 10 percentage points were seen within three weeks, and increases in ferrokinetics of three to four times basal values, as measured by erythron transferrin uptake, were observed. Of 18 patients receiving effective doses of recombinant human erythropoietin, 12 who had required transfusions no longer needed them, and in 11 the hematocrit increased to 35 percent or more. Along with the rise in hematocrit, four patients had an increase in blood pressure, and a majority had increases in serum creatinine and potassium levels. No organ dysfunction or other toxic effects were observed, and no antibodies to the recombinant hormone were formed. These results demonstrate that recombinant human erythropoietin is effective, can eliminate the need for transfusions with their risks of immunologic sensitization, infection, and iron overload, and can restore the hematocrit to normal in many patients with the anemia of end-stage renal disease.
Abstract: Energy expenditure was studied in ten patients with chronic obstructive pulmonary disease (COPD) and weight loss, and in five malnourished patients without clinical evidence of COPD (control group) prior to and after a two-week refeeding regimen. Patients received 5 percent dextrose solution (plus electrolytes) for 36 hours to establish standard baseline conditions and were then randomly assigned to either a carbohydrate-based (CB; 53 percent of calories) or fat-based (FB; 55 percent of calories) diet for the first week. The alternate diet was given the following week. Total calorie intake was set at 70 percent above the energy expenditure measured prior to institution of nutritional support. During energy repletion, energy expenditure was greater than predicted (116 percent) in patients with COPD and less than predicted (90 percent) in the control patients. Thermic effect of nutrients during administration of either regimen was significantly greater (p less than .05) in patients with COPD than in those without COPD during both diets. The difference between the two groups was enhanced during the CB regimen. These observations suggest that malnourished patients with COPD have an elevated resting energy expenditure, and an enhanced thermic response to nutrients as compared to malnourished patients without COPD. Increased diet-induced thermogenesis may contribute to weight loss in patients with COPD, in addition to factors previously described such as decreased caloric intake and increased resting energy expenditure.
Abstract: To determine the increment in cardiac output and in O2 consumption (Vo2) from quiet breathing to maximal sustained ventilation, Vo2 and cardiac output were measured using an acetylene rebreathing technique in five subjects. Cardiac output and Vo2 were measured multiple times in each subject at rest and during sustained maximal ventilation. During maximal ventilation subjects breathed 5% CO2 to prevent hypocapnia. The increase in cardiac output from rest to maximal breathing was taken as an estimate of respiratory muscle blood flow and was used to calculate the arteriovenous O2 content difference across the respiratory muscles from the Fick equation. Cardiac output increased by 4.3 +/- 1.0 l/min (mean +/- SD), from 5.6 +/- 0.7 l/min at rest to 9.9 +/- 1.1 l/min, during maximal ventilations ranging from 127 to 193 l/min. Vo2 increased from 312 +/- 29 to 723 +/- 69 ml/min during maximal ventilation. O2 extraction across the respiratory muscles during maximal breathing was 9.6 +/- 1.0 vol% (range 8.5 to 10.7 vol%). These values suggest an upper limit of respiratory muscle blood flow of 3-5 l/min during unloaded maximal sustained ventilation.
Abstract: It has been generally accepted that carboxyhemoglobin levels between 10-20% produce mild headaches, dizziness and/or nausea. Experimental double blind exposures of 18 healthy, nonsmoking young men at rest to 7,000-24,000 ppm CO, designed to elevate COHb to 15-20% in 3-5 minutes, were followed by exposure to 232 ppm CO designed to maintain COHb level for a total of 130 minutes. Resulting COHb values were 16-23%. These COHb values did not produce significantly more symptoms (as reported in an open-ended questioning) than reported in the control group (n = 23). Subjects were especially queried about headache, dizziness and nausea. The symptoms which were previously reported in clinical studies of CO poisoning may have resulted from CO exposure in combination with (a) exposure to other substances, (b) stress due to the event that precipitated medical attention or (c) higher COHb levels before the first blood sample was taken.
Abstract: Activation of the sympathetic nervous system attends traumatic brain injury, but the association of the severity of neurological impairment and recovery with the extent of sympathetic nervous system stimulation is poorly defined. In this study, plasma norepinephrine (NE), epinephrine (E), and dopamine (DA) levels were measured serially in 33 patients with traumatic brain injury and compared with the Glasgow Coma Score (GCS), which was obtained concurrently. A catecholamine gradient that reflected the extent of brain injury was demonstrated within 48 hours of the injury. In patients with a GCS of 3 to 4, NE and E levels increased four- to fivefold and the DA level increased threefold above normal (NE, 1686 +/- 416 pg/ml; E, 430 +/- 172 pg/ml; DA, 236 +/- 110 pg/ml), while patients with mild brain injury (GCS, greater than 11) had slightly elevated or normal levels. Patients with marked (GCS, 5 to 7) and moderate (GCS, 8 to 10) traumatic brain injuries had intermediate levels. The prognostic value of determining admission levels of NE was shown in patients with an admission GCS of 3 to 4 1 week after injury. Patients with severe and unchanging neurological impairment 1 week after injury had markedly elevated initial NE levels (2,176 +/- 531 pg/ml), whereas initial NE levels (544 +/- 89 pg/ml) were only mildly elevated in patients who improved to a GCS of greater than 11. These data indicate that markedly elevated NE levels predict outcome in patients with comparable neurological deficits. Thus levels of circulating catecholamines are excellent endogenous and readily quantifiable markers that appear to reflect the extent of brain injury and that may predict the likelihood of recovery.
Abstract: Erythropoietin titers when related to the hematocrit percentage and measured by bioassay in 33 normal volunteers and in 61 patients with anemias not complicated by renal or chronic disease were found to overlap with titers measured by radioimmunoassay in 20 normals and 28 patients with similar anemias. Erythropoietin titers measured by radioimmunoassay in 34 patients with rheumatoid arthritis, 25 patients with sickle cell anemia (58 separate samples), and 28 patients with erythroid hypoplasia caused by hematologic malignancies were compared with those in the control group of patients with uncomplicated anemias and found not to differ significantly from titers in this group. Erythropoietin titers measured by bioassay in 12 patients with aplastic anemia also fell within the range of those in the control group. Consequently, erythropoietin titers in these anemias appear to be determined primarily by the degree of anemia and not by any specific effect of these illnesses on the production of erythropoietin.
Abstract: The synthesis rates of different myosin isoenzymes in a single muscle, and of the same isoenzymes in different muscles (soleus, masseter and plantaris), were measured. The rate of total protein synthesis was significantly higher in the soleus [greater than 95% slow myosin (SM)] than in the plantaris [greater than 95% fast myosin (FM)]. Two fast isoenzymes, FM2 and FM3, were synthesized at different rates in the masseter, and SM was synthesized at a faster rate than FM. Intermediate myosin had a synthesis rate similar to that of FM. There was a small but significant difference between the synthesis rates of the SM isoenzymes of the soleus and masseter muscles. FM3 was synthesized faster in the masseter than in the plantaris, whereas FM2 was synthesized faster in the plantaris than in the masseter.
Abstract: ANF is a peptide hormone with peripheral and central effects on several physiologic control systems, which suggests broad involvement in the regulation of intravascular volume and cardiovascular homeostasis. ANF acts directly on the kidney to modulate renal vascular resistance, increase glomerular filtration rate, and decrease inner medullary hypertonicity. These hemodynamic effects act in concert to promote marked natriuresis and diuresis and to inhibit renin secretion by the kidney; the potential role of direct effects on tubular transport and on the juxtaglomerular cells remains to be clarified. ANF also inhibits steroidogenesis, most prominently affecting agonist-induced aldosterone biosynthesis by the adrenal cortex. ANF exerts a smooth muscle relaxant effect on isolated vessels constricted with various hormonal agonists. ANF causes especially pronounced antagonism of the adrenal and vascular actions of angiotensin II and antagonizes the latter peptide’s central nervous system effects. Although complex systemic hemodynamic mechanisms are involved, ANF-induced vasorelaxation may contribute to its depressor action, particularly in states characterized by angiotensin II-induced vasoconstriction. Distention of the atria is a major stimulus to ANF release and evokes many responses that are mimicked by ANF infusion. Although ANF is not the sole or even dominant mediator of the responses to atrial distention, available data suggest that it plays a role in the renal and hormonal responses to intravascular volume expansion. Definitive assessment of its physiologic and pathophysiologic significance must await development of specific antagonists, but further studies on the mechanisms of action of ANF at the molecular, cellular, and systemic levels are likely to contribute significantly to our understanding of the complex process of volume regulation and cardiovascular homeostasis.
Abstract: The suggestion that hyperventilation caused by increased gravity is mediated by a decrease in brain perfusion has led us to propose a mathematical model based on: (1) the CO2 balance equation for the respiratory center (RC), and (2) the relationship between RC blood flow (QRC), foot-to-head acceleration (Gz) and PRCCO2, namely, QRC = [1 - a(Gz - 1)](b X PRCCO2 + c), where the coefficients a, b and c can be calculated from data in the literature. QRC is significantly affected by + GZ only at high PaCO2. The model can be used to calculate oxygen pressure in the RC; the numbers so obtained are in good agreement with measurements of jugular vein PO2 obtained by others.
Abstract: To learn modes of CO2 elimination during cardiac arrest, we continuously measured end-tidal CO2 concentration (ETCO2) in acutely arrested dogs with constant ventilation. A decrease in peak ETCO2 during cardiac arrest in each dog showed a washout biexponential function when graphed on semilog paper. The average half-times of each compartment were 19.2 +/- 3.1 (SD) sec for the fast compartment and 108.1 +/- 23.8 sec for the slow compartment; the fast compartment of the CO2 elimination curve suggested that CO2 was eliminated from the functional residual capacity, while the slow compartment indicated CO2 elimination from the pulmonary capillary blood and tissue stores. Neither pretreatment with sodium bicarbonate (1 mEq/kg iv) nor a 5-min cardiorespiratory arrest altered the mode of CO2 elimination. The ETCO2 also reflected the potential effects of external cardiac compressions on pulmonary blood flow, as previously reported. Besides mixed venous blood CO2 flowing back to the lungs by cardiac compressions, it should be noted that both alveoli and pulmonary capillary blood CO2 are also reflected in the ETCO2 during the first minute of CPR.
Abstract: 1. In ten young men the ventilatory, cardiovascular, catecholamine and metabolic responses to maximal dynamic leg exercise on a stationary bicycle were followed during partial neuromuscular blockade with tubocurarine. Maximal exercise was performed when the drug effect was at its maximum as well as during the subsequent reduction in the effect allowing a gradually increasing work intensity. The results were compared with those obtained during submaximal and maximal exercise performed without tubocurarine. Partial neuromuscular blockade decreased hand-grip strength to 41 +/- 1.1% (S.E. of mean) and the maximal work load to 27 +/- 2.4% of control values. Voluntary effort was maximal and the rate of perceived exertion was high at all levels of exercise with tubocurarine indicating a maintained intense central nervous motor command. 2. During maximal action of the drug oxygen uptake was 1.67 +/- 0.11 l/min while only 0.91 +/- 0.13 l/min (P less than 0.01) at the same work intensity without neuromuscular blockade. This difference may reflect a dominant reliance on fast-twitch muscle fibres when work was performed under the influence of tubocurarine. 3. Compared at a given oxygen uptake ventilation was higher during work with tubocurarine than during control exercise (e.g. 55 +/- 4.2 and 40 +/- 2.2 l/min, respectively (P less than 0.01), at a mean oxygen uptake of 1.9 l/min), while heart rate did not differ significantly (146 +/- 4.4 and 139 +/- 3.0 beats/min). With decreasing drug effect both variables increased towards the maximum values of 138 +/- 4.5 l/min and 183 +/- 3.9 beats/min, respectively, achieved in control experiments at an oxygen uptake of 3.8 +/- 0.2 l/min. Like heart rate the mean arterial blood pressure increased with increasing work load and was similar at a given oxygen uptake with and without tubocurarine. 4. During maximal exercise at peak tubocurarine effect plasma adrenaline and noradrenaline concentrations were smaller than during control maximum, 1.6 +/- 0.27 versus 3.4 +/- 0.55 nmol/l (P less than 0.01) and 7.5 +/- 1.3 versus 12.6 +/- 1.8 nmol/l (P less than 0.05), respectively. However, comparisons at identical oxygen uptake rates revealed that catecholamine responses were markedly enhanced during tubocurarine treatment. Also, blood lactate concentrations were smaller at peak tubocurarine action than during control maximum, 1.9 +/- 0.42 mmol/l and 6.1 +/- 0.49 mmol/l (P less than 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)
Abstract: During antidiuresis, the medullary collecting duct (MCD) reabsorbs sodium in load-dependent fashion. However, attempts to characterize reabsorption when sodium delivery to the MCD is elevated have not led to clear results, largely due to interfering effects of the strategies employed to raise delivery. In the present study, microcatheterization was performed in rats undergoing water diuresis induced solely by infusion of 2.5% dextrose in water, and in rats where solute delivery to the MCD was markedly elevated by the combination of water diuresis with acute potassium chloride loading. The results show that delivery of sodium was elevated by the experimental maneuvers, averaging 7.01 +/- 0.83 mumol . min-1 . g kidney wt-1 compared with a normal antidiuretic value in the literature of 3.50 +/- 0.40 mumol . min-1 . g-1. Sodium and chloride reabsorptions were increased proportionally, indicating that the MCD has a large capacity to transport sodium chloride. Normalized sodium reabsorption remained high, varying in different series between 80 +/- 10 and 96 +/- 1% of the delivered load. Thus the MCD reabsorbed an average of 6.37 +/- 0.70 mumol . min-1 . g-1 of sodium while sodium excretion was 0.52 +/- 0.11 mumol . min-1 . g-1. The results emphasize the importance of MCD sodium chloride reabsorption for determination of final urinary salt excretion, and thus for regulation of body salt balance.
Abstract: The efficiency of coupling between salt delivery to the sensing site in the macula densa and the glomerular vascular effector response is altered by changes in extracellular fluid volume, in the amount of dietary protein, and many other conditions, including growth and maturation, and the development of hypertension in Okamoto-Aoki and Milan strains of genetically hypertensive rats. Examination of feedback-mediated responses by perfusion of Henle’s loop reveals a tendency for multiple changes in characteristics of feedback curves for SNGFR and SFP. In general, inhibition of TGF activity is evidenced by a smaller maximum glomerular response, reduced reactivity, and a shift in the inflection point to a higher flow rate. The opposite responses are frequently noted during exaggerated TGF activity. It is not known at present whether one or more mechanisms are involved in mediating or modulating the functional correlates of these characteristics. Insight into these functional correlates may be provided by selective, graded inhibition and stimulation of the sensing and effector elements in the feedback loop. Investigations of potential extrarenal mechanisms of resetting indicate that atrial natriuretic factor and an unidentified factor present in the proximal tubular fluid may play a role under certain circumstances. In addition to the renin-angiotensin and arachidonic acid-prostanoid systems, the kallikrein-kinin system appears to modulate TGF activity. A large body of evidence indicates TGF activity is inversely correlated with renal interstitial pressure. Whether this correlation reflects causality or a phenomenological association awaits further investigation.
Abstract: Constriction of vascular smooth muscle in response to the stimulus of raised intravascular pressure–the myogenic response–represents a positive feedback mechanism which, if unopposed, could theoretically lead to instability in the intact circulation. Dilation in response to increased intraluminal flow would provide an opposing feedback mechanism which could confer overall stability. Flow-dependent dilation in conduit vessels is mediated by endothelium-derived relaxing factor (EDRF), but the relationship between flow and EDRF activity has not been studied in resistance vessels in situ. We here demonstrate that EDRF can coordinate the aggregate hydrodynamic properties of an intact network. Under control conditions, EDRF maintains a fourth-power relationship between diameter and flow so that the pressure gradient in each vessel asymptotically approaches a constant value at high flow rates. Basal EDRF release may also maintain a similar spatial distribution of flow at different flow rates, even under conditions of moderate pharmacological constriction.
Abstract: The classic proposal of intracellular K+ for extracellular H+ exchange as responsible for the hyperkalemia of diabetic ketoacidosis (DKA) has been questioned because experimentally induced organic anion acidosis fails to produce hyperkalemia. It has been suggested, instead, that the elevated serum [K+] of DKA might be the result of the compromised renal function, secondary to volume depletion, that usually accompanies DKA. However, several metabolic derangements other than volume depletion and acidosis, which are known to alter potassium metabolism, also develop in DKA. This study of 142 admissions for DKA examines the possible role of alterations in plasma pH, bicarbonate, glucose (G), osmolality, blood urea nitrogen (BUN) and plasma anion gap (AG) on the levels of [K+]p on admission. Significant (p less than 0.01) correlations of [K+]p with each of these parameters were found that could individually account for 8 to 15 percent of the observed variance in the plasma potassium levels; however, the effects of some or all of these parameters on the [K+]p could be independent and therefore physiologically additive. Since the parameters under study are themselves interrelated, having statistically significant correlations with each other, their possible independent role on [K+]p was evaluated by multiple regression analysis. Only plasma pH, glucose and AG emerged as having a definite independent effect on [K+]p, with no independent role found for bicarbonate, BUN and osmolality. The equation that best describes [K+]p on admission for DKA was: [K+]p = 25.4 - 3.02 pH + 0.001 G + 0.028 AG, (r = 0.515). These results indicate that the endogenous ketoacidemia and hyperglycemia observed in DKA, which result primarily from insulin deficit, are the main determinants of increased [K+]p. Since exogenous ketoacidemia and hyperglycemia in the otherwise normal experimental animal do not increase [K+]p, it is postulated that insulin deficit itself may be the major initiating cause of the hyperkalemia that develops in DKA. Renal dysfunction by enhancing hyperglycemia and reducing potassium excretion also contributes to hyperkalemia.
Abstract: The unique architecture and organization of medullary vasculature permit regional regulation of medullary hemodynamics by vasoactive hormones and are conducive to the operation of the countercurrent multiplication system. Recent studies suggest that an increase in inner medullary blood flow causes medullary solute washout, which in turn decreases passive sodium transport in the thin ascending limb of Henle’s loop. In canine models of chronic sodium retention accompanied by activation of the renin-angiotensin system, glomerular filtration rate (GFR), renal blood flow (RBF), and intracortical blood flow distribution were similar to those in normal dogs; however, papillary plasma flow (PPF) was markedly reduced and papillary tissue solute content was increased significantly both during hydropenia and after saline loading. During euvolemic diuresis with loop diuretics, there was an increased renin release associated with a marked reduction in PPF, despite an increase in total RBF. Direct intrarenal infusion of angiotensin II (AngII) (at a dose not affecting GFR and RBF) induced ipsilateral sodium retention, conservation of urinary concentration, and papillary ischemia. These studies provide evidence for regional regulation of medullary hemodynamics by AngII, possibly contributing to sodium retention in chronic salt-retaining states.
Abstract: For many years experimental evidence has suggested the existence of a circulating factor able to enhance sodium excretion. Very recently peptides with natriuretic activity in experimental animals have been isolated from mammalian and human cardiac tissue. In order to determine whether this natriuretic activity has relevance to man we have studied the effects of an infusion of alpha-human atrial natriuretic peptide (alpha-h-ANP) in normal subjects. Sodium excretion trebled (P = less than 0.005) during the infusion of a calculated dose of 15 pmol of alpha-h-ANP min-1 kg-1 and there was an accompanying diuresis; radioimmunoassay of plasma alpha-h-ANP during the natriuresis indicated a mean peak incremental concentration of 203 +/- 78 (SEM) pmol/l. The infusion of a calculated dose of 1.5 pmol min-1 kg-1 did not affect sodium excretion. There were no haemodynamic changes and no side effects were noted.
Abstract: A sensitive radioimmunoassay for atrial natriuretic peptide was used to examine the relation between circulating atrial natriuretic peptide and cardiac filling pressure in normal human subjects, in patients with cardiovascular disease and normal cardiac filling pressure, and in patients with cardiovascular disease and elevated cardiac filling pressure with and without congestive heart failure. The present studies establish a normal range for atrial natriuretic peptide in normal human subjects. These studies also establish that elevated cardiac filling pressure is associated with increased circulating concentrations of atrial natriuretic peptide and that congestive heart failure is not characterized by a deficiency in atrial natriuretic peptide, but with its elevation.
Abstract: A theoretical two-dimensional model is used to investigate oxygen gradients in a red skeletal muscle fiber. The model describes the steady state, free and myoglobin-facilitated diffusion of oxygen into a respiring cylindrical muscle fiber cross section. The oxygen tension at the sarcolemma is assumed to vary along the sarcolemma as an approximation to the discrete capillary oxygen supply around the fiber. Maximal oxygen gradients are studied by considering parameters relevant to a maximally-respiring red muscle fiber. The model predicts that angular variations in the oxygen tension imposed at the sarcolemma due to the discrete capillary sources do not penetrate deeply into the fiber over a range of physiological values for myoglobin concentration, diffusion coefficients, number of surrounding capillaries, and oxygen tension level at the sarcolemma. Also, the oxygen tension in the core of the fiber is determined by the average oxygen tension at the sarcolemma. The drop in oxygen tension from fiber periphery to core, however, does depend significantly on the myoglobin concentration, the oxygen tension level at the sarcolemma, and the oxygen and myoglobin diffusivities. This dependence is summarized by calculating the minimum average sarcolemmal oxygen tension for maximal respiration without the development of an intracellular anoxic region. For a myoglobin-rich muscle fiber (0.5 mM myoglobin), the model predicts that maximal oxygen consumption can proceed with a relatively flat (less than 5 mm Hg) oxygen tension drop from fiber periphery to core over a large range for diffusion coefficients.
Abstract: The effect of alterations of dietary potassium intake on the plasma concentration and the urinary excretion of vasopressin was studied in male rats. Ingestion of a high potassium diet resulted in increases in the plasma concentrations of potassium and vasopressin, systolic blood pressure, urine flow, and urinary vasopressin excretion. Ingestion of a low potassium diet had little effect on the plasma vasopressin concentration and systolic blood pressure but caused decreases in the plasma potassium concentration and urinary vasopressin excretion. The results indicate that physiological changes in the plasma potassium concentration or some other consequence of altered dietary potassium intake can affect vasopressin release and excretion.
Abstract: Controversy persists on whether atrial natriuretic factor (ANF) raises renal solute excretion simply by increasing glomerular filtration rate (GFR) or whether it directly inhibits tubular transport (independent of changes in flow rate). Free-flow micropuncture techniques were used in 10 Munich-Wistar rats. ANF caused a significant increase in single-nephron and whole-kidney GFR (41.6 +/- 1.4 to 52.7 +/- 2.3 nl/min and 0.95 +/- 0.05 to 1.24 +/- 0.09 ml/min, respectively). Although absolute proximal sodium, bicarbonate, and chloride reabsorption increased, the increment in reabsorption was less than the increase in load; therefore solute delivery out of the proximal tubule increased by approximately 30-35%. Whole-kidney electrolyte excretion also rose markedly. When single-nephron and whole-kidney GFR were reduced back to a control level by aortic constriction (40.2 +/- 1.8 nl/min and 0.93 +/- 0.05 ml/min, respectively), proximal transport reverted to normal values despite persistent ANF administration. Ninety percent of the ANF-induced natriuresis and chloruresis were simultaneously abolished when GFR was normalized. In conclusion, ANF has no direct effect on reabsorption in the superficial proximal convoluted tubule independent of changes in filtration rate. Although direct effects on more distal or deeper nephron segments are not precluded, the present data suggest that ANF can increase renal solute excretion predominantly by acutely augmenting GFR.
Abstract: We investigated atrial natriuretic factor (ANF) in humans, measuring plasma immunoreactive (ir) ANF (in femtomoles per milliliter), and renal, hormonal, and hemodynamic responses to ANF infusion, in normal subjects (NL) and congestive heart failure patients (CHF). Plasma irANF was 11 +/- 0.9 fmol/ml in NL and 71 +/- 9.9 in CHF (P less than 0.01); the latter with twofold right ventricular increment (P less than 0.05). In NL, ANF infusion of 0.10 microgram/kg per min (40 pmol/kg per min) induced increases (P less than 0.05) of absolute (from 160 +/- 23 to 725 +/- 198 mueq/min) and fractional (1-4%) sodium excretion, urine flow rate (from 10 +/- 1.6 to 20 +/- 2.6 ml/min), osmolar (from 3.2 +/- 0.6 to 6.8 +/- 1.2 ml/min) and free water (from 6.8 +/- 1.6 to 13.6 +/- 1.6 ml/min) clearances, and filtration fraction (from 20 +/- 1 to 26 +/- 2%). Plasma renin and aldosterone decreased 33% and 40%, respectively (P less than 0.01). Systolic blood pressure fell (from 112 +/- 3 to 104 +/- 5 mmHg, P less than 0.05) in seated NL; but in supine NL, the only hemodynamic response was decreased pulmonary wedge pressure (from 11 +/- 1 to 7 +/- 1 mmHg, P less than 0.05). In CHF, ANF induced changes in aldosterone and pulmonary wedge pressure, cardiac index, and systemic vascular resistance (all P less than 0.05); however, responses of renin and renal excretion were attenuated. ANF infusion increased hematocrit and serum protein concentration by 5-7% in NL (P less than 0.05) but not in CHF.
Abstract: To determine the value of sodium bicarbonate in resuscitation from ventricular fibrillation and the prevention of spontaneous refibrillation, sodium bicarbonate (1 meq/kg) or placebo was administered on a random basis to 16 pentobarbital-anesthetized dogs 18 min after the induction of ventricular fibrillation and cardiopulmonary resuscitation. Defibrillation was attempted 2 min after the administration of bicarbonate or placebo. All animals were successfully defibrillated, but three of eight bicarbonate-treated and two of eight control animals died in electromechanical dissociation (p = NS). Spontaneous refibrillation occurred in three animals in each group (p = NS). Successful resuscitation was not dependent on treatment, arterial or mixed venous Pco2, or arterial or mixed venous pH but correlated strongly with coronary perfusion pressure (p less than .003). Spontaneous refibrillation occurred without relation to any identifiable variable. The gradient between diastolic aortic and right atrial pressures was 24 +/- 2 mm Hg in controls and 23 +/- 2 mm Hg in treated animals over the entire 20 min of cardiopulmonary resuscitation (p = NS). However, among animals successfully resuscitated, mean diastolic coronary perfusion pressure averaged 27 +/- 2 mm Hg compared with 20 +/- 1 mm Hg among those dying in electromechanical dissociation (p less than .02). For the final 2 min of resuscitation, after drug administration, these gradients were 31 +/- 2 and 23 +/- 2 mm Hg, respectively (p less than .01). Microsphere determined myocardial perfusion correlated with the diastolic aortic-right atrial perfusion pressure gradient (r = .86) and was 0.43 +/- 0.03 ml/min/g in survivors and 0.22 +/- 0.01 ml/min/g in nonsurvivors (p less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Whether blood flow during cardiopulmonary resuscitation (CPR) results from intrathoracic pressure fluctuations or direct cardiac compression remains controversial. From modeling considerations, blood flow due to intrathoracic pressure fluctuations should be insensitive to compression rate over a wide range, but dependent on the applied force and compression duration. If direct compression of the heart plays a major role, however, flow should be dependent on compression rate and force, but above a threshold, insensitive to compression duration. These differences in hemodynamics produced by changes in rate and duration form a basis for determining whether blood flow during CPR results from intrathoracic pressure fluctuations or from direct cardiac compression. Manual CPR was studied in eight anesthetized, 21 to 32 kg dogs after induction of ventricular fibrillation. There was no surgical manipulation of the chest. Myocardial and cerebral blood flows were determined with radioactive microspheres. At nearly constant peak sternal force (378 to 426 newtons), flow was significantly increased when the duration of compression was increased from 14 +/- 1% to 46 +/- 3% of the cycle at a rate of 60/min. Flow was unchanged, however, after an increase in rate from 60 to 150/min at constant compression duration. The hemodynamics of manual CPR were next compared with those produced by vest inflation with simultaneous ventilation (vest CPR) in eight other dogs. Vest CPR changed intrathoracic pressure without direct cardiac compression, since sternal displacement was less than 0.8 cm. At a rate of 150/min, with similar duration and right atrial peak pressure, manual and vest CPR produced similar flow and perfusion pressures. Finally, the hemodynamics of manual CPR were compared with the hemodynamics of direct cardiac compression after thoracotomy. Cardiac deformation was measured and held nearly constant during changes in rate and duration. As opposed to changes accompanying manual CPR, there was no change in perfusion pressures when duration was increased from 15% to 45% of the cycle at a constant rate of 60/min. There was, however, a significant increase in perfusion pressures when rate was increased from 60 to 150/min at a constant duration of 45%. Thus, vital organ perfusion pressures and flow during manual external chest compression are dependent on the duration of compression, but not on rates of 60 or 150/min. These data are similar to those observed for vest CPR, where intrathoracic pressure is manipulated without sternal displacement, but opposite of those observed for direct cardiac compression.(ABSTRACT TRUNCATED AT 400 WORDS)
Abstract: Binding of tritium-labeled vasopressin [( 3H]AVP) to a broken epithelial cell preparation of the toad’s urinary bladder has been related to hormonal action on water and urea transport across the intact tissue. Hormone binding to receptor sites and permeability changes were initiated at the same concentration of hormone (0.4 nM). Half-maximal urea and water permeability responses were observed with 3.1 and 5.6 nM AVP, respectively, although half-maximal receptor saturation required considerably higher concentrations of hormone (less than 500 nM). Because maximal permeability responses were obtained with occupation of approximately 200 fmol/mg protein receptor sites and the total receptor density was in excess of 2,000 fmol/mg protein, there is apparently a receptor reserve in this tissue. The antidiuretic hormone employed by the toad is vasotocin (AVT). This compound was 60-fold more effective than AVP in displacing [3H]AVP from receptor sites. Preincubation of bladders with AVT resulted in downregulation of receptor sites. Although the magnitude of receptor loss was equivalent in the presence or absence of a transmembrane osmotic pressure gradient, the capacity of AVT to induce permeability changes was more markedly reduced in the presence of an osmotic gradient. This observation suggests that the negative-feedback signal initiated by water flow through the hormone target cell diminishes sensitivity to hormone by a mechanism other than by a reduction in the number of surface receptors or by a decrease in their affinity for the hormone.
Abstract: Using chronically instrumented dogs with a healed anterior wall myocardial infarction, we have assessed the effect of acute beta-adrenergic blockade on exercise tolerance, left ventricular (LV) performance, and myocardial VO2. Mongrel dogs were instrumented with Doppler flow probes around the left circumflex coronary artery, LV pressure cells, epicardial ECG electrodes, and left atrial and coronary sinus catheters. Myocardial infarction was produced by ligation of the left anterior descending coronary artery at time of instrumentation (approximately 20% LV mass). After a 1-month recovery period, dogs were subjected to two identical submaximal graded exercise tests on a treadmill on separate days, once without (control) and once with (propranolol, 1 mg X kg-1, i.v.) acute beta-adrenergic blockade. Heart rate, LV pressure, dP/dt max, left circumflex blood flow velocity, and myocardial VO2 index were measured at each stage of the graded exercise test. All variables were significantly reduced from control during beta-block in exercise. beta-Adrenergic blockade in the presence of a 1-month-old anterior wall myocardial infarction did not compromise exercise capacity during submaximal exercise.
Abstract: Synthetic atrial natriuretic peptide, containing 26 amino acids in the rat sequence, L-364, 343 (Ileu-ANP), was infused intravenously at increasing rates (1-40 micrograms/min) into four normal volunteers. Mean intraarterial blood pressure decreased and heart rate increased in cumulative-dose-dependent fashion. Skin blood flow as measured with a laser Doppler device rose already with a cumulative dose of 55 micrograms Ileu-ANP and further rises were directly related to dose. The only side effects observed were those accompanying symptomatic hypotension at higher doses. These findings provide strong evidence that Ileu-ANP acts as a vasodilator in normal volunteers.
Abstract: Previous studies in rats have demonstrated that superficial proximal tubule sodium reabsorption does not change in response to alterations in renal perfusion pressure (RPP). The first objective of the present study was to estimate sodium reabsorption in response to acute changes in RPP utilizing fractional lithium reabsorption (FRLi) as an index of fractional sodium reabsorption (FRNa) by the proximal tubule of the kidney as a whole. FRLi decreased in response to increases in RPP, suggesting that sodium reabsorption by the proximal tubule of some nephron population is decreased. Therefore, the second objective of the present study was to test the hypothesis that superficial and deep proximal tubules respond differently to changes in RPP by comparing proximal tubule sodium reabsorption from both nephron populations. In response to an acute change in RPP from 114 +/- 4 to 138 +/- 5 mmHg, FRNa by the proximal tubule and descending limb of Henle’s loop in deep nephrons decreased from 71.3 +/- 2.3 to 55.8 +/- 5.6%, but FRNa by the superficial late proximal tubule was not changed: (44.3 +/- 4.8 to 45.1 +/- 3.9%). The urinary fractional reabsorption of sodium decreased from 96.7 +/- 0.6 to 94.5 +/- 0.5%. In summary, these studies demonstrate that increases in RPP have no effect on sodium reabsorption by the proximal tubule of superficial nephrons. In contrast, sodium delivery to the point of micropuncture in the descending limb of Henle’s loop of deep nephrons was increased, suggesting inhibition of sodium reabsorption by proximal tubules of deep nephrons in response to increases in RPP.
Abstract: With some, but not all, types and intensities of exercise, lactate accumulates in the blood and in the muscles engaged in the exercise. A great deal of attention has been directed towards attempting to understand the dynamics of lactate production and removal at the onset of exercise, during exercise, and during the recovery process following exercise. It has been hoped that an unravelling of these events would provide a key to understanding cellular metabolism and its regulation during exercise. The purpose of this introductory paper to a symposium on lactate is to present a brief overview of some of the conditions that influence the rate and magnitude of lactate accumulation during exercise. It is pointed out that many conditions influence the rate and magnitude of the accumulation of lactate in blood and muscles. Included are diet, state of physical fitness, and the type and duration of the exercise. We have cautioned against trying to evaluate the state of oxygen delivery to muscle and the state of tissue oxygenation from the appearance of lactate in blood. We have pointed out the positive aspects of lactate production based on how it augments the cellular supply of ATP, thereby allowing for high intensity exercise, and also the negative aspects that develop as a result the reduction in pH which adversely influences many cellular processes essential for muscular activity.
Abstract: Several important differences exist between the training responses in normal patients and those in patients with chronic obstructive pulmonary disease (COPD). Chief among these is the lack of cardiovascular and metabolic changes in patients with COPD. Despite this, important and significant improvements do occur in exercise endurance after exercise training programs. Experience has shown that simple forms of exercise training and testing are effective and safe.
Abstract: The reliability of the lithium clearance method in studies of the effect of renal nerve activity upon tubular sodium and water handling in the dog kidney was investigated. Following unilateral acute surgical denervation of the kidney a significant increase in urinary flow rate (40 +/- 7%), sodium clearance (26 +/- 4%), lithium clearance (9 +/- 2%) and fractional lithium clearance (8 +/- 2%) was seen, as compared to the contralateral kidney with preserved innervation. Calculated absolute proximal reabsorption rate decreased significantly by 7 +/- 2%, while calculated absolute rates of distal reabsorption of sodium and water increased significantly by 9 +/- 2% and 8 +/- 2%. Low-frequency electrical stimulation of the distal nerve bundle of the denervated kidney caused a significant decrease in urine flow rate (37 +/- 6%), sodium clearance (31 +/- 4%), lithium clearance (17 +/- 5%) and in fractional lithium clearance (18 +/- 5%). Calculated absolute proximal reabsorption rate increased significantly by 17 +/- 3%, while calculated absolute rates of distal sodium and water reabsorption decreased significantly by 16 +/- 5% and 16 +/- 5%. These changes in tubular sodium and water reabsorption during alterations in renal nerve activity occurred without measurable changes in renal blood flow (RBF) and glomerular filtration rate (GFR). Administration of amiloride had no significant effect either on the lithium clearance, RBF or GFR, while the sodium excretion rate increased and potassium excretion rate decreased, supporting that significant distal lithium reabsorption did not occur under the present experimental conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: To examine the relative roles of apical and basolateral membrane transport mechanisms in the regulation of cell pH in the proximal convoluted tubule, cell pH was measured in the in vivo microperfused rat tubule using fluorescence. Decreasing luminal pH by 0.7 pH units caused cell pH to decrease by 0.08 pH units, whereas a similar decrease in peritubular pH caused cell pH to decrease by 0.32 pH units. Inhibition of basolateral membrane bicarbonate transport with peritubular 4-acetamido-4’-isothiocyanostilbene-2,2’-disulfonate (SITS) enhanced the response to luminal fluid acidification. Removal of luminal sodium caused a small transient acidification which was followed by a late alkalinization. Peritubular SITS increased the magnitude of the transient acidification, and eliminated the late alkalinization. The acidification was partially inhibited by luminal amiloride. The results demonstrate sodium-coupled processes on both the apical (Na/H antiport) and basolateral (Na/HCO3 symport) membranes. Basolateral membrane transporters are more important determinants of cell pH.
Abstract: In the human species, follicle growth is a very long process. The ovulatory follicle originates from a cohort of pre-antral follicles that have differentiated their theca interna 85 days earlier under the control of the high peri-ovulatory steroid and gonadotrophin levels. During growth the number of follicles decreases by atresia under the influence of factors relating to the size of the follicles. Their growth rate is regulated by intra- and extra-ovarian hormonal factors. At the end of the luteal phase, 15-20 days before ovulation, the next ovulatory follicle is recruited among a follicle population of 2-5 mm in diameter. At the beginning of the menstrual cycle it can be distinguished only by its size; a few days later it starts its maturation and exhibits its dominance on the other healthy follicles present in the two ovaries.
Abstract: Following the ingestion of a high-potassium-content diet for only a few days, the plasma potassium of rats rises only modestly in response to a previously lethal dose of potassium salts. This acquired tolerance, termed potassium adaptation, is principally the result of increased capacity to excrete potassium into the urine. However, a substantial portion of the acute potassium dose is not immediately excreted and is apparently translocated into cells. Previous studies have failed to show an increase in the content of potassium of a variety of tissues from such animals. Using 86Rb as a potassium analogue, we have shown that the skeletal muscle of potassium-adapted rats takes up significantly greater amounts of potassium in vivo in response to an acute challenge than does that of control animals. Furthermore, the same animals exhibit greater efflux of 86Rb following the termination of the acute infusion. We have also shown that the Na+-K+-ATPase activity and ouabain-binding capacity of skeletal muscle microsomes are increased by the process of potassium adaptation. We conclude that skeletal muscle is an important participant in potassium adaptation and acts to temporarily buffer acute increases in the extracellular concentration of potassium.
Abstract: Regulation of pHi in the face of acidosis resulting from contracture would appear to be of such fundamental importance to the physiology of the muscle cell that a process common to all muscle types seems a reasonable prediction. However, this has not been found to be the case. The transmembrane Na+ gradient clearly plays a major role and the process appears to be electroneutral in all three classes of muscle, but the transport mechanisms, even within the mammal, are different. It is an interesting observation that the ability of the muscle cell to regulate pHi in the presence of CO2, presumably governed by PHCO3, is related to PCl although there is little evidence for HCO3- permeation through Cl- channels. Virtually no recovery from CO2-induced acidosis is observed in normally polarized frog skeletal muscle, where PCl forms a large part of the resting conductance, whereas the same steady state pHi is recorded in the presence of various CO2 levels in mammalian smooth muscle, where PCl is very low. The study of pHi regulation in vertebrate muscle has provided important lessons for the subject as a whole. Experience in cardiac muscle has shown that if Na+-Ca2+ exchange is present, great care is required in interpretation of results where the transmembrane Na+ gradient is altered or where Ca2+ levels are changed. Interpretation may be even more complex, bearing in mind the recent reports that Ca2+ inhibits Na+-H+ exchange. "Indeed," it seems appropriate to conclude, "if a little knowledge is dangerous, where is the man who has so much as to be out of danger?" (Thomas Huxley).
Abstract: The loop diuretics inhibit a transport system that moves sodium, potassium and chloride across cell membranes of many tissues, including the thick ascending loop of Henle. This inhibitory effect is responsible for their natriuretic effect. Of the agents available for clinical use, bumetanide is the most powerful; it has an in vitro transport inhibitory potency and an in vivo natriuretic effectiveness that is approximately 50-fold that of furosemide. This increased potency and the consequent decreased dose requirement give bumetanide the potential for increased effectiveness and decreased incidence of adverse effects.
Abstract: The present study was designed to examine the short-term and long-term effects of increased plasma levels of atrial natriuretic peptide on the glomerular filtration rate, sodium excretion, and arterial pressure. Intravenous infusion of synthetic atrial natriuretic peptide (2 micrograms/kg/bolus, 50 ng/kg/min continuous infusion) for 45 minutes in six conscious dogs increased plasma levels of immunoreactive atrial natriuretic peptide from 69 +/- 10 to 233 +/- 14 pg/ml. Short-term increases in plasma levels of atrial natriuretic peptide increased the glomerular filtration rate from 53 +/- 15 to 82 +/- 16 ml/min and increased sodium excretion from 74.4 +/- 32.6 to 146.9 +/- 38.1 microEq/min. Mean arterial pressure decreased slightly, from 88 +/- 3 to 83 +/- 3 mm Hg, whereas no changes occurred in plasma renin activity (2.0 +/- 0.6 to 1.6 +/- 0.8 ng of angiotensin I per milliliter per hour) or plasma aldosterone concentration (6.9 +/- 2.3 to 8.1 +/- 3.9 ng/dl). To determine whether the short-term effects of atrial natriuretic peptide on the glomerular filtration rate and sodium excretion lead to a sustained reduction in mean arterial pressure, atrial natriuretic peptide (50 ng/kg/min) was infused intravenously for 5 days in six conscious dogs. Long-term infusion increased plasma levels of immunoreactive atrial natriuretic peptide from 27 +/- 5 to 292 +/- 31 pg/ml. The infusion caused only a transient increase in sodium excretion and had no significant long-term effect on the glomerular filtration rate. Mean arterial pressure decreased from 90 +/- 3 to 74 +/- 3 and 75 +/- 4 mm Hg by Days 4 and 5 of the infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Interpretation of the material properties of biological tissues under biaxial loading conditions has been hampered by wide variability in the coefficients. This variability has been attributed to experimental noise, numerical instability of the fitting algorithms, or to history dependence of the tissue. We have recently described quantitative methods for addressing some of these difficulties in interpretation. This study describes the application of these methods to anterior sheets of mongrel canine pericardium studied in vitro. Each specimen was stretched biaxially with three different combinations of strains and the resulting stress-strain relationships were fitted with a 5-parameter pseudo strain-energy function. Results show that each specimen is highly nonlinear, anisotropic, and history dependent. In addition there was wide inter-specimen variability in the material coefficients. In some cases the direction of the anisotropy was also history dependent. Possible explanations for this unexpected behaviour are discussed.
Abstract: Renal intracellular pH (pHi) was measured in vivo from the chemical shift (sigma) of inorganic phosphate (Pi), obtained by 31P-nuclear magnetic resonance spectroscopy (NMR). pH was calculated from the difference between sigma Pi and sigma alpha-ATP. Changes of sigma Pi closely correlated with changes of sigma monophosphoesters; this supports the hypothesis that the pH determined from sigma Pi represents pHi. Renal pH in control rats was 7.39 +/- 0.04 (n = 8). This is higher than pHi of muscle and brain in vivo, suggesting that renal Na-H antiporter activity raises renal pHi. To examine the relationship between renal pH and ammoniagenesis, rats were subjected to acute (less than 24 h) and chronic (4-7 days) metabolic acidosis, acute (20 min) and chronic (6-8 days) respiratory acidosis, and dietary potassium depletion (7-21 days). Acute metabolic and respiratory acidosis produced acidification of renal pHi. Chronic metabolic acidosis (arterial blood pH, 7.26 +/- 0.02) lowered renal pHi to 7.30 +/- 0.02, but chronic respiratory acidosis (arterial blood pH, 7.30 +/- 0.05) was not associated with renal acidosis (pH, 7.40 +/- 0.04). At a similar level of blood pH, pHi was higher in chronic metabolic acidosis than in acute metabolic acidosis, suggesting an adaptive process that raises pHi. Potassium depletion (arterial blood pH, 7.44 +/- 0.05) was associated with a marked renal acidosis (renal pH, 7.17 +/- 0.02). There was a direct relationship between renal pH and cardiac K+. Rapid partial repletion with KCl (1 mmol) significantly increased renal pHi from 7.14 +/- 0.03 to 7.31 +/- 0.01.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Whole animal clearance studies and in vitro microperfusion studies were performed to examine the effect of atrial natriuretic factor (ANF) on the rabbit proximal tubule. Infusion of ANF into rabbits resulted in an increase in glomerular filtration rate and a natriuresis and diuresis. To determine whether ANF has a direct proximal tubule effect to account for part of the observed natriuresis, proximal convoluted tubules (PCT) and proximal straight tubules (PST) were perfused in vitro. Addition of 10(-9) M ANF, a concentration recently measured in vivo during volume expansion, to the bathing solution of PCT caused no significant change in volume absorption. Addition of a pharmacological concentration of ANF (10(-7) M) to either the bathing solution or the luminal perfusate of PCT resulted in no change in volume absorption. When added to the bathing solution of PST, 10(-7) M ANF did not have an effect on volume absorption. ANF did not affect the transepithelial potential difference in any protocol. In conclusion, these data show that ANF does not affect transport directly in the proximal tubule.
Abstract: Lactic acidosis is not generally recognized as a complication of pheochromocytoma. We review three prior case reports of lactic acidosis in patients with pheochromocytoma and one report of lactic acidosis following epinephrine poisoning and describe an additional case report of a patient with lactic acidosis in whom an unsuspected pheochromocytoma was discovered at autopsy. The pathophysiology of lactic acidosis in pheochromocytoma is related to the effect of catecholamines on intermediary metabolism and the peripheral circulation. Although the possible development of lactic acidosis in persons with pheochromocytoma is underappreciated, the differential diagnosis of lactic acidosis should include this tumor.
Abstract: Correction of chloride-depletion alkalosis (CDA) may involve renal as well as extrarenal mechanisms. To determine the relative contribution of these mechanisms in a rat model of CDA produced by peritoneal dialysis (PD), we studied six groups of anesthetized Sprague-Dawley rats after PD. Groups II-IV and IIa were subjected to functional bilateral nephrectomy, and groups I and Ia were sham-operated. Groups I, Ia, II, and IIa were infused with isotonic fluid containing 70 mM Cl- and 40 mM HCO3-; the infusate in group III was 140 mM Cl- and in group IV, 70 mM neutral PO4 was substituted for Cl-. Groups I and Ia were infused at 0.5 ml . h-1 X 100 g body wt-1 and groups II, IIa, III, and IV at 0.25 ml . h-1 X 100 g-1. After 3 h of infusion, early partial correction with reciprocal changes in plasma Cl (+6.1 +/- 1.9 mmHg) and total CO2 (-6.0 +/- 0.8 meq/liter) occurred (P less than 0.01) only in group I. Hypokalemia (3.1 +/- 0.1 meq/liter) also occurred only in group I. The responses of groups Ia and IIa studied at 5 h were similar to those of groups I and II. These data suggest that the kidney, and not extrarenal mechanisms, is primarily responsible for the correction of CDA during infusion of chloride.
Abstract: Whether the material properties of the pericardial membrane are the key determinants of the in situ pericardial pressure-volume relation is not known. Although both the pressure-volume relation of the intact pericardium and the stress-strain relation of isolated pericardial samples are nonlinear, it is not clear how closely these phenomena are related. To directly examine this question we compared the pressure-volume, pressure-normalized volume, and stress-strain relations of pericardia from six dogs tested both in situ and in vitro. The curves generated under the two sets of conditions were different. The transition from the compliant to the noncompliant portion of the curve was more acute under in vitro conditions. Nonlinear regression analysis using a monoexponential function of the form Y = alpha (e beta chi-1) showed beta, the proportionality constant for the slope of the curve, to be larger for each form of analysis under in vitro testing conditions as follows: 0.002 +/- 0.009 vs. 0.078 +/- 0.029, P less than 0.002 for pressure-volume; 3.52 +/- 1.75 vs. 11.03 +/- 5.31, P less than 0.005 for pressure-normalized volume; and 19.6 +/- 6.6 vs. 62.3 +/- 18.8, P less than 0.001 for stress-strain. These differences in the pressure-volume relation of the intrapericardial space in situ and the isolated pericardium in vitro suggest that pericardial attachments present in situ may buffer the loading of the membrane itself. We conclude that the pressure-volume relation of the intrapericardial space is only partly determined by the properties of the isolated pericardium alone and is also influenced by other components of the intact pericardium.
Abstract: Arginine vasopressin (AVP) was infused into the renal artery of seven uninephrectomized conscious dogs at successive rates of 0.09, 0.36, and 1.46 ng X kg-1 X min-1 for 18, 9, and 5 days, respectively; subsequently, the nonpressor analogue of AVP, 1-desamino-8-D-arginine vasopressin (DDAVP), was infused intrarenally for 7 additional days. The lowest infusion rate of AVP produced a high concentration of AVP in the renal circulation (maximal antidiuresis) with only a relatively moderate increase in peripheral plasma AVP concentration. For comparison, the effects of a comparable increase in peripheral plasma AVP concentration during intravenous infusion at this same rate were observed in an additional group of dogs. Acutely, when this low dose of AVP was infused either intrarenally or intravenously, there was marked antidiuresis, but there were no significant changes in mean arterial pressure (MAP), renal hemodynamics, or urinary electrolyte excretion. Chronically, in both groups of animals, cumulative water balance was positive, and glomerular filtration rate, effective renal plasma flow, and MAP (16-18 mmHg) all increased; plasma renin activity decreased. Similar changes were observed during DDAVP infusion. When elevated peripheral plasma levels of AVP were achieved during the higher infusion rates of AVP, natriuresis and diuresis occurred, but, otherwise there was little change in the above variables, including MAP. Thus the hydrosmotic effects of AVP appear to account for its moderate hypertensive activity. Further, the failure of AVP to produce prominent hypertension, even when pronounced systemic vasoconstrictor effects are manifested, may be a result of its inability to promote significant renal vasoconstriction and antinatriuresis.
Abstract: The effects of passive tilt on arterial and central venous pressures (MAP and CVP), heart rate (HR), arterial concentrations of vasopressin (AVP) and aldosterone (ALDO), osmolality, and hematocrit were studied in eight healthy young men. Tilting was performed at 30 degrees/min to 20 or 40 degrees and maintained for 45 min. The 20 degrees tilt did not change MAP while CVP fell by 5.9 mmHg (P less than 0.01) and HR increased by 5 beats/min (51-56 beats/min, P less than 0.05). AVP and ALDO concentrations were unchanged. At 40 degrees, MAP increased by 5.7 mmHg (86.0-91.7 mmHg, P less than 0.01), CVP decreased by 7.4 mmHg (P less than 0.01), HR rose by 8 beats/min (55-63 beats/min, P less than 0.01), and pulse pressure fell by 6 mmHg (P less than 0.05). ALDO increased fivefold (P less than 0.05), but AVP did not change. Infusions of AVP at 0.25 or 1.0 ng X min-1 X kg body wt-1 elevated plasma AVP to 11 +/- 1 and 52 +/- 8 pg/ml. Only the larger dose caused a small increase in MAP while CVP and HR remained unchanged; however, washout of a subcutaneous depot of Xe was reduced greater than 60% even by the lower dose. It is concluded that small-angle nonhypotensive passive tilt does not affect AVP measurably despite substantial reductions of CVP and a marked increase in ALDO. Elevations of AVP elicit marked subcutaneous vasoconstriction also in the absence of changes in CVP, HR, and MAP.
Abstract: Colloid osmotic pressure in plasma (COPp) and interstitial fluid (COPi), plasma volume (PV) and interstitial fluid volume (IFV) were measured in 14 patients with hypoproteinaemia due to glomerulonephritis and in five healthy controls. In controls, COPp averaged 24.2 mmHg and COPi 12.0 mmHg. In patients with COPp above 12 mmHg, COPi was reduced nearly identical to the fall in COPp. The transcapillary COP gradient (COPp-COPi) was maintained, and PV and IFV were unchanged. When COPp was reduced below 12 mmHg, the transcapillary COP gradient was decreased. Both IFV increased and renal fluid retention occurred. This study demonstrates the relationship between COPp, transcapillary fluid transport, and renal fluid retention in nephrotic syndrome.
Abstract: The effects of mixing short- and intermediate-acting insulins (Actrapid MC and Monotard MC) were studied in seven diabetic patients. On different days, 0.16 IU/kg of Actrapid and 0.24 IU/kg of Monotard were administered to each subject in separate injections and combined in the same syringe. Free-insulin curves and the biologic effect of insulin, assessed by the glucose-clamp technique, were compared. The absorption rate of regular insulin was higher when injected separately from the intermediate-acting preparation: the incremental areas of free insulin above basal levels, up to 90 min after the administration of the hormone, were 32 +/- 5 vs. 21 +/- 3 microU X ml-1 X min-1 (P less than .02). In the same period, glucose infused to sustain glycemia showed no significant differences (2.8 +/- 0.4 vs. 2.4 +/- 0.3 mg X kg-1 X min-1 after the administration of insulin in separate and combined injection, respectively). The difference in insulin profiles is not translated into a significant difference in glucose requirement. This might be a consequence of a flattening of the insulin dose-response curve due to insulin resistance of diabetic subjects. The slight delay in insulin action of Actrapid when mixed with Monotard is probably irrelevant in clinical practice.
Abstract: Blood flow, lactate extraction, and tissue lactate concentration were measured in an autoperfused pure red muscle (dog gracilis). Muscles were frozen in situ during steady-twitch contraction at frequencies of 1-8 Hz [10-100% of maximum O2 consumption (VO2max)]. Myoglobin saturation was determined spectrophotometrically with subcellular spatial resolution. Intracellular PO2 (Pto2) was calculated from the oxymyoglobin-dissociation curve. Tissue lactate was well correlated with VO2 but not with Pto2. Lactate efflux increased markedly above a threshold work rate near 50% VO2max. Efflux was neither linearly correlated with tissue lactate nor related to Pto2. Pto2 exceeded the minimum PO2 for maximal VO2 in each of 2,000 cells examined in muscles frozen at 1-6 Hz. A small population of anoxic cells was found in three muscles at 8 Hz, but lactate efflux from these muscles was not greater than from six other muscles at 8 Hz. Our conclusions are that 1) the concept of an anaerobic threshold does not apply to red muscle and 2) in absence of anoxia neither tissue lactate nor blood lactate can be used to impute muscle O2 availability or glycolytic rate. A mechanism by which the blood-tissue lactate gradient could support aerobic metabolism is discussed.
Abstract: In a porcine preparation of cardiac arrest, we demonstrated that there is a marked paradox of venous acidemia and arterial alkalemia. This paradox is related to decreased clearance of CO2 from the lungs when pulmonary blood flow is critically reduced. Accordingly, increased venous PCO2 rather than metabolic acidosis due to lactic acidosis predominates during the initial 8 min of cardiopulmonary resuscitation. Arterial blood gases fail as indicators of systemic acid-base status and therefore as indicators of tissue acidosis.
Abstract: Angiotensin II (ANG II) is one of the body’s most powerful regulators of Na excretion, operating through extrarenal mechanisms, such as stimulation of aldosterone secretion, as well as intrarenal mechanisms. Considerable evidence suggests that the intrarenal actions of ANG II are quantitatively more important than changes in aldosterone secretion in the normal day-to-day regulation of Na balance and arterial pressure. ANG II at physiological concentrations increases proximal tubular reabsorption, but further studies are needed to determine whether ANG II also has an important effect on more distal tubular segments. ANG II also markedly constricts efferent arterioles, tending to increase Na reabsorption by altering peritubular capillary physical forces and also helping to prevent excessive decreases in glomerular filtration rate. ANG II may also decrease Na excretion and increase urine concentrating ability by reducing renal medullary blood flow. Regulation of Na excretion by ANG II is closely linked with arterial pressure control and volume homeostasis through the renal pressure natriuresis mechanism. Under many physiological conditions, such as changes in Na intake, ANG II greatly multiplies the effectiveness of the pressure natriuresis mechanism to prevent fluctuations in body fluid volume and arterial pressure. In circumstances associated with circulatory depression, such as decreased cardiac function, reductions in blood pressure and increased ANG II formation cause Na retention until arterial pressure is restored to normal. However, in pathophysiological conditions in which ANG II is inappropriately elevated, increased arterial pressure (hypertension) is required for the kidney to "escape" the potent antinatriuretic actions of ANG II and to return Na excretion to normal via the pressure natriuresis mechanism.
Abstract: Using data derived from clinical and experimental observations, we examine the role of the myocardial beta-adrenergic receptor system in pathophysiologic processes involved in heart muscle disease and heart failure. The available data suggest that the sympathetic nervous system exerts important influences on myocardial structure and function. As such the beta-adrenergic pathways represents an obvious locus for therapeutic intervention in evolving cardiomyopathic states.
Abstract: The purpose of this study was to examine regional autoregulation of blood flow in the brain during acute hypertension. In anesthetized cats severe hypertension increased blood flow more in cerebrum (159%) and cerebellum (106%) than brain stem (58%). In contrast to the heterogeneous autoregulatory response, hypocapnia produced uniform vasoconstriction in the brain. We also compared vasodilatation during severe hypertension with vasodilatation during hypercapnia. During hypercapnia, blood flow increased as much in brain stem, as in cerebrum and cerebellum. Thus regional differences in autoregulation appear to be specific for autoregulatory stimulus and are not secondary to nonspecific differences in vasoconstrictor or vasodilator capacity. To determine whether the blood-brain barrier is more susceptible to hypertensive disruption in regions with less effective autoregulation, permeability of the barrier was quantitated with 125I-albumin. Severe hypertension produced disruption of the barrier in cerebrum but not in brain stem. Thus there are parallel differences in effectiveness of autoregulation and susceptibility to disruption of the blood-brain barrier in different regions of the brain.
Abstract: The effects of metabolic acidosis were examined in isolated rat hepatocytes under substrate-free oxygenated or anoxic conditions. Lowering extracellular pH to 6.6 under aerobic conditions had no deleterious effects on the cells as determined by trypan blue exclusion, lactate dehydrogenase (LDH) release, cellular K+ and Ca2+ content, and ability to increase ATP levels after nutrients and adenosine were added to media. Cytosolic pH was measured in aerobic cells at varying extracellular pH using 6-carboxyfluorescein. By using values for cytosolic pH obtained in this manner together with 5,5-dimethyl[2-14C]oxazolidine-2,4-dione (DMO) distribution data, a method was derived for determining intramitochondrial pH. The pH gradient across the mitochondrial membrane was found not to change with a decrease in extracellular pH from 7.4 to 6.9. At pH 6.9 hepatocytes were protected against anoxic injury as compared with cells incubated at pH 7.5 or 6.6. This protection was manifested by a decrease in vital dye uptake and LDH release, maintenance of higher cellular K+ content, less stimulation of respiration with succinate, improved recovery of ATP levels after return to an oxygenated nutrient environment, and maintenance of normal cellular Ca2+ content after reoxygenation. Recovery of cellular ATP content was independent of ATP levels, total adenine nucleotide pool, and energy charge ratio at the end of the anoxic period. Measurement of cytoplasmic pH in anaerobic cells by [14C]DMO distribution showed progressive cellular acidification with lowering of extracellular pH. The protective effects observed at pH 6.9 are not unique to hepatocytes since isolated renal cortical tubules exposed to anoxia have improved ATP levels on reoxygenation at this pH when compared with tubules incubated at pH 7.5.
Abstract: Ventilatory responses to chemostimulation are reduced during NREM sleep and fall further during REM sleep. These reductions are probably due to a combination of decreased basal metabolic rate during sleep, altered neuromuscular function, and increased cerebral blood flow. The decreased responses are important in the production of hypoxemia during sleep in patients with hypoxic lung disease.
Abstract: Although it has been known for more than a century that digitalis glycosides exert a powerful beneficial effect on patients with heart failure, atrial fibrillation and a rapid ventricular rate, it was believed for many years that the drug exerts this clinical effect primarily by slowing the heart rate. It was also thought that the extra-cardiac vascular actions of digitalis might be responsible for its therapeutic effect. It has now been established that cardiac glycosides cause arteriolar and venous constriction in a variety of mammalian species including human beings, and that this vasoconstriction involves the coronary vascular bed as well, but it is believed that these actions are not responsible for any beneficial clinical effect. A variety of investigations on cardiac muscle in vitro, anesthetized and conscious dogs and anesthetized and conscious human subjects have shown that cardiac glycosides improve the contractility of failing mammalian myocardium. It has become clear that digitalis also stimulates the contractility of the nonfailing heart. The degree of augmentation of contractility induced by cardiac glycosides is related inversely to the baseline contractile state. Myocardial oxygen consumption, which is increased in the normal heart by the positive inotropic action of glycosides, is actually reduced or remains constant in the failing heart. Cardiac glycosides increase the contractility of the globally ischemic heart, but their actions in chronic ischemic heart disease with regional impairment of function are complex. Deterioration of segmental performance occurs in ischemic and necrotic segments, while improvement of contractility occurs in adjacent normal segments.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: The concentration of lactate in the blood is the result of (1) those processes which produce lactate and contribute to its appearance in the blood and (2) those processes which catabolize lactate after its removal from the blood. Consequently, the concentration of lactate in the blood provides minimal information about the rate of lactate production in muscle. The accumulation of lactate beyond the lactate threshold [T(lact)] does provide an indication that the mechanisms of lactate removal fail to keep pace with lactate production. Lactate is produced in skeletal muscle as a direct result of increased metabolic rate and glycolytic carbon flow. Factors which influence lactate production in muscle include: the Vmax of lactic dehydrogenase (LDH), which is several times greater than the combined activities of enzymes which provide alternative pathways of pyruvate metabolism; the kM of LDH for pyruvate, which is sufficiently low to assure maximal stimulation of LDH in the conversion of pyruvate to lactate; and the K’eq of pyruvate to lactate conversion, which exceeds 1000. Recent studies on dog gracilis muscle in situ clearly indicate that lactate production occurs in contracting pure red muscle for reasons other than an O2 limitation on mitochondrial ATP production. In addition to failure of the essential assumption of the anaerobic threshold [T(an)] hypothesis that there exist limitations on O2 availability in muscles of healthy individuals during submaximal exercise, several groups of investigators have produced results which indicate that parameters associated with changes in pulmonary minute ventilation [i.e., the ventilatory threshold, T(vent)] do not always track changes in blood lactate concentration. Therefore, the T(an) hypothesis fails on the bases of theory and prediction. A series of kinetic tracer experiments to better understand lactate kinetics during exercise is proposed.
Abstract: Diabetic ketoacidosis is usually associated with marked secondary hyperaldosteronism. Plasma levels of renin, angiotensin II, and aldosterone are markedly raised before treatment in most patients, with values falling rapidly toward normal as metabolic control is restored. In a few patients, mostly those with long-term complications of diabetes, plasma levels of renin, angiotensin II, and aldosterone before treatment remain within the normal range. In moderately hyperglycemic patients who have glycosuria but not ketonuria, plasma levels of all three substances are significantly higher than when control is improved. Occasionally, moderately hyperglycemic patients have mild secondary hyperaldosteronism. Improved metabolic control in such patients causes a rise in plasma volume and a rise in total exchangeable sodium, the latter to levels significantly above normal. Plasma catecholamine levels are markedly elevated in diabetic ketoacidosis, probably as a consequence of the ketoacidotic state. In nonketotic patients with moderate hyperglycemia, basal plasma norepinephrine levels are normal; catecholamine responses to exercise may be exaggerated, however. Epidemiological and animal studies suggest a relationship between blood pressure and blood glucose levels. There are few clinical studies of the effects of altering metabolic control of diabetes on blood pressure, and this is an important area for further study.
Abstract: The role of ammonia in exercise-induced fatigue is reviewed. Implications for integrated activity of developing hyperammoneic states, caused by various precipitating conditions such as exercise, liver dysfunction, hypoxia, hyperoxia, and chemical poisoning are described. The central role of ammonia in diverse important metabolic pathways indicates its ubiquitous role in a spectrum of activity ranging from elite exhaustive performance of sportsmen and -women to life-threatening organ dysfunction. The action of ammonia and metabolites from associated pathways in producing seemingly dangerous short term conditions, but inducing possible long term protection against degenerative processes associated with ageing (free radical-induced cellular damage) indicate the paradoxical position of ammonia and its associated metabolic pathways for health and disease processes.
Abstract: Rate of O2 consumption (VO2), intracellular PO2, lactate extraction, and tissue contents of phosphocreatine, creatine, ATP, lactate, and pyruvate were measured during rest-work transitions in dog gracilis muscles. Samples were taken at rest and after 5, 10, 15, 30, 60, and 180 s of twitch contraction at 4/s. There was no anoxia at any time or location [companion paper, Am. J. Physiol. 248 (Heart Circ. Physiol. 17): H914-H921, 1985]. Energy was supplied by a continuous utilization of phosphocreatine stores, a slow rise in VO2, and two distinct bursts of glycolysis. Glycolytic rate was independent of tissue PO2 and VO2 and was poorly correlated with phosphocreatine under the aerobic conditions of our experiments. The glycolytic bursts served as a source of ATP, and the bulk of the lactate formed remained in the tissue. Lactate efflux was a small fraction of tissue lactate; it depended on blood flow but not on tissue lactate content. At steady state a small glycolytic flux maintained the high tissue lactate mainly by matching rates of pyruvate production and oxidation. We propose that this flux and the high tissue lactate concentration buffer cytosolic redox and/or substrate supply in support of the aerobic functions of mitochondria during exercise.
Abstract: Conscious SHR and WKY rats were infused during 7 days with synthetic ANF (Arg 101-Tyr 126), 100 ng/hr/rat (35 pmol/hr/rat) by means of miniosmotic pumps. The SHR initial blood pressure of 177 +/- 5 mmHg gradually dropped to 133 +/- 3 and 142 +/- 4 mmHg the last two days of infusion. No significant change in blood pressure was observed in the ANF-infused WKY group. No apparent difference in natriuresis or diuresis was observed in ANF-infused SHR and WKY when compared with non-infused control groups. A slight but significant lower immunoreactive ANF concentration was found in the atria of SHR than in their normotensive controls. No difference in cardiac weight was found between infused and non-infused rats. It is suggested that the hypotensive response observed in SHR and not in WKY is due to a decrease in vascular peripheral resistance. Whether ANF is involved in the development and maintenance of high blood pressure in SHR remains to be elucidated.
Abstract: Our knowledge of the structure and function of the renal glomerulus is reviewed in a historical context. The glomerular corpuscles were first described by Malpighi in 1666. Subsequent injection studies led to conflicting claims concerning a glomerular-tubular connection. This connection was accepted only after the convincing demonstration of the anatomical relationship essentially as we now know it by Bowman in 1842. Ludwig was the first to propose that the mechanism of separation of fluid in the glomeruli was by ultrafiltration. Estimates of the ultrafiltration forces in mammals led to conflicting speculation as to whether or not filtration-pressure equilibrium was reached in glomerular capillaries. Results of direct determinations in some Munich-Wistar rats indicate filtration pressure equilibrium, an ultrafiltration coefficient (Kf) of 0.08 nl X s-1 X mmHg-1, and a strong influence of plasma flow on filtration rate (GFR). In contrast, evidence has been presented that filtration dynamics in other Munich-Wistar rats and several other strains of rats are characterized by filtration disequilibrium, a Kf of 0.04 nl X s-1 X mmHg-1, and a weak dependence of GFR on plasma flow. In conscious and anesthetized rats, kidney GFR is usually relatively stable in the presence of renal vasodilation. Filtration disequilibrium is reported in the dog and equilibrium in the squirrel monkey. Although predictions for humans suggest filtration disequilibrium, final conclusions await an in-depth analysis of direct measurements.
Abstract: CO intoxication, by producing cerebral hypoxia-ischaemia, may trigger neuropathological events which result in delayed neurological relapse even in patients whose earlier clinical course has appeared deceptively benign. The physician’s index of suspicion must therefore be high, and it should be remembered that, even in major CO exposures, blood COHb levels may be low if a period of several hours has elapsed since exposure. The importance of recognising occult CO exposure and of treating symptomatic patients promptly cannot be overemphasized. Immediate administration of high concentrations of inspired oxygen (including hyperbaric oxygenation, if available) is the primary therapy. Hypotension and acid-base abnormalities should be promptly reversed. Prolonged bed rest is recommended to discourage delayed relapse.
Abstract: Lactic acidosis, a clinical syndrome caused by the accumulation of lactic acid, is characterized by lactate concentration in blood greater than 5 mM. Therapy usually consists of intravenous sodium bicarbonate (NaHCO3), but resultant mortality is greater than 60 percent. The metabolic and systemic effects of NaHCO3 therapy of hypoxic lactic acidosis in dogs were studied and compared to the effects of sodium chloride or no therapy. Sodium bicarbonate elevated blood lactate concentrations to a greater extent than did either sodium chloride or no treatment. Despite the infusion of NaHCO3, both arterial pH and bicarbonate concentration decreased by a similar amount in all three groups of dogs. Additional detrimental effects of NaHCO3 were observed on the cardiovascular system, including decreases in cardiac output and blood pressure that were not observed with either sodium chloride or no treatment. Thus there is evidence for a harmful effect of NaHCO3 in the treatment of hypoxic lactic acidosis.
Abstract: The relationship between acid base parameters and serum potassium concentration was studied in controls and in patients during acute ammonium chloride-induced metabolic acidosis. Serum potassium was best correlated with serum bicarbonate during control (r = -0.323; p less than 0.01) and acidosis (r = -0.437; p less than 0.001). The slopes and intercepts were similar in both instances and the combined correlation was highly significant (r = -0.493; p less than 0.001). Examination of the 95% joint confidence region revealed that during acidosis serum potassium was rarely above 5.0 mEq/l when serum bicarbonate was greater than 16 mEq/l. It is probably not sound clinical practice to ascribe hyperkalemia to acute mild metabolic acidosis.
Abstract: The early physiopathologic responses to transection of the cervical spinal cord (C-4) were studied in the experimental animal. After transection, increases were seen in the mean arterial pressure, pulmonary capillary wedge pressure, intracranial pressure, brain water, blood–brain barrier permeability, and extravascular lung water with a marked decrease occurring in cerebral blood flow. Pretreatment with an alpha-adrenergic blocker, phentolamine (Regitine Ciba-Geigy Corp.), followed by transection blocked the rise in mean arterial blood pressure and pulmonary capillary wedge pressure but did not affect the increases in intracranial pressure, brain water, blood–brain barrier permeability, and extravascular lung water and decreases in cerebral blood flow. Transection of the cervical spinal cord initiates a complex series of events involving intracranial compliance and pulmonary permeability, placing both brain and lungs at risk.
Abstract: Ammonia, an important urinary buffer in mammals, is synthesized primarily in the proximal tubules and is transferred to the final urine by a sequence of specialized transport processes. The pathway of ammonia transfer to the urine involves secretion into the proximal tubules, absorption from the loops of Henle, accumulation in the renal medullary interstitium, and secretion into the collecting ducts. Ammonia is transported as NH3 at some nephron sites and as NH+4 at others. In this paper, we discuss the physical basis of NH3 and NH+4 transport in epithelia and then describe ammonia transport mechanisms in individual nephron segments. Information about ammonia transport in individual nephron segments from isolated perfused tubule studies is integrated with data from in vivo studies to obtain an expanded overall model of renal ammonia handling.
Abstract: This experiment was designed to estimate the optimum pedal rates at various power outputs on the cycle ergometer. Five trained bicycle racers performed five progressive maximal tests on the ergometer. Each rode at pedal rates of 40, 60, 80, 100, and 120 rev X min-1. Oxygen uptake and heart rate were determined from each test and plotted against pedal rate for power outputs of 100, 150, 200, 250, and 300 W. Both VO2 and heart rate differed significantly among pedal rates at equivalent power outputs, the variation following a parabolic curve. The low point in the curve was taken as the optimal pedal rate; i.e., the pedal rate which elicited the lowest heart rate or VO2 for a given power output. When the optimum was plotted against power output the variation was linear. These results indicate that an optimum pedal rate exists in this group of cyclists. This optimum pedal rate increases with power output, and when our study is compared to studies in which elite racers, or non-racers were used, the optimum seems to increase with the skill of the rider.
Abstract: This study investigates the mechanisms underlying the perception of breathlessness induced by hypoxia and hypercapnia in both naive normal subjects and patients with respiratory mechanical problems. In normal subjects separately receiving both oscillating hypercapnic and hypoxic ventilatory stimulation, equivalent peak stimulus intensities in end-tidal gas were associated with a ’damped’ ventilatory response when the frequency of stimulation was increased. A concomitant fall in peak breathlessness levels on a visual analogue scale was recorded in each case. In normal subjects and patients, the voluntary copying of a ventilatory pattern recorded during oscillating hypercapnic stimulation was associated with a marked diminution or complete absence of breathlessness despite equivalent levels of peak ventilations achieved. Voluntary copying of hypercapnic stimulated ventilation was not associated with any demonstrable change in the distribution of muscle movements between the chest wall and abdomen. These results suggest that the intensity of breathlessness depends on the level of effective reflex stimulation of the respiratory-related neurones in the medulla. They cannot be explained solely in terms of perception of afferent neural information arising from either chemoreceptors or respiratory mechanoreceptors.
Abstract: Systematic studies on the significance of the secretory-like morphological characteristic of cardiac atrial muscle cells of mammals led to the finding that these cells produce a polypeptide hormone. This hormone, described in 1981 as atrial natriuretic factor (ANF), is diuretic (natriuretic), hypotensive, and has an inhibitory effect on renin and aldosterone secretion. Thus, ANF probably intervenes in the short- and long-term control of water and electrolyte balance and of blood pressure. Phylogenetically, ANF appears early, suggesting different functions for this peptide in accordance with each species’ environment. Knowledge of the properties of the hormone should provide insights into the pathophysiology of important clinical entities and lead to the development of new pharmaceutical products.
Abstract: To characterize the influence of extracellular volume status on vasopressin pharmacokinetics, eleven young (aged 19-31 yr) and four old (aged 62-80 yr) subjects received bolus injections of 1 mU/kg Pitressin or synthetic arginine vasopressin following 6 days of sodium depletion (10 meq Na/day) or sodium loading (250 meq Na/day). In six young subjects the rapid decline in plasma vasopressin (pAVP) following the initial peak was interrupted by a second peak 5-30 pg/ml in magnitude 7.5-20 min after injection. In four of these subjects the second peak was larger following sodium depletion as compared with sodium loading. In the elderly a small (4 pg/ml) second peak was present in one sodium-depleted subject. Of five sodium-depleted subjects with central diabetes insipidus, none showed a secondary rise in pAVP. These results indicate that exogenous vasopressin may stimulate the release of endogenous AVP, an effect that appears to be enhanced by sodium depletion and is virtually absent in the elderly. There was no effect of age, volume status, or diabetes insipidus on AVP pharmacokinetics.
Abstract: From 1979 to 1982, in the United States, at least 95 persons were electrocuted in bathtubs; 66% of the deaths occurred during the winter and spring. Children younger than 5 years had the greatest mortality rate, and hair dryers were responsible for 60% of the deaths. Until electric appliances used in bathrooms are made safer, the appliances should be disconnected when not in use, not used in wet bathtubs, and kept away from children.
Abstract: The etiology of cranial diabetes insipidus (CDI) in adult patients has been studied in 164 cases hospitalized in the "G. I. Parhon" Institute of Endocrinology, over the last 10 years. Of those, 109 cases (66,9%) had the idiopathic form whereas 55 had secondary CDI. In the latter group, the most frequently encountered etiologies were traumatic (surgical and accidental head trauma) and tumoral (the primary hypothalamo-pituitary tumors and the metastatic ones had the same incidence). Sex distribution shows males and females to be equally affected. Fifteen cases (9,2%) showed associated allergic syndromes due to the wide use of posterior pituitary powder in Romania. The association of pregnancy with CDI was observed in 13 patients, and a normal evolution of gestation and delivery in 9 patients under therapy with desmopressin (DDAVP). The authors suggest that, at present, there is an increasing incidence both of posttraumatic CDI in adults and of well borne pregnancies.
Abstract: A systematic steady-state analysis of the forces and membrane coefficients governing transcapillary and lymphatic fluid fluxes was performed in the cat ileum under absorptive and nonabsorptive conditions. Net transmucosal fluid flux, lymph flow, capillary pressure, blood flow, capillary filtration coefficient, and lymph and plasma oncotic pressures were measured before and during perfusion of the ileal lumen with a glucose (20 mM)–Tyrode’s solution. Interstitial fluid pressure was calculated for the two conditions from measured parameters. Stimulation of mucosal fluid absorption resulted in an increase in lymph flow (which tripled), capillary filtration coefficient (which doubled), capillary pressure (which increased by 9%), interstitial fluid pressure (which doubled), and blood flow (which increased by 16%), whereas interstitial (lymph) oncotic pressure fell (by 20%). These changes converted filtering capillaries to absorbing capillaries, thereby allowing 82% of the absorbed fluid to be removed from the mucosal interstitium via the capillaries, while the lymphatics removed the remaining 18%. The results of this study indicate that hydrostatic and oncotic forces within the interstitium are primarily responsible for preventing interstitial fluid accumulation during periods of net fluid absorption in the small bowel.
Abstract: The effect of acute changes in arterial PCO2 on absolute proximal reabsorption of bicarbonate, chloride, and water has not been systematically studied. In the present free-flow micropuncture studies in Munich-Wistar rats, arterial PCO2 was increased or decreased by 20 mmHg. Under conditions of stable SNGFR, proximal and whole kidney electrolyte reabsorption was measured. Acute hypocapnia decreased absolute proximal bicarbonate reabsorption by 23% (from 1,008 +/- 38 to 773 +/- 36 pmol/min). Proximal volume reabsorption also decreased. Although bicarbonate delivery out of the superficial proximal convoluted tubule did not exceed normal levels, bicarbonaturia developed, suggesting an additional suppression of acidification by distal and/or juxtamedullary nephron segments. Acute hypercapnia increased absolute proximal bicarbonate reabsorption by only 10% in chronically alkalotic animals (from 1,050 +/- 68 to 1,176 +/- 77 pmol/min). In acutely alkalotic animals, hypercapnia caused no significant increment in the higher basal level of absolute proximal bicarbonate reabsorption (from 1,158 +/- 120 to 1,234 +/- 97 pmol/min). Whole kidney bicarbonate reabsorption rose, again suggesting a distal and/or juxtamedullary effect. Hypercapnia inhibited proximal chloride reabsorption and caused a chloruresis. In conclusion, acute hypo- and hypercapnia caused alterations in proximal bicarbonate, chloride, and sodium transport that may participate, at least in part, in the changes in whole kidney electrolyte reabsorption observed in these conditions. Distal and/or juxtamedullary nephrons also appeared to contribute to the changes in renal acidification induced by alterations in systemic PCO2.
Abstract: Studies were performed in anesthetized dogs (n = 5) to determine the effects of synthetic atrial natriuretic factor on renal function and renin release. Intrarenal infusion of synthetic atrial natriuretic factor (ANF) (0.3 microgram X kg-1 X min-1) resulted in a transient increase in renal blood flow (126 +/- 8 to 148 +/- 11 ml/min). The duration of this transient vasodilation was 3.1 +/- 0.4 min. Continued infusion was followed by a slight decrease in renal blood flow (126 +/- 8 to 117 +/- 8 ml/min) and an increase in glomerular filtration rate (23.1 +/- 3.5 to 30.7 +/- 1.9 ml/min), with filtration fraction thus being increased (0.19 +/- 0.04 to 0.27 +/- 0.03). These hemodynamic alterations were associated with increases in fractional sodium excretion (0.6 +/- 0.2 to 5.8 +/- 0.8%), fractional potassium excretion (30.8 +/- 9.4 to 56.3 +/- 7.4%), fractional lithium excretion (32.2 +/- 7.1 to 60.3 +/- 5.7%), and fractional phosphate excretion (8.7 +/- 3.5 to 41.6 +/- 11.7%). Intrarenal infusion of synthetic ANF markedly suppressed renin secretion rate (295.5 +/- 84.6 to 17.2 +/- 10.6 ng/min) despite a slight reduction in arterial pressure (123 +/- 9 to 118 +/- 9 mmHg). Our studies demonstrate that synthetic ANF results in a marked natriuretic response that is in part mediated by an increase in glomerular filtration rate. The increase in fractional lithium and phosphate excretion suggests that this factor may also have an action on proximal tubule reabsorption. Further, these studies demonstrate that synthetic ANF markedly inhibits renin secretion.
Abstract: Tissue lactate was measured in dog gracilis muscles frozen at rest and during phasic twitch contractions, which evoked 10-100% of maximum O2 consumption (VO2 max). Myoglobin cryomicrospectroscopy was used to obtain the distribution of PO2 in subcellular volumes. Tissue sampling was designed to estimate lactate concentration in the population of cells used for spectroscopy. Covariates included vascular resistance, functional capillary density, VO2, tissue pyruvate, ATP, phosphocreatine, and creatine, as well as lactate efflux. Myoglobin saturation did not decrease in the first seconds of stimulation at 1 or 4/s. In the steady state, muscle lactate accumulation was linear with stimulation rate and VO2. At 1 and 4/s the minimum PO2 found was greater than 5 Torr during the rest-work transition and greater than 2 Torr in the steady state. VO2 did not increase when flow was increased during contraction at⅟s, although the minimum PO2 found rose to approximately 10 Torr. If flow was restricted during stimulation, PO2 was 0 at many loci, and lactate concentration was elevated above the value predicted by its linear relationship with twitch rate. We conclude that fully aerobic lactate accumulation occurs in this pure red muscle. This accumulation results from causes other than a simple O2 limit on mitochondrial ATP production.
Abstract: The mechanism of sodium retention in the nephrotic syndrome remains controversial, though the classic pathophysiological explanation is stimulation of the renin-angiotensin-aldosterone system. Recent evidence has shown that many patients with the nephrotic syndrome have a normal or low plasma renin activity suggesting that there might be an intrarenal cause for their sodium retention. We gave captopril, an oral angiotensin-converting enzyme inhibitor, during 10 separate episodes of sodium retention in nephrotic syndrome. There was evidence of stimulation of the renin system in 7 of these episodes. Despite a marked fall in plasma aldosterone, all patients continued to retain sodium and water and gain weight. This demonstrates that the sodium retention of nephrotic syndrome is not due to stimulation of the renin-angiotensin-aldosterone system, but must be due to some other mechanism, which is probably intrarenal.
Abstract: To ascertain whether the dawn phenomenon occurs in nondiabetic individuals and, if so, whether it is due to an increase in glucose production or a decrease in glucose utilization, we determined plasma concentrations of glucose, insulin, C-peptide, and counterregulatory hormones, as well as rates of glucose production, glucose utilization, and insulin secretion at one-half-hourly intervals between 1:00 and 9:00 a.m. in eight normal volunteers. After 5:30 a.m., plasma glucose, insulin, and C-peptide concentrations all increased significantly; rates of glucose production, glucose utilization, and insulin secretion also increased (all P less than 0.05). Plasma cortisol, epinephrine, and norepinephrine increased significantly from nocturnal nadirs between 4:00 and 6:30 a.m. Plasma growth hormone, which had increased episodically between 1:00 and 4:30 a.m., decreased thereafter nearly 50% (P less than 0.05). Plasma glucagon did not change significantly throughout the period of observation. These results indicate that a dawn-like phenomenon, initiated by an increase in glucose production, occurs in nondiabetic individuals. Thus, early morning increases in plasma glucose concentrations and insulin requirements observed in IDDM and NIDDM may be an exaggeration of a physiologic circadian variation in hepatic insulin sensitivity induced by antecedent changes in catecholamine and/or growth hormone secretion.
Abstract: The anatomy of the bronchial artery in sheep has recently been described. However, the course of the bronchial veins has not been well established. It has been suggested that the bronchial veins are the major site of fluid leakage following histamine infusion, and it has been postulated that the bronchial circulation may play a role in fluid reabsorption. We studied the anatomy of the bronchial circulation in 18 sheep with emphasis on bronchial venous drainage and bronchopulmonary communications. Following anesthesia animals were heparinized and exsanguinated. Evans blue dye was infused into the bronchial artery in six sheep and the gross and subgross anatomy of the bronchial circulation studied. In six other sheep the bronchial artery, pulmonary artery, and tracheobronchial tree were filled with Batson’s solution of varying colors. The subgross anatomy was studied under a dissecting microscope, and samples were taken for scanning electron microscopy. In six separate sheep we studied the anatomy of the proximal vein by infusing dye directly into the vein and found that the extrapulmonary bronchial blood drained into the left azygos vein via a single vessel. Intrapulmonary bronchi are surrounded by a dense bronchial microvascular plexus which drains into the pulmonary vessels at the precapillary level.
Abstract: The purposes of this study were to evaluate a method that predicts transthoracic impedance in advance of defibrillating shocks in humans and to assess the importance of transthoracic impedance in low-energy defibrillation. Via defibrillator electrodes we applied 31 kHz current to the chest during the defibrillator charge cycle, before the defibrillating shock was actually delivered. The current flow was limited by transthoracic impedance; a microprocessor monitored the predischarge current flow and determined the predischarge impedance by calibration against known resistance values. Actual impedance to the defibrillating shock was also determined and compared with the predicted impedance. With this approach we predicted impedance in 19 patients who received 66 shocks for ventricular and atrial arrhythmias. Predicted impedance (y) correlated very well with actual impedance ⊗:y = .90x + 11.3; r = .97. To determine the importance of impedance in defibrillation and cardioversion, we prospectively gathered data from 96 patients who received shocks of various energies for ventricular or atrial arrhythmias. In patients with high transthoracic impedance (greater than 97 omega), low-energy shocks (less than or equal to 100 J) for ventricular defibrillation had only a 20% success rate as opposed to a 70% success rate for low-energy shocks in patients with low or average impedance (p less than .05). We conclude that transthoracic impedance can be accurately predicted in advance of defibrillation and cardioversion. This method permits the preshock identification of patients with high impedance in whom attempts to defibrillate with low-energy shocks are inappropriate.
Abstract: To study the effects of ADH on the transport of potassium by the distal tubule and collecting duct system, we performed simultaneous clearance and micropuncture experiments in homozygous Brattleboro rats (with hereditary hypothalamic diabetes insipidus), before and after intravenous infusion of the hormone. Final urinary flow rate was reduced by a factor of 7 after ADH, but fractional potassium excretion increased by 77% for the group as a whole. During free-flow micropuncture, there was no significant difference in fractional delivery of potassium up to the late distal tubule between control (water diuresis) and ADH conditions; thus, the increase in final urinary potassium excretion was mediated beyond this tubular site. However, flow rate of tubular fluid was decreased significantly after ADH in late distal tubular segments, where potassium secretion is a flow-dependent process. To evaluate the possibility of a direct effect of ADH on distal tubular potassium secretion, independent of changes in flow rate, we studied another group of animals by continuous microperfusion, in vivo, of single distal tubules, using an isotonic perfusion fluid so that water reabsorption would be minimal after as well as before the addition of ADH. Under these conditions, a significant stimulation of distal tubular potassium secretion by ADH could be demonstrated. We suggest that this property of ADH may serve to prevent potassium retention during periods of antidiuresis.
Abstract: Osmoregulation was studied in eight women during late pregnancy and again 8-10 wk postpartum. Base-line plasma osmolality (Posmol) was significantly lower during (280.9 +/- 2.1 mosmol/kg, SD) than after (289.4 +/- 2.1 mosmol/kg) pregnancy yet 24-h urinary volume and plasma arginine vasopressin (PAVP) measured in vasopressinase-inactivated blood was similar in both groups (pregnancy, 1.39 +/- 0.56 pg/ml; postpartum, 1.25 +/- 0.62 pg/ml). After 12 h of dehydration PAVP rose similarly and significantly both during (2.25 +/- 0.81 pg/ml) and after (2.89 +/- 1.19 pg/ml) gestation, and Uosmol was similar on both occasions (pregnancy, 779 +/- 121 mosmol/kg; postpartum, 784 +/- 102 mosmol/kg). When Posmol was increased by the slow infusion of 5% saline PAVP increased as soon as body tonicity did both during and after pregnancy. PAVP correlated significantly with Posmol in each subject (range of r, 0.75-0.99) and the mean regression lines [pregnancy, PAVP = 0.32 (Posmol; -279), r = 0.79; postpartum, PAVP = 0.38 (Posmol, -285), r = 0.86] demonstrated that the apparent osmotic threshold for AVP secretion was 6 mosmol/kg lower during than after gestation. Similarly the Posmol at which the subject experienced a conscious desire to drink was lower in pregnant (287 +/- 1.6 mosmol/kg) compared with postpartum subjects (298 +/- 2.0 mosmol/kg; P less than 0.001). These data demonstrate decreased osmotic thresholds for AVP release and thirst during human pregnancy and explain why gravidas can maintain their new lower Posmol within narrow limits.
Abstract: We determined whether angiotensin II (ANG II) modulates the arterial baroreflex control of lumbar sympathetic nerve activity (LSNA) in chloralose-anesthetized rabbits. Intravenous infusion (iv) of ANG II caused significantly less reflex bradycardia and less inhibition of LSNA than iv phenylephrine (PE) for equivalent increments in arterial pressure. During a background iv infusion of ANG II, which caused a small sustained increase in arterial pressure, the reflex inhibition of heart rate (HR) and LSNA in response to further increases in pressure with graded doses of PE was attenuated, but the reflex increase in HR and LSNA in response to hypotension with graded doses of nitroprusside was unchanged. This modulation of the baroreflex by ANG II is specific since a similar background infusion of PE did not alter baroreflex responses to further increases or to decreases in arterial pressure. The frequency of aortic baroreceptors was comparable for equivalent increases in pressure caused by iv ANG II or PE. When ANG II was confined to the isolated carotid sinuses, the reflex inhibition of HR and LSNA during distension of carotid sinuses was unchanged. An excitatory effect of ANG II on the efferent limb of the baroreflex that would oppose the reflex bradycardia or inhibition of LSNA is unlikely because when the pressor effect of ANG II was prevented by nitroprusside, there were no changes in HR and LSNA. We conclude that through an effect on the central nervous system iv ANG II has a selective effect on the arterial baroreflex; it impairs reflex decreases in HR and LSNA during hypertension but not reflex increases in HR and LSNA during hypotension.
Abstract: Reactive hyperemia has been characterized in many vascular beds, but little is known about quantitative characteristics of reactive hyperemia in the cerebral circulation. We measured velocity of blood flow and pial artery diameter to characterize the time course of reactive hyperemia and used microspheres to study regional blood flow in the brain. Cerebral ischemia was produced by raising intracranial pressure or by arterial occlusion with a cuff around the neck. Five seconds of ischemia produced virtually maximal peak reactive hyperemia, and 30 s of ischemia produced maximal peak reactive hyperemia. During reactive hyperemia after 30 s of cerebral ischemia, there was a three- to fourfold increase in cerebral blood flow. The magnitude of reactive hyperemia was greater in gray matter than in white matter. Minimal resistance during reactive hyperemia, after ischemia produced by arterial occlusion, is similar to minimal resistance during seizures or hypercapnia, which suggests that reactive hyperemia produces maximal vasodilatation. Oxygen saturation of cerebral venous blood increased almost twofold during reactive hyperemia, which indicates that factors in addition to venous (and presumably tissue) oxygen are important determinants of reactive hyperemia. In summary, 1) we have characterized the time course of reactive hyperemia in the cerebral circulation; 2) reactive hyperemia after arterial occlusion produces maximal cerebral vasodilatation; and 3) there is marked heterogeneity of the response, with much larger increases in flow in cortical gray matter than white matter.
Abstract: Inactive renin comprises well over half the total renin in normal human plasma. There is a direct relationship between active and inactive renin levels in normal and hypertensive populations, but the proportion of inactive renin varies inversely with the active renin level; as much as 98% of plasma renin is inactive in patients with low renin, whereas the proportion is consistently lower (usually 20-60%) in high-renin states. Two hypertensive patients with proven renin-secreting carcinomas of non-renal origin (pancreas and ovary) had high plasma active renin (119 and 138 ng/h per ml) and the highest inactive renin levels we have ever observed (5,200 and 14,300 ng/h per ml; normal range 3-50). The proportion of inactive renin (98-99%) far exceeded that found in other patients with high active renin levels. A third hypertensive patient with a probable renin-secreting ovarian carcinoma exhibited a similar pattern. Inactive renins isolated from plasma and tumors of these patients were biochemically similar to semipurified inactive renins from normal plasma or cadaver kidney. All were bound by Cibacron Blue-agarose, were not retained by pepstatin-Sepharose, and had greater apparent molecular weights (Mr) than the corresponding active forms. Plasma and tumor inactive renins from the three patients were similar in size (Mr 52,000-54,000), whereas normal plasma inactive renin had a slightly larger Mr than that from kidney (56,000 vs. 50,000). Inactive renin from each source was activated irreversibly by trypsin and reversibly by dialysis to pH 3.3 at 4 degrees C; the reversal process followed the kinetics of a first-order reaction in each instance. The trypsin-activated inactive renins were all identical to semipurified active renal renin in terms of pH optimum (pH 5.5-6.0) and kinetics with homologous angiotensinogen (Michaelis constants, 0.8-1.3 microM) and inhibition by pepstatin or by serial dilutions of renin-specific antibody. These results indicate that a markedly elevated plasma inactive renin level distinguishes patients with ectopic renin production from other high-renin hypertensive states. The co-production of inactive and active renin by extrarenal neoplasms provides strong presumptive evidence that inactive renin is a biosynthetic precursor of active renin. The unusually high proportion of inactive renin in plasma and tumor extracts from such patients is consistent with ineffective precursor processing by neoplastic tissue, suggesting that if activation of "prorenin" is involved in the normal regulation of active renin levels it more likely occurs in the tissue of origin (e.g., kidney) than in the circulation.
Abstract: Brain oxidative metabolism was examined with positron emission tomography and [18F]2-deoxy-D-glucose in 40 healthy men aged 21 to 83 years, under conditions of reduced visual and auditory stimulation. The mean cerebral metabolic rate for glucose (CMRglc) equaled 4.6 to 4.7 mg X 100 gm-1 X min-1 and did not correlate significantly with age (p greater than 0.05). Regional cerebral metabolic rates for glucose (rCMRglc) and Q ratios (rCMRglc/CMRglc), which had lower coefficients of variation than did rCMRglc, also did not correlate with age. Hyperfrontality of cerebral metabolism was absent at all ages. Age decrements were demonstrated in the error score on the Benton Revised Visual Retention Test and in the Performance Subtest scaled score of the Wechsler Adult Intelligence Scale (WAIS) but not in the Verbal Subtest scaled score of the WAIS. The cognitive test scores did not correlate with brain metabolic rates. The results indicate that brain oxidative metabolism, when measured under resting conditions with reduced sensory input, is not reduced in relation to age in healthy men. Furthermore, no significant relations between intelligence and resting cerebral metabolism are evident.
Abstract: The objective of this investigation was to determine if thick ascending limb (TAL) solute removal is impaired in potassium-depleted rats, in vivo. We estimated TAL NaCl concentration by measuring in situ conductivity of tubular fluid presented to the early distal site after stop-flow periods of 10-60 s, during which a proximal equilibrium solution remained in contact with the reabsorbing epithelium. This allowed us to calculate the rate constant of the decrease in tubular fluid NaCl concentration and to determine equilibrium values for control, potassium-depleted, and potassium-repleted rats. After 60 s of stop-flow, NaCl concentration of TAL fluid decreased to 18.3 +/- 2.73 mM in control rats, while potassium-depleted rats had values almost twice as high (36.5 +/- 2.97 mM, P less than 0.01). The amount of NaCl remaining after 60 s of stop-flow in K-depleted rats was highly correlated with the plasma K concentration. Calculated rates of NaCl efflux from the TAL appeared to be normal in K-depleted rats while the concentration of NaCl achieved at equilibrium was nearly twice that measured in control rats. Acute systemic administration of KCl by gavage or infusion in K-depleted rats was associated with a decrease in TAL NaCl concentration to normal values. Addition of K to the perfusate, however, did not repair the defect. Our results can best be explained by assigning a special role to the peritubular K concentration. We suggest that the defect in TAL solute removal in K-depletion can be rapidly reversed, because decreases in peritubular K concentration limit Na efflux across the peritubular membrane by decreasing the activity of the Na-K-ATPase pump. We recognize that factors such as regional renal blood flow, local angiotensin II levels, and products of the cyclo-oxygenase enzyme system may play a role.
Abstract: The element concentrations in various intra- and extracellular compartments of the tip of the rat renal papilla were determined during antidiuresis using electron microprobe analysis. Urinary concentrations (means +/- SEM) were: urea, 1509 +/- 116; potassium, 268 +/- 32; sodium, 62 +/- 19 mmoles X 1(-1); and osmolality, 2548 +/- 141 mOsm X kg-1. Electrolyte concentrations in the interstitial space were: sodium, 437 +/- 19; chloride, 438 +/- 20; and potassium, 35 +/- 2 mmoles X kg-1 wet wt. The vasa recta plasma exhibited almost identical element concentrations. The values in the papillary collecting duct cells were: sodium, 28 +/- 1; chloride, 76 +/- 3; potassium, 135 +/- 3; and phosphorus, 316 +/- 7 mmoles X kg-1 wet wt. Similar concentrations were observed in the papillary epithelial cells. In interstitial cells potassium and phosphorus concentrations were virtually identical to those of the collecting duct cells, whereas sodium and chloride concentrations were higher by about 30 mmoles X kg-1 wet wt. The element composition of the various papillary cells is, thus, not substantially different from that of proximal tubular cells. This finding demonstrates that cellular accumulation of electrolytes is not the regulatory mechanism by which papillary cells adapt osmotically to their high environmental osmolality and sodium chloride concentration.
Abstract: The effect of captopril up to 450 mg/day on blood pressure and renal function were investigated during sustained treatment of 10 patients whose severe hypertension had not responded to previous therapy. All the patients were kept on diuretics and most of them on beta-blockers, too. A control determination of glomerular filtration rate (GFR) and para-aminohippuric acid clearance (CPAH) was performed during the prior treatment. The effect of the addition (or substitution) of captopril were assessed after an average of 25 days (short-term) and 26 weeks (long-term). Short-term treatment produced a 15.5% decrease in mean blood pressure and interindividually variable effects on renal function. On average GFR was somewhat lower and CPAH slightly higher than the control values (not significant). This pattern is quite similar to the effects of most other antihypertensive drugs. On long-term therapy GFR rose by a mean of 9% (NS) and CPAH by 17% (p less than 0.02). However, in a patient who developed a captopril-induced nephrotic syndrome, GFR dropped to 56% and CPAH to 50% of the control values. In another patient a transient rise in serum creatinine accompanied a severe drug reaction.
Abstract: We assessed glucose counterregulation during intensive insulin therapy in 20 patients with insulin-dependent diabetes mellitus (IDDM) by injecting therapeutic doses of regular insulin subcutaneously after overnight maintenance of euglycemia. As compared with nondiabetic controls matched for age and weight, 17 of the patients had more severe and more prolonged hypoglycemia (nadir, 42 +/- 2 in patients vs. 60 +/- 2 mg per deciliter in controls P less than 0.01; duration, 6.2 +/- 0.4 vs 2.1 +/- 0.6 hours, P less than 0.01). Most patients had decreased responses of several counterregulatory hormones. Marked rebound hyperglycemia (approximately equal to 300 mg per deciliter) ultimately developed in 11 patients. The only features distinguishing patients with rebound hyperglycemia from those without it were plasma free insulin concentrations during recovery from hypoglycemia (those with vs. those without, 7 +/- 1 vs. 22 +/- 2 microU per milliliter, P less than 0.01) and insulin-antibody binding (5 +/- 1 vs. 30 +/- 5 per cent, P less than 0.01). Rates of plasma glucose recovery from hypoglycemia were inversely correlated with plasma free insulin concentrations (r = -0.84, P less than 0.01); the latter in turn were directly correlated with insulin-antibody binding (r = 0.94, P less than 0.01). We conclude that many patients with IDDM have impaired glucose counterregulation due to multiple defects in counterregulatory-hormone secretion. This is associated with increased insulin-antibody binding, which prolongs the half-life of insulin. In such patients, intensive insulin therapy may be hazardous.
Abstract: A model of the left ventricle which combines a spheroidal geometry with a spatial fiber angle distribution is presented. The mechanics of each muscle fiber is described by its passive stress-strain relationship, active stress-strain relationship, and an activation function (half a sinusoid) which represents the time-dependent degree of activation of the fiber. A stress-strain rate relationship which characterizes the muscle fibers is used to calculate the mechanics of left ventricular contraction during ejection. Furthermore, a radial electrical signal propagation from the endocardium to the epicardium is used here as a first approximation to the actual depolarization sequence. The model is used to describe the process of contraction throughout the systole. The different calculated parameters and indices of left ventricular function are presented and discussed for different preloading, afterloading and contractility conditions. The maximum elastance is found to be an optimal macroscale parameter of contractility, as it is completely preload and afterload independent, and is a good reflection of the active microscale sarcomere stress-strain relationship.
Abstract: The effects of chronic salt depletion on medullary hemodynamics remain unknown. In the present study, sodium excretion, renal hemodynamics including papillary plasma flow, measured by the albumin-accumulation technique, and papillary tissue solute content were determined during hydropenia in 13 anesthetized sodium-replete and 10 sodium-depleted dogs. Salt depletion induced a significant rise in plasma renin activity and aldosterone without potassium depletion. Mean arterial pressure, GFR, and renal blood flow were similar in sodium-depleted and sodium-replete dogs. Despite a similar distribution of cortical blood flow (measured by the microsphere method) in the two groups, papillary plasma flow was markedly reduced in sodium-depleted dogs (8.8 +/- 1.7 vs. 22.8 +/- 1.9 ml X min-1 X 100 g-1 in sodium-replete dogs), associated with a significant decrease in renal sodium excretion. Furthermore, papillary osmolality and sodium concentration were significantly greater in sodium-depleted dogs. Ultrastructure examination revealed smooth muscle cells surrounding the efferent arterioles and pericytes with contractile potential encircling descending vasa recta. These results suggest that included in the complex hemodynamic adjustment to chronic sodium depletion is a significant reduction in inner medullary blood flow that may be important in maintaining enhanced papillary solute concentration. In addition, the anatomy of the medullary vasculature is compatible with regional regulation of medullary blood flow.
Abstract: Colloid osmotic pressure in plasma (IIp) and in subcutaneous interstitial fluid (IIi) (wick technique), plasma volume (PV) and interstitial fluid volume (IFV) were measured in nephrotic patients (n = 11) and in healthy controls. Six of the patients were treated with ultrafiltration and the parameters were measured before and after withdrawal of mean 7460 ml (total ultrafiltrate in two sessions). In the nephrotic patients mean IIp was 11.6 mmHg and IIi was 3.9 mmHg compared to 28.6 mmHg and 15.8 mmHg, respectively, in healthy controls. PV was in the normal-to-high range and IFV was increased to 150% of the valued in controls. No statistically significant change in PV, IIp or IIi was found after ultrafiltration, and IFV was reduced by 20%. The results indicate that reduction in IIi is an important oedema-preventing factor and that the reduction in interstitial protein mass is more than proportional compared to the degree of hypoproteinaemia. Ultrafiltration in the rate and magnitude we have used, leads to reduction in IFV, but small changes in PV, IIp or IIi.
Abstract: The influence of vasopressin on renal hemodynamics was assessed by treating conscious Brattleboro homozygotes (DI rats) both acutely and chronically with physiologic doses of vasopressin. Intravenous infusions of vasopressin for 1 h, resulting in plasma vasopressin concentrations of less than 1.25, 2.3, and 8.0 pg/ml, respectively, failed to change glomerular filtration rate (GFR) or effective renal blood flow (ERBF) significantly, nor were there significant changes during 5 h of infusion. Body weight was not altered during these infusions. When synthetic vasopressin was given by osmotic minipumps for 10 days, with the rats gaining weight and thus changing the volume of their body fluids, GFR and ERBF increased significantly, by approximately 45 and 55%, respectively. Acute administration of volume alone, as well as acute vasopressin plus acute administration of volume, did not alter GFR or ERBF significantly. The data are compatible with the view that vasopressin, in physiologic plasma concentrations, exerts an influence on renal hemodynamics, that may be mediated through the long-term alteration of body fluid volumes. Alternatively or additionally, prolonged exposure of DI rats to vasopressin may increase their renal hemodynamics through tubuloglomerular feedback.
Abstract: We determined the incidence of exercise-induced arterial hypoxaemia and its determinants in sixteen highly trained, healthy runners who were capable of achieving and sustaining very high metabolic rates (maximal O2 uptake = 72 +/- 2 ml kg-1 min-1 or 4.81 +/- 0.13 l min-1). Arterial blood gases and acid-base status were determined at each load of a progressive short-term exercise test and repeatedly during constant-load treadmill running while breathing air and during inhalation of mildly hypoxic, hyperoxic, and helium-enriched gases. Three types of responses to heavy and maximum exercise were evident and highly reproducible within subjects. Four runners maintained arterial PO2 (Pa, O2) within 10 mmHg of resting values, another four showed 10-15 mmHg reductions in Pa, O2, and the remaining eight showed reductions of 21-35 mmHg, i.e. in all cases to a Pa, O2 of less than 75 mmHg and to less than 60 mmHg in two cases. During constant-load exercise, Pa, O2 was often maintained during the initial 30 s when hyperventilation was greatest; then hypoxaemia occurred and in most cases was either maintained or worsened over the ensuing 3-4 min. The most severe hypoxaemia during heavy exercise was associated with no or little alveolar hyperventilation (Pa, CO2 greater than 35 mmHg and PA, O2 less than 110 mmHg) and an alveolar to arterial PO2 difference [(A-a)DO2] in excess of 40 mmHg. During 3-4 min of heavy exercise alveolar PO2 (PA, O2) decreased by 20 mmHg in mild hypoxia (0.17 FI, O2; inspired % O2) and increased by 20 mmHg during mild hyperoxia (0.24 FI, O2) and 10 mmHg during the hyperventilation which accompanied normoxic helium breathing. In all cases Pa, O2 changed in proportion to PA, O2 with no consistent change in the alveolar to arterial PO2 difference [(A-a)DO2]. In view of the correction of hypoxaemia with mild hyperoxia and the very high ratios of alveolar ventilation to pulmonary blood flow (VA/QC = 4-6) achieved during heavy exercise, we think it unlikely that non-uniformity of the VA/QC distribution or veno-arterial shunt could explain the hypoxaemia observed in most of our subjects. By exclusion, we suggest that hypoxaemia may be attributed to a diffusion limitation secondary to very short red cell transit times in at least a portion of the pulmonary circulation.(ABSTRACT TRUNCATED AT 400 WORDS)
Abstract: The hyperbicarbonatemia of chronic respiratory acidosis might be maintained by a reduction in filtration rate or an enhancement of tubular bicarbonate reabsorption. To investigate this question, 12 Munich-Wistar rats were exposed to a 10% CO2 atmosphere for 6-8 d. Chronic respiratory acidosis developed, with arterial pH 7.30 +/- 0.01, partial pressure of CO2 (pCO2) 80 +/- 2 mmHg, and total CO2 concentration 45 +/- 1 mM. Single nephron glomerular filtration rate was normal (42 +/- 1 nl/min). Chronic hypercapnia caused absolute proximal reabsorption to be significantly stimulated (1,449 +/- 26 pmol/min) as compared with reabsorption previously observed in normal animals (1,075 +/- 74 pmol/min) or in animals subjected to acute hypercapnia (1,200 +/- 59 pmol/min). This is the first demonstration that proximal bicarbonate reabsorption can be stimulated above normal euvolemic values. When eight animals were subsequently allowed to return toward a normocapnic state (arterial pCO2 46 +/- 1 mmHg) over the course of 1-1.5 h, bicarbonate reabsorption was still significantly higher (1,211 +/- 34 pmol/min) than in similarly alkalotic, normocapnic control groups (994 +/- 45 pmol/min). In conclusion, chronic, but not acute, hypercapnia stimulates absolute proximal bicarbonate reabsorption to exceed the level found in normal euvolemic rats.
Abstract: An analysis of 70 observations in patients with the nephrotic syndrome (NS) on a low sodium diet is presented. The following parameters were determined: plasma volume, plasma renin activity, plasma aldosterone concentration, serum albumin, urinary sodium and protein excretion, and creatinine clearance. In 41 instances glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined on the basis of 51Cr-EDTA and 125I-hippuran clearances, and the filtration fraction (FF) was calculated. The results in patients with minimal lesions (ML) and those with histological glomerular lesions (HL) were compared to determine whether these groups can be separated on the basis of signs of hypovolemia and primary renal sodium retention. Although a higher proportion of the ML patients showed extreme sodium retention and elevated plasma renin and aldosterone levels, these values tended to overlap and no differences were found for blood volume, blood pressure, and overall renal function between the groups. FF was markedly and equally depressed in both groups: 13.5 +/- 1.6% in the ML and 14.2 +/- 1.1% SEM in the HL group (NS). Analysis of the within-group relationships between the parameters under study revealed relatively few correlations, which supports the hypothesis that primary impairment of renal water and salt excretion is an important if not overruling factor in patients with the NS.
Abstract: We investigated the relationship between renal arterial pressure (RAP) and systemic plasma renin activity (PRA) in five uninephrectomized conscious dogs on normal salt (80 meq Na+/day) and low salt (10 meq Na+/day) diets. The RAP was controlled by an inflatable cuff placed around the origin of the renal artery. In both salt states the PRA was an exponential function of the RAP: log (PRA) = (-0.026 X RAP) + 2 on the normal salt diet (r = 0.96) and log (PRA) = (-0.026 X RAP) + 2.5 on the low salt diet (r = 0.99). At any RAP, the value of the low salt PRA was 3 times that of the normal salt PRA. Accordingly, a reduction in salt intake increases the sensitivity of the renal baroreceptor so that the absolute value of PRA increases at any RAP, but the percentage change in PRA caused by any change in RAP is the same in both normal and low salt states.
Abstract: 1. Lactic acidosis is a clinical syndrome characterized by metabolic acidaemia (pH less than 7.25) and hyperlactaemia (lactate greater than 5 mmol/l). Many patients with type B lactic acidosis have no evidence of tissue hypoxia or myocardial dysfunction when first evaluated. Although it is considered that cardiac dysfunction is secondary to the systemic effects of lactic acidosis, the reverse may sometimes be true. To evaluate this possibility, studies were carried out in 43 dogs consisting of a control group and three groups which had hyperlactataemia and metabolic acidaemia related to either: (1) phenformin infusion; (2) hepatectomy; (3) lactic acid infusion. Serial studies of cardiac function, as well as measurements of GFR (glomerular filtration rate) and hepatic portal vein (HPV) blood flow, were carried out. 2. In dogs infused with phenformin for 99 min, the arterial pH, lactate, bicarbonate, heart rate and mean blood pressure (BP) were normal. However, there was significant deterioration (P less than 0.01) in several indices of cardiac function, including the peak positive dP/dt, cardiac output, LVEDP (left ventricular end-diastolic pressure) and percentage extraction of oxygen and lactate by the heart. After 3 h of phenformin, the blood lactate exceeded 5 mmol/l and there were further significant decrements (P less than 0.01) in cardiac output, LVEDP and dP/dt, as well as BP and heart rate. In dogs subjected to hepatectomy, the decrement in cardiac output was similar to that with phenformin infusion. However, in animals infused with lactic acid, despite a similar blood pH and lactate, cardiac output was unaffected. Although percentage myocardial oxygen extraction declined in phenformin-infused animals, there was a concomitant increase in coronary sinus blood flow such that myocardial oxygen utilization was probably unaltered. 3. Thus, in certain types of experimental type B lactic acidosis, myocardial dysfunction may be a primary event, with other associated systemic manifestations being secondary.
Abstract: The effects of systemic bicarbonate concentration and extracellular fluid volume status on proximal tubular bicarbonate absorption, independent of changes in luminal composition and flow rate, were examined with in vivo luminal microperfusion of rat superficial proximal convoluted tubules. Net bicarbonate absorption and bicarbonate permeability were measured using microcalorimetry. From these data, net bicarbonate absorption was divided into two parallel components: proton secretion and passive bicarbonate diffusion. The rate of net bicarbonate absorption was similar in hydropenic and volume-expanded rats when tubules were perfused with 24 mM bicarbonate, but was inhibited in volume-expanded rats when tubules were perfused with 5 mM bicarbonate. Volume expansion caused a 50% increase in bicarbonate permeability, which totally accounted for the above inhibition. The rate of proton secretion was unaffected by volume expansion in both studies. The rate of net bicarbonate absorption was markedly inhibited in alkalotic expansion as compared with isohydric expansion. Bicarbonate permeabilities were not different in these two conditions, and the calculated rates of proton secretion were decreased by greater than 50% in alkalosis. Net bicarbonate absorption was stimulated in acidotic rats compared to hydropenic rats. This stimulation was attributable to a 25% increase in the rate of proton secretion. We conclude that (a) proton secretion is stimulated in acidosis, inhibited in alkalosis, and is not altered by volume status; (b) bicarbonate permeability is increased by volume expansion but is not altered by increases in plasma bicarbonate concentration; (c) when luminal bicarbonate concentrations are similar to those of plasma, net bicarbonate absorption is dominated by proton secretion and is thus sensitive to peritubular bicarbonate concentrations, and insensitive to extracellular fluid volume; (d) when luminal bicarbonate concentrations are low and proton secretion is slowed, bicarbonate permeability and thus extracellular fluid volume have a greater influence on net bicarbonate absorption.
Abstract: The effect of beta-blockade on glycogen metabolism during isometric and dynamic exercise in humans has been investigated. Isometric exercise increased the glycogenolytic rate in muscle but had no effect on the cAMP content. Neither the metabolic pattern nor the time of contraction was affected by beta-blockade. Dynamic exercise increased the cAMP content in muscle by about 100%. The cAMP content at rest was significantly reduced after propranolol infusion and did not increase during exercise. Total hexosemonophosphates increased sixfold during exercise but little or no increase occurred after administration of propranolol. The accumulation of lactate in muscle was slightly reduced during exercise following beta-blockade. The fraction of phosphorylase in the alpha form was 22.5% of the total at rest but decreased to 16% at exhaustion. Synthetase I was similarly decreased. During exercise with propranolol phosphorylase alpha decreased further to 3%, whereas synthetase I was unchanged. It is concluded that beta-blockade has no effect on muscle glycogenolysis during isometric contraction but decreases the rate of glycogen degradation during dynamic exercise at high work loads due to changes in the phosphorylase-synthetase system.
Abstract: We studied the immediate cardiovascular effects of unilateral tension pneumothorax in sheep, a species with an intact mediastinal pleura similar to that in humans. Adult animals were restrained in the prone position and studied in the conscious state to permit spontaneous respiratory adjustments. We measured pressures in the ipsilateral pleural space (Ppli), contralateral pleural space (Pplc), esophagus (Pes), pulmonary artery (Ppa), superior vena cava (Pcv), carotid artery (Ps), as well as thermodilution cardiac output (CO) and heart rate (HR). Acute unilateral pneumothorax of 0, 10, and 20 cmH2O tension produced no significant changes in mean Ps, Pcv, and CO at any level of tension, but it did produce a marked increase in HR at 10 and 20 cmH2O tension (p less than 0.05). Similar observations were made with unilateral pneumothorax of 15 cmH2O for 30 min. These results suggested that tension was transmitted incompletely to the mediastinum and contralateral hemithorax. This was confirmed by an increase from baseline of mean (+/- SE) end-expiratory Pes by 6.6 +/- 4.9 cmH2O and Pplc by 6.7 +/- 6.0 cmH2O, for an increase in Ppli by 20.5 +/- 4.0 cmH2O. The respiratory intrathoracic pressure fluctuations were accentuated with mean increases of 211, 78, and 117% in the ipsilateral pleural space, esophagus, and contralateral pleural space, respectively (p less than 0.05). When the increase in respiratory intrathoracic pressure fluctuations was prevented by artificial hyperventilation, CO decreased. We conclude that unilateral tension pneumothorax does not directly lower CO and Ps because of (1) incomplete transmission of the ipsilateral pleural pressure to the mediastinum and contralateral hemithorax, (2) marked respiratory intrathoracic pressure swings, and (3) compensatory tachycardia.
Abstract: Previous workers have shown that metabolic acidosis increases the apparent space through which administered bicarbonate is distributed. This finding has been ascribed to the accompanying acidemia and to the consequent availability of a large quantity of hydrogen ion that accumulates on nonbicarbonate tissue buffers during the development of acidosis. To test this hypothesis, bicarbonate space was measured in dogs with a broad range of steady-state plasma [HCO-3] in association with alkalemia as well as with acidemia. Appropriate combinations of pH and plasma [HCO-3] were achieved by pretreating the animals to produce graded degrees of each of the four cardinal, chronic acid-base disorders. Metabolic acidosis (n = 15) was produced by prolonged HCl-feeding; metabolic alkalosis (n = 17) by diuretics and a chloride-free diet; and respiratory acidosis (n = 9) and alkalosis (n = 8) by means of an environmental chamber. Animals with normal acid-base status (n = 4) were also studied. Sodium bicarbonate (5 mmol/kg) was infused over 10 min to the unanesthetized animals; observations were carried out over 90 min. The results obtained from animals with metabolic acid-base disturbances demonstrated an inverse relationship between bicarbonate space and initial plasma pH, confirming the previous findings of others. By contrast, the results obtained in animals with respiratory acid-base disturbances demonstrated a direct relationship between bicarbonate space and initial plasma pH. The pooled data revealed that bicarbonate space is, in fact, quite independent of the initial pH but is highly correlated with the initial level of extracellular [HCO-3]; dogs with low extracellular [HCO-3] (congruent to 10 meq/liter) whether acidemic or alkalemic, have a bicarbonate space that is 25% larger than normal and some 50% larger than in dogs with high extracellular [HCO-3] (congruent to 50 meq/liter). We conclude from these results that the increased bicarbonate space in metabolic acidosis (and respiratory alkalosis) does not reflect the availability of more hydrogen ions for release during bicarbonate administration, but merely evidences the wider range of titration (delta pH) of nonbicarbonate buffers that occurs during alkali loading whenever plasma [HCO-3] is low.
Abstract: We examined the effects of external H+ on the kinetics of Na+-H+ exchange in microvillus membrane vesicles isolated from the rabbit renal cortex. The initial rate of Na+ influx into vesicles with internal pH 6.0 was optimal at external pH 8.5 and was progressively inhibited as external pH was reduced to 6.0. A plot of 1/V versus [H+]o was linear and yielded apparent KH = 35 nM (apparent pK 7.5). In vesicles with internal pH 6.0 studied at external pH 7.5 or 6.6, apparent KNa was 13 or 54 mM, Ki for inhibition of Na+ influx by external Li+ was 1.2 or 5.2 mM, Ki for inhibition by external NH4+ was 11 or 50 mM, and Ki for inhibition by external amiloride was 7 or 25 microM, respectively. These findings were consistent with competition between each cation and H+ at a site with apparent pK 7.3-7.5. Lastly, stimulation of 22Na efflux by external Na+ (i.e. Na+-Na+ exchange) was inhibited as external pH was reduced from 7.5 to 6.0, also consistent with competition between external H+ and external Na+. Thus, in contrast with internal H+, which interacts at both transport and activator sites, external H+ interacts with the renal microvillus membrane Na+-H+ exchanger at a single site, namely the external transport site, where H+, Na+, Li+, NH4+, and amiloride all compete for binding.
Abstract: In rats, muscle glycogen depletion has been associated with increased insulin action. Whether this also occurs in man has not been reported. After 4 d rest, 13 males (E Group) had a percutaneous muscle biopsy of the vastus lateralis muscle followed by a euglycemic clamp at plasma insulin congruent to 100 microU/ml and congruent to 1,900 microU/ml, with simultaneous indirect calorimetry. This was repeated 1 wk later, but after glycogen-depleting exercise the night before the euglycemic clamp. Seven subjects underwent the same protocol but were also re-fed 100 g carbohydrate (CHO) after the exercise (EF group). In both groups, the mean muscle glycogen content was approximately 40% lower (P less than 0.01) after exercise compared with the muscle glycogen content measured after rest. In the E group, the mean muscle glycogen synthase activity (percent independent of glucose-6-phosphate) increased threefold (P less than 0.001) after exercise, but increased only twofold in the EF group (P less than 0.02 between groups). In both groups, the mean basal and insulin-stimulated CHO oxidation rates were lower in the post-exercise, glycogen-depleted condition compared with the rested, glycogen-replete condition. The mean insulin-stimulated CHO storage rate increased significantly in the E group after exercise but not in the EF group. In the E group, the total insulin-stimulated CHO disposal rate (M) was 17 (P less than 0.04) and 10% (P less than 0.03) higher after exercise during the low and high dose insulin infusion, respectively. No significant changes in M were observed in the EF group. For all subjects, after rest and exercise, the M correlated with the CHO storage rates during the low (r = 0.80, P less than 0.001) and high dose (r = 0.77, P less than 0.001) insulin infusions. After exercise, the muscle glycogen synthase activity correlated with the CHO storage rate (r = 0.73, P less than 0.002; r = 0.75, P less than 0.002) during the low and high dose insulin infusions, respectively, and also with M (r = 0.64, P less than 0.008; r = 0.57; P less than 0.02).
Abstract: Papillary and surface micropuncture were used to study the handling of ammonium and the formation of net acid by surface nephrons, deep nephrons, and the terminal segment of collecting duct (CD) after renal mass was reduced by two-thirds. Net acid excretion by the remnant kidney (RK) was significantly reduced, averaging 794+/-81 neq/min (SE) compared with 1,220+/-105 neq/min after sham operation (P \textbackslashtextless 0.001), due to a decrease in ammonium excretion (494+/-54 vs. 871+/-79 nmol/min in controls, P \textbackslashtextless 0.001). Urinary pH and titratable acid excretion were not different in the two groups of animals. After RK formation, ammonium delivery to the end of the proximal tubule increased nearly threefold and averaged 66.2+/-5.6 compared with 18.4+/-2.9 pmol/min in controls, (P \textbackslashtextless 0.001). This greater delivery of ammonium was primarily due to renal tubule entry rather than to changes in the filtered load and was only partially related to the differences in flow rate. Ammonium processing by deep nephrons was profoundly affected by a reduction in renal mass. Although absolute delivery of ammonium was greater to the bend of Henle’s loop (BHL), the difference could be accounted for on the basis of an increase in nephron size. Thus, fractional delivery (FD(NH+4)) to this site was not different for the two groups of animals, averaging 1,567+/-180% in controls and 1,400+/-181% in the group with the RK. Hydrogen secretion in the proximal segments of deep and surface nephrons did not increase in proportion to the decrease in renal mass and as a consequence bicarbonate delivery to the end of the proximal tubule of surface nephrons and to the BHL of deep nephrons was increased. When renal mass was reduced FD(NH+4) to the base of the terminal CD doubled but did not change by the tip. In both groups FD(NH+4) to the base of the CD was greater than to the end of the distal tubule. However, the increase was the same. On the other hand, the increase in the net acid index between the end of the distal tubule and the base of the CD was profoundly greater in rats with an RK. This difference was primarily due to bicarbonate reabsorption rather than enhanced ammonium reentry. Indeed, \textbackslashtextgreater400% of the fractional ammonium delivered to the end of the proximal tubule was lost from the tubule fluid. The data suggest that the decrease in acid excretion by the RK is due to two factors. First, hydrogen secretion in the proximal segments of both nephron populations fails to increase in the proportion to the reduction in renal mass. Second, a reduced reentrapment of ammonia, rather than its impaired production, causes ammonium excretion to decrease.
Abstract: We used the noninvasive 133-xenon inhalation technique to determine cerebral hemodynamics in 55 normal volunteers aged 18 to 88. Values for cerebral blood flow and cerebrovascular CO2 reactivity in fast-clearing tissue (flow gray) and slow-clearing tissue (flow white) were examined as functions of age and in relation to hematocrit, blood pressure, and evidence of extracranial vascular disease. Flow gray declined linearly with age, but no corresponding change was found in flow white or in CO2 reactivity. The data suggest that the progressive fall in flow gray is due to a physiologic aging process.
Abstract: Brain glucose content is an important experimental variable that affects the value of the "lumped constant" of the 2-deoxyglucose method. The apparent volume of distribution in brain of the nonmetabolizable glucose analog, 3-O-methylglucose, depends only on the glucose content. From the kinetic constants of glucose transport and the apparent volume of distribution, we used autoradiography to calculate the regional glucose content of the normal rat brain. The regional glucose content varied only insignificantly in gray matter regions; the average glucose content of all rat brain slices examined was 4 mumol g-1, with an average plasma glucose concentration of 8.6 mM. Regional values varied between 3.4 and 4.6 mumol g-1. Thus, there is no reason to believe that the regional values of the lumped constant vary significantly in normal rat brains.
Abstract: This study had two purposes: 1) to determine the effects of varying the pH of lactic acid infusion solutions on the acid-base status of anesthetized dogs, and 2) to determine the effect of elevated blood lactate concentration on muscle lactate concentration. The experiments were performed on the in situ gastro cnemius-plantaris muscle group in 14 mongrel dogs. The infusions increased the arterial blood lactate concentration to 11.0 +/- 0.5 (SE) mM after 20 min. Above an infusate pH of 4.4, the arterial pH increased by 0.118-0.167 during infusion; the arterial pH was unchanged when the infusate pH was between 3.4 and 4.0; and the arterial pH decreased as infusate pH decreased below 3.0. The effect of lactic acid infusion on blood pH appears to be the result of two opposing effects: 1) an acidifying effect due to its weak acid properties, and 2) an alkalinizing effect due to the metabolism of sodium lactate. The estimated ratio between intracellular muscle lactate and venous plasma water lactate averaged 0.647 +/- 0.038, indicative of a substantial gradient between blood and muscle. The infusion produced a significant change from lactate output to lactate uptake by the muscles. The infusion also transiently increased muscle blood flow and oxygen uptake.
Abstract: Using the glucose clamp technique, glucose uptake was determined isotopically in normal human volunteers at plasma glucose concentrations of congruent to 60, 95, and 160 mg/dl during insulin infusions that increased plasma insulin to congruent to 20, 80, and 160 microU/ml. Because glucose uptake was found to be a linear function of plasma insulin at each plasma glucose concentration (r greater than 0.92, P less than 0.01), glucose uptake at 0 plasma insulin was estimated by linear regression analysis. The values thus derived (1.30, 1.62, and 2.59 mg . kg-1 . min-1 for plasma glucose concentrations of 60, 95, and 160 mg/dl, respectively) produced a linear Eadie-Hofstee plot, suggesting that insulin-independent glucose uptake followed Michaelis-Menten kinetics. The Km for glucose uptake at 0 plasma insulin (congruent to 10 mM) was similar to those observed for glucose uptake at the other plasma insulin concentrations studied (congruent to 9-12 mM), but its Vmax was less (5.2 vs. 6.4, 18.5, and 26.8 mg . kg-1 . min-1 for congruent to 20, 80, and 160 U/ml, respectively). These results indicate that in postabsorptive human subjects 75-85% of glucose uptake is noninsulin-mediated and provide additional support for the concept that insulin may increase glucose uptake merely by providing additional transport sites. The method described herein provides an assessment of insulin-independent glucose uptake in vivo that may prove useful in distinguishing between intrinsic defects of the glucose transport system and those due to defects in insulin action.
Abstract: Since the initial proposal of the glucose fatty acid cycle, considerable controversy has arisen concerning its physiologic significance in vivo. In the present study, we examined the effect of acute, physiologic elevations of FFA concentrations on glucose production and uptake in normal subjects under three controlled experimental conditions. In group A, plasma insulin levels were raised and maintained at approximately 100 microU/ml above base line by an insulin infusion, while holding plasma glucose at the fasting level by a variable glucose infusion. In group B, plasma glucose concentration was raised by 125 mg/100 ml and plasma insulin was clamped at approximately 50 microU/ml by a combined infusion of somatostatin and insulin. In group C, plasma glucose was raised by 200 mg/100 ml above the fasting level, while insulin secretion was inhibited with somatostatin and peripheral glucagon levels were replaced with a glucagon infusion (1 ng/min X kg). Each protocol was repeated in the same subject in combination with a lipid-heparin infusion designed to raise plasma FFA levels by 1.5-2.0 mumol/ml. With euglycemic hyperinsulinemia (study A), lipid infusion caused a significant inhibition of total glucose uptake (6.3 +/- 1.3 vs. 7.4 +/- 0.6 mg/min X kg, P less than 0.02). Endogenous glucose production (estimated by the [3-3H]glucose technique) was completely suppressed both with and without lipid infusion. With hyperglycemic hyperinsulinemia (study B), lipid infusion also induced a marked impairment in glucose utilization (6.2 +/- 1.1 vs. 9.8 +/- 1.9 mg/min X kg, P less than 0.05); endogenous glucose production was again completely inhibited despite the increase in FFA concentrations. Under both conditions (A and B), the percentage inhibition of glucose uptake by FFA was positively correlated with the total rate of glucose uptake (r = 0.69, P less than 0.01). In contrast, when hyperglycemia was associated with relative insulinopenia and hyperglucagonemia (study C), thus simulating a diabetic state, lipid infusion had no effect on glucose uptake (2.9 +/- 0.2 vs. 2.6 +/- 0.2 mg/min X kg) but markedly stimulated endogenous glucose production (1.4 +/- 0.5 vs. 0.5 +/- 0.4 mg/min X kg, P less than 0.005). Under the same conditions as study C, a glycerol infusion producing plasma glycerol levels similar to those achieved with lipid-heparin, enhanced endogenous glucose production (1.5 +/- 0.5 vs. 0.7 +/- 0.6 mg/min X kg, P less than 0.05). We conclude that, in the well-insulinized state raised FFA levels effectively compete with glucose for uptake by peripheral tissues, regardless of the presence of hyperglycemia. When insulin is deficient, on the other hand, elevated rates of lipolysis may contribute to hyperglycemia not by competition for fuel utilization, but through an enhancement of endogenous glucose output.
Abstract: Relationships between regional myocardial perfusion and transmural function, both during treadmill exercise and at rest, were examined in conscious dogs with varying degrees of coronary stenosis produced by a hydraulic occluder. In 13 dogs we measured myocardial blood flow with microspheres (10-12 microns in diameter) and regional systolic wall thickening (%). During exercise with coronary stenosis, myocardial blood flow was characterized by nonuniform distribution, and associated with regional dysfunction. The relationships between normalized myocardial blood flow and normalized %wall thickening during exercise with coronary stenosis were linear, with significantly different slopes (mean myocardial blood flow: y = 1.23x - 0.16, r = 0.93; subendocardial myocardial blood flow: y = 1.50x - 0.02, r = 0.86; subepicardial myocardial blood flow: y = 0.83x - 0.18, r = 0.87). To fill the gap between available subendocardial and subepicardial data during exercise with coronary stenosis and control points, however, would require nonlinear components. In 10 of the dogs, coronary stenosis at rest was also produced to compare regional myocardial blood flow - %wall thickening relations at rest with those during steady state exercise. The absolute mean myocardial blood flow - %wall thickening relation during exercise with coronary stenosis (y = 11.6x - 1.9, r = 0.90) was significantly shifted rightward from the resting relation (y = 25.3x -2.1, r = 0.80). However, when changes in %wall thickening were plotted vs. myocardial blood flow per beat, the relationships at rest and exercise were nearly superimposable. Likewise, relations between normalized myocardial blood flow and changes in %wall thickening at rest and exercise were not significantly different. We conclude: %wall thickening during exercise is directly related to changes in mean myocardial blood flow but is related in nonlinear fashion to changes in subepicardial and subendocardial myocardial blood flow; %wall thickening may provide a reliable index of the relative transmural flow distribution during exercise as well as at rest; during brief bouts (5-8 minutes) of exercise with coronary stenosis, the relationship between stabilized regional contractile dysfunction and level of myocardial blood flow per beat is the same as that during coronary stenosis at rest.
Abstract: The goal of these experiments was to determine if isoproterenol-stimulated renin secretion in the rat is mediated by activation of beta 1- and/or beta 2-adrenoceptors. The rat renal cortical slice preparation was used. The renin secretory rate was a sigmoid function of the logarithm of the isoproterenol concentration; half-maximal and maximal stimulation occurred at approximately 0.01 and 0.1 microM isoproterenol, respectively. Neither timolol (a nonselective beta-antagonist) nor atenolol (a beta 1-selective antagonist) had a significant effect on basal secretory rate, but both shifted the isoproterenol dose-response curve to the right without changing its slope, suggesting competitive antagonism. Timolol was the more potent, but the response to a maximally effective concentration of isoproterenol could be blocked by timolol (0.9 microM), atenolol (110 microM), or a combination of the two (0.45 microM timolol plus 55 microM atenolol). This latter finding is consistent with action of the two antagonists at one and the same site. If it is assumed that timolol antagonizes both beta 1- and beta 2-adrenoceptors and that atenolol antagonizes only beta 1-adrenoceptors, it follows that isoproterenol-stimulated renin secretion in this preparation is mediated by activation of beta 1-adrenoceptors.
Abstract: Vasa recta blood flow autoregulation was studied by measuring flow velocity in individual vessels on the papilla surface with a video adaptation of the dual-slit erythrocyte velocity method. Vessel diameter did not vary with arterial pressure in the range of 60-150 mmHg, allowing the calculation of the ratio of flows in a single vessel at two pressures from the ratio of velocities. Flow velocity in single vasa recta increased with arterial pressure to 75 mmHg, remained constant in the range of 75-125 mmHg, and increased with higher pressures. In a second series of animals, whole kidney blood flow auto-regulated above 90 mmHg. Vasa recta and whole kidney flow patterns were not changed by extracellular fluid volume expansion. Volume expansion caused a greater increase in ascending than in descending vasa recta flow, reflecting the volume load from enhanced collecting duct reabsorption in diuresis. In a final series, Na excretion varied with arterial pressure in the range of 90-130 mmHg. Because vasa recta velocity remains constant within this range, pressure diuresis cannot be caused by the lack of autoregulation of vasa recta blood flow, at least to 130 mmHg.
Abstract: Norepinephrine extraction and spillover rates were determined in the heart and lungs of anesthetized dogs under resting conditions, during sympathetic stimulation, and during epicardial pacing. The fractional extraction of norepinephrine across the coronary and pulmonary vascular beds was measured from the venoarterial difference in tritiated norepinephrine after infusion of a tracer dose to a steady state level. Cardiac extraction averaged 0.299 +/- 0.03 and pulmonary extraction averaged 0.215 +/- 0.014; extraction was unaffected by sympathetic stimulation or pacing. Norepinephrine spillover from sympathetic nerve terminals in the heart and lungs was measured from the venoarterial difference in endogenous norepinephrine and plasma flow after correction for the extraction component. Cardiac norepinephrine spillover increased linearly with increasing frequency of sympathetic stimulation to 7.44 times resting levels at 2 Hz. During pacing, there was no change in cardiac norepinephrine spillover despite marked changes in heart rate. Norepinephrine spillover was demonstrated under resting conditions in the lung and was greater than observed in the heart. Pulmonary norepinephrine spillover increased with sympathetic stimulation to 4.15 times resting levels at 2 Hz. It is possible to separate the contributions of norepinephrine extraction and spillover to measured venoarterial differences of norepinephrine under physiological conditions in the dog.
Abstract: 1. Dogs were anaesthetized with chloralose, ventilated artificially, and the regions of the aortic arch and carotid sinuses were isolated vascularly and perfused with blood. The abdominal circulation was isolated vascularly, perfused at constant flow and drained from the inferior vena cava at constant venous pressure. Changes in vascular resistance were determined by calculating changes in abdominal aortic perfusion pressure, and changes in capacitance by integrating the changes in venous outflow. 2. Stimulation of aortic body chemoreceptors, either by changing the aortic arch perfusate from arterial to venous blood at constant perfusion pressure or by injection of sodium cyanide into the aortic arch, resulted in an increase in abdominal vascular resistance and a decrease in abdominal vascular capacitance. 3. After both cervical vagosympathetic trunks had been cut, stimulation of aortic chemoreceptors no longer resulted in resistance or capacitance responses. 4. These results indicate that stimulation of aortic chemoreceptors, like carotid chemoreceptors, results in reflex constriction of both resistance and capacitance vessels in the abdominal circulation.
Abstract: The purpose of this study was to investigate the interrelationship between the ventilatory anaerobic threshold (VAT), the blood lactate anaerobic threshold (LAT), and the alteration in muscle metabolism. Ten subjects (5 men and 5 women) performed progressive exercise to exhaustion on two occasions for determination of the VAT and the LAT. For both AT criteria, the initial breakpoints (P less than 0.05) in the relationship between ventilation (VE) and O2 uptake (VO2VAT) and lactate (La) and power output (POLAT) were determined by multisegmental linear regression. During three subsequent tests the subjects performed progressive exercise to various percentages of the VO2VAT. Biopsies were obtained from the musculus vastus lateralis for determination of selected glycolytic intermediates at the cessation of exercise. It was found that the VO2VAT, expressed in terms of power output (POVAT), occurred at a higher value (P less than 0.05) than the POLAT (1,004 vs. 621 kg X min-1). Blood La values at these power outputs were 2.09 and 1.25 mM, respectively. Determination of the muscle La concentration at 79, 94, and 110% of VO2VAT indicated significant increases (P less than 0.05) from rest values of 1.59 to 4.49, 6.37, and 11.3 mmol X kg wet wt-1, respectively. It is concluded that the gas exchange AT as determined by the relationship between VE and VO2VAT and the AT as determined by blood La accumulation (LAT) are not coincidental. In addition the elevation in muscle anaerobic glycolysis precedes both the VAT and the blood LAT in this progressive exercise test.
Abstract: The localization of corticotropin (ACTH) and of the N-terminal fragment (NTF) of pro-opiomelanocortin were assessed by light and electron microscope immunochemistry. Using the unlabeled technique of Sternberger at the light microscope level, a strongly positive reaction for both NTF and ACTH antisera was observed in all secretory cells of the pars intermedia. In the pars distalis, immunostaining with ACTH antiserum was localized in stellate cells dispersed throughout the lobe. As observed in serial, consecutive sections, the NTF antiserum stained exactly the same cells. At the electron microscope level, using the protein A-gold technique, all the secretory granules of the cells of the pars intermedia showed a positive reaction with both antisera. In the pars distalis, after exposure to either of the antisera, gold particles were found over secretory granules of typical stellate corticotrophs. Making use of the possibility of reacting both faces of a fine section with gold particles of different sizes, it was found that the same secretory granules in all the cells of the pars intermedia and in corticotrophs of the pars distalis contained particles of both sizes. These results indicate that ACTH and NTF are contained in the same secretory granules and released together in the circulation where NTF is found in high amounts.
Abstract: Recent findings indicate that glucose uptake by contracting hindlimb #Acta Physiol. Scand. (1982) 116, 215-222 #and heart #Biochem. Biophys. Res. Commun. (1982) 108, 124-131 # of the rat is stimulated by epinephrine acting through alpha-adrenergic mechanisms. Since in exercise hepatic glucose output may be increased markedly by activation of alpha-adrenergic receptors and matched by the increase in muscle glucose uptake (maintaining blood glucose levels relatively constant), it is now proposed that a general coordination of glucose metabolism may operate via alpha-adrenergic receptor mechanisms. The basis for this proposal is discussed.
Abstract: Increased oxygen transport by the circulation is normally tightly coupled to increased oxygen uptake (VO2) during exercise; cardiac output (Q) increases 5 to 6 liters for every liter of increased oxygen utilization (delta Q/delta VO2 congruent to 5). We measured cardiac output and oxygen uptake at rest and during bicycle exercise in 7 patients with myalgia without evident muscle disease and 15 patients with myopathies. Resting circulation was normal in all patients, and during exercise the increase in cardiac output relative to oxygen uptake was normal in all myalgia and most myopathy patients. However, in four patients (with dermatomyositis, phosphorylase deficiency, carnitine deficiency, and ocular myopathy with "ragged-red fibers") exercise cardiac output was excessive and delta Q/delta VO2 high, resulting in an abnormally high level of cardiac work for a given level of exercise. This hyperkinetic response may represent aberrant regulation of the circulation by skeletal muscle as a consequence of some myopathies.
Abstract: Aldosterone stimulates transepithelial Na+ transport in the toad bladder, and thyroid hormone antagonizes this mineralocorticoid action. In the present study, we assessed the influence of these two hormones on the biosynthesis of (Na+,K+)ATPase, the major driving force of Na+ transport. Rates of enzyme synthesis were estimated by immunoprecipitation with monospecific alpha (96,000 daltons) and beta (60,000 daltons) subunit antibodies. After a 30-min pulse of intact tissue with [35S]methionine, the anti-alpha-serum recognized the 96,000-dalton alpha subunit and the anti-beta-serum, a 42,000-dalton protein, in total cell extracts. The biosynthesis rates of both these proteins were increased 2.8- and 2.4-fold respectively, over controls by 80 nM aldosterone after 18 h of hormone treatment. The hormonal effect was not apparent up to 3 h of incubation and was dose dependent between 0.2 and 20 nM aldosterone. The hormonal induction was antagonized by spironolactone (500-fold excess) but not by amiloride. The action of aldosterone thus seems to be a receptor-mediated process and a primary event independent of the Na+ permeability of the apical membrane. Thyroid hormone, on the other hand, had no effect on either basal or aldosterone-stimulated synthesis rates of both enzyme proteins. The results demonstrate a direct effect of aldosterone on gene expression of the (Na+,K+)-ATPase. Ultimately, this phenomenon could be linked to the late mineralocorticoid action of this hormone. On the other hand, thyroid hormone, in contrast to the situation in mammals, does not stimulate de novo enzyme synthesis in amphibia. Neither can the antimineralocorticoid action of thyroid hormone in the toad bladder be explained by an inhibition of the (Na+,K+)-ATPase synthesis.
Abstract: 12 patients with the nephrotic syndrome during a phase of spontaneous sodium retention were studied on a sodium balance. When retaining sodium and gaining weight for more than 3 days, 6 patients had an elevated plasma renin activity; plasma aldosterone was elevated or at the upper range of normal, and blood volume was less than predicted in 5. The other 6 patients had a low or normal plasma renin activity and plasma aldosterone; blood volume was greater than predicted in 5 of these patients. There was a significant inverse correlation between plasma albumin and plasma renin activity (r = -0.70, p less than 0.02). Thus the renin-angiotensin-aldosterone system is not stimulated in many patients with the nephrotic syndrome when spontaneously retaining sodium. In these patients, sodium retention is probably due to some other mechanism, possibly intrarenal. Stimulation of the renin-angiotensin-aldosterone system in other patients may be a compensatory mechanism to the lower plasma albumin and reduced blood volume, and may not be the underlying mechanism for sodium retention.
Abstract: Specific saturable binding of 125I-arginine-vasopressin to human platelets is described. For ten normal volunteers the mean (+/- S.D.) KD is 5.6 nM (+/- 2.1) and the mean (+/- S.D.) Bmax is 115 fmoles/mg protein (+/- 30). Association studies indicate that equilibrium is reached after 90 minutes on ice. Pharmacological inhibition studies with analogues indicate that the platelet receptor is very similar to the kidney medulla receptor. The function of the receptor may involve serotonin release and platelet aggregation. Vasopressin binding to platelets should provide a readily means of assessing vasopressin receptor function in man.
Abstract: Several theories have been advanced to explain the elevation in urinary PCO2 during bicarbonate loading and include: (a) H+ secretion, (b) countercurrent system for CO2, (c) the "ampholyte" properties of bicarbonate, and (d) mixing of urine of disparate bicarbonate and butter concentrations. In this study microelectrodes were used to measure in situ and equilibrium pH (pHis and pHeq) and PCO2 in control and bicarbonate loaded rats before and after infusion of carbonic anhydrase. The disequilibrium pH method (pHdq = pHis - pHeq) was used to demonstrate H+ secretion. Control rats excreting an acid urine (pH = 6.04 +/- 0.06) failed to display a significant disequilibrium pH at the base (BCD), or tip (TCD) of the papillary collecting duct. Urine pH (7.54 +/- 0.12), and urine to blood (U-B) PCO2 increased significantly during NaHCO3 loading while PCO2 at the BCD and TCD also increased (95 +/- 4 and 122 +/- 4). Furthermore, an acid disequilibrium pH was present at both the BCD and TCD (-0.42 +/- 0.04 and -0.36 +/- 0.03) and was obliterated by carbonic anhydrase. Comparison of the PCO2 in the BCD or TCD with the adjacent vasa recta revealed similar values (r = 0.97). It is concluded that H+ secretion by the collecting duct into bicarbonate containing fluid with delayed dehydration of H2CO3, is the most likely determinant of the U-B PCO2 in alkaline urine. Similar values for PCO2 in the collecting duct and the adjacent vasa recta suggests trapping of CO2 in the medullary countercurrent system. The rise in PCO2 occurs both along the collecting duct and after exit from the papilla.
Abstract: To evaluate the partial contributions and interaction of three vasopressor systems in blood pressure maintenance, nephrectomized rats and rats with intact kidneys were submitted sequentially to catecholamine depletion, elimination of vasopressin’s vasoconstrictor action, and (for those with kidneys in situ) angiotensin blockade. Catecholamine depletion decreased blood pressure and stimulated vasopressin levels in all rats, but significantly more so in the anephric ones. Subsequent injection of an antagonist to the vasopressor effect of vasopressin produced a lasting fall of blood pressure in anephric rats, but only transient fall in those with intact kidneys. Infusion of teprotide–an angiotensin converting enzyme inhibitor–in the latter animals also produced transient blood pressure fall, but if this were followed by injection of the vasopressin antagonist, the pressure remained low for several hours. Blood pressure levels were closely correlated with those of plasma catecholamines throughout these maneuvers. Catecholamine levels were inversely correlated with those of plasma vasopressin, which were far greater in anephric rats through both stimulation and accumulation. Plasma renin activity was increasingly stimulated by falling blood pressure after each maneuver in rats with intact kidneys. Thus, it appears that in the resting state the sympathetic nervous system is more involved in the maintenance of blood pressure, whereas vasopressin and renin are important backup mechanisms.
Abstract: The effects of hypoxaemia on regional cerebral blood flow (CBF) and brain cortical metabolite concentrations were investigated at different blood glucose concentrations in rats under nitrous oxide anaesthesia. Tissue hypoxia of 15-min duration was induced by a combination of arterial hypoxaemia, hypotension, and clamping of the right carotid artery. Blood glucose concentrations were manipulated by varying the food intake in the 24 h before the experiment, and by glucose administration. Cortical CBF doubled during hypoxia on the intact side, but did not differ significantly from control values on the clamped side. In the clamped hemisphere there was a substantial decrease in adenylate energy charge. At brain tissue glucose concentration of 1 mumol g-1 and above, there was an inverse correlation between adenylate energy charge and brain lactate concentration. In starved animals with mean brain glucose of 0.32 +/- 0.00 mumol g-1, lactate concentration was significantly lower, in spite of equally severe disruption of energy state. Recovery of brain adenylate energy charge was worse in fed and glucose-infused groups than in the fasted group. These results demonstrate that limitation of substrate supply during severe hypoxia in the rat allows enhanced recovery of brain energy metabolism following the hypoxic episode.
Abstract: The uptake of L⊕lactate into rat renal cortical brush border (BBV) and basolateral (BLV) membrane vesicles, isolated through differential centrifugation and free flow electrophoresis, were studied using a rapid filtration technique. In contrast to the lactate transport into the BBV, that into the BLV: 1) was found to proceed only towards equilibrium, 2) showed Na+ -independent coupling of the influx of L⊕lactate and the efflux of L⊕ but not to the efflux of D⊖lactate, 3) was not inhibited by D⊖lactate, 2-thiolactate or 3-phenyl-lactate, but 4) was inhibited by 3-thiolactate and alpha-hydroxybutyrate and 5) was accelerated by changes in inwardly directed ionic gradients or by increases in cation conductance both of which led to increased intravesicular positivity. The latter changes had the opposite effect on the uptake of L⊕lactate by BBV. Thus, while the L⊕lactate transport system present in BBV showed the characteristics of Na-dependent electrogenic cotransport system, that in the BLV was consistent with a carrier mediated Na-dependent, facilitated diffusion system.
Abstract: In 12 diabetic patients who were being treated with maintenance hemodialysis or maintenance peritoneal dialysis, coma and other neurologic deficits did not occur in spite of extremely elevated serum glucose levels. The mean serum values of these patients were: glucose 1,174 +/- 248 (SD) mg/100 ml, sodium 125 +/- 5 mEq/l, calculated total osmolality 342 +/- 13 mOsm/kg water and calculated effective osmolality (without urea) 316 +/- 13 mOsm/kg water. It is suggested that the absence of osmotic diuresis and the lack of substantial osmotic ultrafiltration prevented the development of hypernatremia and marked hyperosmolality. The osmolar effect of glucose alone at these serum concentrations apparently was not sufficient to induce neurologic impairment.
Abstract: The hemodynamic effects of PEEP ventilation were studied in 6 patients with adult respiratory distress syndrome (ARDS). Cardiac index (CI), blood pressure (BP), heart rate (HR), left cardiac work index (LCWI), and left ventricular stroke work index (LVSWI) were evaluated in each patient at 0, 5, 10, 15, and 20 cm H2O of PEEP. All patients were able to tolerate even the highest level of PEEP without evident clinical sequelae. BP did not change significantly. HR fell significantly at 20 cm H2O of PEEP. LCWI and CI fell at 20 cm H2O of PEEP but the mean fall in CI was only 6% (from 3.47 to 3.27 L/min . M2). LVSWI did not change significantly. PEEP did not produce clinically significant hemodynamic changes. We believe that the avoidance of hypovolemia, limited use of sedative and paralytic drugs, and use of assisted ventilation in the management of our patients contributed substantially to these results though other possible factors cannot be excluded.
Abstract: The estimation of sympathetic nervous activity by measurement of plasma norepinephrine (NE) concentration assumes a constant relation between this and the synaptic cleft concentration. This assumption would be incorrect if the clearance of plasma NE could be varied without affecting its removal from the synaptic cleft, so we compared the clearance of plasma NE in mild hypertensives and normal subjects by measurement of its plasma concentration during a 0.5-hr infusion at 0.07 microgram/kg/min; there were no differences. The simultaneous infusion of isoproterenol, 0.02 microgram/kg/min, led to an increase in heart rate and NE clearance. There was partial inhibition of catechol-O-methyltransferase by a single oral dose of alpha-methyldopa, 250 mg, which reduced the clearance of both catecholamines (CAs) by about 20%. After the end of the infusions containing isoproterenol, the tachycardia persisted for more than 1 hr and declined more slowly in the hypertensives than the normals. In contrast, plasma concentrations of both CAs returned to basal values within a few minutes. The persistent tachycardia may be due to rerelease of isoproterenol into the synaptic cleft, since stimulation of sympathetic activity by assumption of the erect posture was associated with an exaggerated increase in heart rate (by 48/min after infusion and 23/min before infusion). The study therefore suggests that synaptic cleft and plasma CA concentrations can be independently manipulated and the relation between them may be different in hypertensive patients and normal control subjects.
Abstract: 8 of 16 patients with nephrotic syndrome had normal or low plasma renin activity while spontaneously retaining sodium. The other 8 patients had a high plasma renin activity which may have caused the sodium retention. Oral captopril and albumin infusion given separately both suppressed the renin system in these patients. Despite this, urinary sodium excretion remained less than sodium intake and patients continued to retain sodium and gain weight. These results suggest that, even in patients with nephrotic syndrome who do have stimulation of the renin angiotensin system, some other overriding mechanism is responsible for sodium retention. Therefore it seems unlikely that angiotensin-converting enzyme inhibitors will be useful in the treatment of sodium retention in nephrotic syndrome.
Abstract: The ability of patients with severely impaired left ventricle function to perform short-term exercise and to participate in a cardiac rehabilitation program and attain physical training effects was evaluated. Treadmill exercise tests were performed before and after physical conditioning in 10 patients with a prior myocardial infarction and a left ventricular ejection fraction at rest of less than 27 percent (range 13 to 26) determined by radionuclide angiography. All patients participated in a supervised exercise program with a follow-up period of 4 to 37 (mean 12.7) months. Baseline exercise capacity showed marked variability, ranging from 4.5 to 9.4 (mean 7.0 +/- 1.9) METS, and improved to 5.5 to 14 (mean 8.5 +/- 2.9) METS after conditioning (p = 0.05). The oxygen pulse (maximal oxygen uptake/maximal heart rate) before and after conditioning was used to assess a training effect and increased significantly from 12.8 +/- 2.0 to 15.7 +/- 3.2 ml/beta (p less than 0.01). There was no exercise-related morbidity or mortality, although two patients died during the study period. It is concluded that selected patients with severely imparied left ventricular function can safely participate in a conditioning program and achieve cardiovascular training effects.
Abstract: Twelve male subjects were exposed to a toluene concentration of about 300 mg/m3 in the inspiratory air during rest and/or physical exercise on a bicycle ergometer. Each subject was exposed during four 30-min periods. Before exposure the subjects’ body fat was calculated by means of underwater weighing and skeletal measurements. Needle biopsies of subcutaneous adipose tissue were taken up to 12 d after the exposure was concluded. The concentration of toluene in the adipose tissue was determined by gas chromatography after evaporation into nitrogen at a high temperature. After exposure at rest for 2 h, the mean concentration of toluene in adipose tissue was 0.7 mg (7.7 mumol)/kg. The corresponding value after 2 h of work at 50 W was 9.9 mg (109 mumol)/kg. There was a declining concentration of toluene in adipose tissue with an increasing degree of obesity. The half-time for toluene in adipose tissue ranged between 0.5 and 2.7 d. It increased with increasing amounts of body fat.
Abstract: Eighty excised human lungs were placed in a volume-displacement plethysmograph, and expiratory pressure-volume (PV) data points were obtained between transpulmonary pressures of 30 and 0 cmH2O. An exponential function of the form V = A - Be-KP was fitted to the PV data points (V is the volume at pressure P, A is the maximal lung volume at infinite pressure, B is A minus the intercept of the exponential on the volume axis, and K is a shape constant directly related to lung compliance). Thirty-two lungs were emphysema-free and 48 lungs had emphysema ranging from grade 2 to grade 80. In the emphysema-free lungs the exponential fit was excellent in terms of r2, but systematic deviations from the PV data occurred in both young and old lungs. Both K and B/A were significantly age related (P less than 0.01). In the emphysematous lungs the exponential fit was equivalent to that in the emphysema-free lungs although, again, systematic deviations from the PV data occurred. With age constant, K (P less than 0.01) but not B/A was significantly correlated with the emphysema grade. However, the overlap with values of K in the emphysema-free lungs was too great for K to be useful in the diagnosis of emphysema.
Abstract: The net exchange of glucose and lactate across the leg and the splanchnic bed and the arterialdeep venous (A-DV) differences for these substrates in the forearm were determined in healthy subjects during 3-3.5 h of leg exercise (bicycle ergometer) at 58% maximum O(2) uptake and during a 40-min post-exercise recovery period. Leg glucose uptake rose 16-fold during exercise and throughout the exercise period exceeded splanchnic glucose output. The latter reached a peak increment (3.5 times basal) at 90 min and fell by 60% during the third hour. As a result, blood glucose declined 40%, reaching frank hypoglycemia (blood glucose, \textbackslashtextless45 mg/dl) in 50% of subjects at 3.5 h. Splanchnic lactate uptake rose progressively during exercise to values four times the basal rate at 3 h in association with a rise in arterial lactate to 1.5 mM. There was, however, no significant net output of lactate from the legs beyond 90 min of exercise. In contrast, the A-DV lactate difference in the forearm became progressively more negative throughout exercise, reaching values three times the basal level at 3.5 h. The rise in arterial lactate during exercise was proportional to the elevation in plasma epinephrine, which rose ninefold. During recovery, splanchnic lactate uptake rose further to values six times the basal rate, whereas lactate output by the legs was no greater than in the basal state. The A-DV lactate difference in the forearm became even more negative than during exercise, reaching values four times basal. During exercise as well as recovery, forearm uptake of blood glucose could account for no more than 25-67% of forearm lactate release. Leg glucose uptake during recovery was threefold to fivefold higher than in the basal state in the face of plasma insulin concentrations that were 60% below basal and in association with a respiratory exchange ratio of 0.7. We conclude that (a) during prolonged leg exercise at 58% maximum O(2) uptake an imbalance between splanchnic glucose production and leg glucose utilization results in a fall in blood glucose that may reach hypoglycemic levels in healthy subjects; (b) there is a marked increase in the uptake of lactate by the splanchnic bed that cannot be attributed to increased output of lactate from the exercising legs; (c) lactate is released by forearm muscle and, together with other relatively inactive muscle, may be an important source of the increased lactate turnover during and after prolonged leg exercise; (d) the increasingly negative A-DV lactate difference in the forearm cannot be accounted for by uptake of blood glucose, suggesting the breakdown of glycogen in forearm muscle during and after leg exercise; (e) increased glucose uptake by the legs in association with hypoinsulinemia during recovery suggests an increase in insulin sensitivity that permits glycogen repletion in previously exercising muscle in the absence of food ingestion; and (f) the evidence for increased lactate output in the forearm and augmented glucose uptake in the legs during recovery raises the possibility that after leg exercise glycogen stores are decreasing in muscle that was relatively inactive (e.g., that of the forearm) while increasing in the previously exercising leg muscles.
Abstract: Eleven healthy male volunteers were studied to determine the amount of blood displaced by the inflation of the antishock trousers (AST) at pressures of 40 and 100 mm Hg. Radioisotope scans were used to determine the blood volume distribution and the change in the volume of distribution with inflation of the AST. The volunteers were then phlebotomized approximately one liter of blood and the study was repeated. Less than 5% of the total blood volume was displaced with inflation of the AST. It is unlikely that the clinical improvement seen with inflation of the AST in hypovolemic shock is due to autotransfusion of blood alone.
Abstract: CPR with simultaneous chest compression and ventilation at high airway pressure (SCV-CPR) improves blood flow in some studies but not in others, perhaps because of differences in the animal models employed. To resolve such discrepancies, we compared SCV-CPR to standard CPR in 4 mechanically different canine models, using both small and large dogs and small and large compression pads. The 4 groups were: large dogs receiving chest compression through a large pad (model A), large dogs receiving chest compression through a small pad (model B), small dogs receiving chest compression through a large pad (model C), and small dogs receiving chest compression through a small pad (model D). Cardiac output (CO) during CPR was determined by a specially modified indicator dilution method. Models A, B, and C all had similar mean COs of 14 ml/min . kg body weight during standard CPR, and 27 ml/min . kg during SCV-CPR. However, in model D, there was no significant difference during standard vs. SCV-CPR, and the mean output was 33 ml/min . kg. We conclude that in models A, B, and C, little direct heart compression occurred and the higher intrathoracic pressure pulses produced by SCV-CPR improved blood flow. However it seems likely that there was effective cardiac compression in model D. In the absence of direct cardiac compression, SCV-CPR provides an alternative means of generating satisfactory flow in a mechanically appropriate animal model.
Abstract: When A1 noradrenergic neurons in the caudal ventrolateral medulla of rabbits are destroyed electrolytically or by local injection of the neurotoxin kainic acid, the concentration of vasopressin in plasma increases, causing hypertension. The A1 neurons may tonically inhibit the activity of vasopressin-secreting neuroendocrine cells through a direct hypothalamic projection.
Abstract: The effects of severe hypoglycemia on brain pH, cerebral blood flow (CBF), and other physiologic and metabolic parameters were studied in 26 cats subjected to insulin hypoglycemia. Two groups were utilized to compare the effects of anesthesia. The halothane group was composed of 14 animals and the barbiturate group contained 12 animals. Insulin was administered by both the intravenous and intramuscular routes until there was a severe electroencephalographic (EEG) change or until 6 h had elapsed. The cerebral responses to hypoglycemia demonstrated the following: CBF was unaffected by severe hypoglycemia in normotensive animals with or without EEG changes; brain pH was essentially constant in all groups regardless of glucose levels, CBF, or EEG; and the EEG abnormalities corresponded closely to brain glucose levels. Cerebral adenosine triphosphate and phosphocreatine levels were lowest in the animals with isoelectric EEGs. We conclude that CBF and brain pH in the normotensive cat under general anesthesia are relatively unaffected by insulin hypoglycemia despite the presence of severe EEG changes and diminished cerebral energy reserves. The study suggests tha the PaCO2-CBF response curve is ot dependent upon the metabolic integrity of cerebral tissue and is mediated by pathways separate from those of autoregulation.
Abstract: To identify the role of the myocardial beta-adrenergic pathway in congestive heart failure, we examined beta-adrenergic-receptor density, adenylate cyclase and creatine kinase activities, muscle contraction in vitro, and myocardial contractile protein levels in the left ventricles of failing and normally functioning hearts from cardiac-transplant recipients or prospective donors. Eleven failing left ventricles had a 50 to 56 per cent reduction in beta-receptor density, a 45 per cent reduction in maximal isoproterenol-mediated adenylate cyclase stimulation, and a 54 to 73 per cent reduction in maximal isoproterenol-stimulated muscle contraction, as compared with six normally functioning ventricles (P less than 0.05 for each comparison). In contrast, cytoplasmic creatine kinase activity, adenylate cyclase activities stimulated by fluoride ion and by histamine, histamine-stimulated muscle contraction, and levels of contractile protein were not different in the two groups (P less than 0.05). We conclude that in failing human hearts a decrease in beta-receptor density leads to subsensitivity of the beta-adrenergic pathway and decreased beta-agonist-stimulated muscle contraction. Regulation of beta-adrenergic receptors may be an important variable in cardiac failure.
Abstract: Despite numerous studies which have characterized the regulation of antidiuretic hormone (ADH), the role of volume in governing ADH release remains incompletely defined. Most studies have examined the quantitative effects of hypovolemia on arginine vasopressin (AVP). In contrast, few have assessed the role of hypervolemia on AVP regulation. Furthermore, there are no data to date on the effect of acute isoosmotic volume expansion on plasma AVP in man. The successful characterization of the water immersion model (NI) and the demonstration that it induces an acute central volume expansion without changes in plasma composition commended its utilization in the present study. Twelve normal subjects were studied after 14 h of dehydration on two occasions: control and during 4 h of NI. Blood was obtained every 30 min for AVP. AVP was unaltered during the control period. In contrast, there was a prompt and sustained suppression of AVP throughout NI (P \textbackslashtextless 0.05 vs. control). There were no concomitant changes in plasma osmolality. Since the changes in AVP occurred consequent to central volume expansion but in the absence of concomitant changes in plasma composition, the current data support the concept that acute isoosmotic central volume expansion in man results in a suppression of plasma AVP.
Abstract: To determine whether alterations in the mechanical properties (i.e., stiffening) of the right and left ventricles contribute to the decrease in right and left ventricular end-diastolic volumes during continuous positive-pressure ventilation (CPPV), we studied six dogs anesthetized with chloralose urethane and ventilated with a volume ventilator. We varied ventricular volumes by withdrawing or infusing blood. Pressure-volume curves, constructed by plotting transmural ventricular end-diastolic pressures against ventricular end-diastolic volumes, did not change during CPPV (12 cmH2O positive end-expiratory pressure) compared to intermittent positive-pressure ventilation (IPPV, 0 cmH2O end-expiratory pressure). We conclude that decreased ventricular end-diastolic volumes during CPPV result primarily from a decrease in venous return. Alterations in the mechanical properties of the ventricles do not play a significant role in this response.
Abstract: The evanescence of glucagon’s effect on glucose production (GP) is well documented, but it is unclear (1) whether this response involves both glycogenolysis and gluconeogenesis and (2) whether the liver becomes dependent on the increased glucagon level for the maintenance of a basal supply of glucose. To answer these questions, conscious overnight-fasted dogs were given somatostatin (0.8 microgram/kg . min) plus basal intraportal replacement amounts of insulin (273 microU/kg . min) and glucagon (0.65 ng/kg . min) for 2 h, after which the rate of glucagon infusion was increased fourfold for 3 h and then returned to basal for 1.5 h. GP was determined using a primed infusion of [3-3H]glucose, and gluconeogenesis (GNG) was estimated by determining the conversion rate of alanine and lactate to glucose. An increase in the plasma glucagon level from 55 to 206 pg/ml resulted in an initial 180% increase in GP, followed by a decline such that after 3 h of hyperglucagonemia GP was increased by only 41%. Contrary to overall GP, gluconeogenesis increased progressively throughout the hyperglucagonemic period, eventually reaching a rate 3 times basal. Restoration of the basal glucagon level (63 pg/ml) caused a marked decline in GP and GNG. In fact, GP fell to a level 29% below the initial control rate and consequently the plasma glucose level fell rapidly. The data suggest that (1) the downregulation of glucagon-stimulated GP is attributable to a decline in glycogenolysis and not gluconeogenesis, and (2) following adaptation to the hormone, the liver becomes dependent on the elevated glucagon concentration for the maintenance of basal glucose production.
Abstract: Studies were conducted to determine whether the direction of hepatic carbohydrate and lipid metabolism in the rat could be switched simultaneously from a "fasted" to a "fed" profile in vitro. When incubated for 2 h under appropriate conditions hepatocytes from fasted animals could be induced to synthesize glycogen at in vivo rates. There was concomitant marked elevation of the tissue malonyl-coenzyme A level, acceleration of fatty acid synthesis, and suppression of fatty acid oxidation and ketogenesis. In agreement with reports from some laboratories, but contrary to popular belief, glucose was not taken up efficiently by the cells and was thus a poor substrate for eigher glycogen synthesis or lipogenesis. The best precursor for glycogen formation was fructose, whereas lactate (pyruvate) was most efficient in lipogenesis. In both case the addition of glucose to the gluconeogenic substrates was stimulatory, the highest rates being obtained with the further inclusion of glutamine. Insulin was neither necessary for, nor did it stimulate, glycogen deposition or fatty acid synthesis under favorable substrate conditions. Glucagon at physiological concentrations inhibited both glycogen formation and fatty acid synthesis. Insulin readily reversed the effects of glucagon in the submaximal range of its concentration curve. The following conclusions were drawn. First, the fasted-to-fed transition of hepatic carbohydrate and lipid metabolism can be accomplished in vitro over a time frame similar to that operative in vivo. Second, reversal appears to be a substrate-driven phenomenon, in that insulin is not required. Third, unless an unidentified factor (present in protal blood during feeding) facilitates the uptake of glucose by liver it seems unlikely that glucose is the immediate precursor for liver glycogen or fat synthesis in vivo. A likely candidate for the primary substrate in both processes is lactate, which is rapidly formed from glucose by the small intestine and peripheral tissues. Fructose and amino acids may also contribute. Fourth, the requirement for insulin in the reversal of the fasting state of liver metabolism in vivo can best be explained by its ability to offset the catabolic actions of glucagon.
Abstract: Thiopentone was given to eight women and eight men (60 - 70 yr). The disappearance of thiopentone from the venous blood was described by a three-compartment open model. The only significant difference between the sexes was a higher initial venous concentration in males. The dose (mg kg-1) for induction was 70% of the value (P less than 0.05) previously reported for a comparable group of younger men and women (20 - 40 yr). The volume of distribution V2 and V2 were larger in the elderly (P less than 0.05). The terminal half-lives were increased with advancing age (from 75% to 100% on average) (P less than or equal to 0.01). The clearance value was 50% greater in the older women than in a group of young women. For all groups a significant correlation between initial drug concentration and k12 supported th hypothesis that there distribution rate constant k12 is the predominant factor in the pharmacokinetic profile of a dose of thiopentone sufficient to obtund the eyelash reflex.
Abstract: Subcutaneous, ingvinal adipose tissue from dogs was perfused with blood to which had been added isoprenaline and theophyllamine in order to stimulate lipolysis. The supply of free fatty acid (FFA) carrier to the tissue was varied either by variations in the rate of blood flow or by changes in the albumin concentration of the perfusing blood at constant flow rate. The net production of FFA from the tissue was found to depend on the supply of carrier over a range from 0.1 – 12 mumoles of albumin x 100 g tissue-1 x min-1. The corresponding molar FFA/albumin ratios in adipose venous blood varied between 12.1 and 1.2. The changes in FFA production appeared to be due to varying degrees of reesterification rather than changes in the rate of lipolysis. The findings suggest that the increase in adipose tissue blood flow demonstrated during various lipolytic conditions is of physiological importance by facilitating the removal of FFA from adipose tissue. Equilibration experiments showed the FFA binding capacity of both dog serum and human plasma to be above than calculated from the association constants of purified human albumin, suggesting the binding of FFA to other plasma carriers than albumin.
Abstract: The effect of potassium removal by hemodialysis on the plasma potassium concentration (PK) was observed during 20 studies on 7 anuric patients. The following was observed: (1) The pattern of change in PK is consistent with at least a two-compartment distribution; hence, in contrast to urea, PK shows a marked postdialytic rebound and the simple equation for solute removal from a single pool cannot predict postdialysis PK. (2) The magnitude of the fall in PK correlated with the predialysis PK; this was not only due to increased potassium removal, but also due to a dependence of the apparent volume of distribution of potassium on the state of potassium balance. The fractional decrement in plasma potassium concentration, contrary to that of urea, is a function of predialysis concentration, and prediction of the effect of dialysis on plasma potassium concentration can assume neither a single pool nor a constant distribution volume for this ion.
Abstract: Normal potassium homeostasis is regulated by both renal and extrarenal mechanisms. Although chronic potassium balance is primarily regulated by the kidneys, acute potassium tolerance is largely determined by extrarenal tissues. During the first 4-6 h following an acute potassium load, only about 50% of the potassium is excreted by the kidneys. Of the remaining 50% that is retained, over 80% is translocated into cells, and this provides the primary defense against hyperkalemia. Potassium uptake by both liver and muscle and intestinal secretion of potassium are the most important mechanisms of extrarenal potassium disposal. Several hormones, including insulin and epinephrine, have been shown to play an important role in the maintenance of normal extrarenal potassium metabolism. These hormones function by enhancing potassium uptake by liver and muscle. There is also evidence that aldosterone is necessary in the maintenance of normal extrarenal potassium tolerance. Although the major extrarenal site of action of aldosterone has not yet been clearly defined, gastrointestinal potassium secretion and muscle transport of potassium are both affected by the hormone. Evidence exists that glucocorticoids may also have an effect on extrarenal potassium homeostasis. In addition to this hormonal regulation, cellular shifts of potassium are influenced by changes in acid-base balance. Extrarenal potassium tolerance is impaired in chronic renal insufficiency. These uremia-related changes are discussed in the context of our present understanding of normal extrarenal potassium metabolism.
Abstract: Normal fasting subjects received regular insulin and mixtures of regular with NPH or lente to assess the effects of the combinations on serum insulin concentrations (SIC) and blood glucose responses (BGR). In addition, the influence of concentration, depth, and method and site of administration was investigated. In studies of mixtures of regular with NPH and with lente, it was observed that the regular: lente ratio needed to achieve peak SIC was higher than with the regular: NPH combination. Increased SIC, including either the peak and/or the time interval required to achieve the peak, were related to the depth and site (deltoid and abdominal greater than anterior thigh or buttocks). Assuming linear kinetics of absorption, significant quantities of insulin fail to reach the serum. Marked intra- and intersubject variations in SIC and BGR to regular, NPH, and lente insulins were observed.
Abstract: Five relatively fit men performed cycle ergometer exercise (65-70% VO2max) for up to 30 min at 30 degrees C, 40% rh. The data from control (normo-volemic), hypovolemic [8.7% reduction in blood volume (BV) induced by diuretics], and hypervolemic [7.9% expansion of BV induced by infusion if isotonic serum albumin] tests revealed significant effects of BV on body fluid and sweating responses. During control exercise, BV decreased an average (+/- SE) 370 +/- 64 ml at 20 min. A significantly smaller loss occurred after 20 min of hypovolemic exercise (270 +/- 29 ml). The decrease in BV during 30 min of hypervolemic exercise (541 +/- 43 ml) was significantly greater than during control (421 +/- 50 ml). Blood volume reduction also significantly altered the control of sweating rate independent of changes in plasma osmolality. The slope of the sweating rate-to-esophageal temperature relationship (SR/Tes) was significantly reduced from the mean value of 1.07 +/- 0.16 and 1.09 +/- 0.18 mg X min-1 X cm-2 X degrees C-1 during control tests, measured from the chest and arm, respectively, to 0.64 +/- 0.11 and 0.63 +/- 0.11 mg X min-1 X cm-2 X degrees C-1 during hypovolemia. The SR/Tes slope was unchanged in hypovolemia over active tissues (calf). Hypervolemia had no effect on the control of sweating at any site. Both the body fluid and sweating responses during hypovolemia act to conserve circulating blood volume during exercise.
Abstract: The effects of changes in luminal flow rate on fluid absorption in rat renal proximal convoluted tubules were studied by continuous luminal and peritubular microperfusion methods. Luminal flow rate was varied over a range from 5 to 45 nl . min-1, and the effects of transepithelial chloride and bicarbonate gradients were tested. Fluid absorption across the proximal convoluted tubule increased with luminal flow rate in the absence of luminal bicarbonate and organic solutes but in the presence of transepithelial chloride and bicarbonate gradients and active sodium transport. Augmenting perfusion rate from 5 to 45 nl . min-1 resulted in an increase of volume absorption from 0.49 to 3.37 nl . min-1 per millimeter length of tubule-1. The chloride concentration change in the collected perfusate decreased from 5.9 to 2.6 mEq . liter-1 . mm length tubule-1 over the same perfusion range. Thus, tubular chloride concentration rises with perfusion rate such that the steepest transepithelial chloride gradients are maintained at the highest flow rates. Flow dependence continued, albeit at reduced rate, in the absence of active sodium transport (cyanide perfusion) but in the presence of chloride and bicarbonate gradients. Flow dependence disappeared in the absence of both active sodium transport and transepithelial anion gradients. Luminal and peritubular perfusion experiments with symmetrical bicarbonate-free solutions that contained only phosphate buffer showed that even under those conditions fluid movement driven by cyanide-sensitive active transport increased with flow rate.
Abstract: The authors describe an 18-compartment hybrid computer multiple model of the uptake and distribution of halothane. This model uses 88 equations and 124 parameter settings. Three submodels are incorporated into the basic model: 1) The mass transport of halothane is simulated on the digital portion of the hybrid computer. 2) A breath-by-breath pulmonary model with two compartments describes air pressure-flow relations in the airway system. 3) A beat-to-beat cardiovascular model with 15 compartments describes in detail blood pressure-flow relations. In addition, a baroreceptor-heart rate loop is included: an increase in arterial pressure causes a decrease in heart rate. The slope of the baroreceptor response is progressively decreased by halothane until at 2 per cent there is no response. The model of halothane uptake and distribution is separate from the blood and air pressure-flow models, but is, in effect, driven by them. Myocardial "contractility" (stroke volume) and certain regional vascular resistances can be affected by the concentration of halothane in one or any proportion of any combination of three compartments: arterial blood (arteriolar concentrations), cerebral gray matter, or myocardial. In turn, these factors significantly affect the uptake and distribution of halothane. The responses to three steady-state concentration, as well as to a step change in concentration from 0 to 2 per cent, were examined. Twenty-four outputs were recorded, including halothane concentrations in ten compartments; myocardial "contractility"; left and right ventricular and right atrial pressures; cardiac output; stroke volume, R-R interval; and blood flows in six regions. Two variables–alveolar concentration of halothane and arterial blood pressure–were recorded during a step change of 0 to 5 per cent. The model describes the appropriate steady-state and dynamic cardiovascular responses to halothane. It also demonstrates the complex interrelationships among caridac output, regional blood flow distribution, and the uptake and distribution of halothane. During step change in halothane concentration, most of the responses occur early, a phenomenon also seen in man and goats. Thus, the model is useful not only for representing organ and tissue halothane concentrations, but also for gaining new insights into cardiovascular alterations produced by rapidly changing concentrations of halothane and into the complex interactions between the circulation and the uptake and distribution of halothane.
Abstract: Diabetic patients with increased plasma glucose concentrations may develop cerebral symptoms of hypoglycemia when their plasma glucose is rapidly lowered to normal concentrations. The symptoms may indicate insufficient transport of glucose from blood to brain. In rats with chronic hyperglycemia the maximum glucose transport capacity of the blood-brain barrier decreased from 400 to 290 micromoles per 100 grams per minute. When plasma glucose was lowered to normal values, the glucose transport rate into brain was 20 percent below normal. This suggests that repressive changes of the glucose transport mechanism occur in brain endothelial cells in response to increased plasma glucose.
Abstract: We studied the effect of a single oral dose of the neuronal norepinephrine uptake blocker, desipramine 125 mg, on norepinephrine kinetics. Desipramine reduced the plasma norepinephrine clearance by approximately 20%, from 1.33 +/- 0.22 to 1.08 +/- 0.19 l/m2/min (p less than 0.01). Similarly, plasma norepinephrine clearance was slowed in patients with sympathetic nerves damaged by disease (idiopathic peripheral autonomic insufficiency). Desipramine also reduced the rate of spillover of norepinephrine to plasma, 0.27 +/- 0.07 to 0.15 +/- 0.04 micrograms/m2/min, leaving the plasma norepinephrine concentration unchanged. Disappearance of tritiated norepinephrine from plasma, after infusion to steady state, was biexponential, with half-time of the rapid-removal phase (t1⅟2) = 2.0 +/- 0.4 min and half-time of the second exponential (t2⅟2) = 34 +/- 10 min. The rapid-removal phase was sensitive to disturbances in the neuronal uptake of norepinephrine, the t1⅟2 being prolonged by desipramine and lengthened in the patients with peripheral autonomic insufficiency. In contrast, the selective extraneuronal norepinephrine uptake blocker, cortisol, 500 mg intravenously, had no effect in normal subjects on either plasma norepinephrine clearance or the t1⅟2 value. Neuronal uptake of norepinephrine contributes to the overall removal of norepinephrine from plasma. Extraneuronal uptake of norepinephrine could not be demonstrated at existing plasma norepinephrine concentrations.
Abstract: This investigation was undertaken to determine the effect of pedal frequency on submaximal exercise responses. Seven well-trained competitive cyclists were studied riding their road-racing bicycles on a motor-driven treadmill at 80% of maximum O2 consumption (VO2 max) using different gear ratios. Cyclists were also studied during a series of unloaded trials to assess the effects of varying rates of limb movements independent of external work load. Heart rate (HR) increased, whereas net HR (after subtracting the HR during unloaded cycling) decreased with increasing pedal frequency during loaded cycling. Expiratory flow (VE), O2 consumption (VO2), blood lactate, net VO2 (after subtracting the VO2 of unloaded cycling), and net VE (after subtracting the VE during unloaded cycling) were quadratically related to pedal frequency. The quadratic relationships evident after corrections were made for the additional work needed to move the legs more frequently may be explained at the lower pedaling rates by a less uniform pattern of blood flow caused by increasing the force requirement per pedal stroke and, at the higher pedal frequencies, by the recruitment of additional musculature to stabilize the trunk. The average of preferred frequency for the group, which was also the most economical pedaling rate judged by most of the variables was 91 rpm, although the preferred pedaling rate for each subject ranged from 72 to 102 rpm.
Abstract: 1. The effect of bilateral carotid occlusion on carotid sinus pressure, systemic blood pressure, heart rate, renal blood flow, renal-venous and arterial plasma renin activity was studied in twelve trained conscious foxhounds on a normal sodium diet (4.7 mmol/kg per day). 2. When renal perfusion pressure was allowed to rise with systemic pressure by 51.0 +/- 6.3 mmHg during carotid occlusion, renin release decreased by 72.3 +/- 22.2 ng/min (78% of control; P less than 0.05) while renal blood flow remained at its resting level of 232.7 +/- 20.1 ml/min (n = 8 dogs). 3. When renal perfusion pressure was maintained constant at 93.0 +/- 3.6 mmHg during carotid occlusion (suprarenal aortic cuff), renin release increased by 154.6 +/- 60.4 ng/min (73% of control; P less than 0.05), again there was no significant change of renal blood flow (n = 7 dogs). 4. After beta-adrenergic blockade carotid occlusion increased systemic blood pressure by 47.7 +/- 7.8 mmHg, decreased renin release by 34.6 +/- 9.9 ng/min (67% of control; P less than 0.05) and had no effect on renal blood flow (n = 4 dogs). 5. When renal perfusion pressure was controlled at its resting level, no significant change of renin release and renal blood flow was observed during carotid occlusion in the surgically denervated kidney (n = 3 dogs) or in the intact kidney after beta-adrenergic blockade (n = 4 dogs). 6. It is concluded that a reduction of carotid sinus pressure in the conscious dog increases renin release by a direct beta-adrenergic stimulation without exerting vasomotor effects provided renal perfusion pressure is maintained at control level. The vascular receptor mechanism can effectively counteract the stimulating influence of the renal sympathetic nerves when perfusion pressure is allowed to rise.
Abstract: Hypoxia is commonly invoked to explain alterations in mental function, particularly in patients with cardiac pulmonary failure. The effects of acute graded hypoxia or higher integrative functions are well documented experimentally in man. Hypoxia in experimental animal models demonstrates that the pathophysiology is complex. In mild to moderate hypoxia, in contrast to severe hypoxia and to ischemia, the supply of energy for the brain is not impaired; cerebral levels of adenosine triphosphate (ATP) and adenylate energy charge are normal. In contrast, the turnover of several neurotransmitters is altered by mild hypoxia. For example, acetylcholine synthesis is reduced proportionally to the reduction in carbohydrate oxidation. This relationship holds in vitro and with several in vivo models of hypoxia. Pharmacologic and physiologic studies in man and experimental animals are consistent with acetylcholine having an important role in mediating the cerebral effects of mild hypoxia. These observations raise the possibility that treatments directed to cholinergic or other central neurotransmitter systems may benefit patients with cerebral syndromes secondary to chronic hypoxia.
Abstract: The responses of alterations in regional hemodynamics and oxygen transport rate to hematocrit (Hct) were studied in 20 pentobarbitalized dogs. Hemodilution was carried out by isovolemic exchange with plasma in 12 dogs and the hemoconcentration with packed cells in 8 dogs. The cardiac output and regional blood flows were determined with the microsphere technique. In hemodilution, the increases of blood flow to the myocardium and the brain were out of proportion to the increase of cardiac output; the oxygen supply to the myocardium remained unchanged while that to the brain decreased only slightly. In hemoconcentration, vasodilation occurred in the myocardium and the brain to maintain constant oxygen supply. Splenic vessels had marked vasoconstriction with Hct alteration in either direction. Blood vessels in the liver, intestine, and kidney responded with a milder vasoconstriction and maintained a constant oxygen supply between Hct of 30-55%. Therefore, during Hct alteration, redistribution of blood flow to myocardium and brain occurred. The optimal Hct range for constant oxygen supply was different among various organs.
Abstract: To determine the plasma epinephrine thresholds for its metabolic and hemodynamic actions and plasma epinephrine metabolic clearance rates, 60-min intravenous epinephrine infusions at nominal rates of 0.1, 0.5, 1.0, 2.5, and 5.0 microgram/min were performed in each of six normal human subjects. These 30 infusions resulted in steady-state plasma epinephrine concentrations ranging from 24 to 1,020 pg/ml. Plasma epinephrine thresholds were 50-100 pg/ml for increments in heart rate, 75-125 pg/ml for increments in blood glycerol and systolic blood pressure, 150-200 pg/ml for increments in plasma glucose (the resultant of increments in glucose production and decrements in glucose clearance), blood lactate, blood beta-hydroxybutyrate, and diastolic blood pressure, and greater than 400 pg/ml for early decrements in plasma insulin. Changes in blood alanine, plasma glucagon, plasma growth hormone, and plasma cortisol were not detected. At steady-state plasma epinephrine concentrations of 24-74 pg/ml, values overlapping the basal normal range, the mean (+/-SE) plasma metabolic clearance rate of epinephrine was 52 +/- 4 ml x min-1 x kg-1; this value rose to 89 +/- 6 ml x min-1 x kg-1 (P less than 0.01) at steady-state epinephrine concentrations of 90-1,020 pg/ml. We conclude that in human subjects: (a) the plasma epinephrine thresholds for its hemodynamic and metabolic actions lie within the physiologic range, (b) epinephrine and norepinephrine accelerate their own metabolic clearance, and (c) epinephrine is 10 times more potent than norepinephrine.
Abstract: The effects of graded brain hypoxia on respiratory cycle timing, the lung inflation reflex, and respiratory compensation for an inspiratory flow-resistive load were studied in unanesthetized goats. Two models, inhalation and CO and acute reduction of brain blood flow (BBF) were used to produce comparable levels of brain hypoxia. The lung inflation reflex was assessed as the ratio of inspiratory time of an occluded breath to that of the preceding spontaneous breath (TIoccl/TIspont). Compensation for flow-resistive loading was assessed as the effect of the load upon the airway occlusion pressure response to rebreathing CO2 (delta P 0.1/delta PCO2). Major findings were 1) severe brain hypoxia (HbCO of 60% or BBF of 42%) caused tachypnea due to a 50% or more reduction of expiratory time but only a 20% or less reduction of inspiratory time; 2) moderate carboxyhemoglobinemia (HbCO of 25-30%) enhanced TIoccl/TIspont from 1.5 +/- 0.1 at control to 2.1 +/- 0.1, while severe brain hypoxia (HbCO of 60% and BBF of 42%) reduced the ratio to 1.0 +/- 0.2; and 3) compensation for a flow-resistive load, manifested by increases of delta P 0.1/delta PCO2 of 75-300% in the control state, was abolished at HbCO of 45-50% and BBF of 60%. The data suggest that in unanesthetized animals brain hypoxia elicits tachypnea largely by an effect on the expiratory phase of the bulbopontine timing mechanism. The observed enhancement of the lung inflation reflex and abolition of flow-resistive load compensation are best explained by hypoxic depression of higher than brain stem neural function.
Abstract: A chi-square analysis of 66 cases, including the author’s eight cases and 58 from the literature, was undertaken to determine prognostic signs for death in patients seriously injured by lightning. A review of the injuries and of the physics and pathophysiology of lightning is presented. Prognosis was poor for those victims suffering leg burns (mortality 30%), cranial burns (37%), or cardiopulmonary arrest (76%). Death occurred in 30% of the cases studied. Permanent sequelae were found in 74% of the survivors. Nonsignificant factors were age, sex, and trunk and arm burns. Resuscitation of victims exhibiting loss of consciousness should begin immediately, as these are the most likely to die.
Abstract: We investigated the mechanism(s) responsible for the decreased cardiac output during continuous positive-pressure ventilation (CPPV). Seven dogs were anesthetized with chloralose-urethane, intubated, and ventilated using a volume ventilator. We measured heart rate, stroke volume, and the determinants of stroke volume: left and right ventricular end-diastolic volumes, isovolumic and ejection phase indices of myocardial contractility, and pulmonary and systemic arterial pressures. Myocardial blood flow was estimated using radioactive microspheres. Variables were measured during a control period of intermittent positive-pressure ventilation (IPPV), 8-20 minutes after the initiation of CPPV using 12 cm H2O positive end-expiratory pressure (PEEP), and 8-20 minutes after the removal of PEEP. CPPV decreased cardiac output but did not affect total or regional myocardial blood flow or the ratio of subendocardial to subepicardial blood flow. Isovolumic and ejection phase indices of myocardial cointractility, heart rate, and systemic arterial pressure did not change during CPPV. Right and left ventricular end-diastolic and end-systolic volumes decreased markedly during CPPV. We conclude that CPPV decreases cardiac output in accordance with Starling’s law by decreasing preload.
Abstract: Medullary thick ascending limbs of Henle’s loop of the Swiss-Webster mouse were perfused in vitro with an isotonic perfusate and a Ringer’s bathing medium. In five studies, addition of a supramaximal concentration of synthetic arginine vasopressin (AVP) to the bathing medium resulted in an increase in electrical potential difference (PD) from 5.0 +/- 1.5 mV, lumen positive, to 10.7 +/- 1.4 mV (P \textbackslashtextless 0.001). When AVP was removed, the PD returned to 2.6 +/- 0.9 mV (P \textbackslashtextless 0.001), then increased again to 6.9 +/- 1.7 mV (P \textbackslashtextless 0.01) when AVP was added a second time. A significant, but submaximal, increase in PD of 2.3 +/- 0.6 MV (P \textbackslashtextless 0.05) was observed in five medullary thick ascending limbs when AVP was added to the bathing medium at a concentration of 10 microunits/ml. This increase was approximately one-third of the response observed at a concentration of 100 microunits/ml in the same tubule. No further increment in PD was observed in five medullary thick ascending limbs when the AVP concentration was increased from 100 to 1,000 microunits/ml. In seven thick ascendcing limbs, the effect of AVP on PD was reproduced by the addition of 8-[p-chlorophenylthio]-cyclic 3’,5’-adenosine monophosphate to the bathing medium at a final concentration of 0.1 mM. AVP increased unidirectional chloride flux from lumen to bath from 29.3 +/- 3.2 to 69.8 +/- 6.2 peq/cm per s (P \textbackslashtextless 0.001) in spite of an increase in the lumen positive PD from 1.6 +/- 0.5 mV to 7.0 +/- 0.6 mV (P \textbackslashtextless 0.001). Unidirectional chloride flux from bath to lumen was not affected by AVP. In another series of experiments, net chloride flux increased from 15.6 +/- 3.0 to 41.7 +/- 5.3 peq/cm per s (P \textbackslashtextless 0.05) after addition of AVP. The effect of AVP on hydraulic water permeability (Lp) was examined by adding raffinose to the bathing medium in both the presence and the absence of AVP. The calculated Lp of 16 +/- 2 nm/s per atm in the absence of AVP, although very low, was significantly different from zero (P \textbackslashtextless 0.01). However, the Lp did not increase significantly when AVP was added to the bathing medium. These results suggest that AVP has a second site of action in the kidney to increase chloride transport by the medullary thick ascending limb in addition to its well-known effect on the water permeability of the collecting tubule. The former effect would contribute to urinary concentrating ability by increasing the axial osmotic gradient in the renal medulla.
Abstract: The circumstances under which furosemide increases renal blood flow was examined in mongrel dogs as it may relate to a tubuloglomerular feedback mechanism. Two maneuvers, desoxycorticosterone (DOCA) plus salt treatment and inhibition of tubular fluid flow, were used in the dogs to evaluate the renal vascular effects of furosemide because these maneuvers have been reported to blunt the tubuloglomerular feedback in micropuncture studies. In addition, we also used two structurally different nonsteroidal antiinflammatory drugs to assess the importance of prostaglandins to achieve furosemide’s renal vasodilatation. Furosemide (5 mg/kg, i.v.) increased renal blood flow in volume-depleted animals from a baseline flow of 141 +/- 28 ml/min to a maximum of 176 +/- 35 ml/min at 6 min after furosemide administration. If the animals were pretreated with a high-salt diet and i.m. DOCA for 5 days, furosemide administration produced no renal vascular effects but still caused a large diuresis, and these dogs still had a responsive renal vascular bed to infused prostaglandin E2. In addition, kidneys rendered non-filtering in volume-depleted animals had no renal vascular response to furosemide. Volume-depleted animals, pretreated with either indomethacin or sodium meclofenamate, did not have a renal vascular response to furosemide although they did have a diuretic response and a responsive renal vasculature to prostaglandin E2. From our data, we hypothesize that the renal vascular response to furosemide is secondary to a tubular mechanism mediated by a vasodilatory prostaglandin. Because furosemide has been shown to disrupt the tubuloglomerular feedback mechanism, and the two maneuvers, DOCA plus salt treatment and lack of filtration, blunt the tubuloglomerular feedback response as well as inhibit the renal vascular response to furosemide, we further hypothesize that furosemide-induced renal vasodilation may be secondary to the disruption of an active tubuloglomerular feedback mechanism.
Abstract: The early cardiovascular adaptation to zero gravity, simulated by head-down tilt at 5 degrees, was studied in a series of 10 normal young men. The validity of the model was confirmed by comparing the results with data from Apollo and Skylab flights. Tilt produced a significant central fluid shift with a transient increase in central venous pressure, later followed by an increase in left ventricular size without changes in cardiac output, arterial pressure, or contractile state. The hemodynamic changes were transient with a nearly complete return to the control state within 6 hr. The adaptation included a diuresis and a decrease in blood volume, associated with ADH, renin and aldosterone inhibition.
Abstract: Six normotensive volunteers were infused with L-adrenaline at 0.01, 0.03, 0.05, 0.075 and 0.10 microgram/kg-1 min-1, each increment lasted 10 min. Plasma adrenaline rose from 0.27 to 4.61 nmol/l, and there were dose-related increases in plasma renin activity, blood glucose, plasma cyclic AMP and plasma free fatty acids, but not in plasma noradrenaline and cyclic GMP. Levels of circulating adrenaline previously noted in essential hypertensives had minimal cardiovascular effects. The secretion rate of adrenaline and its rate of clearance from the circulation were calculated from plasma samples taken during an hour-long infusion (0.083 +/- 0.006 microgram kg-1 min-1) of L-adrenaline in the same individuals. The secretion rate ranged from 1.40 to 6.01 nmol/min with a mean (+/- SEM, 6) of 2.82 +/- 0.76 nmol/min. Mean clearance (+/- SEM, 6) was 9.41 +/- 1.37 l/min and ranged from 4.86 to 14.61 l/min. The decline of plasma adrenaline following the infusion was biexponential. Plasma adrenaline is unlikely to be of primary importance in the elevation of blood pressure, either directly, via renin release or by noradrenaline release via presynaptic beta receptors. However, variation in clearance between subjects limits the use of plasma levels as an interindividual index of adrenal release of adrenaline. The relationship between sympathoadrenal activity and plasma adrenaline may be further perturbed by equilibration between the circulation and sites of tissue uptake. The lower levels of plasma adrenaline than of noradrenaline appear to result from both a slower rate of secretion and a higher rate of clearance from the circulation.
Abstract: The microvessels responsible for the major decrease in intestinal vascular resistance during the presence of glucose were defined. In addition, the normal distribution of tissue PO2 in the various layers of the intestinal tissue was measured at rest and during glucose exposure to determine if part of the absorptive hyperemia mechanism is related to a decrease in tissue PO2. In the rat small intestine, exposure of the mucosa only to glucose concentrations of 25–500 mg/100 causes a 20–25% dilation of all submucosal vessels in series with the mucosal vessels and mucosal arterioles. Total intestinal blood flow increased to 200-210% of control at all glucose concentrations. The tissue and perivascular PO2 in the villus apex decreased from 14.8 +/- 1.2 (SE) mmHg at rest to 6–8 mmHg during glucose exposure; the PO2 in the muscle and submucosal layers tended to slightly increase above a normal of 26.4 +/- 1.6 mmHg during glucose exposure. The data indicate virtually all intestinal arterioles are equally involved in absorptive hyperemia. The dilation of mucosal vessels may be related to a decrease in tissue PO2, but submucosal vessels dilate even though PO2 is slightly increased.
Abstract: To investigate the time course and mechanism of the increase in blood volume (BV) during isotonic exercise training, blood hemoglobin, hematocrit, and plasma volume (PV), osmotic, electrolyte, renin activity (PRA), vasopressin (AVP), and protein fractions were measured periodically in eight trained men 20-22 yr (Vo2max = 57 ml . min-1 . kg-1) before, during, and after ergometer exercise training (approximately 160 W, 65% Vo2max) for 2 h/day for 8 days. During training, plasma total osmolar and albumin contents increased to maintain a constant plasma osmolality and protein concentration during PV expansion. After training, BV increased by 457 ml (+8.1% P less than 0.05), due to an increase in PV of 427 ml (+12.1%, P less than 0.05); red cell volume was essentially constant (delta = +30 ml, NS). Plasma hypervolemia during training was associated with two major factors: 1) a ninefold elevation in PRA and AVP during exercise that facilitated Na+ and H2O retention, and 2) a progressive, chronic increase in plasma albumin content that provided increased H2O-binding capacity for the blood. Thus an efficient procedure for increasing PV is the daily performance of high-intensity isotonic leg exercise (65% Vo2max) for 2 h/day.
Abstract: To investigate the relationship between serum T3 levels and thermogenesis in euthyroid subjects, the conversion of T4 to T3 was partially blocked over a period of 3 weeks by weekly ingestion of 2 g iopanoic acid. Serum T3 decreased by 56 +/- 6 ng/100 ml without affecting the metabolic rate or total heat loss. Because an increase in serum T4 levels was observed (3.70 +/- 0.2 microgram/100 ml), the experiment was repeated in T4-substituted subjects. Serum T3 decreased even more in these subjects, (by 85 +/- 12 ng/100 ml), and the increase of serum T4 was also larger (4.6 +/- 0.7 microgram/100 ml). Again, the metabolic rate did not change. Experiments performed on hypothyroid patients and T3-substituted subjects demonstrated that iopanoic acid alone was without effect on the metabolic rate. Furthermore, the effect of a low energy, high protein diet (1672 kilojoules or 400 Cal) on the metabolic rate was confirmed. These results show that the decrease in magnitude of serum T3 seen with iopanoic acid is not sufficient by itself to reduce the metabolic rate.
Abstract: Pretreatment of spontaneously hypertensive rats (SHR) with the converting enzyme inhibitor captopril (10 or 100 mg/kg p.o.) had no effect on pressor responses to angiotensin II or norepinephrine whereas the response to angiotensin I was markedly inhibited. In contrast, pressor responses to sympathetic stimulation in pithed SHR were inhibited by captopril whereas the positive chronotropic responses to stimulation were unaltered. These results suggest that captopril causes a prejunctional inhibition of norepinephrine release to sympathetic nerve stimulation which is selective for the vasculature. This is probably due to inhibition of angiotensin II formation in the vasculature.
Abstract: A patient with delayed neurologic injury secondary to high-tension current, with recovery, is presented. The mechanism of injury and pathophysiology are felt to be either vascular or direct damage to the spinal cord. This case demonstrates the need for frequent, repeated neurologic examinations of electrical injury victims. The cause of delay in onset of neurologic injury and the mechanism of recovery need further experimental study.
Abstract: Pulmonary carbonic anhydrase (CA) activity was studied in rabbit lungs perfused with solutions containing no CA. Measurements were made of the amount of 14CO2 appearing in the expired gas following injections of H14CO3⊖, 14CO2, or a 20:1 mixture of each into the pulmonary artery. The fraction of the injected label in the expired gas was only 17% greater for 14CO2 than for the mixture, suggesting that equilibration between H14CO3⊖ and 14CO2 was nearly complete during the capillary transit time. Inhibition of pulmonary CA decreased excretion of H14CO3⊖ and the mixture by 40 and 49% and increased the excretion of 14CO2 by 96%. Addition of CA to the perfusate had no effect. Thus, CO2 exchange is not significantly limited by pulmonary CA if inhibitors are absent. Tissue binding of [3H]acetazolamide injected into the pulmonary artery was diminished by 50% when acetazolamide concentrations reached 0.13 x 10(-6) M. Each liter of extravascular lung water contained 1.25 x 10(-6) mol of receptors for acetazolamide that were accessible to plasma during a single circulation. Binding of [3H]acetazolamide was also observed in lungs of anesthetized rabbits, suggesting that pulmonary CA is accessible to plasma in vivo as well as in situ.
Abstract: The effects of the administration of 100% oxygen on minute ventilation (VE) and arterial blood gases were studied in patients with chronic obstructive pulmonary disease during acute respiratory failure. The administration of O2 resulted in an early decrease in VE, which averaged 18% +/- 2 SE of the control VE, and was due to a decrease in both tidal volume (VT) and respiratory frequency (f). This was followed by a slow increase in VE, such that after 15 min of breathing O2, VE rose to 93 +/- 6% of the control room air value, with both VT and f similar to control values. Despite the small difference between VE while breathing room air and that at the fifteenth minute of O2 inhalation, PaCO2 increased by 23 +/- 5 mmHg, and no significant correlation was found between the changes in VE and PaCO2. By the fifteenth minute of O2 inhalation the PaO2 averaged 225 +/- 23 mmHg, and it was concluded that despite the removal of the hypoxic stimulus of O2 inhalation, the activity of the respiratory muscles remained great enough to maintain VE at nearly the same degree as that while breathing room air. Consequently, the changes in PaCO2 after the administration of O2 were mainly due to increased inhomogeneity of VA/Q distribution within the lungs.
Abstract: The present study was designed to quantitate the role of the renin-angiotensin system (RAS) in determining the chronic relationships between arterial pressure (AP), renal hemodynamics, and Na excretion. In six control dogs, Na balance was achieved during chronic step increases in Na intake from 5 to 500 meq/day with small increases in AP (\textbackslashtextless7 mmHg), moderate increases in GFR (19%), and decreases in filtration fraction (FF) and plasma renin activity. Similar increases in Na intake in six dogs with angiotensin II (AII) fixed, due to constant intravenous infusion of 5 ng . kg-1 . min-1 AII, caused large increases in AP (42%), GFR (31%) FF, and calculated renal Na reabsorption (TNa) above control. In six dogs with AII formation blocked with SQ 14,225, Na balance at intakes of 5-80 meq/day occurred at reduced AP, GFR, FF, and TNa, although plasma aldosterone concentration (PAC) was not substantially different from that in control dogs. At Na intakes above 240 meq/day, AP was not altered by SQ 14,225. These data indicate that during chronic changes in Na intake the RAS plays a major role, independent of changes in PAC, in allowing Na balance without large changes in GFR or AP. The mechanism whereby AII conserves Na chronically is through increased TNa, since steady-state TNa was increased by AII and decreased by SQ 14,225.
Abstract: The vascular reactions of the parallel-coupled vascular sections of the small intestine were studied during hypotension at two different levels of intestinal arterial inflow pressure, using a 85Kr elimination technique. The regional hypotension was accomplished by partially occluding the superior mesenteric artery with a clamp and maintained for 2 h. At the higher level (50-55 mmHg) total intestinal blood flow decreased but not to the same relative extent as blood pressure due to the autoregulatory capacity of the intestinal vascular bed. The flow autoregulation was also reflected in a decreased blood flow resistance. The distribution of blood to the muscularis and mucosa-submucosa layer, respectively, did not change significantly during or after hypotension as compared to the prehypotensive level, since the relative flow decrease was the same in the mucosa-submucosa and in themuscularis. At the lower arterial pressure level (30-35 mmHg) a more marked decrease of intestinal blood flow and flow resistance was observed as compared to the experiments performed at the 50-55 mmHg pressure level. Moreover, muscularis blood flow was relatively more decreased than blood flow in the mucosa-submucosa implying the fraction of total blood flow diverted to the muscularis was significantly decreased. Despite this redistribution of blood flow, a histological damage was apparent only in the mucosa, particularly at the villous tips.
Abstract: This free-flow micropuncture study examined the dependence of bicarbonate reabsorption in the rat superficial proximal convoluted tubule to changes in filtered bicarbonate load, and thereby the contribution of the proximal tubule to the whole kidney’s response to such changes. The independent effects of extracellular fluid (ECF) volume expansion and of acidosis on proximal bicarbonate reabsorption were also examined. When the plasma volume contraction incurred by the micropuncture preparatory surgery was corrected by isoncotic plasma infusion ( congruent with1.3% body wt), single nephron glomerular filtration rate (SNGFR), and the filtered total CO(2) load increased by 50%. Absolute proximal reabsorption of total CO(2) (measured by microcalorimetry) increased by 30%, from 808+/-47 during volume contraction to 1,081+/-57 pmol/min.g kidney wt after plasma repletion, as fractional total CO(2) reabsorption decreased from 0.90 to 0.77. Aortic constriction in these plasma-repleted rats returned the filtered load and reabsorption of total CO(2) to the previous volume contracted levels. In other animals isohydric ECF expansion with plasma (5% body wt) or Ringer’s solution (10% body wt), or both, produced no further diminution in fractional proximal total CO(2) reabsorption (0.76-0.81). Metabolic acidosis was associated with very high fractional proximal total CO(2) reabsorptive rates of 0.82 to 0.91 over a wide range of SNGFR and ECF volumes. At a single level of SNGFR, end-proximal total CO(2) concentration progressively decreased from 5.6+/-0.5 to 1.6 +/-0.2 mM as arterial pH fell from 7.4 to 7.1. Expansion of ECF volume in the acidotic rats did not inhibit the ability of the proximal tubule to lower end-proximal total CO(2) concentrations to minimal levels. In conclusion, bicarbonate reabsorption in the superficial proximal convoluted tubule is highly load-dependent (75-90%) in normal and acidotic rats. No inhibitory effect of ECF volume per se on proximal bicarbonate reabsorption, independent of altering the filtered bicarbonate load, could be discerned. Acidosis enabled the end-proximal luminal bicarbonate concentration to fall below normal values and reduced distal bicarbonate delivery.
Abstract: Known physiologic mechanisms explain the elevated blood ADH levels observed in most patients with the syndrome of inappropriate ADH. Therefore the word "inappropriate" is a misnomer. It implies that the mechanisms that regulate ADH release are not functioning normally–which is not true. The term misleads the physician who, ideally, should determine why a patient has an excessive blood ADH level and initiate appropriate treatment. Patients with ectopic production of ADH and hyponatremia should be so labeled: "Hyponatremia due to ectopic ADH production." The term SIADH, if used at all, should be reserved for the rare patient with CNS injury or disease that causes increased ADH release and in which the hypothalamic center does not respond normally to afferent peripheral stimuli.
Abstract: We measured ventilatory responses to CO2 (delta VI/delta PCO2) and transient hypoxia (delta VI/delta SaO2) during reductions of brain blood flow (BBF) to 70% and 50% of control in unanesthetized goats. Increase in inspiratory volume per change in CO2 tension (delta VI/delta PCO2) was measured during rebreathing with sampling of both arterial and cerebral venous blood; increase in inspiratory volume per fall in arterial oxygen saturation (delta VI/delta SaO2) was assessed by the transient N2 inhalation method. Delta VI/delta SaO2 did not significantly change at 70% BBF, but was depressed at 50% BBF. Delta VI/delta PCO2 increased (0.94 +/- 0.18 to 1.29 +/- 0.24 l . min-1 . Torr-1) at 70% BBF if arterial CO2 tension were used to represent the CO2 stimulus but was unchanged if venous CO2 tension were used. At 50% BBF, delta VI/delta PCO2 was depressed (0.38 +/- 0.13 l . min-1 . Torr-1) for both representations of the CO2 stimulus. Brain ischemia increased blood pressure and heart rate but blunted the increase in BBF caused by hypercapnia. We conclude that 1) moderate brain ischemia (70% BBF) does not affect chemosensitivity to hypoxia and CO2, 2) delta VI/delta PCO2 may not be accurately determined from PaCO2 during brain ischemia because cerebrovascular reactivity to CO2 is depressed, and 3) severe brain ischemia (50% BBF) blunts delta VI/delta SaO2 and delta VI/delta PCO2, probably as a consequence of hypoxic depression of the respiratory neurons.
Abstract: Left ventricular dysfunction is common in respiratory-distress syndrome, asthma and obstructive lung disease. To understand the contribution of intrathoracic pressure to this problem, we studied the effects of Valsalva and MÃŒller maneuvers on left ventricular function in eight patients. Implantation of intramyocardial markers permitted beat-by-beat measurement of the velocity of fiber shortening (VCF) and left ventricular volume. During the MÃŒller maneuver, VCF and ejection fraction decreased despite an increase in left ventricular volume and a decline in arterial pressure. In addition, when arterial pressure was corrected for changes in intrapleural pressure during either maneuver it correlated better with left ventricular end-systolic volumes than did uncorrected arterial pressures. These findings suggest that negative intrathoracic pressure affects left ventricular function by increasing left ventricular transmural pressures and thus afterload. We conclude that large intrathoracic-pressure changes, such as those that occur in acute pulmonary disease, can influence cardiac performance.
Abstract: The ventilatory effects of graded reductions in brain bloow flow (BBF) were studied in unanesthetized goats. At a BBF of 85% of control (PVO2 = 29.2 Torr, PVCO2 = 47.3 Torr) there were no clear ventilatory effects. At BBF of 70% of control (PVO2 = 25.2, PVCO2 = 50.5) and 50% of control (PVCO2 = 22.3, PVCO2 = 53.0) there was hyperpnea, due primarily to an increase of tidal volume. Further reduction of BBF (avg of 42% of control) first produced intense tachypnea and then (30–40% of control) caused apnea that was reversible. At 50% BBF there was a reduction of brain O2 consumption, (4.67–4.00 ml/min) and an increase in systemic O2 consumption. beta-Adrenergic blockade prevented the increase in systemic O2 consumption and reduced the hyperpnea by two-thirds at 50% BBF; the residual hyperpnea was associated with hypocapnia in contrast to the hyperpnea prior to beta-adrenergic blockade, which was virtually isocapnic. The data suggest that hyperpnea due to brain ischemia is a result of both brain acidosis and systemic hypermetabolism. The similarity of the pattern of responses to that previously reported for progressive carboxyhemoglobinemia suggests that brain hypoxia is a determinant of the ventilatory responses to brain ischemia.
Abstract: Three biochemical tests for the diagnosis of pheochromocytoma were evaluated in 24 patients with proved tumors and 40 patients whose clinical picture was suspect but who had no evidence of the disease. Measurement of resting, supine plasma catecholamines (by radioenzymatic assay) was more useful than either 24-hour urinary vanillylmandelic acid (VMA) or metanephrines or both. In only one of 23 patients with pheochromocytoma were plasma catecholamines within the range of those in patients without pheochromocytoma, as compared with urinary VMA in 11 of 22, urinary metanephrines in five of 22 and both metabolites in three of 22. These studies reaffirm the value of plasma catecholamines in the diagnosis of pheochromocytoma and indicate that urinary catecholamine metabolites are less useful. The poor correlation between the height of arterial pressure and circulating levels of catecholamines suggests that the regulation of arterial pressure in pheochromocytoma is complex.
Abstract: A model for left ventricular diastolic mechanics is formulated that takes into account noneligible wall thickness, incompressibility, finite deformation, nonlinear elastic effects, and the known fiber architecture of the ventricular wall. The model consists of a hollow cylindrical mass of muscle bound between two plates of negligible mass. The wall contains fiber elements that follow a helical course and carry only axial tension. The fiber angle (i.e., helical pitch) is constant along the length of each fiber but varies through the wall in accordance with the known distribution of fiber orientations in the canine left ventricle. To simplify the analysis and reduce the number of degrees of freedom, the anatomic distribution of fiber orientations is divided into a clockwise and counterclockwise system. The reference configuration for the model corresponds to a state in which, by hypothesis, the transmural pressure gradient is zero, the tension is zero for all fibers across the wall, and all fibers are assumed to have a sarcomere length of 1.9 micrometer. This choice of reference configuration is based on the empirical evidence that canine ventricles, fixed in a state of zero transmural pressure gradient and dissected, demonstrate sarcomere lengths between 1.9 and 2.0 micrometer in inner, middle, and outer wall layers, while isolated ventricular muscle bundles are observed to have zero resting tension when the sarcomere length ranges from 1.9 to 2.0 micrometer. An equation representing the global condition for equilibrium is derived and solved numerically. It is found that the model’s pressure-volume relation is representative of diastolic filling in vivo over a wide range of filling pressures, and the calculated midwall sarcomere lengths in the model compare favorably with published experimental data. Subendocardial fibers are stretched beyond Lmax even at low filling pressures, i.e., 5 mm Hg, while fibers located between 60-80% of wall thickness extend minimally between 5 and 12 mm Hg. The hydrostatic pressure field within the wall is highly nonlinear. The pressure rises steeply in the subendocardial layers so that the net gain in pressure in the inner third of the wall is 85% of the filling pressure. It is demonstrated that these results are independent of heart size for a family of heart models that are scale models of each other. They are, however, critically dependent on the existence of longitudinally oriented fibers in the endocardial and epicardial regions of heart wall.
Abstract: The present study was designed to investigate the mechanisms by which the renin-angiotensin system (RAS) regulates arterial pressure (AP) and renal function during chronic sodium deprivation. Intravenous infusion of the converting enzyme inhibitor SQ 14225 (14 microgram.kg-1.mm-1) for 8 days in 12 sodium-deficient dogs caused a marked decrease in AP from 90 +/- 1 to 67 +/- 2 mmHg and a reduction in glomerular filtration rate (GFR), filtration fraction (FF), and plasma aldosterone concentration (PAC). Despite the fall in AP and GFR, urinary Na excretion and effective renal plasma flow (ERPF) increased above control levels. In four dogs, infusion of aldosterone (200 micrograms/day) for 8 days during continuous SQ 14225 infusion restored PAC to levels above control, but did not significantly change AP or renal function from the values observed during SQ 14225 infusion alone. However, infusion of angiotensin II (AII) (10 or 20 ng.kg-1.min-1) for 5–8 days during continuous SQ 14225 infusion almost completely restored AP and renal function to control levels. These data indicate that the RAS plays a major role in regulating AP, renal hemodynamics, and Na excretion during Na deprivation, probably through the direct effects of AII rather than through changes in PAC.
Abstract: Differential nerve block from peridural anesthesia was used to determine a) if the pressor response to muscle ischemia in man is caused by stimulation of small sensory nerve fibers and b) if these fibers contribute to cardiovascular-respiratory responses during dynamic exercise. Four men exercised at 50-100 W for 5 min. Muscle ischemia and a sustained pressor response were produced by total circulatory occlusion of both legs beginning 30 s before the end of exercise and continuing for 3 min postexercise. During regression of full motor and sensory block, motor strength recovered while sensory block continued; the pressor response was blocked as long as sensory anesthesia persisted (two subjects). During blockade of the pressor response, cardiovascular-respiratory responses to exercise gradually returned from augmented to normal (preblock) levels. Sensory blockade was incomplete in two subjects and the pressor response was not fully blocked. We conclude that stimulation of small sensory fibers during ischemia elicits the pressor response, but that these fibers appear not to contribute to cardiovascular-respiratory responses during mild dynamic exercise with adequate blood flow.
Abstract: The present study was designed to evaluate the spectrum of responses of PRA and plasma aldosterone (PAldo) to a range of oral potassium intakes (0 to 300 mEq of potassium chloride per day) in 20 normal human subjects receiving an electrolyte-free diet. Potassium exhibited a dose-dependent natriuretic effect. The results of the PRA studies indicate that normal dietary amounts (50 mEq/day) of potassium chloride do not prevent the increase in PRA with absolute sodium deprivation and that PRA is maximally stimulated on 150 mEq of potassium chloride per day. The rise in PRA is directly correlated with serum potassium concentration. The results of the PAldo studies indicate that potassium chloride deprivation attenuates PAldo increases due to sodium deprivation and that PAldo is maximally stimulated on 150mEq of potassium chloride per day. The rise in PAldo is directly correlated with serum potassium concentration and with PRA. The administration of 300 mEq/day of potassium chloride caused significant hyperkalemia and blunted both PRA and PAldo increases. Our results suggest that potassium chloride has an important role in the regulation of PRA and PAldo, and that only following potassium chloride deprivation is the PRA/PAldo response dissociated.
Abstract: To study the relationship between morphologic changes and alteration of lung function, the excised lobes of 21 smokers and one nonsmoker who required lobectomy for small peripheral tumors were inflated and fixed in formalin, and measurements of bronchiolar narrowing and degree of emphysema were made. All patients had comprehensive pulmonary function tests (including diffusing characteristics, the single-breath N2 test, measurements of elastic recoil, and flow-volume measurements with air and helium) performed before lobectomy. Eight of the lobes excised from the smokers had emphysema of grade 15 or more, the greatest being grade 50. Lobes from 11 patients had evidence of airway narrowing. There were 6 lobes with both emphysema and airway narrowing. Pulmonary function was abnormal in some aspect in all lobes except that from the nonsmoker. Whereas the tests of diffusing capacity, particularly the fractional uptake of CO, correlated with the degree of emphysema, the tests of elastic recoil were not predictive of this early degree of emphysema. The degree of small-airway narrowing correlated with maximal mid-expiratory flow rate and the single-breath N2 test. The maximal flow/static recoil pressure curves were the most sensitive indicators of airway abnormality in the patients with emphysema.
Abstract: Acute acid-base disturbances cause rapid changes in renal ammonia production in the rat. To investigate the regulation of ammonia production in acute acid-base stresses, we examined the effects of such conditions on tissue levels of metabolites such as alpha-ketoglutarate (KG), which inhibits kidney mitochondrial glutamine uptake and deamidation at physiological concentrations. In rats given low (5 mmol/kg) or high (20 mmol/kg) doses of NH4Cl by stomach tube or placed in a 10% CO2 atmosphere, kidney KG levels fell after 1-h by 44, 69, or 73%, respectively. NaHCO3 administration produced no change in KG levels. Renal glutamate and glutamine levels changed little, if at all, in any group, and renal phosphoenolpyruvate levels were not altered except for a decrease in the NH4HCO3 group. In livers of the same rats, treatments produced different patterns of metabolite changes; KG fell only in the NaHCO3 and NH4HCO3 groups. These results support the concept that KG is a specific regulator of renal ammonia production in acute acid-base stresses.
Abstract: We investigated the antihypertensive effect of the angiotensin converting-enzyme inhibitor SQ 14225 in 12 hypertensive patients for periods of three to 24 weeks. Blood pressure decreased in all patients (from 177 +/- 8/110 +/- 2 to 136 +/- 6/88 +/- 2 mm Hg–mean +/- S.E.); oral doses ranged from 400 to 1000 mg daily. Concomitant effects noted were small increases in plasma potassium concentration and pulse rate. One patient experienced a transient febrile reaction. Plasma renin activity rose during treatment, plasma aldosterone decreased, and angiotensin-converting-enzyme activity was virtually eliminated. There was no significant correlation between pretreatment plasma renin activity and degree of blood-pressure fall with SQ 14225. The exact mechanisms contributing to the blood-pressure-lowering effect of this agent remain unclear. SQ 14225 is a promising new antihypertensive agent, effective in patients refractory to traditional medical therapy.
Abstract: The tidal volume-inspiratory duration relationship was studied during air breathing and rebreathing in conscious and anesthetized human subjects using three different intravenous agents. The results observed have been compared with similar experiments carried out in cats. Its has been shown that anesthesia provokes an increase in breathing rate associated with a decrease in tidal volume in human subjects; an opposite effect on breathing rate was observed in cats. Thus, the tidal volume-inspiratory duration relationship, although very similar in the conscious cat or human subject, is very different under anesthesia. The results were quite consistent in a given species whatever the nature of the drug used. It is suggested that modifications of the breathing rate by anesthesia, related to animal species, are caused by central effects of the drug. These effects are probably mediated by different actions on inputs to the inspiratory "off-switch" mechanisms in the two species.
Abstract: To examine the role of basal insulin and glucagon secretion in potassium and sodium homeostasis, somatostatin, a potent inhibitor of insulin and glucagon secretion, was infused for 5 h into healthy human subjects, maturity-onset diabetes, juvenile-onset diabetics, and normal dogs. Infusion of somatostatin resulted in an increase in serum potassium (0.5-0.6 meq/liter) in normal subjects and maturity-onset diabetics, but not in juvenile-onset diabetics despite equivalent reductions in plasma glucagon in all three groups. A similar rise in serum potassium was observed in normal conscious dogs given somatostatin and was reversed by insulin replacement. Urinary excretion of potassium was unaffected by somatostatin. In dogs given intravenous potassium chloride in doses (0.375 meq/kg per h) which do not alter basal insulin levels, the rise in serum potassium (0.6 meq/liter in controls) increased 100% when somatostatin was administered together with the KCl infusion. Addition of replacement doses of insulin to the somatostatin infusion resulted in increments in serum potassium which were comparable to infusion of KCl alone. Urinary potassium excretion rose after KCl administration and was unchanged by the addition of somatostatin. Serum sodium concentration was unaffected by somatostatin administration in both the human and dog studies. However, urinary sodium excretion displayed a biphasic response falling by 20-60% within the first 2 h of somatostatin administration and then rising to values 50-80% above basal levels at 3-4 h. Inulin and p-aminohippurate clearances were unaffected by somatostatin. It is concluded that (a) potassium homeostasis is influenced by basal insulin levels in the absence of which serum potassium concentration rises and potassium tolerance declines; (b) this effect of insulin is mediated via extrarenal mechanisms of potassium disposal; (c) somatostatin has a biphasic effect on urinary sodium secretion, the mechanism of which remains to be established.
Abstract: Over the past 5 years, 107 patients have been evaluated for acute traumatic hemothorax at the University of Kentucky Medical Center. Immediate tube thoracostomy was performed on 90 patients for evacuation of blood and air. Only 2 patients died. Thoracotomy was performed as part of the initial therapy in 9 patients. Thoracotomy for continued hemorrhage from a pulmonary parenchymal injury was required in 3 patients from the entire group. Thoracentesis or observation was the initial therapy for limited hemothorax in 8 stable patients. Three of these patients subsequently required tube thoracostomy 2 to 23 days following injury due to expanding effusions, and 1 patient required multiple thoracotomies for sepsis, fibrothorax, and empyema. These observations indicate that early evacuation of blood by means of a tube thoracostomy is essential to minimize morbidity in acute traumatic hemothorax. If continuing hemorrhage after tube thoracostomy occurs, there is a higher association of injury to additional vital structures.
Abstract: The cardiovascular effects of plasma levels of thiopental necessary for anesthesia were studied using systolic time intervals (STI). In ten healthy patients anesthesia was induced with thiopental, 2-2.5 mg/kg, intravenously, and maintained with an infusion of 1-1.5 mg/kg/min. STI and thiopental plasma levels were measured before induction and when corneal reflex and trapezius muscle response, indicators of anesthetic depth equivalent to response to surgical stimulation, were lost. Significant changes included: an increase in heart rate with induction of anesthesia; a decrease in⅟pre-ejection period2–indexed for heart rate (1/PEP2-I) at loss of corneal reflex; a decrease in systolic blood pressure and 1/PEP2-I at loss of trapezius muscle response. No other variable was significantly different from control. Control values for STI were in the high-normal range, indicating some sympathetic stimulation. With induction of anesthesia these values decreased to a normal range. Free and total plasma levels were 5.4 and 37.6 microgram/ml at loss of corneal reflex; 6.1 and 41.6 microgram/ml at loss of trapezius muscle response. In comparison with other studies, thiopental causes less cardiac depression than inhalational agents at approximately the same anesthetic depth. It is concluded from this study in healthy patients that plasma levels of thiopental producing surgical anesthesia result in minimal cardiac depression as determined by systolic time intervals.
Abstract: Blood-brain and blood-CSF barriers to inulin were compared in 11 vertebrate species. Twenty hours after systemic administration, [14C]inulin penetrated into the central nervous system to an equivalent extent in mudpuppy, salamander (adult and larval), red sculpin, big skate, little skate, southern stingray, and Atlantic stingray with values for RB (dpm/g brain divided by dpm/ml plasma) in the range 0.01- 0.04 and for RCSF (dpm/ml CSF divided by dpm/ml plasma) from 0.02 to 0.04. These values are similar to those reported for mammals. For dogfish, nurse shark, and lemon shark, RB ranged from 0.04 to 0.09 and RCSF from 0.08 to 0.29 and for hagfish RB=0.12, indicating that barrier systems to inulin are poorly developed in sharks and possibly absent in hagfish. Analyses of radiolabeled urea and sucrose penetration into brain and CSF revealed further differences in shark barrier function. Brain barriers to insulin in dogfish and little skate developed with age; in nurse shark there was no detectable change in the inulin ratios over the weight range, 0.2-110 kg.
Abstract: Lower body negative pressure (9-12 kPa) was applied to ten normal subjects. Large increases in plasma arginine vasopression concentration occurred only in subjects that experienced syncopal symptoms and developed hypotension. Blood samples obtained from the superior vena cava at⅟2 min intervals during application of negative pressure showed that maximal plasma vasopressin concentrations occurred with hypotension. Chromatography of the presyncopal plasma on Sephadex G-25 gave a large peak which eluted in the position of synthetic arginine vasopressin.
Abstract: Arterioles and capillaries in the hamster cremaster muscle were observed during electrical stimulation of striated muscle fibers in order to characterize the microcirculatory basis of functional hyperemia. When contraction was restricted to single muscle fibers, responses were variable and frequently transient. Stimulation of either small bundles of muscle fibers or the entire cremaster muscle resulted in reproducible responses typified by: 1) a latency period, 2) an early, often transient phase of dilation, and 3) a second, slower phase of dilation. The latency varied inversely with contraction frequency, and the magnitude of the dilation varied directly with contraction frequency over the range 1–8/s. With stimulation of single fibers and small groups of fibers, arteriolar vasodilation was highly localized to regions of the arterioles that were in close apposition to the stimulated fibers. The number of capillaries with red blood cell flow increased during contraction, and the increase was graded with contraction frequency. The changes observed suggest that the vascular response during functional hyperemia is a two-part process and that the control processes are influenced by contraction frequency.
Abstract: Pulmonary congestion, hemorrhage, and edema, produced in the experimental animal by various methods of disturbing the central nervous system, have led to the concept that such neurogenically-initiated changes are mediated through the autonomic nervous system. Blocking the sympathetic nervous mechanisms prevents these changes. Little is found concerning the expected role of catecholamines. In this study, using a standard model of increasing intracranial pressure (ICP), intense cardiovascular changes, with blood pressure rising above 320 mm Hg and heart rate of 180 beats per minute, were noted. Within seconds, plasma catecholamine levels rose as much as 1200 times the highest normal values for epinephrine, 145 times for norepinephrine, and 35 times for dopamine. These changes occurred only when raised ICP was sustained and spatial compensation of the brain was exceeded. It is not unlikely that these events are related not only to increased ICP, but also to the effects of physical distortion of the brain stem with structural, functional, and vascular alterations within it.
Abstract: To evaluate the effect of acute histamine H2-receptor blockade on renal function, renal function studies were performed in a control state and after cimetidine. Studies included acid excretion in response to acid loading, bicarbonate reabsorption during bicarbonate infusion, and urinary concentrating ability. Cimetidine produced no significant effect on any of these functions. During bicarbonate infusion, inulin clearance remained constant while creatinine clearance fell, possibly because of an effect on tubular creatinine secretion.
Abstract: This study examined the effect of changing hindlimb metabolic rate on hindlimb blood flow control in anesthetized dogs. The hyperemias induced by graded levels of arterial hypoxia and the degree of steady state autoregulation evoked by changes in blood pressure were measured. Metabolic rate was increased above the resting value by direct electrical stimulation of hindlimb muscles at rates from 0.5 to 1.5 pulses/second, and in three dogs was reduced by cooling. In response to 6 minutes of arterial hypoxia, hindlimb blood flow steadily increased. At rest, and at each level of muscle stimulation, the steepness of the response increased as arterial oxygen saturation (SAO2) decreased. At all levels of SAO2, the response was steeper at increasing stimulation rates. For SAO2 greater than 50%, the relationship between the percentage increase in blood flow from control and SAO2, however, was unaffected by the degree of muscle activity, suggesting that during mild to moderate hypoxia the dynamics of the response were similar whether the muscles were at rest or exercising. The responses to severe hypoxia (SAO2 less than 50%) during stimulation were significantly enhanced compared with those at rest. Autoregulation of blood flow was measured in the steady state by comparing the relative change in blood flow from control with the relative change in blood pressure that produced it. Steady state autoregulation was weak at rest, but improved markedly with increasing muscle stimulation. Conversely, cooling the hindlimb depressed the resting steady state autoregulation. A close correlation was found between the degree of autoregulation and the hindlimb metabolic rate. The results suggest that tissue metabolic rate determines the precision of local blood flow control.
Abstract: Calcium and sodium transport were studied in the distal convoluted tubule of the rat by micropuncture and microperfusion techniques. The animals received either control infusions, 0.9% saline at 0.02 ml/min, or chlorothiazide (CTZ), 0.5 mg/min-kg. In free-flow micropuncture, distal calcium reabsorption occurred against an electrochemical gradient; it was 9% of the filtered load in the controls and 13.8% in the CTZ-treated rats. The drug dissociated calcium and sodium transport along the distal tubule. Absolute reabsorptive rates for calcium and sodium, measured in pump perfusion experiments, were proportional to the distal loads. CTZ, acting from the lumen, enhanced net calcium (P less than 0.01) and reduced net sodium (P less than 0.01) reabsorption. In stationary microperfusion experiments, sodium backflux produced rapid establishment of a steady-state concentration of 50 mM. In contrast, net backflux of calcium was negligible. With calcium in the luminal perfusion fluid, there was a concentration-dependent reabsorptive efflux which was not saturated at a luminal calcium concentration of 9.5 mM and which was enhanced by CTZ.
Abstract: Current physiologic knowledge about glucose-insulin homeostasis in liver, brain, pancreas, kidney, peripheral tissues, and central vascular organs has been synthesized to form a whole-system mathematical model of glucose metabolism in normal, ideal man. In addition to data of other workers, results from more than 100 intravenous glucose tolerance tests, including variable dosage, variable duration of infusion, and double pulse studies, were used to determine model structure and parameters. Model and clinical testing have focused particularly on the fast phase of insulin response to vascular glucose. The model incorporates blood circulation and equilibration of substances between vascular and interstitial spaces, and it assumes constant fractional clearance of insulin by liver and kidney. Studies using a double pulse of glucose suggest that the time derivative of glucose level is not the sole or predominant influence on fast phase insulin release, but that preinfusion glucose level and/or previous glucose exposure of the pancreas are also important. Variable dosage glucose studies suggest that the amount of insulin released during the fast phase rather than the insulin release rate is regulated by the glucose level. A two-pool, heterogeneous threshold mechanism for beta cell response to glucose is presented that is compatible with the clinical results.
Abstract: Fifty-six cases with blunt hepatic injuries occurred in 255 laparotomies on patients with multiple injuries. Pre-operatively, one-half of the patients were in profound shock. In these cases hepatic bleeding was often accompanied by bleeding in other sites, usually from a ruptured spleen or into a retroperitoneal haematoma. Diagnosis was aided by laparocentesis and peritoneal lavage. In 3 cases the diagnosis was delayed for 8–12 hours. The lacerations were sutured in 43 cases, a local resection was made in 10 cases and a lobar resection in 3 cases. Manual compression of the liver was the best way of achieving temporary haemostasis. In cases where haemodynamic stability was not achieved post-operatively, immediate re-operation to attain haemostasis was definitely advantageous. The mortality from multiple blunt injuries was high (17%) but especially so in cases with hepatic injury (41%). Liver injuries after blunt trauma can often be managed by suturing, and hepatic resection in seldom necessary.
Abstract: Subcutaneous and perirenal adipose tissue blood flows (ATBF) were measured by the 133Xe washout method before, during and after 4h exercise on a bicycle ergometer. The load corresponded to about 50% of VO2 max (i.e. about 1.7l/min). Subcutaneous and perirenal ATBF increased at an average to 3–400 and 700% of their initial control values respectively. In six of nine measuring sites ATBF remained increased in the hour following work. During work plasma glycerol concentrations increased 8 fold. The core temperature increased 0.9 degree C, skin temperature did not change significantly. During passive elevation of body temperature (core temperature +1.5 degree C; skin temperature +3 degree C) neither subcutaneous ATBF nor plasma glycerol concentrations changed significantly. It is concluded that the increase in subcutaneous ATBF during exercise is not a reaction to increased body temperature.
Abstract: The importance of autonomic nervous activity for the pancreatic hormonal response to exercise in man was studied. 7 men ran at 58% of V(O2)max (determined without administration of drugs) to exhaustion during alpha-adrenergic blockade with phentolamine (P), during parasympathetic blockade with atropine (A), or without drugs (C). At rest phentolamine increased the plasma concentrations of both insulin and norepinephrine. During exercise norepinephrine concentrations increased and were in P experiments 3 times the concentrations in C experiments. Insulin always declined during exercise but in P experiments never decreased below basal levels. At identical times neither glucagon nor glucose differed significantly in the different expts. Thus during exercise alpha-adrenergic blockade increased insulin concentrations but did not diminish the glucagon response. Nor was this response increased when beta-receptor stimulation in P experiments was intensified by the particularly high catecholamine concentrations. The concentrations of FFA, glycerol and lactate were highest in P experiments and identical in A and C experiments. These findings indicate that during prolonged moderate exercise in man insulin secretion is depressed by stimulation of alpha-adrenergic receptors whereas glucagon secretion is not influenced by adrenergic receptors. Stimulation of beta-adrenergic receptors enhances lipolysis but neither lipolysis nor pancreatic hormonal secretion is influenced by cholinergic activity during exercise.
Abstract: Furosemide was administered intravenously to 5 healthy volunteers and 15 patients with various degrees of renal failure. Two patients were given the drug orally. The plasma half-life of furosemide averaged 0.79 hr in the healthy subjects. Although most patients with kidney disease had a prolonged half-life (t1/2), up to 24.58 hr, some with advanced renal failure had an almost normal t1/2. The plasma clearance of furosemide, which in the normal subjects averaged 194 ml/min, decreased proportionally with decreasing creatinine clearance, as did the renal clearance, which in the healthy subjects averaged 95 ml/min. There was no correlation between kidney function and the apparent volume of distribution or of nonrenal clearance. One patient was given 35S-labeled furosemide intravenously. Although the furosemide plasma t1/2 was essentially normal, the elimination rate of metabolites was decreased. Unlike that of healthy subjects, the main route of excretion of label was in the feces.
Abstract: Experiments were carried out on 42 Munich-Wistar rats with surface glomeruli accessible to micropuncture to investigate the effects of reduction in systemic plasma protein concentration. CA, and thus afferent oncotic pressure, IIA, on the determinants of glomerular ultrafiltration. In animals in which CA was reduced by a variety of maneuvers, observed values for single-nephron GFR were lower than values predicted by the Starling relation, when the latter were calculated assuming that the observed increase in the net driving pressure for ultrafiltration (due to the reduction in IIA) was the only factor perturbed. In all experimental conditions where CA was reduced, rats were invariably observed to be at filtration pressure disequilibrium, permitting calculation of unique values of the ultrafiltration coefficient, Kt. In all low-CA groups, mean values of Kf were uniformly lower than values obtainedin normoproteinemic control animals. The failure of SNGFR to rise to predicted values when CA is reduced is therefore due to the concomitant reduction in Kf. No morphological basis for this reduction in Kf was discerned.
Abstract: Thyroid hormone formation requires the coincident presence of peroxidase, H2O2, iodide, and acceptor protein at one anatomic locus in the cell. The peroxidase enzyme appears to be a protoporphyrin lX containing heme protein, with binding sites for both iodide and tyrosine. It is probable that both iodide and tyrosine are oxidized to free radical forms which unite to form iodotyrosine. The peroxidase is also involved through an uncertain mechanism in iodotyrosine coupling and probably in oxidation of sulfhydryl bonds in thyroglobulin. H2O2 may be supplied by microsomal NADPH-cytochrome c reductase or NADH-cytochrome b5 reductase. Other possible intracellular H2OI generating systems include monoamine oxidase and xanthine oxidase. The usual acceptor for iodide is thyroglobulin, which is currently believed to be iodinated within apical secretory vesicles at the cell border just prior to liberation into the colloid, or possibly after liberation into the colloid. Other soluble an insoluble proteins are also iodinated within the gland. The peroxidase is present in numerous cellular structures, but iodination activity occurs primarily, if not only, at the apical cell border. The controls of iodination are imperfectly known. Thyrotrophin modulation of iodide uptake, H2O2 generation, thyroglobulin synthesis, and peroxidase enzyme level obviously are the main regulations. Many of these actions are thought to involve mediation of adenyl cyclase and subsequent activation of intracellular phosphokinases. Antithyroid drugs of the thiocarbamide group are competitive inhibitors of iodination under some circumstances, but if much iodide is present, they react with the oxidized iodine intermediate and are irreversibly inactivated themselves. Clinical problems involving defective peroxidase function are among the most frequent hereditary defects of thyroid hormone formation. Recognized abnormalities include deficient peroxidase, abnormality in binding of the peroxidase apoprotein to its prosthetic group, and other less well-identified abnormalities in peroxidase structure and function. Peroxidase is typically elevated in thyroid tissue from patients with hyperthyroidism sometimes deficient in cold thyroid nodules, and frequently diminished in tissue from patients with Hashimoto’s thyroiditis.
Abstract: Described here is a patient who had an islet cell carcinoma containing both glucagon (glucagonoma) and insulin (insulinoma). Complete removal of the tumor was possible. Immunoreactive glucagon (IRG) could be extracted from all parts of the tumor (approximately 50 mug./gm.) and was shown to be fully bioactive. Immunoreactive insulin (IRI) could be extracted only from one section of the tumor (approximately 30 mug./gm.). The clinical and biochemical manifestations of the disease were dermatitis, diabetes, weight loss, anemia, hypoaminoacidemia, and hyperketonemia. The diabetes was characterized by low or normal fasting blood glucose concentrations and by impaired glucose tolerance (Kg = 0.4). After complete removal of the tumor, the dermatitis cleared, the catabolic state changed into an anabolic state, blood amino acid concentrations increased, and blood ketone-body concentrations decreased. Fasting blood glucose concentrations, however, rose above 200 mg./dl., and glucose tolerance declined further (Kg = 0.15). Hourly blood sampling for 24 hours, intravenous and oral glucose tolerance tests, intravenous arginine and tolbutamide tolerance tests with serial determinations of IRG, IRI, and blood glucose were performed preoperatively and again two weeks and two months postoperatively. The results of these studies demonstrated marked abnormalities in the stimulation and suppression of glucagon and insulin release. In addition, they failed to demonstrate a glycemic effect on the chronically elevated glucagon concentrations in this patient, while identifying insulin as the dominant factor determining blood glucose homeostasis.
Abstract: In three groups of normal subjects and in one group of patients with latent diabetes mellitus a study has been made of the effects of chlorpromazine (CPZ) on blood glucose and plasma insulin. CPZ 75 mg/day for 7 days did not alter the plasma insulin response after oral glucose; nor did CPZ 50 mg/day for 7 days affect the glucose assimilation rate or insulin response to glucose injection. Infusion of CPZ 50 mg in 60 min slightly increased the basal blood glucose level but had no significant effect on basal plasma insulin. The insulin/glucose ratio after the end of the infusion was significantly higher than during the period of infusion of the drug. In latent diabetic patients CPZ infusion significantly diminished the insulin/glucose ratio during an intravenous glucose tolerance test. These results suggest that, whereas prolonged treatment with low doses of CPZ did not modify glucose tolerance and glucose-stimulated pancreatic response, higher acute doses of the drug may induce hyperglycaemia and can inhibit insulin secretion both in normal man and in patients with latent diabetes mellitus.
Abstract: The influence of changes in blood volume distribution on the carotid baroreflex was studied in 18 subjects. Blood volume distribution was changed by varying the pressure around the lower body above and below ambient, thereby varying the amount of blood pooled in this region and exerting a secondary influence on the central blood volume. The carotid arterial stretch receptors were stimulated by varying the pressure in air-tight box enclosing the neck. To obtain a standardized carotid sinus stimulus (SCS) the pressure in the box was varied sinusoidally between - 10 and - 40 mmHg with a fixed freqency of 0.03 Hz. The effects on heart rate and blood pressure were assessed by harmonic analysis performed off-line on a digital computer. During lower body negative pressure of -40 mmHg (LBNP -40), i.e. during a procedure known to reduce the central blood volume, SCS induced an augmented effect on the blood pressure regulating capacity but not on the heart rate response. Expressing the blood pressure regulating capacity as peak-to-peak changes in systolic arterial pressure, the response during LBNP -40 mmHg was almost twice the control value. The opposite stimulus-lower body postive pressure-influenced the SCS-induced effects only slightly but on the average a minor reduction in both blood pressure and heart rate regulating capacity was found compared with the control condition, though the difference did not reach significant levels. The results support the hypothesis that changes in blood volume distribution modify the function of the carotid baroreflex, possibly via intrathoracic receptors sensitive to changes in central blood volume and/or central venous pressure.
Abstract: In 8 healthy subjects the pressure around the lower body was changed to 40 mmHg above (LBPP) and below (LBNP) atmospheric, thereby altering the amount of blood pooled in the lower body. Heart rate, intraarterial blood pressure, central venous pressure, cardiac output (dye dilution technique) and forearm blood flow (venous occlusion plethysmography) were measured. Plasma renin activity was determined with a radioimmunological method. 6 subjects maintained a relative circulatory steady state during LBNP. LBNP caused significant decrease in central venous pressure (CVP), stroke volume and cardiac output (Q) with an unchanged mean arterial pressure (MAP). Heart rate (HR) increased significantly. Calculated total peripheral vascular resistance (TPVR) and regional vascular resistance (RVR) in the forearm were significantly increased when measured 5-9 min after the onset of LBNP, whereas plasma renin activity (PRA) showed a definite increase only after 19 min of LBNP stimulation. No correlation was found between the changes in PRA and TPVR or RVR. Increasing the pressure around the lower body (LBPP) resulted in a slight but significant increase in MAP as well as a significant but transient increase in CVP. No significant changes were found in HR, Q or TPVR. In the forearm a decrease in RVR was demonstrated. PRA was not significantly changed. The results demonstrate that peripheral vascular resistance and PRA are both influenced by changes in blood volume distribution, possibly elicited via intrathoracic receptors sensitive to changes in central blood volume and/or CVP. The results also suggest that PRA does not play any significant part in the vasoconstriction during LBNP stimulation.
Abstract: Large stores of intramuscular substrates are found in the different fiber types of human skeletal muscle, and with prolonged exercise both glycogen and triglyceride stores are utilized. The contribution from intramuscular glycogen stores is greatest at higher work intensities while triglyceride stores are utilized at moderate intensities. In man all fiber types have a similar glycogen content whereas the highest lipid content is found in the more oxidative fibers. The muscle metabolism is well adapted to the supply of substrate as well as to the demand for energy. Among several regulatory mechanisms, changes in citrate concentration seems to be an important factor in the interplay between carbohydrate and lipid metabolism.
Abstract: The purpose of this study was to characterize the response of the human left ventricle to lower body negative pressure (LBNP) and to delineate the relation between left ventricular function and hemodynamic response. Ventricular function curves relating stroke volume to end-diastolic volum were obtained in 12 normal men. Volume data were derived from echocardiographic measurements of left ventricular end-systolic and end-diastolic diameters at rest and during LBNP at -40 mm Hg. End-diastolic volume decreased by 19% (p less than 0.01) and stroke volume by 22% (p less than 0.05). There were no significant changes in heart rate, arterial blood pressure, or end-systolic volume. Thus, moderate levels of LBNP significantly reduce preload and stroke volume, i.e. produce a Starling effect, without affecting contractile state. The absence of significant changes in heart rate and arterial blood pressure in the presence of a significant reduction in stroke volume is consistent with an increase in systemic peripheral resistance medicated by low-pressure baroreceptors.
Abstract: Plasma adrenaline, noradrenaline, and dopamine concentrations and plasma renin activity were measured in the supine position and after standing for 10 minutes in 14 patients with sustained benign essential hypertension and in five patients with labile hypertension. Results were compared with values obtained in 11 normotensive control subjects. In controls plasma noradrenaline concentrations increased with age, while plasma adrenaline values tended to decrease with age. No significant difference in mean plasma noradrenaline was found between hypertensive and control subjects, but plasma noradrenaline seemed slightly increased in a proportion of hypertensive patients aged less than 50. Plasma adrenaline was considerably raised in both supine and standing positions in eight patients with sustained hypertension and in two with labile hypertension. Dopamine concentrations and plasma renin activity were similar in all groups studied. The finding of significantly raised plasma adrenaline concentrations in a large proportion of hypertensive patients supports the hypothesis that the activity of the sympathetic nervous system is increased in essential hypertension. Measurement of plasma adrenaline seems to be a more sensitive index of this activity than that of plasma noradrenaline.
Abstract: A case of lactic acidosis presented the opportunity for review of the association between lactic acidosis and ketoacidosis. The diagnosis of lactic acidosis or the combination of lactic acidosis and ketoacidosis is established clinically by the detection of a metabolic acidosis of the "unmeasured anion gap" type in the absence of significant renal failure, poison intake or a strongly positive clinical test for ketones. Before treatment can be planned the biochemical basis of lactic acidosis and ketoacidosis must be understood – especially the fact that lactic acidosis is not a single disease entity but has many possible causes. Among important considerations is the relation between the blood concentrations of bicarbonate and organic acid anions. After recovery from metabolic acidosis of the unmeasured anion gap type, metabolic alkalosis is common. Decreased bicarbonate excretion plays an important role in the pathogenesis of the latter and may be the result of potassium or chloride loss, or both. The deficits, if present, should be corrected with appropriate therapy.
Abstract: In a canine preparation designed to separate myocardial from peripheral cardiovascular effects of the drug. It was found that thiopentone produced minimal depression of the heart. Only in much greater concentrations was significant depression found. It is concluded that the cardiovascular effects of thiopentone i.v. are not a direct effect on the heart.
Abstract: 1. Intracellular pH (pH(i)) of surface fibres of the mouse soleus muscle was measured in vitro by recessed-tip pH-sensitive micro-electrodes. pH(i) was displaced in an acid direction by removal of external (NH(4))(2)SO(4) after a short exposure, and the mechanism of recovery from this acidification was investigated.2. Removal of external K caused a very slow acidification (probably due to the decreasing Na gradient) but had no effect on the rate of pH(i) recovery following acidification. This indicates that K⊕-H⊕ exchange is not involved in the pH(i) regulating system.3. Short applications of 10(-4)M ouabain had no obvious effect on pH(i) and did not alter the rate of pH(i) recovery following acidification. This suggests that there is no direct connexion between the regulation of pH(i) and the Na pump.4. Reduction of external Ca from 10 to 1 mM caused a transient fall in pH(i), but the rate of pH(i) recovery following acidification was unaffected. This suggests that Ca(2+)-H⊕ exchange is not involved in the pH(i) regulating system.5. An 11% reduction in external Na caused a significant slowing of pH(i) recovery following acidification. 90% or complete removal of external Na almost stopped pH(i) recovery. This suggests that Na⊕-H⊕ exchange is involved in pH(i) regulation.6. Amiloride (10(-4)M) reversibly reduced the rate of pH(i) recovery to much the same extent as removal of external Na. Its effect was not additive to that of removal of external Na.7. Internal Na ion concentration ([Na⊕](i)), measured using Na⊕-sensitive micro-electrodes, fell on application of (NH(4))(2)SO(4) and increased on its removal. The increase transiently raised [Na⊕](i) above the level recorded before (NH(4))(2)SO(4) application. This overshoot of [Na⊕](i) was almost completely inhibited by amiloride. This is consistent with the involvement of Na⊕-H⊕ exchange in the pH(i) regulating system.8. Removal of external CO(2) or application of SITS (10(-4)M) caused some slowing of the rate of pH(i) recovery following acidification by removal of (NH(4))(2)SO(4). The effect of SITS was additive to that of Na-free Ringer or amiloride. These results suggest that Cl⊖-HCO(3) ⊖ exchange is also involved in the pH(i) regulating system and that it is a separate mechanism. Under the conditions used, Cl⊖-HCO(3) ⊖ exchange formed about 20% of the pH(i) regulating system.9. Decreasing the temperature from 37 to 28 degrees C not only caused an increase in pH(i), but also considerably slowed the rate of pH(i) recovery following acidification. We have calculated a Q(10) for Na⊕-H⊕ exchange of 1.4 and for Cl⊖-HCO(3) ⊖ exchange, 6.9.10. We conclude that the pH(i) regulating system is comprised of two separate ionic exchange mechanisms. The major mechanism is Na⊕-H⊕ exchange, which is probably driven by the transmembrane Na gradient. The other mechanism is Cl⊖-HCO(3) ⊖ exchange, which probably requires metabolic energy.
Abstract: With a two-compartment model, a method is described for quantitative determination of peritoneal drainage rates in malignant ascites. Data on twenty-four patients are presented and comparison is made with the qualitative assessment of the integrity of diaphragmatic and mediastinal lymphatics on the basis of lymphoscintigrams. It is concluded that flow rates less than 50 ml/hour are usually associated with abnormalities of the diaphragmatic and mediastinal lymphatics, indicating that tumor permeation of these structures is a significant contributing factor to persistent, intractable ascites in patients with malignant diseases.
Abstract: To study the determinants of carbon monoxide (CO) induced hyperpnea simultaneous measurements were made of carboxyhemoglobin level in arterial blood (HbCO), ventilation (VE), cerebral blood flow (CBF), O2 delivery to the brain (CBF X O2 content of arterial blood), O2 consumption of the brain (CMRO2), and O2 tension in cerebral venous blood (PVO2) during inhalation of 1% CO in 40% O2 by six unanesthetized goats. HbCO increased to 65% in 10 min; VE remained constant until a HbCO level of approximately 50% was reached and then increased abruptly; CBF increased progressively; O2 delivery to the brain and CMRO2 decreased somewhat with CO inhalation; these decreases reached statistical significance at a HbCO level of 30-40% whereupon the rate of decline with respect to HbCO level increased substantially; and PVO2 decreased progressively from an average of from 31 to 14.6 Torr and averaged 19.2 Torr when hyperpnea was manifest. When considered in the light of previous studies which indicate that CO-induced hyperpnea is not caused by stimulation of the carotid bodies, these data suggest that this phenomenon is related to brain hypoxia. Calculations of brain tissue O2 tension with the Krogh equation support this contention.
Abstract: Serum stimulates the production of prostaglandins by transformed mouse fibroblasts. Hydrocortisone (cortisol) inhibits this stimulation. The half-maximal inhibition occurs at 6x10-9 M. Studies with cells labeled with [3H]arachidonic acid in their lipids show that the stimulation by serum results in the release of arachidonic acid from the cellular lipids, mostly phospholipids. Hydrocortisone inhibits this release but does not inhibit the production of prostaglandins from exogenously supplied arachidonic acid. This inhibition of arachidonic acid release from phospholipids may be the mechanism for the anti-inflammatory action of corticosteroids.
Abstract: Sodium L⊕-lactate was infused at rates of 5 to 12 mmol/min intravenously for 30 min in health volunteers, and the exchange of lactate, glucose, and free fatty acids (FFA) was measured in the leg, the forearm muscle, and the splanchnic region. Arterial lactate levels were 3 to 5 mmol/l during the infusion. Leg blood flow increased about 2.5-fold and leg oxygen uptake rose by 35%. Blood flow, oxygen uptake, and glucose production in the splanchnic area remained unaltered. The fractional uptake of lactate by the leg, the splanchnic region, and the forearm decreased during the course of the infusion.
Abstract: pH and bicarbonate affect many metabolic reactions but each may change independently. To study bicarbonate’s effect onplasma potassium, blood bicarbonate in normal, hypokalemic or hyperkalemic rats was either maintained constant, lowered by hydrochloric acid or raised by sodium bicarbonate administraion. Blood pH was maintained constant by changing PCO2. In normokalemia lowering bicarbonate increased plasma potassium 2.0mEq above values obtained in the other groups. To eliminate urinary potassium losses, experiments were also performed in rats with bilateral ureteral ligation. Again, plasma potassium concentration rose significantly more in the lowered bicarbonate group. Similarly, in hypokalemia, plasma potassium rose 1.2 and 0.4mEq in the lowered and unchanged groups, but fell 0.2mEq/liter in the elevated group. Differences could not be ascribed to renal potassium losses as potassium excretion was essentially zero in each group. In hyperkalemia, plasma potassium concentration remained elevated for 150 min in the lowered bicarbonate group but fell 1.3 and 2.0mEq in the unchanged and elevated groups, respectively. Urinary potassium losses in the three groups were statistically identical. In all experiments blood pH was maintained unchanged during the experiment. The data show that bicarbonate, independent of blood pH, alters transcellular potassium distribution suggesting the usefulness of bicarbonate therapy in hyperkalemia even at a compensated blood pH.
Abstract: Studies are reviewed in which the roles of insulin and glucagon in normal physiology and in diabetes are examined. In normal man, glucose ingestion is accompanied by a rise in insulin and fall in glucagon and is primarily disposed of in the liver, an organ sensitive to both hormones. However, infusions of glucagon in physiologic amounts indicate that insulin secretion rather than glucagon inhibition is the primary factor determining glucose disposal. Furthermore, minor elevations in blood glucose elicit increments in insulin concentration and inhibition of hepatic glucose output in the absence of changes in plasma glucagon. The primary physiologic role of glucagon is to prevent the hypoglycemia that would otherwise accompany noncarbohydrate (protein)-mediated insulin secretion. In diabetic as well as normal patients the stimulatory effect of glucagon on hepatic glucose production is evanescent. Increases in glucagon or changes in the I/G ratio can bring about deterioration in glucose tolerance or in diabetic control only so long as absolute insulin deficiency is present or pharmacologic elevations in glucagon are produced. After somatostatin administration, prolonged hypoinsulinemia in normal subjects is observed to result in fasting hyperglycemia in the absence of basal glucagon secretion. In diabetic patients the improvement in postprandial hyperglycemia produced by somatostatin can be accounted for by its inhibitory action on carbohydrate absorption in the gastrointestinal tract. It is concluded that insulin deficiency is the primary pathophysiologic disturbance in diabetes. While glocagon may worsen the consequences of insulin lack, it is neither sufficient nor necessary for the development of diabetes.
Abstract: Children with lipoid nephrosis were studies during clinical relapse and after complete remission. As expected, the calculated serum oncotic pressure was reduced severely from the remission value of 28.6 +/- 0.9 mm Hg to 15.4 +/- 1.1 (P less than 0.005) during relapse. Although no apparent change in plasma volume was noted using the volume of distribution of labeled human albumin, calculated plasma volume was reduced 13 +/- 8% during relapse when estimated from changes in hematocrit. After a water load, the ability to excrete water was markedly blunted during relapse. The clearance of solute-free water (CH2O) was 0.9 +/- 0.8 ml/min during relapse, compared with 3.6 +/- 0.6 ml/min during remission (P less than 0.005). In addition, there was a reduced maximal urinary concentrating ability during relapse in four of the six patients examined. Mean urine osmolality for the group during relapse was 778 +/- 82 mOsm/kgH2O and 991 +/- 71 during remission (P less than 0.05). The demonstrated alteration in nephron function during relapse of nephrotic syndrome could result from either (1) a decrease in the amount of sodium delivered to the ascending limb of the loop of Henle because of increased proximal reabsorption or (2) a change in the intrinsic characteristics for sodium reabsorption in that segment. Although this observation does not prove that proximal reabsorption is increased, it suggests a common underlying mechanism for altered nephron function in all of the major edema-forming conditions.
Abstract: The suppressive effect of insulin on hepatic glucose production is generally recognized. Though it is well established that this effect is at least partially due to inhibition of glycogenolysis, controversy still exists about insulin’s effect on gluconeogenesis. The present study was undertaken to determine whether insulin could affect gluconeogenesis from alanine in the intact dog and to compare the effect of insulin on glycogenolysis and gluconeogenesis. In anesthetized dogs fasted overnight, blood samples were drawn simultaneously from a femoral artery and hepatic vein. Alanine-U-14C, 10 mu Ci./kg., was infused over 110 minutes. A constant insulin infusion at either 1 or 5 mU./kg./min. was begun at 50 minutes, and blood glucose concentration was maintained by a variable glucose infusion. When insulin was infused at 1 mU./kg./min., resulting in plasma immunoreactive insulin (IRI) levels of 73 +/- 10 muU./ml., the net splanchnic glucose production (NSGP) was suppressed from 2.7 +/- 2 mg./kg./min. to virtually zero. In constrast, this small increment in insulin concentration had no demonstrable effect on the net splanchnic uptake of alanine or on the conversion of plasma alanine to glucose (7.9 +/- 0.3 mu mol/min.). Insulin infused at 5 mU./kg./min. resulted in IRI levels of 240 +/- 25 muU./ml. This higher insulin concentration was associated with a marked suppression of both the NSGP (100 per cent) and the conversion of plasma alanine to glucose (90 per cent) but did not affect the extraction of alanine by the splanchnic bed. Doses of both 1 and 5 mU./kg./min. were associated with a 35 per cent fall in immunoreactive glucagon levels. These data demonstrate that (1) glycogenolysis is more sensitive than gluconeogenesis to the inhibitory effect of small increments in insulin concentrations, (2) gluconeogenesis could be suppressed by insulin but only at higher insulin concentrations, (3) this suppression of gluconeogenesis from alanine by insulin was due to an intrahepatic effect rather than an effect on the splanchnic extraction of alanine, and finally, (4) that insulin can suppress glucagon in the absence of hyperglycemia.
Abstract: The possibility that an alteration of the vasopressin-dependent cyclic AMP system plays a pathogenic role in the urinary concentrating defect in K+ depletion was investigated in the rat. The antidiuretic response to vasopressin was significantly less in K+-depleted rats. In these K+-depleted rats, the increase in urinary cyclic AMP excretion in response to vasopressin was also significantly less. However, repletion of K+ for 1 wk by feeding high-K+ diets restored the ability to increase urinary cyclic AMP excretion in response to vasopressin. In the in vitro incubation of renal medullary slices, the increase in cyclic AMP concentration in response to vasopressin was also significantly less in the slices obtained from K+-depleted rats than in those obtained from control rats. These findings suggest that, in K+ depletion, there is a reversible impairment of the vasopressin-dependent cyclic AMP system in the renal medulla; this impairment may play a pathogenic role in the urinary concentrating defect in K+ depletion.
Abstract: While 3, 3’, 5’-triiodothyronine (reverse T3, rT3) has been detected both in human serum and in thyroglobulin, no quantitative assessment of its metabolic clearance rate (MCR), production rate (PR), or secretion by the thyroid is yet available. This study examines this information in euthyroid subjects and evaluates it in light of similar information about two other iodothyronines in the thyroid: 3, 5, 3’-triiodothyronine (T3) and thyroxine (T4). Thus, it was noted that rT3 is cleared from human serum at a much faster rate than are T3 and T4; the mean (+/-SE) MCR of rT3 was 76.7+/-5.4 liters/day in 10 subjects, whereas MCR-T3 and MCR-T4 in 8 of them were 26.0+/-2.2 liters/day and 1.02+/-0.06 liters/day, respectively. Therefore, even though the mean serum concentration of rT3, 48+/-2.8 ng/100 ml, was much lower than that (128+/-6.7 ng/100 ml) of T3, the mean PR-rT3 (36.5+/-2.8 mug/day) and the mean PR-T3 (33.5+/-3.7 mug/day) were similar; in comparison, the mean serum concentration and PR of T4 were 8.6+/-0.5 mug/100 ml and 87.0+/-3.9 mug/day, respecitvely. These data and those on the relative proportion of rT3, T3, and T4 in 10 thyroid glands were used to assess the significance of the contribution of thyroidal secretion to PR-rT3 and PR-T3. It was estimated that whereas thyroidal secretion may account for about 23.8% of serum T3 (or PR-T3), it may account for only about 2.5% of serum rT3 (or PR-rT3). Since peripheral metabolism of T4 is the only known source of rT3 and T3 other than the thyroidal secretion, it could be calculated that as much as 73.0 mug or 84% of daily PR-T4 may normally be metabolized by monodeiodination either to T3 or to rT3. MCR and PR of various iodothyronines were also examined in five cases with hepatic cirrhosis, where, as documented previously, serum rT3 may be elevated while serum T3 is diminished. The mean MCR-rT3 in these cases (41.0 liters/day) was clearly (P is less than 0.005) less than that (76.7 liters/day) in normal subjects. This was the case at a time when the mean MCR-T3 (26.7 liters/day) and the mean MCR-T4 (1.19 liters/day) did not differ from those (vide supra) in normal subjects. Distinct from changes in MCRs, the mean PR-rT3 (33.0 mug/day) was similar to, and the mean PR-T3 (10.1 mug/day) and the mean PR-T4 (66.4 mug/day) were much less than, the corresponding value in normal subjects. Furthermore, while the ratio of PR-rT3 and PR-T4 (rT3/T4) in individual patients was either supranormal or normal, the ratio of PR-T3 and PR-T4 (T3/T4) was clearly subnormal. The various data suggest that: (a) just as in the case of T3, the thyroid gland is a relatively minor source of rT3; peripheral metabolism of T4 is apparently its major source; (b) the bulk of T4 metabolized daily is monodeiodinated to T3 or to rT3; (c) monodeiodination may be an obligatory step in metabolism of T4; (d) monodeiodination of T4 to rT3 is maintained normal or is increased in hepatic cirrhosis at a time when monodeiodination of T4 to T3 is decreased.
Abstract: Blood perfusing isolated dog gracilis muscles was equilibrated with CO2 tensions ranging from 30 to 120 mm Hg, resulting in venous P CO2 from 35 to 135 mm Hg. Extracellular pH values ranged from 6.96 to 7.41, and muscle cell pH, calculated from DMO distribution, ranged from 6.64 to 6.94. When intracellular pH was plotted as a function of the corresponding extracellular pH, a linear relationship (r = 0.92) was observed throughout the entire pH range. The slope deltapHi/deltapHe was 0.64, without evidence of a difference in slope at different pH values. These results do not support the previous observations in rat diaphragms that cell pH is not affected by PCO2 changes over a certain extracellular pH range. pHe was 0.64, without evidence of a difference in slope at different pH values. Theses results do not support the previous observations in rat diaphragms that cell pH is not affected by PCO2 changes over a certain extracellular pH range.
Abstract: The effect of increased plasma oncotic pressure on renal blood flow (RBF), glomerular filtration rate (GFR), electrolyte excretion, and renin secretion rate (RSR) was studied in dogs anesthetized with sodium pentobarbital. Renal artery infusions of hyperoncotic dextran or human serum albumin raised renal venous colloid osmotic pressure an average of 7.3 and 10.1 mmHg, respectively, and caused small but consistent increases in RBF, large increases in RSR, marked decreases in urine flow rate and electrolyte excretion, with either no change or small decreases in GFR, and no change in renal artery pressure. Renal vasodilation was confined primarily to afferent arterioles and was not measureable until approximately 45 s after the start of infusions. The renal responses to increased plasma oncotic pressure appeared to be an autoregulatory phenomenon, consistent with a tubular mechanism dependent on an altered distal tubular fluid flow and/or composition. The increased renin release during increased plasma oncotic pressure is not compatible with a renal baroreceptor mechanism that responds to decreases in afferent arteriolar pressure because calculated glomerular pressure increased during albumin and dextran infusions.
Abstract: Hemodynamic and blood-gas variables were studied before and after pentolinium tartrate administration in six patients anesthetized with nitrous oxide-halothane and maintained at PaCO2 35-40 torr. Measurements were made prior to induction of anesthesia; before and 10, 20, and 60 minutes after administration of pentolinium (0.3 mg/kg); 15 minutes after return of arterial blood pressure to control values. Mean arterial blood pressure (MAP) was significantly decreased at 20 (P less than 0.02) and 60 (P less than 0.001) minutes, in association with significant decreases in systemic vascular resistance (SVR) (P less than 0.05 and P less than 0.005). At 60 minutes MAP was significantly lower than that at 10 minutes (P less than 0.01). Cardiac output (CO) was increased (P less than 0.05) after 10 minutes secondary to a significant increase in heart rate. Neither variable changes significantly thereafter. CO and HR were significantly lower (P less than 0.01) 60 minutes after pentolinium than at 10 minutes; both returned to 10-minute values after intravenous administration of atropine. Changes in stroke volume (SV) and mean right atrial pressure (MRAP) were not significant. Whole-body O2 uptake (VO2) was not significantly altered by pentolinium. However, a substantial diminution of myocardial O2 consumption (MVO2) was deduced from a significant decrease in the heart rate-arterial systolic pressure produce (HR X ASP). Fifteen minutes after return of MAP to control levels, SVR was 11.5 per cent lower, while CO was still significantly higher (P less than 0.02) than control values. Following ganglionic blockade with pentolinium during halothane-N2O anesthesia, HR is a valuable index of changes in CO, while the HR X ASP index may be utilized to evaluate changes in MVO2. Assessment of myocardial performance during controlled hypotension is possible by the use of routinely available measurements.
Abstract: The substitution of the 4-glutamine of oxytocin by a lipophilic aliphatic amino acid leucine yields [4-Leu] oxytocin which possesses natriuretic-diuretic anti-arginine-vasopressin (anti-ADH) activities. Alkyl substitutions of the beta-carbon of the 1 half-cystine of oxytocin yield a series of antioxytocin analogs which inhibit the uterotonic response to oxytocin. In this paper, the results of our further investigations on the molecular requirements for natriuretic, anti-ADH and antioxytocic activities of these peptides are reported. A total of 12 analogs of oxytocin and lysine-vasopressin (LVP) with leucine and/or beta-carbon alkyl substitutions were studied. Our findings reveal that the effect of 4-leucine substitution may not be to enhance the natriuretic activity but rather to abolish the antidiuretic activity of oxytocin. The lack of antidiuretic activity of these 4-leucine analogs makes it possible to unmask the intrinsic natriuretic activity of these peptides at the high dose level. Structure-activity correlations suggest that the oxytocin molecule may be the optimal requirement for natriuretic activity of these peptides. Substitution of 4-glutamine by lipophilic aromatic phenylalanine yields [4-Phe] oxytocin which possesses anti-ADH activity with little or no natriuretic activity. The "hybrid" antioxytocin and anti-ADH molecules, beta-carbon alkyl and 4-leucine substituted analogs did not possess enhanced antihormone activity. Although they had antioxytocic and antipressor activities, they were less potent than their respective singly alkyl substituted analogs. Furthermore, they had no demonstrable anti-ADH activity. The single alkyl substituted oxytocin and LVP also had no anti-ADH activity. It therefore appears that beta-carbon alkyl substitution had different effects on activities depending on the morphological features and the functions of the target cell. In target cells of contractile smooth muscles (uterus and vascular), the alkyl substituted analogs had no intrinsic activity but retained a relatively high receptor affinity to become effective antagonists to the natural hormone. On the other hand, in target cells of the renal tubule which are noncontractile epithelial cells, both intrinsic activity and receptor affinity were reduced or abolished. Thus none of these alkyl substituted analogs possessed more than very slight antidiuretic activity, and none had any natriuretic or anti-ADH activity.
Abstract: A clinical and investigative study is reported of 19 patients with ’idiopathic oedema of women’. The resons for defining this as a specific syndrome unrelated to the menstrual cycle are given, and the clinical features reviewed. During a forced water diuresis the flow and composition of the urine and the plasma volume were studied on tilting from the supine to the upright position seven premenopausal and four postmenopausal patients with this disorder. No differences were found in the results obtained in the follicular and luteal phases of the menstrual cycle or in the pre- and post-menopausal patients. The reductions in urinary volume and electrolyte excretion on upright tilting were greater than those observed under similar circumstances during the luteal phase of the menstrual cycle in normal female controls, and attributed to increased proximal renal tubular reabsorption. The rate of loss of isotopically labelled albumin from the intravascular compartment was greater in patients with idiopathic oedema than in control subjects. A reduction in blood volume on tilting occurred in control subjects and patients with idiopathic oedema, but was greater in the latter; and the larger the fall, the greater were the reductions in urinary flow and electrolyte excretion. The effect of administering 9-alpha-fluorohydrocortisone was studied in nine patients with idiopathic oedema. One patient failed to ’escape’ from the sodium-retaining action of this mineralocorticoid and developed pulmonary oedema; the others ’escaped’ normally. The pathophysiological disturbance in this condition is related to increased loss of fluid from the vascular compartment but the precise aetiological mechanism remains unknown.
Abstract: Underfed rats infused intravenously with a glucose-amino acid solution at the rate of 390 kcal/kg/day developed a syndrome of muscular weakness, neuropathy, lethargy and precoma or coma associated with severe hypophosphatemia. The movement of phosphate into the cells was studied to determine where it went and into which organic compounds it was incorporated. All but 8% of the labeled phosphate was found in liver, muscle, bone, and carcass residue. Liver cells took up as much phosphate as bone and twice as much as muscle, on weight basis. About 90% of the labeled phosphate entering liver was found in the acid-soluble fraction. The specific activity of liver phosphate increased in the infused underfed rats compared to uninfused underfed rats. Infusion of the underfed rat until signs of the syndrome appeared was associated with a 2.7- to 5-fold increase over the correspondingly infused normal rat in the labeling of glucose-6-phosphate, glucose-1-phosphate, and 6-phosphogluconate. No increase over the infused normal rat was observed in most of the other sugar phosphate compounds nor in the non-sugar phosphate compounds such as phospholipids, nucleic acids or proteins. he changes in sugar phosphates observed in the underfed rats probably reflect the enzymatic atrophy associated with underfeeding and the consequent inability to respond to the huge glucose load.
Abstract: Subcutaneous adipose tissue blood flow (ATBF) was examined in 8 subjects during 6 h exercise on a bicycle ergometer. The initial work load was 118 W corresponding to about 50% of maximal work capacity. The oxygen uptake increased from 0.261 - min-1 at rest to about 1.61-min-1 during work. In 7 subjects ATBF increased, in 1 it remained constant. After 3 h exercise ATBF at an average reached values 3–4 times the control value. This increase was maintained for the remaining work periods. The increase was significant at the 5% level. Plasma free fatty acids increased 7-, plasma glycerol 10-fold during work.
Abstract: The objects of these experiments were to determine to what extent oleic acid, removed from plasma by forearm muscles, was oxidized immediately, and to search for evidence of an intramuscular lipid pool which may be composed to triglycerides synthesized from plasma free fatty acids and which may supply substantial portions of lipid substrates for oxidation by muscle. To these ends (1-14C]oleic acid was infused at constant rate into the brachial artery of seven healthy young men at rest in the postabsorptive state. Results were: (1) muscle respiratory quotient (0.76) implied that about 80% of the oxygen consumed was for the oxidation of lipid. (2) Muscle free fatty acid uptake, had it been oxidized directly, could account for more than 100% of observed oxygen uptake. (3) There was a lag of at least 30 min before 14CO2 appeared in forearm venous blood. (4) 14CO2 release from forearm muscle tended to reach an apparent plateau after 3 h of infusion of [14C]oleic acid. (5) During the time of plateau 14CO2 release, oleic acid extracted from plasma could account for only 20% of oxygen consumption; most of the oleic acid taken up was not oxidized directly. (6) 14CO2 release persisted at a high level during the 1-3 h follow-up period after the infusion ended. (7) Neither the delay in initial appearance of 14CO2 nor its continued release after cessation of infusion was due to delay and distribution in a forearm CO2 pool, since intra-arterial infusion of NaH14CO3 in additional subjects demonstrated much more rapid distribution of 14CO2 in the forearm. Results show that most, if not all, free fatty acids taken up by resting muscle are not oxidized directly, but probably enter an intramuscular pool which has a slow turnover during resting metabolism and is the immediate source of oxidized lipid substrate.
Abstract: In a significant number of patients with blunt abdominal trauma, the diagnosis of ruptured spleen is not readily apparent. Is is in these cases that echographic evaluation appears to aid significantly in diagnosis. Seventy patients with blunt abdominal trauma were studied by echography. Results indicated 61 true negative cases, 1 false negative, 4 true positives, and 4 false positives. Criteria for splenic rutures are set forth. Ultrasound is considered to be an excellent screening procedure for suspected splenic rupture.
Abstract: The relationship between lactic acid concentration and twitch tension was reevaluated in electrically stimulated frog sartorius muscle. In muscles stimulated under anaerobic conditions at a rate of 30 stimuli/MIN CONTRACTILE FORCE DECREASED TO 36% OF THE INITIAL VALUE IN 15 MIN, Concomitantly lactate increased from 3.3 to 18.7 mumol/g of muscle. The correlaiton between the increase in lactate and the decrease in contractile force was significant (r = -0.99, P less than 0.000001). Recovery occurred in two phases. A rapid increase in contractile force, which represented 20% of the total recovery, took place during the first 15 s and occurred concomitantly with an increase in ATP from 3.9 to 4.6 mumol/g. Lactate concentration did not change significantly during this period. The second phase of recovery of contractile force was complete in 50 min. Lactate concentration and contractile force were significatly correlated during recovery (r = -0;92, P less than 0.00001). However, recovery of contractile force lagged behind the decrease in lactate; a given concentration of muscle lactate was associated with a higher contractile force early during development of fatigue than late during recovery.
Abstract: In the intact dog, decreases in both glomerular filtration rate and net renal Na+ reabsorption due to raised ureteral pressure were not associated with a decrease in renal lactate oxidation rate, although total renal CO2 production decreased in proportion to the changes in net renal reabsorption of Na+ and glomerular filtration rate. 2. In order to determine whether, in the absence of other added substrates, the metabolism of lactate supports only the ’basal’ renal metabolism or can enhance renal function as well, the rate of lactate utilization and decarboxylation by the isolated perfused rat kidney have been quantified in relation to renal function and one measure of renal basal metabolism, glucose production. 3. The perfusate was Krebs-Ringer bicarbonate (pH 7-35-7-48) with Fraction V bovine serum albumin, 6g/100 ml. L-⊕-lactate was added to raise the lactate concentration from endogenous levels to 2-5, 5-0 or 10 mM. 4. We determined: net lactate utilization rate, lactate decarboxylation rate (14CO2 produced from L-⊕-[U-14C]lactate), net glucose production rate, and net re-absorptive rate of Na+. 5. The apparent Km and Vmax for lactate oxidation were 2-1 mM and 1-29 mumole.g-1.min-1 respectively. There was no apparent maximum for total lactate utilization rate due to continuing increases in glucose production rate as lactate concentration was raised. At ca. 10 mM lactate, glucose production accounted for about half of the total lactate utilized. Therefore the basal energy requirements of the kidney need not be constant since glucose production increases as lactate concentration is raised. 6. Both lactate oxidation rate and lactate utilization rate were significantly correlated with the net reabsorption of Na+ by the renal tubules, with the percentage of filtered Na+ reabsorbed and with the glomerular filtration rate. The major fraction of the net renal reabsorption of Na+ was probably supported by the metabolism of substrates either bound to albumin or derived from renal tissue since the percentage of filtered Na+ reabsorbed increased from ca. 78%, when no lactate was added, to 97% when initial lactate concentration was 10 mM. Therefore, addition of lactate increased both the basal mebabolism and tubular function. However, these observations do not permit us to conclude whether it was the presence of lactate, or its utilization by oxidative or by other pathways which enhanced net renal reabsorption of Na+ and the glomerular filtration rate.
Abstract: Nephrectomized, open chested dogs were infused with 25-30 ml.kg(-1) body weight of 0.15 M NaCl (group I), 0.15 MHCl (Group II) or 0.3 M lactic acid (Group) III). Pulmonary ventilation was maintained constant in the three groups. Intracellular pH was calculated with the CO2 method. No significant intracellular or extracellular acid-base changes were produced in Group I. A similar degree of extracellular acidosis was achieved in Groups II and III. In spite of constant arterial PCO2, the PCO2 of mixed, coronary sinus and femoral vanous blood increased moderately after the infusion in Groups II and III. It was calculated that less than half of the HCl acid infused remained in the extracellular space. However, no significant changes were observed in the acid-base composition of skeletal muscle in either Group II or III. Comparison of the cardiac muscle cell acid-base composition of Group I with that of Groups II and III whows that metabolic acidosis of the degree and duration produced in these experiments does not produce appreciable myocardial acidosis.
Abstract: Plasma and total body potassium have been measured in 151 patients with chronic heart-disease, 83 of whom were taking diuretics and potassium supplements. After allowance for age and body-size, the deficit in total body-potassium was only 3-5% (100-150 mmol) in the diuretic group. 13 of the 83 patients taking diuretic had hypokalaemia (less than 3-5 mmol/1) but the potassium deficit was no greater than in the patients with normal plasma-potassium. There was no relation between the dose of potassium supplements and either the plasma-potassium or the total body-potasium. It is suggested that potassium depletion is not a major problem in patients with heart-failure treated with diuretics. The dose of potassium supplements should therefore be determined entirely by the plasma-potassium.
Abstract: The effect of renal denervation on the reactivity of the renin release mechanism to circulating norepinephrine was studied in six dogs with renal autografts. The renin release was determined simultaneously in the transplanted and the untouched kidney. Both kidneys showed an increased release of renin when norepinephrine was given. A slight reduction in renal blood flow and increase in arterial blood pressure was recorded. Propranolol blocked the release of renin induced by norepinephrine without affecting either the reduced blood flow thorugh the autograft or the elevated blood pressure. The denervation of the autotransplanted kidney was histochemically verified. The findings indicate that the renin release induced by circulating norepinephrine is independent of the intrarenal adrenergic nerves, and rather suggest that it is the result of an action of norepinephrine directly on the renin-producing juxtaglomerular cells. In this mechanism a beta-adrenergic receptor system appears to be involved.
Abstract: An earlier study showed that unidirectional glucose transport from blood to brain decreases during perfusion with anoxic blood (Betz, A. L., Gilboe, D. D. and Drewes, L. R. (1974) Brain Res. 67, 307-316). Brain glucose levels also decrease during anoxia. Therefore, the present study was designed to investigate whether the decreased transport might be the result of decreased accelerative exchange diffusion when brain glucose levels are low. The rate of undirectional transport into brain (v) of D-[6-3H]glucose was studied in 22 isolated, perfused dog brains by means of an indicator dilution technique using 22Na as the intravascular reference. The kinetics of transport were determined over a range of blood glucose concentrations (S1) at each of five different brain glucose levels (S2). The existence of accelerative exchange diffusion for glucose was indicated by a decrease in the intercept (increase of apparent V) of a double reciprocal plot (1/v versus 1/S1) as S2 increased. This phenomenon is consistent with a model for facilitated diffusion in which the mobility of the loaded carrier is greater than that of the unloaded carrier. Although the data predict a decrease in glucose transport during anoxia, the predicted decrease (5%) is less than the observed decrease (35%). It is concluded that the simple mobile-carrier model for facilitated diffusion cannot, by itself, describe all properties of blood-brain glucose transport.
Abstract: To evaluate the effect of different levels of arterial oxygen content on hemodynamic parameters during exercise nine subjects performed submaximal bicycle or treadmill exercise and maximal treadmill exercise under three different experimental conditions: 1) breathing room air (control); 2) breathing 50% oxygen (hyperoxia); 3) after rebreathing a carbon monoxide gas mixture (hypoxia). Maximal oxygen consumption (Vo2 max) was significantly higher in hyperoxia (4.99⅟min) and significantly lower in hypoxia (3.80⅟min) than in the control experiment (4.43⅟min). Physical performance changes in parallel with Vo2 max. Maximal cardiac output (Qmax) was similar in hyperoxia as in control but was significantly lower in hypoxia mainly due to a decreased stroke volume. A correlation was found between Vo2 max and transported oxygen, i.e., Cao2 times Amax, thus suggesting that central circulation is an important limiting factor for human maximal aerobic power. During submaximal work HR was decreased in hyperoxia and increased in hypoxia. Corresponding Q values were unchanged except for a reduction during high submaximal exercise in hyperoxia.
Abstract: Awake, intact dogs trained to wear a respiratory mask were studied in a hypobaric chamber at 140 m and at various stages of a 4-week exposure to 3,550 m. Resting ventilation, pulmonary gas exchanges, arterial blood gases and pH, acid-base status of the cisternal fluid (CSF) and ventilatory responses to transient O2 inhalation were measured. Attention is focussed on the time course of ventilatory acclimatization to altitude, characterized by hyperventilation with hypocapnia and a consequent increase of arterial Po2. (1) 75 percent of the increment in pulmonary ventilation due to hypoxia was achieved in 30 minutes; (2) the further increase, 25 percent of the total hyperventilation, was complete after 3 hr, with a corresponding Pco2 drop and pH increase in blood and CSF, and an increase in Pao2; (3) the secondary increase in ventilation, beyond the acute exposure period, was not related to return of [H+] in CSF towards control value; (4) the large transient decrease of ventilation following brief oxygen inhalation demonstrated a strong arterial chemoreflex drive in acclimatized animals. The extremely rapid ventilatory acclimatization to moderately high altitude in normal dogs appears to be mediated not by CSF hydrogen ion concentration but by a strong chemoreflex drive of ventilation.
Abstract: Left ventricular (LV) diastolic pressure (P), volume (V), and rate of change of volume (dV/dt) were determined at 16.7 msec intervals in 17 patients (simultaneous micromanometer and single plane volume angiography). Four patients had mitral stenosis with atrial fibrillation and 13 patients (three normal, two congestive cardiomyophathy, three LV hypertrophy, and five coronary artery disease) were in normal sinus rhythm. Maximum early diastolic filling rates (max dV/dt) in the normal and cardiomyopathy patients were similar and ranged from 269 to 370 cc/m-2/sec; in coronary artery disease and LV hypertrophy, max dV/dt ranged from 197 to 290 cc/m-2/sec and 213 to 255 cc/m-2/sec respectively; in mitral stenosis, max dV/dt ranged from 215 to 270 cc/m-2 sec. The peak filling rate during atrial systole ranged form 60 to 240 cc/m-2/sec in the 13 patients with sinus rhythm. The instantaneous diastolic P-V data were fit by an exponential equation (P = be-kV) and the P-V relation throughout diastole was represented by the best fit line. The rate constant (k) in the equation was highest in the patient with IHSS and lowest in those with large dilated hearts. In mitral stenosis with atrial fibrillation the fit of the equation to the P-V data appeared better than in the patients with normal sinus rhythm. Peak ventricular filling rate during atrial systole varied directly with LV volume distensibility at the onset of atrial systole (r = 0.64). Data suggest that dynamic mechanical properties of the LV influence the diastolic P-V relations and that pressure "deviations" (deltaP) from the best fit line during atrial systole may be related to viscous drag. In a given ventricle the velocity dependence of deltaP appears to be modified by the volume distensibility of the ventricle. Variable rates of filling may preclude the assumption of an exponential relation between P and V throughout diastole and therefore may limit estimates of diastolic distensibility or compliance which rely on such an assumption.
Abstract: To evaluate the role of splanchnic and peripheral tissues in the disposal of an oral glucose load, splanchnic exchange of glucose, lactate, pyruvate, glycerol and amino acids was determined in ten healthy subjects in the basal state and for three hours following the oral ingestion of 100 gm. of glucose. Following glucose ingestion, splanchnic glucose output rose rapidly, reaching values two to three times the basal rate at fifteen minutes and returning to baseline by ninety minutes. A secondary rise in splanchnic glucose output occurred at 150 minutes and coincided with a secondary increment in arterial glucose. Total splanchnic glucose output over three hours was 40 plus or minus 3 gm., representing a total increase of only 15 plus or minus 3 gm. above basal splanchnic glucose output. The peak rise in blood glucose was directly proportional to the increase in splanchnic glucose output. Arterial concentrations of alanine, lactate and pyruvate rose by 15, 65 and 80 per cent, respectively, following oral glucose. These arterial elevations were preceded by a 75-100 per cent inhibition of splanchnic uptake of alanine and lactate; in the case of pyruvate there was a reversal from a net uptake in the basal state to a significant net splanchnic output after glucose ingestion. Arterial glycerol fell by 50 per cent and was accompanied by a comparable fall in splanchnic uptake. It is concluded that in normal, postabsorptive man, (a) the major portion of a 100 gm. oral glucose load is retained within the splanchnic bed; (b) only 15 per cent of the ingested glucose is available for disposal by peripheral tissues as increased (above-basal) glucose utilization; (c) the height and shape or the oral glucose tolerance curve are largely determined by the rate and pattern of splanchnic glucose escape; (d) glucose-induced hyperlactatemia, hyperpyruvicemia and hyperalaninemia are due at least in part, to altered splanchnic exchange of these substrates.
Abstract: The effect of sympathetic alpha-receptor coronary vasoconstriction on myocardial oxygen tension was studied in open- and closed-chest, chloralose-anesthetized dogs. Blood oxygen tension in the coronary sinus and blood flow in the circumflex coronary artery were continuously measured in a three-part experiment. With stimulation of the left stellate ganglion (15 Hz, 3 msec, 4-7 v, 90-second train) under vagotomy control conditions (part 1), heart rate, blood pressure, and coronary blood flow increased, but coronary sinus oxygen tension decreased from 19 mm Hg to 15 mm Hg. In part 2, beta-receptor blockade with propranolol (2.0 mg/kg. iv) in the same dogs blunted the positive inotropic and chronotropic effects of sympathetic stimulation; coronary alpha-receptor vasoconstriction was unmasked, and coronary sinus blood oxygen tension fell from 17 mm Hg to 11 mm Hg. Since increases in oxygen metabolism were blunted, it appeared that the decrease in coronary sinus oxygen tension was caused by alpha-receptor coronary artery vasoconstriction. This hypothesis was tested in part 3 by the addition of alpha-receptor blockade with Dibozane (3.0 mg/kg, iv). Sympathetic stimulation no longer resulted in a change in either coronary vascular resistance or coronary sinus oxygen tension. These results indicate that the fall in oxygen tension during beta-receptor blockade in part 2 was due to alpha-receptor coronary vasoconstriction. Thus, myocardial oxygen tension may be regulated by coronary sympathetic vasomotion as well as by myocardial oxygen metabolism and local vascular control mechanisms.
Abstract: Studies were undertaken to characterize the renal responses to acute unilateral renal denervation and the mechanisms involved in these responses. Denervation was produced in anesthetized nondiuretic rats by application of phenol to the left renal artery. Studies were also performed in sham-denervated nondiuretic rats. Whole kidney and individual nephron studies were performed before and after denervation or sham denervation. Denervation increased urine volume from the left kidney to about twice its control value (P less than 0.001) and increased urinary sodium excretion from 332 neq min minus -1 to 1,887 neq min minus -1 (P less than 0.001). Glomerular filtration rate (GFR) and renal plasma flow (RPF) remained unchanged in both kidneys after the procedure. The innervated right kidney showed no changes in urine volume or in sodium excretion. After denervation, late proximal ratio of tubular fluid inulin concentration to that of plasma [(F/P)In] decreased from 2.23 to 1.50 (P less than 0.001) while single nephron GFR remained unchanged. Absolute reabsorption decreased from 16.5 to 9.9 n. min minus -1 (P less than 0.001). (F/P)In ratios were also decreased in early distal (from 6.21 to 3.18, P less 0.001) and late distal convolutions (from 16.41 to 8.33, P less than 0.001) during the experimental period. (F/P)Na ratios remained unchanged in the early distal convolutions, but increased from 0.18 to 0.38 (P less than 0.01) in late distal convolutions after denervation. Absolute Na reabsorption after denervation increased in the loop of Henle, distal convolution, and collecting ducts. Any changes in intrarenal hydrostatic pressures after denervation were always small. There were no changes in GFR, RPF, urine volume, urinary sodium excretion, or late proximal (F/P)In after sham denervation. We conclude that the diuresis and natriuresis seen after acute renal denervation were caused by a marked depression of sodium and water reabsorption in the proximal tubule with partial compensation in more distal nephron segments. These responses appeared to be unrelated to systemic or intrarenal hemodynamic changes. The results demonstrate an effect of the renal nerves on proximal tubular function.
Abstract: Cardiopulmonary resuscitation (CPR) may be followed by slow recovery of brain function. The possible role of bicarbonate therapy was assessed by analysis of arterial blood and cerebrospinal fluid (CSF) in 20 dogs during cardiac arrest and CPR. Samples were taken in the control period and every 5 minutes post-arrest of 20 minutes. Group I received no post-arrest CPR. Arterial pH fell from 7.37 to 7.31 (P less than 0.01) and CSF pH from 7.34 to 6.94 (P less than 0.001). Arterial pCO2 rose from 39 to 65 mm Hg (P less than 0.005) and CSF pCO2 increased from 47 to 123 (P less than 0.02). With CPR alone (group II) arterial pH decreased from 7.39 to 7.19 (P less than 0.005), while arterial pCO2 and CSF pH and pCO2 were undhanged. CPR with bicarbonate therapy (mEq = weight in kg times 0.43 times 1.1 mEq/min of arrest) given every 5 minutes (group III), resulted in a rise in arterial pH from 7.41 to 7.81 (P less than 0.02). Excess bicarbonate administration during CPR may result in a marked dissociation between arterial and CSF pH as a consequence of rapid CO2 diffusion across the blood-brain barrier. Large ampounts of NaHCO3 given during CPR may contribute to post-CPR cerebral depresssion.
Abstract: Glucagon suppression by somatostatin reduces or abolishes hyperglycemia in dogs made insulin-deficient by somatostatin, alloxan, or total pancreatectomy. This suggests that the development of severe diabetic hyperglycemia requires the presence of glucagon, whether secreted by pancreatic or newly identified gastrointestinal A cells, as well as a lack of insulin. Glucagon suppression could improve therapeutic glucoregulation in diabetes.
Abstract: This study has assessed the regulation of arterial blood and cerebrospinal fluid acid-base status in seven healthy men, at 250 m altitude and after 5 and 10-11 days sojourn at 4,300 m altitude (PaO2 = 39 mmHg day 1 to 48 mmHg day 11). We assumed that observed changes in lumbar spinal fluid acid-base status paralleled those in cisternal CSF, under these relatively steady-state conditions. Ventilatory acclimatization during the sojourn (-14 mmHg PaCO2 at day 11) was accompanied by: 1) reductions in [HCO3-] (-5 to -7 meq/1) which were similar in arterial blood and CSF; 2) substantial, yet incomplete, compensation (70-75%) of both CSF and blood pH; and 3) a level of CSF pH which was maintained significantly alkaline (+0.05 +/- 0.01) to normoxic control values. These data at 4,300 m confirmed and extended our previous findings for more moderate conditions of chronic hypoxia. It was postulated that the magnitude and time course of pH compensation in the CSF during chronic hypoxia and/or hypocapnia are determined by corresponding changes in plasma [HCO2-].
Abstract: The localization and characterization of carbohydrates in adrenal medullary cells were studied by histochemical and cytochemical methods. Adrenaline (A)-and noradrenaline (N)-storing granules were argentaphobic when ultrathin sections of Araldite-embedded medullae were stained according to the periodic acid-thiocarbohydrazide-silver proteinate technique of Thiery. A small amount of glycogen in the form of single beta-particles as well as lysosomes were, however, visualized by this technique. The entire core of the A granules was markedly positive after ultrathin sections of glutaraldehyde-fixed, glycol methacrylate (GMA)-embedded medullae were stained with phosphotungstic acid (PTA) at low pH (0.3). The N granules, in contrast, were mostly unreactive. In the A cells, PTA stained a large part of the Golgi complex, whereas in the N cells the Golgi complex was mostly unstained. In both cell types, the cell coat, lysosomes, and multivesticular bodies reacted to PTA. The periodic acid-Schiff (PAS) technique showed A but not N granules in semithin sections of GMA- or Araldite-embedded medullae. The PTA and PAS stains were abolished by acetylation, restored by saponification, unchanged by methylation, and greatly diminished by sulfation. In ultrathin sections of GMA- or Araldite-embedded medullae incubated with colloidal iron according to various techniques, the cell coat and lysosomes of both cell types were stained, unlike all the other cytoplasmic organelles. These results indicate that A granules and the Golgi complex of A cells, unlike the same structures in N cells, are rich in glycoproteins which are probably not acidic.
Abstract: Eight men were studied during graded (47, 77, and 100% of maximal oxygen uptake) and prolonged (76%) exhaustive treadmill running. During graded exercise the glucagon concentration increased 35% from 81 plus or minus 7 pg/ml (mean and SE) at rest to 109 plus or minus 17 after the heaviest load. During prolonged exercise glucagon increased progressively to three times (226 plus or minus 40) the resting value. Norepinephrine increased from 0.40 plus or minus 0.06 ng/ml to 2.22 plus or minus 0.39, epinephrine from 0.07 plus or minus 0.01 to 0.42 plus or minus 0.13 during graded, and to 1.51 plus or minus 0.08 and 0.33 plus or minus 0.04, respectively, during prolonged exercise. Insulin concentrations were depressed during work except for the heaviest load. Fatty acids rose throughout prolonged exercise, whereas blood glucose significantly diminished 30 min afterward. Glucagon concentrations correlated significantly with norepinephrine and epinephrine concentrations during prolonged and with epinephrine during graded exercise. Although increments in catecholamines were similar, the glucagon secretion was larger during prolonged than during graded exercise. While increments in catecholamines might explain increased glucagon secretion during graded exercise, they cannot account completely for the rise of glucagon during prolonged exercise.
Abstract: These experiments were undertaken to determine the comparative relationships between chemical structure and biologic (contractile) activity of a series of vasopressin hormone analogs on different rat blood vessels (e.g., aorta, mesenteric arteriole and mesenteric venule). The functional contributions to, and interactions with, phenolic hydroxyl and aromatic groups as well as basicity in positions 2, 3 and 8, respectively, to or with hormone-receptor affinity and intrinsic (contractile) activity, were determined by analyzing the dose-response curves of five vasopressin peptides lacking one or more of these functional groups. The findings demonstrate that: 1) the structure-action relationships for vasopressin peptide-induced contractions on rat blood vessels vary with the particular type of macro- or microvessel (i.e., aorta, arteriole and venule); 2) the phenolic and aromatic groups in positions 2 and 3, respectively, are not only important for hormone-receptor affinity but intrinsic activity as well; 3) the potency (EC50) values for arginine vasopressin as well as the potencies and intrinsic activities of synthetic vasopressin analogs varied between the three different types of rat blood vessels examined; and 4) circulating levels (i.e., 10- minus 11- minus 10- minus 12 M) of [8-arginine]-vasopressin are capable of inducing contractile effects on mesenteric arterioles and venules. The quantitative data obtained in this study support the notion that a heterogeneity of the receptor, which subserves contraction, probably exists in blood vessels within and between vascular beds of a single mammalian species.
Abstract: Stupor in patients with nonketotic hyperglycemia has been ascribed to hyperosmolarity, but the cause of depressed consciousness in patients with ketoacidosis has been puzzling. In this study, blood pH, serum glucose and sodium concentrations, and serum osmolality were measured in eighty-five consecutive episodes of diabetic ketoacidosis and forty-seven of nonketotic hyperglycemia. In the acidotic patients, as in those with nonketotic hyperglycemia, stupor closely paralleled hyperosmolarity and not the severity of acidemia. Indeed, the mean elevations of serum osmolarity were almost the same in the ketotic and in the nonketotic patients who were deeply obtunded. It seems likely that depression of consciousness in patients with severely uncontrolled diabetes mellitus, if not due to a nonmetabolic disorder, such as acute stroke, is attributable to hyperosmolarity, whether or not ketoacidosis is present.
Abstract: Plasma arginine vasopressin (PAV) concentration was determined by radioimmunoassay during the diurnal cycle in 8 recombent healthy male subjects. Two subjects were studied again 3 weeks later while receiving 1 mycles. In 8 out of 10 cycles, a nocturnal increase in PAV was found; there was a progressive rise during the night in 5 subjects and a peak occurred at 2400 or 3400 h. In 1 subject no variation was detected and in another, the pattern was compleetly different. The mean PAV in the 10 cycles was significantly (P less than 0.001) higher during the night than during the day. Dexamethasone did not modify the pattern of variation, but induced a significant (P less than 0.001) decrease in PAV. Hematocrit remained stable throughout the study as did osmolality, except at 2000 h, when a significant (P less than 0.001) increase (5 mOsm) on average occurred in every subject. Blood sugar, sodium or chloride did not account for the observed rise in osmolality and no simultaneous change in PAV occurred. A rise in PAV explains, to some extent, the known nocturnal decrease in urine output. Diurnal variations in PAV must be taken into account in clinical investigations involving vasopressin.
Abstract: The effects of 26 h of normoxic hypocapnia (PaCO2, 31 MMHg) vs. 26 h of hypocapnia plus hypobaric hypoxia (PaCO2 32, PaO2 57 mmHg) were compared with respect to: a) CSF acid-base status; and b) the spontaneous ventilation (at PIO2 145 mmHg) which followed the imposed (voluntary) hyperventilation. For each condition of prolonged hypocapnia, PaCO2 was held constant throughout and pHa and [HCO3-]a were constant over the final 6-10 h. We assumed that measured changes in lumbar CSF acid-base status paralleled those in cisternal CSF. Spontaneous hyperventilation followed both normoxic and hypoxic hypocapnia but was significantly greater following hypoxic hypocapnia. In the CSF, pH compensation after 26 h of hyperventilation was incomplete (similar to 45-50%), was similar to that in arterial blood, and was unaffected by a superimposed hypoxemia. These data were inconsistent with current theory which proposes the regulation of CSF [HCO2] via local mechanisms and, in turn, the mediation of ventilatory acclimatization to hypoxemia and/or hypocapnia via CSF [H+]. Alternative mediators of ventilatory acclimatization were postulated, including mechanisms both dependent on and independent of "chemoreceptor" stimuli.
Abstract: The relation between serum osmolality and blood-alcohol was studied prospectively in 565 acute trauma patients. The two measurements were closely correlated. It is therefore possible to estimate the blood-alcohol from serum osmolality to assist in the clinical management of acutely injured patients.
Abstract: Fed and starved rats were studied on successive days during a 5-day starvation period. The ability of ketone bodies to pass the blood-brain barrier was estimated by single common carotid injections of labeled ketone bodies and water, and results were expressed as the ratio between the normalized activities of tracers in tissue and blood, the brain uptake index (BUI). BUI of D-3-hydroxybutyrate and acetoacetate decreased as their total concentrations increased in the injectate bolus: BUI of D-3-hydroxybutyrate decreased significantly from 8% at 0.2 mM to 3–4% at 20.2 mM in fed rats and from 11.5% at 0.2 mM to 6% at 20.2 mM in starved rats, indicating saturation of the uptake mechanism. The BUI of both ketone bodies increased significantly with increasing duration of starvation, indicating adaptation to ketonemia. Enzymatic kinetics explained the uptake behavior of D-3-hydroxybutyrate in both fed and starved rats and involved a rise of Km and Vmax during starvation consistent with a doubling of the transport rate at the degree of ketonemia found in starved rats. The uptake of glucose was not influenced by starvation or ketonemia.
Abstract: To examine the mechanism(s) responsible for high serum concentration of 3,3’,5’-triiodothyronine (reverse T3, rT3) and low serum concentration of 3,3’,5-triiodothyronine (T3) in the fetus, we studied metabolic clearance rates (MCR) and production rates (PR) of rT3, T3, and thyroxine (T4) in adult nonpregnant sheep and sheep fetuses in utero. The mean fetal MCR-rT3 was significantly lower than that in adult sheep, and the mean fetal PR-rT3 significantly higher. The mean fetal MCR-T3 was higher than, and the mean fetal PR-T3 similar to that in adult sheep. The mean fetal MCR-T4 and PR-T4 were both significantly higher than the corresponding values in adult sheep. The ratios of mean PR-rT3 to PR-T4 (rT3/T4) were similar in fetal and adult sheep. However, the ratio of mean PR-T3 to PR-T4 (T3/T4) in the fetal sheep was much lower than that in the adult sheep. The low fetal MCR-rT3 was not attributable to high serum binding of rT3. On the basis of the thyroidal content and kinetics of iodothyronines, it was estimated that whereas thyroidal secretion may account for nearly all of serum T3 (or PR-T3) in the fetus and about 50% of serum T3 in adults, it accounts for only about 3% of the serum rT3 (or PR-rT3) in both fetal and adult sheep. The results suggest a) that elevated serum rT3 in the fetus is due to its decreased clearance and increased production by mono-deiodination of T4, and b) that low serum T3 in the fetus is due to its increased clearance and decreased production by mono-deiodination of T4. In addition, on the basis of discordant changes in the production of T3 and rT3 from T4, it appears that there may exist two separate, apparently specific, iodothyronine deiodinating activities–one cleaving the iodine atom at the 5’-position and the other acting in the iodine atom at the 5-position of the T4 molecule; 5’-iodothyronine deiodinating activity is apparently reduced in the fetus.
Abstract: Ten normal males were given 100 mug TRH, and blood samples obtained for serum TSH and serum prolactin. After a period of at least one week, the TRH test was repeated while the patients were receiving a dopamine infusion. Both the TSH and prolactin response to TRH were inhibited by dopamine. Dopaminergic neurons may act through the pituitary-portal system to play a role in the regulation of TSH and prolactin secretion.
Abstract: Male rats rendered diabetic by the intravenous injection of streptozotocin (150mg/kg) were treated with a long-acting insulin for 1 week, then allowed to develop ketoacidosis. By using sampling techniques designed to avoid the use of anaesthesia and extended anoxic periods, sequential measurements of metabolic intermediates were made in blood, liver, cerebrospinal fluid and brain at 24h intervals after the last insulin injection. Measurements in blood and liver suggested a rapid increase in hepatic glycogenolysis and gluconeogenesis and peripheral-depot lipolysis between 24 and 48h after the last insulin injection, whereas blood and liver ketone-body and triglyceride concentrations rose more slowly. The changing metabolic patterns occurring with increasing time of insulin deprivation stress the importance of sequential compared with static measurements in experimental diabetes. Data are presented for brain metabolic intermediates in diabetic ketoacidosis, and support recent evidence that glucose plays a less important role in brain oxidative metabolism in ketotic states.
Abstract: 1. These experiments were designed to measure how much blood is mobilized from or pooled in the liver, spleen and gastro-intestinal tract to compensate for a haemorrhage or infusion of blood.2. Hepatic volume, splenic weight and intestinal volume were recorded in cats anaesthetized with sodium pentobarbitone. Whole blood was removed or infused at rates of 0.5-0.6 ml. kg(-1).min(-1) until 10 ml./kg (19% blood volume) had been removed or 18 ml./kg (34% blood volume) had been infused. These blood volume changes produced only small changes in arterial and portal pressures except after removal of 8 ml./kg (15% blood volume) when arterial pressure began to decrease rapidly.3. With small haemorrhages of up to 4% blood volume, the liver contributed 16%, the gastro-intestinal tract 23% and the spleen a negligible proportion of the blood volume removed. With haemorrhages of 15% blood volume, the liver contributed 21%, the gastro-intestinal tract 22% and the spleen 19% of the volume removed; a total splanchnic contribution of 62%.4. During infusions of 5-18 ml./kg (10-34% blood volume), the liver pooled 20%, the gastro-intestinal tract 40% and the spleen 6% of the volume infused; a total splanchnic contribution of 66%.5. It is concluded that the splanchnic bed mobilizes or pools up to 65% of the volume of blood removed from or infused into the cats. The mechanisms responsible for this blood reservoir function are discussed. While several factors may be involved, it seems likely that a reflex regulation involving atrial receptors and the sympathetic innervation of the splanchnic capacitance vessels is of predominant importance.
Abstract: The effect of mannitol upon glomerular ultrafiltration was examined in hydropenic Munich-Wistar rats. Superficial nephron filtration rate (sngfr) rose from 32.0+/-0.9 nl/min/g kidney wt to 42.0+/-1.6 (P \textbackslashtextless 0.001) in eight rats. Hydrostatic pressure gradients acting across the glomerular capillary (DeltaP) were measured in glomerular capillaries and Bowman’s space with a servo-nulling device, systemic (piA) and efferent arteriolar oncotic pressures (piE) were determined by microprotein analysis. These data were applied to a computer-based mathematical model of glomerular ultrafiltration to determine the profile of effective filtration pressure (EFP = DeltaP - pi) and total glomerular permeability (L(p)A) in both states. Filtration equilibrium obtained in hydropenia (L(p)A \textbackslashtextgreater≠0.099+/-0.006 nl/s/g kidney wt/mm Hg) and sngfr rose because EFP increased from a maximum value of 4.2+/-1.1 to 12.8+/-0.5 mm Hg after mannitol (P \textbackslashtextless0.01). This increase was due to both increased nephron plasma flow and decreased piA. Computer analysis of these data revealed that more than half (\textbackslashtextgreater58%) of this increase was due to decreased piA, consequent to dilution of protein. Since EFP was disequilibrated after mannitol, L(p)A could be calculated accurately (0.065 +/- 0.003 nl/s/g kidney wt/mm Hg) and was significantly lower than the minimum estimate in hydropenia.Therefore, sngfr does increase with mannitol and this increase is not wholly dependent upon an increase in nephron plasma flow since the major factor increasing EFP was decreased piA.
Abstract: A highly specific antiserum to 3,3’,5’-triiodothyronine (reverse T(3), rT(3)) was prepared by immunization of rabbits with D,L-rT(3)-human serum albumin conjugate. Of the various thyroid hormone derivatives tested, only 3,3’-diiodothyronine (3,3’-T(2)) cross-reacted significantly (10%) with rT(3)-binding sites on the antiserum, while thyroxine (T(4)) and triiodothyronine (T(3)) cross-reacted by less than 0.1%. The antiserum was used in a simple, sensitive, precise, and reproducible radioimmunoassay (RIA) for measurement of rT(3) in ethanolic extracts of serum. The dose-response curves of inhibition of the binding of [(125)I]rT(3) to antibody obtained by serial dilutions of serum extracts were essentially parallel to the standard assay curve. Recovery of nonradioactive rT(3) added to serum before extraction averaged 93%. Serum rT(3) concentrations were found to be (mean+/-SD) 41+/-10 ng/100 ml in 27 normal subjects, 103+/-49 ng/100 ml in 22 hyperthyroid patients, 19+/-9 ng/100 ml in 12 hypothyroid patients, and 54+/-7 ng/100 ml in five subjects with elevated serum thyroxine-binding globulin: the values in each of the latter three groups of individuals were significantly different from normal. Reverse T(3) was detected regularly in normal or supranormal concentrations in serum of 12 hypothyroid patients rendered euthyroid or mildly hyperthyroid by treatment with synthetic T(4). It is suggested that serum rT(3) values noted here should be taken to reflect the relative changes in serum rT(3) rather than its absolute values in health and thyroid disease. True serum rT(3) may be somewhat different because: (a) D.L-rT(3) employed in the standard curve and L-rT(3) present in human serum may react differently with anti-D,L-rT(2). (b) Even though 3,3’-T(2), which cross-reacted 10% in rT(3) RIA, has been considered unlikely to be present in human serum, it may circulate in low levels. (c) Cross-reaction of T(4) in rT(3) RIA of 0.06% although small, could contribute to RIA estimates of rT(2); the effect of T(4) would be particularly important in case of serum of hyperthyroid patients. Thus, serum rT(3) concentration in hyperthyroid patients averaged 89+/-48 mug/100 ml after correction for cross-reaction effects of T(4): this value was about 14% lower than that before correction (see above). Serum rT(3) concentration in cord sera of seven newborns averaged 136+/-19 ng/100 ml; it was clearly elevated and within the range of values seen in hyperthyroid patients. This was the case when the mean T(4) concentration in the newborn cord sera was moderately higher than normal and about one-half that in hyperthyroid patients, whereas serum T(3) was markedly below the normal adult level. A Pronase hydrolysate of thyroglobulin prepared from pooled normal thyroid glands contained 0.042, 3.0, and 0.16 mug/mg protein of rT(3), T(4), and T(3), respectively. The various data suggest that: (a) rT(3) is a normal component of human serum and thyroglobulin: (b) peripheral metabolism of T(4) is an important source of the rT(3) present in serum: (c) peripheral conversion of T(4) to T(3) and rT(3) may not necessarily be a random process.
Abstract: 1. Hepatic volume was recorded by plethysmography in dogs anaesthetized with sodium pentobarbitone. Histamine infusions into the hepatic artery or portal vein increased hepatic volume while hepatic sympathetic nerve stimulation decreased the volume. Simultaneous nerve stimulation and histamine infusion decreased hepatic volume.2. The hepatic volume responses to histamine and nerve stimulation could not be explained on the basis of differences in the responses of the larger hepatic veins and the possibility of a histamine-sensitive sphincter at the junction of the hepatic vein with the inferior vena cava was excluded. Differences in the responses of the hepatic arterial bed contributed to but did not explain the different hepatic volume responses.3. It is suggested that histamine produced an intense and specific constriction of the sublobular veins with passive distension of post-sinusoidal venules, sinusoids and portal venules while hepatic nerve stimulation produced a uniform and generalized constriction of both pre- and post-sinusoidal vessels.4. Intravenous infusions of histamine produced a marked hypotension but small variable effects on hepatic volume. It is concluded that hepatic pooling is not the cause of the hypotension produced by intravenous histamine and that significant hepatic pooling will only be produced by mechanisms which release endogenous histamine within the liver.
Abstract: New methods are described by which the buffer content and the rate and pattern of net gastric acid secretion in human subjects fed normal meals can be measured by use of sodium bicarbonate infusion to control intragastric pH. With these techniques, it was shown that the rate of acid secretion in response to a steak meal in seven duodenal ulcer patients was twice the rate achieved in six control subjects and that the amount of acid secreted after eating exceeded the peak histamine response in the ulcer patients but not in the controls. Meal-stimulated acid secretion, expressed as a function of the peak histamine response, was roughly correlated with the serum gastrin concentration (r = 0.45), but it was concluded that other factors must also contribute to the higher than normal secretory responses to a meal found in duodenal ulcer patients. Measurement of buffer content of the stomach revealed that the duodenal ulcer patients emptied the meal buffer at a much more rapid rate than the normal subjects. By 2 h after eating, the ulcer subjects had less than half as much buffer in their stomachs as the controls. The combination of acid hypersecretion and rapid buffer emptying leads to abnormally high gastric acidity after a meal in duodenal ulcer patients. These results suggest that, in addition to a large parietal cell mass, parietal cell responsiveness to a meal and the rate of buffer emptying may be important in the pathogenesis of duodenal ulcer.
Abstract: Micropuncture techniques in the rat were used to reinvestigate the possibility that intraluminal flow rate per se may influence net volume reabsorption by the proximal tubule. An experimental design was devised which lowered intraluminal flow without affecting filtration rate of the nephron under study or without directly affecting other renal hemodynamics. In 11 rats flow of tubular fluid between early and late proximal tubular sites was reduced by partially collecting tubular fluid at the early puncture site. In 42 nephrons the rate of flow of tubular fluid was reduced an average of 45% without changing nephron filtration rate and there was an associated reduction in reabsorption between the two sites which averaged 29%. This indicated 63% balance between delivery of tubular fluid and the rate of reabsorption between two sites along proximal tubules. The results of these studies indicate that a reduction in delivery of normal filtrate along the proximal tubule is associated with a concordant reduction in the absolute rate of reabsorption. Since this relationship occurred in the absence of changes in renal hemodynamics or even a change in filtration rate of the nephron under study it is concluded that changes in intraluminal load per se play an important role in the phenomenon of glomerulotubular balance.
Abstract: 1. The carbamate (HbCO(2)) concentration in oxygenated and deoxygenated human adult and foetal red blood cells was estimated at a constant pressure of carbon dioxide (P(CO2) = 40 mm Hg) and various pH values of the serum. The Donnan ratio for chloride and bicarbonate ions was used to calculate the bicarbonate concentration in the red cells. With this figure the carbamate concentration was calculated as follows:[HbCO(2)] = [Total CO(2)] - [HCO⊖ (3)] - [dissolved CO(2)].2. At a given pH value in the red cell deoxygenated foetal red cells contain more HbCO(2) than deoxygenated adult ones. Upon oxygenation (at constant pH) HbCO(2) drops in both types of erythrocytes to lower values than in deoxygenated cells. The fraction of ;oxylabile carbamate’ (-DeltaHbCO(2)/DeltaHbO(2)) at a red cell pH of 7.2 and a P(CO2) of 40 mm Hg is 0.117 in foetal and 0.081 in adult erythrocytes.3. From the fraction of moles carbamate formed per Hb monomer (moles CO(2)/mole Hb(i)) K’(c) and K’(z), the apparent carbamate equilibrium constants were calculated which can be used to estimate the carbamate concentration in normal adult and foetal blood.4. The first apparent dissociation constant of carbonic acid is significantly higher in oxygenated (-log(10)K’(1) = pK’(1) = 6.10) than in deoxygenated (pK’(1) = 6.12) adult red cells, whereas in foetal red cells the difference is smaller and statistically not significant.5. For a given set of physiological conditions in arterial and mixed venous blood in respect to oxygen saturation, P(CO2) and pH, the fractional contribution of carbamino compounds of haemoglobin to the amount of carbon dioxide which is exchanged during the respiratory cycle was computed on the basis of the present results and found to be 10.5% in adult and 19% in foetal blood.
Abstract: 1. The changes in urinary and renal tissue composition induced by continuous, intravenous infusion of lysine-vasopressin (2.5, 5, 15 and 60 mu-u./min. 100 g body wt.) for up to 4(1/2) hr in water-loaded, conscious rats were determined.2. Both the magnitude of, and the time required to attain, maximal and stable responses, in respect to both urinary and tissue composition, varied with the dose.3. The dose-dependent changes in medullary composition were compounded of graded decreases in water content and graded increases in solute (mainly Na and urea) content.4. The relative contribution of the changes in water, Na and urea contents varied with time and with dose. Significant increases in papillary urea content occurred with all doses. The range of change in urea content was wider than that for any other solute.5. At low doses, the changes in urinary flow and osmolality were ascribable, almost entirely, to large decreases in free-water clearance, with minor changes in medullary composition; at higher doses, the increases in urinary osmolality were accompanied by steep increases in medullary solute concentrations.6. A variable, dose-dependent, transient natriuresis occurred during the phase of increasing medullary Na concentration; the peak natriuresis preceded the times of maximal osmolal and Na concentrations in the papilla and urine.7. The differences in osmolal, urea and Na concentrations between papilla and urine also changed with time.8. Both the transitional and steady-state changes induced by lysine-vasopressin are discussed in terms of intrarenal mechanisms. It is concluded that the data are most reasonably interpreted on the basis that several hormone-sensitive loci exist in the kidneys, each with individual dose-response and kinetic characteristics.
Abstract: 1. A study has been made of the effect of spontaneous and induced muscle spasms on blood pressure, heart rate, hand blood flow, calf blood flow and occluded vein pressure in the hand and foot in non-bedridden patients with chronic, closed, complete, localized transection of the cervical spinal cord.2. Both types of spasm produced a similar response consisting of an increase in blood pressure and occluded vein pressure and a decrease in heart rate and hand and calf blood flow. The changes commenced within 2-3 sec and usually reached maxima in 20-30 sec. On some occasions there was a temporary initial increase in heart rate and calf blood flow.3. The changes occurred independently of changes in bladder pressure.4. It is concluded that the changes in peripheral blood vessels result from a spinal sympathetic reflex to somatic afferents associated with muscular contraction.
Abstract: 1. In the anaesthetized dog, the carotid sinuses and aortic arch were isolated from the circulation and separately perfused with blood by a method which enabled the mean pressure, pulse pressure and pulse frequency to be varied independently in each vasosensory area. The systemic circulation was perfused at constant blood flow by means of a pump and the systemic venous blood was oxygenated by an extracorporeal isolated pump-perfused donor lung preparation.2. We have confirmed our previous observations that under steadystate conditions the vasomotor responses elicited reflexly by changes in mean carotid sinus pressure are modified by alterations in carotid sinus pulse pressure, whereas those evoked by changes of mean aortic arch pressure are only weakly affected by modifications of aortic pulse pressure.3. When the carotid sinus and aortic arch regions are perfused in combination at constant pulse frequency (110 c/min), the relationship between mean carotid sinus-aortic arch pressure and systemic arterial perfusion pressure is dependent on the size of the pulse pressure.4. Increasing the pulse pressure alters the curve relating the mean carotid sinus-aortic arch pressure to systemic arterial perfusion pressure in such a way that the perfusion pressure is lower at a given carotid sinus-aortic arch pressure within the range 80-150 mm Hg. The larger the pulse pressure, up to about 60 mm Hg, the greater the fall in systemic arterial perfusion pressure. Above a mean carotid sinus-aortic arch pressure of about 150 mm Hg, alterations of pulse pressure have little effect.5. There is a family of curves representing the relation between mean carotid sinus-aortic arch pressure and systemic vascular resistance, depending on the pulse pressure.
Abstract: Arterial concentration and net exchange across the leg and splanchnic bed of 19 amino acids were determined in healthy, postabsorptive subjects in the resting state and after 10 and 40 min of exercise on a bicycle ergometer at work intensities of 400, 800, and 1200 kg-m/min. Arterio-portal venous differences were measured in five subjects undergoing elective cholecystectomy. In the resting state significant net release from the leg was noted for 13 amino acids, and significant splanchnic uptake was observed for 10 amino acids. Peripheral release and splanchnic uptake of alanine exceeded that of all other amino acids, accounting for 35-40% of total net amino acid exchange. Alanine and other amino acids were released in small amounts (relative to net splanchnic uptake) by the extrahepatic splanchnic tissues drained by the portal vein. During exercise arterial ananine rose 20-25% with mild exertion and 60-96% at the heavier work loads. Both at rest and during exercise a direct correlation was observed between arterial alanine and arterial pyruvate levels. Net amino acid release across the exercising leg was consistently observed at all levels of work intensity only for alanine. Estimated leg alanine output increased above resting levels in proportion to the work load. Splanchnic alanine uptake during exercise exceeded that of all other amino acids and increased by 15-20% during mild and moderate exercise, primarily as a consequence of augmented fractional extraction of alanine. For all other amino acids, there was no change in arterial concentration during mild exercise. At heavier work loads, increases of 8-35% were noted for isoleucine, leucine, methionine, tyrosine, and phenylalanine, which were attributable to altered splanchnic exchange rather than augmented peripheral release. The data suggest that (a) synthesis of alanine in muscle, presumably by transamination of glucose-derived pyruvate, is increased in exercise probably as a consequence of increased availability of pyruvate and amino groups; (b) circulating alanine serves an important carrier function in the transport of amino groups from peripheral muscle to the liver, particularly during exercise; (c) a glucose-alanine cycle exists whereby alanine, synthesized in muscle, is taken up by the liver and its glucose-derived carbon skeleton is reconverted to glucose.
Abstract: 1. The changes in urinary and renal tissue composition induced by continuous, intravenous infusion of lysine-vasopressin (60 mu-u./min. 100 g body wt. until steady-state conditions prevailed) in normally hydrated, hydropaenic, saline-loaded (0.9%, w/v) and mannitol-loaded (15%, w/v) rats were determined and compared with those induced in water-loaded rats.2. Previous reports that the urinary responses to antidiuretic hormones vary both with hydration status and with concurrent solute excretion rate were confirmed.3. The data show that variations in urinary responses were accompanied by differences in the papillary responses to lysine-vasopressin.4. The results are discussed in terms of the effects of hydration and concurrent solute excretion on factors influencing (a) medullary accumulation of water and solute, (b) osmotic water reabsorption and (c) osmotic equilibration across the collecting duct; and of the effects of lysine-vasopressin on these factors.5. It is concluded that the effects of hydration and solute excretion on the antidiuretic responses to lysine-vasopressin may be interpreted by differences in (a) the medullary composition prevailing at the start and (b) any further changes in medullary composition that can be induced under the experimental circumstances.
Abstract: The mechanism of glomerulotubular balance was investigated by microperfusion of the rat proximal tubule at two different rates before and after contriction of the aorta sufficient to produce a 50% reduction in whole kidney filtration rate and plasma flow. At a perfusion rate of 28 nl/min the absolute rate of proximal tubular reabsorption averaged 4.80+/-0.28 nl/mm.min in the absence of aortic constriction. Reducing the perfusion rate by one-half resulted in only a 22% decrease in the absolute rate of reabsorption, and imbalance between load and reabsorption resulted as fractional reabsorption of the perfused volume increased from 0.56 to 0.83 at 3 mm length of perfused tubule. These observations support other studies indicating that changing the load presented to the individual proximal tubule does not change reabsorptive rate sufficiently to result in glomerulotubular balance. Aortic constriction decreased the absolute rate of proximal tubular reabsorption approximately 50%, resulting in imbalance between load and reabsorption at the higher perfusion rate (fractional reabsorption of the perfused volume fell to 0.23 at 3 mm). Thus, the decrease in proximal tubular reabsorption necessary for glomerulotubular balance will occur independent of a change in the load presented for reabsorption. Balance between load and reabsorption was produced artificially by combining aortic constriction and a reduction in perfusion rate proportional to the reduction in whole kidney filtration rate. Mathematical analysis of the data suggests that the absolute rate of reabsorption along the accessible length of the proximal tubule is constant and is not proportional to the volume of fluid reaching a given site. Thus, there appears to be no contribution to glomerulotubular balance of any intra- or extratubular mechanism directly coupling load and the rate of proximal tubular reabsorption. It is concluded that glomerulotubular balance during aortic constriction is a consequence of hemodynamic effects of the maneuver to decrease filtration rate and the rate of proximal tubular reabsorption independently but in an approximately proportional manner.
Abstract: 1. A study has been made of the effect of head-up tilt on blood pressure, heart rate, forearm blood flow and occluded vein pressure in the hand and foot in non-bedridden patients with chronic, closed, complete, localized traumatic transection of the cervical spinal cord.2. In typical responses the blood pressure fell and the heart rate rose progressively for about 2 min, tending to plateau thereafter. The average falls in mean blood pressure for tilts of +30, +45 and +60 degrees were from 68 to 44, 74 to 36 and 70 to 44 mm Hg respectively, and the corresponding heart rate increases were from 67 to 85, 62 to 97 and 62 to 103 beats/min respectively. One patient lost consciousness when his blood pressure was 29/19 mm Hg and one other patient experienced symptoms suggesting cerebral ischaemia.3. Following the return to horizontal, the blood pressure and heart rate usually returned to their previous values within 1 min and the blood pressure tended to overshoot slightly in the following few minutes. No immediate blood pressure overshoot occurred after the tilt except in association with a spasm of skeletal muscles.4. There was consistently a decrease in forearm blood flow, sometimes to unrecordably low levels and a venoconstriction with postural change and it is argued that these changes are the result of spinal cardiovascular reflexes to peripheral vessels. Following the return to the horizontal position, there was occasionally a large immediate increase in forearm blood flow.5. Following the intravenous administration of 3 mg atropine on two occasions, head-up tilting produced further small heart rate increases.6. Spasms of skeletal muscle occur frequently in these patients and greatly modify the effects of postural stimuli. Bladder percussion also modifies the normal response.
Abstract: 1. Changes in water and solute outputs of hydropaenic, normal and hydrated conscious rats were determined during intravenous infusion (0.2 ml./min) of isotonic (0.9%) saline for 4 hr; renal tissue composition was determined before, and after 1 or 2 hr, infusion.2. In normal and hydrated rats increased excretion of water and sodium was such that urinary output matched intravenous input from about 2 hr. In hydropaenic rats, the diuretic and natriuretic response was much reduced; a retention of infused saline, equivalent to 15% body weight, occurred over 4 hr.3. A considerable increase in urea output and clearance, and a smaller increase in potassium and ammonium outputs, occurred in all groups.4. The corticomedullary osmolal gradients characteristic of non-diuretic rats were largely dissipated during saline infusion: by 1 hr in normal and hydrated rats, and by 2 hr in the hydropaenic group.5. These changes were ascribable mainly to an increase in tissue water content in all segments, particularly in the hydropaenic group; and to a profound decrease in urea content in all groups.6. Changes in tissue sodium content were smaller, and differed between segments and between the differently hydrated groups. A decrease in papillary content occurred in hydropaenic and normal groups and an increase in cortical and outer medullary content occurred in all groups.7. After 2 hr saline infusion, incomplete papillary-urinary osmotic equilibration was evident in all groups.8. These changes in medullary osmolality and in papillary-urinary osmotic equilibration preceded the maximal diuresis, and must contribute to the diuresis induced by saline infusion, as in water and osmotic diureses.
Abstract: Two patients with severe postural hypotension associated with upper motor neuron and cerebellar impairment (Shy-Drager syndrome) have been studied. Head-up tilt and lower body negative pressure application caused marked falls in arterial pressure; in one patient, paradoxical vasodilatation was observed. Ice application did not increase arterial pressure or calculated forearm vascular resistance. Intravenous atropine in one patient increased heart rate by 18 beats per min, a cardioacceleratory response similar to exhausting recumbent exercise in that patient. 24 hr urinary catecholamine excretion was low, but aldosterone secretory rate was normal in the more severely afflicted patient. A prolonged elevation of plasma renin activity was noted when post-tilt hypertension occurred. When head-up tilt was not followed by this hypertensive period, plasma renin activity response to tilting was normal. Intra-arterial norepinephrine and tyramine both elicited a vasoconstrictor response. Intra-arterial infusions of norepinephrine and tyramine were repeated after administration of the monoamine oxidase inhibitor tranylcypromine. Norepinephrine was potentiated 4.1- and 0.5-fold in the two patients; tyramine was potentiated 3.7-and 1.1-fold in the two patients, respectively. A therapeutic program of tranylcypromine and tyramine (in the form of cheddar cheese) resulted in substantial clinical improvement. It is concluded that in at least some patients with idiopathic postural hypotension, norepinephrine is present in postganglionic sympathetic fibers. A therapeutic program of tyramine and a monoamine oxidase inhibitor may be of value when more conventional modes of therapy fail.
Abstract: Serial determinations of the renal clearance for inulin and para-aminohippuric acid (PAH), maximum renal tubular reabsorptive rate for glucose, maximum urinary concentrating ability, total exchangeable potassium, extracellular volume, and plasma sodium and potassium concentrations were done in seven dogs before and after dietary potassium depletion. The same measurements were also made in two of the dogs during potassium repletion. Inulin and PAH clearances and transport maxima for glucose decreased progressively during depletion. These changes correlated well with both the duration of depletion and the extent of depletion as measured by total exchangeable potassium. Decreases in inulin and PAH clearance closely paralleled each other, suggesting that there might be a renal hemodynamic basis for both effects. The decreases in transport maxima for glucose were greater than those for inulin or PAH clearance, indicating the presence of a defect in the cellular transport mechanism for glucose. In the dogs that were repleted, renal function gradually returned to the predepletion state. No significant changes were found in extracellular volume or plasma sodium concentration during depletion. Renal concentrating ability decreased only moderately during depletion, with the decrease correlating better with plasma potassium concentration than with total exchangeable potassium. This finding contrasts with the marked decrease in concentrating ability and the severe polydipsia and polyuria found in animals depleted of potassium with the aid of corticosteroids. The results of the present study emphasize the importance of considering species differences and the method of producing depletion in interpreting studies of the effects of hypokalemia on renal function.
Abstract: The evidence from previous micropuncture studies for an inhibitory effect of furosemide on proximal sodium reabsorption in the rat has been conflicting. Intrinsic reabsorptive capacity, estimated in free flow and shrinking drop experiments, has been reported to be depressed, whereas fractional reabsorption usually remains unchanged. We have recently reported that, during conditions of elevated intraluminal hydrostatic pressure, unless care is taken to prevent retrograde flow of tubule fluid from more distal sites, the concentration of inulin in late proximal fluid is often factitiously elevated. Since furosemide raises intraluminal pressures, often markedly, the failure to detect a depression of fractional reabsorption might be the consequence of retrograde contamination during fluid collection. Experiments were designed to compare the effect of furosemide on fractional sodium reabsorption by the proximal tubule when collections were obtained with distal oil blocks of conventional length as well as with unusually long blocks of oil of low and high viscosities. When reflux is prevented, fractional sodium reabsorption is usually depressed by furosemide, whereas when conventional distal blocks are used, the calculated values for fractional reabsorption either remain unchanged or increase. Simultaneous measurements of nephron glomerular filtration rate indicate that the latter is the consequence of retrograde contamination.
Abstract: Rats fed a diet high in potassium for several days survive an acute load of potassium that is lethal to animals on a regular diet. Previous data suggested that this survival occurred because of enhanced kaluresis. Although increased urinary excretion may occur, the major mechanism of this potassium adaptation phenomenon has been found to be extrarenal. Despite nephrectomy just before study, rats previously fed a high potassium diet maintained lower plasma potassium concentrations for at least 2 hr after an acute potassium load than did rats fed a regular diet. Prior adrenalectomy abolished adaptation. Furthermore, rats fed a low sodium diet as an alternative stimulus to aldosterone secretion demonstrated adaptation to potassium loading, as did adrenalecomized rats given large doses of deoxycorticosterone for several days. Adrenalectomy just before the test load of potassium did not abolish adaptation nor did a large dose of aldosterone at that time reproduce it. These data indicate that adaptation is dependent on a chronic increase in aldosterone secretion. The extra potassium removed from the extracellular fluid by adapted rats was not lost into the gastrointestinal tract. It is concluded that more rapid lowering of plasma potassium after acute potassium loads by adapted rats is due to enhanced uptake of potassium by one or more tissues stimulated by chronic aldosteronism.
Abstract: Glomerulotubular balance was investigated in isolated, perfused rabbit proximal tubules in vitro in order to evaluate some of the mechanisms proposed to account for the proportionate relationship between glomerular filtration rate and fluid absorption generally observed in vivo. The rate of fluid transport from lumen to bath in proximal convoluted tubules in vitro was approximately equal to the estimated normal rate in vivo. The absorption rate in proximal straight tubules however was approximately one-half as great. If the mechanism responsible for maintenance of glomerulotubular balance is intrinsic to the proximal tubule, as has been proposed on the basis of micropuncture studies, the rate of fluid absorption in vitro should be directly related to the perfusion rate and/or tubule volume. In the present studies absorption rate was only minimally affected when perfusion rate was increased or the tubule distended. Thus, glomerulotubular balance is not mediated by changes in velocity of flow of the tubular fluid or tubular diameter and therefore is not an intrinsic property of the proximal tubule. It has also been proposed that glomerulotubular balance results from a humoral feedback mechanism in which angiotensin directly inhibits fluid absorption by the proximal convoluted tubule. In the present experiments, angiotensin was found to have no significant effect on absorption rate.
Abstract: 1. Recordings have been made of the activity in carotid body chemoreceptor afferent fibres and in the cervical sympathetic of the cat during passive movement of the hind limbs.2. The chemoreceptor activity increases immediately the limbs are moved and is maintained at a raised level with preservation of the chemoreceptor rhythm fluctuations throughout. In some cases, the increase persists for a time after the movements are stopped.3. This early change does not occur if the cervical sympathetic on the same side as the carotid body from which recordings are made is cut, nor does it occur if the femoral and sciatic nerves are cut.4. The carotid artery oxygen tension (P(a, O2)) increases early; in the majority of experiments, there was no significant change in end-tidal P(CO2) although the minute volume of ventilation (V) increased by about 20% of control with passive movement of the hind limbs.5. Passive movement of the hind limbs also causes an immediate rise in cervical sympathetic activity which is sustained, and which is abolished if the femoral and sciatic nerves are cut.6. Electrical stimulation of the cervical sympathetic causes an increase in chemoreceptor afferent discharge.7. Bilateral cervical sympathectomy causes the respiratory lag to increase from approximately 1 sec to some 20 sec and, when passive movements cease, the fall in V is more sluggish than control.8. These results are discussed in the light of the controversy regarding humoral and neurogenic causes for the increase in respiration in exercise.
Abstract: In the present study oxygen uptake, cardiac output, stroke volume (dye-dilution technique) and oxygen content of arterial blood were determined in 11 women and 12 men, 20–31 years of age, at rest, and when performing submaximal and maximal work. At rest plasma volume (T-1824) and heart volume were determined. Sitting on the bicycle ergometer the stroke volume was 40–90% (mean 63%) of the maximum attained during exercise. Maximal stroke volume was essentially reached at a workload with an oxygen uptake of about 40% of the maximum and a heart rate about 110. No tendency to a decrease in stroke volume was noticed when maximal work was performed. The variation in stroke volume was ±4% during exercise in the range from 40 to 100% of the individual’s aerobic work capacity. The maximal cardiac output was 18.5 liters/min for women and 24.1 liters for men. The correlation between heart volume on one side and maximal stroke volume and cardiac output on the other side was high and the expected one from the dimension of the individual. On submaximal as well as maximal exercise the women had a higher cardiac output per liter oxygen uptake than the men, and this can be explained by the lower concentration of hemoglobin in the women’s blood. cardiac function during exercise; cardiac output stroke volume; cardiac output and arterial O2 content
