Abstract: Metabolic regulation in mammals requires communication between multiple organs and tissues. The rise in the incidence of obesity and associated metabolic disorders, including type 2 diabetes, has renewed interest in interorgan communication. We used mouse models to explore the mechanism whereby obesity enhances pancreatic beta cell mass, pathophysiological compensation for insulin resistance. We found that hepatic activation of extracellular regulated kinase (ERK) signaling induced pancreatic beta cell proliferation through a neuronal-mediated relay of metabolic signals. This metabolic relay from the liver to the pancreas is involved in obesity-induced islet expansion. In mouse models of insulin-deficient diabetes, liver-selective activation of ERK signaling increased beta cell mass and normalized serum glucose levels. Thus, interorgan metabolic relay systems may serve as valuable targets in regenerative treatments for diabetes.
Abstract: Dietary carbohydrates regulate hepatic lipogenesis by controlling the expression of critical enzymes in glycolytic and lipogenic pathways. We found that the transcription factor XBP1, a key regulator of the unfolded protein response, is required for the unrelated function of normal fatty acid synthesis in the liver. XBP1 protein expression in mice was elevated after feeding carbohydrates and corresponded with the induction of critical genes involved in fatty acid synthesis. Inducible, selective deletion of XBP1 in the liver resulted in marked hypocholesterolemia and hypotriglyceridemia, secondary to a decreased production of lipids from the liver. This phenotype was not accompanied by hepatic steatosis or compromise in protein secretory function. The identification of XBP1 as a regulator of lipogenesis has important implications for human dyslipidemias.
Abstract: YiiP is a membrane transporter that catalyzes Zn2+/H+ exchange across the inner membrane of Escherichia coli. Mammalian homologs of YiiP play critical roles in zinc homeostasis and cell signaling. Here, we report the x-ray structure of YiiP in complex with zinc at 3.8 angstrom resolution. YiiP is a homodimer held together in a parallel orientation through four Zn2+ ions at the interface of the cytoplasmic domains, whereas the two transmembrane domains swing out to yield a Y-shaped structure. In each protomer, the cytoplasmic domain adopts a metallochaperone-like protein fold; the transmembrane domain features a bundle of six transmembrane helices and a tetrahedral Zn2+ binding site located in a cavity that is open to both the membrane outer leaflet and the periplasm.
Abstract: A mathematical model of the whole-body metabolism is developed to predict fuel homeostasis during exercise by using hormonal control over cellular metabolic processes. The whole body model is composed of seven tissue compartments: brain, heart, liver, GI (gastrointestinal) tract, skeletal muscle, adipose tissue, and "other tissues". Each tissue compartment is described by dynamic mass balances and major cellular metabolic reactions. The glucagon-insulin controller is incorporated into the whole body model to predict hormonal changes during exercise. Moderate [150 W power output at 60% of peak oxygen consumption (VO(2max))] exercise for 60 min was implemented by increasing ATP utilization rates in heart and skeletal muscle. Arterial epinephrine level was given as an input function, which directly affects heart and skeletal muscle metabolism and indirectly other tissues via glucagon-insulin controller. Model simulations were validated with experimental data from human exercise studies. The exercise induced changes in hormonal signals modulated metabolic flux rates of different tissues in a coordinated way to achieve glucose homeostasis, demonstrating the efficacy of hormonal control over cellular metabolic processes. From experimental measurements of whole body glucose balance and arterial substrate concentrations, this model could predict the dynamic changes of hepatic glycogenolysis and gluconeogenesis, which are not easy to measure experimentally, suggesting the higher contribution of glycogenolysis ( approximately 75%). In addition, it could provide dynamic information on the relative contribution of carbohydrates and lipids for fuel oxidation in skeletal muscle. Model simulations indicate that external fuel supplies from other tissue/organ systems to skeletal muscle become important for prolonged exercise emphasizing the significance of interaction among tissues. In conclusion, this model can be used as a valuable complement to experimental studies due to its ability to predict what is difficult to measure directly, and usefulness to provide information about dynamic behaviors.
Abstract: Exercise is a key component for the successful management of many obesity-related metabolic complications, including insulin resistance. This review addresses the effect of chronic and acute endurance exercise on insulin action in obesity and the role of exercise-induced alterations in fatty acid partitioning within the muscle cell on insulin sensitivity.
Abstract: Assessment of the rate of muscle oxygen consumption, UO(2m), in vivo during exercise involving a large muscle mass is critical for investigating mechanisms regulating energy metabolism at exercise onset. While UO(2m) is technically difficult to obtain under these circumstances, pulmonary oxygen uptake, VO(2p), can be readily measured and used as a proxy to UO(2m). However, the quantitative relationship between VO(2p) and UO(2m) during the nonsteady phase of exercise in humans, needs to be established. A computational model of oxygen transport and utilization–based on dynamic mass balances in blood and tissue cells–was applied to quantify the dynamic relationship between model-simulated UO(2m) and measured VO(2p) during moderate (M), heavy (H), and very heavy (V) intensity exercise. In seven human subjects, VO(2p) and muscle oxygen saturation, StO(2m), were measured with indirect calorimetry and near infrared spectroscopy (NIRS), respectively. The dynamic responses of VO(2p) and StO(2m) at each intensity were in agreement with previously published data. The response time of muscle oxygen consumption, tauUO(2m) estimated by direct comparison between model results and measurements of StO(2m) was significantly faster (P \textless 0.001) than that of pulmonary oxygen uptake, tauVO(2p) (M: 13 +/- 4 vs. 65 +/- 7 s; H: 13 +/- 4 vs. 100 +/- 24 s; V: 15 +/- 5 vs. 82 +/- 31 s). Thus, by taking into account the dynamics of oxygen stores in blood and tissue and determining muscle oxygen consumption from muscle oxygenation measurements, this study demonstrates a significant temporal dissociation between UO(2m) and VO(2p) at exercise onset.
Abstract: The atomic structures of the first members of the Amt/MEP/Rh family show that they are 11-crossing membrane proteins that form trimers in the membrane. Each monomer supports a hydrophobic channel that conducts NH(3) but not any water or ions. The reprotonation of NH(3) on the receiving side raises the pH on that side in the absence of metabolism of NH(3), and there is no transfer of protons through the protein.
Abstract: Contraction induces marked metabolic changes in muscle, and the AMP-activated protein kinase (AMPK) is a good candidate to explain these effects. Recent work using a muscle-specific knockout of the upstream kinase, LKB1, has confirmed that the LKB1–\textgreaterAMPK cascade is the signaling pathway responsible for many of these effects.
Abstract: We tested the hypothesis that arterial baroreflex (ABR)-mediated beat-to-beat control over muscle sympathetic nerve activity (MSNA) is progressively modulated as orthostatic stress increases in humans, but that this control becomes impaired just before the onset of orthostatic syncope. In 17 healthy subjects, the ABR control over MSNA (burst incidence, burst strength and total MSNA) was evaluated by analysing the relationship between beat-to-beat spontaneous variations in diastolic blood pressure (DAP) and MSNA during supine rest (control) and during progressive, stepwise increases in lower body negative pressure (LBNP) that were incremented by -10 mmHg every 5 min until presyncope (nine subjects) or -60 mmHg was reached. (1) The linear relationships between DAP and burst strength and between DAP and total MSNA were shifted progressively upward as LBNP increased until the level at which syncope occurred. The relationship between DAP and burst incidence, however, gradually shifted upward from control only to LBNP = -30 mmHg; there was no further upward shift at higher LBNPs. (2) Although the slope of the relationship between DAP and burst strength and between DAP and total MSNA remained constant at all LBNPs tested, except at the level where syncope occurred, the slope of the relationship between DAP and burst incidence was reduced at LBNPs of -40 mmHg and higher (versus control). (3) In syncopal subjects, the slopes of the relationships between DAP and burst incidence, burst strength, and total MSNA were all substantially reduced during the 1-2 min period prior to the onset of syncope. Taken together, these results suggest baroreflex control over MSNA is progressively modulated as orthostatic stress increases, so that its sensitivity is substantially reduced during the period immediately preceding the severe hypotension associated with orthostatic syncope.
Abstract: The purpose of the present investigation was to determine how fasted-state protein synthesis was affected, acutely, by resistance training. Eight men (24.8+/-1.7 years, body mass index=23.2+/-1.0 kg m-2; means+/-s.e.m.) undertook an 8 week programme of unilateral resistance exercise training (3 sessions week-1, progression from two to four sets; intensity was 80% of the subjects’ single repetition maximum (1RM): knee extension and leg press). Following training, subjects underwent two primed constant infusions of l-[ring-13C6]phenylalanine to determine mixed and myofibrillar muscle protein synthesis (MPS) at rest and 12 h after an acute bout of resistance exercise at the same exercise intensity–each leg 80% of 1RM. Biopsies (vastus lateralis) were taken to measure incorporation of labelled phenylalanine into mixed and myofibrillar skeletal muscle proteins and yield fractional MPS. Training resulted in significant dynamic strength gains that were greater (P\textless0.001) in the trained leg. Hypertrophy of type IIa and IIx fibres (P\textless0.05) was observed following training. After training, resting mixed MPS rate was elevated (+48%; P\textless0.05). Acutely, resistance exercise stimulated mixed MPS only in the untrained leg (P\textless0.05). Myofibrillar MPS was unchanged at rest following training (P=0.61). Myofibrillar MPS increased after resistance exercise (P\textless0.05), but was not different between the trained and untrained legs (P=0.36). We observed divergent changes in resting mixed versus myofibrillar protein synthesis with training. In addition, resistance training modified the acute response of MPS to resistance exercise by dampening the increased synthesis of non-myofibrillar proteins while maintaining the synthesis of myofibrillar proteins.
Abstract: In humans, the strong statistical association between fitness and survival suggests a link between impaired oxygen metabolism and disease. We hypothesized that artificial selection of rats based on low and high intrinsic exercise capacity would yield models that also contrast for disease risk. After 11 generations, rats with low aerobic capacity scored high on cardiovascular risk factors that constitute the metabolic syndrome. The decrease in aerobic capacity was associated with decreases in the amounts of transcription factors required for mitochondrial biogenesis and in the amounts of oxidative enzymes in skeletal muscle. Impairment of mitochondrial function may link reduced fitness to cardiovascular and metabolic disease.
Abstract: The mechanism by which increased central adiposity causes hepatic insulin resistance is unclear. The "portal hypothesis" implicates increased lipolytic activity in the visceral fat and therefore increased delivery of free fatty acids (FFA) to the liver, ultimately leading to liver insulin resistance. To test the portal hypothesis at the transcriptional level, we studied expression of several genes involved in glucose and lipid metabolism in the fat-fed dog model with visceral adiposity vs. controls (n = 6). Tissue samples were obtained from dogs after 12 wk of either moderate fat (42% calories from fat; n = 6) or control diet (35% calories from fat). Northern blot analysis revealed an increase in the ratio of visceral to subcutaneous (v/s ratio) mRNA expression of both lipoprotein lipase (LPL) and peroxisome proliferator-activated receptor-gamma (PPARgamma). In addition, the ratio for sterol regulatory element-binding transcription factor-1 (SREBP-1) tended to be higher in fat-fed dogs, suggesting enhanced lipid accumulation in the visceral fat depot. The v/s ratio of hormone-sensitive lipase (HSL) increased significantly, implicating a higher rate of lipolysis in visceral adipose despite hyperinsulinemia in obese dogs. In fat-fed dogs, liver SREBP-1 expression was increased significantly, with a tendency for increased fatty acid-binding protein (FABP) expression. In addition, glucose-6-phosphatase (G-6-Pase) and phosphoenolpyruvate carboxykinase (PEPCK) increased significantly, consistent with enhanced gluconeogenesis. Liver triglyceride content was elevated 45% in fat-fed animals vs. controls. Moreover, insulin receptor binding was 50% lower in fat-fed dogs. Increased gene expression promoting lipid accumulation and lipolysis in visceral fat, as well as elevated rate-limiting gluconeogenic enzyme expression in the liver, is consistent with the portal theory. Further studies will need to be performed to determine whether FFA are involved directly in this pathway and whether other signals (either humoral and/or neural) may contribute to the development of hepatic insulin resistance observed with visceral obesity.
Abstract: Ciliary neurotrophic factor (CNTF) induces weight loss in obese rodents and humans, and for reasons that are not understood, its effects persist after the cessation of treatment. Here we demonstrate that centrally administered CNTF induces cell proliferation in feeding centers of the murine hypothalamus. Many of the newborn cells express neuronal markers and show functional phenotypes relevant for energy-balance control, including a capacity for leptin-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3). Coadministration of the mitotic blocker cytosine-beta-d-arabinofuranoside (Ara-C) eliminates the proliferation of neural cells and abrogates the long-term, but not the short-term, effect of CNTF on body weight. These findings link the sustained effect of CNTF on energy balance to hypothalamic neurogenesis and suggest that regulated hypothalamic neurogenesis in adult mice may play a previously unappreciated role in physiology and disease.
Abstract: Obesity occurs when energy intake exceeds energy expenditure. Humans expend energy through purposeful exercise and through changes in posture and movement that are associated with the routines of daily life [called nonexercise activity thermogenesis (NEAT)]. To examine NEAT’s role in obesity, we recruited 10 lean and 10 mildly obese sedentary volunteers and measured their body postures and movements every half-second for 10 days. Obese individuals were seated, on average, 2 hours longer per day than lean individuals. Posture allocation did not change when the obese individuals lost weight or when lean individuals gained weight, suggesting that it is biologically determined. If obese individuals adopted the NEAT-enhanced behaviors of their lean counterparts, they might expend an additional 350 calories (kcal) per day.
Abstract: OBJECTIVE: To examine whether adiponectin is independently associated with diabetes and whether adiponectin and other adipocytokines account for the relationship between fat and diabetes. RESEARCH DESIGN AND METHODS: A nested case-control study from the Health, Aging, and Body Composition (Health ABC) study. We measured four adipocytokines: adiponectin, interleukin (IL)-6, tumor necrosis factor-alpha, and plasminogen activator inhibitor 1 (PAI-1). Regional fat area was determined by computed tomography scan. The 519 case subjects had diabetes defined by fasting plasma glucose level \textgreater or =126 mg/dl or by use of diabetes medications. The 519 control subjects had normal glucose tolerance and were matched by sex, race, and study site. Sex-specific logistic models were adjusted for age, race, site, total adiposity, smoking, and physical activity. RESULTS: Higher adiponectin levels were associated with lower risk of diabetes (P \textless 0.001). Visceral fat was the only adiposity measure associated with diabetes after adjusting for BMI (odds ratio 3.0 [2.1-4.3] in women and 1.3 [1.0-1.6] in men, P \textless 0.001 between-sex comparison). Adipocytokines attenuated the association between visceral fat and diabetes for both sexes but more strongly in men (women 2.3 [1.5-3.3], men 1.1 [0.9-1.4]). In men, adiponectin, IL-6, and PAI-1 remained independently associated with diabetes after adjusting for fat depots; in women, adiponectin was the only independently associated adipocytokine. Controlling for insulin, HDL, triglycerides, and blood pressure did not change these results. CONCLUSIONS: Adiponectin is associated with lower odds of diabetes in older men and women. Whereas several adipocytokines explained the relationship between visceral adiposity and diabetes in men, only adiponectin partially mediated this association among women.
Abstract: Early reports suggested that resistin is associated with obesity and insulin resistance in rodents. However, subsequent studies have not supported these findings. To our knowledge, the present study is the first assessment in human subjects of serum resistin and insulin sensitivity by the insulin clamp technique. Thirty-eight nonobese subjects [age, 23 +/- 4 yr; body mass index (BMI), 25.4 +/- 4.3 kg/m(2)], 12 obese subjects (age, 54 +/- 8 yr; BMI, 33.0 +/- 2.5 kg/m(2)), and 22 obese subjects with type 2 diabetes (age, 59 +/- 7 yr; BMI, 34.0 +/- 2.4 kg/m(2)) were studied. Serum resistin concentrations were not different among nonobese (4.1 +/- 1.7 ng/ml), obese (4.2 +/- 1.6 ng/ml), and obese diabetic subjects (3.7 +/- 1.2 ng/ml), and were not significantly correlated to glucose disposal rate during a hyperinsulinemic glucose clamp across groups. Serum resistin was, however, inversely related to insulin sensitivity in nonobese subjects only (r = -0.35; P = 0.05), although this association was lost after adjusting for percent body fat. Serum resistin was not related to percent fat, BMI, or fat cell size. A strong correlation was observed between serum resistin and resistin mRNA expression from abdominal sc adipose tissue in a separate group of obese subjects (r = 0.62; P \textless 0.01; n = 56). Although the exact function of resistin is unknown, we demonstrated only a weak relationship between resistin and insulin sensitivity in nonobese subjects, indicating that resistin is unlikely to be a major link between obesity and insulin resistance in humans.
Abstract: Two principal forms of temperature-control strategies have evolved, i.e., poikilothermic and homeothermic life. Even in homeothermic animals, the temperature field of the body is not homogeneous. These observed temperature differences can affect cellular function directly or via the expression of heat shock or cold shock proteins.
Abstract: The key question is not why some patients have proteinuria but rather why not all people have it. In the present review, we will present an update on the glomerular barrier after the recent breakthroughs in podocyte biology. In particular, we will discuss the role of the endothelium, which seems to be a neglected part of the glomerular membrane.
Abstract: A critical defect in type 2 diabetes is impaired insulin-stimulated glucose transport and metabolism in muscle and adipocytes. To understand the metabolic adaptations this elicits, we generated mice with targeted disruption of the GLUT4 glucose transporter in both adipocytes and muscle (AMG4KO). In contrast to total body GLUT4-null mice, AMG4KO mice exhibit normal growth, development, adipose mass, and longevity. They develop fasting hyperglycemia and glucose intolerance and are at risk for greater insulin resistance than mice lacking GLUT4 in only one tissue. Hyperinsulinemic-euglycemic clamp studies showed a 75% decrease in glucose infusion rate and markedly reduced 2-deoxyglucose uptake into skeletal muscle (85-90%) and white adipose tissue (65%). However, AMG4KO mice adapt by preferentially utilizing lipid fuels, as evidenced by a lower respiratory quotient and increased clearance of lipids from serum after oral lipid gavage. While insulin action on hepatic glucose production and gluconeogenic enzymes is impaired, hepatic glucokinase expression, incorporation of 14C-glucose into lipids, and hepatic VLDL-triglyceride release are increased. The lipogenic activity may be mediated by increased hepatic expression of SREBP-1c and acetyl-CoA carboxylase. Thus, inter-tissue communication results in adaptations to impaired glucose transport in muscle and adipocytes that involve increased hepatic glucose uptake and lipid synthesis, while muscle adapts by preferentially utilizing lipid fuels. Genetic determinants limiting this "metabolic flexibility" may contribute to insulin resistance and type 2 diabetes in humans.
Abstract: We used a mathematical model of the urine concentrating mechanism of rat inner medulla (IM) to investigate the implications of experimental studies in which immunohistochemical methods were combined with three-dimensional computerized reconstruction of renal tubules. The mathematical model represents a distribution of loops of Henle with loop bends at all levels of the IM, and the vasculature is represented by means of the central core assumption. Based on immunohistochemical evidence, descending limb portions that reach into the papilla are assumed to be only moderately water permeable or to be water impermeable, and only prebend segments and ascending thin limbs are assumed to be NaCl permeable. Model studies indicate that this configuration favors the targeted delivery of NaCl to loop bends, where a favorable gradient, sustained by urea absorption from collecting ducts, promotes NaCl absorption. We identified two model modes that produce a significant axial osmolality gradient. One mode, suggested by preliminary immunohistochemical findings, assumes that aquaporin-1-null portions of loops of Henle that reach into the papilla have very low urea permeability. The other mode, suggested by perfused tubule experiments from the literature, assumes that these same portions of loops of Henle have very high urea permeabilities. Model studies were conducted to determine the sensitivity of these modes to parameter choices. Model results are compared with extant tissue-slice and micropuncture studies.
Abstract: One component of the macula densa (MD) tubuloglomerular feedback (TGF) signaling pathway may involve basolateral release of ATP through a maxi-anion channel. Release of ATP has previously been studied during a maximal luminal NaCl concentration ([NaCl](L)) stimulus (20-150 mmol/l). Whether MD ATP release occurs during changes in [NaCl](L) within the physiological range (20-60 mmol/l) has not been examined. Also, because TGF is known to be enhanced by low dietary salt intake, we examined the pattern of MD ATP release from salt-restricted rabbits. Fluorescence microscopy, with fura 2-loaded cultured mouse mesangial cells as biosensors, was used to assess ATP release from the isolated, perfused thick ascending limb containing the MD segment. The mesangial biosensor cells, which contain purinergic receptors and elevate intracellular Ca(2+) concentration ([Ca(2+)](i)) on ATP binding, were placed adjacent to the MD basolateral membrane. Elevations in [NaCl](L) between 0 and 80 mmol/l, in 20-mmol/l increments, caused stepwise increases in [Ca(2+)](i), with the highest increase at [NaCl](L) of approximately 60 mmol/l. Luminal furosemide at 10(-4) mol/l blocked ATP release, which suggests that the efflux of ATP required MD Na-2Cl-K cotransport. A low-salt diet for 1 wk increased the magnitude of [NaCl](L)-dependent elevations in biosensor [Ca(2+)](i) by twofold, whereas high-salt intake had no effect. In summary, ATP release occurs over the same range of [NaCl](L) (20-60 mmol/l) previously reported for TGF responses, and, similar to TGF, ATP release was enhanced by dietary salt restriction. Thus these two findings are consistent with the role of MD ATP release as a signaling component of the TGF pathway.
Abstract: This study describes a protocol to determine acute cerebrovascular and ventilatory (AHVR) responses to hypoxia. Thirteen subjects undertook a protocol twice, 5 days apart. The protocol started with 8 min of eucapnic euoxia (end-tidal P(CO2) (PET(CO2)= 1.5 Torr) above rest; end-tidal P(O2) (PET(O2)) = 88 Torr) followed by six descending 90 s hypoxic steps (PET(O2) = 75.2, 64.0, 57.0, 52.0, 48.2, 45.0 Torr). Then, PET(O2) was elevated to 300 Torr for 10 min while PET(O2) remained at eucapnia (5 min) then raised by 7.5 Torr (5 min). Peak blood flow velocity in the middle cerebral artery (MCA) and regional cerebral oxygen saturation (Sr(O2)) were measured with transcranial Doppler ultrasound and near-infrared spectroscopy, respectively, and indices of acute hypoxic sensitivity were calculated (AHR(CBF) and AHRSr(O2)). Values for AHR(CBF), AHRSr(O2) and AHVR were 0.43 cm s(-1) % desaturation(-1), 0.80% % desaturation(-1) and 1.24l min(-1) % desaturation(-1), respectively. Coefficients of variation for AHR(CBF), AHRSr(O2) and AHVR were small (range = 8.0-15.2%). This protocol appears suitable to quantify cerebrovascular and ventilatory responses to acute isocapnic hypoxia.
Abstract: OBJECTIVES: To investigate the changes in post-meal plasma ghrelin levels in people with different breakfast hours. DESIGN AND INTERVENTIONS: The subjects adhered to strict breakfast times starting 2 weeks before the study. Blood was drawn hourly from 0530 or 0630 until 1130. Plasma ghrelin, leptin, and insulin levels were measured by radioimmunoassay. SETTING: Medical Research Institute, Pusan National University Hospital, Korea. SUBJECTS: A total of 16 healthy volunteers. RESULTS: The mean plasma ghrelin level in subjects consuming breakfast was 548.7 +/- 239.6 fmol/ml before breakfast and 384.8 +/- 168.7 fmol/ml 1 h after breakfast, with leptin levels of 6.8 +/- 2.6 and 6.5 +/- 2.5 ng/ml, respectively. Plasma ghrelin levels were lowest 1 h after the meal, although the breakfast times differed. The plasma ghrelin level was lowest at 0730 in subjects not eating breakfast. CONCLUSIONS: These findings suggest that the plasma ghrelin levels are lowest 1 h after breakfast despite the variance in breakfast times. This timing might best reflect an individual’s plasma ghrelin level and enable reasonable comparisons.
Abstract: BACKGROUND: Resistin is a recently identified adipocyte-secreted hormone in rodents, and has been proposed to serve as a link between obesity and insulin resistance. The aim of this study was to develop a sensitive enzyme-linked immunosorbent assay (ELISA) for human resistin and evaluate serum resistin concentrations in normal subjects and patients with type 2 diabetes. METHODS: Using ELISA developed by two polyclonal antibodies, resistin concentrations were measured in 90 patients with type 2 diabetes and compared to 74 healthy control subjects. RESULTS: This ELISA has high specificity and sensitivity over the concentration of range 0.5-100 ng/ml with good percentage recovery (97.1 +/- 4.7%) and reproducibility (within-day assay, CV = 4.8-8.6%; between-day assay, CV = 5.6-9.7%). The mean concentration of resistin in sera from type 2 diabetic patients was significantly higher than that in normal subjects (mean +/- S.E.: 20.8 +/- 0.7 vs. 14.9 +/- 0.5 ng/ml, p \textless 0.001). A moderate positive correlation was observed between serum resistin levels and body mass indices in both normal subjects (r = 0.412, p \textless 0.0003) and patients with type 2 diabetes (r = 0.395, p \textless 0.0001). CONCLUSIONS: Our ELISA will be useful to confirm the physiological and pathophysiological role of resistin in humans.
Abstract: Hormones produced by adipose tissue play a critical role in the regulation of energy intake, energy expenditure, and lipid and carbohydrate metabolism. This review will address the biology, actions, and regulation of three adipocyte hormones-leptin, acylation stimulating protein (ASP), and adiponectin-with an emphasis on the most recent literature. The main biological role of leptin appears to be adaptation to reduced energy availability rather than prevention of obesity. In addition to the well-known consequences of absolute leptin deficiency, subjects with heterozygous leptin gene mutations have low circulating leptin levels and increased body adiposity. Leptin treatment dramatically improves metabolic abnormalities (insulin resistance and hyperlipidemia) in patients with relative leptin deficiency due to lipoatrophy. Leptin production is primarily regulated by insulin-induced changes of adipocyte metabolism. Dietary fat and fructose, which do not increase insulin secretion, lead to reduced leptin production, suggesting a mechanism for high-fat/high-sugar diets to increase energy intake and weight gain. ASP increases the efficiency of triacylglycerol synthesis in adipocytes leading to enhanced postprandial lipid clearance. In mice, ASP deficiency results in reduced body fat, obesity resistance, and improved insulin sensitivity. Adiponectin production is stimulated by thiazolidinedione agonists of peroxisome proliferator-activated receptor-gamma and may contribute to increased insulin sensitivity. Adiponectin and leptin cotreatment normalizes insulin action in lipoatrophic insulin-resistant animals. These effects may be mediated by AMP kinase-induced fat oxidation, leading to reduced intramyocellular and liver triglyceride content. The production of all three hormones is influenced by nutritional status. These hormones, the pathways controlling their production, and their receptors are promising targets for managing obesity, hyperlipidemia, and insulin resistance.
Abstract: Obesity is highly correlated with insulin resistance and the development of type 2 diabetes. Insulin resistance will result in a decrease in insulin’s ability to stimulate glucose uptake into peripheral tissue and will suppress glucose production by the liver. However, the development of peripheral and hepatic insulin resistance relative to one another in the context of obesity-associated insulin resistance is not well understood. To examine this phenomena, we used the moderate fat-fed dog model, which has been shown to develop both subcutaneous and visceral adiposity and severe insulin resistance. Six normal dogs were fed an isocaloric diet with a modest increase in fat content for 12 weeks, and they were assessed at weeks 0, 6, and 12 for changes in insulin sensitivity and glucose turnover. By week 12 of the diet, there was a more than twofold increase in trunk adiposity as assessed by magnetic resonance imaging because of an accumulation in both subcutaneous and visceral fat depots with very little change in body weight. Fasting plasma insulin had increased by week 6 (150% of week 0) and remained increased up to week 12 of the study (170% of week 0). Surprisingly, there appeared to be no change in the rates of insulin-stimulated glucose uptake as measured by euglycemic-hyperinsulinemic clamps throughout the course of fat feeding. However, there was an increase in steady-state plasma insulin levels at weeks 6 and 12, indicating a moderate degree of peripheral insulin resistance. In contrast to the moderate defect seen in the periphery, there was a marked impairment in insulin’s ability to suppress endogenous glucose production during the clamp such that by week 12 of the study, there was a complete inability of insulin to suppress glucose production. Our results indicate that a diet enriched with a moderate amount of fat results in the development of both subcutaneous and visceral adiposity, hyperinsulinemia, and a modest degree of peripheral insulin resistance. However, there is a complete inability of insulin to suppress hepatic glucose production during the clamp, suggesting that insulin resistance of the liver may be the primary defect in the development of insulin resistance associated with obesity.
Abstract: BACKGROUND: Many studies have reported that blocking the renin-angiotensin-system (RAS) with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker in the patient with diabetes mellitus leads to an increase in renal plasma flow (RPF), no change in glomerular filtration rate (GFR), and a fall in filtration fraction. This constellation is generally attributed to predominant efferent arteriolar dilation. METHODS: This study examined the renal hemodynamic response to blocking the RAS with both captopril and candesartan on separate days in 31 patients with type 1 diabetes mellitus. RESULTS: There was a wide range of changes in RPF and GFR in response to the two agents, each administered at the top of its dose-response range. The RPF response to the two agents was strongly concordant (r = 0.65; P \textless 0.001), as was the GFR response (r = 0.81; P \textless 0.001). Moreover, there was a strong correlation between the RPF response and the change in GFR with each agent (r = 0.83 and 0.66; P \textless 0.01). A significant rise in RPF was followed by a rise in GFR. The RPF dependency of GFR in the type 1 diabetics suggests strongly that glomerular filtration equilibrium exists in the glomeruli of the diabetic kidney: Simple notions of local control based on afferent:efferent arteriolar resistance ratios are too simplistic. CONCLUSION: Our data suggest that the intrarenal RAS is activated in over 80% of patients with type 1 diabetes mellitus. Abundant evidence suggests that this activation predisposes to diabetic nephropathy.
Abstract: Obesity has become a worldwide public health problem affecting millions of people. A disruption of the balance between energy intake and energy expenditure is believed to be the major cause of obesity. Substantial progress has been made in deciphering the pathogenesis of energy homeostasis over the past few years. The fact that obesity is under strong genetic control has been well established. Human monogenic obesity is rare in large populations, the most common form of obesity is considered to be a polygenic disorder arising from the interaction of multiple genetic and environmental factors. Here, we attempt to briefly review the most recent understanding of molecular mechanisms involved in energy homeostasis and adipogenesis. We discuss the advantages and disadvantages of various approaches commonly used in search for susceptibility genes for obesity. The main results from these genetic studies are summarized, with comments made on the most striking or representative findings. Finally, the implications of the recent advances in the understanding of molecular genetic mechanisms of body weight regulation on prevention and therapeutic intervention of obesity will be discussed.
Abstract: BACKGROUND: Fusion of the carboxyterminal peptide (CTP) of hCG to FSH results in a follitropin agonist with an extended half-life, presumably due to the four O-oligosaccharides on the CTP. Alternatively, an rhFSH analogue containing additional N-linked carbohydrate is described in this report. METHODS: A DNA sequence containing two N-oligosaccharide signal sequences was ligated into a vector containing hFSHbeta- and alpha-subunit encoding cDNA, and expressed in CHO-K1 cells. In-vitro bioactivity of the single-chain hormone was assessed in CHO cells expressing the hFSH receptor. Pharmacokinetic values were derived from serial serum assays of the analogue in immature female rats following a single i.v. injection. In-vivo bioactivity was assessed by measuring ovarian weight gain 3 days post-injection. RESULTS: rhFSH-N2 and native rhFSH induced comparable levels of cAMP in vitro. t(1/2) for native rhFSH, rhFSH-CTP and rhFSH-N2 were 3.7, 7.1 and 7.3 h respectively. Rats receiving rhFSH-N2 had a mean +/- SD ovarian weight 3 days post-i.v. injection (22 +/- 3.6 mg) significantly greater than rats receiving rhFSH and saline (16.7 +/- 1.5 and 15.3 +/- 0.47 mg respectively, P \textless 0.05). CONCLUSIONS: rhFSH-N2 has prolonged half-life and increased bioactivity compared with native rhFSH. This rhFSH agonist, and other analogues containing additional N-oligosaccharides may have important clinical applications.
Abstract: The use of angiotensin converting enzyme inhibitors (ACEIs) along with good blood pressure control have been shown to significantly decrease the level of proteinuria and slow the progression of renal insufficiency in patients with nondiabetic glomerular disease including focal segmental glomerulosclerosis (FSGS). Thus, this should be part of the therapeutic approach for all proteinuric patients with FSGS and should be considered the mainstay of therapy for patients with FSGS secondary to conditions associated with hyperfiltration and/or reduced nephron mass and those patients with nonnephrotic primary FSGS. However, nephrotic patients with primary FSGS may continue to have marked proteinuria and progression of renal disease despite these measures and thus require a more aggressive approach with the use of steroids and immunosuppressive agents. Although primary FSGS was once thought to be a steroid-nonresponsive lesion, recent experience has provided a note of optimism in the use of steroids and immunosuppressive agents in treating this otherwise progressive glomerulopathy. As a result, a course of steroid therapy in primary FSGS is now warranted in nephrotic patients with reasonably well preserved renal function in whom it is not otherwise contraindicated.
Abstract: To investigate the regulation of leptin secretion and pulsatility by fat mass, we performed overnight leptin sampling every 20 min for 12 h and compared leptin dynamics with total body and regional fat measurements in 20 healthy male subjects. Simultaneous growth hormone (GH), cortisol, and insulin levels were assessed to determine relatedness and synchronicity during overnight fasting. Deconvolution analyses were performed to determine simultaneous hormonal dynamics, synchronicity, and interrelatedness using cross-correlation and cross-approximate entropy (X-ApEn) analyses. Subjects demonstrated 4.7 +/- 0.4 leptin pulses/12 h. Leptin secretion correlated highly with total body fat (r = 0.78, P \textless 0.001) and regional fat depots. In contrast, leptin pulsatility did not correlate with total fat (r = 0.07, P = 0.785) or other measures of fat. There was synchronicity between GH and leptin (lag -39 minutes), cortisol and leptin (lag -211 min), and leptin and insulin, with leptin following insulin by 275 min. The mean random X-ApEn was significant between leptin and GH (0.854 +/- 0.030), cortisol (0.891 +/- 0.023), and insulin (0.868 +/- 0.034), demonstrating a high degree of regularity and pattern frequency. These data demonstrate differential regulation of leptin secretion and pulsatility in adipocytes and suggest that the leptin pulse generator is extrinsic to fat, whereas fat mass acts as an amplifier to modulate secretion and amplitude for a given pulsatility. We demonstrate synchronicity between leptin and GH, cortisol, and insulin. The directionality of the cross correlation suggests a temporal construct in which changes in leptin follow those of insulin but precede those of GH and cortisol during overnight fasting.
Abstract: Selective immunoglobulin A (IgA) deficiency may result in a predisposition to recurrent sinopulmonary infection and allergic diseases. IgA deficiency may also play a role in the development of autoimmune disorders. Selective IgA deficiency associated with glomerulonephritis was rare, while the clinical presentation in IgA deficiency-associated glomerulonephritis was variable. We report an 83 year-old male with selective IgA deficiency associated with membranous glomerulonephritis. He presented with nephrotic syndrome. Percutaneous renal needle biopsy showed diffuse global thickening and rigidity of glomerular capillary walls, mildly diffuse segmental expansion of mesangial matrix, focal and cortical scar with segmental obsolescence of glomeruli. Heavy IgG and moderate C3 deposits were found on immunofluorescence. We also review the previous cases of IgA deficiency with glomerulonephritis. Several clues were rendered to establish the association between IgA deficiency and membranous glomerulonephritis.
Abstract: To study effects of sex on free fatty acid (FFA)-induced insulin resistance, we have examined the effects of acute elevations of plasma FFA levels on insulin-stimulated total body glucose uptake in nine healthy young women. Euglycemic-hyperinsulinemic (approximately 500 pmol/l) clamps were performed for 4 h with coinfusion of either lipid/heparin (L/H) to acutely raise plasma FFA levels (from approximately 600 to approximately 1,200 micro mol/l) or saline/glycerol to lower fatty acids (from approximately 600 to approximately 50 micro mol/l). L/H infusion inhibited insulin-stimulated glucose uptake (determined with [3-(3)H]glucose) and glycogen synthesis by 31 and 40%, respectively (P \textless 0.01), almost completely abolished insulin suppression of endogenous glucose production (EGP) (13.6 vs. 10.0 micro mol x kg(-1) x min(-1), NS), prevented the insulin induced increase in carbohydrate oxidation (8.1 vs. 7.4 micro mol x kg(-1) x min(-1), NS), and stimulated fat oxidation (from 3.6 to 5.1 micro mol x kg(-1) x min(-1), P \textless 0.01). These data showed that acute increases in plasma FFA levels inhibited the actions of insulin on glucose uptake, glycogen synthesis, and EGP in women to a degree similar to that previously reported in men. We conclude that at insulin and FFA levels in the postprandial range, women and men were susceptible to FFA-induced peripheral and hepatic insulin resistance.
Abstract: Low-dose dopamine administration (ie, doses \textless 5 microg/kg/min) has been advocated for 30 years as therapy in oliguric patients on the basis of its action on dopaminergic renal receptors. Recently, a large, multicenter, randomized, controlled trial has demonstrated that low-dose dopamine administered to critically ill patients who are at risk of renal failure does not confer clinically significant protection from renal dysfunction. In this review, we present the best evidence and summarize the effects of low-dose dopamine infusion in critically ill patients. We review the history and physiology of low-dose dopamine administration and discuss the reasons why dopamine is not clinically effective in the critically ill. In addition to the lack of renal efficacy, we present evidence that low-dose dopamine administration worsens splanchnic oxygenation, impairs GI function, impairs the endocrine and immunologic systems, and blunts ventilatory drive. We conclude that there is no justification for the use of low-dose dopamine administration in the critically ill.
Abstract: Heat acclimation enhances cardiac efficiency by increasing stroke volume and decreasing heart rate. These adaptations involve biochemical changes in the contractile apparatus, switched on by altered expression of genes coding contractile and calcium-regulatory proteins and partially mediated by persistent low thyroxine. Heat acclimation also produces cross-tolerance to oxygen deprivation, thus reinforcing cardiac adaptation to oxygen demand/supply mismatching via energy-sparing pathways.
Abstract: There is marked variation in the frequency of focal segmental glomerulosclerosis (FSGS) around the world. Recent studies of renal biopsy specimen archives from several institutions in the United States suggest that the incidence of FSGS has increased over the past 20 years. Indeed, FSGS has become the leading cause of idiopathic nephrotic syndrome in adults and has become increasingly common in children as well. Further, the data indicate that black individuals are at increased risk for developing idiopathic FSGS as well as FSGS in the setting of human immunodeficiency virus (HIV)-1 infection. Data from around the world suggest great variability in the proportion of glomerular disease that is attributed to FSGS, with recent increases seen in some countries and not in others. Epidemiologic data from the United States Renal Data Systems (USRDS) show that the incidence of end-stage renal disease (ESRD) owing to idiopathic FSGS has increased considerably, both as absolute numbers and as a fraction of the total ESRD incident population, with FSGS now accounting for 3.3% of incident ESRD cases. In the United States, the annual rate of incident FSGS ESRD cases is 7 per million for the general population, 20 per million for black individuals, and 5 per million for white individuals. The numbers of acquired immune deficiency syndrome (AIDS) nephropathy incident ESRD cases increased rapidly until reaching a plateau after 1995. The reasons for the recent increase in idiopathic FSGS and FSGS incident ESRD cases are complex, but these trends are likely caused, at least in part, by a real increase in the incidence of FSGS over the past 10 to 20 years.
Abstract: 1. Left ventricular hypertrophy (LVH) of the heart is an adaptive response to sustained increases in blood pressure and hormone imbalances. Left ventricular hypertrophy is associated with programmed responses at the molecular and biochemical level in different subsets of cardiac cells, including the cardiac muscle cells (cardiomyocytes), fibroblasts, conductive tissue and coronary vasculature. 2. Regardless of the initiating cause, the actual increase in chamber enlargement is, in each case, due to an increase in size of a pre-existing cardiomyocyte population, with little or no change in their number; a process referred to as cellular hypertrophy. 3. An accelerated rate of global protein synthesis is the primary mechanism by which protein accumulation increases during cardiomyocyte hypertrophy. In turn, increased rates of synthesis are a result of increased translational rates of existing ribosomes (translational efficiency) and/or synthesis and recruitment of additional ribosomes (translational capacity). 4. The present review examines the relative importance of translational capacity and translational efficiency in the response of myocytes to acute and chronic demands for increased protein synthesis and the role of these mechanisms in the development of LVH.
Abstract: A mathematical description of the regulation of ATP production in muscle cells is presented whereby the activity of OxP can be calculated as a function of (1) free [ADP] as the substrate and (2) a second driving force PhiDelta G (kilojoules per mole) resulting from the difference of free energy Delta G(ox,ap) (kilojoules per mole)-Delta G(ATP,cyt) (kilojoules per mole). In turn, the term Delta G(ox,ap) results from the proton motive force and the generation of ATP in the matrix space including the ATP-ADP exchange, whereas the phosphorylation state of the CHEP-sytem is described by Delta G(ATP,cyt). Regulation of glycolysis is calculated as a function of free [ADP] and [AMP] at the level of PFK. The PFK is inhibited by a decreasing pH resulting from lactate accumulation. The ATP/PCr equilibrium of the CHEP-system is calculated by algebraic equations. The dynamic behaviour of the metabolic control of ATP production as a function of ATP consumption is calculated by a system of two 1st-order non-linear differential equations, including a time delay considering oxygen transport. Lactate distribution and elimination is calculated using a two-compartment model with an active lactate producing, and a passive, space including lactate elimination by combustion. The simulation of the dynamics of energy metabolism of muscle cells is performed by the stepwise solution of the differential equations with a 5th-order Runge-Kutta-Fehlberg-routine. Examples of various applications of the simulation of the dynamics of energy supply demonstrate the qualitative and quantitative congruence to the behaviour of metabolic processes in experiments during rest, exercise and recovery.
Abstract: It is well established that altering O2 delivery to contracting skeletal muscle affects human performance. In this respect, a reduced O2 supply (e.g., hypoxia) increases the rate of muscle fatigue, whereas increasing O2 supply (e.g., hyperoxia) reduces the rate of fatigue. Interestingly, the faster onset of fatigue in moderate hypoxia does not appear to be a consequence of mitochondrial O2 limitation because these effects occur at submaximal rates of O2 consumption for these conditions and at O2 tensions well above that which impairs mitochondrial O2 uptake in vitro. Alterations in O2 supply modulate the regulation of cellular respiration and may affect the onset of impaired Ca2+ handling with fatigue. Specifically, changes in O2 supply alter the coupling between phosphocreatine hydrolysis and O2 uptake in contracting muscles, which by determining the rate of inorganic phosphate (Pi) accumulation may affect Ca2+ release. Partial ischemia differs somewhat in that the reduction in force could be due to reduced O2 supply and/or impaired removal of metabolic by-products secondary to insufficient blood flow. Nonetheless, recent evidence shows a parallel decline and restoration of force with alterations in O2 supply but not blood flow alone during submaximal contractions. Furthermore, the causes of fatigue are similar when O2 is plentiful and when it is reduced.
Abstract: Obese patients show marked impairment in spontaneous secretion as well as in the somatotroph responsiveness to all provocative stimuli. GH insufficiency in obese patients has been reported reversible after long-term diet and marked weight loss but somatotroph secretion is not restored by fasting. Among potential neuroendocrine causes, GHRH hypoactivity has been shown but it is likely that alterations in the influence of ghrelin, the gastric-derived natural ligand of the GHS-R, and or of the NPY/leptin interplay could have a role. Among metabolic alterations, the chronic elevation of FFA levels and hyperinsulinism probably have a key role in causing GH insufficiency in obesity. Despite marked GH insufficiency, total IGF-I levels are basically preserved while free IGF-I levels are even increased thus questioning real hypoactivity of GH/IGF-I axis in obesity. Peripheral GH hypersensitivity due to increased GH receptor status, hyperinsulinism and reduced IGFBP-I levels likely explain almost normal total IGF-I and increased free IGF-I levels which, in turn, probably exert an increased negative feedback action on somatotroph cells.
Abstract: We have developed a mathematical model of the regulation of ventilation that successfully simulates breathing in the awake as well as in sleeping states. In previous models, which were used to simulate Cheyne-Stokes breathing and respiration during sleep, the controller was only responsive to chemical stimuli, and allowed no ventilation at sub-normal carbon dioxide levels. The current model includes several new features. The chemical controller responds continuously to changes in P(CO(2)) with a lower sensitivity during hypocapnia than in the hypercapnic ranges. Hypoxia interacts multiplicatively with P(CO(2)) over the entire range of activity. The controller in the current model, besides the chemical drive, includes also a neural component. This neural drive increases and decreases as the level of alertness changes, and adds or subtracts from ventilation levels demanded by the chemical controller. The model also includes the effects of post-stimulus potentiation (PSP) and hypoxic ventilatory depression (HVD). While PSP eliminates apneas after a disturbance and also dampens the subsequent dynamics of the respiration, it is not a major factor in the damping of the response. Another finding is that HVD is destabilizing. The model is the first to reproduce results reported in conscious humans after hyperventilation and after acute and longer-term hypoxia. It also reproduces the effects of NREM sleep.
Abstract: The brain possesses an intrinsic regulatory mechanism to maintain an adequate supply of O(2) and nutrition despite local increases in neuronal activity. Brain astrocytes function as an intermediary cell type by responding to glutamate released from activated neurons, and they couple cerebral blood flow by producing cytochrome P-450-derived epoxyeicosatrienoic acids that induce vasodilation and increase capillary density.
Abstract: OBJECTIVE: To examine associations between weight gain and changes in blood pressure and the incidence of hypertension in four ethnicity-gender groups. DESIGN: Longitudinal closed cohort studied over an average of 6 y. SUBJECTS: Total of 9309 white and African-American men and women 45-64 y of age who participated in the Atherosclerosis Risk in Communities (ARIC) Study. METHODS: Weight and blood pressure were measured at baseline and after an average of 3 and 6 y of follow-up. Proportional hazard models with weight gain as a time-dependent variable were used to examine the association between weight gain and changes in blood pressure and hypertension. Multivariate models were used with baseline SBP, DBP, age, BMI, height, WHR, smoking, physical activity, education, caloric intake, fat intake and study center as covariates. RESULTS: Weight gain was associated with increases in SBP and DBP in all groups. Hazard ratios for hypertension associated with 1 kg annual weight gain were 1.36 (95% CI, 1.29, 1.45) in white women, 1.12 (95% CI, 1.03, 1.21) in African-American women, 1.35 (95% CI, 1.27, 1.43) in white men and 1.43 (95% CI, 1.27,1.61) in African-American men. CONCLUSION: Weight gain was associated with increased blood pressure and increased incidence of hypertension. The association was weaker among African-American women compared to other ethnicity-gender groups.
Abstract: For many years, physiologists have puzzled over the observation that, during maximum aerobic exercise, high-altitude natives generate lower-than-expected amounts of lactate; the higher the altitude, the lower the postexercise blood lactate peak. This paradoxical situation may be caused mainly by upregulated metabolic control contributions from cell ATP demand and ATP supply pathways.
Abstract: The textbook view that projections of the arachnoid membrane into the cranial venous sinuses represent the primary cerebrospinal fluid (CSF) absorption sites seems incompatible with many clinical and experimental observations. On balance, there is more quantitative evidence suggesting a function for extracranial lymphatic vessels than exists to support a role for arachnoid villi and granulations in CSF transport.
Abstract: Bed rest reduces orthostatic tolerance. Despite decades of study, the cause of this phenomenon remains unclear. In this report we examined hemodynamic and sympathetic nerve responses to graded lower body negative pressure (LBNP) before and after 24 h of bed rest. LBNP allows for baroreceptor disengagement in a graded fashion. We measured heart rate (HR), cardiac output (HR x stroke volume obtained by echo Doppler), and muscle sympathetic nerve activity (MSNA) during a progressive and graded LBNP paradigm. Negative pressure was increased by 10 mmHg every 3 min until presyncope or completion of -60 mmHg. After bed rest, LBNP tolerance was reduced in 11 of 13 subjects (P \textless.023), HR was greater (P \textless.002), cardiac output was unchanged, and the ability to augment MSNA at high levels of LBNP was reduced (rate of rise for 30- to 60-mmHg LBNP before bed rest 0.073 bursts x min(-1) x mmHg(-1); after bed rest 0.035 bursts x min(-1) x mmHg(-1); P \textless 0.016). These findings suggest that 24 h of bed rest reduces sympathetic nerve responses to LBNP.
Abstract: The intramuscular microdialysate lactate concentration during dynamic exercise with various degrees of blood flow restriction and its relation to lactate concentration in skeletal muscle biopsy and venous blood were studied. Nine healthy males performed three one-legged knee extension exercises (Ex 1-3). Blood flow was restricted stepwise by applying supra-atmospheric pressure over the working leg. Microdialysate mean (range) lactate concentrations at the end of the exercise periods were 3.2 (0.5-6.6), 4.4 (1.1-9.8) and 7.9 (1.1-11.6) mmol.l(-1)during unrestricted, moderately restricted and severely restricted blood flow respectively. There was a significant correlation between microdialysate and venous lactate concentrations at the end of all three exercise periods. Microdialysate lactate concentration correlated significantly to skeletal muscle biopsy lactate concentration at the end of Ex 1. In conclusion, microdialysate lactate concentration in the working muscle increased step-wise with increasing blood flow restriction. It showed a better correlation to venous than to muscle biopsy lactate, which is possibly partly explained by the characteristics of diffusion between body compartments and differences in time resolution between the methods used.
Abstract: This study was designed to study the influence of gender and lateral hemispheric asymmetry on heart rate modulation during temporal lobe seizures. Heart rate was recorded during complex partial seizures in 10 female and 11 male patients (12 with a right temporal lobe focus, nine with a left focus), with simultaneous video monitoring and bilateral subdural electrode placement. Heart rate changes were analysed during the seizure, at a time when the epileptic activity was restricted to one hemisphere. In this analysed interval, the heart rate of patients with a right temporal lobe focus showed a significant increase, from 73.5 to 91.0 beats/min (F = 10.7, df = 2.3/27, p \textless 0.001), while the heart rate of patients with a left sided focus only increased slightly, from 77.0 to 82.5 beats/min (NS). An effect of sex was demonstrated, in that the influence of focus laterality could only be shown in male patients (F = 14.24, df = 2.58/27, p \textless 0.001). These results confirm the right hemispheric lateralisation of sympathetic cardiac control in male patients.
Abstract: OBJECTIVES: Obesity is an important risk factor for the development of insulin resistance and type 2 diabetes. Recently, a newly described circulating hormone resistin, which is expressed primarily in adipocytes, has been shown to antagonize insulin action in mice. Resistin, therefore, has been suggested to play a role in the pathogenesis of insulin resistance. RESEARCH METHODS AND PROCEDURES: We studied the expression of the resistin gene in primary cultured human adipocytes and preadipocytes. We also examined resistin gene expression in subcutaneous abdominal adipocytes in women (n = 24) over a wide range of body weight and insulin sensitivity. RESULTS: Whereas resistin gene expression was barely detectable in mature adipocytes, it was highly expressed in preadipocytes. Adipogenic differentiation of preadipocytes was associated with a time-dependent down-regulation of resistin gene expression. There was no relationship between body weight, insulin sensitivity, or other metabolic parameters and adipocyte resistin gene expression in the clinical study. DISCUSSION: Together these findings do not support an important role of adipose-tissue resistin gene expression in human insulin resistance.
Abstract: Cardiovascular, cerebrovascular and peripheral vascular diseases are the largest cause-specific reason for morbidity and mortality in end-stage renal disease (ESRD) patients. High prevalence of cardio- and cerebrovascular death may be explained by multiple factors present in patients with progressive renal disease, including hypertension, hyprelipidemia, hyperhomocysteinemia, diabetes mellitus, and hyperparathyroidism. Experimental studies have provided in vivo and in vitro data to support the notion that lipid abnormalities contribute to glomerular and interstitial injury of the renal parenchyma. Hypercholesterolemia and increased low-density lipoprotein (LDL) cholesterol are prevalent in patients with the nephrotic syndrome. Plasma high-density lipoprotein (HDL) cholesterol is decreased, and reverse cholesterol transport is impaired in hemodialysis (HD) and pre-ESRD patients. Chronic renal failure patients treated with HD have an increased prevalence of intermediate-density lipoprotein (IDL), and lipoprotein(a). The findings in the diabetic patients corresponded to those in non-diabetic patients with renal failure, but diabetic patients have higher apolipoprotein C-III and apolipoprotein E concentrations. Impaired lipid metabolism is common in patients receiving peritoneal dialysis (PD). In the most of the ESRD patients treated with peritoneal dialysis hypercholesterolemia and hypertriglyceridemia are found. Wide panels of therapeutic interventions aimed at correcting the lipid abnormalities that may develop in chronic renal patients, as well as in ESRD patients are currently available. Although some novel pharmacological agents are remarkably effective for returning the lipid abnormalities to normal, there is still no convincing evidence based on long-term prospective studies which clearly demonstrate a significant reduction in cardiovascular morbidity and mortality of ESRD patients. The therapeutic approaches, which may be considered, include mainly dietary and life-style modifications, selective use of some technical components of dialysis systems, and the judicious prescriptions of lipid-lowering drugs.
Abstract: Orthostatic intolerance is common when astronauts return to Earth: after brief spaceflight, up to two-thirds are unable to remain standing for 10 min. Previous research suggests that susceptible individuals are unable to increase their systemic vascular resistance and plasma noradrenaline concentrations above pre-flight upright levels. In this study, we tested the hypothesis that adaptation to the microgravity of space impairs sympathetic neural responses to upright posture on Earth. We studied six astronauts approximately 72 and 23 days before and on landing day after the 16 day Neurolab space shuttle mission. We measured heart rate, arterial pressure and cardiac output, and calculated stroke volume and total peripheral resistance, during supine rest and 10 min of 60 deg upright tilt. Muscle sympathetic nerve activity was recorded in five subjects, as a direct measure of sympathetic nervous system responses. As in previous studies, mean (+/- S.E.M.) stroke volume was lower (46 +/- 5 vs. 76 +/- 3 ml, P = 0.017) and heart rate was higher (93 +/- 1 vs. 74 +/- 4 beats min(-1), P = 0.002) during tilt after spaceflight than before spaceflight. Total peripheral resistance during tilt post flight was higher in some, but not all astronauts (1674 +/- 256 vs. 1372 +/- 62 dynes s cm(-5), P = 0.32). No crew member exhibited orthostatic hypotension or presyncopal symptoms during the 10 min of postflight tilting. Muscle sympathetic nerve activity was higher post flight in all subjects, in supine (27 +/- 4 vs. 17 +/- 2 bursts min(-1), P = 0.04) and tilted (46 +/- 4 vs. 38 +/- 3 bursts min(-1), P = 0.01) positions. A strong (r(2) = 0.91-1.00) linear correlation between left ventricular stroke volume and muscle sympathetic nerve activity suggested that sympathetic responses were appropriate for the haemodynamic challenge of upright tilt and were unaffected by spaceflight. We conclude that after 16 days of spaceflight, muscle sympathetic nerve responses to upright tilt are normal.
Abstract: The objective of this study was to compare renal interstitial hydrostatic pressure (RIHP) and sodium excretion in female and male Sprague-Dawley (SD) rats. The RIHP and pressure natriuresis responses were determined in female (n=13) and male (n=8) SD rats. Renal perfusion pressure (RPP) was controlled at two levels (100 and 120 mm Hg). Clearances were taken at each level and RIHP was measured with a chronically implanted polyethylene matrix in all rats. At the lower RPP level, RIHP was similar in both groups of rats (5.2+/-0.2 mm Hg for female, and 5.5+/-0.4 mm Hg for male), whereas fractional excretion of sodium (FENa) was significantly lower (P \textless .05) in male (1.10+/-0.27%) as compared to female (2.23+/-0.32%) rats at similar lower RPP. Allowing RPP to increase from 100 to 120 mm Hg resulted in similar increases in FENa (deltaFENa), urine flow rate (deltaV), and RIHP (deltaRIHP) in both groups of rats. The deltaFENa, deltaV, and deltaRIHP were 1.67+/-0.43%, 38.45+/-4.74 microL/min/g kidney weight, and 2.7+/-0.2 mm Hg for female, and 1.79+/-0.42%, 30.40+/-4.37 microl/min/g kidney weight, and 2.8+/-0.3 mm Hg for male rats. In conclusion, RIHP is similar in female and male SD rats at similar RPP levels. Both female and male SD rats increase RIHP and sodium excretion similarly in response to increases in RPP. The lower basal FENa in male as compared to female rats may play an important role in the more significant elevation of blood pressure in males with age.
Abstract: Most astronauts lose body mass during their stay in microgravity. The early hypothesis, which attributed this phenomenon to an increase in diuresis and natriuresis after entering microgravity, is now untenable. Although a fluid shift from the lower to the upper body occurs, it does not lead to a marked fluid loss in the first 2 days of space flight. The continuous day-by-day body mass measurement during the Euromir 94 mission showed that there was a gradual reduction over the entire mission instead of a rapid loss of 2 to 3 kg at the beginning of a mission. The daily energy intake during this mission and the negative energy balances found in the Skylab and LMS-Mission show that lowered body mass is very likely caused by an insufficient energy consumption and its accompanying effects. These include the metabolization of endogenous energy stores, ie, glycogen, protein, and fat. Mobilization of glycogen and protein buffers will also cause the water that is bound to both to be lost. Thus, a gradual decrease in body mass and a concomitant reduction in total body fluid occurs without a significant increase in urine flow or natriuresis. In conclusion, the body mass loss in microgravity is likely a result of undernutrition instead of diuresis and natriuresis caused by the fluid shift.
Abstract: Humans subjected to prolonged periods of bed rest or microgravity undergo deconditioning of the cardiovascular system, characterized by resting tachycardia, reduced exercise capability, and a predisposition for orthostatic intolerance. These changes in cardiovascular function are likely due to a combination of factors, including changes in control of body fluid balance or cardiac alterations resulting in inadequate maintenance of stroke volume, altered arterial or venous vascular function, reduced activation of cardiovascular hormones, and diminished autonomic reflex function. There is evidence indicating a role for each of these mechanisms. Diminished reflex activation of the sympathetic nervous system and subsequent vasoconstriction appear to play an important role. Studies utilizing the hindlimb-unloaded (HU) rat, an animal model of deconditioning, evaluated the potential role of altered arterial baroreflex control of the sympathetic nervous system. These studies indicate that HU results in blunted baroreflex-mediated activation of both renal and lumbar sympathetic nerve activity in response to a hypotensive stimulus. HU rats are less able to maintain arterial pressure during hemorrhage, suggesting that diminished ability to increase sympathetic activity has functional consequences for the animal. Reflex control of vasopressin secretion appears to be enhanced following HU. Blunted baroreflex-mediated sympathoexcitation appears to involve altered central nervous system function. Baroreceptor afferent activity in response to changes in arterial pressure is unaltered in HU rats. However, increases in efferent sympathetic nerve activity for a given decrease in afferent input are blunted after HU. This altered central nervous system processing of baroreceptor inputs appears to involve an effect at the rostral ventrolateral medulla (RVLM). Specifically, it appears that tonic GABAA-mediated inhibition of the RVLM is enhanced after HU. Augmented inhibition apparently arises from sources other than the caudal ventrolateral medulla. If similar alterations in control of the sympathetic nervous system occur in humans in response to cardiovascular deconditioning, it is likely that they play an important role in the observed tendency for orthostatic intolerance. Combined with potential changes in vascular function, cardiac function, and hypovolemia, the predisposition for orthostatic intolerance following cardiovascular deconditioning would be markedly enhanced by blunted ability to reflexly activate the sympathetic nervous system.
Abstract: OBJECTIVE: We compared the effects of thromboxane receptor antagonist and synthase inhibitor DTTX30 on systemic and liver blood flow, oxygen (O2) exchange and energy metabolism during 24 h of hyperdynamic endotoxemia with untreated endotoxemia. DESIGN: Prospective, randomized, experimental study with repeated measures. SETTING: Investigational animal laboratory. SUBJECTS: Twenty-seven domestic pigs: 16 during endotoxemia with volume resuscitation alone; 11 with endotoxemia, volume resuscitation and treatment with DTTX30. INTERVENTIONS: Continuous infusion of Escherichia coli lipopolysaccharide (LPS) for 24 h together with volume resuscitation. After 12 h of endotoxemia, DTTX30 was administered as a bolus of 0.12 mg kg-1 followed by 12 h continuous infusion of 0.29 mg kg-1 per h. MEASUREMENTS AND RESULTS: DTTX30 effectively counteracted the endotoxin-associated increase in TXB2 levels and increased 6-keto-PGF1 alpha with a significant shift of the thromboxane/prostacyclin ratio towards predominance of prostacyclin. DTTX30 prevented the significant progressive endotoxin-induced decrease of mean arterial pressure (MAP) below baseline while maintaining cardiac output (CO), and increased the fractional contribution of liver blood flow to CO without an effect on either hepatic O2 delivery or O2 uptake. The mean capillary hemoglobin O2 saturation (HbO2) on the liver surface and HbO2 frequency distributions remained unchanged as well. CONCLUSIONS: DTTX30 significantly attenuated the endotoxin-induced derangements of cellular energy metabolism as reflected by the diminished progressive decrease in hepatic lactate uptake rate and a blunted increase in hepatic venous lactate/pyruvate ratios. While endotoxin significantly increased the endogenous glucose production (EGP) rate, EGP returned towards baseline levels in the DTTX30-treated group. Thus, in our model DTTX30 resulted in hemodynamic stabilization concomitant with improved hepatic metabolic performance.
Abstract: Skeletal muscle is capable of producing and releasing large amounts of lactate and at the same time taking up lactate and using it as a respiratory fuel. The release and uptake of lactate both involve transmembrane transport, which is mediated mainly by a membrane protein called the monocarboxylate transporter (MCT). MCTs mediate membrane transport with an obligatory 1:1 coupling between lactate and H+ fluxes, and is therefore of great importance for pH regulation, especially during intense muscle activity. The total lactate and H+ transport capacity is higher in membranes from oxidative fibers than in membranes from more glycolytic fibers. There are two isoforms of MCT present in skeletal muscle, MCT1 and MCT4. In human muscle samples, there is a positive correlation between the proportion of type I fibers and MCT1 density. In contrast, the MCT4 density in human muscle is independent of fiber type and displays a large interindividual variation. Although the two isoforms have identical transport kinetics (Km), they may have different roles in muscle. MCT1 and MCT4 respond differently to a high-intensity training session, which suggests that these two isoforms are regulated differently.
Abstract: Mice homozygous for the Leprdb3J (db3J) mutation are null for all known isoforms of the leptin receptor (LEPR). These animals are obese, hyperphagic, cold intolerant, insulin resistant, and infertile. Mice homozygous for the Leprdb (db) mutation (lacking the B isoform only) have the same phenotype as db3J animals. To better understand the function(s) of the LEPR isoforms in vivo, we generated db3J/db3J and db/db mice bearing a transgene (neuron-specific enolase [NSE]-Rb) expressing the B isoform of LEPR, the isoform capable of activating the signal transducer and activator of transcription (STAT) pathway, under the control of the neuron-specific enolase enhancer/promoter. The NSE-Rb transgene was expressed in the brain, with low levels of expression in adrenals, testis, and white adipose tissue. LEPR-B transgene expression in NSE-Rb db3J/db3J mice partially corrected the increased fat mass, hyperphagia, and glucose intolerance while restoring fertility in males and rescuing the cold intolerance in both sexes. The body weights of NSE-Rb transgenic mice that possessed the full complement of short LEPR isoforms (NSE-Rb db/db mice) were similar to those of NSE-Rb db3J/db3J mice, suggesting that the short LEPR isoforms play little role in body weight regulation. Based on quantitative analysis of hypothalamic neuropeptide gene expression in the transgenic animals, we infer full restoration of leptin sensitivity to proopiomelanocortin (POMC) neurons, partial correction of leptin sensitivity in agouti gene-related protein (AGRP)/neuropeptide Y (NPY) neurons, and a lack of effect on leptin sensitivity of melanin concentrating hormone neurons. Thus, hypothalamic POMC and AGRP/NPY neurons are primary candidates as the mediators of the effects of the NSE-Rb transgene on energy homeostasis, ingestive behavior, the neuroendocrine system, and glucose metabolism.
Abstract: Renal excretory function and hemodynamics are determined by the effective circulating plasma volume as well as by the interplay of systemic and local vasoconstrictors and vasodilators. Microgravity results in a headward shift of body fluid. Because the control conditions of astronauts were poorly defined in many studies, controversial results have been obtained regarding diuresis and natriuresis as well as renal hemodynamic changes in response to increased central blood volume, especially during the initial phase of space flight. Renal excretory function and renal hemodynamics in microgravity are affected in a complex fashion, because during the initial phase of space flight, variable mechanisms become operative to modulate the effects of increased central blood volume. They include interactions between vasodilators (dopamine, atrial natriuretic peptide, and prostaglandins) and vasoconstrictors (sympathetic nervous system and the renin-angiotensin system). The available data suggest a moderate rise in glomerular filtration rate during the first 2 days after launch without a significant increase in effective renal plasma flow. In contrast, too few data regarding the effects of space flight on renal function during the first 12 hours after launch are available and are, in addition, partly contradictory. Thus, detailed and well-controlled studies are required to shed more light on the role of the various factors besides microgravity that determine systemic and renal hemodynamics and renal excretory function during the different stages of space flight.
Abstract: The purpose of this study was to examine the histologic and functional changes that occur in the kidney in the early stages of obesity caused by a high-fat diet. Lean dogs (n = 8) were fed a standard kennel ration, and obese dogs (n = 8) were fed the standard kennel ration plus a supplement of cooked beef fat each day for 7 to 9 wk or 24 wk. Body weights were 58 +/- 5% greater and kidney weights were 31 +/- 7% greater in obese dogs, compared with the average values for lean dogs. Plasma renin activity and insulin concentrations were both 2.3-fold greater in obese dogs, compared with lean dogs. Obesity was associated with a mean arterial pressure increase of 12 +/- 3 mmHg, a 38 +/- 6% greater GFR, and a 61 +/- 7% higher renal plasma flow, compared with lean dogs. The glomerular Bowman’s space area was significantly greater (+41 +/- 7%) in dogs fed the high-fat diet, compared with lean animals, mainly because of expansion of Bowman’s capsule (+22 +/- 7%). There was also increased mesangial matrix and thickening of the glomerular and tubular basement membranes and the number of dividing cells (proliferating cell nuclear antigen-stained) per glomerulus was 36 +/- 8% greater in obese dogs, compared with lean dogs. There was also a trend for glomerular transforming growth factor-beta1 expression, as estimated by semiquantitative immunohistochemical analysis, to be elevated with the high-fat diet. Therefore, a high-fat diet caused increased arterial pressure, hyperinsulinemia, activation of the renin-angiotensin system, glomerular hyperfiltration, and structural changes in the kidney that may be the precursors of more severe glomerular injury associated with prolonged obesity.
Abstract: To test the hypothesis that diaphragm fatigue leads to an increase in neural respiratory drive, we measured the esophageal diaphragm electromyogram (EMG) during CO(2) rebreathing before and after diaphragm fatigue in six normal subjects. The electrode catheter was positioned on the basis of the amplitude and polarity of the diaphragm compound muscle action potential recorded simultaneously from four pairs of electrodes during bilateral anterior magnetic phrenic nerve stimulation (BAMPS) at functional residual capacity. Two minutes of maximum isocapnic voluntary ventilation (MIVV) were performed in six subjects to induce diaphragm fatigue. A maximal voluntary breathing against an inspiratory resistive loading (IRL) was also performed in four subjects. The reduction of transdiaphragmatic pressure elicited by BAMPS was 22% (range 13-27%) after 2 min of MIVV and was similar, 20% (range 13-26%), after IRL. There was a linear relationship between minute ventilation (VE) and the root mean square (RMS) of the EMG during CO(2) rebreathing before and after fatigue. The mean slope of the linear regression of RMS on VE was similar before and after diaphragm fatigue: 2.80 +/- 1.31 vs. 3.29 +/- 1.40 for MIVV and 1.51 +/- 0.31 vs 1.55 +/- 0.31 for IRL, respectively. We conclude that the esophageal diaphragm EMG can be used to assess neural drive and that diaphragm fatigue of the intensity observed in this study does not affect respiratory drive.
Abstract: BACKGROUND: Although only poor data exist on changes in myocardial blood flow (MBF) under acute hypoxia, patients with known coronary artery disease are advised not to exceed a moderate altitude exposure of about 2000 m above sea level. METHODS AND RESULTS: We measured MBF with positron emission tomography using O-15–labeled water in 8 healthy human volunteers (aged 26 +/- 3 years [mean +/- SD]) at baseline (450 m above sea level, Zurich, Switzerland) and during acute hypoxic hypoxemia induced by inhalation of 2 hypoxic gas mixtures corresponding to altitudes of 2000 and 4500 m. MBF remained unchanged at 2000 m (increase of 10%, not significant) but increased significantly at 4500 m (62%, P \textless.001), exceeding the relative increase in rate pressure product. CONCLUSIONS: Our results may explain why exposure to an altitude of 2000 m (corresponding to the cabin pressure in most airplanes during flight) is clinically well tolerated, even by patients with reduced coronary flow reserve, such as those with coronary artery disease. However, at an altitude of 4500 m, MBF increases significantly, supporting the recommendation that patients with impaired flow reserve avoid exposure to higher altitudes.
Abstract: Several studies suggest hemispheric lateralization of autonomic cardiovascular control. There is controversy regarding which hemisphere dominates sympathetic or parasympathetic activity. Hemispheric influences on baroreflex sensitivity (BRS) have not yet been evaluated. To determine hemispheric autonomic control in epilepsy patients, we assessed cardiovascular and baroreflex modulation before and during hemispheric inactivation. For 15 patients with drug-refractory epilepsy, we analyzed autonomic heart rate (HR) and blood pressure (BP) modulation and BRS before and during left and right intracarotid amobarbital procedure (IAP). After Blackman-Tukey spectral analysis, we calculated the low-frequency (LF: 0.04-0.15 Hz) and high-frequency (HF: 0.15-0.5 Hz) power of HR and BP as well as BRS as the LF transfer function gain between BP and HR. Right hemispheric inactivation induced a significant decrease of BP and an increase of HF power of HR and BP (p \textless 0.05). Left inactivation increased HR, BP, and LF power of both signals and decreased BRS by nearly 30% (p \textless 0.05). The results confirm previous IAP studies showing sympathetic lateralization in the right hemisphere and, moreover, demonstrate parasympathetic predominance and up-regulation of BRS in the left hemisphere. In epilepsy patients, unilateral electrical activity might derange autonomic balance between both hemispheres and contribute to cardiovascular dysregulation and sudden fatalities.
Abstract: Experimental data for tubular pressure oscillations in rat kidneys are analyzed in order to examine the different types of synchronization that can arise between neighboring functional units. For rats with normal blood pressure, the individual unit (the nephron) typically exhibits regular oscillations in its tubular pressure and flow variations. For such rats, both in-phase and antiphase synchronization can be demonstrated in the experimental data. For spontaneously hypertensive rats, where the pressure variations in the individual nephrons are highly irregular, signs of chaotic phase and frequency synchronization can be observed. Accounting for a hemodynamic as well as for a vascular coupling between nephrons that share a common interlobular artery, we develop a mathematical model of the pressure and flow regulation in a pair of adjacent nephrons. We show that this model, for appropriate values of the parameters, can reproduce the different types of experimentally observed synchronization. (c) 2001 American Institute of Physics.
Abstract: A commonly accepted hypothesis is that a chronically high-sodium diet expands extracellular volume and finally reaches a steady state where sodium intake and output are balanced whereas extracellular volume is expanded. However, in a recent study where the main purpose was to investigate the role of natriuretic peptides under day-to-day sodium intake conditions (Heer M, Drummer C, Baisch F, and Gerzer R. PflÃŒgers Arch 425: 390-394, 1993), our laboratory observed increases in plasma volume without any rise in extracellular volume. To scrutinize these results that were observed as a side effect, we performed a controlled, randomized study including 32 healthy male test subjects in a metabolic ward. The NaCl intake ranged from a low level of 50 meq NaCl/day to 200, 400, and 550 meq/day, respectively. Plasma volume dose dependently increased (P \textless 0.01), being elevated by 315 +/- 37 ml in the 550-meq-NaCl-intake group. However, in contrast to the increased plasma volume, comparable to study I, total body water did not increase. In parallel, body mass also did not increase. Mean corpuscular volume of erythrocytes, as an index for intracellular volume, was also unchanged. We conclude from the results of these two independently conducted studies that under the chosen study conditions, in contrast to present opinions, high sodium intake does not induce total body water storage but induces a relative fluid shift from the interstitial into the intravascular space.
Abstract: The objective of this study was to test the hypothesis that a decrease in renal interstitial hydrostatic pressure (RIHP) accounts for the blunted pressure natriuresis during pregnancy. RIHP was measured in nonpregnant (NP; n = 9), midterm pregnant (MP; 12-14 days after conception; n = 10), and late-term pregnant (LP; 18-21 days after conception; n = 12) female Sprague-Dawley rats at two renal perfusion pressure (RPP) levels (99 and 120 mmHg). At the lower RPP level, RIHP was 5.9 +/- 0.3 mmHg for NP, 3.4 +/- 0.4 mmHg for MP (P \textless 0.05 vs. NP), and 2.9 +/- 0.1 mmHg for LP (P \textless 0.05 vs. NP) rats. The increase in RPP from 99 to 120 mmHg resulted in pressure natriuretic and diuretic responses in all groups; however, the increases in fractional excretion of sodium (DeltaFE(Na)), urine flow rate (DeltaV), and DeltaRIHP were significantly greater (P \textless 0. 05) in NP compared with both MP and LP rats. DeltaFE(Na), DeltaV, and DeltaRIHP were 2.06 +/- 0.28%, 81.44 +/- 14.10 microl/min, and 3. 0 +/- 0.5 mmHg for NP; 0.67 +/- 0.13%, 28.03 +/- 5.28 microl/min, and 0.5 +/- 0.2 mmHg for MP; and 0.48 +/- 0.12%, 18.14 +/- 4.70 microl/min, and 0.4 +/- 0.1 mmHg for LP rats. In conclusion, RIHP is significantly lower in pregnant compared with nonpregnant rats at similar RPP levels. Also, the ability of pregnant rats to increase RIHP in response to an increase in RPP is blunted. These changes in RIHP may play an important role in the blunted pressure natriuresis and contribute to the conservation of sodium and water that is critical for fetal growth and development during normal pregnancy.
Abstract: During exercise regional cerebral blood flow (rCBF), as blood velocity in major cerebral arteries and also blood flow in the internal carotid artery increase, suggesting an increase in blood flow to a large part of the brain. Such an increase in CBF is independent of the concomitant increase in blood pressure but is modified by the alteration in arterial carbon dioxide tension (PaCO(2)). Also, the increase in middle cerebral artery mean blood velocity (MCA V(mean)) reported with exercise appears to depend on the ability to increase cardiac output (CO), as demonstrated in response to beta-1 blockade and in patients with cardiac insufficiency or atrial fibrillation.Near-infrared spectroscopy (NIRS) determined cerebral oxygenation supports the alterations in MCA V(mean) during exercise. Equally, the observation that the cerebrovascular CO(2)-reactivity appears to be smaller in the standing than in the sitting and especially in the supine position could relate to the progressively smaller CO.In contrast, during exercise "global" cerebral blood flow (gCBF), as determined by the Kety-Schmidt technique is regarded as being constant. One limitation of the Kety-Schmidt method for measuring CBF is that blood flow in the two internal jugular veins depends on the origin of drainage and it has not been defined which internal jugular venous flow is evaluated. Such a consideration is equally relevant for an evaluation of cerebral metabolism during exercise.While the regional cerebral uptake of oxygen (O(2)) increases during exercise, the global value is regarded as being constant. Yet, during high intensity exercise lactate is taken up by the brain and its O(2) uptake also increases. Furthermore, in the initial minutes of recovery immediately following exercise, brain glucose and O(2) uptake are elevated and lactate uptake remains high.A maintained substrate uptake by the brain after exercise suggests a role for brain glycogen in cerebral activation, but the fate of brain substrate uptake has not yet been determined.
Abstract: Previous studies have indicated that frequency of stimulation is a major determinant of glucose transport in contracting muscle. We have now studied whether this is so also when total force development or metabolic rate is kept constant. Incubated soleus muscles were electrically stimulated to perform repeated tetanic contractions at four different frequencies (0.25, 0.5, 1, and 2 Hz) for 10 min. Resting length was adjusted to achieve identical total force development or metabolic rate (glycogen depletion and lactate accumulation). Overall, at constant total force development, glucose transport (2-deoxyglucose uptake) increased with stimulation frequency (P \textless 0.05; basal: 25 +/- 2, 0.25 Hz: 50 +/- 4, 0.5 Hz: 50 +/- 3, 1 Hz: 81 +/- 5, 2 Hz: 79 +/- 3 nmol. g(-1). 5 min(-1)). However, glucose transport was identical (P \textgreater 0.05) at the two lower (0.25 and 0.5 Hz) as well as at the two higher (1 and 2 Hz) frequencies. Glycogen decreased (P \textless 0.05; basal: 19 +/- 1, 0.25 Hz: 13 +/- 1, 0.5 Hz: 12 +/- 2, 1 Hz: 7 +/- 1, 2 Hz: 7 +/- 1 mmol/kg) and 5’-AMP-activated protein kinase (AMPK) activity increased (P \textless 0. 05; basal: 1.7 +/- 0.4, 0.25 Hz: 32.4 +/- 7.0, 0.5 Hz: 36.5 +/- 2.1, 1 Hz: 63.4 +/- 8.0, 2 Hz: 67.0 +/- 13.4 pmol. mg(-1). min(-1)) when glucose transport increased. Experiments with constant metabolic rate were carried out in soleus, flexor digitorum brevis, and epitrochlearis muscles. In all muscles, glucose transport was identical at 0.5 and 2 Hz (P \textgreater 0.05); also, AMPK activity did not increase with stimulation frequency. In conclusion, muscle glucose transport increases with stimulation frequency but only in the face of energy depletion and increase in AMPK activity. This indicates that contraction-induced glucose transport is elicited by metabolic demands rather than by events occurring early during the excitation-contraction coupling.
Abstract: The purpose of this study was to elucidate the role of circulating ANG II in mediating changes in systemic and renal hemodynamics, salt and water balance, and neurohormonal activation during the early progression of heart failure. This objective was achieved by subjecting six dogs to 14 days of rapid ventricular pacing (240 beats/min) while fixing plasma ANG II concentration (by infusion of captopril + ANG II) either at approximately normal (days 1-8, 13-14) or at high physiological (days 9-12) levels. Salt and water retention occurred during the initial days of pacing before sodium and fluid balance was achieved by day 8. At this time, cardiac output and mean arterial pressure were reduced to approximately 55 and 75% of control, respectively; compared with cardiac output, reductions in renal blood flow were less pronounced. Although plasma ANG II concentration was maintained at approximately normal levels, there were sustained elevations in total peripheral resistance (to approximately 135% of control), filtration fraction (to approximately 118% of control), and plasma norepinephrine concentration (to 2-3 times control). During the subsequent high rate of ANG II infusion on days 9-12, there were no additional sustained long-term changes in either systemic or renal hemodynamics other than a further rise in right atrial pressure. However, high plasma levels of ANG II induced sustained antinatriuretic, sympathoexcitatory, and dipsogenic responses. Because these same long-term changes occur in association with activation of the renin-angiotensin system during the natural evolution of this disease, these results suggest that increased plasma levels of ANG II play a critical role in the spontaneous transition from compensated to decompensated heart failure.
Abstract: The effects of acetazolamide (Acz)-induced carbonic anhydrase inhibition (CAI) on muscle intracellular thresholds (T) for intracellular pH (pH(i)) and inorganic phosphate-to-phosphate creatine ratio (P(i)/PCr) and the plasma lactate (La(-)) threshold were examined in nine adult male subjects performing forearm wrist flexion exercise to fatigue. Exercise consisted of raising and lowering (1-s contraction, 1-s relaxation) a cylinder whose volume increased at a rate of 200 ml/min. The protocol was performed during control (Con) and after 45 min of CAI with Acz (10 mg/kg body wt iv). T(pH(i)) and T(P(i)/PCr), determined using (31)P-labeled magnetic resonance spectroscopy (MRS), were similar in Acz (722 +/- 50 and 796 +/- 75 mW, respectively) and Con (855 +/- 211 and 835 +/- 235 mW, respectively). The pH(i) was similar at end-exercise (6.38 +/- 0.10 Acz and 6.43 +/- 0.22 Con), but pH(i) recovery was slowed in Acz. In a separate experiment, blood was sampled from a deep arm vein at the elbow for determination of plasma lactate concentration ([La(-)](pl)) and T(La(-)). [La(-)](pl) was lower (P \textless 0.05) in Acz than Con (3.7 +/- 1.7 vs. 5.0 +/- 1.7 mmol/l) at end-exercise and in early recovery, but T(La(-)) was higher (1,433 +/- 243 vs. 1,041 +/- 414 mW, respectively). These data suggest that the lower [La(-)](pl) seen with CAI was not due to a delayed onset or rate of muscle La(-) accumulation but may be related to impaired La(-) removal from muscle.
Abstract: Sympathetic activation produced by various stimuli, eg, mental stress or handgrip, evokes regional vascular responses that are often nonhomogeneous. This phenomenon is believed to be the consequence of the recruitment of differential central neural pathways or of a sympathetically mediated vasodilation. The purpose of this study was to determine whether a similar heterogeneous response occurs with cold pressor stimulation and to test the hypothesis that local differences in adrenergic receptor function could be in part responsible for this diversity. In 8 healthy subjects, local norepinephrine spillover and blood flow were measured in arms and legs at baseline and during sympathetic stimulation induced by baroreflex mechanisms (nitroprusside infusion) or cold pressor stimulation. At baseline, legs had higher vascular resistance (27+/-5 versus 17+/-2 U, P=0.05) despite lower norepinephrine spillover (0.28+/-0.04 versus 0.4+/-0.05 mg. min(-1). dL(-1), P=0.03). Norepinephrine spillover increased similarly in both arms and legs during nitroprusside infusion and cold pressor stimulation. On the other hand, during cold stimulation, vascular resistance increased in arms but not in legs (20+/-9% versus -7+/-4%, P=0.03). Increasing doses of isoproterenol and phenylephrine were infused intra-arterially in arms and legs to estimate beta-mediated vasodilation and alpha-induced vasoconstriction, respectively. beta-Mediated vasodilation was significantly lower in legs compared with arms. Thus, we report a dissociation between norepinephrine spillover and vascular responses to cold stress in lower limbs characterized by a paradoxical decrease in local resistance despite increases in sympathetic activity. The differences observed in adrenergic receptor responses cannot explain this phenomenon.
Abstract: Leptin is a protein produced by adipose tissue that acts in the central nervous system (CNS) to decrease appetite and increase energy expenditure. Leptin thus functions as the afferent component of a negative feedback loop that maintains stable adipose tissue mass. Intravenous leptin increases norepinephrine turnover and sympathetic nerve activity to thermogenic brown adipose tissue. Leptin also increases sympathetic nerve activity to tissues not usually considered thermogenic, including the kidney, hindlimb, and adrenal gland. Chronic systemic CNS administration of leptin increases arterial pressure and heart rate in conscious animals. However, leptin has additional cardiovascular actions that may act to oppose sympathetically mediated vasoconstriction. These actions include natriuresis, insulin sensitization, endothelium-dependent dilatation, and angiogenesis. Thus, the overall effect of leptin on arterial pressure has been unclear. Recent studies have demonstrated that leptin-deficient ob/ob obese mice have lower arterial pressure than lean controls with normal leptin levels. These studies suggest that leptin contributes physiologically to maintenance of arterial pressure. Leptin expression and plasma leptin concentrations are elevated in obese humans. Abnormalities in the generation or actions of leptin may, therefore, have implications for the sympathetic, cardiovascular, and renal changes associated with obesity.
Abstract: The objectives of this investigation were to study the effects of thigh cuffs (bracelets) on cardiovascular adaptation and deconditioning in 0 g. The cardiovascular parameters of six cosmonauts were measured by echocardiography, Doppler, and plethysmography, during three 6-month MIR spaceflights. Measurements were made at rest during preflight (-30 days), inflight (1, 3-4, and 5-5.5 months) without cuffs (morning) and after 5 h with cuffs, and during postflight (+3 and +7 days). Lower-body negative pressure (LBNP) measurements were performed 1 day after each resting session. Inflight values of left ventricle end-diastolic volume and stroke volume measured without the thigh cuffs (-8 to -24% and -10 to -16%, respectively, both P \textless 0.05) were lower than corresponding preflight values. The jugular and femoral vein cross-sectional areas (Ajv and Afv, respectively) were enlarged (Ajv: by 23-30%, P \textless 0.001; Afv: by 33-70% P \textless 0.01). The renal and femoral vascular resistances (Rra and Rfa, respectively) decreased (Rra: by -15 to -16%, P \textless 0.01; Rfa: by -5 to -11%, P \textless 0.01). Inflight, the thigh cuffs reduced the Ajv (by -12 to -20%, P \textless 0.02), but enlarged the Afv (Afv: by 9-20%, P \textless 0.02) and increased the vascular resistance (Rra: by 8-13%, P \textless 0.05; Rfa: by 10-16%, P \textless 0.01) compared to corresponding inflight, without-cuffs values. During LBNP (-45 mmHg, where 1 mmHg = 133.3 N/ m2), Rfa and the ratio between cerebral and femoral blood flow (Qca/Qfa) increased less inflight and postflight (+25% for Rfa and +30% for Qca/Qfa) than during preflight (60% for Rfa and 75% for Qca/Qfa, P \textless 0.01). This reduced vasoconstrictive response and less efficient flow redistribution toward the brain was associated with orthostatic intolerance during postflight stand tests in all of the cosmonauts. The calf circumference increased less inflight and postflight (6% P \textless 0.05) than preflight (9% P \textless 0.05). The vascular response to LBNP remained similarly altered throughout the flight. The thigh cuffs compensated partially for the cardiovascular changes induced by exposure to 0 g, but did not interfere with 0 g deconditioning.
Abstract: A system analysis of ATP free energy metabolism in skeletal muscle was made using the principles of metabolic control theory. We developed a network model of ATP free energy metabolism in muscle consisting of actomyosin ATPase, sarcoplasmic reticulum (SR) Ca(2+)-ATPase, and mitochondria. These components were sufficient to capture the major aspects of the regulation of the cytosolic ATP-to-ADP concentration ratio (ATP/ADP) in muscle contraction and had inherent homeostatic properties regulating this free energy potential. As input for the analysis, we used ATP metabolic flux and the cytosolic ATP/ADP at steady state at six contraction frequencies between 0 and 2 Hz measured in human forearm flexor muscle by (31)P-NMR spectroscopy. We used the mathematical formalism of metabolic control theory to analyze the distribution of fractional kinetic control of ATPase flux and the ATP/ADP in the network at steady state among the components over this experimental range and an extrapolated range of stimulation frequencies (up to 10 Hz). The control analysis showed that the contractile actomyosin ATPase has dominant kinetic control of ATP flux in forearm flexor muscle over the 0- to 1.6-Hz range of contraction frequencies that resulted in steady states, as determined by (31)P-NMR. However, flux control begins to shift toward mitochondria at \textgreater1 Hz. This inversion of flux control from ATP demand to ATP supply control hierarchy progressed as the contraction frequency increased past 2 Hz and was nearly complete at 10 Hz. The functional significance of this result is that, at steady state, ATP free energy consumption cannot outstrip the ATP free energy supply. Therefore, this reduced, three-component muscle ATPase system is inherently homeostatic.
Abstract: We determined whether short-term weight-lifting exercise increases the synthesis rate of the major contractile proteins, myosin heavy chain (MHC), actin, and mixed muscle proteins in nonfrail elders and younger women and men. Fractional synthesis rates of mixed, MHC, and actin proteins were determined in seven healthy sedentary 23- to 32-yr-old and seven healthy 78- to 84-yr-old participants in paired studies done before and at the end of a 2-wk weight-lifting program. The in vivo rate of incorporation of 1-[(13)C]leucine into vastus lateralis MHC, actin, and mixed proteins was determined using a 14-h constant intravenous infusion of 1-[(13)C]leucine. Before exercise, the mixed and MHC fractional synthetic rates were lower in the older than in the younger participants (P \textless or = 0.04). Baseline actin protein synthesis rates were similar in the two groups (P = not significant). Over a 2-wk period, participants completed ten 1- to 1. 5-h weight-lifting exercise sessions: 2-3 sets per day of 9 exercises, 8-12 repetitions per set, at 60-90% of maximum voluntary muscle strength. At the end of exercise, MHC and mixed protein synthetic rates increased in the younger (88 and 121%) and older participants (105 and 182%; P \textless 0.001 vs. baseline). These findings indicate that MHC and mixed protein synthesis rates are reduced more than actin in advanced age. Similar to that of 23-32 yr olds, the vastus lateralis muscle in 78-84 yr olds retains the capacity to increase MHC and mixed protein synthesis rates in response to short-term resistance exercise.
Abstract: We hypothesized that excessive sympathoactivation observed during strenuous exercise in subjects with heart failure (HF) may result from tonic activation of the muscle metaboreflex (MMR) via hypoperfusion of active skeletal muscle. We studied MMR responses in dogs during treadmill exercise by graded reduction of terminal aortic blood flow (TAQ) before and after induction of HF by rapid ventricular pacing. At a low workload, in both control and HF experiments, large decreases in TAQ were required to elicit the MMR pressor response. During control experiments, this pressor response resulted from increased cardiac output (CO), whereas in HF CO did not increase; thus the pressor response was solely due to peripheral vasoconstriction. In HF, MMR activation also induced higher plasma levels of vasopressin, norepinephrine (NE), and renin. At a higher workload, in control experiments any reduction of TAQ elicited MMR pressor responses. In HF, before any vascular occlusion, TAQ was already below MMR control threshold levels and reductions in TAQ again did not result in higher CO; thus SAP increased via peripheral vasoconstriction. NE rose markedly, indicating intense sympathetic activation. We conclude that in HF, the MMR is likely tonically active at moderate workloads and contributes to the tonic sympathoactivation.
Abstract: In the last decade, significant progress has been made in the characterization of pH regulation in nervous tissue in vitro. However, little work has been directed at understanding how pH regulatory mechanisms function in vivo. We are interested in how ischemic acidosis can effect pH regulation and modulate the extent of post-ischemic brain damage. We used 31P-MRS to determine normal in vivo pH(i) and pH(e) simultaneously in both the isolated canine brain and the intact rat brain. We observed that the 31P(i) peak in the 31P-MRS spectrum is heterogeneous and can be deconvoluted into a number of discrete constituent peaks. In a series of experiments, we identified these peaks as arising from either extracellular or intracellular sources. In particular, we identified the peak representing the neurons and astrocytes and showed that they maintain different basal pH (6.95 and 7.05, respectively) and behave differently during hypoxic/ischemic episodes.
Abstract: OBJECTIVE: To evaluate evidence supporting the use of spironolactone in managing congestive heart failure. DATA SOURCES: Literature accessed through MEDLINE (January 1966-December 1999) and cross-referencing of selected articles. Search terms included spironolactone and heart failure. DATA SYNTHESIS: Heart failure is a leading cause of morbidity and mortality. Through aldosterone antagonism, spironolactone may be an effective pharmacotherapeutic addition to patients not responding to standard drug therapy for heart failure. RESULTS: Clinical trials have demonstrated that, in patients with heart failure, spironolactone improves laboratory indices, quality of life, and morbidity. Recently, spironolactone has been demonstrated to improve the survival of patients with New York Heart Association (NYHA) III or IV heart failure. CONCLUSIONS: Spironolactone use should be considered in patients with NYHA Class III or IV heart failure.
Abstract: BACKGROUND: Previously, we showed that mesenteric lymph generated following hemorrhagic shock increases endothelial cell permeability and contributes to lung injury. It has also been shown that lymph produced at the site of burn injury plays a role in altering pulmonary vascular hemodynamics. In addition, previous experimental work has suggested that organs and tissues distant from the injury site may contribute to pulmonary dysfunction. One explanation would be that gut-derived inflammatory factors (in addition to those produced locally at the site of injury) are reaching the pulmonary circulation, where they exert their effects via the gut lymphatics. HYPOTHESES: The 2 hypotheses herein were that (1) gut-derived factors carried in the mesenteric lymph of rats generated following thermal injury will contribute to lung injury and (2) intestinal bacterial overgrowth will potentiate the degree of burn-induced lung injury. These hypotheses were tested by examining the effect of mesenteric lymph flow interruption prior to thermal injury on burn-induced lung injury in rats with a normal intestinal bacterial flora and in rats with intestinal Escherichia coli overgrowth. These rats were termed E. coli-monoassociated rats. METHODS: Normal intestinal bacterial flora and monoassociated male Sprague-Dawley rats were subjected to sham burn, 40% total body surface area burn, or lymphatic division plus burn. After 3 hours, 10 mg of Evans blue was injected to measure lung permeability. After the rats were killed, a bronchoalveolar lavage was performed and the fluid analyzed spectrophotometrically. Bronchoalveolar lavage fluid protein content, pulmonary myeloperoxidase activity, and alveolar apoptosis served to further quantitate lung injury. RESULTS: Both normal intestinal bacterial flora and monoassociated-burned rats exhibited significant increases in lung permeability, bronchoalveolar lavage fluid protein content, myeloperoxidase activity, and alveolar apoptosis. The combination of monoassociation and thermal injury resulted in even further increases in lung injury over thermal injury alone. Lymphatic division prior to thermal injury ameliorated burn-induced increases in lung permeability, bronchoalveolar lavage fluid protein content, pulmonary myeloperoxidase accumulation, and alveolar apoptosis in both normal intestinal bacterial flora and monoassociated rats. CONCLUSIONS: The results of this study support the hypothesis that gut-derived factors carried in the mesenteric lymph contribute to burn-induced lung injury and may therefore play a role in postburn respiratory failure and suggest that intestinal bacterial overgrowth primes the host such that when animals are exposed to a second stimulus (such as thermal injury) an exaggerated response occurs.
Abstract: Small synthetic molecules called growth-hormone secretagogues (GHSs) stimulate the release of growth hormone (GH) from the pituitary. They act through GHS-R, a G-protein-coupled receptor for which the ligand is unknown. Recent cloning of GHS-R strongly suggests that an endogenous ligand for the receptor does exist and that there is a mechanism for regulating GH release that is distinct from its regulation by hypothalamic growth-hormone-releasing hormone (GHRH). We now report the purification and identification in rat stomach of an endogenous ligand specific for GHS-R. The purified ligand is a peptide of 28 amino acids, in which the serine 3 residue is n-octanoylated. The acylated peptide specifically releases GH both in vivo and in vitro, and O-n-octanoylation at serine 3 is essential for the activity. We designate the GH-releasing peptide ’ghrelin’ (ghre is the Proto-Indo-European root of the word ’grow’). Human ghrelin is homologous to rat ghrelin apart from two amino acids. The occurrence of ghrelin in both rat and human indicates that GH release from the pituitary may be regulated not only by hypothalamic GHRH, but also by ghrelin.
Abstract: Reflex mechanisms from contracting skeletal muscle have been shown to be important for cardiovascular, neuroendocrine, and extramuscular fuel-mobilization responses in exercise. Furthermore, because hypoxia results in exaggerated metabolic changes in contracting muscle, the present study evaluated whether enhancement of cardiovascular and neuroendocrine responses by hypoxia during exercise is influenced by neural feedback from contracting muscle. Seven healthy males cycled at 46% maximal O(2) uptake for 20 min both during normoxia and at 11.5% O(2), and both without and with epidural anesthesia (EA; 20 ml 0.25% bupivacain, resulting in cutaneous hypesthesia below T10-T12 and 25% reduction in maximal leg strength). Exercise to exhaustion was also performed at 7.8% O(2). The exercise-induced increases in heart rate; cardiac output; leg blood flow; plasma concentrations of growth hormone, adrenocorticotropin, cortisol, and catecholamines; renin activity; glucose production and disappearance; norepinephrine spillover [2, 190 +/- 341 ng/min (exercise at 11.5% O(2)) vs. 988 +/- 95 ng/min (exercise during normoxia)]; lactate release from and glucose uptake in the leg; and the decreases in plasma insulin and free fatty acids were exaggerated in hypoxia (P \textless 0.05). In muscle, concentrations of lactate, creatine, and inosine 5’-monophosphate were higher, and those of phosphocreatine were lower after exercise in hypoxia compared with normoxia. The exercise-induced increase in mean arterial blood pressure was not affected by hypoxia, but it was reduced by EA [108 +/- 4 mmHg (control) vs. 97 +/- 4 mmHg (EA); P \textless 0.05], and the reduction was more pronounced during severe hypoxia compared with normoxia. Apart from this, time to exhaustion at extreme hypoxia, circulatory responses, concentrations of neuroendocrine hormones, and extramuscular substrate mobilization were not diminished by EA. In conclusion, in essence the hypoxia-induced enhancement of systemic adaptation to exercise is not mediated by neural feedback from working muscle in humans.
Abstract: A unique method for simultaneously measuring interstitial (pHe) as well as intracellular (pHi) pH in the brains of lightly anesthetized rats is described. A 4-mm microdialysis probe was inserted acutely into the right frontal lobe in the center of the area sampled by a surface coil tuned for the collection of 31P-NMR spectra. 2-Deoxyglucose 6-phosphate (2-DG-6-P) was microdialyzed into the rat until a single NMR peak was detected in the phosphomonoester region of the 31P spectrum. pHe and pHi values were calculated from the chemical shift of 2-DG-6-P and inorganic phosphate, respectively, relative to the phosphocreatine peak. The average in vivo pHe was 7.24+/-0.01, whereas the average pHi was 7.05+/-0.01 (n = 7). The average pHe value and the average CSF bicarbonate value (23.5+/-0.1 mEq/L) were used to calculate an interstitial Pco2 of 55 mm Hg. Rats were then subjected to a 15-min period of either hypercapnia, by addition of CO2 (2.5, 5, or 10%) to the ventilator gases, or hypocapnia (PCO2 \textless 30 mm Hg), by increasing the ventilation rate and volume. pHe responded inversely to arterial Pco2 and was well described (r2 = 0.91) by the Henderson-Hasselbalch equation, assuming a pKa for the bicarbonate buffer system of 6.1 and a solubility coefficient for CO2 of 0.031. This confirms the view that the bicarbonate buffer system is dominant in the interstitial space. pHi responded inversely and linearly to arterial PCO2. The intracellular effect was muted as compared with pHe (slope = -0.0025, r2 = 0.60). pHe and pHi values were also monitored during the first 12 min of ischemia produced by cardiac arrest. pHe decreases more rapidly than pHi during the first 5 min of ischemia. After 12 min of ischemia, pHe and pHi values were not significantly different (6.44+/-0.02 and 6.44+/-0.03, respectively). The limitations, advantages, and future uses of the combined microdialysis/31P-NMR method for measurement of pHe and pHi are discussed.
Abstract: Idiopathic edema is a syndrome of real or perceived excessive weight gain. This article reviews what is known about the possible causes, evaluation, and treatment. Although the cause is unknown but often thought to be due to secondary hyperaldosteronism, primary abnormalities of the hypothalamus, thyroid, dopaminergic release or renal dopaminergic metabolism, vascular basement membrane, or capillary sphincter control could perhaps contribute in some patients. The diagnosis requires careful attention to possible abnormalities of the liver, heart, kidneys, gastrointestinal tract, thyroid, and pancreas. The history must include an evaluation for risks of bulimia and purging; diuretic and laxative screening should be performed. Specific records of daily weights, urinary outputs, and menstral cycle dates are useful. Treatment may include dietary counseling to provide weight control and a constant carbohydrate intake, treatments for depression, compression stockings, spironolactone, amiloride, angiotensin II inhibitors, or sympathomimetic agents, depending on the severity and timing of the patient’s symptoms. Unfortunately, idiopathic edema may be a multifactorial disorder that has not been completely delineated. Further research into possible causative mechanisms is required before a more useful algorithm for evaluation and treatment is available.
Abstract: Previous studies of brain glucose metabolism in people indigenous to high-altitude environments uncovered two response patterns: Quechuas native to the high Andes of South America sustained modest hypometabolism in most brain regions interrogated, whereas Sherpas, native to the Himalayas and considered by many biologists to be most effectively high-altitude adapted of all humans, showed brain metabolic patterns similar to lowlanders, with no acclimation effects noted. In the present study, the database was expanded to include hypoxia acclimation effects in lowlanders. Positron emission tomography (PET) and [(18)F]-2-deoxy-2-fluro-D-glucose (FDG) imaging techniques were used to assess regional cerebral glucose metabolic rates (rCMR(glc)) in six US marines (Caucasian lineage) before and after a 63-day training program for operations at high altitudes ranging from 10,500 to 20,320 ft. Significant changes in rCMR(glc) were found for 7 of 25 brain regions examined. Significant decreases in absolute cerebral glucose metabolism after high-altitude exposure were found in five regions: three frontal, the left occipital lobe, and the right thalamus. In contrast, for the right and left cerebellum significant increases in metabolism were found. The magnitudes of these differences, in terms of absolute metabolism, were large, ranging from 10 to 18%. Although the results may not be solely the result of lower oxygen levels at high altitude, these findings suggest that the brain of healthy human lowlanders responds to chronic hypoxia exposure with precise, region-specific fine tuning of rCMR(glc). The observed short-term hypoxia acclimation responses in these lowlanders clearly differ from the long-term hypoxia adaptations found in brain metabolism of people indigenous to high-altitude environments.
Abstract: The heterotypic aggregation of cell mixtures or colloidal particles such as proteins occurs in a variety of settings such as thrombosis, immunology, cell separations, and diagnostics. Using the set of population balance equations (PBEs) to predict dynamic aggregate size and composition distributions is not feasible. The stochastic algorithm of Gillespie for chemical reactions (. J. Comput. Phys. 22:403-434) was reformulated to simulate the kinetic behavior of aggregating systems. The resulting Monte Carlo (MC) algorithm permits exact calculation of the decay rates of monomers and the temporally evolving distribution of sizes and compositions of the aggregates. Moreover, it permits calculation of all moments of these distributions. Using this method, we explored the heterotypic aggregation of fully activated platelets and neutrophils in a linear shear flow of shear rate G = 335 s(-1). At plasma concentrations, the half-lives of homotypically aggregating platelet and neutrophil singlets were 8.5 and 2.4 s, respectively. However, for heterotypic aggregation, the half-lives for platelets and neutrophils decreased to 2.0 and 0.11 s, respectively, demonstrating that flowing neutrophils accelerate capture of platelets and growth of aggregates. The required number of calculations per time step of the MC algorithm was typically a small fraction of Omega(1/2), where Omega is the initial number of particles in the system, making this the fastest MC method available. The speed of the algorithm makes feasible the deconvolution of kernels for general biological heterotypic aggregation processes.
Abstract: Glutamate transporters play important roles in the termination of excitatory neurotransmission and in providing cells with glutamate for metabolic purposes. In the kidney, glutamate transporters are involved in reabsorption of filtered acidic amino acids, regulation of ammonia and bicarbonate production, and protection of cells against osmotic stress.
Abstract: Natriuretic peptide (NP) receptors (NPRs) located at the endocardial endothelium are suggested to be involved in regulating myocardial contractility. However, the characteristics and modulation of NPRs in relation to cardiac failure are not well defined. This study examined the properties of NPRs in ventricular endocardium using quantitative receptor autoradiography, RT-PCR, Southern blot analysis, and activation of particulate guanylyl cyclase (GC) by NPs. In control rats, specific 125I-labeled rat atrial NP (rANP)(1-28) binding sites were localized in right (RV) and left ventricular (LV) endocardium. Binding affinities of 125I-rANP(1-28) were remarkably higher in RV than LV endocardium. Radioligand binding at these sites was mostly inhibited by des[Gln18,Ser19,Gly20,Leu21, Gly22]ANP(4-23), a specific NP clearance receptor ligand. mRNAs for all three recognized NPRs were detected in endocardial cells by RT-PCR and confirmed by Southern blot analysis. Production of cGMP by particulate GC in endocardial cell membranes was stimulated by NPs with a rank order of potency of C-type NP(1-22) \textgreater\textgreater brain NP (BNP)(1-26) \textgreater ANP(1-28). We also examined the modulation of these NPRs during cardiac hypertrophy induced by monocrotaline (MCT). In MCT-treated rats with pulmonary hypertension, specific (125)I-rANP(1-28) binding to hypertrophied RV endocardium almost disappeared and cGMP production by NPs was significantly decreased. In rats with pulmonary hypertension, plasma levels of ANP and BNP were increased by fivefold compared with controls. The results indicate that there is a differential distribution of NPRs in the cardiac chambers, with the most abundant binding sites in RV endocardium, that NPR-B is the predominant GC-coupled NPR in ventricular endocardium, and that endocardial NPRs are downregulated with ventricular hypertrophy. Downregulation of NPRs may be associated with an increment of endogenous NP production caused by mechanical overload in hypertrophied ventricle.
Abstract: CONTEXT: The protein hormone leptin is important to the homeostatic regulation of body weight. Treatment with exogenous leptin may affect weight loss. OBJECTIVE: To determine the relationship between increasing doses of exogenous leptin administration and weight loss in both lean and obese adults. DESIGN: A randomized, double-blind, placebo-controlled, multicenter, escalating dose cohort trial conducted from April 1997 to October 1998. SETTING: Four university nutrition and obesity clinics and 2 contract clinical research clinics. PARTICIPANTS: Fifty-four lean (body mass index, 20.0-27.5 kg/m2; mean [SD] body weight, 72.0 [9.7] kg) and 73 obese (body mass index, 27.6-36.0 kg/m2; mean [SD] body weight, 89.8 [11.4] kg) predominantly white (80%) men (n = 67) and women (n = 60) with mean (SD) age of 39 (10.3) years. INTERVENTIONS: Recombinant methionyl human leptin self-administered by daily morning subcutaneous injection (0 [placebo], 0.01, 0.03, 0.10, or 0.30 mg/kg). In part A, lean and obese subjects were treated for 4 weeks; in part B, obese subjects were treated for an additional 20 weeks. Lean subjects consumed a eucaloric diet to maintain body weight at the current value, and obese subjects were prescribed a diet that reduced their daily energy intake by 2100 kJ/d (500-kcal/d) from the amount needed to maintain a stable weight. MAIN OUTCOME MEASURES: Body weight, body fat, and incidence of adverse events. RESULTS: Weight loss from baseline increased with increasing dose of leptin among all subjects at 4 weeks (P = .02) and among obese subjects at 24 weeks (P = .01) of treatment. Mean (SD) weight changes at 4 weeks ranged from -0.4 (2.0) kg for placebo (n = 36) to -1.9 kg (1.6) kg for the 0.1 mg/kg dose (n = 29). Mean (SD) weight changes at 24 weeks ranged from -0.7 (5.4) kg for the 0.01 mg/kg dose (n = 6) to -7.1 (8.5) kg for the 0.30 mg/kg dose (n = 8). Fat mass declined from baseline as dose increased among all subjects at 4 weeks (P = .002) and among obese subjects at 24 weeks of treatment (P = .004); more than 95% of weight loss was fat loss in the 2 highest dose cohorts at 24 weeks. Baseline serum leptin concentrations were not related to weight loss at week 4 (P = .88) or at week 24 (P = .76). No clinically significant adverse effects were observed on major organ systems. Mild-to-moderate reactions at the injection site were the most commonly reported adverse effects. CONCLUSIONS: A dose-response relationship with weight and fat loss was observed with subcutaneous recombinant leptin injections in both lean and obese subjects. Based on this study, administration of exogenous leptin appears to induce weight loss in some obese subjects with elevated endogenous serum leptin concentrations. Additional research into the potential role for leptin and related hormones in the treatment of human obesity is warranted.
Abstract: Functional activation stimulates CMRglc more than CMRO2 and raises lactate levels in brain. This has been interpreted as evidence that brain work is supported mainly by energy derived from anaerobic glycolysis. To determine if lactate production accounts for the "excess" glucose consumption, cerebral arteriovenous differences were measured in conscious rats before, during, and 15 minutes after sensory stimulation; the brains were rapidly frozen in situ immediately after completion of blood sampling and assayed for metabolite levels. The molar O2/glucose uptake ratio fell from 6.1+/-1.1 (mean+/-SD) before stimulation to 5.0+/-1.1 during activation (P\textless0.01); lactate efflux from brain to blood was detectable at rest but not during stimulation. By 15 minutes after activation, O2 and lactate arteriovenous differences normalized, whereas that for glucose fell, causing the O2/glucose ratio to rise above preactivation levels to 7.7+/-2.6 (P\textless0.01). Brain glucose levels remained stable through all stages of activity. Brain lactate levels nearly doubled during stimulation but normalized within 15 minutes of recovery. Brain glycogen content fell during activation and declined further during recovery. These results indicate that brain glucose metabolism is not in a steady state during and shortly after activation. Furthermore, efflux from and increased content of lactate in the brain tissue accounted for less than 54% of the "excess" glucose used during stimulation, indicating that a shift to anaerobic glycolysis does not fully explain the disproportionately greater increases in CMRglc above that of CMRO2 in functionally activated brain. These results also suggest that the apparent dissociation between glucose utilization and O2 consumption during functional activation reflects only a temporal displacement; during activation, glycolysis increases more than oxidative metabolism, leading to accumulation of products in intermediary metabolic pools that are subsequently consumed and oxidized during recovery.
Abstract: Exercise performance can be compromised by a body water deficit, particularly when exercise is performed in hot climates. It is recommended that individuals begin exercise when adequately hydrated. This can be facilitated by drinking 400 mL to 600 mL of fluid 2 hours before beginning exercise and drinking sufficient fluid during exercise to prevent dehydration from exceeding 2% body weight. A practical recommendation is to drink small amounts of fluid (150-300 mL) every 15 to 20 minutes of exercise, varying the volume depending on sweating rate. Core temperature, heart rate, and perceived effort remain lowest when fluid replacement comes closest to matching the rate of sweat loss. During exercise lasting less than 90 minutes, water alone is sufficient for fluid replacement. During prolonged exercise lasting longer than 90 minutes, commercially available carbohydrate electrolyte beverages should be considered to provide an exogenous carbohydrate source to sustain carbohydrate oxidation and endurance performance. Electrolyte supplementation is generally not necessary because dietary intake is adequate to offset electrolytes lost in sweat and urine; however, during initial days of hot-weather training or when meals are not calorically adequate, supplemental salt intake may be indicated to sustain sodium balance.
Abstract: The purpose of this study was to use 31P-magnetic resonance spectroscopy to examine the relationships among muscle PCr hydrolysis, intracellular H+ concentration accumulation, and muscle performance during incremental exercise during the inspiration of gas mixtures containing different fractions of inspired O2 (FIO2). We hypothesized that lower FIO2 would result in a greater disruption of intracellular homeostasis at submaximal workloads and thereby initiate an earlier onset of fatigue. Six subjects performed plantar flexion exercise on three separate occasions with the only variable altered for each exercise bout being the FIO2 (either 0.1, 0.21, or 1.00 O2 in balance N2). Work rate was increased (1-W increments starting at 0 W) every 2 min until exhaustion. Time to exhaustion (and thereby workload achieved) was significantly (P \textless 0.05) greater as FIO2 was increased. Muscle phosphocreatine (PCr) concentration, Pi concentration, and pH at exhaustion were not significantly different among the three FIO2 conditions. However, muscle PCr concentration and pH were significantly reduced at identical submaximal workloads (and thereby equivalent rates of respiration) above 4-5 W during the lowest FIO2 condition compared with the other two FIO2 conditions. These results demonstrate that exhaustion during all FIO2 occurred when a particular intracellular environment was achieved and suggest that during the lowest FIO2 condition, the greater PCr hydrolysis and intracellular acidosis at submaximal workloads may have contributed to the significantly earlier time to exhaustion.
Abstract: Type 2 diabetes is characterized by decreased rates of insulin-stimulated glucose uptake and utilization, reduced hexokinase II mRNA and enzyme production, and low basal levels of glucose 6-phosphate in insulin-sensitive skeletal muscle and adipose tissues. Hexokinase II is primarily expressed in muscle and adipose tissues where it catalyzes the phosphorylation of glucose to glucose 6-phosphate, a possible rate-limiting step for glucose disposal. To investigate the role of hexokinase II in insulin action and in glucose homeostasis as well as in mouse development, we generated a hexokinase II knock-out mouse. Mice homozygous for hexokinase II deficiency (HKII(-/-)) died at approximately 7.5 days post-fertilization, indicating that hexokinase II is vital for mouse embryogenesis after implantation and before organogenesis. HKII(+/-) mice were viable, fertile, and grew normally. Surprisingly, even though HKII(+/-) mice had significantly reduced (by 50%) hexokinase II mRNA and activity levels in skeletal muscle, heart, and adipose tissue, they did not exhibit impaired insulin action or glucose tolerance even when challenged with a high-fat diet.
Abstract: This paper attempts to integrate some important concepts about the various mechanisms that are thought to cause blood flow to rise during rhythmic exercise. Mechanisms including the muscle pump, substances released by skeletal muscle, substances transported by blood, and factors released by nerves have been postulated to contribute to the rise in muscle blood flow during exercise. Additionally, the factors that initiate the dilation may not be those which sustain it. Although there is normally a close relationship between contractile activity, metabolic rate, and muscle blood flow, this relationship can be disrupted under a variety of circumstances and the active skeletal muscle overperfused. This delinking of flow and metabolism raises important questions about the nature of the vasodilating substances responsible for the rise in blood flow during exercise. We propose that understanding the mechanisms responsible for the "delinking" of flow and metabolism, along with a more synergistic view of current concepts, can provide new insight into the mechanisms which govern exercise hyperemia.
Abstract: PURPOSE: The purpose of this study was to determine the effects of rhythmic muscle contraction on the dynamics of venous outflow in rat skeletal muscle. METHODS: The effects of frequency and duration of tetanic contraction on venous blood flow (BF) were examined with transonic flow probes placed on the femoral artery and vein. RESULTS: Results reveal that instrumentation of the venous system with cannulas or flow probes alters vascular mechanics so that the muscle pump effect is masked. Measurements conducted without instrumentation of the venous vasculature in situ, as well as experiments with conscious exercising animals, indicate that the muscle pump enhances BF during exercise. Also, recent in vivo studies of humans indicate an important role for the muscle pump. In contrast, results reported herein and recent results from in situ experiments, which allow control of more parameters, indicate that there is no measurable muscle pump effect on BF during rhythmic muscle contraction. Review of the literature indicates that many in vitro/in situ experiments used instrumented veins that may have altered venous vascular mechanics and the interactions of muscle contraction and venous vascular mechanics, thus minimizing or abolishing the muscle pump effect. CONCLUSIONS: The muscle pump contributes to the initial increase in BF at exercise onset and to maintenance of BF during exercise.
Abstract: We questioned the general view that contraction-induced muscle glucose transport only depends on stimulation frequency and not on workload. Incubated soleus muscles were electrically stimulated at a given pattern for 5 min. Resting length was adjusted to achieve either no force (0% P), maximum force (100% P), or 50% of maximum force (50% P). Glucose transport (2-deoxy-D-glucose uptake) increased directly with force development (P \textless 0.05) [27 +/- 2 (basal), 45 +/- 2 (0% P), 68 +/- 3 (50% P), and 94 +/- 3 (100% P) nmol. g(-1). 5 min(-1)]. Glycogen decreased at 0% P but did not change further with force development (P \textgreater 0.05). Lactate, AMP, and IMP concentrations were higher (P \textless 0.05) and ATP concentrations lower (P \textless 0.05) when force was produced than when it was not. 5’-AMP-activated protein kinase (AMPK) activity increased directly with force [20 +/- 2 (basal), 60 +/- 11 (0% P), 91 +/- 12 (50% P), and 109 +/- 12 (100% P) pmol. mg(-1). min(-1)]. Passive stretch (approximately 86% P) doubled glucose transport without altering metabolism. In conclusion, contraction-induced muscle glucose transport varies directly with force development and is not solely determined by stimulation frequency. AMPK activity is probably an essential determinant of contraction-induced glucose transport. In contrast, glycogen concentrations per se do not play a major role. Finally, passive stretch per se increases glucose transport in muscle.
Abstract: During the past decade, it has become evident that dopamine plays an important role in the regulation of renal function and blood pressure. Dopamine exerts its actions via a class of cell-surface receptors coupled to G-proteins that belong to the rhodopsin family. Dopamine receptors have been classified into two families based on pharmacologic and molecular cloning studies. In mammals, two D1-like receptors that have been cloned, the D1 and D5 receptors (known as D1A and D1B, respectively, in rodents), are linked to stimulation of adenylyl cyclase. Three D2-like receptors that have been cloned (D2, D3, and D4) are linked to inhibition of adenylyl cyclase and Ca2+ channels and stimulation of K+ channels. All the mammalian dopamine receptors, initially cloned from the brain, have been found to be expressed outside the central nervous system, in such sites as the adrenal gland, blood vessels, carotid body, intestines, heart, parathyroid gland, and the kidney and urinary tract. Dopamine receptor subtypes are differentially expressed along the nephron, where they regulate renal hemodynamics and electrolyte and water transport, as well as renin secretion. The ability of renal proximal tubules to produce dopamine and the presence of receptors in these tubules suggest that dopamine can act in an autocrine or paracrine fashion; this action becomes most evident during extracellular fluid volume expansion. This renal autocrine/paracrine function is lost in essential hypertension and in some animal models of genetic hypertension; disruption of the D1 or D3 receptor produces hypertension in mice. In humans with essential hypertension, renal dopamine production in response to sodium loading is often impaired and may contribute to the hypertension. The molecular basis for the dopaminergic dysfunction in hypertension is not known, but may involve an abnormal post-translational modification of the dopamine receptor.
Abstract: Pure autonomic failure has been conceptualized as deficient sympathetic and parasympathetic innervation. Several recent observations in chronic autonomic failure, however, cannot be explained simply by loss of autonomic innervation, at least according to our current understanding. To simulate acute autonomic failure, we blocked N(N)-nicotinic receptors with intravenous trimethaphan (6+/-0.4 mg/min) in 7 healthy subjects (4 men, 3 women, aged 32+/-3 years, 68+/-4 kg, 171+/-5 cm). N(N)-Nicotinic receptor blockade resulted in near-complete interruption of sympathetic and parasympathetic efferents as indicated by a battery of autonomic function tests. With trimethaphan, small postural changes from the horizontal were associated with significant blood pressure changes without compensatory changes in heart rate. Gastrointestinal motility, pupillary function, saliva production, and tearing were profoundly suppressed with trimethaphan. Plasma norepinephrine level decreased from 1.1+/-0.12 nmol/L (180+/-20 pg/mL) at baseline to 0.23+/-0.05 nmol/L (39+/-8 pg/mL) with trimethaphan (P\textless.001). There was a more than 16-fold increase in plasma vasopressin (P\textless.01) and no change in plasma renin activity. We conclude that blockade of N(N)-cholinergic receptors is useful to simulate the hemodynamic alterations of acute autonomic failure in humans. The loss of function with acute N(N)-cholinergic blockade is more complete than in most cases of chronic autonomic failure. This difference may be exploited to elucidate the contributions of acute denervation and chronic adaptation to the pathophysiology of autonomic failure. N(N)-Cholinergic blockade may also be applied to study human cardiovascular physiology and pharmacology in the absence of confounding baroreflexes.
Abstract: We have recently demonstrated that changes in the work of breathing during maximal exercise affect leg blood flow and leg vascular conductance (C. A. Harms, M. A. Babcock, S. R. McClaran, D. F. Pegelow, G. A. Nickele, W. B. Nelson, and J. A. Dempsey. J. Appl. Physiol. 82: 1573-1583, 1997). Our present study examined the effects of changes in the work of breathing on cardiac output (CO) during maximal exercise. Eight male cyclists [maximal O2 consumption (VO2 max): 62 +/- 5 ml . kg-1 . min-1] performed repeated 2.5-min bouts of cycle exercise at VO2 max. Inspiratory muscle work was either 1) at control levels [inspiratory esophageal pressure (Pes): -27.8 +/- 0.6 cmH2O], 2) reduced via a proportional-assist ventilator (Pes: -16.3 +/- 0.5 cmH2O), or 3) increased via resistive loads (Pes: -35.6 +/- 0.8 cmH2O). O2 contents measured in arterial and mixed venous blood were used to calculate CO via the direct Fick method. Stroke volume, CO, and pulmonary O2 consumption (VO2) were not different (P \textgreater 0.05) between control and loaded trials at VO2 max but were lower (-8, -9, and -7%, respectively) than control with inspiratory muscle unloading at VO2 max. The arterial-mixed venous O2 difference was unchanged with unloading or loading. We combined these findings with our recent study to show that the respiratory muscle work normally expended during maximal exercise has two significant effects on the cardiovascular system: 1) up to 14-16% of the CO is directed to the respiratory muscles; and 2) local reflex vasoconstriction significantly compromises blood flow to leg locomotor muscles.
Abstract: The old division of lung edema into two categories–cardiogenic (hydrostatic) and noncardiogenic (increased permeability)–is no longer adequate. For instance, it fails to distinguish between the capillary leak caused by acute respiratory distress syndrome from that caused by interleukin-2 treatment. Further, it fails to account for the capillary leak (’stress-failure’) that may accompany edema. A modern view of edema must recognize the natural barriers to the formation and spread of edema. These barriers are the capillary endothelium and the alveolar epithelium. Varying degrees of damage to them can account for the varying radiographic and clinical manifestations of lung edema. Thus, interleukin-2 administration causes increased endothelial permeability without causing alveolar epithelial damage. The result is lung edema that is largely confined to the interstitium, causing little hypoxia and clearing rapidly. However, acute respiratory distress syndrome, which is characterized by extensive alveolar damage, causes air-space consolidation, severe hypoxia, and slow resolution. Thus, a reasonable classification of lung edema requires at least four categories: 1) hydrostatic edema; 2) acute respiratory distress syndrome (permeability edema caused by diffuse alveolar damage); 3) permeability edema without alveolar damage; and (4) mixed hydrostatic and permeability edema. The authors emphasize the importance of the barriers provided by the capillary endothelium and the alveolar epithelium in determining the clinical and radiographic manifestations of edema. In general, when the alveolar epithelium is intact, the radiographic manifestations are those of interstitial (not air-space) edema; this radiographic pattern predicts a mild clinical course and prompt resolution.
Abstract: The mechanisms responsible for the competition between glucose and fatty acids as oxidative fuels are not yet completely understood in humans. Maintenance of plasma fatty acid concentrations by means of lipid and heparin infusion during hyperinsulinemic, euglycemic clamps in humans first suppresses glucose oxidation and only later decreases nonoxidative glucose disposal; muscle pyruvate dehydrogenase activity is inhibited when plasma fatty acid concentrations are maintained during hyperinsulinemic, euglycemic clamps. The maintenance of plasma fatty acid concentrations impairs insulin-stimulated muscle glucose uptake only if fatty acid uptake by skeletal muscles is increased. The role of hyperglycemia in glucose-fatty acid competition has recently been emphasized. Fatty acid utilization by muscle is impaired in patients with type 2 diabetes mellitus during fasting hyperglycemia: both lipid oxidation and uptake of plasma fatty acids by skeletal muscle are impaired during postabsorptive conditions. Hyperglycemia indirectly activates pyruvate dehydrogenase, the rate-limiting enzyme for glucose oxidation. The ability of increased glucose availability to stimulate glucose oxidation and reduce lipid oxidation by skeletal muscle can be considered a corollary of the Randle glucose-fatty acid cycle. It can be concluded that within a reasonable range of carbohydrate-to-fat ratios, the addition of fat to a meal does not decrease postprandial carbohydrate oxidation. Furthermore, high-fat meals do not promote fat oxidation leading to fat storage in adipose tissue.
Abstract: We wished to determine whether the increased ACTH during prolonged exercise was associated with changes in peripheral corticotropin-releasing hormone (CRH) and/or arginine vasopressin (AVP). Six male triathletes were studied during exercise: 1 h at 70% maximal oxygen consumption, followed by progressively increasing work rates until exhaustion. Data obtained during the exercise session were compared with a nonexercise control session. Venous blood was sampled over a 2-h period for cortisol, ACTH, CRH, AVP, renin, glucose, and plasma osmolality. There were significant increases by ANOVA on log-transformed data in plasma cortisol (P = 0.002), ACTH (P \textless 0.001), CRH (P \textless 0.001), and AVP (P \textless 0.03) during exercise compared with the control day. A variable increase in AVP was observed after the period of high-intensity exercise. Plasma osmolality rose with exercise (P \textless 0.001) and was related to plasma AVP during submaximal exercise (P \textless 0.03) but not with the inclusion of data that followed the high-intensity exercise. This indicated an additional stimulus to the secretion of AVP. The mechanism by which ACTH secretion occurs during exercise involves both CRH and AVP. We hypothesize that high-intensity exercise favors AVP release and that prolonged duration favors CRH release.
Abstract: Energy balance refers to the dynamic homeostasis of ATP and related forms of chemical potential within cells. This regulation is accomplished mainly by oxidative metabolism in most mammals. This homeostasis matches dynamically the energy demands of cellular ATPases (net decrease in chemical potential energy) with the energy supply by mitochondrial oxidative phosphorylation (net increase in chemical potential energy). Muscle cells are distinguished from most other cell types in their ability to attain energy balance with more than a 10-fold range of ATPase demand. Creatine kinase maintains a near to equilibrium flux: PCr + ADP\textless–\textgreaterATP + Cr. One important function of creatine kinase is to buffer ATP and ADP concentrations. A system of differential equations describe the coupled operation of cellular ATPase, creatine kinase and oxidative phosphorylation. These equations used experimentally measured concentrations of relevant metabolites and enzyme activities to simulate energy balance in muscle cells. The principle of energy balance is adequately illustrated by simulations with only a three component system.
Abstract: As part of a joint NASA-ESA-DARA study on the effects of chronically increased CO2 concentrations in ambient air, changes in parameters indicating aerobic capacity were investigated by cycle ergometry. Two potential sources for reductions of aerobic capacities were hypothesized: 1) the adaptations to CO2 such as reduction in H(+)-buffer capacities which may influence muscle metabolism; 2) the reduced physical activities which may lead to a detraining effect. Four subjects were exposed to 0.7% and 1.2% CO2 concentration in a confined compartment for 23 d each with 3 mo in between the two campaigns. A combined exercise test was applied before, during (on days 5, 11, and 22) and after CO2 exposure. Comparing steady-states at 30 W and 80 W power, elevated ventilation was found increased during CO2 exposure with significant differences between the two campaigns. Peak oxygen uptake decreased over the period of CO2 exposure, but was found not significantly different on day 5 compared to pre-exposure measurements. This decrease was not dependent on the CO2 concentration. The lactate concentration at low exercise intensities was found elevated during CO2 exposure. A shift in reverse direction was observed after the CO2 exposure. Since peak oxygen uptake did not differ on day 5 and the lactate concentration was found increased, it was concluded that the potential changes in muscle metabolism by adaptation to elevated CO2 concentrations did not influence the aerobic capacities. Therefore, it was concluded that the changes in aerobic capacities are the result of the reduced physical activities of the subjects while living in the confined compartment.
Abstract: As humans venture into space to colonize the moon and travel to distant planets in the 21st century, they will be confronted with a bone disease that could potentially limit their space exploration activities or put them at risk for fracture when they return to earth. It is now recognized that an unloading of the skeleton, either due to strict bed rest or in zero gravity, leads on average to a 1%-2% reduction in bone mineral density at selected skeletal sites each month. The mechanism by which unloading of the skeleton results in rapid mobilization of calcium stores from the skeleton is not fully understood, but it is thought to be related to down regulation in PTH and 1,25-dihydroxyvitamin D3 production. Bone modeling and mineralization in chick embryos is not affected by microgravity, suggesting that bone cells adapt and ultimately become addicted to gravity in order to maintain a structurally sound skeleton. Strategies need to be developed to decrease microgravity-induced bone resorption by either mimicking gravity’s effect on bone metabolism, or enhancing physically or pharmacologically bone formation in order to preserve astronauts’ bone health.
Abstract: This study aimed to characterize the cellular pathways along which nitric oxide (NO) influences the secretion of renin from the kidney. Using the isolated perfused rat kidney model, we found that the NO donor sodium nitroprusside (SNP) (1-30 mumol/l) induced a prompt, concentration-dependent fourfold increase of basal renin secretion. The membrane-permeable cGMP analogs 8-bromo-cGMP and 8-(4-chlorophenylthio)-cGMP (8-pCPT-cGMP; each 5-50 mumol/l) inhibited basal renin secretion and attenuated the stimulation of renin secretion by SNP. Conversely, the renin stimulatory effect of SNP was enhanced in the presence of the G kinase inhibitor Rp-8-CPT-cGMPS (10 mumol/l). The renin stimulatory effect of SNP was amplified in nominally calcium-free perfusate and was abolished in the presence of angiotensin II (1 nmol/l). Renin secretion stimulated by SNP was clearly attenuated by the A kinase inhibitor Rp-8-CPT-cAMPS (25 mumol/l). These findings indicate that the renin stimulatory effect of NO donors in renal juxtaglomerular cells cannot be explained by activation of G kinase and is also less likely to be causally related to the regulation of renin secretion by calcium. Because A kinase activity is required for the stimulation of renin secretion by SNP, it appears as if the renin stimulatory effect is causally related to the cAMP pathway controlling renin secretion.
Abstract: To survive, cells have to avoid excessive alterations of cell volume that jeopardize structural integrity and constancy of intracellular milieu. The function of cellular proteins seems specifically sensitive to dilution and concentration, determining the extent of macromolecular crowding. Even at constant extracellular osmolarity, volume constancy of any mammalian cell is permanently challenged by transport of osmotically active substances across the cell membrane and formation or disappearance of cellular osmolarity by metabolism. Thus cell volume constancy requires the continued operation of cell volume regulatory mechanisms, including ion transport across the cell membrane as well as accumulation or disposal of organic osmolytes and metabolites. The various cell volume regulatory mechanisms are triggered by a multitude of intracellular signaling events including alterations of cell membrane potential and of intracellular ion composition, various second messenger cascades, phosphorylation of diverse target proteins, and altered gene expression. Hormones and mediators have been shown to exploit the volume regulatory machinery to exert their effects. Thus cell volume may be considered a second message in the transmission of hormonal signals. Accordingly, alterations of cell volume and volume regulatory mechanisms participate in a wide variety of cellular functions including epithelial transport, metabolism, excitation, hormone release, migration, cell proliferation, and cell death.
Abstract: We compared the difference in brain tissue oxygen pressure (pO2), carbon dioxide pressure (pCO2), pH and temperature with 2 probes inserted 1 cm apart, in 7 patients. Following a craniotomy for cerebrovascular surgery, two Neurotrend probes which measure pO2, pCO2, pH and temperature were inserted into the brain 1 cm apart. Measures were compared between the probes under baseline anesthetic conditions and during the course of surgery. Under baseline conditions, tissue pO2, pCO2, pH and temperature were not different between the 2 probes. A significant correlation was seen between the probes in pH and temperature. During the course of surgery, variation in tissue gases and pH occurred with changes in ventilation and blood pressure but the difference between the probes remained stable. Ischemic changes in pO2, pCO2 and pH were seen in one of the 2 probes during brain artery occlusion or retractor placement. These results show that tissue pO2, pCO2 and pH are consistent in local brain regions during steady state conditions. The relationship between local measures is disrupted by regional ischemia.
Abstract: While sustaining a load that leads to task failure, it is unclear whether diaphragmatic fatigue develops progressively or occurs only at task failure. We hypothesized that incremental loading produces a progressive decrease in diaphragmatic contractility ever before task failure. Ten subjects generated 60% of maximal transdiaphragmatic pressure (Pdimax) for 2 min, 4 min, and until task failure. Before loading, 20 min after each period of loading, and approximately 20 h after the last period of loading, Pdimax, nonpotentiated and potentiated Pdi twitch pressure (Pditw), and the pattern of respiratory muscle recruitment during a CO2 challenge were recorded. Sensation of inspiratory effort at the 4th min of the task-failure protocol was greater than at the same time in the preceding 4-min protocol. Surprisingly, potentiated Pditw and Pdimax were reduced after 2 min of loading and decreased further after 4 min of loading and after task failure; nonpotentiated Pditw was reduced after 4 min of loading and after task failure. The gastric pressure contribution to tidal breathing during a CO2 challenge decreased progressively in relation to duration of the preceding loading period, whereas expiratory muscle recruitment progressively increased. A rest period of approximately 20 h after task failure was not sufficient to normalize these alterations in respiratory muscle recruitment or fatigue-induced changes in diaphragmatic contractility. In conclusion, while sustaining a mechanical load, the diaphragm progressively fatigued, ever before task failure, and when challenged the rib cage-to-diaphragmatic contribution to tidal breathing and recruitment of the expiratory muscles increased pari passu with duration of the preceding loading.
Abstract: Skeletal muscle fatigue develops gradually during all forms of exercise, and develops more rapidly in heart failure patients. The fatigue mechanism is still not known, but is most likely localized to the muscle cells themselves. During high intensity exercise the perturbations of the Na+ and K+ balance in the exercising muscle favour depolarization, smaller action potentials and inexcitability. The Na+, K+ pump becomes strongly activated and limits, but does not prevent the rise in extracellular Na+, K+ pump concentration and intracellular Na+ concentration. However, by virtue of its electrogenic property the pump may contribute in maintaining excitability and contractility by keeping the cells more polarized than the ion gradients predict. With prolonged exercise perturbations of Na+ and K+ are smaller and fatigue may be associated with altered cellular handling of Ca2+ and Mg2+. Release of Ca2+ from the sarcoplasmic reticulum (SR) is reduced in the absence of changes of the cellular content of Ca2+ and Mg2+. In heart failure several clinical reports indicate severe electrolyte perturbations in skeletal muscle. However, in well controlled studies small or insignificant changes are found. We conclude that with high intensity exercise perturbations of Na+ and K+ in muscle cells may contribute to fatigue, whereas with endurance type of exercise and in heart failure patients the skeletal muscle fatigue is more likely to reside in the intracellular control of Ca2+ release and reuptake.
Abstract: When severe ischemia, such as that resulting from a sudden and complete coronary artery occlusion, is prolonged for more than 20-40 min, myocardial infarction develops, and there is irreversible loss of contractile function. When myocardial ischemia is less severe but nevertheless prolonged, the myocardium is dysfunctional but can remain viable. In such ischemic and dysfunctional myocardium, contractile function is reduced in proportion to the reduction in regional myocardial blood flow; i.e. a state of ’perfusion-contraction matching’ exists. The metabolic status of such myocardium improves over the first few hours, as myocardial lactate production is attenuated and creatine phosphate, after an initial reduction, returns towards control values. Ischemic myocardium, characterized by perfusion-contraction matching, metabolic recovery and lack of necrosis, has been termed ’short-term hibernating myocardium’. Short-term hibernating myocardium can respond to inotropic stimulation with increased contractile function, although at the expense of renewed worsening of the metabolic status. This occurrence of increased regional contractile function at the expense of metabolic recovery during inotropic stimulation can be used to identify short-term hibernating myocardium. When inotropic stimulation is prolonged, short-term hibernation is impaired and myocardial infarction develops. The mechanisms responsible for the development of short-term myocardial hibernation remain unclear at present. Significant involvement of adenosine and activation of ATP-dependent potassium channels have been excluded. The role of triggering events and acidosis is controversial. Short-term hibernating myocardium is, however, characterized by reduced calcium responsiveness.
Abstract: OBJECTIVE: Brain death-induced haemodynamic collapse in rats is not caused by intrinsic myocardial damage as shown in the accompanying paper. We investigated whether this collapse could be caused by the withdrawal of the basal adrenergic tone. METHODS: Heart rate and blood pressure variability was studied in rats before and after brain death. The effect of high doses of phentolamine, propranolol or their combination administered before or after brain death was assessed. RESULTS: Heart rate variability in the respiratory frequency range significantly increased, whereas in the low-frequency range it tended to decrease after brain death. Systolic and diastolic blood pressure variability up to 0.18 Hz largely disappeared, but stayed unchanged in the respiratory frequency range. High-dose combined phentolamine and propranolol pretreatment induced a haemodynamic picture comparable to the situation seen after brain death without pharmacological intervention. Brain death did not further deteriorate the haemodynamic situation after combined pretreatment. On the other hand, once the haemodynamic collapse after brain death had settled, adrenergic blockade had no important influence any more. CONCLUSION: We conclude that the haemodynamic situation seen after brain death is one of profound sympathetic withdrawal.
Abstract: This article presents a brief discussion of pulmonary function and panic attacks in the context of respiratory psychophysiology. Ley’s (Behaviour Research and Therapy, 27, 549-554, 1989) earlier dyspnea/suffocation theory of panic is contrasted with Klein’s (Archives of General Psychiatry, 50, 306-316, 1993) later false suffocation alarm theory. The distinction between "dyspnea" (the sensation of difficulty in breathing) and "suffocation" (a condition that sometimes gives rise to dyspnea) is emphasized. The brief discussion is followed by a critical comparison of two recent studies on pulmonary function and panic. Asmundson and Stein (Journal of Anxiety Disorders, 8, 63-69, 1994) reported an association between forced expiratory flow rate (a measure of pulmonary function) in panic disorder patients and the severity of panic-related symptoms. They interpreted their findings as support for the dyspnea/suffocation theory of panic since severity of dyspnea is a consequence of pulmonary function. Spinhoven et al. (Behaviour Research and Therapy, 33, 457-460, 1995) failed to replicate the findings of Asmundson and Stein. The present paper provides a critical analysis of the study by Spinhoven et al. and concludes that the failed attempt to replicate may have been a consequence of a flawed methodology (the subjects of the two studies are not comparable on a crucial pulmonary test) and a statistical anomaly (disproportionately small differences between means that exceed predictions based on sampling error). A recommendation is made that future attempts to replicate should pay special care to avoid the possibility of experimenter-demand effects.
Abstract: Acute intravenous infusions of leptin markedly alter hepatic glucose fluxes (Rossetti, L., Massillon, D., Barzilai, N., Vuguin, P., Chen, W., Hawkins, M., Wu, J., and Wang, J. (1997) J. Biol. Chem. 272, 27758-22763). Here we examine whether intracerebroventricular (ICV) leptin administration regulates peripheral and hepatic insulin action. Recombinant mouse leptin (n = 14; 0.02 or 1 microgram/kg.h) or vehicle (n = 9) were administered ICV for 6 h to conscious rats, and insulin action was determined by insulin (3 milliunits/kg.min) clamp and tracer dilution techniques. During physiologic hyperinsulinemia (approximately 65 microunits/ml), the rates of glucose uptake (Rd, 20.1 +/- 0.6 and 23.1 +/- 0.7 versus 21.7 +/- 0.6 mg/kg.min; p = NS), glycolysis and glycogen synthesis were similar in rats receiving low- and high-dose leptin versus vehicle. ICV leptin resulted in a 2-3-fold increase in hepatic phosphoenolpyruvate carboxykinase mRNA levels. Glycogenolysis and PEP-gluconeogenesis (2.1 +/- 0.3 mg/kg. min) contributed similarly to endogenous glucose production (GP) in the vehicle-infused group. However, gluconeogenesis accounted for approximately 80% of GP in both groups receiving ICV leptin, while hepatic glycogenolysis was markedly suppressed (0.7 +/- 0.3 and 1.2 +/- 0.3 versus 2.2 +/- 0.4 mg/kg.min, in rats receiving low- and high-dose leptin versus vehicle, respectively; p \textless 0.01). In summary, short-term ICV leptin administration: 1) failed to affect peripheral insulin action, but 2) induced a striking re-distribution of intrahepatic glucose fluxes. The latter effect largely reproduced that of leptin given systemically at much higher doses. Thus, the regulation of hepatic glucose fluxes by leptin is largely mediated via its central receptors.
Abstract: BACKGROUND: On exposure to microgravity, astronauts lose up to 12% of their plasma volume which may contribute to post-flight orthostatic intolerance. HYPOTHESIS: Whole-body dehydration during prolonged microgravity, simulated by 6(0) head-down tilt (HDT), may increase plasma colloid osmotic pressure (COP). METHODS: There were seven healthy male subjects (30-55 yr of age) were placed in 6(0) HDT for 16 d. Plasma COP was measured from blood samples drawn immediately before HDT, on day 14 of HDT, and 1 h following bed rest termination using a 20 muL colloid osmometer. Plasma volume was determined before HDT, on day 16 of HDT, and 1 h following bed rest termination using a modified Evans blue dye technique. RESULTS: Plasma COP on day 14 of bed rest (29.9 +/- 0.7 mm Hg) was higher (p = 0.01) than pre-HDT value (23.1 +/- 0.8 mm Hg), coinciding with a decrease of plasma volume. At 1 h of upright recovery following HDT, plasma volume stayed below baseline and plasma COP remained elevated (26.6 +/- 0.6 mm hg; p = 0.003) as compared with the pre-HDT value. CONCLUSION: Our results indicate that reduced plasma volume and significantly elevated plasma COP probably reflect an overall loss of extracellular fluids during simulated microgravity.
Abstract: Tubuloglomerular feedback (TGF), which operates between the tubule and the parent glomerulus, is important to renal autoregulation and homeostasis of body fluid and electrolytes. The juxtaglomerular apparatus (JGA) has long been suggested as the anatomical site of TGF. To study the function of the JGA directly, we developed an in vitro preparation in which both the afferent arteriole (Af-Art) and macula densa (MD) of a microdissected rabbit JGA are microperfused simultaneously. We see that increasing the [NaCl] of the MD perfusate constricts the afferent arteriole in the segment close to the glomerulus. This constriction is blocked by furosemide, a loop diuretic known to inhibit TGF. On the other hand, microperfusion of Af-Arts alone showed the myogenic response to exist in the more proximal segments. Such an anatomical relationship between the myogenic response and TGF may enable the kidney to achieve its extremely efficient autoregulation.
Abstract: Although an anion gap at less than 20 mEq/L rarely has a defined etiology, significant elevations in the anion gap almost always signify presence of an acidosis that can be easily identified. Anion gap acidoses can be divided into those caused by lactate accumulation, ketoacid production, toxin/drugs, and uremia. Lactic acidoses caused by decreased oxygen delivery or defective oxygen utilization are associated with high mortality. The treatment of lactic acidosis is controversial. The use of bicarbonate to increase pH is rarely successful and, by generating PCO2, may worsen outcome. Ketoacidosis is usually secondary to diabetes or alcohol. Treatment is aimed at turning off ketogenesis and repairing fluid and electrolyte abnormalities. Methanol, ethylene glycol, and salicylates are responsible for the majority of toxin-induced anion gap acidoses. Both methanol and ethylene glycol are associated with severe acidoses and elevated osmolar gaps. Treatment of both is alcohol infusion to decrease formation of toxic metabolites and dialyses to remove toxins. Salicylate toxicity usually is associated with a mild metabolic acidosis and a respiratory alkalosis. Uremia is associated with a mild acidosis secondary to decreased ammonia secretion and an anion gap caused by the retention of unmeasured anions. A decrease in anion gap is caused by numerous mechanisms and thus has little clinical utility.
Abstract: In the acinus of the sheep and mouse liver, lymphatic vessels are restricted to the portal tracts. Vessels less than about 25 microm across form a network around portal venules, and are closely associated with the limiting plate of hepatocytes. The perisinusoidal space of Disse is continuous with the interstitial space of the portal tracts at the origin of the sinusoids. It seems likely that excess interstitial fluid derived from the sinusoids flows along the perisinusoidal space of Disse to enter the portal tracts near the portal venules, and then enters the small lymphatics which lie adjacent to those venules. It then enters the larger vessels, which are adjacent to hepatic arterioles and bile ductules.
Abstract: To determine whether the sympathetic nervous system contributes to the hypertension induced by pathophysiological increments in plasma angiotensin II (Ang II) concentration, we determined the neurally induced changes in renal excretory function during chronic intravenous infusion of Ang II. Studies were carried out in five conscious chronically instrumented dogs subjected to unilateral renal denervation and surgical division of the urinary bladder into hemibladders to allow separate 24-hour urine collection from the denervated and innervated kidneys. After control measurements, Ang II was infused for 5 days at a rate of 4.8 pmol/kg per minute (5 ng/kg per minute); this was followed by a 5-day recovery period. Twenty-four-hour control values for mean arterial pressure (MAP) and for the ratio of denervated to innervated kidneys (DEN/INN) for urinary sodium, potassium, and creatinine excretion were 93+/-5 mm Hg, 1.17+/-0.09, 1.10+/-0.10, and 1.00+/-0.02, respectively. As expected, Ang II infusion caused sodium retention for several days before sodium balance was achieved at an elevated MAP (day 5=124+/-4 mm Hg). Moreover, by day 2 of Ang II-induced hypertension, there were significant reductions in the DEN/INN for sodium and potassium, which persisted for the 5 days of Ang II infusion; on day 5, the DEN/INN values for sodium and potassium were 0.71+/-0.10 and 0.91+/-0.12, respectively. In contrast, the DEN/INN for creatinine was unchanged from control levels during Ang II infusion, and measurements of renal hemodynamics indicated comparable reductions in glomerular filtration rate (approximately 13%) and renal plasma flow (approximately 25%) during Ang II infusion. This indicates that the renal nerves promoted sodium and potassium excretion during Ang II-induced hypertension by inhibiting tubular reabsorption of these electrolytes. Thus, this study provides no support for the hypothesis that increased renal sympathetic nerve activity impairs sodium excretion and contributes to Ang II-induced hypertension.
Abstract: Experimentally, enhanced glycolytic flux has been shown to confer many benefits to the ischemic heart, including maintenance of membrane activity, inhibition of contracture, reduced arrhythmias, and improved functional recovery. While at moderate low coronary flows, the benefits of glycolysis appear extensive, the controversy arises at very low flow rates, in the absence of flow; or when glycolytic substrate may be present in excess, such that high glucose concentrations with or without insulin overload the cell with deleterious metabolites. Under conditions of total global ischemia, glycogen is the only substrate for glycolytic flux. Glycogenolysis may only be protective until the accumulation of metabolites (lactate, H+, NADH, sugar phosphates and Pi ) outweighs the benefit of the ATP produced. The possible deleterious effects associated with increased glycolysis cannot be ignored, and may explain some of the controversial findings reported in the literature. However, an optimal balance between the rate of ATP production and rate of accumulation of metabolites (determined by the glycolytic flux rate and the rate of coronary washout), may ensure optimal recovery. In addition, the effects of glucose utilisation must be distinguished from those of glycogen, differences which may be explained by functional compartmentation within the cell.
Abstract: The pattern of muscle glycogen synthesis following its depletion by exercise is biphasic. Initially, there is a rapid, insulin independent increase in the muscle glycogen stores. This is then followed by a slower insulin dependent rate of synthesis. Contributing to the rapid phase of glycogen synthesis is an increase in muscle cell membrane permeability to glucose, which serves to increase the intracellular concentration of glucose-6-phosphate (G6P) and activate glycogen synthase. Stimulation of glucose transport by muscle contraction as well as insulin is largely mediated by translocation of the glucose transporter isoform GLUT4 from intracellular sites to the plasma membrane. Thus, the increase in membrane permeability to glucose following exercise most likely reflects an increase in GLUT4 protein associated with the plasma membrane. This insulin-like effect on muscle glucose transport induced by muscle contraction, however, reverses rapidly after exercise is stopped. As this direct effect on transport is lost, it is replaced by a marked increase in the sensitivity of muscle glucose transport and glycogen synthesis to insulin. Thus, the second phase of glycogen synthesis appears to be related to an increased muscle insulin sensitivity. Although the cellular modifications responsible for the increase in insulin sensitivity are unknown, it apparently helps maintain an increased number of GLUT4 transporters associated with the plasma membrane once the contraction-stimulated effect on translocation has reversed. It is also possible that an increase in GLUT4 protein expression plays a role during the insulin dependent phase.
Abstract: Decreased myocardial contraction occurs as a consequence of a reduction in blood flow. The concept of hibernation implies a downregulation of contractile function as an adaptation to a reduction in myocardial blood flow that serves to maintain myocardial integrity and viability during persistent ischemia. Unequivocal evidence for this concept exists in scenarios of myocardial ischemia that lasts for several hours, and sustained perfusion-contraction matching, recovery of energy and substrate metabolism, the potential for recruitment of inotropic reserve at the expense of metabolic recovery, and lack of necrosis are established criteria of short-term hibernation. The mechanisms of short-term hibernation, apart from reduced calcium responsiveness, are not clear at present. Experimental studies with chronic coronary stenosis lasting more than several hours have failed to continuously monitor flow and function. Nevertheless, a number of studies in chronic animal models and patients have demonstrated regional myocardial dysfunction at reduced resting blood flow that recovered upon reperfusion, consistent with chronic hibernation. Further studies are required to distinguish chronic hibernation from cumulative stunning. With a better understanding of the mechanisms underlying short-term hibernation, it is hoped that these adaptive responses can be recruited and reinforced to minimize the consequences of acute myocardial ischemia and delay impending infarction. Patients with chronic hibernation must be identified and undergo adequate reperfusion therapy.
Abstract: Hepatic glucose production increases during exercise as a sum of liver glycogenolysis and gluconeogenesis. Whereas the former dominates during intense exercise, the latter contributes substantially with prolonged exercise and the concomitant decline in liver glycogen stores and with increased gluconeogenic precursor supply. Afferent neural feedback signals from contracting muscle and feedback signals mediated via the blood stream, can stimulate glucose production to maintain euglycemia. A rise in blood glucose directly inhibits hepatic glucose production, whereas a decline in blood glucose enhances liver glucose production via release of glucoregulatory hormones. In addition to this, central mechanisms coupled to the degree of motor center activity can be responsible for part of the increase in glucose mobilization, especially during intense exercise where hepatic glucose release exceeds peripheral glucose uptake and plasma glucose rises. A decline in plasma insulin is important for the rise in glucose production during exercise in a variety of species, whereas an increase in plasma glucagon is probably more important in other species than man, where glucagon plays a role only in prolonged exercise. Sympathetic nervous activity to the liver and circulating norepinephrine has been demonstrated to be without any role in glucose production, whereas epinephrine has a minor stimulating effect on hepatic glucose mobilization during intense exercise. Growth hormone and cortisol contribute only minimally to the exercise induced rise in liver glucose output.
Abstract: OBJECTIVE: (i) To examine the usefulness of urinary net charge (UNa + UK - UCl) in the evaluation of hyperchloremic metabolic acidosis secondary to diarrhea, distal RTA and proximal RTA and (ii) To characterize the type of distal RTA on the basis of the underlying defect. SETTING: Pediatrics division of a tertiary referral center. SUBJECTS: Thirty four children with hyperchloremic metabolic acidosis secondary to diarrhea (n = 16), distal RTA (n = 11) and proximal RTA (n = 7). Ten normal children with ammonium chloride induced acidosis were also studied. METHODS: All subjects underwent urine collection of 30-60 minutes duration for measurement of Na, K, Cl, pH and pCO2. The measurements were also made on the blood samples collected at the midpoint of urine collection. The urinary net charge was calculated by subtracting Cl values from the sum of the Na and K. RESULTS: Patients with proximal and distal RTA had a positive urine net charge. Patients with diarrhea and ammonium chloride induced acidosis showed negative urine net charge. Patients with diarrhea with extremely low urine sodium levels showed an inappropriately high urine pH despite persistent metabolic acidosis. All patients with distal RTA were found to have a secretory type of defect. CONCLUSION: Measurement of urine net charge is helpful in the initial evaluation of a patient with hyperchloremic metabolic acidosis.
Abstract: During exercise, large pleural, abdominal, and transdiaphragmatic pressure swings might produce substantial rib cage (RC) distortions. We used a three-compartment chest wall model (J. Appl. Physiol. 72: 1338-1347, 1992) to measure distortions of lung- and diaphragm-apposed RC compartments (RCp and RCa) along with pleural and abdominal pressures in five normal men. RCp and RCa volumes were calculated from three-dimensional locations of 86 markers on the chest wall, and the undistorted (relaxation) RC configuration was measured. Compliances of RCp and RCa measured during phrenic stimulation against a closed airway were 20 and 0%, respectively, of their values during relaxation. There was marked RC distortion. Thus nonuniform distribution of pressures distorts the RC and markedly stiffens it. However, during steady-state ergometer exercise at 0, 30, 50, and 70% of maximum workload, RC distortions were small because of a coordinated action of respiratory muscles, so that net pressures acting on RCp and RCa were nearly the same throughout the respiratory cycle. This maximizes RC compliance and minimizes the work of RC displacement. During quiet breathing, plots of RCa volume vs. abdominal pressure were to the right of the relaxation curve, indicating an expiratory action on RCa. We attribute this to passive stretching of abdominal muscles, which more than counterbalances the insertional component of transdiaphragmatic pressure.
Abstract: The effect of physiological concentrations of angiotensin II on proximal tubular fluid reabsorption remains controversial. To investigate the effect of blockade of intratubular AT1 receptors on tubular reabsorption, losartan (10(-5) M) was administered by microperfusion into an early proximal convolution of halothane-anesthetized Sprague-Dawley rats. Four parameters that depend on the rate of proximal fluid reabsorption were measured: proximal intratubular pressure (Pprox), early and late proximal flow rate, and early distal NaCl concentration. Pprox decreased by 0.5 +/- 0.1 mmHg, late proximal flow rate decreased by 2.0 +/- 0.8 nl/min, and early distal NaCl concentration decreased by 4.3 +/- 0.8 mM (mean +/- SE). No changes were observed after microperfusion with saline. Because the tubuloglomerular feedback mechanism was operating in the closed-loop mode, the decreased NaCl load to the macula densa will be compensated by an increase in the single-nephron glomerular filtration rate. In agreement with this, the early proximal flow rate, measured proximal to the site of losartan administration, increased by 5.7 +/- 1.3 nl/min. The increase in the rate of proximal reabsorption between the early and late proximal convolutions was estimated to be 7.8 nl/min (approximately 36%). It is concluded that a decrease in local luminal angiotensin II levels and/or AT1 receptor activity under free flow conditions increases the rate of proximal tubular fluid reabsorption.
Abstract: OBJECTIVE: The objectives of this study were: 1) to determine whether obtaining intraosseous (IO) blood samples was practical during cardiopulmonary resuscitation (CPR), and 2) to compare the acid-base status (pH and partial pressure of CO2 (PCO2) of venous and IO blood during CPR. DESIGN: A prospective repeated measure study. SETTING: An animal laboratory at a university medical center. INTERVENTIONS: Nine mixed breed piglets (mean weight 43 kg) were anesthetized, tracheotomized, and placed on a ventilator (Siemens 900C Elema, Sweden). Placement of a pulmonary artery catheter was done via a surgical incision in the neck. An IO cannula was then placed in the tibial marrow cavity. The animals were positioned under a mechanical thumper (Thumper, Michigan Instruments, Grand Rapids, MI) for chest compressions. Blood gases were analyzed during steady state (baseline) after five minutes of ventricular fibrillation and during CPR at seven, nine, 11, 13, 15 and 18 minutes. MAIN RESULTS: Blood samples for acid-base analysis were easily obtained from the IO sites during all sampling times. Mixed venous blood was slightly more acidic than IO blood, especially at 13, 15, and 18 minutes. However, there were no significant differences in pH and Pco2 values between IO and central venous (CV) gases at all time intervals except the PCO2. At nine minutes, a significant difference (P \textless 0.006) was found in PCO2 (59 +/- 4 vs 47 +/- 5 torr) for the CV versus IO sample, respectively. As the duration of CPR progressed, the differences in PCO2 between IO and CV sites were clinically relevant (though not statistically significant). CONCLUSION: Obtaining blood from the IO site is practical during CPR. The divergence in values as CPR progresses suggests that, during longer periods of CPR, IO blood may reflect local acidosis and yield lower PCO2 and higher pH values that CV blood. This finding may limit the usefulness of IO blood to judge acid base status as CPR progresses.
Abstract: Although previous results have shown unequivocally that pre-ischaemic hyperglycaemia aggravates brain damage due to transient ischaemia, several questions have remained unanswered. First, is the effect of hyperglycaemia due to a further fall in intra- and extracellular pH? Second, is aggravation of damage a step function of a continuous function of plasma glucose concentration or of pH? Third, which are the mechanisms responsible for aggravation of damage, notably for the transformation of selective neuronal damage to infarction, for oedema development, and for post-ischaemic seizures? Recent results have provided new information on all of these issues. Thus, normoglycaemic animals with superimposed hypercapnia showed a similar, albeit not identical, aggravation of ischaemic damage, suggesting that acidosis is one major mediator. Furthermore, experiments with graded increase in plasma glucose concentration revealed a threshold effect at values of 10-12 mM, while microelectrode measurements showed a narrow extracellular pH range (6.4-6.5) for post-ischaemic seizure development. These results suggest that aggravation of damage due to excessive acidosis is due to mechanisms with a steep pH dependence. Finally, results are now at hand suggesting that the effect of acidosis is not mediated by a further perturbation of cell calcium metabolism. The more likely mediators are free radicals. Thus, acidosis is known to enhance iron-catalysed production of reactive oxygen species, probably by releasing iron from its bindings to transferrin, ferritin and other proteins.
Abstract: The objective of this study was to determine the contribution of renal nerves to the enhanced afferent arteriolar reactivity observed in angiotensin II (Ang II)-induced hypertension. Uninephrectomized Sprague-Dawley rats were divided into four groups: sham rats, renal-denervated rats, Ang II-infused (at 40 ng/min for 13 days) rats, and Ang II-infused+renal-denervated rats. With the use of an implanted arterial catheter, mean arterial pressure (MAP) was monitored in conscious rats. Ang II infusion resulted in a progressive increase in MAP from 98 +/- 1 (day 0) to 166 +/- 7 mm Hg (day 13). This increase in MAP was attenuated in denervated rats and averaged 136 +/- 3 mm Hg on day 13. Kidneys were harvested on day 13 for microcirculatory experiments or measurement of intrarenal Ang II levels. Basal afferent arteriolar diameter was similar in all groups, and group averages ranged from 19.6 to 20.7 microns. Chronic Ang II infusion increased intrarenal Ang II levels. Renal denervation did not alter this effect. Increasing perfusion pressure from 100 to 160 mm Hg reduced afferent arteriolar diameter significantly by 11.2 +/- 0.6% in the sham group and by a similar degree in the remaining three groups. Superfusion with Ang II (10 nmol/L) reduced afferent arteriolar diameter by 34.3 +/- 2.0% in the sham group. This response was enhanced in Ang II-infused (62.3 +/- 3.4%) but not in renal-denervated or Ang II-infused+renal-denervated rats. Additionally, the enhanced afferent arteriolar reactivity to Ang II was not influenced by adrenergic receptor blockade. The afferent arteriolar response to norepinephrine was enhanced in renal-denervated, Ang II-infused, and Ang II-infused+renal-denervated rats compared with sham controls. Administration of the calcium ionophore A23187 decreased afferent arteriolar diameter similarly in all four groups. These results indicate that renal nerves contribute to the development of hypertension and to the enhanced afferent arteriolar responsiveness to Ang II elicited by chronic Ang II infusion.
Abstract: The term homeostasis traditionally refers to the maintenance of a relatively constant internal milieu in the face of changing environmental conditions or changing physiological function. Tissues such as skeletal and cardiac muscles must sustain very large-scale changes in ATP turnover rate during equally large changes in work. In many skeletal muscles, these changes can exceed 100-fold. In unique biological circumstances (for example, during periods of oxygen limitation, vasoconstriction and hypometabolism), tissues such as skeletal muscles may be obliged to sustain further decreases in ATP turnover rates and operate for varying periods at seriously suppressed ATP turnover rates. Examination of a number of cellular and whole-organism systems identifies ATP concentration as a key parameter of the interior milieu that is nearly universally "homeostatic’; it is common to observe no change in ATP concentration even while the change in its turnover rate can increase or decrease by two orders of magnitude. A large number of other intermediates of cellular metabolism are also regulated within narrow concentration ranges, but none seemingly as precisely as is [ATP]. In fact, the only other metabolite in aerobic energy metabolism that is seemingly as "homeostatic’ is oxygen-at least in working muscles. The central regulatory question is how such homeostasis of key intermediates in pathways of energy supply and energy demand is achieved.
Abstract: BACKGROUND: The cardiovascular adaptation to bed rest leads to orthostatic intolerance, characterized by an excessive fall in stroke volume (SV) in the upright position. We hypothesized that this large fall in SV is due to a change in cardiac mechanics. METHODS AND RESULTS: We measured pulmonary capillary wedge pressure (PCWP), SV, left ventricular end-diastolic volume (LVEDV), and left ventricular mass (by echocardiography) at rest, during lower-body negative pressure, and after saline infusion before and after 2 weeks of bed rest with -6 degrees head-down tilt (n=12 subjects aged 24+/-5 years). Pressure (P)-volume (V) curves were modeled exponentially by P=ae(kV)+b and logarithmically by P=-Sln[(Vm-V)/(Vm-V0)], where V0 indicates volume at P=0, and the constants k and S were used as indices of normalized chamber stiffness. Dynamic stiffness (dP/dV) was calculated at baseline LVEDV. The slope of the line relating SV to PCWP during lower-body negative pressure characterized the steepness of the Starling curve. We also measured plasma volume (with Evans blue dye) and maximal orthostatic tolerance. Bed rest led to a reduction in plasma volume (17%), baseline PCWP (18%), SV (12%), LVEDV (16%), V0 (33%), and orthostatic tolerance (24%) (all P\textless.05). The slope of the SV/PCWP curve increased from 4.6+/-0.4 to 8.8+/-0.9 mL/mm Hg (P\textless.01) owing to a parallel leftward shift in the P-V curve. Normalized chamber stiffness was unchanged, but dP/dV was reduced by 50% at baseline LVEDV, and cardiac mass tended to be reduced by 5% (P\textless.10). CONCLUSIONS: Two weeks of head-down-tilt bed rest leads to a smaller, less distensible left ventricle but a shift to a more compliant portion of the P-V curve. This results in a steeper Starling relationship, which contributes to orthostatic intolerance by causing an excessive reduction in SV during orthostasis.
Abstract: Animal studies have demonstrated a threshold below which renin release increases proportionally to a decrease in renal perfusion pressure. Demonstration of a similar mechanism in humans, however, has proved difficult, as any attempt to lower blood pressure below the putative renin threshold results in renin release mediated by reflex activation of the sympathetic nervous system. In this study, we report on our observations in a 71-year-old woman who presented with a 20-year history of faintness and syncope and was diagnosed as having pure autonomic failure. Graded head-up tilting resulted in a stepwise reduction in mean arterial blood pressure to a minimum of 54 mm Hg, with no signs of increased sympathetic activity. A fall in blood pressure below 80 mm Hg resulted in a distinct rise in plasma renin activity, and a similar threshold pressure was observed under both a 50- and a 100-mmol/d sodium chloride diet. Below the threshold, response to changes in perfusion pressure was proportionally greater under the 50-mmol/d diet than under a 100- or 200-mmol/d diet. These observations demonstrate that a pressure threshold for renin release at 10 to 15 mm Hg below ambient blood pressure, as described previously in animal studies, is also present in humans. The significance of this pressure-dependent mechanism of renin release for the long-term regulation of blood pressure and water and mineral balance in humans remains to be determined.
Abstract: We hypothesized that during exercise at maximal O2 consumption (VO2max), high demand for respiratory muscle blood flow (Q) would elicit locomotor muscle vasoconstriction and compromise limb Q. Seven male cyclists (VO2max 64 +/- 6 ml.kg-1.min-1) each completed 14 exercise bouts of 2.5-min duration at VO2max on a cycle ergometer during two testing sessions. Inspiratory muscle work was either 1) reduced via a proportional-assist ventilator, 2) increased via graded resistive loads, or 3) was not manipulated (control). Arterial (brachial) and venous (femoral) blood samples, arterial blood pressure, leg Q (Qlegs; thermodilution), esophageal pressure, and O2 consumption (VO2) were measured. Within each subject and across all subjects, at constant maximal work rate, significant correlations existed (r = 0.74-0.90; P \textless 0.05) between work of breathing (Wb) and Qlegs (inverse), leg vascular resistance (LVR), and leg VO2 (VO2legs; inverse), and between LVR and norepinephrine spillover. Mean arterial pressure did not change with changes in Wb nor did tidal volume or minute ventilation. For a +/-50% change from control in Wb, Qlegs changed 2 l/min or 11% of control, LVR changed 13% of control, and O2 extraction did not change; thus VO2legs changed 0.4 l/min or 10% of control. Total VO2max was unchanged with loading but fell 9.3% with unloading; thus VO2legs as a percentage of total VO2max was 81% in control, increased to 89% with respiratory muscle unloading, and decreased to 71% with respiratory muscle loading. We conclude that Wb normally incurred during maximal exercise causes vasoconstriction in locomotor muscles and compromises locomotor muscle perfusion and VO2.
Abstract: Energy requirements during space flight are poorly defined because they depend on metabolic-balance studies, food disappearance, and dietary records. Water turnover has been estimated by balance methods only. The purpose of this study was to determine energy requirements and water turnover for short-term space flights (8-14 d). Subjects were 13 male astronauts aged 36-51 y with normal body mass indexes (BMIs). Total energy expenditure (TEE) was determined during both a ground-based period and space flight and compared with the World Health Organization (WHO) calculations of energy requirements and dietary intake. TEE was not different for the ground-based and the space-flight periods (12.40 +/- 2.83 and 11.70 +/- 1.89 MJ/d, respectively), and the WHO calculation using the moderate activity correction was a good predictor of TEE during space flight. During the ground-based period, energy intake and TEE did not differ, but during space flight energy intake was significantly lower than TEE; body weight was also less at landing than before flight. Water turnover was lower during space flight than during the ground-based period (2.7 +/- 0.6 compared with 3.8 +/- 0.5 L/d), probably because of lower fluid intakes and perspiration loss during flight. This study confirmed that the WHO calculation can be used for male crew members’ energy requirements during short space flights.
Abstract: Exercise increases the rate of glucose uptake into the contracting skeletal muscles. This effect of exercise is similar to the action of insulin on glucose uptake, and the mechanism through which both stimuli increase skeletal muscle glucose uptake involves the translocation of GLUT-4 glucose transporters to the plasma membrane and transverse tubules. Most studies suggest that exercise and insulin recruit distinct GLUT-4-containing vesicles and/or mobilize different "pools" of GLUT-4 proteins originating from unique intracellular locations. There are different intracellular signaling pathways that lead to insulin- and exercise-stimulated GLUT-4 translocation. Insulin utilizes a phosphatidylinositol 3-kinase-dependent mechanism, whereas the exercise signal may be initiated by calcium release from the sarcoplasmic reticulum leading to the activation of other signaling intermediaries, and there is also evidence for autocrine- or paracrine-mediated activation of transport. The period after exercise is characterized by increased sensitivity of muscle glucose uptake to insulin, which can be substantially prolonged in the face of carbohydrate deprivation. The ability of exercise to utilize insulin-independent mechanisms to increase glucose uptake in skeletal muscle has important clinical implications, especially for patients with diseases that are associated with peripheral insulin resistance, such as non-insulin-dependent diabetes mellitus.
Abstract: Leptin is a peptide hormone produced by adipose tissue which acts centrally to decrease appetite and increase energy expenditure. Although leptin increases norepinephrine turnover in thermogenic tissues, the effects of leptin on directly measured sympathetic nerve activity to thermogenic and other tissues are not known. We examined the effects of intravenous leptin and vehicle on sympathetic nerve activity to brown adipose tissue, kidney, hindlimb, and adrenal gland in anesthetized Sprague-Dawley rats. Intravenous infusion of mouse leptin over 3 h (total dose 10-1,000 microg/kg) increased plasma concentrations of immunoreactive murine leptin up to 50-fold. Leptin slowly increased sympathetic nerve activity to brown adipose tissue (+286+/-64% at 1,000 microg/kg; P = 0.002). Surprisingly, leptin infusion also produced gradual increases in renal sympathetic nerve activity (+228+/-63% at 1,000 microg/kg; P = 0.0008). The effect of leptin on sympathetic nerve activity was dose dependent, with a threshold dose of 100 microg/kg. Leptin also increased sympathetic nerve activity to the hindlimb (+287+/-60%) and adrenal gland (388+/-171%). Despite the increase in overall sympathetic nerve activity, leptin did not increase arterial pressure or heart rate. Leptin did not change plasma glucose and insulin concentrations. Infusion of vehicle did not alter sympathetic nerve activity. Obese Zucker rats, known to possess a mutation in the gene for the leptin receptor, were resistant to the sympathoexcitatory effects of leptin, despite higher achieved plasma leptin concentrations. These data demonstrate that leptin increases thermogenic sympathetic nerve activity and reveal an unexpected stimulatory effect of leptin on overall sympathetic nerve traffic.
Abstract: The contribution of carbon monoxide (CO) to the acute cardiovascular effects of smoking is not clear. Using a double-blind, randomized, vehicle-controlled study design, we examined the sympathetic and vascular responses to modest increases in carboxyhemoglobin in 10 healthy humans. We measured muscle sympathetic nerve activity (microneurography), forearm blood flow (plethysmography), heart rate, blood pressure, and minute ventilation at baseline and during 60 minutes of CO inhalation (1000 ppm during the first 30 minutes and 100 ppm during the last 30 minutes). The same measurements were made in a vehicle session (room air inhalation) on a separate day. During the first 30 minutes of CO inhalation, carboxyhemoglobin levels increased progressively from 0.2 +/- 0.1% to 8.3 +/- 0.5% and were maintained at about this level for a further 30 minutes. Forearm vascular resistance did not change with CO but increased slightly with vehicle; the effects of CO on muscle sympathetic nerve activity, forearm blood flow, blood pressure, heart rate, and minute ventilation were not significantly different from the effects of vehicle. Modest increases in carboxyhemoglobin levels equivalent to those resulting from cigarette smoking are unlikely to contribute to the acute sympathetic and hemodynamic effects of smoking in healthy humans.
Abstract: Muscle glycogen and blood glucose are important substrates for contracting skeletal muscle during exercise. The possibility exists for considerable interaction between muscle glycogen and blood glucose and their effects on muscle glucose uptake and glycogenolysis, respectively. Increases in blood glucose availability have little effect on net muscle glycogen utilization during prolonged, strenuous cycling exercise, but this may be dependent upon the mode and intensity of exercise. No data exist on the direct effect of reduced blood glucose levels on muscle glycogen metabolism. In rats, studies using the perfused hindlimb suggest an inverse relationship between muscle glycogen levels and glucose uptake. A similar conclusion can be drawn from a number of human studies albeit, on occasion, from indirect evidence. The influence of muscle glycogen on glucose uptake involves effects on both membrane glucose transport and intracellular glucose metabolism. Such a relationship would, under conditions of adequate muscle glycogen availability, limit muscle glucose uptake, thereby preserving the relatively small blood glucose supply for the brain, nerves, and blood cells, which are dependent on it for their energy metabolism.
Abstract: The terms ’dyspnoea’ or ’breathlessness’ refer to an individual’s subjective awareness of discomfort related to the act of breathing. Elevations in CO2 above normal levels have been shown to cause breathlessness although it is unlikely to be the sole cause of breathlessness in a clinical setting. Several studies suggest that supplemental O2 during exercise will diminish the sensation of breathlessness although not all work has confirmed this finding. Much about the role of gas exchange in dyspnogenesis remains controversial. Phrenic blockade can abolish dyspnoea in response to breath-holding, while work in quadriplegics suggests that the intercostal muscles are not involved. A separate and direct pathway from the respiratory centre to the sensory cortex has also be implicated. Threshold discrimination has established that patients with chronic airflow limitation (CAL) have a blunted response to the addition of resistive loads to breathing, while category scaling methods (e.g. the Borg scale) have added descriptive terms to these physiological measures. Questionnaires often appear limited by their subjectivity and lack of correlation with physiological changes, but remain a useful tool in the clinical setting. In regard to therapy of dyspnoea high fat diets have a theoretical advantage in the CAL group but are generally not well tolerated. Resistive training devices and exercise training in CAL have been widely researched but in general, measures of lung remain unaltered and many of the studies would suggest that they have little, if any, inpact on functional status. Beta-agonists have been widely shown to be useful in CAL patients, despite the fact that bronchodilatation is not always demonstrable. Anticholinergics have be shown to be effective bronchodilators, but whether there is an improvement in dyspnoea above that expected from improvement in lung function is unclear. Animal studies and work in normal individuals would suggest that methylxanthines have a theoretical role in CAL possibly by increasing diaphragmatic muscle strength and decaying fatigue, but toxicity and lack of clear benefit in this group suggest that they should not be used as monotherapy. There is little evidence to support the use of opioids in chronic CAL although their role in the acute dyspnoea of end-stage CAL remains defined. The use of benzodiazepines has also been disappointing. Bullectomy remains widely accepted in clinical practice. New techniques such as ’reduction surgery’ for diffuse emphysema are showing promise, although still in need of further testing and validation.
Abstract: Energy transformation at the main energy consuming processes of the myocardium takes place with high efficiency, i.e., with relatively small differences between the free energy level provided and the free energy level required for the two coupled processes. Thus, the free energy of ATP is only moderately higher than that of various ATP dependent processes. Under energy deficiency caused by hypoxia, free energy of ATP can drop to a level that critically affects subsequent steps. Detailed evaluation of cell energetics was carried out with the following approach: Cell shortening, oxygen consumption and intracellular calcium transients of isolated rat cardiomyocytes which were investigated under the influence of inotropic interventions. Increased extracellular Ca2+ and isoproterenol reduced the economy of contraction (contraction amplitude/VO2), whereas Ca-sensitizing agent EMD 57033 did not. This seems to be a consequence of the increased costs of ion cycling under the effect of Ca2+ and isoproterenol. Our current investigation suggests that alterations of ion transport processes and crossbridge kinetics have substantial impact on myocardial energetics.
Abstract: The objective of the present study was to explore the interrelationships among cumulative sodium loss, renin activation, and blood pressure changes during sodium restriction in essential hypertensive patients. Specifically, we wanted to know whether the degree of sodium sensitivity of blood pressure depends on renin activation during steady state or on initial renin activation during the first days of sodium restriction. Sixty-seven untreated essential hypertensive patients were admitted to a metabolic ward for 8 days and put on a sodium restricted diet of 55 mmol/d from the second to the last day. Urinary excretions of sodium, potassium, and creatinine were determined along with mean arterial pressure and weight during 7 days. Besides measurements in steady state condition (after 7 days), active plasma renin concentration, aldosterone, and catecholamines were also assessed during the first 3 days of sodium restriction. Analyzable data are available for 55 patients. Baseline sodium excretion and the activation of renin during the first 3 days both appeared to be predictors of total sodium loss after 7 days. Changes in blood pressure were not related to changes in sodium balance, but they were to baseline blood pressure, baseline norepinephrine, and renin activation during the early phase of sodium restriction. In addition, blood pressure appeared to fall more when the normal relationship between sodium loss and early (but not late) activation of renin was disturbed. We conclude that sodium sensitivity of blood pressure during sodium restriction is associated with a relative unresponsiveness of the renin system during the early phase of sodium loss rather than to absolute renin levels during steady state.
Abstract: 1. The balance of vascular tone of the afferent and efferent arteriole is a crucial determinant of glomerular haemodynamics. Despite their intimate anatomical relationship in the juxtaglomerular apparatus, the mechanisms that regulate afferent and efferent arteriolar tone are different. 2. In the afferent arteriole, two intrinsic mechanisms, the myogenic response and macula densa-mediated tubuloglomerular feedback (TGF) play a dominant role, maintaining the glomerular filtration rate (GFR) at a constant level over a wide range of renal perfusion pressure. Studies have shown that these two mechanisms are modulated by nitric oxide (NO). In addition, an interaction between TGF and angiotensin II (AngII) seems to be essential to maintaining GFR despite large variations in daily intake of salt and water. 3. In the efferent arteriole, neither myogenic response nor TGF seems to be important, while AngII is one major factor involved in the control of vascular resistance. In addition, recent studies have provided evidence that NO and prostaglandins produced by the glomerulus may control resistance of the downstream efferent arteriole. 4. As the early segment of the efferent arteriole resides within the glomerulus, various autacoid hormones produced by the glomerulus may reach and directly act on this segment, thereby controlling the glomerular capillary pressure. Thus, it would be important to understand the differences in the mechanisms operating at the afferent and efferent arteriole, as well as their alterations in various physiological and pathological conditions.
Abstract: A number of normal daily and athletic activities require isometric or static exercise. Sports such as weight lifting and other high-resistance activities are used by power athletes to gain strength and skeletal muscle bulk. Static exercise, the predominant activity used in power training, significantly increases blood pressure, heart rate, myocardial contractility, and cardiac output. These changes occur in response to central neural irradiation, called central command, as well as a reflex originating from statically contracting muscle. Studies have demonstrated that blood pressure appears to be the regulated variable, presumably because the increased pressure provides blood flow into muscles whose arterial inflow is reduced as a result of increases in intramuscular pressure created by contraction. Thus, static exercise is characterized by a pressure load on the heart and can be differentiated from the hemodynamic response to dynamic (isotonic) exercise, which involves a volume load to the heart. Physical training with static exercise (i.e., power training) leads to concentric cardiac (particularly left ventricular) hypertrophy, whereas training with dynamic exercise leads to eccentric hypertrophy. The magnitude of cardiac hypertrophy is much less in athletes training with static than dynamic exercise. Neither systolic nor diastolic function is altered by the hypertrophic process associated with static exercise training. Many of the energy requirements for static exercise, particularly during more severe levels of exercise, are met by anaerobic glycolysis because the contracting muscle becomes comes deprived of blood flow. Power athletes, training with repetitive static exercise, derive little benefit from an increase in oxygen transport capacity, so that maximal oxygen consumption is increased only minimally or not at all. Peripheral cardiovascular adaptations also can occur in response to training with static exercise. Although the studies are controversial, these adaptations include modest decreases in resting blood pressure, reduced increases in blood pressure and sympathetic nerve activity during a given workload, enhanced baroreflex function, increases in muscle capillary-to-fiber ratio, possible improvements in lipid and lipoprotein profiles, and increases in glucose and insulin responsiveness. Some of these adaptations can occur in cardiac or hypertensive patients with no concomitant cardiovascular complications. In both healthy individuals and those with cardiovascular disease, the manner in which resistance training is performed may dictate the extent to which these adjustments take place. Specifically, training that involves frequent repetitions of moderate weight (and hence contains dynamic components) seems to produce the most beneficial results.
Abstract: The fluid and electrolyte regulation experiment with seven subjects was designed to describe body fluid, renal, and fluid regulatory hormone responses during the Spacelab Life Sciences-1 (9 days) and -2 (14 days) missions. Total body water did not change significantly. Plasma volume (PV; P \textless 0.05) and extracellular fluid volume (ECFV; P \textless 0.10) decreased 21 h after launch, remaining below preflight levels until after landing. Fluid intake decreased during weightlessness, and glomerular filtration rate (GFR) increased in the first 2 days and on day 8 (P \textless 0.05). Urinary antidiuretic hormone (ADH) excretion increased (P \textless 0.05) and fluid excretion decreased early in flight (P \textless 0.10). Plasma renin activity (PRA; P \textless 0.10) and aldosterone (P \textless 0.05) decreased in the first few hours after launch; PRA increased 1 wk later (P \textless 0.05). During flight, plasma atrial natriuretic peptide concentrations were consistently lower than preflight means, and urinary cortisol excretion was usually greater than preflight levels. Acceleration at launch and landing probably caused increases in ADH and cortisol excretion, and a shift of fluid from the extracellular to the intracellular compartment would account for reductions in ECFV. Increased permeability of capillary membranes may be the most important mechanism causing spaceflight-induced PV reduction, which is probably maintained by increased GFR and other mechanisms. If the Gauer-Henry reflex operates during spaceflight, it must be completed within the first 21 h of flight and be succeeded by establishment of a reduced PV set point.
Abstract: The purpose of this study was to gain insight into the mechanism of vasovagal syncope and to test the efficacy of theophylline to prevent syncope. Twenty-six patients with vasovagal syncope underwent two-dimensional echocardiography and theophylline test during head-up tilt test. A standard parasternal short-axis view of echocardiography at the level of the papillary muscle was recorded to measure fraction shorting of the left ventricle, and left ventricular end-diastolic and end-systolic dimensions. Heart rate, blood pressure, and symptoms were recorded. There were three groups; Group 1: no syncope with and without isoproterenol (n = 5); Group 2: syncope only after the infusion of isoproterenol (n = 16); Group 3: syncope without isoproterenol (n = 5). Groups 2 and 3 proceeded to theophylline injection (250 mg). The study showed that the 80 degrees tilt induced an increase in heart rate of 6.6 +/- 4.0, 12.4 +/- 6.6, and 25.4 +/- 4.5 beats/min in Groups 1, 2, and 3, respectively (p \textless 0.05 in Groups 1 and 2, p \textless 0.05 in Groups 1 and 3). The addition of isoproterenol during posture change from supine to an 80 degrees tilt made the significant change of fractional shortening from 0.4 +/- 5% to 6 +/- 13% in Group 2 (p = 0.05), compared with no significant change in Group 1. There were no significant differences in left ventricular end-diastolic dimension and end-systolic dimension in each group between baseline and isoproterenol infusion during posture change. Vasovagal syncope was associated with vigorous myocardial contraction, rather than with contraction against an empty left ventricle. The acute loading of theophylline was not effective in preventing vasovagal syncope.
Abstract: OBJECTIVE: To study the associations between changes in body fatness, visceral adipose tissue (AT), and indexes of plasma glucose-insulin homeostasis over a 7-year follow-up period. RESEARCH DESIGN AND METHODS: A sample of 30 nondiabetic women aged 35.2 +/- 5.6 (SD) years at baseline was studied. RESULTS: Changes in visceral AT and in subcutaneous AT (measured by computed tomography) as well as changes in body fat mass (obtained by hydrostatic weighting) were significantly related to changes in fasting plasma insulin levels and in plasma insulin area measured after a 75-g oral glucose load (0.47 \textless or = r \textless or = 0.62; P \textless 0.01). Changes in visceral AT but not in body fat mass or in subcutaneous AT area were significantly associated with changes in plasma glucose area (r = 0.37; P \textless 0.05). When two subgroups of women with similar mean increases in body fat mass but with either small or large increases in visceral AT were compared, the subgroup with the largest gain in visceral AT showed the greatest deterioration in indexes of plasma glucose-insulin homeostasis. On the other hand, when two subgroups with similar mean increases in visceral AT but with different changes in body fat mass were compared, both subgroups showed similar changes in plasma glucose and insulin concentrations. CONCLUSIONS: Results of this 7-year follow-up study in women suggest that changes in indexes of plasma glucose-insulin homeostasis are significantly associated with changes in visceral AT, even after control for changes in body fat mass.
Abstract: The hypothesis that tissue oxygen delivery in excess of metabolic demand results in vasoconstriction and reduced blood flow was tested in the cremaster muscle of anesthetized Sprague-Dawley rats by studying the effects of an intravenous infusion of RSR-13, an allosteric effector of hemoglobin. RSR-13 reduces the affinity of hemoglobin for oxygen, causing a right shift in the oxygen dissociation curve. Thus, oxygen delivery to the tissues was increased without elevations in blood flow or blood pressure. Tissue PO2, arteriolar diameter, and RBC velocity were measured and volume flow was calculated from diameter and RBC velocity in third-order arterioles. In rats receiving RSR-13 at a rate of 200 mg kg-1 in 15 min (n = 18) P50 (the PO2 at which hemoglobin is 50% saturated) increased from 36 +/- 1 to 52 +/- 3 mm Hg, and tissue PO2 increased to a maximum of 146 +/- 12% above its control value. P50 and tissue PO2 did not change in the control group (n = 8) receiving vehicle at a rate equivalent to that in the experimental group. In a separate group of rats receiving RSR-13 (n = 7), P50 increased from 38 +/- 1 to 51 +/- 3 mm Hg, calculated arteriolar flow decreased from 9 +/- 3 to a minimum of 1.4 +/- 1 nl sec-1, and arteriolar diameter decreased from 27 +/- 3 to a minimum of 13 +/- 3 micrograms P50, volume flow, and arteriolar diameter did not change in the control group (n = 10). These results suggest that an increased tissue oxygen delivery, caused by a right shift in the oxygen dissociation curve, may cause an increase in vascular resistance independent of an elevated blood flow.
Abstract: Eight conscious chronically instrumented sheep were exposed to 1% inspired carbon monoxide (CO) for 35 min. In all sheep, carboxyhaemoglobin (COHb) levels at the end of the exposure were approximately 65%. Mean arterial blood pressure was unchanged with the exception of 2 sheep in which administration was stopped at 25 min following the sudden onset of hypotension. Oxygen delivery to the brain was sustained throughout the administration of CO due to a significant increase in cerebral blood flow (CBF). There was no evidence of either a metabolic acidosis or of lactate production by the brain suggesting the brain did not become hypoxic during the time-course of this study. Despite the apparent lack of hypoxia, oxygen consumption by the brain fell progressively and the sheep showed behavioural changes which varied from agitation to sedation and narcosis. The mechanism of these changes was therefore probably unrelated to hypoxia, but may have been due to raised intracranial pressure or a direct effect of CO on brain function. It is proposed that the time-course of progressive CO poisoning includes a phase in which CBF is elevated, blood pressure is unchanged and the brain is normoxic despite high COHb levels, but that this situation can rapidly evolve into a phase of haemodynamic collapse and severe hypoxia.
Abstract: Insulin sensitivity may be improved with the angiotensin-converting enzyme inhibitor captopril, suggesting that inhibition of angiotensin II (Ang II) improves insulin resistance. However, the administration of systemic Ang II has also been associated with an improvement in rather than worsening of glucose utilization. Since both stimulating and antagonizing the renin-angiotensin system improve glucose uptake and both angiotensin-converting enzyme inhibitors and intravenous Ang II elicit skeletal muscle vasodilation, it is conceivable that hemodynamic factors rather than a direct effect of either Ang II or angiotensin-converting enzyme inhibitors on skeletal muscle metabolism modulate the increase in glucose utilization. The direct effects of Ang II on glucose extraction in intact human skeletal muscle have not been previously described. We investigated the effects of local infusion of Ang II on glucose uptake in the forearm of 20 healthy subjects. With the use of the isolated insulin-perfused forearm model, local plasma insulin values were raised to 100 mU/mL over fasting values and maintained there for a 90-minute infusion period. After the first 60 minutes of insulin alone, Ang II was infused into the brachial artery for the last 30 minutes. Intra-arterial Ang II infusion caused a 38% decrease in forearm blood flow (P \textless.05) and 59% increase in the arteriovenous glucose gradients (P \textless.05) to maintain a steady glucose utilization (a decrease of 4%, P=NS). Thus, local Ang II infusion does not impair insulin-stimulated glucose utilization. Furthermore, glucose extraction increases to compensate for the decrease in forearm blood flow (as the Fick principle would predict for freely diffusible substances). We conclude that the described increase in glucose utilization from systemic infusion of Ang II and during angiotensin-converting enzyme inhibitor treatment is mediated by hemodynamic factors rather than a direct effect of Ang II on skeletal muscle metabolism.
Abstract: Intraluminal resistance to gas transport between the microcirculation and tissue was neglected for a half-century following the early work of Krogh. In recent years it has come to be understood that this neglect is seriously in error. This paper reviews the background for the long period of misdirection, and progress in placing the simulation of gas transport processes on a more accurate, quantitative basis.
Abstract: The ventilatory muscles perform various functions such as ventilation of the lungs, postural stabilization, and expulsive maneuvers (e.g., coughing). They are classified in functional terms as inspiratory muscles, which include the diaphragm, parasternal intercostal, external intercostal, scalene, and sternocleidomastoid muscles; and expiratory muscles, which include the abdominal muscles, internal intercostal, and triangularis sterni. The ventilatory muscles require high-energy phosphate compounds such as ATP to fuel the biochemical and physical processes of contraction and relaxation. Maintaining adequate intracellular concentrations of these compounds depends on adequate intracellular substrate levels and delivery of these substrates by arterial blood flow. In addition to the delivery of substrates, blood flow influences muscle function through the removal of metabolic by-products, which, if accumulated, could exert negative effects on several excitatory and contractile processes. Skeletal muscle substrate utilization is also dependent on the ability to extract substrates from arterial blood, which, in turn, is accomplished by increasing the total number of perfused capillaries. It follows that matching perfusion to metabolic demands is critical for the maintenance of normal muscle contractile function. In this article, I review the factors that influence ventilatory muscle blood flow. Major emphasis is placed on the diaphragm because a large number of published reports deal with diaphragmatic blood flow. The second reason for focusing on the diaphragm is because it is the largest and most important inspiratory muscle.
Abstract: The purpose of the present study was to test the hypothesis that a component of the afferent arteriolar vasoconstrictor response to angiotensin II (Ang II) requires an intact tubuloglomerular feedback (TGF) mechanism. Enalaprilat-treated male Sprague-Dawley rats served as tissue donors for study of renal microvascular function using the in vitro blood-perfused juxtamedullary nephron technique. Arteriolar lumen diameter responses to exogenous Ang II were determined before and after TGF blockade (papillectomy or 50 microM furosemide). Before TGF blockage, 10 nM Ang II significantly reduced diameters of both mid-afferent (53 +/- 5%) and efferent (43 +/- 9%) arterioles. TGF blockade did not alter baseline diameter of either arteriole, but significantly blunted the mid-afferent vasoconstriction evoked by 10 nM Ang II (44 +/- 7% inhibition by papillectomy; 43 +/- 10% inhibition by furosemide). Similar behavior was observed at afferent arteriolar sites near the glomerulus; however, efferent arteriolar Ang II responsiveness was not altered by papillectomy. The impact of TGF blockade on afferent arteriolar Ang II responsiveness was most prominent at high peptide concentrations (10 nM), while not significantly influencing the response to 1 nM Ang II. In contrast, the afferent vasoconstrictor effect of norepinephrine was unaffected by papillectomy. These data indicate that the vasoconstrictor influence of exogenous Ang II on afferent, but not efferent, arterioles of intact juxtamedullary nephrons includes both TGF-dependent and TGF-independent components.
Abstract: The purpose of this study was to determine whether high plasma levels of atrial natriuretic peptide (ANP) in compensated heart failure are important in the maintenance of sodium balance. This was achieved by subjecting eight dogs to bilateral atrial appendectomy (APX) to blunt the ANP response to pacing-induced heart failure. Five intact dogs served as controls. In controls, 14 days of left ventricular pacing at 240 beats/min produced a sustained fall in cardiac output and mean arterial pressure of approximately 40 and 20%, respectively; compared with cardiac output, reductions in renal blood flow (up to approximately 25%) were less pronounced and even smaller decrements in GFR occurred (up to 9%). Despite these changes and a threefold elevation in plasma norepinephrine concentration, plasma renin activity (PRA) did not increase and sodium balance was achieved during the second week of pacing in association with a six- to eightfold rise in plasma levels of ANP. Similar responses occurred in four dogs in which APX was relatively ineffective in blunting the ANP response to pacing. In marked contrast, there were substantial increments in PRA and in plasma norepinephrine concentration, and marked sodium and water retention during the last week of pacing in four dogs with APX and severely deficient ANP. These results indicate that ANP plays a critical role in promoting sodium excretion in the early stages of cardiac dysfunction.
Abstract: Lymphatics serve to remove from the interstitium a range of materials, including plasma proteins, colloid materials, and cells. Lymph flow rates can be enhanced by periodic tissue compression or venous pressure elevation, but little is known to what degree enhancement of lymph flow affects material transport. The objective was to examine the uptake of plasma proteins, a colloidal perflubron emulsion (LA-11063, mean particle diameter = 0.34 micron), and leukocytes into lymphatics. Prenodal collecting lymphatics in the lower hindlimb of rabbits were cannulated with and without foot massage and after elevation of venous pressure (40 mmHg). The average lymph flow rates were elevated approximately 22-fold by the skin massage but only about threefold by venous pressure elevation. Lymph-to-plasma protein concentration ratio remained unchanged by the massage but decreased significantly after venous pressure elevation. Lymph colloid concentration and leukocyte counts were elevated on average 47 and 8.5 times, respectively, by foot massage, but both decreased after venous pressure elevation. These results suggest that skin movement by massage and elevation of the venous pressure lead to opposite lymph transport kinetics of protein, colloids, and cells. Massage is more effective to enhance material transport out of the interstitium into the initial lymphatics.
Abstract: The effect of cytoplasmic Cl concentration ([Cl]i) on the activation state ([3H]benzmetanide binding rate) and phosphorylation state (32P incorporation) of the Na-K-Cl cotransporter was evaluated in secretory tubules isolated from the dogfish shark rectal gland. Reduction of [Cl]i at relatively constant cell volume (by removal of extracellular Cl or Na or by addition of bumetanide) increased cotransporter activation and phosphorylation. Raising extracellular K concentration ([K]o) from 4 to 80 mM, a maneuver that elevated [Cl]i above normal, reduced basal cotransport activity and rendered it entirely refractory to forskolin. High [K]o also blocked activation and phosphorylation in response to cell shrinkage, despite the fact that [Cl]i was already greatly elevated as a consequence of osmotic water loss. The phosphatase inhibitor calyculin A also promoted activation, but not in cells preexposed briefly to high [K]o. In summary, maneuvers than lower [Cl]i activate the cotransporter, whereas those that elevate [Cl]i (or prevent it from decreasing) block activation in response to secretory stimuli. Cell Cl appears to govern its own rate of entry via Na-K-Cl cotransport by impeding regulatory phosphorylation of the Na-K-Cl cotransport protein.
Abstract: Fatty acid binding proteins (FABPs) are small cytoplasmic proteins that are expressed in a highly tissue-specific manner and bind to fatty acids such as oleic and retinoic acid. Mice with a null mutation in aP2, the gene encoding the adipocyte FABP, were developmentally and metabolically normal. The aP2-deficient mice developed dietary obesity but, unlike control mice, they did not develop insulin resistance or diabetes. Also unlike their obese wild-type counterparts, obese aP2-/- animals failed to express in adipose tissue tumor necrosis factor-alpha (TNF-alpha), a molecule implicated in obesity-related insulin resistance. These results indicate that aP2 is central to the pathway that links obesity to insulin resistance, possibly by linking fatty acid metabolism to expression of TNF-alpha.
Abstract: BACKGROUND: This study evaluated brain tissue oxygen pressure (PO2), carbon dioxide pressure (PCO2), and pH in a patient during hypothermic circulatory arrest. METHODS: A combined PO2, PCO2, and pH sensor was placed in cortex tissue. Brain temperature was then decreased to 17 degrees C followed by circulatory arrest for 44 minutes during an endarterectomy of the M1 segment of the middle cerebral artery. RESULTS: Brain tissue PO2 increased during brain cooling from 10 mmHg-30 mmHg and decreased to zero following exsanguination. During circulatory arrest, tissue PCO2 increased to \textgreater200 mmHg and pH decreased to 6.0. Tissue PCO2 and pH recovered during circulatory rewarming but the increase in PO2 was delayed. Tissue parameters continued to improve during 2 days of postsurgical monitoring and were correlated with neurologic recovery. CONCLUSIONS: These results show that brain tissue PO2, PCO2, and pH measures indicate the severity of ischemia during hypothermic cardiac arrest and recovery in the postoperative period.
Abstract: The brain of hypoxia-tolerant vertebrates is known to survive extreme oxygen limitation at least in part because of very low rats of ATP utilization and ATP production. To asses whether similar adaptations are involved in healthy humans during hypoxia adaptation over generational time, we initially used positron-emission tomography measurements of glucose metabolic rates in the brain of Quechuas, whose ancestors have been indigenous to the Andes at altitudes between approximately 3,300 and 4,500 m for several hundred years. Workers in this field generally believe that the lineage of Sherpas has been indigenous to the Himalayas for even longer and that Sherpas and other peoples indigenous to the Tibetan plateau are perhaps the most exquisitely hypoxia adapted of all humans. For this reason, in this study we extended our database to include Sherpas. With the use of the same protocol as before, two metabolic states were analyzed: 1) the presumed normal (hypoxia-adapted) state, monitored as soon as possible after subjects left the Himalayas and 2) the deacclimated state, monitored after 3 wk at low altitudes. Positron-emission tomography measurements of 2-[18F]deoxy-2-fluoro-D-glucose metabolic rates, quantified in 26 regions of the brain, indicated that the Sherpas’ brain metabolism differed significantly from that of Quechuas but was essentially identical to that of lowlanders. Region-by-region patterns were similar in all three groups, indicating that the regional organization of glucose metabolism in the brain is a conservative, relatively constant characteristic.
Abstract: Within a few seconds after a sudden reduction of coronary blood flow regional contractile dysfunction ensues. The mechanisms responsible for the rapid reduction in contractile function during acute myocardial ischemia remain unclear, but may involve a rise in inorganic phosphate. When severe ischemia, such as resulting from a sudden and complete coronary artery occlusion, is prolonged for more than 20-40 min, myocardial infarction develops, and there is irreversible loss of contractile function. When myocardial ischemia is less severe but nevertheless prolonged, the myocardium is dysfunctional but can remain viable. In such ischemic and dysfunctional myocardium, contractile function is reduced in proportion to the reduction in regional myocardial blood flow; i.e. a state of "perfusion-contraction matching" exists. The metabolic status of such myocardium improves over the first few hours, as myocardial lactate production is attenuated and creatine phosphate, after an initial reduction, returns towards control values. Ischemic myocardium, characterized by perfusion-contraction matching, metabolic recovery and lack of necrosis, has been termed "short-term hibernating myocardium". Short-term hibernating myocardium can respond to an inotropic stimulation with increased contractile function, however, at the expense of a renewed worsening of the metabolic status. This situation of an increased regional contractile function at the expense of metabolic recovery during inotropic stimulation can be used to identify short-term hibernating myocardium. When inotropic stimulation is prolonged, the development of short-term hibernation is impaired and myocardial infarction develops. The mechanisms responsible for the development of short-term myocardial hibernation remain unclear at present; a significant involvement of adenosine and of activation of ATP-dependent potassium channels has been excluded. Whereas short-term hibernation is well characterized in animal experiments, the existence of hibernation over weeks or months (long-term hibernation) can only be inferred from clinical studies. Hibernation, as defined by Rahimtoola, is a state of chronic contractile dysfunction which is fully reversible upon reperfusion. Clinical syndromes consistent with the existence of myocardial hibernation include unstable and stable angina, acute myocardial infarction and left ventricular dysfunction and/or congestive heart failure. In long-term hibernating myocardium morphological alterations occur; the myofibrils are reduced in number and disorganized and myocardial glycogen content as well as the extracellular collagen network are increased. Thus, despite the fact that the myocardium remains viable during persistent ischemia and contractile dysfunction is reversible upon reperfusion, there are severe morphological alterations. Understandably, full functional recovery following reperfusion might therefore require weeks or even months.
Abstract: Brain death can have an impact on donor organ function. This is often attributed to an altered hormonal, mainly thyroidal, status after brain death. A second possible explanation is that during the brain death process, blood flow is redistributed, causing ischemic damage in underperfused organs or regions. We investigated blood flow redistribution with colored microspheres in the rat early and late after brain death, induced by inflation of an intracranial balloon, and correlated this with the global hemodynamic situation and plasma catecholamine concentrations. Brain death was proven by the demonstration of lasting absence of brain perfusion in all animals. Myocardial blood flow closely followed the myocardial oxygen need as estimated by the rate-pressure product. The abdominal organs showed intense vasoconstriction early after brain death, which led to significantly decreased perfusion of these organs despite the highly increased perfusion pressure, followed by significant vasodilation. Total plasma catecholamine concentration was 57 times higher at 30 sec after brain death as compared with basal levels. Plasma noradrenaline concentration fell significantly below basal levels late after brain death. We conclude that brain death importantly alters regional perfusion, with possible implications for donor organ function. These changes are probably due to the tremendous alterations in the activity of the sympathetic nervous system.
Abstract: Carbonic anhydrase (CA) is a central enzyme to both transport and metabolic processes at the cellular level. In metabolically active tissue such as muscle, CA in the cytoplasm and on the sarcolemma appears to be important in facilitating CO2 transport out of the cell. Membrane-associated CA, with an extracellular orientation, also appears to be important in acidifying the outer boundary layer through the catalyzed hydration of excreted CO2. This facilitates cellular ammonia transport by providing H+ ions for the protonation of NH3, thus maintaining the trans-membrane NH3 gradient. Mitochondrial CA is known to supply HCO3- for the initial reactions of gluconeogenesis and ureagenesis in mammalian tissues, but systematic comparative studies of CA as a metabolic enzyme are lacking. CA probably evolved as an enzyme of trans-membrane facilitated CO2 transport and took on a secondary metabolic role later in metazoan evolution.
Abstract: Several studies have shown that exogenous human growth hormone (HGH) exerts an anabolic effect on protein metabolism in surgical patients with mild or moderate catabolism. However, contradictory results have been demonstrated in polytrauma patients where HGH did not improve protein metabolism. Aim of this study was to evaluate whether the pharmacokinetics of recombinant biosynthetic human GH (r-HGH) are altered in critically ill patients. After an overnight fast, r-HGH was infused at a rate of 460 micrograms/h/kg/bw during 120 min to five intensive care unit (ICU) patients. The patients were catabolic (nitrogen balance -11 +/- 0.5), showed normal liver function, and only one patient had a slightly impaired kidney function (creatinine \textgreater 1.5 mg/dl). Endogenous GH secretion was suppressed by continuous infusion of 50 micrograms/m2/h somatostatin. From plasma GH curves, elimination half life (t1/2kle), whole body clearance (Cltot) and steady state distribution space (DS) were calculated in an open two compartment model. Additionally, the effects of r-HGH infusion on plasma insulin, glucagon and amino acid concentrations were evaluated. T1/2kle was 19.6 +/- 2.3 min, Cltot 2.9 +/- 0.4 ml/kg/bw/min and DS 76.4 +/- 3.8 ml/kg/bw for 90 min. The plasma levels of total amino acids including the branched chain amino acids valine, leucine and isoleucine and of glutamine were significantly higher during r-HGH infusion than during the basal and somatostatin periods. In conclusion, the elimination of r-HGH in catabolic ICU patients is not different from that of healthy volunteers.
Abstract: We studied osmoregulation of plasma vasopressin in 5 patients with newly diagnosed diabetes mellitus. All patients showed typical symptoms of uncontrolled diabetes mellitus such as marked hyperglycemia, polyuria, and polydipsia, but did not have advanced diabetic complications. Vasopressin release was studied using 5% hypertonic saline infusion test twice: before treatment when the patient was hyperglycemic, and after treatment 1 to 2 months later when the patient was euglycemic. Plasma vasopressin was measured by a sensitive and specific radioimmunoassay. The mean basal plasma vasopressin value in the patients was significantly higher in the hyperglycemic compared with the euglycemic state (3.75 +/- 0.70 vs 1.18 +/- 0.46 pmol/l, respectively; P \textless 0.05). The relationship of plasma vasopressin with serum sodium, but not plasma osmolality, during hyperglycemia showed an apparent hypersecretion of vasopressin. In both cases, the sensitivity of the vasopressin response to osmotic stimuli was significantly decreased. During euglycemia, the sensitivity of vasopressin secretion to either sodium or osmolality was almost normal, although a slight rise in the osmostat was observed compared with normal subjects. Together, we found that the positive correlation of vasopressin with sodium or osmolality is maintained but significantly altered in patients with untreated diabetes mellitus. Especially noteworthy is the lowered threshold and decreased sensitivity of osmotically-induced vasopressin secretion during hyperglycemia, which may be caused by multiple factors such as diabetes-associated hypovolemia, osmogenic effects of glucose and other osmoles, depletion of the pool of vasopressin available for release, and the metabolic derangement of osmoreceptor/magnocellular neurons.
Abstract: 1. The effects of angiotensin II (AngII) on water and electrolyte transport are biphasic and dose-dependent, such that low concentrations (10(-12) to 10(-9) mol/L) stimulate reabsorption and high concentrations (10(-7) to 10(-6) mol/L) inhibit reabsorption. Similar dose-response relationships have been obtained for luminal and peritubular addition of AngII. 2. The cellular responses to AngII are mediated via AT1 receptors coupled via G-regulatory proteins to several possible signal transduction pathways. These include the inhibition of adenylyl cyclase, activation of phospholipases A2, C or D and Ca2+ release in response to inositol-1,4,5,-triphosphate or following Ca2+ channel opening induced by the arachidonic acid metabolite 5,6,-epoxy-eicosatrienoic acid. In the brush border membrane, transduction of the AngII signal involves phospholipase A2, but does not require second messengers. 3. Angiotensin II affects transepithelial sodium transport by modulation of Na+/H+ exchange at the luminal membrane and Na+/HCO3 cotransport, Na+/K(+)-ATPase activity and K+ conductance at the basolateral membrane. 4. Atrial natriuretic factor (ANF) does not appear to affect proximal tubular sodium transport directly, but acts via specific receptors on the basolateral and brush border membranes to raise intracellular cGMP levels and inhibit AngII-stimulated transport. 5. It is concluded that there is a receptor-mediated action of ANF on proximal tubule reabsorption acting via elevation of cGMP to inhibit AngII-stimulated sodium transport. This effect is exerted by peptides delivered at both luminal and peritubular sides of the epithelium and provides a basis for the modulation by ANF of proximal glomerulotubular balance. The evidence reviewed supports the concept that in the proximal tubule, AngII and ANF act antagonistically in their roles as regulators of extracellular fluid volume.
Abstract: Muscle sympathetic nerve activity (MSNA) has been correlated with percent body fat (%BF) in males. Because MSNA is typically lower and %BF higher in females, we tested whether this relationship could be generalized to females. Because abdominal-visceral body fat in men may be responsible for elevated sympathetic activity, we hypothesized that an estimate [waist-to-thigh ratio (W/T)] would correlate positively with MSNA in both genders and account for higher MSNA in males. Microneurography, hydrodensitometry, and W/T measures were obtained in 14 males and 14 females with a large range of %BF and W/T. Regression analyses revealed positive correlations between MSNA and %BF in males (r = 0.55, P = 0.04) and in females (r = 0.63, P = 0.02), with no difference in the slopes of the regression lines but a higher intercept in males (P \textless 0.01). When genders were pooled, MSNA and W/T were correlated (r = 0.68, P \textless 0.0001); this positive correlation was also found in males (r = 0.57, P = 0.04) but not as strongly in females (r = 0.49, P = 0.07). Forward stepwise multiple-regression analysis using %BF, W/T, gender, and age indicated that W/T was the primary factor related to MSNA (R2 = 0.46); the other factors were not independent predictors. It is concluded that %BF is related to MSNA in both males and females but that the regression line is shifted downward in females because of lower levels of MSNA. W/T is a better correlate of MSNA than %BF and partially explains the higher MSNA in males. These findings may be relevant to the cardiovascular and metabolic disease risk associated with abdominal obesity.
Abstract: A simple compartmental model for myogenic regulation of interstitial pressure in bone is developed, and the interaction between changes in interstitial pressure and changes in arterial and venous resistance is studied. The arterial resistance is modeled by a myogenic model that depends on transmural pressure, and the venous resistance is modeled by using a vascular waterfall. Two series capacitances model blood storage in the vascular system and interstitial fluid storage in the extravascular space. The static results mimic the observed effect that vasodilators work less well in bone than do vasoconstrictors. The static results also show that the model gives constant flow rates over a limited range of arterial pressure. The dynamic model shows unstable behavior at small values of bony capacitance and at high enough myogenic gain. At low myogenic gain, only a single equilibrium state is present, but a high enough myogenic gain, two new equilibrium states appear. At additional increases in gain, one of the two new states merges with and then separates from the original state, and the original state becomes a saddle point. The appearance of the new states and the transition of the original state to a saddle point do not depend on the bony capacitance, and these results are relevant to general fluid compartments. Numerical integration of the rate equations confirms the stability calculations and shows limit cycling behavior in several situations. The relevance of this model to circulation in bone and to other compartments is discussed.
Abstract: The vascular response to changes in oxygen levels in the blood and tissue is a highly adaptive physiological response that functions to match tissue oxygen supply to metabolic demand. Defining the cellular mechanisms that can sense physiologically relevant changes in PO2 and adjust vascular diameter are vital to our understanding of this process. A cytochrome P450 (P450) enzyme of the 4A family of omega-hydroxylases was localized in renal microvessels, renal cortex, and a striated muscle microvascular bed (cremaster) of the rat. In the presence of molecular oxygen, this P450 enzyme catalyzes formation of 20-HETE from arachidonic acid (AA). Prior studies have shown that 20-HETE potently contracts renal and cerebral arteries and arterioles. The present study demonstrates that 20-HETE constricts striated muscle arterioles as well. In both intact renal microvessels and enriched renal cortical microsomal enzyme preparations, the formation of 20-HETE was linearly dependent on PO2 between 20 and 140 mm Hg. Homogenates of cremaster tissue produced 20-oxygen HETE when incubated with AA. They also expressed message for P450 4A enzyme, as determined by Southern and Western blots. Administration of 17-octadecynoic acid (17-ODYA), which is a P450 4A inhibitor, attenuated the constriction of third-order cremasteric arterioles in response to elevation of superfusion solution PO2 from approximately equal to 3 to 5 mm Hg to approximately equal to 35 mm Hg. 17-ODYA had no effect on basal vascular tone or response of cremaster arterioles to vasoactive compounds. These results demonstrate the existence of P450 omega-hydroxylase activity and 20-HETE formation in the vasculature and parenchyma of at least two microvascular beds. Our data suggest that a P450 enzyme of the 4A family has the potential to function as an oxygen sensor in mammalian microcirculatory beds and to regulate arteriolar caliber by generating 20-HETE in an oxygen-dependent manner.
Abstract: Tilt table test (TTT) is done in 110 cases of unexplained syncope and 37 healthy controls. As a result, there is no significant difference in basal diastolic blood pressure (DBP), basal heart rate (HR) x DBP among TTT positive, TTT negative and healthy controls; but DBP and HR x DBP of TTT positive patients at the instant of syncope is not significantly different from their basal values, the HR at the instant of syncopy statistically in not different from the basal HR. These data suggest that not the same mechanism is responsible for the changes of BP and HR. In seventy percent of the TTT positive patients vasovagal syncope (VS) may be provoked by isoproterenol. So the occurrence of VS may be related to hypersensitivity of beta-receptor. TTT may be an approach to unravel the pathogenesis of VS.
Abstract: 1. Lower body negative pressure provides a means to examine neurocirculatory reflexive responses to decreases in venous return to the heart. We assessed whether the pattern of catecholaminergic responses to lower body negative pressure depends on the intensity of the stimulus (-15 versus -40 mmHg). 2. In 14 healthy subjects, responses of forearm blood flow and noradrenaline spillover and of total body noradrenaline and adrenaline spillover were assessed during infusion of [3H]noradrenaline and [3H]adrenaline during -15 and -40 mmHg of lower body negative pressure. 3. During lower body negative pressure at -15 mmHg, heart rate and pulse pressure did not change, but forearm vascular resistance increased by 25-50%. Forearm noradrenaline spillover increased by about 50%, from 0.63 +/- 0.16 to 0.94 +/- 0.23 pmol min-1 100 ml-1 (P \textless 0.05). Total body noradrenaline spillover did not change, and total body adrenaline spillover increased significantly by about 30%. Clearances of noradrenaline and adrenaline were unchanged. 4. During lower body negative pressure at -40 mmHg, heart rate increased and pulse pressure decreased. Forearm vascular resistance increased by about 100%, and forearm noradrenaline spillover increased by 80%, from 0.73 +/- 0.19 to 1.32 +/- 0.36 pmol min-1 100 ml-1 (P \textless 0.05). Total body noradrenaline spillover increased by 30%, and total body adrenaline spillover increased by about 50%. Clearances of both noradrenaline and adrenaline decreased. 5. The results are consistent with the view that selective deactivation of cardiopulmonary baroreceptors during low-intensity lower body negative pressure increases sympathoneural traffic to forearm skeletal muscle and increases adrenomedullary secretion without a concomitant generalized increase in sympathoneural outflows. Concurrent deactivation of cardiopulmonary and arterial baroreceptors during high-intensity lower body negative pressure evokes a more generalized increase in sympathoneural activity, accompanied by further increased adrenomedullary secretion and decreased plasma clearances of noradrenaline and adrenaline. The findings support differential increases in skeletal sympathoneural and adrenomedullary outflows during orthostasis, with more generalized sympathoneural responses to systemic hypotension.
Abstract: To maintain ATP constant in the cell, mitochondria must sense cellular ATP utilization and transduce this demand to F0-F1-ATPase. In spite of a considerable research effort over the past three decades, no combination of signal(s) and kinetic function has emerged with the power to explain ATP homeostasis in all mammalian cells. We studied this signal transduction problem in intact human muscle using 31P NMR spectroscopy. We find that the apparent kinetic order of the transduction function of the signal cytosolic ADP concentration ([ADP]) is at least second order and not first order as has been assumed. We show that amplified mitochondrial sensitivity to cytosolic [ADP] harmonizes with in vitro kinetics of [ADP] stimulation of respiration and explains ATP homeostasis also in mouse liver and canine heart. This result may well be generalizable to all mammalian cells.
Abstract: This study examined 1) effects of prostaglandins (PG) on renin secretion and renin gene expression from isolated juxtaglomerular granular cells and 2) expression of cyclooxygenases in juxtaglomerular structures. Incubation of granular cell cultures with PGE2, -I2, -F2 alpha, and thromboxane B2 identified PGI2 and PGE2 as stimulators of renin secretion; the effects were dose and time dependent. PGE2 also increased renin mRNA accumulation time and dose dependent. PGE2 and PGI2 activated adenylate cyclase concentration dependent in granular cells. PGE2 stimulations of renin secretion and renin mRNA were nonadditive to those of forskolin and were inhibited by endothelin. The findings are compatible with cellular actions through adenosine 3’,5’-cyclic monophosphate (cAMP). On total RNA harvested from whole kidneys, from microdisected glomeruli with attached afferent arterioles and from mesangial cells in primary culture, reverse transcription-polymerase chain reaction revealed significant expression of cyclooxygenase I and II. By direct interaction with PG receptors on renal juxtaglomerular cells, PGE2 and PGI2 can act as potent and rapid stimulators of renin secretion and renin mRNA probably through cAMP-dependent pathways.
Abstract: Heavy whole-body exercise, requiring a 10- to 15-fold increase in minute ventilation, encroaches on the capacities of the respiratory muscle system to respond. Recently, using the technique of bilateral phrenic nerve stimulation, it has been shown that heavy endurance exercise (\textgreater 85% of VO2max) lasting \textgreater 8-10 min causes diaphragmatic fatigue (15-30% reduction in transdiaphragmatic pressures when electrically stimulated at low frequencies [1-20 Hz] supramaximally). The fatigue appears to be due to an interaction of diaphragmatic work (i.e., pressure production) combined with effects related to exercise intensity (i.e., increased blood flow competition with the locomotor muscles and increased production of metabolic by-products) and requires \textgreater 60 min for recovery. Fitness (i.e., as implied from VO2max) appears to allow greater diaphragmatic work for a similar degree of fatigue. Unloading the respiratory muscles (with helium/oxygen gas or using a pressure-assist device) during heavy exercise \textless 90-95% of VO2max does not appear to alter exercise time, VO2max, or minute ventilation, implying that respiratory muscle fatigue plays little role in altering human performance at these work intensities. However, unloading the respiratory system with helium at work intensities \textgreater 90-95% of VO2max has been shown to improve exercise time. This would imply that respiratory muscle fatigue may play a role in limiting human performance at the extremes of human performance or that other factors related to the respiratory system (i.e., alterations in the sensation of dyspnea or mechanical load) may play an important role.
Abstract: The present studies in perfused specimens of the juxtaglomerular apparatus microdissected from rabbit kidneys were performed to quantitatively evaluate the relation between macula densa NaCl concentration and renin secretion and to study the effect of furosemide and verapamil on NaCl dependency of renin release. Renin secretion was found to decrease exponentially when macula densa NaCl concentration was increased from 26/7 mmol/L (Na/Cl) to 46/27, 66/47, and 86/67 mmol/L. Increasing Na/Cl concentrations from 86/67 to 106/87 mmol/L had no further effect on renin secretion. [Cl]1/2, the chloride concentration producing the half-maximal effect, was 30 mmol/L. Addition of 50 mumol/L furosemide to the luminal fluid caused renin secretion to become essentially independent of macula densa NaCl concentration. This effect was due to both an increase of renin secretion at high NaCl concentrations and a decrease of renin release at low NaCl concentrations. Verapamil added to the superfusate at a concentration of 1 mumol/L also abolished NaCl dependency of renin secretion; most of this effect was due to an increase of renin release at high luminal NaCl. These results suggest that Na-2Cl-K cotransport and calcium flux through voltage-gated channels are two mechanisms required for the expression of NaCl-dependent renin release. Identification of the cellular localizations of these two critical membrane proteins in the renin control pathway requires further study.
Abstract: It was the purpose of this study to investigate how the endocrine and renal mechanisms of fluid volume control in humans (n = 4) adapt to microgravity by applying an intravenous isotonic saline infusion. The acute ground-based supine (Sup) and seated (Seat) positions were chosen as references. During microgravity, renal sodium excretion (UNaV) was doubled during the second and third hours after infusion compared with during Seat (P \textless 0.05) but blunted during the first hour after infusion compared with during Sup, leading to a reduction in cumulative UNaV (59 +/- 15 vs. 108 +/- 12 mmol/5 h; P \textless 0.05). Plasma norepinephrine (NE) attained the highest value 3 h after infusion during microgravity (31 +/- 5 x 10(-2) ng/ml vs. 19 +/- 1 and 13 +/- 3 x 10(-2) ng/ml for Seat and Sup, respectively; P \textless 0.05). Inflight levels of plasma renin and aldosterone were very similar to levels during Seat. In conclusion, 1) the microgravity-adapted renal responses to infusion reflected a condition in between that of ground-based Seat and Sup, respectively, and 2) the plasma levels of NE, renin, and aldosterone were elevated inflight and not related to the changes in UNaV and urinary flow rate. These observations are in contrast to results of ground-based simulation experiments and might partly have been caused by a prior inflight reduction in extracellular fluid volume. The high levels of NE during microgravity warrant further investigation.
Abstract: To examine the possible role of NO in macula densa control of renin secretion, we examined the effects of varying NO availability on renin release in the isolated perfused rabbit juxtaglomerular apparatus (JGA). Gradual increments of luminal Na/Cl concentration ratio (mM/mM) from 26/7 over 46/27, 66/47, to 86/67 caused a progressive decrease in renin secretion from (as log of nano-Goldblatt hog units vs. time, i.e., log nGU/min) 1.09 +/- 0.34 to 0.46 +/- 0.24 log nGU/min, with the greatest change occurring at the first concentration step. The presence of 0.7 mM N omega-nitro-L-arginine (NNA), an NO synthase inhibitor, in the luminal fluid significantly reduced renin secretion at the lowest Na/Cl concentration ratio to 0.65 +/- 0.32 log nGU/min (P \textless 0.01 compared with control). Renin secretion at the higher Na/Cl concentration ratios was not significantly affected by NNA compared with control. In contrast to these results, the addition of the NO donor nitroprusside (1 mM) to the bath caused a reduction in renin secretion from 1.0 +/- 0.39 to 0.47 +/- 0.46 log nGU/min (P \textless 0.05), an effect that was reversed by bath addition of 0.01 mM methylene blue. Similarly, addition of L-arginine (0.7 mM) to the bath reduced renin secretion from 0.99 +/- 0.37 to 0.81 +/- 0.38 log nGU/min (P \textless 0.01), whereas addition of L-arginine to the luminal fluid increased renin secretion from 0.85 +/- 0.43 to 1.94 +/- 0.46 log nGU/min (P \textless 0.05). The stimulatory effect of luminal L-arginine was reversed by the luminal addition of NNA.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Recently Zhang et al. cloned a gene that is expressed only in adipose tissue of the mouse. The obese phenotype of the ob/ob mouse is linked to a mutation in the obese gene that results in expression of a truncated inactive protein. Human and rat homologues for this gene are known. Previous experiments predict such a hormone to have a hypothalamic target. Hypothalamic neuropeptide Y stimulates food intake, decreases thermogenesis, and increases plasma insulin and corticosterone levels making it a potential target. Here we express the obese protein in Escherichia coli and find that it suppresses food intake and decreases body weight dramatically when administered to normal and ob/ob mice but not db/db (diabetic) mice, which are thought to lack the appropriate receptor. High-affinity binding was detected in the rat hypothalamus. One mechanism by which this protein regulated food intake and metabolism was inhibition of neuropeptide-Y synthesis and release.
Abstract: To clarify the cause and pathophysiology of hyponatremia after intracranial bleeding, we analyzed the possible causative factors, and examined the response of vasopressin (AVP) secretion to osmotic stimulus in six patients. Despite hyponatremia, urinary sodium excretion persisted, with urinary osmolality exceeding plasma osmolality. Serum levels of urea nitrogen, creatinine, and uric acid were not elevated in any of them. PRA was normal or subnormal in four patients, and all had normal adrenocortical and thyroid functions. Although these laboratory findings may support the diagnosis of the syndrome of inappropriate antidiuretic hormone secretion, the cause of hyponatremia in our patients was attributed to excessive renal excretion of sodium, because water load performed in an euvolemic state showed no impairment in diuresis, and replenishment of sodium without water restriction improved hyponatremia as well as clinical conditions. Plasma AVP levels relative to plasma osmolality in these patients were constantly elevated. When challenged by an osmotic stimulus, AVP secretion increased with increasing plasma osmolality in one patient, but no consistent pattern of AVP secretion was observed in others. The potentiating effect of hypovolemia on osmotic secretion of AVP was not demonstrated in any of the patients. These results show that hyponatremia after intracranial bleeding with clinical features almost indistinguishable from those of syndrome of inappropriate antidiuretic hormone secretion may result from an impaired renal sodium-conserving mechanism of unknown cause. Persistent AVP secretion without an alteration in the sensitivity of the osmostat in this pathological state may be due to an incomplete suppression by plasma hypotonicity per se of the baroreceptor-mediated stimulation of AVP release.
Abstract: BACKGROUND: Symptom-limited incremental exercise tests are used to estimate the severity of cardiovascular disease and the patient’s daily activity. However, there is a need for objective parameters for submaximal exercise. To test the hypothesis that a decrease in maximal exercise capacity can be estimated by oxygen uptake (VO2) kinetics, we measured the time constant of VO2 both during the onset of constant work rate exercise at 50 W and during recovery from this exercise and compared it with data obtained during maximal exercise in patients with cardiovascular disease and in normal subjects. METHODS AND RESULTS: A total of 34 patients with cardiovascular disease and 14 normal subjects performed 6 minutes of 50-W constant work rate exercise and an incremental exercise test to the symptom-limited maximum on a cycle ergometer. VO2 was calculated from respiratory gas analysis on a breath-by-breath basis. The time constant of VO2 during the onset of 50-W exercise was 61.4 +/- 15.2 seconds in patients with cardiovascular disease, significantly longer (the kinetics of VO2 were slower) than that in normal subjects (48.8 +/- 10.4 seconds, P = .008). The time constant of VO2 during the onset of exercise was significantly negatively correlated with peak VO2 (r = -.67) and maximal work rate (r = -.66). The time constant during recovery, which did not differ significantly from that of exercise, was also prolonged in patients with cardiovascular disease; it showed a negative correlation with peak VO2 (r = -.63) and maximum work rate (r = -.54). CONCLUSIONS: The time constant of VO2 during and after recovery from 50 W of constant work rate exercise, which does not require the subject’s maximal effort, is a useful and objective measure of exercise capacity in patients with mild to moderate cardiovascular disease.
Abstract: Recent studies have indicated that obesity is associated with hypertension, sodium retention, and increased sympathetic nervous system activity. The purpose of this study was to determine the role of renal nerves in mediating the sodium retention and hypertension associated with obesity. We determined the hemodynamic and renal excretory responses to a high-fat diet in control (n = 6) and bilaterally renal-denervated (n = 7) chronically instrumented dogs. After a control period of 8 days, dogs were placed on a high-fat diet for 5 weeks. In response to a high-fat diet, body weight increased from 19.9 +/- 2.2 to 29.9 +/- 2.4 kg in the control group and from 21.1 +/- 2.0 to 32.4 +/- 1.9 kg in the bilaterally renal-denervated group. Heart rate increased from 81 +/- 8 to 113 +/- 7 beats per minute in the control group and from 79 +/- 7 to 103 +/- 8 beats per minute in the bilaterally renal-denervated group. Arterial pressure increased significantly from 95 +/- 2 to 109 +/- 4 mm Hg in the control group. In contrast, 5 weeks of a high-fat diet in the bilaterally renal-denervated group did not significantly increase arterial pressure (which went from 87 +/- 3 to 90 +/- 4 mm Hg). Furthermore, the decrease in sodium excretion in response to the high-fat diet was significantly greater in the control group than in the bilaterally renal-denervated group.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: PURPOSE: This paper describes the calculation of the strong ion gap (SIG), a physical chemical methodology similar to the anion gap (AG), as a measure of the anion/cation balance exclusive of sodium, potassium, chloride, and bicarbonate. We compared the SIG and AG methodologies in three groups of subjects with and without unexplained anions. These groups were (1) healthy volunteers with hyperlacticemia during exercise; (2) intensive care unit (ICU) patients with sepsis; and (3) ICU patients with severe liver disease. METHODS: The SIG, AG, and corrected AG (AGc) were calculated for each group from data available in the original reports (groups 1 and 2) and by retrospective chart review (group 3). RESULTS: The SIG correlated poorly with the AG in group 2, whereas no correlation was seen in groups 1 and 3. The AGc correlated with SIG in all three groups (r = .99, .93, and .91 respectively; P \textless .01 for each group). Although the AG was similar, the SIG differed for each group. Group 1 had levels of SIG near zero, and groups 2 and 3 had mean SIG’s of 4.80 +/- 4.67 mEq/L and 9.60 +/- 6.43 mEq/L respectively. The composition of the anion gap differed markedly among subject types. CONCLUSIONS: The SIG correlates with the AG once corrected for all known anions. The SIG technique can detect unknown anions in a patient population known to have them and does not detect unknown anions in healthy volunteers during exercise. This test detects large amounts of unknown anions in some patients with sepsis or liver disease. Therefore, the test is both sensitive and specific in characterizing metabolic acidosis.
Abstract: While the interactions between angiotensin II (Ang II) and norepinephrine (NE) on cardiovascular responses are well known, their effects on renin responses are not. We determined the renin secretion rate (RSR) and intracellular calcium level in juxtaglomerular cells harvested from Sprague-Dawley rats using a radioimmunoassay and a two-dimensional calcium analyzer. The effect of Ang II and NE was inhibitory on RSR and stimulatory on intracellular calcium. The NE-induced RSR response was amplified in the presence of Ang II (20 nmol/l). The NE-induced intracellular calcium response was also potentiated by the Ang II. There was a significant correlation (r = 0.994, p \textless 0.0001) between the changes in the RSR and those in intracellular calcium levels. Losartan (0.1 mumol/l). an Ang II type 1 receptor antagonist, blocked the Ang II threshold RSR responses and completely abolished the Ang II-related enhancements. The exclusion of calcium from the buffer reduced the maximal RSR response to NE but did not prevent the enhancement, suggesting the importance of the mobilization of intracellular calcium in the mechanism. The Ang II-induced RSR was amplified in the presence of NE (0.2 mumol/l). The Ang II-induced intracellular calcium response was also potentiated by the NE. A significant correlation (r = 0.996, p \textless 0.0001) between the changes in the RSR and the changes in intracellular calcium levels was also noted. Prazosin (1 mumol/l), an alpha 1-adrenoceptor antagonist, blocked the NE threshold RSR responses and abolished the agonist-related enhancements. The calcium-free buffer diminished this amplication with a slight decrease in the maximum RSR response to Ang II.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Muscular activity converts chemical energy into useful work and metabolism restores muscle to its original state. This essay explores the organization and interactions of the regulatory system(s) which allow this energy balance to occur. The term "energy balance" is used in a biochemical rather than a thermodynamic sense–concerned not with deductions from the physical principles of thermodynamics, but rather with those enzymatic processes which nature evolved and which operate at remarkably fixed stoichiometry. Energy balance is a statement of conservation of energy put into biochemical observables. 31P NMR spectroscopy is one of the most useful techniques for investigating these questions quantitatively under physiological conditions in vivo. The author (1) describes the rules or principles of biochemical energy balance; (2) discusses sample results from human muscle to demonstrate its use in studying this class of questions; (3) presents a simple model of integrated cellular respiration to demonstrate its sufficiency to account for the main observations.
Abstract: The mechanism by which angiotensin-converting enzyme (ACE) inhibition influences renal perfusion and function has assumed growing importance as alternatives for blocking the system have emerged. Neither renin inhibitors nor angiotensin II (Ang II) antagonists are likely to trigger responses similar to ACE inhibitor-induced involvement of kinins, prostaglandins, or nitric oxide. Several observations suggest species variation in the contribution of these pathways to the renal response to ACE inhibition. In humans, recent investigation suggests that virtually all of the renal response is due to a fall in Ang II formation. Perhaps most persuasive is the surprising observation that the renal hemodynamic response to renin inhibitors exceeds by more than 50% the response to ACE inhibition in healthy humans. To the extent that kinins or prostaglandins contribute to the renal response to ACE inhibition, one would anticipate a smaller response to renin inhibition. Possible explanations include an unanticipated additional action of renin inhibitors, better tissue penetration of these highly lipophilic agents, or more effective blockade of Ang II formation through an action at the rate-limiting step or non-ACE-dependent Ang II generation. Substantial evidence favors the latter two possibilities. Whatever the explanation, these observations raise the intriguing possibility that the undoubted therapeutic efficacy of ACE inhibition in renal injury, documented most rigorously for type I diabetes mellitus, might be exceeded with the newer classes of agent.
Abstract: We have studied the cardiovascular effects of incremental doses of three catecholamines in dogs subjected to lactic (LAC) and hydrochloric (HCl) acidosis. Fifty-four dogs were allocated randomly to one of three groups: control, LAC and HCl acidosis (n = 18 each group). In the acidotic models, 2 mol litre-1 of lactic acid (4 ml kg-1 h-1) or 2 mol litre-1 of HCl (1 ml kg-1 h-1) was infused i.v. until arterial pH was reduced to 7.00 +/- 0.1. Within each group, six dogs received one of three different drugs in logarithmically incremental doses: adrenaline 0.1, 0.2, 0.4, 0.8, 1.6, 3.2 micrograms kg-1 min-1, noradrenaline 0.1, 0.2, 0.4, 0.8, 1.6, 3.2 micrograms kg-1 min-1 and dobutamine 5, 10, 20, 40, 80, 160 micrograms kg-1 min-1. Cardiovascular variables were monitored, with periodic measurements of plasma electrolyte and lactate concentrations. The pH reduction induced by HCl or lactic acid was associated with a statistically significant increase in mean pulmonary arterial pressure (MPAP), prominent especially in the LAC group where MPAP increased from mean 18 (SD 5) to 27 (6) mm Hg. In the acidotic models, the reduction in myocardial responsiveness to adrenaline or noradrenaline was more prominent than that for the control for corresponding doses of drugs. In the LAC group mean cardiac index decreased significantly from 5.2 (1.8) to 2.2 (0.7) litre min-1 m-2 after infusion of adrenaline 3.2 micrograms kg-1 min-1 and decreased from 5.1 (1.1 to 2.4 (0.9) litre min-1 m-2 after infusion of noradrenaline 3.2 micrograms kg-1 min-1.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Klatzo’s classification of brain edema into two types, vasogenic and cytotoxic, has been in general use since 1967. The former involves overall brain swelling due to fluid entry from the vasculature because of openings in the blood-brain barrier (BBB), whereas the latter refers to cell swelling without any loss of the normal impermeability of the BBB. This review principally covers new work that identifies the intracellular swelling of astrocytes as a major form of cytotoxic edema seen in many different kinds of brain injury. The term edema should be retained because of its familiarity; however, because such intracellular swelling is usually not a response to toxins, it is suggested that the term cellular edema is preferable to cytotoxic edema. The difficulties involved in measuring cellular edema clinically are discussed, and the belief that a "pure" form of either edema is unlikely to exist. It is emphasized that the mechanisms and direct consequences of vasogenic and cellular edema are so different that the connection is mainly semantic. Studies conducted in vitro have identified several potentially damaging secondary consequences of astrocytic swelling. One of the most important of these seems likely to be the increased release of excitatory amino acids from swollen astrocytes. Potential mechanisms for inhibition of the increased release of amino acids have been identified in vitro and could prove therapeutically useful.
Abstract: The purpose of this study was to compare the external mechanical efficiency (ME) between power-trained athletes (n = 5) and endurance-trained athletes (n = 5). The relationships between biomechanical variables and metabolic cost were also investigated. The subjects ran at 3 different speeds (2.50 m.s-1, 3.25 m.s-1 and 4.00 m.s-1) both on the treadmill and on the track. The external work of the subjects was determined by a kinematic arm, and energy expenditure was determined by measuring oxygen consumption and respiratory exchange ratio. Biomechanical parameters included ground reaction forces, angular displacements of the knee and ankle joints and electromyography (EMG) of the selected muscles. The mean ME (+/- SD) values during running on treadmill were as follows: 49.6 +/- 8.9%, 60.1 +/- 9.6% and 61.2 +/- 10.4% for the endurance group, and 47.1 +/- 3.7%, 52.0 +/- 4.3% and 57.4 +/- 5.5% for the power group. In running on the track the respective values were 57.5 +/- 11.9%, 51.5 +/- 6.1% and 62.2 +/- 9.2% for the endurance group, and 47.0 +/- 8.3%, 45.3 +/- 10.2% and 60.0 +/- 5.9% for the power group. The subject groups did not differ significantly in ME due to high interindividual variance among both subject groups. The metabolic responses such as heart rate, pulmonary ventilation and oxygen uptake differed clearly between the athletic groups but this was not the case for the most of the biomechanical variables (such as EMG, step length and vertical displacement of the centre of the gravity).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: 1. Long-term volume homeostasis is linked very closely to long-term arterial pressure control through the renal-body fluid feedback mechanism. A key feature of this control system is the ability of the kidneys to respond to changes in arterial pressure by altering renal excretion of salt and water, often referred to as renal-pressure natriuresis. 2. Quantitative studies indicate that ANP secretion is relatively sensitive to changes in atrial pressure and that the rate of hormonal secretion does not adapt to continuous long-term stimulation. 3. Under normal conditions, the renal-body fluid feedback mechanism for arterial pressure control is very efficient in minimizing changes in body fluid volumes during alterations in sodium intake. Therefore, only small changes in atrial pressure and ANP secretion occur. Alterations in plasma ANP concentration within physiological levels have little effect on renal-pressure natriuresis and, therefore, have little impact on volume homeostasis. 4. When the renal-body fluid feedback mechanism for arterial pressure control is impaired and body fluid volumes are elevated, such as in heart failure, large increases in atrial pressure and ANP secretion occur. The resultant pathophysiological plasma levels of ANP exert sustained natriuretic effects and chronically shift renal-pressure natriuresis to lower arterial pressures. In the absence of this chronic effect of ANP on renal-pressure natriuresis, reduced arterial pressure in compensated heart failure would result in protracted retention of salt and water and additional increments in body fluid volumes.
Abstract: Chronic infusion of atrial natriuretic peptide (ANP) has been shown to cause natriuresis, diuresis, and hypotension in rats and humans. We explored the effect of a continuous supply of ANP by somatic ANP delivery on genetically hypertensive rats. A DNA construct containing the human ANP gene fused to the Rous sarcoma virus 3’-long terminal repeat (RSV-LTR) was injected intravenously into spontaneously hypertensive rats (SHR) through the tail vein. Expression of human ANP in SHR was identified in the heart, lung, and kidney by radioimmunoassay and reverse transcription-polymerase chain reaction followed by Southern blot analysis. A single injection of naked ANP plasmid DNA (12.3 kb) caused a significant reduction of systemic blood pressure in young SHR (4 weeks old), and the effect continued for 7 weeks. The differences were significant at 1 to 2 weeks (n = 6, P \textless .05) and 3 to 6 weeks after injection (n = 6, P \textless .01) A maximal blood pressure reduction of 21 mm Hg in young SHR was observed 5 weeks after injection with ANP DNA (159.4 +/- 3.02 mm Hg, mean +/- SEM, n = 6) compared with SHR injected with vector DNA alone (180.2 +/- 3.02 mm Hg, mean +/- SEM; n = 6; P \textless .01). Somatic gene delivery of human ANP DNA had no effect on the blood pressure of adult SHR (12 weeks old). After ANP gene delivery, there were significant increases in urinary volume and urinary potassium output (n = 6, P \textless .05) but not in body weight, heart rate, water intake, urinary sodium output, urinary creatine, and urinary protein.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: BACKGROUND: Ten percent to 20% of potential cardiac donors with brain injury and no previous cardiac history have myocardial dysfunction. We assessed components of the beta-receptor-G-protein-adenylyl cyclase complex as well as the contractile response in 10 explanted acutely failing human hearts (donor heart dysfunction [DHD]) and compared the results with 13 age-matched nonfailing (NF) organ donor controls. METHODS AND RESULTS: As measured by echocardiography, all DHD hearts exhibited a decreased shortening fraction (16 +/- 2%, mean +/- SEM). Although total and subpopulation beta-receptor densities measured by [125I]iodocyanopindolol (ICYP) were similar in the DHD and NF groups, DHD hearts exhibited a 30% decrease in maximum isoproterenol-stimulated adenylyl cyclase activity and a 50% decrease in the maximal response to zinterol. DHD hearts also exhibited decreases in adenylyl cyclase maximal stimulation by forskolin (211 +/- 25 [DHD] versus 295 +/- 23 [NF] pmol cAMP.min-1.mg-1, P \textless .05) and 5’-guanylylimidodiphosphate (12.5 +/- 1.8 [DHD] versus 19.6 +/- 3.2 [NF] pmol cAMP.min-1.mg-1, P \textless .05), but there was no significant decrease in adenylyl cyclase stimulation by Mn2+, a direct activator of adenylyl cyclase. Right ventricular trabeculae removed from DHD hearts exhibited a profound decrease in the contractile response to isoproterenol (8.7 +/- 1 [DHD] versus 22 +/- 2 [NF] mN, P \textless .001) as well as reduced calcium responses (7.2 +/- 1.6 [DHD] versus 14 +/- 3 [NF] mN, P = .03). Morphological examination of two hearts revealed some ultrastructural evidence suggestive of catecholamine-mediated injury, but there was no difference in tissue creatine kinase activity between the two groups. CONCLUSIONS: Compared with NF hearts, DHD hearts exhibit marked uncoupling of beta 1- and beta 2-adrenergic receptors from adenylyl cyclase and contractile response stimulation as well as decreased intrinsic systolic function. Thus, acute myocardial dysfunction accompanying brain injury is characterized by marked alterations in beta-adrenergic signal transduction as well as changes in the contractile apparatus, and this profile is markedly different from what occurs in the chronically failing human heart.
Abstract: Although information regarding insulin secretion usually is considered equivalent when generated in the mouse or the rat, it is established that the kinetics of insulin secretion from mouse and rat pancreatic beta cells differ. The mechanisms underlining these differences are not understood. The in vitro perfused pancreas and isolated islets of the mouse or rat were employed in this study to investigate the role of cyclic adenosine monophosphate (cAMP), a major positive modulator of beta-cell function, as one differentiating signal for the uniquely different insulin release from the beta cells of these commonly used rodents. Glucose-stimulated first-phase insulin release from the perfused pancreas of the rat was higher than the mouse when calculated per gram of pancreas or as fractional secretion, but this phase was identical in the two species when results were adjusted for total body weight. Whether related to insulin content, pancreatic weight or body weight, the rat pancreas responded to glucose with a progressively increasing second-phase insulin release compared to the mouse pancreas, which secreted a flat second-phase of lesser magnitude. Isolated islets from rat and mouse were comparable in insulin content whereas the basal cAMP level of mouse islets was less than half that of the rat. At submaximal stimulation with glucose or glucose + IBMX or forskolin, mouse islets exhibited lower cAMP levels to a given stimulus than the rat. In rat islets cAMP levels increased to approximately 1000 fmol per islet, although insulin secretion maximized by 100-150 fmol.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: This brief review describes the main physicochemical factors that contribute to increases in intracellular hydrogen ion concentration ([H+]i) in mammalian skeletal muscle during high intensity exercise. High intensity exercise results in changes in the three main independent physicochemical variables: PCO2, the strong ion difference ([SID]), and total concentration of weak acids and bases ([Atot]), within the intracellular fluid compartment of contracting muscle that result in increased [H+]i. The decrease in [SID] contributes 62% to the increase in [H+]i, due to decreased [K+]i and increased [lactate]i; the decrease in phosphocreatine ([PCr2-]i) exerts an alkalinizing effect. The increase in [Atot], resulting primarily from increases in inorganic phosphate and creatine as a result of PCr2- breakdown, contributes 19% to the increase in [H+]i. An increase in the apparent proton dissociation constant (KA) for [Atot] contributes 7% to the increase in [H+]i. PCO2 is a relatively poor effector of changes in [H+]i, such that a 50-mmHg increase in PCO2 contributes only 12% to the increase in [H+]i during high intensity exercise.
Abstract: To determine the relationship between circulating metabolic fuels and their local concentrations in peripheral tissues we measured glycerol, glucose, and amino acids by microdialysis in muscle and adipose interstitium of 10 fasted, nonobese human subjects during (a) baseline, (b) euglycemic hyperinsulinemia (3 mU/kg per min for 3 h) and, (c) local norepinephrine reuptake blockade (NOR). At baseline, interstitial glycerol was strikingly higher (P \textless 0.0001) in muscle (3710 microM) and adipose tissue (2760 microM) compared with plasma (87 microM), whereas interstitial glucose (muscle 3.3, fat 3.6 mM) was lower (P \textless 0.01) than plasma levels (4.8 mM). Taurine, glutamine, and alanine levels were higher in muscle than in adipose or plasma (P \textless 0.05). Euglycemic hyperinsulinemia did not affect interstitial glucose, but induced a fall in plasma glycerol and amino acids paralleled by similar changes in the interstitium of both tissues. Local NOR provoked a fivefold increase in glycerol (P \textless 0.001) and twofold increase in norepinephrine (P \textless 0.01) in both muscle and adipose tissues. To conclude, interstitial substrate levels in human skeletal muscle and adipose tissue differ substantially from those in the circulation and this disparity is most pronounced for glycerol which is raised in muscle as well as adipose tissue. In muscle, insulin suppressed and NOR increased interstitial glycerol concentrations. Our data suggest unexpectedly high rates of intramuscular lipolysis in humans that may play an important role in fuel metabolism.
Abstract: The purpose of this study was to elucidate the role of the renal nerves in promoting sodium retention during chronic reductions in cardiac output. In five dogs, the left kidney was denervated and the urinary bladder was surgically divided to allow separate 24-h urine collection from the innervated and denervated kidneys. Additionally, progressive reductions in cardiac output were achieved by employing an externally adjustable occluder around the pulmonary artery and by servo-controlling right atrial pressure (control = 0.9 +/- 0.2 mmHg) at 4.7 +/- 0.1, 7.5 +/- 0.1, and 9.8 +/- 0.2 mmHg for 3 days at each level. At the highest level of right atrial pressure, the 24-h values for mean arterial pressure (control = 97 +/- 3 mmHg) and cardiac output (control = 2,434 +/- 177 ml/min) were reduced approximately 25 and 55%, respectively; glomerular filtration rate fell by approximately 35% and renal plasma flow by approximately 65%. However, despite the sodium retention induced by these hemodynamic changes, there were no significant differences in renal hemodynamics or sodium excretion between the two kidneys during pulmonary artery constriction. In contrast, after release of the pulmonary artery occluder on day 9, sodium excretion increased more (approximately 28% during the initial 24 h) in innervated than in denervated kidneys. These results suggest that the renal nerves are relatively unimportant in promoting sodium retention in this model of low cardiac output but contribute significantly to the short-term elimination of sodium after partial restoration of cardiac output and mean arterial pressure.
Abstract: As part of the revision of the Reference Man model of the International Commission on Radiological Protection (ICRP), we have reviewed and reanalyzed available data on blood flow and in previous publications have proposed reference values for total and regional blood volumes, total cardiac output, and the distribution of cardiac output. In this paper we unify these proposed features of the revised Reference Man within the framework of a dynamic blood circulation model and show how the model can be used to predict the distribution of decays of short-lived radionuclides after injection or absorption into blood. The total blood volume is partitioned into the blood contents of 24 separate organs or tissues, right heart chambers, left heart chambers, pulmonary circulation, arterial outflow to the systemic tissues (aorta and large arteries), and venous return from the systemic tissues (large veins). As a compromise between physical reality and computational simplicity, the circulation of blood is viewed as a system of first-order transfers between blood pools, but outflow from any given pool is delayed during the first pass of material through the circulation with the delay time depending on the mean transit time across the pool. The model can be used to predict the movement and gradual dispersal of a bolus of material in the circulation after intravascular injection. In contrast to the treatment of the circulation in ICRP Publication 53, Radiation Dose to Patients from Radiopharmaceuticals, the present model allows consideration of incomplete, tissue-dependent extraction of material during passage through the circulation and return of material from tissues to plasma.
Abstract: The primary objective of this study was to determine whether angiotensin II (ANG II) has direct effects on the atrium to chronically stimulate the secretion of atrial natriuretic peptide (ANP) by actions that are independent of its vasoconstrictor and fluid-retaining effects that increase ANP secretion indirectly by raising atrial pressure. In five dogs, right atrial pressure (RAP) was controlled at approximately 5.5 mmHg above control levels for 8 days by employing an externally adjustable occluder around the pulmonary artery and a servo-control system, and plasma levels of ANG II were fixed at either normal (days 1-3 and 7-8) or high (days 4-6) physiological concentrations by chronic infusion of captopril+ANG II. When plasma ANG II was maintained at normal levels during servo-control of RAP, plasma ANP concentration increased five- to sixfold and sodium balance was achieved at a reduced arterial pressure (-14 mmHg). In contrast, despite increased plasma levels of ANP, the high rate of ANG II infusion produced marked sodium retention during the initial 24 h; however, the antinatriuresis was not sustained because the servo-control system partially deflated the pulmonary artery occluder to prevent fluid-induced increments in RAP. Moreover, in the absence of a change in RAP, high plasma levels of ANG II did not influence plasma ANP concentration. These findings indicate that the plasma levels of ANP achieved in heart failure increase renal excretory capability and allow fluid balance to be achieved at a substantial fall in mean arterial pressure as long as there is minimal involvement of the renin-angiotensin system.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: BACKGROUND: Orthostatic syncope is usually attributed to cerebral hypoperfusion secondary to systemic hemodynamic collapse. Recent research in patients with neurocardiogenic syncope has suggested that cerebral vasoconstriction may occur during orthostatic hypotension, compromising cerebral autoregulation and possibly contributing to the loss of consciousness. However, the regulation of cerebral blood flow (CBF) in such patients may be quite different from that of healthy individuals, particularly when assessed during the rapidly changing hemodynamic conditions associated with neurocardiogenic syncope. To be able to interpret the pathophysiological significance of these observations, a clear understanding of the normal responses of the cerebral circulation to orthostatic stress must be obtained, particularly in the context of the known changes in systemic and regional distributions of blood flow and vascular resistance during orthostasis. Therefore, the specific aim of this study was to examine the changes that occur in the cerebral circulation during graded reductions in central blood volume in the absence of systemic hypotension in healthy humans. We hypothesized that cerebral vasoconstriction would occur and CBF would decrease due to activation of the sympathetic nervous system. We further hypothesized, however, that the magnitude of this change would be small compared with changes in systemic or skeletal muscle vascular resistance in healthy subjects with intact autoregulation and would be unlikely to cause syncope without concomitant hypotension. METHODS AND RESULTS: To test this hypothesis, we studied 13 healthy men (age, 27 +/- 7 years) during progressive lower body negative pressure (LBNP). We measured systemic flow (Qc is cardiac output; C2H2 rebreathing), regional forearm flow (FBF; venous occlusion plethysmography), and blood pressure (BP; Finapres) and calculated systemic (SVR) and forearm (FVR) vascular resistances. Changes in brain blood flow were estimated from changes in the blood flow velocity in the middle cerebral artery (VMCA) using transcranial Doppler. Pulsatility (systolic minus diastolic/mean velocity) normalized for systemic arterial pressure pulsatility was used as an index of distal cerebral vascular resistance. End-tidal PACO2 was closely monitored during LBNP. From rest to maximal LBNP before the onset of symptoms or systemic hypotension, Qc and FBF decreased by 29.9% and 34.4%, respectively. VMCA decreased less, by 15.5% consistent with a smaller decrease in CBF. Similarly, SVR and FVR increased by 62.8% and 69.8%, respectively, whereas pulsatility increased by 17.2%, suggestive of a mild degree of small-vessel cerebral vasoconstriction. Seven of 13 subjects had presyncope during LBNP, all associated with a sudden drop in BP (29 +/- 9%). By comparison, hyperventilation alone caused greater changes in VMCA (42 +/- 2%) and pulsatility but never caused presyncope. In a separate group of 3 subjects, superimposition of hyperventilation during highlevel LBNP caused a further decrease in VMCA (31 +/- 7%) but no change in BP or level of consciousness. CONCLUSIONS: We conclude that cerebral vasoconstriction occurs in healthy humans during graded reductions in central blood volume caused by LBNP. However, the magnitude of this response is small compared with changes in SVR or FVR during LBNP or other stimuli known to induce cerebral vasoconstriction (hypocapnia). We speculate that this degree of cerebral vasoconstriction is not by itself sufficient to cause syncope during orthostatic stress. However, it may exacerbate the decrease in CBF associated with hypotension if hemodynamic instability develops.
Abstract: The haemodynamic changes during 4 h following maximal upright bicycle exercise were evaluated in six normals in a randomized controlled crossover design. Total peripheral resistance was reduced to 2 h (-6.7 mmHg min l-1, P \textless 0.05); exercising and non-exercising vascular beds were vasodilated for 2 h (-24.1 and -23.8 mmHg min ml-1 100 ml-1 tissue, respectively, P \textless 0.05), associated with reductions in systolic (-5.8 mmHg, P \textless 0.05) and diastolic pressure (-8.3 mmHg, P \textless 0.05). Rise in cardiac index for 1 h (+0.51 min-1 m-2, P \textless 0.05) was accounted for by an elevated heart rate (+14.4 beats min-1, P \textless 0.01) as stroke volume was unchanged. Body temperature was elevated until 40 min (+0.20 degrees C, P \textless 0.05). The return of all haemodynamic variables to control by 3 h suggests a 3 h limit for a hypotensive effect of exercise. Rise in body temperature is not the only factor responsible for the hypotension.
Abstract: To assess the relative roles of insulin and hypoglycaemia on induction of neuroendocrine responses, symptoms and deterioration of cognitive function (12 cognitive tests) during progressive decreases in plasma glucose, and to quantitate glycaemic thresholds, 22 normal, non-diabetic subjects (11 males, 11 females) were studied on four occasions: prolonged fast (n = 8, saline euglycaemia study, SA-EU), stepped hypoglycaemia (plasma glucose plateaus of 4.3, 3.7, 3 and 2.3 mmol/l) or euglycaemia during insulin infusion at 1 and 2 mU.kg-1.min-1 (n = 22, high-insulin hypoglycaemia and euglycaemia studies, HI-INS-HYPO and HI-INS-EU, respectively), and stepped hypoglycaemia during infusion of insulin at 0.35 mU.kg-1.min-1 (n = 9, low-insulin hypoglycaemia study, LO-INS-HYPO). Insulin per se (SA-EU vs HI-INS-EU), suppressed plasma glucagon (approximately 20%) and pancreatic polypeptide (approximately 30%), whereas it increased plasma noradrenaline (approximately 10%, p \textless 0.05). Hypoglycaemia per se (HI-INS-HYPO vs HI-INS-EU) induced responses of counterregulatory hormones (CR-HORM), symptoms and deteriorated cognitive function. With the exception of suppression of endogenous insulin secretion, which had the lowest glycaemic threshold of 4.44 +/- 0.06 mmol/l, pancreatic polypeptide, glucagon, growth hormone, adrenaline and cortisol had similar glycaemic thresholds (approximately 3.8-3.6 mmol/l); noradrenaline (3.1 +/- 0.0 mmol/l), autonomic (3.05 +/- 0.06 mmol/l) and neuroglycopenic (3.05 +/- 0.05 mmol/l) symptoms had higher thresholds. All 12 tests of cognitive function deteriorated at a glycaemic threshold of 2.45 +/- 0.06 mmol/l, but 7 out of 12 tests were already abnormal at a glycaemic threshold of 2.89 +/- 0.06 mmol/l. Although all CR-HORM had a similar glycaemic threshold, the lag time of response (the time required for a given parameter to increase) of glucagon (15 +/- 1 min) and growth hormone (14 +/- 3 min) was shorter than adrenaline (19 +/- 3 min) and cortisol (39 +/- 4 min) (p \textless 0.05). With the exception of glucagon (which was suppressed) and noradrenaline (which was stimulated), insulin per se (HI-INS-HYPO vs LO-INS-HYPO) did not affect the responses of CR-HORM, and did not influence the symptoms or the cognitive function during hypoglycaemia. Despite lower responses of glucagon, adrenaline and growth hormone (but not thresholds) in females than males, females were less insulin sensitive than males during stepped hypoglycaemia.
Abstract: We tested the hypothesis that local vascular formation of angiotensin (ANG) II and the sympathetic nervous system potentiate each other. Isolated rat hindquarters were perfused with an artificial medium, and ANG I and II release was measured by high-performance liquid chromatography and radioimmunoassay. Electrical stimulation of the lumbar sympathetic chain (0.5, 2, and 8 Hz) did not affect vascular ANG release in Sprague-Dawley (SD) rats. Hypertensive, ren-2 transgenic (TG+) rat hindquarters released significantly more ANG I (110 +/- 19 vs. 65 +/- 21 fmol/30 min in SD rats) and ANG II (235 +/- 22 vs. 140 +/- 30 fmol/30 min); however, nerve stimulation did not alter ANG release in TG+ rats. Captopril inhibited vascular ANG II release by 90%, but neither captopril nor ANG II receptor blockade by losartan affected the pressor response to nerve stimulation in SD and TG+ rats. Isoproterenol failed to increase either vascular ANG release or pressor response to nerve stimulation in SD or spontaneously hypertensive rat hindquarters. Exogenous renin, which increased vascular ANG release approximately 100-fold, prolonged the pressor responses to nerve stimulation. We conclude that the vascular renin-ANG system does not interact with the sympathetic nervous system locally. However, high concentrations of ANG II, which can be induced by circulation-derived renin, may prolong the duration of sympathetic nerve-induced vasoconstriction.
Abstract: The effects of 120 min of euglycaemic hyperinsulinaemia (UH, approximately 5 mM; 40 mU m-2 min-1), UH plus adrenaline infusion (0.05 microgram kg-1 min-1), and hyperglycaemic normoinsulinaemia (26 mM) on hexokinase kinetics in human skeletal muscle were examined. Biopsies were obtained from the quadriceps femoris muscle before and after each clamp. Total muscle hexokinase activity (HKt) (measured on a 2500 g supernatant) at a saturating level of the substrate glucose (1 mM) averaged 13 mmol kg dry wt-1 min-1 in the basal state and did not change significantly under any condition. Soluble hexokinase activity (HKs) (16,000 g supernatant) accounted for approximately 65% of HKt in the basal state, and this percentage was not significantly affected by any condition, suggesting that there was no major transfer of HK between cytosol and mitochondria. The activity of HKt and HKs was inhibited by glucose 1,6-bisphosphate (G-1,6-P2) in a concentration dependent manner in the basal state, and the sensitivity to G1,6-P2 inhibition was not altered by any condition. The activity of HKt and HKs in the presence of a subsaturating level of glucose (0.1 mM) accounted for approximately 70% of the activity at 1 mM glucose, and this percentage was not altered by any condition. These data suggest that under the present conditions alterations in the rates of whole body glucose disposal cannot be associated with alterations in HK distribution between cellular compartments nor its measured kinetics properties.
Abstract: Maintenance of brain cell volume is of crucial importance for normal central nervous system (CNS) function. This review considers volume regulation primarily in response to disturbances of body fluid osmolality. Brain cells counter the tendency to swell or shrink by appropriate adjustment of their internal osmotic potential. This is achieved by loss or uptake of inorganic ions and low molecular weight organic solutes (osmolytes). The latter comprise mainly amino acids, myoinositol, choline, and methylamines. Taurine may be of particular importance in volume control, especially in young animals. Brain cell volume regulation, however, is only one contributory factor to maintenance of constant brain volume (water content), and operates in parallel with important alterations in bulk fluid and electrolyte movement across the blood-brain barrier and between the interstitium and cerebrospinal fluid, which themselves moderate the requirement for transient alteration in cell volume during acute osmotic imbalance. Although altered cerebral content of inorganic ions and osmolytes are usually regarded as responses, respectively, to acute and chronic osmotic disturbances, osmolytes (especially taurine) may also participate in short-term cell volume regulation.
Abstract: To evaluate mechanisms of late orthostatic intolerance, slow fluid shifts along the body axis were studied during deconditioning by 24-h bed-rest and during 13-min upright tilts before and after this manoeuvre. In 11 healthy male subjects the fluid volumes of a thorax and a calf segment (impedance plethysmography) as well as tissue thickness at the forehead and the tibia (miniature ultrasonic plethysmograph) were recorded. Cardiovascular performance was monitored by recording heart rate (electrocardiogram), brachial and finger arterial pressure (by the Riva Rocci method and by the Finapres technique) as well as stroke volume (by impedance cardiography). Bed-rest led to a cephalad fluid shift with a mean interstitial leg dehydration of 2.2 ml.100 ml-1 with no changes in body mass and plasma volume. No syncope during the tilt occurred before bed-rest, while after bed-rest 8 subjects fainted between min 2.1 and 9.0 of the tilt. Bed-rest resulted in an augmented initial heart rate response to tilting which was similar in all subjects. In later orthostasis, bed-rest caused two- to threefold faster caudad fluid shifts with higher calf filtration rates in fainters (prior to hypotension) than in nonfainters. Through bed-rest the estimated extravasation within 10 min into general lower body tissue spaces increased by 192 ml in (late) fainters as opposed to only 23 ml in nonfainters. It was concluded that contributing factors to orthostatic intolerance may be slow transcapillary fluid shifts which are easily underestimated and whose quantity and time course call for further investigation after various deconditioning manoeuvres. In particular, the postflight fluid shifts in astronauts who will have markedly dehydrated legs, may impose a circulatory stress which needs to be evaluated. In general, the filtration rate in relevant areas appears to be an integrative and easily determined parameter, reflecting hormonal and neurogenic vascular as well as local interstitial control of the Starling forces.
Abstract: Renal clearance and tubule microperfusion experiments were carried out to investigate the effects of chronic potassium depletion upon the renal response to furosemide. Rats kept on a potassium-deficient diet for 3 weeks developed hypokalemia, metabolic alkalosis, and decreased aldosterone levels. These rats responded to an oral administration of furosemide (32 mg/kg) with a blunted excretion rate of urine and sodium. Whereas furosemide increased fractional urine sodium excretion to 5.2% in control rats, the corresponding rate in potassium-depleted rats was 2.8%. The urinary excretion of furosemide was also significantly reduced during potassium depletion from 3.06 mg/kg in control rats to 0.97 mg/kg in potassium-depleted rats. In separate experiments, loops of Henle were pump-perfused with furosemide-containing solutions in control and potassium-depleted rats. No major modification of the inhibitory effects of furosemide on sodium transport was observed when the potassium concentration of the perfusion fluid was kept at the low levels expected in hypokalemic rats. Metabolic alkalosis unaccompanied by potassium deprivation did not decrease the diuretic response to furosemide. These experiments indicate that potassium deprivation reduces the diuretic effects of furosemide by mechanisms including diminished furosemide delivery to its tubule site of action.
Abstract: The purpose of this study was to determine whether dilation of arterial vessels preceding the microcirculation contributes differentially to increases in skeletal muscle blood flow during contractions in anesthetized sedentary (SED) or trained (TR) rats. Experiments were performed in the spinotrapezius muscle of adult male Sprague-Dawley rats. Before and immediately after muscle contractions (2, 4, or 8 Hz), intravascular pressures, red blood cell velocities, and vessel diameters were measured in terminal feed arteries at a site before penetration into the tissue. Pressure was also measured in the accompanying vein. Contraction-induced changes in vascular resistance were calculated for upstream (Rup), spinotrapezius muscle microvascular (Rst), and downstream segments. At rest, Rup accounted for less (32 vs. 40%) and Rst for more (59 vs. 47%) of total resistance in TR than in SED rats. At 8 Hz, contractions produced significantly greater functional dilation (SED, 138 +/- 14 microns; TR, 178 +/- 12 microns) and hyperemia (SED, 11.9 +/- 3.2 x control; TR, 16.8 +/- 3.1 x control) in TR than in SED rats. Inflow pressures did not change, and outflow pressures increased significantly with contractions. Rup and Rst each decreased 60-80% after 2-Hz contractions and \textgreater 90% after 8-Hz contractions. Therefore, feed artery dilation contributes significantly to functional hyperemia in the rat spinotrapezius muscle. Furthermore, it appears that aerobic exercise training results in a redistribution of segmental vascular resistance between feed vessels and the microcirculation.
Abstract: Utilizing a combination of mechanical and chemical unilateral denervation, we have examined the relevance of renal innervation for the expression of renin in kidneys of adult rats. Renal denervation led to a reduction by 57 +/- 4% of renin-containing areas in denervated kidneys as quantitated by morphometry of kidney sections immunoreactive against a polyclonal antirenin antibody. Preprorenin mRNA content in the denervated kidneys fell to 46 +/- 7% of the contralateral innervated kidneys. Treatment of rats with the beta 1-adrenoreceptor antagonist metoprolol (100 mg.kg-1.day-1) for 2 days decreased renal renin mRNA levels to 71% of control levels. Unilateral renal denervation led to a further decrease of renin mRNA levels also in metoprolol-treated animals to 60% of the values found in the contralateral kidneys. Hypotensive hemorrhage led to a 1.4-fold increase of renin mRNA in the kidneys of sham-treated animals. In unilaterally denervated rats renin mRNA increased to levels similar to those in sham-operated animals in both denervated and in contralateral innervated kidneys in response to bleeding. As a consequence, the ratio of abundance of renin mRNA in the denervated to the innervated kidneys rose to 86 +/- 7%. Pretreatment of the animals with metoprolol, on the other hand, prevented the rise of renin mRNA in response to hypotensive hemorrhage. Our findings suggest that in the adult organism renal neural input significantly contributes to the expression of renin under basal conditions, while it appears to be of less importance for stimulation of renin gene expression by severe blood loss.
Abstract: OBJECTIVES: To investigate how minute ventilation affects the partial pressure of end-tidal CO2 and arterial and mixed venous pH, PCO2, PO2, and the concentration of bicarbonate during low blood-flow states. We tested the null hypothesis that acid-base conditions during low rates of blood flow are not significantly different when minute ventilation is doubled or halved. DESIGN: Prospective, experimental, animal study. SETTING: University hospital laboratory. SUBJECTS: Domestic swine. INTERVENTIONS: We studied ten anesthetized and mechanically ventilated swine (weight, 43 to 102 kg) in a new model of controlled systemic and pulmonary blood flow in which each animal was maintained on ventricular assist devices. After electrical induction of ventricular fibrillation, ventricular assist device blood flow was decreased in steps. At each decrease, control minute ventilation, two times the control minute ventilation (hyperventilation), and one-half the control minute ventilation (hypoventilation) were administered; each ventilatory change was maintained for 6 mins. MEASUREMENTS AND MAIN RESULTS: Aortic, pulmonary arterial and central venous pressures, ventricular assist device blood flow, and end-tidal CO2 were recorded continuously. Acid-base conditions were studied at three different mean blood flow rates: 49%, 30%, and 12% of baseline prearrest cardiac index. Arterial pH and PaO2 and mixed venous pH varied directly (p \textless .003) with minute ventilation, while PaCO2 and mixed venous PCO2, and end-tidal CO2 varied inversely (p \textless .0001) with minute ventilation. Mixed venous PO2 was not significantly related to minute ventilation (p = .6). PaCO2 and arterial bicarbonate; mixed venous pH, mixed venous PO2, and mixed venous bicarbonate, and end-tidal CO2 varied directly (p \textless .001) with blood flow, while mixed venous PCO2 varied inversely with blood flow (p \textless .05). Arterial pH was not significantly related to blood flow (p = .3). When minute ventilation changed from hyperventilation to hypoventilation at a mean blood flow rate of 49%, mean arterial pH decreased 0.22 +/- 0.06 (p \textless .05), mean PaCO2 increased 28 +/- 6 torr (3.7 +/- 0.8 kPa) (p \textless .05), and mean PaO2 decreased 99 +/- 77 torr (13.2 +/- 10 kPa); mean mixed venous pH decreased 0.11 +/- 0.02, mean mixed venous PCO2 increased 16 +/- 2.2 torr (2.1 +/- 0.3 kPa) (p \textless .05), and mean mixed venous PO2 did not change; mean end-tidal CO2 increased 18 +/- 2 torr (2.4 +/- 0.3 kPa) (p \textless .05). The effect of changes in minute ventilation on blood gases and end-tidal CO2 was similar for mean blood flow rates of 30% and 12% of baseline cardiac index. CONCLUSIONS: During low rates of blood flow similar to those rates found in shock and cardiopulmonary resuscitation, alterations in minute ventilation significantly influenced end-tidal CO2 and both arterial and mixed venous pH and PCO2. These findings may have clinical importance in improving the treatment of shock and cardiac arrest.
Abstract: STUDY OBJECTIVE: A number of studies have shown that expired CO2 concentration is closely related to cardiac output, but that cardiac output was not controlled as an independent variable. In addition, the partial pressure of end-tidal CO2 (PETCO2) during extremely low cardiac output has not been reported. The objective of the present study was to measure PETCO2 during well-controlled, very low blood flow rates under conditions of constant minute ventilation. DESIGN: Ten anesthetized, intubated, and mechanically ventilated swine (weight, 43 to 102 kg) were placed on two ventricular assist devices in order to control cardiac output. Minute ventilation was measured and kept constant. Ventricular assist device output (measured with an ultrasonic flow probe); PETCO2; and aortic, pulmonary artery, and central venous pressures were recorded continuously. INTERVENTIONS: After electrical induction of ventricular fibrillation, pump output was decreased in steps. MEASUREMENTS AND MAIN RESULTS: Cardiac index ranged from 0 to 5,371 mL/min/m2; 59% of PETCO2 measurements were made at cardiac indexes of less than 1,313 mL/min/m2 (30 mL/min/kg). The relationship of PETCO2 levels to cardiac index was determined with linear regression analysis; P \textless .05 was statistically significant. PETCO2 correlated significantly with cardiac index (P \textless .0001). The best-fit line by least-squares analysis produced the equation: PETCO2 = 4.98 + 0.012 [cardiac index] (r2 = .82). CONCLUSION: Under conditions of constant minute ventilation, PETCO2 correlated closely with cardiac index over a large range of blood flow rates, including extremely low rates.
Abstract: Thrombin is the central enzyme of haemostasis. Information on the production and inhibition of thrombin in plasma is important for evaluating the state of the coagulation system. Measurement of thrombin generation in plasma using small oligopeptide chromogenic substrates gives rise to a signal that not only reflects the enzymatic activity of free thrombin, but also contains a contribution of the complex of thrombin with one of its inhibitors, alpha 2-macroglobulin. This paper describes a mathematical procedure to extract from the measured curves the signal due to free thrombin only. The time integral of this free thrombin curve, which we call the thrombin potential, is a parameter which condenses much of the information present in such a curve. Thrombin production from prothrombin can be calculated from the concentration of free thrombin, when the rate constants governing the decay of thrombin are known. It is described how this calculation can be performed, accounting for the consumption of some of the inhibitors of thrombin during coagulation. Measurement of the time integral of the thrombin concentration promises clinical applicability of thrombin generation tests. It is based on the continuous registration of conversion of chromogenic substrate by thrombin during coagulation in plasma. It is shown how the curves obtained by this test can be analysed by a procedure which is analogous to the analysis of curves measured by subsampling from clotting plasma.
Abstract: Effects of 28 days of continuous 6 degrees head-down tilt bed rest on spontaneous vagally mediated baroreflex response slope were evaluated from beat-by-beat relationships between R-R interval and systolic arterial blood pressure. Twelve healthy men (age 27-42 yr) were assigned to either countermeasure (CM) or no-countermeasure (no-CM) groups. CM consisted of strenuous short-term exercise once per day 6 days/wk from days 7 to 28 and lower body negative pressure (LBNP) for 15 min on days 16, 18, 20, and 22-28. Spontaneous baroreflex slope was evaluated by application of linear regression to sequences of at least three beats in which systolic blood pressure and R-R interval changed in the same direction. Measurements were made pre-, mid- (day 15), and post-bed rest at rest and during progressive LBNP tests (3 min at each of -20, -30, -40, and -50 mmHg). R-R interval decreased progressively and significantly (P \textless 0.0001) over duration of bed rest. Spontaneous baroreflex slope at rest in pre-bed rest was 18.5 +/- 2.1 ms/mm Hg for CM and 14.9 +/- 1.6 ms/mmHg for no-CM. There was a significant reduction in baroreflex slope as a function of bed rest, and it was further reduced during LBNP (P \textless 0.0001). Between CM and no-CM groups differences existed, but these were present pre-bed rest and appeared unaffected by countermeasures.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: This study followed changes in the capacities of uptake and phosphorylation of glucose in response to contractile activity in low-frequency stimulated (10Hz, 24 h/d) rat fast-twitch muscle. We investigated the intracellular distribution of GLUT-4, the major glucose transporter isoform in muscle, changes in the amounts of its specific mRNA and total cellular protein, as well as changes in its relative synthesis rate. These analyses were complemented by measurements of total hexokinase activity and hexokinase II (HKII) expression at the levels of mRNA content and protein synthesis. Changes in protein synthesis were determined by in vivo labeling with [35S]methionine. Translocation of GLUT-4 into the sarcolemma was an immediate response to contractile activity, whereas changes in its total amount were observed only with ongoing stimulation (5 d and longer). A twofold increase in GLUT-4 content after 5 d and longer stimulation periods was preceded by elevations of its mRNA and by enhanced [35S]methionine incorporation. Conversely, increases in HKII expression with a rise in total hexokinase activity occurred soon after the onset of stimulation (30-fold elevations of HKII mRNA after 12 h and 20-fold increases in [35S]methionine incorporation after 24 h). With ongoing stimulation, HKII mRNA and synthesis returned to lower levels (fivefold elevations). Nevertheless, hexokinase activity continued to rise, stabilizing at fivefold-elevated levels after 3 d. These observation suggested that posttranscriptional mechanisms contributed to the upregulation of HKII, e.g. stabilization by elevated intracellular glucose and mitochondrial binding of the enzyme. This suggestion was supported by experiments with cessation after 24 h where hexokinase activity continued to increase, although the mRNA content and, especially, the [35S]methionine incorporation decayed steeply. The increase in HKII prior to GLUT-4 suggests that phosphorylation may be rate limiting in glucose utilization of glycolytic fibers under conditions of sustained contractile activity. Taken together, the changes in distribution and content of GLUT-4, as well as in HKII represent early metabolic adaptations. In addition, they are related to the overall process of stimulation-induced fiber type transformation.
Abstract: The effects of 28 days continuous 6 degrees head-down tilt bed-rest on heart rate variability and the slope of the spontaneous arterial baroreflex were evaluated during supine rest and the first 10 min of 60 degrees head-up tilt. Twelve healthy men were assigned to either a no counter-measure (No-CM), or a counter-measure (CM) group so that there was no difference in maximal oxygen uptake. Counter-measures consisted of short-term, high resistance exercise for 6 days per week from days 7-28, and lower body negative pressure (-28 mmHg) for 15 min on days 16, 18, 20 and 22-28. In spite of balanced between-group fitness, mean RR-interval was different between the No-CM and the CM group prior to bed-rest, but neither this nor any other variables showed significant counter-measure by bed-rest interaction effects. Therefore, all data presented are from the main effects of bed-rest or tilt from the analysis of variance. RR-interval was reduced significantly by bed-rest and by tilt (P \textless 0.0001). Indicators from spectral analysis of heart-rate variability suggested reduced parasympathetic nervous system activity with bed-rest (P \textless 0.01) and head-up tilt (P \textless 0.05), and increased sympathetic nervous system activity after bed-rest (P \textless 0.01). An indicator of complexity of cardiovascular control mechanisms, taken from the slope (beta) of log spectral power vs. log frequency relationship, suggested reduced complexity with bed-rest (P \textless 0.05) and head-up tilt (P \textless 0.01). The spontaneous baroreflex slope was reduced significantly by bed-rest (P \textless 0.03) and by head-up tilt (P \textless 0.04). Taken together, these data support the concept of altered autonomic nervous system function in the aetiology of cardiovascular deconditioning with bed-rest or space travel; and it would appear that no benefit is derived from these specific counter-measures.
Abstract: To evaluate the characteristics of runners with exercise-associated collapse (EAC), we studied the time of onset of collapse, rectal temperatures, cardiovascular status, and incidence of readily identifiable medical conditions in 46 male athletes who collapsed during or after a 56-km ultramarathon footrace run on a cool day. Data were compared with 65 control runners who did not collapse in the same race. Weight changes during recovery were studied in a subsample of both groups. The majority (85%) of runners with EAC collapsed after they had completed the race; rectal temperatures (38.5 +/- 1.3 degrees C, mean +/- SD; range 35.5-42.0 degrees C) and supine heart rates (87.5 +/- 17.2 min-1; range 60-138) were only modestly elevated. Postrace serum sodium concentrations, changes in plasma volume, and mass during recovery were not significantly different from values in control runners. We conclude that: (i) most cases of EAC (85%) occur after the finish line; (ii) runners collapsing during the race are more likely to have a readily identifiable medical condition than runners collapsing after the finish line; (iii) runners collapse most frequently near cutoff times for medals and race closure times; and (iv) 16% of EAC casualties and 19% of control runners have identifable biochemical abnormalities.
Abstract: We assessed the influence of hyperoxemia on erythropoietin secretion in patients with various etiological forms of arterial hypertension (essential, n = 15; renoparenchymal, n = 16; renovascular, n = 15) and in 15 healthy subjects. On the first day of the study, blood was withdrawn at 1-hour intervals for the estimation of erythropoietin during a total of 6 hours and at 2-hour intervals for the assessment of PO2. Three days later the same parameters were assessed again at identical time intervals, but the subjects were breathing pure oxygen during the first 2 hours. Breathing with pure oxygen resulted in a significant increase of blood PO2 (184.85 +/- 4.47 versus 85.92 +/- 2.28 in essential, 185.21 +/- 5.52 versus 84.55 +/- 3.04 in renoparenchymal, and 181.7 +/- 3.14 versus 87.49 +/- 2.25 in renovascular hypertension groups and 189.84 +/- 5.2 versus 85.89 +/- 1.73 mm Hg in healthy subjects; P \textless .001 in all groups). Baseline plasma erythropoietin was not different among the groups (29.33 +/- 4.14 in essential, 24.56 +/- 3.09 in renoparenchymal, and 27.77 +/- 3.29 in renovascular hypertension groups and 24.23 +/- 2.70 mU/mL in the control group). The pattern of erythropoietin decline was different in the groups of hypertensive patients. In patients with essential hypertension, unlike in healthy subjects and patients with other etiological forms of arterial hypertension, only a very short-term suppression of erythropoietin levels was observed during hyperoxemia. No significant changes in blood pressure during breathing with pure oxygen were found in any of the studied groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: This study compared plasma volume (PV) and ion regulation during prolonged exercise in control vs. glycogen-depleted (GD) conditions, with emphasis on the initial minutes of exercise. In two trials separated by 1-2 wk, four adult males cycled at 75% of peak oxygen consumption (VO2) until exhaustion (50 +/- 7 min for GD) or until the GD exhaustion time in the control trial. Blood was sampled from catheters placed in the brachial artery and retrograde in the femoral vein (fv). Arterial PV decreased rapidly and by 15 min PV was 83% (control) and 88% (GD) of initial. The decrease in PV was accompanied by a net osmotic flux of water from plasma and inactive tissues to contracting muscles. The significantly greater decrease in PV in control compared with GD was associated with a higher muscle lactate content (Lac-; 36 vs. 17 mumol/g dry wt, respectively). Increases in plasma [Cl-] and [Na+] were less than predicted from decreased PV, indicating net loss of these ions from the plasma compartment. Increases in arterial and fv [K+] were 50% greater than could be accounted for by decreased PV, corresponding with increased arterial and fv plasma K+ contents. The rapid net release of K+ and Lac- from contracting muscle during the first few minutes of exercise in both trials was abolished (control) or reversed (GD) within 15 min of beginning exercise.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: BACKGROUND: In patients with chronic coronary artery disease (CAD) and left ventricular dysfunction, flow/metabolic studies of the myocardium with positron emission tomography (PET) are able to distinguish viable but dysfunctional myocardium from irreversible ischemic injury and scar tissue. In this study, PET findings of blood flow and metabolism in chronically hypoperfused myocardium were correlated with histology. METHODS AND RESULTS: We studied 33 patients suffering from CAD. In each patient, myocardial blood flow and metabolism were measured with PET 1 or 2 days before revascularization. During surgery, transmural biopsies were taken from the left ventricular anterior wall and planimetrically scored for the degree of myolysis (sarcomere loss). The amount of connective tissue was calculated using morphometric techniques. Contrast ventriculography demonstrated abnormal wall motion in 23 patients. Fourteen patients with a mismatch pattern (decreased flow with preserved metabolism) in the biopsy region after quantitative analysis of the PET data showed 11 +/- 6 vol% fibrosis and 25 +/- 13% cells with sarcomere loss. The space formerly occupied by sarcomeres was mainly replaced by glycogen and mitochondria. A significant wall motion improvement was noted 3 months after surgery. Nine patients showed a match pattern (concordant flow/metabolism defects). The biopsies revealed 35 +/- 25% fibrosis and 24 +/- 15% glycogen-storing cells. The biopsies of the 10 patients with normal anterior wall motion showed 8 +/- 4% fibrosis and 12 +/- 8% glycogen-accumulating cells. CONCLUSIONS: It can be concluded that areas with impaired wall motion and a PET match pattern show extensive fibrosis. Regions with reduced flow and preserved FDG metabolism, however, contain predominantly viable cells. In these regions, significant recovery of wall motion is found after revascularization. Regions with normal wall motion contain predominantly viable cells. Cells with reduced contractile material and increased glycogen content are mainly found in areas with wall motion impairment but are also present in areas with normal wall motion and a severe stenosis of the coronary vessel.
Abstract: We investigated neurohumoral profiles and transmitter and neuroenzyme markers of cardiac autonomic innervation in control (unpaced) dogs and three groups of dogs with pacing-induced heart failure (paced, paced + beta-adrenergic blockade, and paced + cardiac denervation). Left ventricular ejection fraction decreased significantly and to a comparable extent in all paced groups. Pacing increased plasma norepinephrine (NE); increases in NE were not attenuated but instead tended to be exaggerated by treatment with propranolol or cardiac denervation. Atrial hypertrophy occurred in all paced groups compared with the control group. However, atrial and right ventricular hypertrophy were not as pronounced in the paced plus cardiac denervation group as in the paced and paced plus propranolol groups. Pacing also depleted neuropeptide Y and NE from all heart chambers; propranolol treatment did not modify these local tissue changes. Pacing caused selective depletion of neuroenzymes predominantly in the left ventricle; again, propranolol did little to modify these changes. In this study of paced animals with experimentally maintained cardiac dysfunction, failure to modify noradrenergic responses with intrapericardial cardiac denervation suggests that noncardiac sources contribute predominantly to high plasma NE. Failure to modify neurohumoral, neuropeptide, and neuroenzyme responses with beta-antagonist suggests this treatment has little practical direct influence on sympathetic vasomotor activity or neuronal function in heart failure.
Abstract: BACKGROUND: We have found that low-dose infusion of angiotensin II (Ang II) selectively potentiates the mean arterial pressure (MAP) response to phenylephrine in pentobarbital-anesthetized rabbits. OBJECTIVE: To examine whether endogenous Ang II levels in normotensive rabbits maintained on a normal-salt diet exert a potentiating effect on the MAP response to phenylephrine. METHODS: We compared the effects of enalaprilat (0.3 mg/kg per min for 5 min bolus, 1 mg/kg per h infusion), losartan (DuP753; 4 mg/kg bolus, 2 mg/kg per h infusion) and vehicle administration on the MAP response to infusions of phenylephrine that were increased incrementally (2.5, 5 and 10 micrograms/kg per min). RESULTS: Enalaprilat decreased MAP significantly, whereas no maintained change was observed with losartan or vehicle. Phenylephrine infusions elevated MAP significantly and dose-dependently in all of the rabbits studied, but this effect was attenuated significantly in the rabbits given losartan compared with in those given vehicle or enalaprilat. The heart rate responses were not significantly different among the three groups. CONCLUSION: We conclude that inhibition of the renin-angiotensin system at two distinct sites results in different MAP responses to phenylephrine infusion.
Abstract: During prolonged starvation, brain energy requirements are covered in part by the metabolism of ketone bodies. It is unknown whether short-term starvation of a few days’ duration may lead to reduced brain glucose metabolism due to the change toward ketone body consumption. In the present study we measured the cerebral metabolism of glucose and ketone bodies in nine healthy volunteers before and after 3.5 days of starvation. Regional glucose metabolism was measured by dynamic positron emission tomography using [18F]2-fluoro-2-deoxy-D-glucose. The mean value of K1* in gray and white matter increased by 12% (p \textless 0.05), whereas k2* and k3* were unchanged compared with control values. Regional glucose metabolism in cortical gray matter was reduced by 26% from 0.294 +/- 0.054 to 0.217 +/- 0.040 mumol g-1 min-1 (p \textless 0.001). White matter glucose metabolism decreased by 27% (p \textless 0.02). The decrease was uniform in gray and white matter with regional decreases ranging from 24 to 30%. A determination using Fick’s principle confirmed the reduction in glucose metabolism yielding a decrease of 24% from 0.307 +/- 0.050 to 0.233 +/- 0.073 mumol g-1 min-1 (p \textless 0.05), whereas CBF did not change (0.57 +/- 0.07 vs. 0.57 +/- 0.06 ml g-1 min-1). The global net uptake of beta-hydroxybutyrate increased 13-fold from 0.012 +/- 0.024 to 0.155 +/- 0.140 mumol g-1 min-1 (p \textless 0.05). Net uptake of acetoacetate and net efflux of lactate and pyruvate did not change significantly during starvation. The present study shows that the human brain adapts to the changes in energy supply as early as 3 days following initiation of starvation, at which time ketone bodies account for approximately one-fourth of the cerebral energy requirements.
Abstract: The systemic complications of nephrotic syndrome are responsible for much of the morbidity and mortality seen with this condition. This review discusses the causes for the hypoalbuminemia and the associated metabolic abnormalities of the nephrotic syndrome. No unifying hypothesis exists for the induction, maintenance, and resolution of nephrotic edema. In view of the wide spectrum of renal diseases leading to the nephrotic syndrome, more than a single mechanism may be responsible for the renal salt retention in these diverse conditions. Although hypoalbuminemia may be important, especially when plasma oncotic pressure is very low (serum albumin \textless 1.5 to 2.0 g/dL), primary impairment of salt and water excretion by the nephrotic kidney appears to be a major factor in pathogenesis of the edema. However, the decreased serum albumin and/or oncotic pressure seen with nephrotic syndrome is a major contributing factor to the development of the hyperlipidemia of nephrotic syndrome. Patients with unremitting nephrotic syndrome should be considered for combined dietary and lipid-lowering drug therapy. Urinary losses of binding proteins lead to the observed abnormalities in the endocrine system and in trace metals, and urinary losses of coagulation factors contribute to the hypercoagulable state. At present, selective renal venography is recommended when the suspicion of renal vein thrombosis is justified by clinical presentation. The impact on renal function caused by treating asymptomatic chronic renal vein thrombosis is undetermined, but anticoagulation for chronic renal vein thrombosis is associated with relatively few complications.
Abstract: The ability of Dahl salt-sensitive (DS) rats to excrete a sodium load is significantly lower than Dahl salt-resistant (DR) rats. Because renal interstitial hydrostatic pressure (RIHP) is a major mediator of natriuresis in response to a sodium load, we proposed that the renal tubules of DS rats are less responsive to increases in RIHP than those of DR rats. To test this hypothesis, we determined the effect of direct increases in RIHP on renal excretory function in prehypertensive DS and DR rats. RIHP was directly increased by renal interstitial volume expansion via injection of 50 microL of a 2% albumin and saline solution into the renal interstitium through a chronically implanted renal interstitial catheter. RIHP, mean arterial pressure, glomerular filtration rate, urine flow rate, urinary sodium excretion, and fractional excretions of sodium, potassium, and lithium (an indicator of proximal tubule sodium handling) were measured before and after direct increases in RIHP in DS (n = 8) and DR (n = 8) rats. Baseline urine flow rate; urinary sodium excretion; fractional excretions of sodium, potassium, and lithium; RIHP; mean arterial pressure; and glomerular filtration rate were not different between DS and DR rats. Renal interstitial volume expansion in DS rats significantly increased RIHP (delta 4.7 +/- 0.8 mm Hg), urine flow rate (delta 14.5 +/- 3.4 microL/min), urinary sodium excretion (delta 2.62 +/- 0.62 mumol/min), and fractional excretions of sodium (delta 1.54 +/- 0.37%), potassium (delta 17.84 +/- 2.90%), and lithium (delta 19.68 +/- 3.52%).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Angiotensin II (Ang II) exerts complex actions on sympathetic nerve activity and heart rate, but these actions are incompletely understood. We performed three series of experiments in conscious rabbits to analyze the actions of exogenous and endogenous Ang II on renal sympathetic nerve activity and heart rate. (1) Graded intravenous doses of phenylephrine and Ang II suppressed renal sympathetic nerve activity to the same degree, whereas Ang II decreased heart rate much less than phenylephrine. (2) Ang II infusion at 10 ng/kg per minute increased mean arterial pressure by 13 +/- 2 mm Hg (P \textless .01) and decreased renal sympathetic nerve activity by 67 +/- 13% (P \textless .01) but did not change heart rate. In the same rabbits, nitroprusside and phenylephrine infusions were used to generate baroreceptor reflex curves. Ang II shifted the heart rate-mean arterial pressure curve to the right but did not alter the renal nerve activity-mean arterial pressure curve. (3) The Ang II type 1 receptor antagonist losartan decreased mean arterial pressure by 8 +/- 3 mm Hg (P \textless .01) and increased renal sympathetic nerve activity by 63 +/- 15% (P \textless .05) but did not change heart rate. Losartan shifted the heart rate-mean arterial pressure curve to the left but did not alter the renal nerve activity-mean arterial pressure curve. These results demonstrate that whereas exogenous Ang II resets the baroreceptor reflex control of heart rate to a higher pressure, it does not increase resting renal sympathetic nerve activity or alter the baroreceptor reflex control of renal nerve activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: The exchange of purines in liver and active skeletal muscle with short-term exhaustive exercise was investigated. Eight male subjects performed two similar 10-min bouts of exhaustive supine cycling, separated by 75 min of rest. Immediately after termination of the second bout, a tourniquet was applied to the upper part of the thigh for 10 min. After the first bout, the arterial concentration of hypoxanthine and uric acid increased from 4.1 +/- 0.3 (SE) to a peak value of 36.3 +/- 7.9 mumol/l (P \textless 0.05) and from 335 +/- 23 to a peak value of 421 +/- 28 mumol/l (P \textless 0.05), respectively. There was a net release of hypoxanthine from the muscle at 12 and 45 min postexercise and an uptake of hypoxanthine and inosine in the liver at 7 and 42 min postexercise. Uric acid was released from the liver at 7 and 42 min after exercise. Before the second exercise bout and at 2 and 10 min after the release of the tourniquet, there was a significant net uptake of uric acid by the muscle. The present study demonstrates that, after strenuous short-term exercise, the main source of plasma hypoxanthine is the muscle, with no net contribution of this purine from the liver. Hypoxanthine in the blood is taken up by the liver where most of it is converted to uric acid. After exercise and a short period of ischemia, uric acid is taken up by the muscle.
Abstract: Glucose transport and phosphorylation are the first steps in the utilization of extracellular glucose by skeletal muscle. We have examined the relationships between proteins mediating these steps in single fibers of identified type dissected from rabbit skeletal muscle. The level of the glucose transporter isoform GLUT4, measured by immunoblotting, varied among fibers by a factor of 20 (slow oxidative \textgreater fast oxidative glycolytic \textgreater fast glycolytic). In fibers from the tibialis anterior muscle, GLUT4 was correlated (r2 = 0.75) with the activity of malate dehydrogenase, an enzyme representative of oxidative energy metabolism. In these fibers a strong correlation (r2 = 0.70) was also observed between GLUT4 and hexokinase activity. GLUT1 levels were barely detectable, regardless of fiber type. To investigate the possible role of muscle activity in controlling the expression of transporters, tibialis anterior muscles were activated by chronic electrical stimulation of the peroneal nerves. GLUT1 levels increased after 1 day of stimulation to a plateau that was severalfold higher than the level in non-stimulated cells. Hexokinase activity and the GLUT4 level changed in parallel: both were increased by approximately 2.5-fold after 1 day and by 14-fold after 21 days. Thus, while both GLUT1 and GLUT4 were regulated by muscle activity, only GLUT4 expression was coordinated with the expression of hexokinase.
Abstract: Hyperinsulinemia, loss of glucose-stimulated insulin secretion (GSIS), and peripheral insulin resistance coexist in non-insulin-dependent diabetes mellitus (NIDDM). Because free fatty acids (FFA) can induce these same abnormalities, we studied their role in the pathogenesis of the NIDDM of obese Zucker diabetic fatty (ZDF-drt) rats from 5 weeks of age (before the onset of hyperglycemia) until 14 weeks. Two weeks prior to hyperglycemia, plasma FFA began to rise progressively, averaging 1.9 +/- 0.06 mM at the onset of hyperglycemia (P \textless 0.001 vs. controls). At this time GSIS was absent and beta-cell GLUT-2 glucose transporter was decreased. The triacylglycerol content of prediabetic islets rose to 10 times that of controls and was correlated with plasma FFA (r = 0.825; P \textless 0.001), which, in turn, was correlated with the plasma glucose concentration (r = 0.873; P \textless 0.001). Reduction of hyperlipacidemia to 1.3 +/- 0.07 mM by pair feeding with lean littermates reduced all beta-cell abnormalities and prevented hyperglycemia. Normal rat islets that had been cultured for 7 days in medium containing 2 mM FFA exhibited increased basal insulin secretion at 3 mM glucose, and first-phase GSIS was reduced by 68%; in prediabetic islets, first-phase GSIS was reduced by 69% by FFA. The results suggest a role for hyperlipacidemia in the pathogenesis of NIDDM; resistance to insulin-mediated antilipolysis is invoked to explain the high FFA despite hyperinsulinemia, and sensitivity of beta cells to hyperlipacedemia is invoked to explain the FFA-induced loss of GSIS.
Abstract: A mathematical simulation of the tissue factor pathway to the generation of thrombin has been developed using a combination of empirical, estimated, and deduced rate constants for reactions involving the activation of factor IX, X, V, and VIII, in the formation of thrombin, as well as rate constants for the assembly of the coagulation enzyme complexes which involve factor VIIIa-factor IXa (intrinsic tenase) and factor Va-Xa (prothrombinase) assembled on phospholipid membrane. Differential equations describing the fate of each species in the reaction were developed and solved using an interactive procedure based upon the Runge-Kutta technique. In addition to the theoretical considerations involving the reactions of the tissue factor pathway, a physical constraint associated with the stability of the factor VIIIa-factor IXa complex has been incorporated into the model based upon the empirical observations associated with the stability of this complex. The model system provides a realistic accounting of the fates of each of the proteins in the coagulation reaction through a range of initiator (factor VIIa-tissue factor) concentrations ranging from 5 pM to 5 nM. The model is responsive to alterations in the concentrations of factor VIII, factor V, and their respective activated species, factor VIIIa and factor Va, and overall provides a reasonable approximation of empirical data. The computer model permits the assessment of the reaction over a broad range of conditions and provides a useful tool for the development and management of reaction studies.
Abstract: Whether liver glycogen synthesis and breakdown occur simultaneously during net glycogen synthesis was assessed in fed and fasted healthy humans. The peak intensity of the carbon-1 (C1) resonance of the glycosyl units of glycogen was monitored with 13C nuclear magnetic resonance spectroscopy during [1-13C]glucose infusion followed by unlabeled glucose infusion. The C1 peak intensity increased almost linearly during the [1-13C]glucose infusion, reflecting a near linear rate of glycogen synthesis. When switched to unlabeled glucose, the C1 peak intensity reached a plateau in the fasted subjects and declined in the fed subjects, reflecting active glycogenolysis during a time of net glycogen synthesis. We conclude that liver glycogen synthesis and degradation occur simultaneously in humans under conditions of net glycogen synthesis. The relative turnover rate was significantly higher in the fed (57 +/- 3%) than in the fasted state (31 +/- 8%; P \textless 0.01). The results indicate that glycogen may regulate its rate of breakdown and that liver glycogen turnover may be an important factor in limiting the accumulation of liver glycogen in humans.
Abstract: We have reported that inhibition of angiotensin-converting enzyme with captopril attenuates the cardiovascular responses to bilateral carotid occlusion in conscious rabbits and proposed that the attenuation results from removal of a facilitatory action of angiotensin II on the sympathetic nervous system. The aim of the present study was to assess the effect of carotid occlusion on renal sympathetic nerve activity in conscious rabbits and to investigate the effect of the angiotensin II subtype 1 (AT1) receptor antagonist losartan on the cardiovascular and renal sympathetic nerve activity responses to carotid occlusion. In seven conscious, aortic depressor nerve-sectioned rabbits, carotid occlusion elicited prompt and reproducible increases in mean arterial pressure from 75 +/- 2 to 124 +/- 5 mm Hg (P \textless .001), heart rate from 285 +/- 8 to 317 +/- 9 beats per minute (P \textless .01), and renal sympathetic nerve activity to 165 +/- 11% of control (P \textless .01). In the same rabbits, losartan (5 mg/kg i.v.) decreased mean arterial pressure by 9 +/- 2 mm Hg (P \textless .01), increased renal sympathetic nerve activity to 143 +/- 13% of control (P \textless .05), but did not alter heart rate. Losartan significantly attenuated (P \textless .01) the mean arterial pressure (66 +/- 2 to 81 +/- 2 mm Hg), heart rate (282 +/- 9 to 289 +/- 7 beats per minute), and renal sympathetic nerve activity (143 +/- 13% to 159 +/- 15% of control) responses to carotid occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: The present studies were performed to assess, in the isolated perfused juxtaglomerular apparatus of the rabbit kidney, the effect of exogenous adenosine on renin secretion stimulated by a low NaCl concentration at the macula densa. Addition of adenosine to the bath resulted in a change of renin secretion from 30.4 to 23.9 nGU/min at an adenosine concentration of 10(-6) M (n = 7; P = NS), from 38.6 to 17.9 nGU/min at a concentration of 10(-4) M (n = 7; P = 0.038), and from 18.4 to 5.8 nGU/min at 10(-2) M (P = 0.0053). Addition of the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine at 10(-5) M fully reversed the effect of adenosine at 10(-4) M, but not at 10(-2) M. Inhibition of adenosine breakdown by the adenosine deaminase inhibitor pentostatin (10(-6) M) enhanced the inhibitory effect of adenosine with renin secretion falling from 61.7 to 19.5 nGU/min at 10(-6) M adenosine (P = 0.035) and from 44.7 to 13.5 nGU/min at 10(-4) M adenosine (n = 0.027). A marked inhibition of NaCl-dependent renin secretion was caused by both angiotensin II (P = 0.011) and angiotensin III (P = 0.006), both at 10(-8) M. These results show that adenosine is capable of reducing macula densa-mediated renin secretion, but that this effect, even at very high concentrations or during adenosine deaminase blockade, does not fully mimic the inhibitory potency of increasing luminal NaCl concentration. Because the marked effect caused by angiotensins establishes the potential of this preparation to demonstrate inhibitory hormonal influences, it is concluded that adenosine does not appear to be the sole paracrine factor responsible for the NaCl-induced reduction of renin secretion.
Abstract: OBJECTIVE: To test the hypothesis that the induction and maintenance of brain death leads to a decrease in myocardial contractility. DESIGN: Prospective, randomized, controlled trial. SETTING: Laboratory at a large, university-affiliated medical center. SUBJECTS: Sixteen adult, male, mongrel dogs weighing 15 to 25 kg. INTERVENTIONS: Myocardial contractile performance was evaluated after the induction of either brain death (n = 8), sham brain death (n = 4), or an operative procedure serving as a time control (n = 4). Brain death was induced by increasing and maintaining intracranial pressure above arterial systolic pressure. Contractile performance was determined with sonomicrometers arrayed to measure wall thickness in the anterior and posterolateral left ventricle. Brief aortic constrictions enabled derivation of the end-systolic pressure-thickness relationship, a relatively load-insensitive index of contractility. MEASUREMENTS AND MAIN RESULTS: No statistically significant hemodynamic differences were detected between the sham and time control groups. The brain-dead group displayed marked hemodynamic deterioration; 4 hrs after brain death was induced, mean arterial blood pressure, cardiac index, and the peak positive first derivative of left ventricular pressure were 63%, 35%, and 53% lower, respectively, than those values in the two control groups. However, the slope of the end systolic pressure-thickness relationship remained at 92 +/- 12% of baseline levels 4 hrs after brain death was induced and was not significantly different from the two control groups. CONCLUSIONS: The hemodynamic deterioration after the induction of brain death could not be attributed to a decrease of myocardial contractility as measured by the end systolic pressure-thickness relationship.
Abstract: The microgravity environment can be expected in man to induce a swelling of facial tissues and a shrinking of the tissues in the lower limbs together with a loss in body weight. To quantitate fluid shifts into and out of superficial tissues an ultrasound A-mode method was used in one cosmonaut during a 7-day spaceflight. Measurements were taken from frontal and tibia tissues, where the underlying bone provides a good backwall echo. During the spaceflight the cosmonaut showed a swelling of facial tissues during the first 3 days. At the same time the superficial tissues of the caudal areas shrank by 20%. In space he lost 7.7% of body weight. After the spaceflight the superficial tissues were dried out but regained their water content within the next 4 days even before body weight returned to control level. Per kilogram of body weight an increase of 400 cm3 entered the superficial tissue layers of the body. It is concluded that water loss as well as wasting of tissues contribute to the loss in body weight during space flight.
Abstract: The spinal cord vasculature is innervated by noradrenergic nerve fibers, the role of which in the regulation of regional spinal cord blood flow (RSCBF) is presently unclear. We used the distribution of [14C]butanol to simultaneously measure RSCBF at seven cord levels and the regional blood flow in sciatic nerve (NBF), truncal skin, and biceps femoris muscle. The subjects were control rats and rats that had been given parenteral guanethidine sulfate for 5 wk to induce selective postganglionic "chemical sympathectomy." Flows were measured under basal conditions (group I) and immediately after an arterial hemorrhage (group II). The results indicate that RSCBF was unchanged from control after guanethidine administration in both groups; however, NBF was elevated after guanethidine by 47% in group I and by 41% in group II. We conclude that in the spinal cord as in the brain, sympathetic inflow does not appear to have an important role in the regulation of regional blood flow. Sympathetic inflow appears to partly regulate NBF, however, probably by varying vascular tone.
Abstract: The objective of the present experiments was to correlate changes in cellular energy metabolism, dissipative ion fluxes, and lipolysis during the first 90 s of ischemia and, hence, to establish whether phospholipase A2 or phospholipase C is responsible for the early accumulation of phospholipid hydrolysis products. Ischemia was induced for 15-90 s in rats, extracellular K+ (K+e) was recorded, and neocortex was frozen in situ for measurements of labile tissue metabolites, free fatty acids, and diacylglycerides. Ischemia of 15- and 30-s duration gave rise to a decrease in phosphocreatine concentration and a decline in the ATP/free ADP ratio. Although these changes were accompanied by an activation of K+ conductances, there were no changes in free fatty acids until after 60 s, when free arachidonic acid accumulated. An increase in other free fatty acids and in total diacylglceride content did not occur until after anoxic depolarization. The results demonstrate that the early functional changes, such as activation of K+ conductances, are unrelated to changes in lipids or lipid mediators. They furthermore suggest that the initial lipolysis occurs via both phospholipase A2 and phospholipase C, which are activated when membrane depolarization leads to influx of calcium into cells.
Abstract: After a detailed description of early cellular, membrane and intracellular events in rat renal medullary collecting duct cells when exposed to hypotonicity, a synopsis on organic osmolyte transport properties, possible trigger mechanisms, and the cellular location of transport pathways is given. From the data currently available on renal and nonrenal cells, it is concluded that hypotonicity-evoked efflux of all organic osmolytes appears to be mediated by transport proteins which share a variety of properties more typical for channels than for carriers. A large diversity seems to exist, however, for the signalling mechanisms. Such diversity allows the cells to regulate the intracellular concentration of different organic osmolytes independently of each other, giving flexibility to the spectrum of osmotic responses. The site of release also varies from cell to cell; here conservation of organic osmolytes for future reuptake or further metabolism appears to be the major determinant.
Abstract: We investigated the cerebral blood flow (CBF) response to somatosensory stimulation. Stimulation of neuronal activity was performed by deflection (2-3/s) of the mystacial vibrissae in rats over a period of 60 s, and regional cortical CBF was measured continuously in the contralateral somatosensory cortex with laser-Doppler flowmetry. CBF within the somatosensory cortex was studied through the parietal bone thinned to translucency (n = 7) or through a closed cranial window with the dura mater removed (n = 7). In addition, the differential effect of anesthetics (halothane-N2O, n = 5; thiobutabarbiturate, n = 5; and alpha-chloralose, n = 7) on the CBF response to stimulation was investigated. After a rapid increase after stimulation onset (maximum reached within 2-3 s), CBF remained above baseline with a slight tendency to decrease despite continued stimulation. On termination of stimulation, CBF fell to near prestimulation values within 2-3 s. The following mean CBF responses above baseline during the 60-s stimulation period were obtained: halothane-N2O anesthesia, 25.4 +/- 5.9%; thiobutabarbiturate anesthesia, 10.6 +/- 2.4%; and alpha-chloralose anesthesia, 16.9 +/- 2.3 (through the translucent bone) and 16.2 +/- 2.9% (closed cranial window, dura removed). We conclude that coupling of CBF to neuronal function has a very high temporal resolution (\textless 3 s) and that whisker deflection in rats provides a physiological stimulus to study coupling with laser-Doppler flowmetry.
Abstract: OBJECTIVE: To define changes in intramyocardial pH and PCO2 during cardiac arrest and resuscitation. DESIGN: Prospective and observational trial. SETTING: Mammalian research laboratory utilizing a porcine model of cardiac arrest. SUBJECTS: Sixteen domestic pigs. INTERVENTIONS: Ventricular fibrillation was induced by an alternating current delivered to the epicardium. Precordial compression was begun after 3 mins of untreated cardiac arrest and was initially adjusted to produce a coronary perfusion pressure of 10 mm Hg. Electrical defibrillation was attempted after an additional 8 mins of precordial compression. MEASUREMENTS AND MAIN RESULTS: A rapid-response, ion-selective field effect transistor sensor was adapted for measurement of intramyocardial PCO2. Intramyocardial PCO2 progressively increased from 54 to 346 torr (7.2 to 46.1 kPa) during the 11-min interval of cardiac arrest. Intramyocardial hydrogen ion concentrations were simultaneously measured with a glass electrode. The intramyocardial hydrogen ion value increased from 65 nmol/L (pH 7.20) to 441 nmol/L (pH 6.38) over the same interval. The increases in myocardial PCO2 were inversely correlated with coronary perfusion pressure and with the likelihood of successful resuscitation. Within 30 mins after successful cardiac resuscitation, myocardial PCO2 had almost completely returned to prearrest levels. CONCLUSIONS: Striking increases in myocardial PCO2 and hydrogen ion values accompany the global myocardial ischemia of cardiac arrest. The increases in myocardial PCO2, rather than decreases in pH, reflected more precisely the hemodynamic efficacy of the resuscitation effort, correlated inversely with coronary perfusion pressure, and predicted the likelihood of successful resuscitation.
Abstract: OBJECTIVE: To examine the hypothalamic-pituitary sites of clomiphene citrate (CC) action in women with polycystic ovarian syndrome (PCOS). DESIGN: Prospective controlled trial. PATIENTS, PARTICIPANTS: Seventeen women with PCOS and 9 normal-cycling women. INTERVENTIONS: Subjects with PCOS received CC, 150 mg/d for 5 days. MAIN OUTCOME MEASURES: Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels and LH pulse characteristics and their response to gonadotropin-releasing hormone (GnRH, 10 micrograms) were examined before and after 3 days of CC in PCOS subjects during a 12-hour frequent sampling study (n = 8). Daily urinary estrone glucuronide and pregnanediol glucuronide levels after CC were compared with concentrations in normal-cycling women through one menstrual cycle. In another nine PCOS subjects, pituitary and ovarian hormonal cyclicity was monitored by daily blood sampling. RESULTS: Thirteen of 17 treated cycles were ovulatory with normal luteal phases. In the ovulatory cycles, serum LH, FSH, estradiol (E2), and estrone levels increased after CC. Luteinizing hormone pulse frequency was unchanged, but LH pulse amplitude increased significantly after CC. Both LH and FSH response to exogenous GnRH was significantly attenuated after CC treatment. In anovulatory cycles, serum LH, FSH, and E2 increased initially and then returned to baseline and remained unchanged for the ensuring 40 days. CONCLUSIONS: Clomiphene citrate-induced ovulation in women with PCOS is accompanied by increased secretion of LH and FSH with enhanced estrogen secretion. The increased LH pulse amplitude after CC, together with decreased pituitary sensitivity to GnRH, suggests a hypothalamic effect.
Abstract: In hypoproteinemia, increased interstitial hydrostatic and decreased interstitial colloid osmotic pressures, together with increases in lymph flow, prevent interstitial fluid volume expansion, thus forming the edema-preventing mechanisms. Transfer of a substantial portion of the interstitial protein pool into the vascular compartment by increased lymph flow is the major edema-preventing mechanism. The increase in interstitial pressure during progressive interstitial fluid volume expansion is limited by the high compliance of the interstitium in most tissues. During hypoproteinemia low interstitial colloid osmotic pressure and high interstitial compliance permit augmented changes in plasma volume in response to rapid increases (orthostasis, venous constriction) and decreases (hemorrhage) in capillary pressure. Nevertheless, these same forces are responsible for the finding that during the relatively slow changes in sodium balance that occur during volume retention or after treatment with diuretics, the change in plasma volume is relatively small. These phenomena are illustrated by observations gathered in experimental hypoproteinemia and in patients with the nephrotic syndrome.
Abstract: Many questions remain concerning the precise mechanism by which the luminal signal for renin secretion is transmitted from the MD to the JG granular cell. It appears likely that a number of pathways may participate in MD-mediated changes in renin release, some of the agents serving to modulate release, others participating directly in signal transmission. Collectively, the current information suggests a transmission pathway that involves several steps. First, changes occurring in MD NaCl transport, which result directly from alterations in luminal NaCl concentration, act to initiate the response. Second, conveyance of this signal to the extraglomerular mesangial cells via a change in the ionic environment of the EGM field and/or a paracrine factor produced by the MD (perhaps NO) appear likely to be the next step. The subsequent steps probably include changes in prostaglandin production by the EGM, and possible participation of other paracrine factors produced by both endothelial and extraglomerular mesangial cells.
Abstract: OBJECTIVES. The purpose of this study was to investigate the effects of lightning strikes on the cardiovascular system. BACKGROUND. A lightning strike can attack its victims in one of three ways: direct hit, splash or ground strike. The cardiovascular system can be affected directly by mechanical or electrical trauma during a direct hit or can be indirectly affected through effects on the total body with extensive catecholamine release or autonomic stimulation. Reported effects include hypertension, tachycardia, nonspecific electrocardiographic (ECG) changes including prolongation of the corrected QT (QTc) interval, transient T wave inversion and myocardial necrosis with creatine kinase-MB (CK-MB) fraction release. METHODS. Nineteen victims from five separate lightning strikes were studied over a 2-month period. Each patient was evaluated by serial ECG, CK-MB determinations and echocardiography. RESULTS. The early (0 to 72 h) effects of lightning were demonstrated on the ECG by ST segment elevation consistent with acute current of injury, prolonged QTc interval with direct hits and nonspecific ST and T wave changes. On echocardiography, segmental or global ventricular dysfunction was seen, and pericardial effusion was also detected. During the intermediate (3- to 14-day) period, new and often marked ECG changes consistent with pericarditis or ischemia were seen. No new echocardiographic changes were detected, however, and the early abnormalities including severe left ventricular dysfunction with cardiogenic shock have reversed. The late (1 to 12 months) period revealed only one patient with long-term sequelae (recurrent pericarditis that persisted for 5 months). CONCLUSIONS. Unless both entrance and exit sites are limited to the lower limbs, direct and splash lightning strikes cause myocardial damage as assessed by abnormal serum enzyme determinations or abnormal echocardiographic findings. Only direct hits resulted in echocardiographic abnormalities or a prolonged QTc interval. The degree of myocardial injury can be severe with left and right ventricular ejection fraction \textless 15% and can be reversible.
Abstract: Increased tissue oxygen delivery may play a role in the increased vascular resistance that develops in volume-expanded hypertension. This hypothesis was tested by decreasing the affinity of hemoglobin for oxygen in dogs to increase unloading of oxygen to the tissues. Six chronically instrumented dogs were studied before and for 7 days after partial exchange transfusion with red blood cells modified by incorporation of inositol hexaphosphate, which, 1 h after exchange, increased the PO2 value at which hemoglobin is half-saturated with oxygen (P50) to 38.8 +/- 2.1 mmHg from a control value of 31 +/- 1.5 mmHg. Cardiac output (electromagnetic flowmeter) fell to 92.5 +/- 7.4 ml.kg-1.min-1 after 2-4 h from control values between 120.2 +/- 5.7 and 125.8 +/- 4.6 ml.kg-1.min-1. One day later, cardiac output was still significantly decreased to 104.0 +/- 5.9 ml.kg-1.min-1. As P50 returned to control over the next few days, so did cardiac output. Two to four hours after exchange, total peripheral resistance was increased to 1,144 +/- 73 mmHg.l-1.kg.min from control values between 762 +/- 26 and 790 +/- 32 mmHg.l-1.kg.min. It was still increased to 993 +/- 51 mmHg.l-1.kg.min after 1 day. Oxygen consumption did not change significantly. Cardiac output and peripheral resistance changes were significantly different from those measured in a control group of six dogs receiving exchange transfusion with sham-shifted red blood cells without significant P50 changes. These results suggest that an increase in tissue oxygen delivery can raise total peripheral resistance in dogs in the absence of primary changes in fluid volumes, blood flow, or blood pressure.
Abstract: BACKGROUND. More than 300,000 people die each year of cardiac arrest. Studies have shown that raising vascular pressures during cardiopulmonary resuscitation (CPR) can improve survival and that vascular pressures can be raised by increasing intrathoracic pressure. METHODS. To produce periodic increases in intrathoracic pressure, we developed a pneumatically cycled circumferential thoracic vest system and compared the results of the use of this system in CPR (vest CPR) with those of manual CPR. In phase 1 of the study, aortic and right-atrial pressures were measured during both vest CPR (60 inflations per minute) and manual CPR in 15 patients in whom a mean (+/- SD) of 42 +/- 16 minutes of initial manual CPR had been unsuccessful. Vest CPR was also carried out on 14 other patients in whom pressure measurements were not made. In phase 2 of the study, short-term survival was assessed in 34 additional patients randomly assigned to undergo vest CPR (17 patients) or continued manual CPR (17 patients) after initial manual CPR (duration, 11 +/- 4 minutes) had been unsuccessful. RESULTS. In phase 1 of the study, vest CPR increased the peak aortic pressure from 78 +/- 26 mm Hg to 138 +/- 28 mm Hg (P \textless 0.001) and the coronary perfusion pressure from 15 +/- 8 mm Hg to 23 +/- 11 mm Hg (P \textless 0.003). Despite prolonged unsuccessful manual CPR, spontaneous circulation returned with vest CPR in 4 of the 29 patients. In phase 2 of the study, spontaneous circulation returned in 8 of the 17 patients who underwent vest CPR as compared with only 3 of the 17 patients who received continued manual CPR (P = 0.14). More patients in the vest-CPR group than in the manual-CPR group were alive 6 hours after attempted resuscitation (6 of 17 vs. 1 of 17) and 24 hours after attempted resuscitation (3 of 17 vs. 1 of 17), but none survived to leave the hospital. CONCLUSIONS. In this preliminary study, vest CPR, despite its late application, successfully increased aortic pressure and coronary perfusion pressure, and there was an insignificant trend toward a greater likelihood of the return of spontaneous circulation with vest CPR than with continued manual CPR. The effect of vest CPR on survival, however, is currently unknown and will require further study.
Abstract: Recent investigations have demonstrated that there is a sustained reduction in arterial blood pressure after a single bout of exercise, ie, postexercise hypotension (PEH). The purpose of this discussion is to integrate the available information on this topic and to review studies using sustained stimulation of somatic afferents in experimental rats as a model to study the role of somatic afferents in PEH. PEH occurs in response to several types of large-muscle dynamic exercise (ie, walking, running, leg cycling, and swimming) at submaximal intensities greater than 40% of peak aerobic capacity and exercise durations generally between 20 and 60 minutes. PEH is observed in both normotensive and hypertensive humans and in spontaneously hypertensive rats but is generally greater in magnitude in hypertensive subjects. The maximal exercise-induced reductions in systolic and diastolic arterial blood pressures have been on average 18 to 20 and 7 to 9 mm Hg, respectively, in hypertensive humans and 8 to 10 and 3 to 5 mm Hg, respectively, in normotensive humans. PEH has been reported to persist for 2 to 4 hours under laboratory conditions. Whether PEH is sustained for a prolonged period of time under free-living conditions remains controversial, although the results of one study indicate that PEH can persist for up to 13 hours. Possible mechanisms involved in mediating postexercise and poststimulation reductions in arterial blood pressure include decreased stroke volume and cardiac output; reductions in limb vascular resistance, total peripheral resistance, and muscle sympathetic nerve discharge; group III somatic afferent activation; altered baroreceptor reflex circulatory control; reduced vascular responsiveness to alpha-adrenergic receptor-mediated stimulation; and activation of endogenous opioid and serotonergic systems. It appears that the magnitude of PEH in hypertensive subjects is clinically significant; however, more investigation is required to determine if the duration is sufficient under real-life conditions to contribute to the reduction in blood pressure observed with chronic exercise conditioning.
Abstract: Aortic blood flow, heart rate, blood pressure and blood flow distribution were measured in 10 chronically hypoxic rats (3 weeks, PB 370-380 Torr) breathing 10% O2 (chronic hypoxia) and after 30 min of breathing air (acute normoxia). Controls were 10 normoxic littermates breathing air (normoxia) and 10% O2 for 30 min (acute hypoxia). Acute hypoxia resulted in increased aortic blood flow and heart rate, and decreased total peripheral resistance. Blood flow and oxygen supply to vital organs increased, indicating that blood flow redistribution plays an important role in oxygen supply. In chronic hypoxia, aortic blood flow and heart rate remained elevated, and total peripheral resistance remained decreased. Blood flow distribution returned towards normoxia levels. Oxygen supply was maintained via increased arterial oxygen concentration. Acute normoxia resulted in decreased aortic blood flow and heart rate, and increased blood pressure and total peripheral resistance. Blood flow distribution was similar to that of chronic hypoxia except skeletal muscles, in which blood flow decreased markedly. Oxygen supply remained unchanged or increased.
Abstract: Thoracic procedures once requiring open thoracotomy are now being performed with video-assisted thoracoscopy. To visualize adequately the intrathoracic structures, creation of an artificial pneumothorax by carbon dioxide insufflation under positive pressures has been advocated. We hypothesized that positive-pressure insufflation during thorascopy would cause significant hemodynamic compromise. Eight healthy female pigs underwent general endotracheal anesthesia and placement of monitoring lines. After placement of a thorascope, baseline hemodynamic measurements were obtained at 0 mm Hg (atmospheric pressure). Measurements were taken randomly at 5, 10, and 15 mm Hg using carbon dioxide insufflation after stabilization at each pressure. Data were analyzed using Page’s test for noparametric variables. Insufflation pressures of 5 mm Hg or greater resulted in significant decreases in cardiac index, mean arterial pressure, stroke volume, and left ventricular stroke work index, whereas central venous pressure increased (p \textless 0.001). Changes in heart rate were not significant. We do not recommend routine positive-pressure insufflation during thorascopy because of the significant hemodynamic compromise in our experimental model.
Abstract: The in vivo effects on hemoglobin (Hb)-O2 affinity and tissue PO2 were investigated after intraperitoneal administration of 2-[4-(((dichloroanilino)-carbonyl)methyl)phenoxyl]-2-methyl propionic acid (RSR4; 150 mg/kg) or its 3,5-dimethyl derivative (RSR13; 300 mg/kg) in C3Hf/Sed mice. The Hb-O2 dissociation curve was plotted from tail vein blood samples using an O2 dissociation analyzer before and up to 160 min after compound administration. Twenty to 40 min after injection, the PO2 at 50% saturation of hemoglobin (Hb P50) increased by a mean of 25% (range 18-31%) after RSR4 and 53% (range 36-76%) after RSR13. Tissue PO2 was continuously measured using an O2 microelectrode in thigh muscle before and up to 40 min after RSR4 or RSR13 injection. Twenty to 40 min after administration, tissue PO2 increased by a mean of 78% (range 30-127%) after RSR4 and 66% (range 39-97%) after RSR13 administration in anesthetized mice. No change in tissue PO2 was seen in anesthetized controls.
Abstract: The left ventricle (LV) and arterial system are nearly optimally coupled to produce stroke work (SW) at rest. However, the effect of exercise on the coupling between the LV and arterial system has not been directly determined. We evaluated 11 dogs who were instrumented to determine LV volume from three diameters. The LV end-systolic pressure (Pes)-volume (Ves) relation was determined by transient caval occlusion at rest and while the animals ran at 5-7 mph on a treadmill. During exercise, the Pes-Ves relation was shifted toward the left and the slope [end-systolic elastance (Ees)] increased from 7.7 +/- 2.8 to 12.7 +/- 4.2 (SD) mmHg/ml (P \textless 0.05). The arterial end-systolic elastance (Ea), calculated as Pes divided by stroke volume, increased during exercise (8.8 +/- 3.0 to 10.9 +/- 4.7 mmHg/ml, P \textless 0.05). The ratio of Ees to Ea increased during exercise from 0.89 +/- 0.31 to 1.27 +/- 0.12 (P \textless 0.05). The portion of the pressure-volume area expressed as SW increased during exercise from 0.63 +/- 0.07 to 0.69 +/- 0.10 (P \textless 0.05). After adrenergic blockade, the Ees-to-Ea ratio was not significantly altered during exercise (0.90 +/- 0.24 vs. 0.83 +/- 0.15, P = NS). At rest and during exercise, both with intact reflexes and after beta-adrenergic blockade, the ratio of Ees to Ea remained within the range in which SW is \textgreater 95% of maximum. We conclude that during exercise, beta-adrenergic stimulation shifts the LV Pes-Ves relation to the left with an increased slope. This more than offsets the increase in Ea.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: OBJECTIVE: To compare the acid-base status of blood obtained from the tibial intraosseous site with that status obtained from a central venous site during stead- and low-flow states in a piglet model. DESIGN: A prospective, observational study. SETTING: Animal laboratory at a university medical center. SUBJECTS: Nine 2-day-old piglets. INTERVENTIONS: Animals were anesthetized, intubated, and mechanically ventilated. A thermodilution pulmonary artery catheter was inserted via the right internal jugular vein and directed into the pulmonary artery. An arterial catheter was inserted into the right carotid artery and an intraosseous needle was inserted into the proximal tibial marrow cavity. Cardiorespiratory arrest was induced by discontinuation of ventilation. The animals were subsequently resuscitated by precordial compressions and ventilation. Blood samples were obtained from central venous and intraosseous sites during steady state and during resuscitation (low-flow state). RESULTS: No significant differences (p \textless .05) were found for pH, PCO2, and bicarbonate concentration when values that were obtained from the central venous and intraosseous sites were compared during steady- and low-flow states. CONCLUSIONS: The acid-base status of intraosseous blood is similar to that status of central venous blood. Intraosseous blood gas values may be an acceptable alternative to central venous blood gas values in judging central acid-base status during cardiopulmonary resuscitation.
Abstract: The effect of prolonged aortic depressor nerve (ADN) stimulation on carotid sinus baroreflex regulation of arterial pressure (AP) and renal sympathetic nerve activity (RSNA) was examined in anesthetized rabbits. Ramp increases in carotid sinus pressure (CSP) were repeated before and after 5 min of bilateral ADN stimulation. One minute after ADN stimulation the curve relating AP to CSP had shifted up and to the right, characterized by significant increases (P \textless 0.05) in the maximum (91 +/- 2 to 101 +/- 3 mmHg; mean +/- SE), midpoint (118 +/- 7 to 125 +/- 8 mmHg CSP), and minimum (45 +/- 3 to 53 +/- 4 mmHg) of the AP reflex curve. There was a parallel shift downward of the curve relating RSNA to CSP, characterized by significant decreases in the maximum [100 +/- 0 to 66 +/- 8% of maximum control RSNA value (%max)], the range (90 +/- 2 to 59 +/- 8%max), and the gain (-1.0 +/- 0.2 to -0.5 +/- 0.1%max/mmHg) of the RSNA reflex curve. Values returned to control within 10 min of cessation of ADN stimulation. These results suggest that central neurons processing baroreflex information from one set of mechanoreceptors can be reset by convergent signals arising from another baroreceptor site.
Abstract: Persisting coronary vasoconstrictor tone that is responsive to exogenous adenosine administration has been demonstrated during myocardial ischemia. Therefore, the role and extent of endogenous adenosine-mediated coronary vasodilation in opposing coronary vasoconstriction within regions of ischemic myocardium was investigated in 10 chronically instrumented exercising dogs. Studies were performed on dogs with left circumflex coronary artery stenosis during treadmill exercise (6.5 km/h, 6% grade), while myocardial blood flow was measured with radioactive microspheres. Blood flow was measured before and again after inhibition of the effects of endogenously produced adenosine through combined inactivation of adenosine and adenosine receptor antagonism by the administration of intracoronary adenosine deaminase (ADA) (5 micrograms.kg-1 x min-1 x 10 min) plus 8-phenyltheophylline (8-PT) (5 mg/kg i.v.), respectively. Coronary perfusion pressure was held equal during both conditions at approximately 41 mmHg with a hydraulic occluder. During exercise in the presence of a coronary stenosis, blood flow was reduced in all layers of myocardium in regions supplied by the stenosed left circumflex coronary artery compared with blood flow in regions of myocardium supplied by the nonstenotic left anterior descending coronary artery. After ADA plus 8-PT, myocardial blood flow (in ml.min-1 x g-1) was further reduced in all layers of myocardium in regions supplied by the stenotic left circumflex coronary artery compared with baseline (subendocardial layer 0.44 +/- 0.09 vs. 0.67 +/- 0.13 ml.min-1 x g-1, mean transmural flow 0.92 +/- 0.13 vs. 1.25 +/- 0.2 ml.min-1 x g-1, both P \textless 0.05). Blood flow in regions of myocardium supplied by the nonstenotic left anterior descending coronary artery were unchanged following ADA plus 8-PT.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: In the resting awake dog a continuous-wave Doppler flow transducer on the right bronchoesophageal artery inscribes a sharp early systolic spike and low flow in late systole and throughout diastole, indicating a highly resistive bed. An analysis of autonomic factors using intravenous, cumulative, and randomly applied cholinoceptor, beta 1- and beta 2-adrenoceptor, and alpha 1- and alpha 2-adrenoceptor antagonists indicates that the low vascular conductance is due to cholinoceptor and alpha 1- and alpha 2-adrenoceptor effects in a ratio 3.6:1. No beta-adrenoceptor tone is present. Sighing behavior invokes a transient (\textless 2 s) fall in intrapleural pressure (and thus rise in bronchovascular transmural pressure) of 10-30 mmHg, which is followed by a two- to threefold increase over 30 s in bronchial flow and conductance, an effect simulated in 50% of dogs when bronchovascular transmural pressure is acutely raised and maintained over 40-60 s by inflating an intra-aortic balloon distal to the origin of the bronchial artery. Autonomic blockade has no effect on bronchovascular dilatation evoked either by sighing or by balloon inflation. It is concluded that, in the resting bronchial circulation, there exists strong cholinoceptor and alpha-adrenoceptor-based vasoconstrictor activity which can be overpowered by strong nonadrenergic noncholinergic local vasodilator reflexes evoked by sudden changes in intrathoracic transmural pressure possibly acting on stretch-sensitive sensory nerve endings containing substance P, calcitonin gene-related peptide, and neurokinins. The tonic vasoconstrictor but not the sigh-evoked vasodilator effects are sensitive to pentobarbital sodium anesthesia.
Abstract: Orthostatic intolerance may result from either an abnormally large postural decrease in central blood volume, cardiac filling pressures, and stroke volume, or inadequate neurohumoral responses to orthostasis. Endurance athletes have been reported as having a high incidence of orthostatic intolerance, which has been attributed primarily to abnormalities in baroreflex regulation of heart rate and peripheral resistance. In this review, we present evidence that athletes also have structural changes in the cardiovascular system that although beneficial during exercise, lead to an excessively large decrease in stroke volume during orthostasis and contribute to orthostatic intolerance. A unifying hypothesis based on cardiac mechanics that may explain the divergence of findings in conditions such as bed rest or spaceflight, and short- and long-term endurance training is presented.
Abstract: The serum pharmacokinetics of recombinant human inhibin A (rh-inhibin A) and rh-activin A were examined in immature female Sprague Dawley-derived rats after iv and sc injection of the drugs. After iv administration of rh-inhibin A (120 micrograms/kg), the serum concentrations were described by a biexponential equation. The weight-normalized clearance was 21.3 ml/min.kg, and the initial (t1/2 alpha) and terminal (t1/2 beta) half-lives were 2.9 min and 37.9 min, respectively. Subcutaneous administration of 120 micrograms/kg rh-inhibin A resulted in a peak serum concentration of 10.6 ng/ml at 30.8 min after injection. Approximately 24% of the sc administered material was absorbed. Serum concentrations of rh-activin A also declined biexponentially after iv injection of the drug (120 micrograms/kg). The clearance of rh-activin A was 5.1 ml/min.kg, the t1/2 alpha was 6.1 min, and the t1/2 beta was 46.3 min. The peak serum concentration of rh-activin A (104.7 ng/ml) was achieved 24.7 min after sc delivery of the drug. The bioavailability of the sc dose was 38%. Iodinated rh-inhibin A and rh-activin A were used to examine the serum forms and metabolites of the drugs. [125I]rh-inhibin A and [125I]rh-activin A associated with two serum-binding proteins. Within 2 min of iv injection, the labeled hormones bound follistatin and alpha-2-macroglobulin. Even though rh-inhibin A and rh-activin A are structurally similar and appear to bind to the same serum proteins, their disposition in the immature rat differ.
Abstract: The goal of this study was to elucidate the ability of the left ventricle to accommodate an increase in preload (Frank-Starling mechanism) in the presence of congestive heart failure (CHF) but in the absence of the complicating effects of hypertrophy and fibrosis. To accomplish this, the effects of volume loading were examined in eight conscious dogs during the control state and after 3 wk of right ventricular pacing (240 beats/min). CHF increased heart rate (by 16 +/- 5 from 92 +/- 5 beats/min), left ventricular (LV) end-diastolic pressure (by 17 +/- 2 from 10 +/- 1 mmHg), and LV end-diastolic volume (EDV; by 23 +/- 4 from 57 +/- 3 ml). Despite reduced LV ejection fraction (from 54 +/- 3 to 31 +/- 3%), there was no significant change in cardiac output (2.5 +/- 0.3 l/min) compared with control (2.7 +/- 0.2 l/min). Stroke volume was preserved (control 19 +/- 2 ml; CHF 18 +/- 2 ml) at a constant heart rate by a shift to the right in the relationship between LV stroke volume and EDV, indicating the importance of chronic ventricular dilatation in maintaining pump performance. In the control state, acute volume load increased LV EDV (by 17 +/- 2 ml) and stroke volume (by 11 +/- 2 ml), whereas in CHF it did not increase LV EDV or stroke volume. Scanning electron microscopy revealed areas of reduced collagen weave pattern surrounding myofibers. Myocyte cross-sectional area by transmission electron microscopy was significantly reduced, and there were multiple electron-dense expansions of the Z lines with disruption of the normal lateral sarcomere alignment. These morphological findings suggest that chronic ventricular dilatation utilized in CHF results from myocyte stretch and morphological intracellular rearrangement. Furthermore, the failing heart cannot further augment stroke volume by acutely increasing EDV in CHF, suggesting that the Frank-Starling reserve is essentially exhausted.
Abstract: Serum thyroglobulin (Tg) data are presented for 47 infants with congenital thyroid disorders. Abnormal elevation of serum Tg (\textgreater 250 micrograms/L) occurred in 17% of the population studied, whereas values in excess of 1,000 micrograms/L were demonstrated in 11% of infants. The latter group includes the first report of supraphysiologic Tg elevation in an infant with thyroid gland ectopia, and the highest reported thyroglobulin level in the syndrome of generalized thyroid hormone resistance in an infant homozygous for a novel deletion in the c-erbA beta receptor. Mechanisms involved in the pathogenesis of Tg elevation are discussed. We conclude that Tg elevation in congenital thyroid disorders is more common than previously recognized, and values \textgreater 1,000 micrograms/L identify infants with a spectrum of anatomic and biochemical abnormalities.
Abstract: OBJECTIVE: To study the pharmacokinetics of dopamine in hemodynamically stable adult patients. DESIGN: Prospective clinical study. SETTING: University hospital intensive care unit. PATIENTS: Fourteen patients (aged 43 to 73 yrs) recovering from esophageal surgery. INTERVENTION: Dopamine was infused and blood samples were collected. MEASUREMENTS AND MAIN RESULTS: Plasma dopamine concentrations were measured at steady state and subsequently at the end of the dopamine infusion using high-performance liquid chromatography. Clearances, volume of distribution, mean residence times, half-lives, and elimination and distribution rate constants were derived. The clearances were independent of the infusion rate at 1, 3, and 6 micrograms/kg/min, and ranged between 0.050 and 0.056 L/min/kg. A two-compartment open model was fitted to the postinfusion plasma concentration data obtained at 3 and 6 micrograms/kg/min. On average, the steady-state volume of distribution and the apparent terminal elimination half-life increased with the dose: 0.78 to 1.58 L/kg, respectively, and 22.1 to 37.9 mins, respectively, for the rates of 3 and 6 micrograms/kg/min. The rate constant associated with the uptake of dopamine into the peripheral compartment (K12) was on average four to five times higher than the rate constant associated with the reverse process (K21). CONCLUSIONS: The redistribution of dopamine into the central compartment could be the main factor involved in the apparent terminal elimination of dopamine from plasma. Due to the relative rates of distribution and elimination, the attainment of a steady-state plasma concentration of dopamine should only depend on the terminal half-life. These results, which remain to be validated in a greater number of patients, indicate that the attainment of 90% of the plateau (i.e., in 3.3 half-lives) would require 70 to 125 mins, depending on the infusion rate.
Abstract: We developed a novel method to stimulate the sympathetic innervation of the isolated, perfused rat hind limb to investigate whether a subpressor concentration of angiotensin II (Ang II) facilitates noradrenergic transmission in the vascular bed to skeletal muscle. We electrically stimulated the lumbar sympathetic trunk while perfusing the preparation with artificial medium. Seventy-five percent of the resulting frequency-dependent increases in perfusion pressure were mediated by alpha 1-adrenergic receptors. Ang II (10 nM) significantly enhanced the effects of nerve stimulation at 1 and 10 Hz (by 42% and 35%, respectively). At a supramaximal stimulation frequency (20 Hz), Ang II prolonged the duration of the response without changing the peak increase in pressure. The reuptake inhibitor cocaine did not influence the effects of Ang II at 1 and 10 Hz but blocked the effect at 20 Hz. To control for nonspecific synergism with norepinephrine, we compared Ang II with vasopressin. Both peptides potentiated the pressor response to exogenous norepinephrine; however, vasopressin did not change the pressor response to nerve stimulation at any frequency. We conclude that Ang II, but not vasopressin, facilitates noradrenergic transmission in skeletal muscle resistance vessels, independent of its direct vasoconstrictor activity. The neurovascular preparation we describe may be useful in addressing other hypotheses concerning sympathetic transmission in skeletal muscle resistance vessels.
Abstract: OBJECTIVE: To study blood pressure and echocardiographically determined left ventricular mass in children born to mothers who had been hypertensive during the pregnancy and to assess the influence of a maternal factor for hypertension on blood pressure and left ventricular mass. METHODS: Blood pressure was measured and M-mode echocardiography was performed in 42 children (aged 10.6-16.4 years) born to mothers who had been hypertensive during the pregnancy. For comparison, a control group of 17 children born after a normotensive pregnancy was used. RESULTS: Children born to mothers who had had a hypertensive pregnancy and who showed sustained hypertension during a follow-up, had higher systolic (P \textless 0.001) and diastolic (P \textless 0.05) blood pressure. No differences in left ventricular mass were seen. There was a significant correlation between left ventricular mass and systolic blood pressure (r = 0.40; P \textless 0.01). In multivariate analyses both systolic and diastolic blood pressure were independently related to a familial factor for hypertension, whereas left ventricular mass was not related to a familial factor for hypertension. CONCLUSIONS: Children born after a hypertensive pregnancy have higher blood pressure than children born after a normotensive pregnancy. A familial factor for hypertension was correlated with blood pressure, but not left ventricular mass in the children studied.
Abstract: To investigate the role of sympathoadrenergic activity on glucose production (Ra) during exercise, eight healthy males bicycled 20 min at 41 +/- 2 and 74 +/- 4% maximal O2 uptake (VO2max; mean +/- SE) either without (control; Co) or with blockade of sympathetic nerve activity to liver and adrenal medulla by local anesthesia of the celiac ganglion (Bl). Epinephrine (Epi) was in some experiments infused during blockade to match (normal Epi) or exceed (high Epi) Epi levels during Co. A constant infusion of somatostatin and glucagon was given before and during exercise. At rest, insulin was infused at a rate maintaining euglycemia. During intense exercise, insulin infusion was halved to mimic physiological conditions. During exercise, Ra increased in Co from 14.4 +/- 1.0 to 27.8 +/- 3.0 mumol.min-1.kg-1 (41% VO2max) and to 42.3 +/- 5.2 (74% VO2max; P \textless 0.05). At 41% VO2max, plasma glucose decreased, whereas it increased during 74% VO2max. Ra was not influenced by Bl. In high Epi, Ra rose more markedly compared with control (P \textless 0.05), and plasma glucose did not fall during mild exercise and increased more during intense exercise (P \textless 0.05). Free fatty acid and glycerol concentrations were always lower during exercise with than without celiac blockade. We conclude that high physiological concentrations of Epi can enhance Ra in exercising humans, but normally Epi is not a major stimulus. The study suggests that neither sympathetic liver nerve activity is a major stimulus for Ra during exercise. The Ra response is enhanced by a decrease in insulin and probably by unknown stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: It has been shown that nitric oxide (NO) is synthesized in the central nervous system as well as in vascular endothelial cells. However, the physiological role of NO in cardiovascular regulation by the central nervous system remains unclear. This objective of this study was to examine the possibility that NO plays a role in neural transmission in the nucleus tractus solitarius (NTS) and thus contributes to control of sympathetic nerve activity in rabbits. We examined the effects of NG-monomethyl-L-arginine (L-NMMA), an inhibitor of the formation of NO from L-arginine, microinjected into the NTS on arterial pressure (AP), heart rate (HR), and renal sympathetic nerve activity (RSNA). L-NMMA increased AP and RSNA in rabbits with intact as well as denervated sinoaortic baroreceptors and vagi. L-NMMA increased HR only in rabbits with sinoaortic denervation and vagotomy. Pretreatment with L-arginine microinjected into the NTS, which did not alter baseline AP, HR, and RSNA, prevented the increases in AP and RSNA evoked with subsequent L-NMMA. Pretreatment with D-arginine did not alter the effects of subsequent L-NMMA injections into the NTS. The gain of arterial baroreflex control of RSNA assessed by the slope of the regression line relating changes in AP and those in RSNA caused by intravenous phenylephrine or nitroglycerin did not differ before and after microinjections of L-NMMA. L-NMMA microinjected into the area postrema did not alter AP, HR, or RSNA. These results suggest that in rabbits NO is involved in the mechanism in the NTS that mediates tonic inhibition of RSNA.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: 1. In spontaneously breathing rats anaesthetized with Saffan, we have investigated the role of vasopressin in the cardiovascular responses evoked by systemic hypoxia (breathing 8 or 6% O2 for 5 min). 2. Breathing 8% O2 evoked an increase in respiratory frequency and tidal volume; arterial O2 pressure (Pa,O2) fell to 37 mmHg and arterial CO2 pressure (Pa,CO2) fell to 30 mmHg. Concomitantly, there was a fall in arterial pressure, tachycardia and increases in femoral and renal vascular conductances indicating net vasodilatation in skeletal muscle and kidney. The vasopressin V1-receptor antagonist, d(CH2)5Tyr(Me)-arginine vasopressin (20 micrograms kg-1 i.v.), had no significant effect on the baseline values of any recorded variables, nor on the respiratory or blood gas changes evoked by 8% O2. However, it accentuated the fall in arterial pressure and the increase in femoral vascular conductance (+22 vs. +77% at the 5th minute) produced by 8% O2, but had no significant effect on the increase in renal vascular conductance. 3. Breathing 6% O2 evoked qualitatively similar responses as 8% O2 but Pa,O2 fell to 33 mmHg and Pa,CO2 fell to 28 mmHg and the respiratory and cardiovascular changes tended to be larger than those evoked by 8% O2. Again the V1-receptor antagonist accentuated the hypoxia-induced fall in arterial pressure and increase in femoral vascular conductance (+5 vs. +76% at the 5th minute). 4. Infusion of vasopressin (1.5 ng min-1 kg-1 i.v.) for 5 min with the aim of producing a plasma concentration comparable to that reached during 8% O2, induced a rise in arterial pressure (9%), bradycardia (-5%) and a decrease in femoral (-11%) and renal vascular conductance (-4%). 5. These results suggest that vasopressin released during hypocapnic hypoxia helps to limit the evoked fall in arterial pressure by exerting a vasoconstrictor influence on skeletal muscle.
Abstract: Normal and anemic dog gracilis muscles were compared at equal O2 uptake rates (VO2) to locate the principal site of resistance to diffusive O2 transport. Anemia halved the hematocrit and the number of red blood cells per square millimeter of muscle cross section. Flow doubled in anemia, and flow times arterial O2 content, PO2 of effluent blood, and O2 extraction per red blood cell were approximately the same as control. Nevertheless, intracellular PO2 was significantly lower in anemia. At any instant the aggregate red blood cell surface area for O2 release was about half normal. Because the flux (VO2) was the same as control, the driving force for diffusion from red blood cell to myocyte should have doubled. An estimate of the total driving force from red blood cell to mitochondria was greater in anemia. This increase was much less than a factor of 2 because lower intracellular PO2 increases myoglobin-facilitated diffusion, thus decreasing resistance inside the myocyte. The role of myoglobin and the coupling of convective to diffusive transport are discussed. We conclude that the principal resistance to O2 diffusion lies outside the myocyte.
Abstract: A humoral inhibitor of the membrane calcium pump was studied in plasma from 28 normal controls, 33 patients receiving long-term hemodialysis, and 26 with chronic renal failure (CRF; creatinine clearance range was 6 to 97 ml/min). Calcium pump activity was measured as the rate of Sr2+ efflux in normal erythrocytes (RBCs) loaded with Sr2+ (a substitute of Ca2+ in the calcium pump). Plasma, and plasma ultrafiltrates from hemodialysis patients strongly inhibited calcium pump activity compared with controls without plasma (36 +/- 18 vs. 25 +/- 12, %INHIBITION/CONTROL, P \textless 0.05). Inhibition markedly decreased with acute hemodialysis (16 +/- 12 vs. 5 +/- 14, %INHIBITION/NORMAL PLASMA, N = 15, P \textless 0.001). In CRF, degree of inhibition correlated with the serum creatinine concentration (r = 0.75, P \textless 0.001). A kinetic study showed that plasma decreased the maximal rate of the Ca2+ pumps (Vmax) without affecting the apparent affinity for internal cations (KSr). Moreover, the plasma inhibitory factor had a low molecular weight, and was dialyzable and heat stable. In conclusion, we found evidence for an RBC membrane calcium pump inhibitor in uremic plasma, which correlates with the degree of renal insufficiency. Possibly, it may increase calcium content in RBCs and other cells and could thus be related to uremic toxicity and/or hypertension.
Abstract: Elimination half-life is the pharmacokinetic parameter used most commonly to describe duration of pharmacologic action, including that expected of intravenous anesthetic drugs administered by continuous infusion. Little consideration has been given, however, to the relevance of elimination half-life in describing plasma (central compartment) drug concentrations in the context of relevant infusion durations. Therefore, simulations were performed with multicompartment pharmacokinetic models for six intravenous anesthetic drugs. These models had elimination half-lives ranging from 111 to 577 min. The input in each simulation was an infusion regimen designed to maintain a constant plasma drug concentration for durations ranging from 1 min to 8 h and until steady state. The time required for the plasma drug concentration to decline by 50% after terminating each infusion in each of the models was determined and was designated the "context-sensitive half-time," where "context" refers to infusion duration. The context-sensitive half-times were markedly different from their respective elimination half-lives and ranged from 1 to 306 min. The half-times were explained by posing each pharmacokinetic model in the form of a hydraulic model. These simulations demonstrate that elimination half-life is of no value in characterizing disposition of intravenous anesthetic drugs during dosing periods relevant to anesthesia. We propose that context-sensitive half-times are a useful descriptor of postinfusion central compartment kinetics.
Abstract: We labeled rat adipocyte cell surface glucose transporters with an impermeable, photoreactive glucose analogue, 1,3-bis-(3-deoxy-D-glucopyranose-3-yloxy)-2-propyl 4-benzoylbenzoate (B3GL) and its radioactive tracer [3H]B3GL. The labeling did not affect glucose transporter subcellular distribution in basal and insulin-stimulated adipocytes. When basal or insulin-stimulated adipocytes were labeled with [3H]B3GL and incubated at 37 degrees C in steady state, labeled GLUT4 was rapidly reduced at the cell surface and stoichiometrically recovered in microsomes without any change in GLUT4 protein levels in either pool. The labeled GLUT4 equilibrium exchange was found to be a simple first order process describable by two first order rate constants, one for internalization (k(in)) and the other for externalization (kex). Insulin affected both rate constants, reducing k(in) by 2.8-fold and increasing kex by 3.3-fold. It is concluded that GLUT4 constantly and rapidly recycles in adipocytes between the cell surface and its storage pool, and insulin increases the cell surface GLUT4 level in rat adipocytes by modulating both the internalization and the externalization steps of constitutively recycling GLUT4.
Abstract: BACKGROUND: Impaired blood flow below certain critical levels and an insufficient supply of energy-rich substrates cause failure of neuronal function, triggering biochemical disturbances that eventually lead to ischemic cell damage. SUMMARY OF REVIEW: This article reviews experimental studies that attempted to define those ischemic thresholds using functional and histological markers and, more recently, chemical markers of ischemic damage. CONCLUSIONS: The duration of ischemia causing irreversible cell damage still is ill defined. Reestablishment of sufficient perfusion must be induced very early after an ischemic attack to ameliorate the potentially harmful biochemical sequelae of transient ischemia.
Abstract: Absence of oxygen to the brain for even a very few minutes results in loss of consciousness and can cause permanent injury. Can the wanderer to the limits of earth-bound hypoxia suffer similar harm from more prolonged exposure to milder hypoxia that does not cause loss of consciousness? I shall review the results from studies where neurobehavioral function has been compared in mountaineers before and after return from great heights and in individuals with chronic pulmonary disease before and after prolonged, continuous oxygen therapy. Many (although not all) of these studies report mild impairment of neurobehavioral function after fairly prolonged hypoxic exposure. Impairment was manifest by deficits in memory storage and recall, aphasia, concentration, and finger tapping speed; the last deficit was still detectable a year later in one group of mountaineers. Limited evidence suggests that climbers with a high ventilatory response to hypoxia (HVR) may be more susceptible to impairment than those with a lower HVR.
Abstract: This study tested the effects of sympathetically mediated changes in blood flow to active muscles on muscle O2 uptake (VO2) in humans. Four minutes of graded (15-80% of maximum voluntary contraction, MVC) rhythmic handgrip exercise were performed. Forearm blood flow (FBF) (plethysmography) and deep vein O2 saturation were measured each minute. Forearm O2 uptake was calculated using the Fick principle. In protocol 1, exercise was performed while supine and again while upright to augment sympathetic outflow to the active muscles. Standing reduced FBF at rest from 3.6 to 2.2 ml.100 ml-1.min-1 (P \textless 0.05). During light exercise (15-40% MVC) FBF was unaffected by body position. Standing reduced FBF (P \textless 0.05) from 36.0 to 25.2 ml.100 ml-1.min-1 and forearm VO2 from 38.2 to 28.1 ml.kg-1.min-1 during the final work load. In protocol 2, exercise was performed while supine before and after local anesthetic block of the sympathetic nerves to the forearm. Sympathetic block increased FBF at rest from 3.1 to 8.9 ml.100 ml-1.min-1 (P \textless 0.05), and FBF was higher during all work loads At 70-80% of MVC sympathetic block increased FBF from 35.4 to 50.7 ml.100 ml-1.min-1 (P \textless 0.05), and forearm VO2 from 45.5 to 54.2 ml.kg-1.min-1 (P \textless 0.05). These results suggest that in humans sympathetic nerves modulate blood flow to active muscles during light and heavy rhythmic exercise and that this restraint of flow can limit O2 uptake in muscles performing heavy rhythmic exercise.
Abstract: This study in conscious, chronically instrumented dogs investigated the effects of human atrial natriuretic peptide [hANP-(99-126)] at physiological (5 ng.kg-1.min-1) and pharmacological (5-900 ng.kg-1.min-1) doses on angiotensin II (ANG II)-mediated effects on hemodynamics, renal excretion, and aldosterone release. Five female beagle dogs kept chronically on a dietary sodium intake of 2.5 mmol Na.kg body wt-1.day-1 received an intravenous infusion of 1, 4, 10, 20, and 50 ng.kg-1.min-1 ANG II (20-min periods) without (protocol 1) or with (protocol 2) simultaneous intravenous infusion of 5 ng.kg-1.min-1 hANP-(99-126). In protocol 1, glomerular filtration rate (means +/- SD) decreased from 4.0 +/- 0.6 to 2.8 +/- 0.5 ml.kg-1.min-1, renal sodium excretion (UNaV) decreased from 2.8 +/- 1.6 to 0.4 +/- 0.2 mumol.kg-1.min-1, and urine volume (V) decreased from 45 +/- 23 to 6 +/- 8 microliters.kg-1.min-1. There were no differences in the values between protocol 1 and protocol 2. Mean arterial blood pressure (MABP) increased similarly from 118 +/- 16 to 166 +/- 9 mmHg in protocol 1 and from 109 +/- 11 to 162 +/- 7 mmHg in protocol 2. Maximal aldosterone secretion was stimulated less in protocol 2 (481 +/- 92 vs. 362 +/- 158 pg/ml; P less than 0.05). In ANG II-pretreated (20 ng.kg-1.min-1) dogs (n = 4; protocol 3), intravenous hANP-(99-126) doses of 300-900 ng.kg-1.min-1 decreased MABP and central venous pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: We tested the effect of interstitial edema on lung lymph flow when no filtration occurred. In 16 anesthetized open-thorax ventilated supine goats, we set pulmonary arterial and left atrial pressures to nearly zero and measured lymph flow for 3 h from six lungs without edema and ten with edema. Lymph flow decreased exponentially in all experiments as soon as filtration ceased. In the normal lungs the mean half time of the lymph flow decrease was 12.7 +/- 4.8 (SD) min, which was significantly shorter (P less than 0.05) than the 29.1 +/- 14.8 min half time in the edematous lungs. When ventilation was stopped, lymph flow in the edematous lungs decreased as rapidly as in the normal lungs. The total quantity of lymph after filtration ceased was 2.7 +/- 0.8 ml in normal lungs and 9.5 +/- 6.3 ml in edematous lungs, even though extravascular lung water was doubled in the latter (8.4 +/- 2.4 vs. 3.3 +/- 0.4 g/g dry lung, P less than 0.01). Thus the maximum possible clearance of the interstitial edema liquid by the lymphatics was 6.3 +/- 4.8%. When we restarted pulmonary blood flow after 1-2 h in four additional goats, lymph flow recovered within 30 min to the baseline level. These findings support the hypothesis that lung lymph flow originates mainly from alveolar wall perimicrovascular interstitial liquid and that the contribution of the lung lymphatic system to the clearance of interstitial edema (bronchovascular cuffs, interlobular septa) is small.
Abstract: To investigate the influence of carotid baroreflexes on plasma arginine vasopressin (AVP) in humans, eight healthy males underwent two sessions of passive head-up tilt to 60 degrees for 15 min each. During one of the sessions (sequence randomized), carotid baroreflexes were simultaneously stimulated by static neck suction of 23 +/- 1 mmHg during the whole period of head-up tilt. Only subjects who did not develop presyncopal symptoms during head-up tilt were included. Head-up tilt increased AVP significantly from 1.0 +/- 0.3 to 4.2 +/- 1.3 pg/ml (P less than 0.05). In contrast to this, AVP did not at any point in time increase significantly during head-up tilt when neck suction was applied. Plasma renin activity and heart rate were unaffected by neck suction, whereas mean arterial pressure and central venous pressure decreased. We conclude that the moderate but significant increase in plasma AVP during nonhypotensive head-up tilt is in part mediated by deloading of carotid baroreceptors induced by the acute fall in hydrostatic pressure at the level of the carotid sinus.
Abstract: We tested the hypothesis that the larger (greater than 2 mm ID) hepatic veins are the primary site of the portal-to-caval venous pressure gradient in the dog. Double-lumen catheters were inserted through the caval wall into hepatic veins of pentobarbital sodium-anesthetized dogs. One lumen opened at the end, and the other to the side. Each catheter was advanced until stopped and then it was withdrawn. The pressure at either port dropped from 87 +/- 31 to 13 +/- 11% of the portal-to-caval pressure difference as each moved past a transition point (TP). The location of the TP depended on the catheter diameter. Intraportal histamine or norepinephrine, 4 and 2.6 micrograms.min-1.kg body wt-1 respectively, augmented only the pressure measured upstream to the TP. A mathematical model of flow through a vessel with a catheter inside predicted a marked increase in resistance when the ratio of catheter OD to vessel ID exceeded approximately 0.6. Autopsy revealed ratios greater than 0.6 upstream to the TP. A hydraulic model confirmed that this effect caused the appearance of the TP. Given the depth (11.7 cm) at which near caval pressures could be found, even during histamine administration, we conclude that the major pressure gradients in the canine liver must lie upstream to the large hepatic veins.
Abstract: Following traumatic brain injury, cells that are not directly, and thereby irreversibly damaged are subjected to ionic fluxes including potassium and calcium. This injury-induced ionic flux is a result of both neuronal firing via direct mechanical stimulation of the neurons as well as the activation of ligand-gated ion channels primarily associated with excitatory amino acids (e.g. glutamate). This ionic destabilization places enormous energy demands on these cells in order to activate pumping mechanisms to reinstate normal ionic balance. The primary fuel used to acquire this energy is glucose, which results in a period of hyperglycolysis leading to the accumulation of lactate. This acute period of increased glucose metabolism lasts only during the acute period, after which these same cells exhibit a state of chronic metabolic depression for both glucose and oxygen. This metabolic derangement may prevent the necessary energy production for maintaining cellular protein synthesis which is inhibited following traumatic brain injury. This injury-induced metabolic derangement is not uniform throughout all regions. Some structures are more or less affected presumably due to their proximity to the site of trauma and/or to the extent to which they have a preponderance to being more vulnerable to insult. Within these affected regions, the metabolic dysfunction indicates that cells are functionally compromised in their ability to respond to both normal physiologic and pathophysiologic challenges. This results in the expression of neurological deficits and an enhanced vulnerability of these cells to a second insult, both of which dissipate as normal metabolic function returns over time.
Abstract: The most important step in the management of toxicity due to any of the cardiac glycosides is its recognition. Despite the development of an accurate clinical assay for serum levels of digoxin greater than 20 years ago, digitalis toxicity remains common and difficult to confirm, even if suspected, due primarily to 2 factors. First, the signs and symptoms of digitalis toxicity, most commonly an abnormal electrocardiogram showing ventricular or atrial arrhythmias, with or without some degree of concurrent atrioventricular block, often also occur in patients with congestive heart failure (CHF) and underlying coronary atherosclerosis who are not receiving a cardiac glycoside. Second, due to digoxin’s narrow therapeutic ratio, the marked degree of variability in the sensitivity of individual patients to its toxic effects, and the common problem of obtaining blood samples inappropriately during the early distribution phase following dosing, a serum digoxin concentration often does not serve as a reliable indicator of toxicity. Despite these difficulties in diagnosis, the management of digoxin toxicity has been made much more effective with the widespread availability of F(ab) fragments of anti-digoxin antibodies. This drug provides the clinician with a rapidly acting, safe antidote for all commonly used digitalis preparations. Conventional therapy for digoxin toxicity remains the maintenance of serum potassium levels greater than or equal to 4 mEq/liter, reversal of decompensated CHF or overt myocardial ischemia, attention to serum magnesium levels and the patient’s acid-base status, appropriate antiarrhythmics in the event of ventricular arrhythmias, and a temporary pacemaker for high-grade atrioventricular block. Nevertheless, the high specificity and documented safety of the antibody preparation provides a needed safety net for the continuing use of cardiac glycosides as first-line inotropic agents in the modern therapy of chronic CHF.
Abstract: To quantitate hepatic glycogenolysis, liver glycogen concentration was measured with 13C nuclear magnetic resonance spectroscopy in seven type II diabetic and five control subjects during 23 h of fasting. Net hepatic glycogenolysis was calculated by multiplying the rate of glycogen breakdown by the liver volume, determined from magnetic resonance images. Gluconeogenesis was calculated by subtracting the rate of hepatic glycogenolysis from the whole body glucose production rate, measured using [6-3H]glucose. Liver glycogen concentration 4 h after a meal was lower in the diabetics than in the controls; 131 +/- 20 versus 282 +/- 60 mmol/liter liver (P \textless 0.05). Net hepatic glycogenolysis was decreased in the diabetics, 1.3 +/- 0.2 as compared to 2.8 +/- 0.7 mumol/(kg body wt x min) in the controls (P \textless 0.05). Whole body glucose production was increased in the diabetics as compared to the controls, 11.1 +/- 0.6 versus 8.9 +/- 0.5 mumol/(kg body wt x min) (P \textless 0.05). Gluconeogenesis was consequently increased in the diabetics, 9.8 +/- 0.7 as compared to 6.1 +/- 0.5 mumol/(kg body wt x min) in the controls (P \textless 0.01), and accounted for 88 +/- 2% of total glucose production as compared with 70 +/- 6% in the controls (P \textless 0.05). In conclusion: increased gluconeogenesis is responsible for the increased whole body glucose production in type II diabetes mellitus after an overnight fast.
Abstract: This study was designed to establish the normal pattern of serum progesterone and the origin of its secretion during the follicular phase of the normal menstrual cycle. In the first study, 12 normal women were studied on 3 occasions each at different times during a single follicular phase. Serum samples were collected every 10 min over 8 h, for 6 h before and 2 h after an injection of naloxone (5 mg iv). The mean serum progesterone remained constant (0.9 nmol/L) across the follicular phase until just before ovulation; individual subjects showed pulsatility of progesterone (1-6 pulses/6 h) but there was no relationship of this to LH pulsatility and no variation of progesterone pulsatility across the follicular phase. Naloxone caused an increase in the mean serum progesterone in the early follicular phase to 1.9 +/- 0.7 nmol/L and in the mid and late follicular phase to 2.1 +/- 0.7 nmol/L and 3.4 +/- 2.5 nmol/L, respectively. The second study was performed to assess the contribution of the residual corpus luteum and the developing follicle to the pulsatile secretion of progesterone. Seven anovulatory women with low levels of serum LH and absent LH pulsatility were studied before and after clomiphene (100 mg/day for 5 days) by collecting blood samples every 15 min for 6 h before GnRH (10 mg iv) and for 2 h afterwards. The anovulatory women had comparable mean serum concentration of progesterone (0.9 +/- 0.5 nmol/L) to normal women and similar frequency of progesterone pulsatility (2.1 +/- 1.1 pulses/6 h). After administration of clomiphene, there was no significant change in progesterone pulsatility (1.7 +/- 1.0 pulses/6 h) despite a substantial increase in LH pulsatility (from none to 3.0 +/- 1.0 pulses/6 h). There was no significant increase in serum progesterone after clomiphene or GnRH which both caused a substantial increase in serum LH. The third study involved eight normal women studied before and after treatment with dexamethasone (2 mg/day for 2 days) to assess the adrenal component of progesterone secretion. Blood samples were collected every 10 min for 6 h before and 2 h after naloxone (5 mg iv). Dexamethasone reduced serum progesterone to below assay sensitivity (less than 0.2 nmol/L) and obliterated progesterone pulsatility. The increase in serum progesterone and cortisol induced by naloxone was blocked by dexamethasone; the naloxone-induced rise of serum LH was not affected by dexamethasone. We conclude that neither the preceding corpus luteum nor the developing follicle are important contributors to the serum concentration of progesterone during the normal follicular phase.(ABSTRACT TRUNCATED AT 400 WORDS)
Abstract: Alveolar type II epithelial cells in adult mammalian lungs actively transport salt and water, secrete surfactant, and differentiate into type I cells under normal conditions and following lung injury. It has become increasingly apparent that, like all epithelial cells, alveolar pneumocytes have evolved specialized ion transport mechanisms by which they regulate their intracellular pH (pHi). pHi is an important biological parameter in all living cells whose regulation is necessary for normal cellular homeostasis. pHi, and the ion transport mechanisms by which it is regulated, may contribute to many cellular processes, including transcellular transport, cell volume and osmolarity regulation, and intracellular transport, cell volume and osmolarity regulation, and intracellular electrolyte composition. Moreover, changes in pHi may serve as intracellular signals for biological processes such as cell growth, proliferation, and differentiation. We review herein the general principles of pHi regulation in epithelia and describe the mechanisms and effects of pHi regulation in alveolar pneumocytes. Many of the critical issues in current pulmonary research involve processes that pHi is most likely to affect, including maintenance of alveolar epithelial barrier integrity, development and maintenance of epithelial polarity, epithelial proliferation and differentiation, and regulation of transepithelial transport with respect to alveolar fluid balance in normal individuals and in those with excess alveolar fluid (i.e., pulmonary edema). Investigations into the regulation of pHi in alveolar pneumocytes and the regulatory effects of pHi in turn on other cellular processes are likely to yield information important to the understanding of lung biology and pulmonary disease.
Abstract: The objective of the present study was to assess the relationship between the amount of lactate accumulated during complete ischaemia and the ensuing changes in extra- and intracellular pH (pHe and pHi, respectively). The preischaemic plasma glucose concentration of anaesthetized rats was varied by administration of glucose or insulin, pHe was determined in neocortex with ion-sensitive microelectrodes, and tissue lactate and CO2 contents were measured, tissue CO2 tension being known from separate experiments. The experiments were carried out in both normocapnic [arterial CO2 tension (PaCO2) approximately 40 mm Hg] and hypercapnic (PaCO2 approximately 80 mm Hg) animals. Irrespective of the preischaemic CO2 tension, DeltapHe was linearly related to tissue lactate content. Depending on the preischaemic glucose concentration, DeltapHe varied from \textless0.4 to \textgreater1.4 units. The results thus fail to confirm previous results that the changes in pHe describe two plateau functions (DeltapHe approximately 0.5 and 1.1, respectively), with a transition zone at tissue lactate contents of 17 - 20 mmol kg-1. Changes in pHi given in this study are based on the assumption of a uniform intracellular space. The pHi changed from a normal value of approximately 7.0 to 6.5, 6.1 and 5.8 at tissue lactate contents of 10, 20 and 30 mmol kg-1. The intrinsic (non-bicarbonate) buffer capacity, derived from these figures, was 23 mmol kg-1 pH-1. Some differences in pH and in HCO3- concentration between extra- and intracellular fluids persisted in the ischaemic tissue. These differences were probably caused by a persisting membrane potential in the ischaemic cells.
Abstract: We performed simultaneous multifiber recordings of cardiac, renal (RNA), hepatic (HNA), adrenal, and splenic sympathetic nerve activities during 10 min of sustained hemorrhagic hypotension to a mean blood pressure of 50 mmHg. One minute after bleeding in dogs with intact baroreceptors, all measured nerve activities increased significantly, and a gradual decline toward prebleeding level followed. Only RNA showed a great inhibition below prebleeding level. In cervically vagotomized dogs, all nerve activities showed significantly higher levels than prebleeding control throughout the experiment. The initial increase in HNA observed at 1 min postbleeding in animals with intact baroreceptors was attenuated. HNA in the vagotomized group showed a gradual increase so that 5 min postbleeding, HNA reached a peak level that was maintained until the end of the experiment. Sympathoinhibition in RNA and decrease in heart rate during hemorrhagic hypotension were reversed to significant increases after vagotomy. In contrast, animals with denervation of the carotid sinus and aortic nerves showed initial increases in nerve activities followed by recovery to prebleeding control level within 2 min postbleeding. After complete denervation of systemic baroreceptors, rapid hemorrhage did not cause any significant change in sympathetic nerve activity in any nerve. These results indicate that early reflex response to hemorrhage in regional sympathetic nerves is unidirectional sympathoexcitation mediated by summative unloading of both arterial baroreceptors and cardiopulmonary receptors. When greater than 1 min passed after bleeding and sustained hypotension of 50 mmHg was established, a reflex mechanism through the vagal afferents participated to inhibit the unidirectional sympathoexcitation mediated by unloading of arterial baroreceptors, with different magnitude in different innervated organs.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Renal interstitial hydrostatic pressure (RIHP) has been implicated in the regulation of sodium excretion. Studies using vasodilators and other maneuvers to increase RIHP have found a significant correlation between RIHP and sodium excretion. Since correlative studies do not prove a cause-and-effect relationship, it is not known whether the rise in sodium excretion in these studies is the result of increases in RIHP or if RIHP is elevated as a result of decreases in sodium and water reabsorption and increases in intratubular pressure. Therefore, the purpose of the present study was to determine whether elevation of intratubular hydrostatic pressures in response to direct inhibition of tubule transport with loop diuretics results in increases in RIHP in dogs and rats. Intrarenal hydrostatic pressures, renal hemodynamics, and sodium and water excretion were examined in dogs during intravenous administration of furosemide (3 mg/kg bolus followed by 0.03 mg.kg-1 x min-1) or bumetanide (60 micrograms/kg bolus followed by 1 microgram.kg-1 x min-1). Furosemide administration increased urinary flow rate (V; 0.10 +/- 0.02 to 4.6 +/- 0.97 ml/min), urinary sodium excretion (UNaV; 16 +/- 5 to 549 +/- 123 mu eq/min), and proximal tubule hydrostatic pressure (PT; 21 +/- 1 to 28 +/- 1 mmHg) but had no effect on RIHP (7.2 +/- 0.6 to 7.4 +/- 0.7 mmHg) or peritubular capillary hydrostatic pressure (14 +/- 1 to 14 +/- 1 mmHg).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: 1. Independent of its effects on renal haemodynamics and glomerular filtration, angiotensin II (AII) has direct actions on the proximal tubule involving transepithelial Na+, H+, HCO3-, and water reabsorption, ammoniagenesis, gluconeogenesis and renal growth. 2. The effects of AII on water and electrolyte transport are biphasic and dose-dependent, such that low concentrations (10(-12)-10(-9) mol/L) stimulate reabsorption whereas high concentrations (10(-7)-10(-6) mol/L) inhibit reabsorption. Similar dose-response relations have been obtained for luminal and peritubular addition of AII. 3. The cellular responses to AII are mediated via an AT-1 receptor coupled via G-regulatory proteins to several parallel signal transduction pathways. Low doses inhibit the basolateral adenylate cyclase, lower intracellular cAMP and withdraw the inhibitory effect of protein kinase A on the luminal Na/H exchanger. Stimulation of this exchanger may also occur due to AII-receptor activation of phospholipase C to release diacyl glycerol, or by local transduction in the brush-border membrane involving phospholipase A2. 4. Inhibition of proximal fluid reabsorption is associated with increased intracellular Ca2+ released from intracellular stores, or entering via voltage-sensitive channels in response to the release of inositol-1,4,5-trisphosphate, or following Ca2+ channel opening induced by the arachidonic acid metabolite 5,6-epoxy-eicosatrienoic acid. 5. The stimulatory actions of peritubular AII on proximal transport are inhibited by physiological concentrations of atrial natriuretic factor (ANF) and by parathyroid hormone (PTH). 6. It is concluded that intrarenal AII acts to maintain optimal matching of fluid reabsorption and filtered load in response to changes in sodium balance, as well as to promote acidification of the urine during acidosis and perhaps to potentiate tubular growth following renal injury.
Abstract: The amount of lactate formed during ischemia determines the rise in tissue PCO2 (PtCO2). Conflicting results exist on the relationship between lactate and PtCO2. The objective of this study was to settle this issue. We varied the preischemic plasma glucose concentration of normo- and hypercapnic rats, assessed tissue lactate and total CO2 contents, and determined the PCO2/lactate relationship over the lactate range 2-40 mmol kg-1. The results showed that whatever the equilibration time, the PCO2/lactate relationship was linear. The results obtained could be reproduced by a theoretical buffer system that mimics the buffering behavior of intracellular fluid. Our results bear on the question of whether compartmentation of H+ occurs during ischemia, with glial cells becoming more acid than neurons. A discontinuous PCO2/lactate relationship, with a constant PCO2 above a certain lactate content, would support this contention. Since our results demonstrate a linear relationship between lactate and PCO2 over the lactate range 2-40 mmol kg-1, they considerably weaken any argument for gross compartmentation of H+.
Abstract: This article attempts correlating changes in cellular energy metabolism, acid-base alterations, and ion homeostasis in ischemia and other conditions. It is emphasized that loss of ion homeostasis, with thermodynamically downhill fluxes of K+, Ca2+, Na+, Cl-, and H+, occurs because energy production fails and (or) ion conductances are increased. In ischemia, energy failure is the leading event but, in hypoglycemia, activation of ion conductances is what precipitates energy failure. The initial event is a rise in K+ e, at least in part caused by activation of K+ conductances modulated by Ca2+ or ATP/ADP ratio. Secondarily, this leads to release of excitatory amino acids and massive activation of unspecific cation (and anion) conductances. Production of H+ occurs in states characterized by energy failure (ischemia and hypoxia) or by alkalosis (hypocapnia and ammonia accumulation). H+ equilibrates between intra- and extra-cellular fluid via nonionic diffusion of lactic acid, and transmembrane fluxes of H+ or HCO3- via ion channels. Since the relationship between lactate and either pHi or pHe is linear, there are no abrupt pH shifts explaining why hyperglycemia worsens ischemic damage. The reversible insults seem to induce a sustained stimulation of H+ extrusion from cells giving rise to intracellular alkalosis and extracellular acidosis.
Abstract: Cardiac work is a major determinant of heart size and growth. Heterotopic cardiac isografts are hemodynamically unloaded and undergo atrophy. To determine the molecular changes that occur as a result of hemodynamic unloading, we have studied the rate of synthesis of total cardiac proteins and myosin heavy chain (MHC) and the expression of the myosin heavy chain gene as reflected in the messenger RNA levels for alpha- and beta-MHC isoforms. 72 h after transplantation there is a significant decrease in left ventricular size accompanied by a 27% decrease in the rate of total cardiac protein synthesis and a 53% decrease in the rate of myosin heavy chain synthesis. In contrast to isografts 14 d after transplantation which have a decrease in protein synthetic capacity, simultaneous measurements of 18S ribosomal RNA and myosin messenger RNA suggest that after 3 d the decrease in synthesis is due to a change in the efficiency of protein translation. While the working in situ heart expresses primarily alpha-MHC mRNA (97%) hemodynamic unloading leads to a 43% decrease in alpha-MHC mRNA concentration and the de novo expression of the beta-MHC mRNA. Total MHC mRNA (alpha plus beta) concentration analyzed by a quantitative S1 nuclease protection assay was similar in the two groups of hearts. Thus, in association with hemodynamic unloading there are changes in cardiac myosin heavy chain content as a result of both gene transcription and protein translation mechanisms.
Abstract: New Zealand white rabbits were exposed to control conditions (n = 11), or to either a progressive hypoxic hypoxia produced by dilution of oxygen (O2) with nitrogen (n = 10) or a 1% carbon monoxide (CO) admixture for 15 min (n = 11). Both exposures caused a significant increase in cerebral blood flow (CBF) of up to 300% such that O2 delivery to the brain was unchanged. In the hypoxia group, a cortical somatosensory evoked response (CSER) was unaffected until the arterial O2 tension was below 20 mmHg. At this time, the rabbits became hypotensive, O2 delivery to the brain decreased dramatically and the CSER could not be elicited. In contrast, despite the maintenance of O2 delivery to the brain during and after the CO exposure, the CSER voltages were halved during the exposure and only recovered to about 80% of baseline subsequently. We conclude that the primary toxicity of CO to the brain in rabbits is not due to a reduction in O2 delivery.
Abstract: In each nephron of the mammalian kidney, the tubule returns to the hilus of the parent glomerulus, forming the juxtaglomerular apparatus (JGA). The JGA displays a unique arrangement of afferent and efferent arterioles, interstitial cells and macula densa (a specialized plaque of tubular epithelial cells). Because of this intimate anatomical relationship, it has long been suggested that the macula densa may somehow sense changes in the composition of the tubular fluid and control both the glomerular filtration rate and renin release. Despite extensive investigation, attempts to obtain direct evidence of this have been hindered by the anatomical complexity of the JGA. However, recent technical developments now permit direct assessment of the role of the macula densa in the control of both renin release and glomerular hemodynamics. These developments include microdissection/perfusion of the afferent arteriole, the macula densa or both, as well as a sensitive renin assay which permits measurement of renin release from a single JGA. Observations resulting from such developments are discussed in this article.
Abstract: Thyroxine (T4) is required in species possessing brown adipose tissue (BAT) for the maintenance of cold tolerance and adaptation. In humans, who possess negligible quantities of BAT, the importance of T4 has not been demonstrated. We studied the effects of decreased serum T4 and thyrotropin (TSH) on human cold habituation after repeated cold air exposures. Eight men (T3+) received a single daily dose of triiodothyronine (T3; 30 micrograms/day), and another eight men (T3-) received a placebo. All 16 normal thyroid men underwent a standardized cold air test (SCAT) under basal conditions in January and again in March after eighty 30-min 4.4 degrees C air exposures (10/wk). Measurements of basal metabolic rate (BMR), O2 consumption (VO2), mean arterial pressure (MAP), plasma norepinephrine (NE), serum TSH, free and total T4, and free and total T3 were repeated before and after 8 wk of exposure. TSH, free T4, and total T4 were 50% lower for T3+ than for T3- subjects. Total and free T3 were not different between groups. BMR was unchanged after habituation, whereas the cold-stimulated VO2, MAP, and NE were significantly reduced for all subjects in March. The relationship between VO2 and NE (r2 = 0.44, P less than 0.001) during the initial SCAT was unchanged with habituation. We suggest that human cold habituation is independent of major changes in circulating T4 and TSH.
Abstract: During hemorrhagic hypotension, vascular resistance, plasma norepinephrine, and sympathetic nerve activity decrease. Naloxone reverses these effects. We hypothesized that increased sympathetic nerve activity was specific to naloxone and not secondary to the pressor response. Conscious rabbits were hemorrhaged until mean arterial pressure (MAP) was less than 40 mmHg, given naloxone (3 mg/kg) or saline, and monitored for 5 min. In some animals, we attenuated naloxone’s pressor response with alpha-adrenergic blockade or mimicked the pressor response by infusion of phenylephrine. During nonhypotensive hemorrhage, heart rate and renal sympathetic nerve activity (RSNA) increased significantly. During hypotensive hemorrhage, RSNA decreased to significantly less than prehemorrhage control values. After saline treatment, RSNA did not increase. Naloxone significantly increased MAP and RSNA. alpha-Blockade reduced the pressor response to naloxone but not the increase in RSNA. Phenylephrine increased MAP to a level similar to naloxone, but RSNA remained suppressed. Reinfusion of hemorrhaged blood reduced RSNA in all groups treated with naloxone. These data suggest that hypotensive hemorrhage is associated with sympathoinhibition that is not transient. In addition, the pressor response to naloxone is not required for its sympathoexcitatory effects.
Abstract: To explore the roles of endogenous atrial natriuretic peptide (ANP) in the volume regulation, we examined effects of antiserum for ANP or a neutral endopeptidase inhibitor, thiorphan, in rats with monocrotaline (MCT)-induced pulmonary hypertension. ANP concentrations in the plasma and right ventricle and ANP mRNA in the right ventricle of MCT-treated rats were higher than in vehicle-treated rats. The administration of the ANP antiserum into the MCT-treated rats did not affect the right atrial pressure or blood pressure but significantly decreased urinary excretion of Na by 60%. No decrease occurred in the control rats. Thiorphan dose dependently increased the urinary excretion of Na by 140% without influencing the right atrial pressure or blood pressure. This natriuresis was associated with 50 and 450% increases in ANP concentrations in the plasma and urine, respectively. The degrees of increases in urinary Na excretion, ANP, and guanosine 3’,5’-cyclic monophosphate were significantly greater in the MCT-treated rats than in the control rats. Thus an increased secretion of ANP in pulmonary hypertension actually contributes to Na excretion. The augmentation of endogenous ANP activity may further potentiate the compensatory role of this peptide in the regulation of body fluid volume.
Abstract: This study examined the relationship among pseudo-steady-state (constant) serum thiopental concentrations, clinical anesthetic depth as assessed by several perioperative stimuli, and the electroencephalogram (EEG). Twenty-six ASA physical status 1 or 2 patients participated in the study. Two constant serum thiopental concentrations were maintained in each patient using a computer-controlled infusion pump. The first randomly assigned target serum concentration of 10-30 micrograms/ml was maintained for 5 min to allow serum:brain equilibration. Then the following stimuli were applied at 1-min intervals: verbal command, tetanic nerve stimulation, trapezius muscle squeeze, and laryngoscopy. A second, higher, randomly assigned target serum concentration of 40-90 micrograms/ml was then achieved and maintained by the computer-controlled infusion pump. The previously described stimuli were reapplied, after which laryngoscopy and intubation was performed. A positive response was recorded if purposeful extremity movement or coughing was observed. Using the quantal movement or cough response and the measured constant serum thiopental concentration, the probability of no movement to each stimulus was characterized using logistic regression. The serum thiopental concentrations that produced a 50% probability of no movement response for the clinical stimuli were as follows: 15.6 micrograms/ml for verbal command, 30.3 micrograms/ml for tetanic nerve stimulation, 39.8 micrograms/ml for trapezius muscle squeeze, 50.7 micrograms/ml for laryngoscopy, and 78.8 micrograms/ml for laryngoscopy followed by intubation. The EEG was analyzed using aperiodic waveform analysis to derive the number of waves per second. A biphasic relationship between constant serum thiopental concentration and the EEG number of waves per second was observed. Loss of responsiveness to verbal stimulation occurred when the EEG was activated at 15-18 waves/s.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: There is a renewed interest in understanding the precise role of lymphatics in the ultrafiltration kinetics during peritoneal dialysis. In the normal state, lymphatics draining the peritoneal cavity are the principal means of removal of intraperitoneal isosmotic fluid and macromolecules. During a hypertonic peritoneal dialysis exchange, after peak intraperitoneal volume is achieved, fluid removal proceeds at an almost linear rate, causing intraperitoneal fluid volume to reduce. The isosmotic fluid removal from the peritoneal cavity could occur through the microcirculatory capillaries or through the lymphatic capillaries draining the peritoneal cavity. Animal and human studies suggest that this fluid loss occurs primarily through lymphatics. The two indirect methods of lymph flow measurements, plasma appearance and peritoneal disappearance of tracer colloid, show conflicting results. Although direct measurement of lymph flow rates through cannulation of mediastinal lymph vessels in animals suggests a significant flow through the lymph channels in response to intraperitoneal fluid instillation, lymph flow modification at the lymph node level may prevent use of this technique to assess the precise role played by lymphatics in fluid kinetics during peritoneal dialysis. By analogy with ascites and by extrapolation from previous studies of drain volumes after infusion of isotonic and hypertonic solutions, the average daily lymph absorption rate during CAPD may be predicted to be at least 1 liter per day.
Abstract: This study examined the effects of age and physical activity on body composition and fat distribution by comparing differences between young and older endurance trained men and women with differences between young and older sedentary people. Although indices of total body adiposity (fat mass, percent body fat) were higher in the older than in the young people in both the trained and the sedentary groups, the magnitude of the difference was markedly less in the trained group (P less than 0.01). The average differences in fat mass between young and old sedentary men and women were 10.1 kg and 12.2 kg, respectively, but only 4.3 kg and 5.5 kg in trained men and women. Skinfold thicknesses were approximately 24% and approximately 47% larger at all sites (triceps, thigh, subscapula, pectoralis, umbilicus, suprailiac) in the older than in the young trained men and women, respectively. Similar differences were found between young and older sedentary people except at central, upper body sites, where the relative differences in skinfold thicknesses between young and older sedentary people were 2- to 6-fold greater than in trained people. Thus, people who exercise regularly appear to accumulate less adipose tissue in upper, central body regions as they get older, potentially reducing the risk for the metabolic disorders associated with upper body obesity.
Abstract: The cardiovascular actions of three concentrations of desflurane (formerly I-653), a new inhalation anesthetic, were examined in 12 unmedicated normocapnic, normothermic male volunteers. We compared the effects of 0.83, 1.24, and 1.66 MAC desflurane with measurements obtained while the same men were conscious. Desflurane caused a dose-dependent increase in right-heart filling pressure and a decrease in systemic vascular resistance and mean systemic arterial blood pressure. As measured by echocardiography, left ventricular end-diastolic area did not change except for a small increase at 1.66 MAC desflurane, and systolic wall stress was less at all concentrations of desflurane than during the conscious state. Desflurane did not change cardiac index or left ventricular ejection fraction. Heart rate did not change at 0.83 MAC, but progressively increased with deeper desflurane anesthesia. Stroke volume index was less at all concentrations of desflurane than while the men were conscious, but desflurane did not alter the velocity of ventricular circumferential fiber shortening. Mixed venous blood PO2 and oxyhemoglobin saturation were higher during all concentrations of desflurane anesthesia than during the conscious state. No volunteer developed a metabolic acidosis. We conclude that desflurane with controlled ventilation and constant PaCO2 causes cardiovascular depression, as indicated by the increased cardiac filling pressure and decreased stroke volume index and by no change in the velocity of circumferential fiber shortening in the presence of decreased systolic wall stress. However, cardiac output is well maintained, and heart rate does not increase at light levels of anesthesia. The cardiovascular actions of 0.83 and 1.66 MAC desflurane were also reexamined in 6 of the 12 men during the seventh hour of anesthesia. Prolonged desflurane anesthesia resulted in lesser cardiovascular depression than was evidenced during the first 90 min. The measures of cardiac filling (central venous pressure and left ventricular end-diastolic cross-sectional area) did not differ between the early and late periods of anesthesia. Systemic vascular resistance decreased further during the late period, but systolic wall stress did not differ between the two time periods. During the seventh hour of desflurane anesthesia, heart rate and cardiac index were higher at both anesthetic concentrations than during the first 90 min of anesthesia. Left ventricular ejection fraction and velocity of fiber shortening did not change with duration of desflurane anesthesia. Oxygen consumption, oxygen transport, the ratio of the two, mixed venous PO2, and mixed venous oxyhemoglobin saturation (SO2) increased late in the anesthetic in comparison with the first 90 min.
Abstract: The evidence for the functional importance of extravascular Starling pressures now seems overwhelming, and when these terms are taken into account it is difficult to uphold the traditional conception that upstream microvascular filtration is largely matched by a sustained downstream reabsorption. Transient absorption can occur, however, during spontaneous vasomotion cycles, during sympathetic-induced vasoconstriction and during hypovolaemic hypotension. Sustained absorption is possible in specialized tissues where the interstitium is ’flushed’ by an independent stream (intestinal mucosa, renal cortex, lymph nodes). Both theory and experiment show, however, that absorption cannot be maintained across most low-pressure exchange segments due to the finite permeability of microvessels to plasma protein, which leads to a rise in pericapillary interstitial oncotic pressure with time around absorbing microvascular segments. Extravascular hydraulic resistance may be a further determinant of net fluid transfer rate in situations where capillary wall resistance is low.
Abstract: BACKGROUND. Atherosclerosis is characterized by endothelial injury and the proliferation of arterial smooth-muscle cells. The latter may be a result of the release of growth factors from the vessel wall; such growth factors may include an endothelium-derived vasoconstrictor for peptide with mitogenic properties. We tested the hypothesis that plasma endothelin concentrations are elevated in persons with symptomatic atherosclerosis, independently of age. METHODS. We measured plasma endothelin levels in 100 normal subjects and in 40 patients with atherosclerosis predominantly of the following types: aortic and peripheral vascular disease (14 patients), renovascular disease (9 patients) coronary artery disease (9 patients), and carotid disease (8 patients). We also performed immunohistochemical staining for endothelin in the walls of atherosclerotic vessels. RESULTS. In the normal subjects, the mean (+/- SD) plasma endothelin concentration was 1.4 +/- 0.2 pmol per liter, with no correlation between age and plasma endothelin concentration (r = 0.13, P = 0.2). In the patients with symptomatic atherosclerosis, the mean plasma endothelin concentration was 3.2 +/- 1.2 pmol per liter (P less than 0.001), and there was a significant correlation between plasma endothelin and the number of sites of disease involvement (r = 0.89, P less than 0.001). In the immunohistochemical studies, endothelin-1-like immunoreactivity was observed in vascular smooth muscle as well as in endothelial cells. CONCLUSIONS. Endothelin may be a marker for arterial vascular disease. Whether it participates in the atherogenic process or is merely released from damaged endothelial cells is unclear.
Abstract: The syndrome of hypertension and hyperkalemia, hyperchloremic acidosis with normal glomerular filtration rate (Gordon’s syndrome) is characterised by volume expansion, suppressed renin and reduced mineralocorticoid-induced renal clearance of potassium. The clinical and biochemical defects are aggravated by high salt diet and corrected by low salt diet, leading to the hypothesis of excessive sodium reabsorption in the nephron proximal to where aldosterone acts. In this study, we used lithium clearance as a marker of proximal sodium reabsorption in three patients with Gordon’s syndrome, in order to further localise the site in the nephron of defective sodium handling. Fractional excretion of lithium was decreased, and absolute and fractional proximal reabsorption of sodium was increased compared to normal controls. In addition, absolute distal reabsorption of sodium was decreased, consistent with decreased mineralocorticoid activity. Fractional excretion of potassium was markedly decreased and did not rise with increased distal delivery of sodium during saline infusion. However, after severe dietary sodium restriction had elevated plasma aldosterone (lowering plasma potassium levels to normal), fractional excretion of potassium was raised by saline infusion. Reduced lithium clearance in patients with Gordon’s syndrome supports the hypothesis of increased proximal sodium reabsorption in this condition.
Abstract: To determine the frequency and significance of left ventricular wall motion abnormalities in patients without clinical evidence of myocardial infarction, we reviewed the two-dimensional echocardiograms of 252 patients who had no history or electrocardiographic evidence of myocardial infarction and who subsequently underwent coronary angiography. Seventy-seven patients (31%) had one or more segmental wall motion abnormalities. Sixty-six of the 77 patients (86%) had significant coronary artery disease (greater than or equal to 50% luminal diameter stenosis). Seventy-four percent of the patients with coronary artery disease had multivessel disease. The left ventricle was divided into anterior and posterior regions. In the 66 patients, there were 77 separate regions with wall motion abnormalities (49 hypokinesis, 22 akinesis, 6 dyskinesis), including 60 regions (78%) supplied by coronary vessels with greater than or equal to 70% stenosis. Thirty-two patients underwent coronary artery bypass surgery or percutaneous transluminal coronary angioplasty. Follow-up echocardiograms were obtained in 19 patients who had wall motion abnormalities involving 22 regions. Twenty of the 22 regions were revascularized. Wall motion improved in 17 of 20 regions (85%) and returned to normal in 15 regions (75%). We conclude that segmental wall motion abnormalities may be detected by echocardiography in up to one third of patients evaluated for suspected coronary artery disease without documented myocardial infarction. These abnormalities are associated with a high likelihood of multivessel disease as well as with significant narrowing of the artery supplying the region demonstrating abnormal wall motion. Improvement in segmental wall motion abnormalities after revascularization suggests that these areas represent regions of hibernating myocardium.
Abstract: Thirty-seven young healthy subjects with normal renal function were studied to assess the quantitative effect of protein intake on creatinine clearance. A standard 24-h urine collection and blood sample at the end of the collection were obtained for creatinine and urea concentrations. Correlations between creatinine clearance and urinary urea nitrogen excretion (r = 0.8; P less than 0.0001) and calculated protein intake (r = 0.8; P less than 0.0001) were observed. A significant relationship between creatinine clearance and urea nitrogen excretion was also demonstrated in 28 elderly healthy subjects and 33 patients with renal disease. To demonstrate a cause and effect between urea nitrogen excretion and creatinine clearance in healthy subjects, 18 of the 37 healthy subjects repeated the 24-h urine collection and blood sample after ingesting 5 g of urea in addition to their usual diet. Mean urinary urea nitrogen excretion increased from a mean value of 9.8 +/- 4.0 to 11.8 +/- 4.0 g/day. There was a strong correlation between the changes in urea nitrogen excretion and the changes in creatinine clearance. In acute studies with oral protein loading, there was a significant correlation between creatinine clearance and urinary urea nitrogen excretion. It was concluded that protein intake has a direct and quantitative effect on creatinine clearance in healthy subjects. In normal humans, it is likely that GFR is not a fixed function. Thus, a low creatinine clearance is not a categorical sign of renal disease. A low creatinine clearance adjusted for urea nitrogen excretion may be a useful clinical tool to assess renal function.
Abstract: To study the effect of increasing amounts of exercising muscle mass on the relationship between glucose mobilization and peripheral glucose uptake, seven young men (23-28 yr) bicycled for 70 min at a work load of 55-60% VO2max. From minute 30 to 50, arm cranking was added and total work load increased to 82 +/- 4% VO2max. During leg exercise, hepatic glucose production (Ra) increased in parallel with peripheral glucose uptake (Rd) and euglycemia was maintained. During arm + leg exercise, Ra increased more than Rd and accordingly plasma glucose increased from 5.11 +/- 0.22 to 8.00 +/- 0.66 mmol/l (P less than 0.05). Plasma catecholamines increased three- to four-fold more during arm + leg exercise than during leg exercise. Leg glucose uptake increased with time regardless of arm cranking. Net leg lactate release during leg exercise was reverted to a net leg lactate uptake during arm + leg exercise. The rate of glycogen breakdown in exercising leg muscle was not altered by addition of arm cranking. In conclusion, when large amounts of muscle mass are active, plasma catecholamines increase sharply and mobilization of glucose exceeds peripheral glucose uptake. This indicates that mechanisms other than feedback regulation to maintain euglycemia are involved in hormonal and substrate mobilization during intense exercise in humans.
Abstract: We have described the overall process that is responsible for the efficient transfer of ammonium from its production site in the proximal tubule cells to the final urine. The mechanism depends on direct NH4+ transport at a number of sites. There appears to be a predominance of NH3 over NH4+ transport in net total ammonia transport only in the collecting ducts and possibly the descending limbs of Henle’s loop. Several examples of physiologically important direct NH4+ transport in the kidney were described. First, coupled Na/NH4/2Cl transport across the apical membrane of the thick ascending limb of Henle’s loop mediates secondary active transport of ammonium, which drives countercurrent multiplication of ammonium in the renal medulla. Second, part of the NH4+ uptake across the apical membrane of the thick ascending limb may occur as a result of penetration by NH4+ through apical K+ channels. It is unknown whether NH4+ penetrates K+ channels in other tubule segments. Third, NH4+ can be actively transported into cells by substitution of NH4+ for K+ on the Na-K-ATPase. This NH4+ transport process is likely to be rapid enough to be physiologically significant only in the inner medulla, where NH4+ concentrations are high enough to successfully compete with K+. Fourth, NH4+ penetrates the paracellular pathway in some nephron segments such as the proximal tubule and thick ascending limb. Simple passive diffusion of NH4+ via the paracellular pathway is thought to be physiologically important in the thick ascending limb where it contributes to net NH4+ absorption.
Abstract: In the presence of intact endothelium, in control conditions, calculated wall shear rate (WSR) (means +/- SE: 2,658 +/- 123 s-1; n = 21) was independent of arteriolar diameter (16.2-27.2 microns; correlation coefficient: r = 0.12, P greater than 0.05) in cremaster muscle of pentobarbital-anesthetized rats. An increase in blood flow velocity (due to parallel arteriolar occlusion) elicited a significant increase in WSR (to 4,981 +/- 253 s-1) followed by a delayed (6-15 s) increase in diameter (from: 22.5 +/- 0.6 to 29.5 +/- 0.8 microns), which consequently resulted in a significant decrease in WSR (to 3,879 +/- 203 s-1). As a result of the increased flow velocity and dilation, calculated arteriolar blood flow increased by 230%. After impairment of the endothelium of arterioles by a light-dye technique, basal WSR became significantly higher (3,604 +/- 341 s-1), and despite a greater increase in WSR (10,360 +/- 1,471 s-1) the dilation was absent. Now an inverse linear correlation was found between arteriolar diameter and WSR both before (r = 0.58, P less than 0.05) and during increased flow velocity conditions (r = 0.85, P less than 0.05). Also, arteriolar blood flow that was already less after impairment of endothelium increased by only 66% during the period of increased flow velocity due to the absence of dilation. Results suggest that an increase in wall shear stress is the stimulus for the endothelium-dependent mechanism that elicits "flow dependent" arteriolar dilation.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Acute hypoxemia leads to activation of the sympathetic nervous system (SNS), yet adrenergic vasoconstriction does not occur and venous plasma norepinephrine (NE) fails to rise as expected. To examine whether this dissociation between SNS tone and plasma NE is due to altered metabolism of NE, we measured arterial NE kinetics ([3H]NE infusion technique) and sympathetic nervous outflow to muscle (peroneal microneurography) during 25-30 min of hypoxemia (spontaneous breathing, mean O2 saturation 74%) in six healthy young men. During hypoxemia, muscle sympathetic nervous activity (MSNA) rose significantly from 12.2 +/- 3.3 to 18.6 +/- 3.5 bursts/min, and the total amplitude increased from 123 +/- 36 to 255 +/- 50 mm/min. NE spillover, an index of NE release at the sympathetic nerve terminals, rose from 1.66 +/- 0.30 to 2.33 +/- 0.40 nmol.min-1.m-2 (P = 0.014). However, NE clearance increased also from 0.99 +/- 0.05 to 1.19 +/- 0.11 l.min-1.m-2 (P = 0.014), and arterial NE rose from 281 +/- 50 to 339 +/- 64 pg/ml (P = 0.023). Hypoxemia resulted in a significant rise in forearm blood flow and a decrease in forearm vascular resistance. The fact that skin blood flow and vascular resistance did not change implies that forearm vasodilation was localized to skeletal muscle. Our results suggest that during acute hypoxemia in humans the SNS is activated but the rise in plasma NE is attenuated because NE clearance is increased.
Abstract: BACKGROUND. Endurance athletes have a high incidence of orthostatic intolerance. We hypothesized that this is related to an abnormally large decrease in left ventricular end-diastolic volume (LVEDV) and stroke volume (SV) for any given decrease in filling pressure. METHODS AND RESULTS. We measured pulmonary capillary wedge (PCW) pressure (Swan-Ganz catheter), LVEDV (two-dimensional echocardiography), and cardiac output (C2H2 rebreathing) during lower body negative pressure (LBNP, -15 and -30 mm Hg) and rapid saline infusion (15 and 30 ml/kg) in seven athletes and six controls (VO2max, 68 +/- 7 and 41 +/- 4 ml/kg/min). Orthostatic tolerance was determined by progressive LBNP to presyncope. Athletes had steeper slopes of their SV/PCW pressure curves than nonathletes (5.5 +/- 2.7 versus 2.7 +/- 1.5 ml/mm Hg, p less than 0.05). The slope of the steep, linear portion of this curve correlated significantly with the duration of LBNP tolerance (r = 0.58, p = 0.04). The athletes also had reduced chamber stiffness (increased chamber compliance) expressed as the slope (k) of the dP/dV versus P relation (chamber stiffness, k = 0.008 +/- 0.004 versus 0.031 +/- 0.004, p less than 0.005; chamber compliance, 1/k = 449.8 +/- 283.8 versus 35.3 +/- 4.3). This resulted in larger absolute and relative changes in end-diastolic volume over an equivalent range of filling pressures. CONCLUSIONS. Endurance athletes have greater ventricular diastolic chamber compliance and distensibility than nonathletes and thus operate on the steep portion of their Starling curve. This may be a mechanical, nonautonomic cause of orthostatic intolerance.
Abstract: In Okamoto spontaneously hypertensive rats (SHR), elevated arterial blood pressure is not transmitted to the renal interstitium, and therefore pressure natriuretic and diuretic responses are attenuated. The objective of this study was to determine the effect of increasing renal interstitial hydrostatic pressure (RIHP) by direct renal interstitial volume expansion (DRIVE) on natriuresis and diuresis of SHR and Wistar-Kyoto rats (WKY). Unilateral nephrectomy and implantation of two polyethylene (PE) matrices were performed 3-4 wk before the acute experiment. Four groups of rats, two experimental and two time control, were used. A control clearance period was taken in all groups. In experimental groups and at the beginning and middle of the second period DRIVE was accomplished by bolus injection of a solution of 2.5% human albumin in saline directly into interstitium through one of the PE matrices. In time-control groups saline was infused in renal interstitium at the beginning of the second period. The second PE matrix was used to continuously measure RIHP in all groups. In experimental groups, DRIVE produced a significant increase in RIHP from 3.8 +/- 0.4 to 5.7 +/- 0.8 mmHg (P less than 0.05) in SHR and 4.3 +/- 0.4 to 7.1 +/- 0.5 mmHg (P less than 0.05) in WKY. In both groups the significant increase in RIHP was associated with significant increases in urinary sodium excretion (UNaV), fractional excretion of sodium (FENa), and urine flow rate (V).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Hypertension is associated with a rise in arterial pressure and a compensatory increase in cardiac mass, which if not treated effectively, progresses to decompensated congestive heart failure. This decompensation of an initially compensatory hypertrophy has intensified interest in the factors that initiate and maintain the development of cardiac hypertrophy. The potential signals that induce the development of cardiac hypertrophy are grouped as hemodynamic, growth-promoting hormonal, vasoconstriction-promoting hormonal, and genetic factors. Growth-promoting hormones such as insulin and thyroxine appear to play a permissive, but essential, role in the development and maintenance of cardiac hypertrophy. However, changes in cardiac load, both above and below normal, result in parallel changes in cardiac mass, which will return to normal when a normal load is restored. This adaptive response of the myocardium in direct response to elevated and depressed loads demonstrates that cardiac structure, composition, and function are not fixed postneonatal cardiac properties, but instead are regulated dynamically by the cardiocyte loading environment. This adaptive response is subject to modulation by vasoconstriction-promoting hormones and genetic factors. The current thrust in this research area is to elucidate the cellular signals that transduce the physical stimulus for hypertrophy into biochemical events underlying hypertrophic cardiac growth. To remove complex systemic interactions in vivo from the experimental paradigm, several in vitro models have been used to examine three general, but distinct, cellular pathways involving protein kinase C activation, cyclic AMP formation, and increased ion fluxes. Each pathway demonstrated a stimulatory effect on general protein synthesis, which is necessary for growth in all cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: The source of inhibin secretion during the human menstrual cycle was investigated in two ways. The concentration of inhibin was compared in samples obtained from the ovarian and peripheral veins of 41 women undergoing hysterectomy. In 13 of the women, the corpus luteum was enucleated at operation and the peripheral concentration of inhibin measured at intervals for 24 h. Inhibin was assayed by a heterologous RIA using an antiserum raised against 31 kilodalton bovine inhibin. The concentrations of estradiol and progesterone in the peripheral and ovarian veins were similar to those previously reported. During the early follicular phase, the geometric mean inhibin concentrations were found to be significantly higher in both the right and left ovarian veins than the peripheral vein (180.4 and 157.7 vs. 78.7 U/L: P less than 0.02) but no difference was found in the late follicular phase between the vein draining the dominant ovary and the contralateral ovarian vein (231.1 vs. 193.4 U/L: NS). The inhibin concentrations in the veins draining the ovary bearing a corpus luteum were, however, significantly higher than those in the contralateral ovarian veins during the mid (409.1 vs. 203.6 U/L: P less than 0.02) and late (287.1 vs. 153.2 U/L: P less than 0.01) luteal phases. After enucleation of the corpus luteum, the inhibin concentration fell from the level seen before lutectomy (134.4 U/L) to 80.0 U/L at 24 h (P less than 0.01). This study demonstrates conclusively that the human corpus luteum secretes inhibin. No increase in inhibin secretion was seen from the dominant follicle in the late follicular phase. This casts doubt on the hypothesis that the selective suppression of FSH during the follicular phase is due to inhibin from the dominant follicle.
Abstract: We have dissociated the effects of frequency and amplitude of pulsatile flow on flow-induced release of endothelium-derived relaxing factor (EDRF) using cascade bioassay. Rat aortic segments were buffer perfused with a peristaltic pump at a constant mean flow rate of 9 ml/min. EDRF activity in effluent was measured by relaxation of endothelium-denuded rabbit aortic rings preconstricted by phenylephrine. Pulse frequency was varied over the range 0.1-12 Hz at a constant amplitude of 2 mmHg; pulse amplitude was varied over the range 2-16 mmHg at a constant frequency of 0.1 Hz. Relaxation of the detector vessel depended on frequency of flow through the donor; peak response occurred between 4.2 and 6 Hz and was approximately three times greater than that induced at lower or higher frequencies. In contrast, increases in pulse pressure amplitude (maximum 16 mmHg) monotonically augmented constriction of partially preconstricted detector tissue by up to 10%. Incubation of the donor vessel with NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthesis, or removal of its endothelium by rubbing, abolished both the frequency- and the amplitude-dependent effects observed in the detector tissue, indicating that these were mediated by changes in EDRF release. Increasing the amplitude of the pressure pulse also reduced mean perfusion pressure (by up to 50%), implying distension of donor vessel since mean flow rate was constant. This fall in pressure was not affected by incubation with L-NAME or removal of endothelium, indicating that it was not dependent on EDRF activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: To assess the roles of decrements in insulin and increments in glucagon in the prevention of hypoglycemia during moderate exercise (approximately 60% peak O2 consumption for 60 min), normal young men were studied during somatostatin infusions with insulin and glucagon infused to 1) hold insulin and glucagon levels constant, 2) decrease insulin, 3) increase glucagon, and 4) decrease insulin and increase glucagon during exercise. In contrast to a comparison study (saline infusion), when insulin and glucagon were held constant, glucose production did not increase and plasma glucose decreased from 5.5 +/- 0.2 to 3.4 +/- 0.2 mmol/l (P less than 0.001) initially during exercise. Notably, plasma glucose then plateaued and was 3.3 +/- 0.2 mmol/l at the end of exercise. This decrease was at most only delayed when either insulin was decreased or glucagon was increased independently. However, when insulin was decreased and glucagon was increased simultaneously, there was an initial increase in glucose production, and the glucose level was 4.5 +/- 0.2 mmol/l at 60 min, a value not different from that in the comparison study. Thus we conclude that both decrements in insulin and increments in glucagon play important roles in the prevention of hypoglycemia during exercise and do so by signaling increments in glucose production. However, since hypoglycemia did not develop during exercise when changes in insulin and glucagon were prevented, an additional counterregulatory factor, such as epinephrine, must be involved in the prevention of hypoglycemia during exercise, at least when the primary factors, insulin and glucagon, are inoperative.
Abstract: The hearts of rats were transplanted into the abdomens of recipients of the same inbred strain by attaching the stumps of aorta and pulmonary artery end to side to the abdominal aorta and inferior vena cava, respectively, of the recipient. The transplant functions as a denervated "nonworking" Langendorff heart; the recipient in situ heart serves as a normal control. One week after surgery, an onset of atrophy is observed in the transplanted heart, which stabilizes after 2 weeks; the in situ heart grows normally. Using this model, we increased the load of the left ventricle (LV) in the transplant by inserting a permanent polyethylene cannula into its aortic orifice during surgery to induce valvular incompetence and/or stenosis (TPE group). This resulted in significantly increased LV systolic pressure (115 +/- 5 versus 95 +/- 3 mm Hg) and a significantly increased rate-pressure product (34.7 +/- 1.7 versus 24.4 +/- 1.4 mm Hg.min-1 x 10(3) as compared with rats with control transplants (TC group). The LV mass in the TPE group decreased to only 85 +/- 4.8% of the mass of the corresponding in situ recipient heart as compared with 59 +/- 2.6% in the TC group (p less than 0.001). In three cases in the TPE group with highest overload, we observed about 20% larger LV mass in transplanted hearts as compared with the corresponding recipient in situ hearts. These results indicate that the increased load significantly attenuated the atrophy observed in LV of the isotransplants. This attenuation could be correlated with the increment of load as indicated by higher peak LV pressures and higher rate-pressure products.
Abstract: Of 838 patients with severe head injuries admitted since the introduction of computerized tomography, 211 (25.1%) talked at some time between trauma and subsequent deterioration into coma. Of these 211 patients, 89 (42.2%) had brain contusion/hematoma, 46 (21.8%) an epidural hematoma, 35 (16.6%) a subdural hematoma, and 41 (19.4%) did not show focal mass lesions. Thus, four of every five patients who deteriorated into coma after suffering an apparently nonsevere head injury had a mass lesion potentially requiring surgery: the mass was intracerebral in 52.3% of the cases and extracerebral in 47.6%. Patients aged 20 years or less had a 39% chance of having a nonfocal mass lesion (diffuse brain damage), a 29% chance of having an epidural hematoma, and a 32% chance of having an intradural mass lesion; patients over 40 years had only a 3% chance of having a nonfocal mass lesion, an 18% chance of having an epidural hematoma, and a 79% chance of having a intradural mass lesion. Sixty-eight (32.2%) patients died and 143 (67.8%) survived. The following were independent outcome predictors (in order of significance): Glasgow Coma Scale score following deterioration into coma, the highest intracranial pressure during the patient’s course, the degree of midline shift, the type of intracranial lesion, and the age of the patient. In contrast, the mechanism of injury, the verbal Glasgow Coma Scale score during the lucid interval, and the length of time until deterioration or until operative intervention did not influence the final result.
Abstract: This study, in biologically bred hyperglycemic diabetic rats, examined the effect of a intravenous insulin infusion (1.5 units.hr-1) on blood, plasma, and brain glucose concentrations to determine their relationship during decreasing blood and plasma glucose levels. The data were compared to saline-treated diabetic rats and saline-treated nondiabetic littermates. The volume and duration of the treatment infusion were similar in all groups. Insulin infusion in diabetic rats produced the expected reduction in blood and plasma glucose, and normoglycemia was produced within 78 +/- 37 minutes (mean +/- SD). However, once normoglycemia was achieved, brain glucose was still significantly greater by 44% than in nondiabetic rats (p = 0.015). Moreover, the ratio of brain to plasma glucose was more than 50% greater in diabetic than nondiabetic rats, irrespective of whether or not they received insulin (p less than 0.01). We conclude that measurement of blood or plasma glucose in diabetic subjects will tend to underestimate the amount of glucose in the brain and that this relationship is not influenced by acute insulin therapy.
Abstract: We determined whether the rate of metabolic recovery and electrophysiological deficit after incomplete cerebral ischemia is related to intracellular pH (pHi) achieved at the end of ischemia in a dose-dependent manner. End-ischemic pHi was varied by employing two ischemic durations, 12 and 30 min, and by setting preischemic plasma glucose to approximately 80 or 400 mg/dl. Incomplete global ischemia was produced in anesthetized dogs by transient intracranial hypertension followed by 4 h of reperfusion, and pHi, ATP, and phosphocreatine (PCr) were measured with 31P magnetic resonance spectroscopy. Cerebral blood flow was reduced to approximately 6 ml.min-1.100 g-1 during ischemia. End-ischemic pHi was greater than 5.7 in all animals from various treatment groups except for four of seven dogs treated with 30-min hyperglycemic ischemia. When end-ischemic pHi remained greater than 5.7, there was nearly complete recovery of ATP, PCr, pHi, intracellular bicarbonate concentration [( HCO3-]i), and O2 consumption. Partial recovery of somatosensory-evoked potentials (SEP) occurred in most of these animals. In the 30-min hyperglycemic animals in which pHi fell below 5.5, ATP, PCr, and O2 consumption recovered by only one-half over 60 min of reperfusion and then declined to near-zero levels without SEP recovery. In addition, pHi remained less than 6.0, and [HCO3-]i remained less than 2 mM throughout reperfusion. We conclude that there is an apparent in vivo pHi threshold of approximately 5.5-5.7 during incomplete cerebral ischemia that is associated with an inability to significantly restore pHi and [HCO3-]i and with secondary deterioration of high-energy phosphate levels.
Abstract: An investigation was undertaken to examine the effects of vasopressin on blood pressure and perfusion of the cortical and papillary regions of the kidney, and to determine the receptor subtype involved. Pentobarbitone-anaesthetized rats were used and laser-Doppler flowmetry applied to measure regional renal haemodynamics. Infusion of vasopressin at 10, 20 and 40 mU kg-1 min-1 caused dose-related increases in blood pressure and reductions in cortical and papillary perfusion of approximately 21, 35 and 41%, respectively at the highest dose. Administration of the V1-receptor antagonist, [1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid), 2-(o-methyl)tyrosine]-Arg8-vasopressin, at 1 microgram kg-1 plus 5 micrograms kg-1 h-1 or four times this dose had no effect on the basal levels of any variable. Vasopressin administration during the low dose of antagonist increased blood pressure and reduced papillary perfusion, the magnitudes of which were only slightly less than those obtained in the absence of the drug, whereas there was a significant attenuation of the response in cortical perfusion. During infusion of the V1 antagonist at 4 micrograms kg-1 plus 20 micrograms kg-1 h-1, vasopressin had no effect on either blood pressure or renal haemodynamics. Infusion of the V2 antagonist, [d(CH2)5, D-Phe2, Ile4, Arg8, Ala9-NH2]-vasopressin at 1 microgram kg-1 plus 5 micrograms kg-1 h-1, and twice this dose had no effect on the basal value of any variable and had no effect on the ability of vasopressin to induce an increase in blood pressure or cause reductions in renal cortical and papillary perfusions. However, the administration of the V2 antagonist at 4 micrograms kg-1 plus 20 micrograms kg-1 h-1 significantly attenuated blood pressure, cortical and papillary perfusion responses to the vasopressin. These studies have shown that vasopressin, given at doses which increased blood pressure, caused dose-related decreases in perfusion of renal cortex as well as the papilla. The data further show that these systemic and renal actions were mediated primarily by V1-receptors and that the contribution of V2-receptors at these vascular beds was very small.
Abstract: To decide whether tubuloglomerular feedback (TGF) can account for renal autoregulation, we tested predictions of a TGF simulation. Broad-band and single-frequency perturbations were applied to arterial pressure; arterial blood pressure, renal blood flow and proximal tubule pressure were measured. Data were analyzed by linear systems analysis. Broad-band forcings of arterial pressure were also applied to the model to compare experimental results with simulations. With arterial pressure as the input and tubular pressure, renal blood flow, or renal vascular resistance as outputs, the model correctly predicted gain and phase only in the low-frequency range. Experimental results revealed a second component of vascular control active at 100-150 mHz that was not predicted by the simulation. Forcings at single frequencies showed that the system behaves linearly except in the band of 33-50 mHz in which, in addition, there are autonomous oscillations in TGF. Higher amplitude forcings in this band were attenuated by autoregulatory mechanisms, but low-amplitude forcings entrained the autonomous oscillations and provoked amplified oscillations in blood flow, showing an effect of TGF on whole kidney blood flow. We conclude that two components can be detected in the dynamic regulation of renal blood flow, i.e., a slow component that represents TGF and a faster component that most likely represents an intrinsic vascular myogenic mechanism.
Abstract: We have used the isolated perfused tubule technique, measurements of adenosine 3’,5’-cyclic monophosphate (cAMP) content in single tubules, and freeze-fracture electron microscopy to study the basis of high vasopressin-independent (basal) osmotic water permeability (Pf) in the terminal inner medullary collecting duct (IMCD) of the rat. The results confirmed the observation that the basal Pf of the terminal IMCD is considerably higher than that of the initial IMCD. They also showed that the basal Pf of the terminal IMCD is regulated by in vivo factors related to water intake, such that a very high vasopressin-independent Pf can be induced in isolated tubules by prior in vivo thirsting. Tubules from thirsted rats did not display elevated urea permeabilities, nor did they exhibit measurable cAMP levels in the absence of exogenous vasopressin, indicating that the high basal Pf was not due to residual binding of vasopressin to its receptors. Freeze-fracture studies in thirsted rats demonstrated the presence of intramembrane particle (IMP) clusters in both initial and terminal IMCD, with more in the latter. Water loading of the rats suppressed the incidence of clusters almost entirely but did not fully suppress the basal Pf in the terminal IMCD, raising the possibility that a component of transepithelial water transport may occur independently of the vasopressin-regulated IMP clusters. On the basis of these results, we conclude that the vasopressin-independent Pf in the terminal IMCD can be stably elevated to very high levels in response to in vivo thirsting. This elevation appears to be due to a chronic conditioning effect mediated by unknown in vivo factors and is not due to the short-term cAMP-mediated regulatory effect of vasopressin.
Abstract: The tubuloglomerular feedback (TGF) mechanism is of importance in the regulation of glomerular filtration rate (GFR). A second mechanism of potential importance is the change in proximal pressure caused by a change, for example, in the rate of proximal fluid reabsorption. The quantitative contributions of these two mechanisms to the regulation of GFR and the late proximal flow rate are not known. To determine the regulatory efficiency of these two mechanisms, the late proximal flow rate was perturbed by microperfusion with artificial tubular fluid in halothane-anesthetized Sprague-Dawley rats. The resulting changes in late proximal flow rate were measured by pulse injection of rhodamine dextran. Fluorescence was excited by means of a He-Ne laser. Bolus velocity was measured by videomicroscopy. Tubular pressure was measured by the servonulling method. The microperfusion rate was varied from -15 to 20 nl/min in steps of 5 nl/min. The open-loop gain (OLG) was 3.1 (range 1.5-9.9, n = 13) at the unperturbed tubular flow rate, and decreased as the tubular flow rate was either increased or decreased. The proximal pressure increased by 0.21 +/- 0.03 mmHg per unit increase in late proximal flow rate (nl/min). By use of a mathematical model of the glomerulus, it is estimated that under the present experimental conditions the pressure increase contributes 8% (range 3-15%) of the OLG. It is concluded that, for small perturbations around the operating point, TGF accounts for most of the regulation of GFR and the late proximal flow rate, with changes in the proximal pressure of lesser importance. Furthermore, under closed-loop conditions the operating point for the TGF mechanism is at or close to the point of maximal sensitivity.
Abstract: Experimental and clinical studies have revealed a worsened neurologic outcome after cerebral ischemia in hyperglycemic subjects, including hyperglycemic diabetic subjects. A possible therapy to reduce the magnitude of ischemic brain injury in diabetic subjects would be to use an insulin infusion to reduce brain glucose concentrations to values found in those who are normoglycemic and non-diabetic. The present study, using hyperglycemic diabetic rats, examined the effect of an insulin infusion on plasma and brain glucose concentrations to determine their relationship while plasma glucose concentrations decreased. In addition, plasma and brain glucose concentrations were compared to those in diabetic and nondiabetic rats treated with saline. Saline had no effect on the plasma or brain glucose concentrations in the diabetic rats or nondiabetic rats. The saline-treated diabetic rats had increased plasma and brain glucose concentrations as well as an increased brain-to-plasma glucose ratio when compared to the saline-treated nondiabetic rats. When an insulin infusion was used in diabetic rats to decrease plasma glucose to nondiabetic levels over approximately 2 h, the brain glucose concentration decreased. However, the brain-to-plasma glucose ratio remained at the "diabetic" value, so that the brain glucose concentration tended to remain increased when compared to normoglycemic, nondiabetic rats. We conclude that if these results are applicable to humans, measurement of plasma glucose in diabetic patients will underestimate the amount of glucose in the brain and this relationship will not be influenced by acute insulin therapy.
Abstract: 1. This review summarizes current knowledge relating to the volume-regulatory and osmoprotective functions of amino acids in mammalian cells exposed to anisosmotic fluids. 2. Experiments in vivo and in vitro have established that they play a significant role in regulating brain cell volume under these conditions, and that taurine may be of particular importance in this respect. 3. Their possible role in renal medulla is discussed, and it is suggested that they may protect cells against acute (but not long-term) osmotic variation. 4. Evidence is briefly presented regarding adaptive changes in amino acid content of other cell types.
Abstract: We studied the ventilatory effects of desflurane (formerly I-653) with and without N2O in healthy male volunteers. After insertion of venous and arterial (radial and pulmonary) catheters, baseline measurements of tidal volume (VT), respiratory rate (RR), ventilatory response to CO2, and arterial and mixed venous blood gases were made. Subjects were randomly assigned to receive either desflurane with O2 (n = 6) or with O2 and 60% N2O (n = 6). Anesthesia was induced by inhalation of desflurane followed by tracheal intubation without muscle relaxants. In each volunteer, at end-tidal concentrations totaling 0.83, 1.24, and 1.66 MAC, we repeated measurements of VT, RR, response to CO2, and arterial and mixed venous blood gases. As depth of anesthesia increased, VT significantly (P less than 0.05) decreased from 363 +/- 22 ml awake to 76 +/- 22 ml at 1.66 MAC without N2O and from 473 +/- 70 ml awake to 128 +/- 6 ml at 1.66 MAC with N2O (mean +/- SE). Similarly, RR increased from 15 +/- 0.5 breaths per min awake to 32 +/- 2 breaths per min at 1.66 MAC without N2O and from 14 +/- 0.5 breaths per min awake to 40 +/- 3 breaths per min at 1.66 MAC with N2O. Desflurane without N2O depressed the ventilatory response to CO2 to 45 +/- 9, 31 +/- 5, and 11 +/- 4% of the awake values at 0.83, 1.24, and 1.66 MAC, respectively. With N2O, values were 52 +/- 14, 23 +/- 5, and 26 +/- 9% of the awake value at 0.83, 1.24, and 1.66 MAC, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Serious central nervous system injuries after lightning strikes are fortunately rare. Optimal neurological and neurosurgical management has not been firmly established. We describe the successful neurological resuscitation and critical care management using intracranial pressure monitoring of an adult who sustained a lightning strike. The role of intracranial pressure monitoring in this setting is discussed.
Abstract: Work-related electrical injuries and fatalities in Virginia were reviewed for the period 1977 to 1985. Of 196 workers electrocuted (0.9/100,000/year), 65% (127) died between May and September. Death rates were highest for male workers in utility companies (10.0/100,000), mining (5.9/100,000), and construction industries (3.9/100,000), but these high risk groups accounted for only 50% of the deaths. Most accidental electrocutions resulted from power line contact (53%) and machine or tool usage or repair (22%). Only 1.5% (2/101) of the workers who died within 6 hours of injury and had blood alcohol concentration tested were legally intoxicated. All workers need safety education on active measures to prevent hazardous electrical exposures, not just those at high risk for electrical injury. Every work-related electrical injury represents a sentinel health event–an opportunity for preventive intervention in the workplace.
Abstract: Twelve brain-dead patients admitted to the Department of Traumatology, Osaka University Hospital, from July 1988 to August 1989 were studied. A hemodynamic response elicited by passive neck flexion was observed in 10 of the 12 patients. After passive neck flexion, blood pressure began to rise, and the heart rate increased slightly. Blood pressure peaked about 2 minutes after the initiation of neck flexion and then decreased gradually to the baseline level within a few minutes. These responses were suppressed completely by administration of the ganglion blocker trimethaphan camsilate, which suggests that the efferent pathway of the response is mediated by the sympathetic nervous system.
Abstract: Seizures are common in hyperglycemia and are often the first manifestation, particularly in nonketotic hyperglycemia (NKH). Published reports emphasize partial motor seizures almost exclusively. In a 3-year period, we observed three patients in whom occipital seizures, documented by ictal EEG recording, were the initial symptom of hyperglycemia. One patient was mildly ketotic at first. Seizures were visual in two patients and visual and adversive in the third. Seizures regressed with correction of abnormal glucose levels and did not recur during follow-up of less than or equal to 1 year despite discontinuation of antiepileptic drugs (AEDs) in two. Computed tomography (CT) scans did not show correlative abnormalities. Although published reports suggest that frontal lobe structures are particularly susceptible to the epileptogenic effects of NKH, our experience indicates that in NKH epileptic foci may originate in other cortical areas, such as occipital.
Abstract: Estimates of regional blood volumes (BVs) in man are needed for the dosimetry of radionuclides that decay in the circulation to a significant extent. The tabulation of regional BVs in Publication No. 23 of the International Commission on Radiological Protection (ICRP Reference Man document) may be the best available for dosimetric applications but is not consistent with current information for some organs and does not address some important blood pools. The purpose of this paper is to suggest an improved set of reference values for regional BVs in adult humans. The total blood volume (TBV) is viewed as comprising 22 separate pools, including several pools not addressed in the ICRP Reference Man document. Values suggested here for brain, liver, skin, active marrow, inactive marrow, and bone differ by at least a factor of two from those given for ICRP Reference Man.
Abstract: By use of a combined tc-pO2 skin blood flow sensor E5250 and measurement of cutaneous and subcutaneous blood flows with the 133Xenon washout method it was demonstrated that blood flow in both tissues increases with a factor of 3-4 when the electrode temperature increases from 37 to 45 degrees C. In order to examine the influence of the gas diffusion barrier within the epidermal membrane the stratum corneum of the forearm was removed selectively by stripping with adhesive tape. Stripping increased the oxygen tension values from 10.98 +/- 0.63 kPa to 14.58 +/- 1.03 kPa, and skin oxygen consumption ranged from 0.208 to 0.251 ml O2.(100g.min)-1. The combination of a Clark type electrode with a heat sensor allows determination of oxygen delivery to the skin as well as the oxygen supplying cutaneous blood flow. The distribution of blood flow between nutritional and shunt vessels at various local temperatures remains to be clarified.
Abstract: The metabolic changes associated with the sudden onset of ischemia caused by occlusion of a major coronary artery include (a) cessation of aerobic metabolism, (b) depletion of creatine phosphate (CP), (c) onset of anaerobic glycolysis, and (d) accumulation of glycolytic products, such as lactate and alpha glycerol phosphate (alpha GP), and catabolites of the nucleotide pools in the tissue. These changes are associated with contractile failure and electrocardiographic alterations. Since the demand of the myocardium for high-energy phosphate (approximately P) exceeds the available supply, the net amount of ATP in tissue decreases. Eighty percent of the supply of approximately P utilized by severely ischemic tissue comes from anaerobic glycolysis using glycogen as the principal substrate. Early in ischemia, contractile activity utilizes ATP, but much of the continuing utilization of ATP by the ischemic tissue is energy wasted via the mitochondrial ATPase. A lesser quantity of ATP is used by ion transport ATPases. Metabolic changes slow as the duration of ischemia increases. Irreversibly injured myocytes exhibit (a) very low levels of ATP (less than 10% of control); (b) cessation of anaerobic glycolysis; (c) high levels of H+, AMP, INO, lactate, and alpha GP; (d) a greatly increased osmolar load; (e) mitochondrial swelling and formation of amorphous matrix densities; and (f) disruption of the sarcolemma. The latter event is generally recognized as lethal, but its pathogenesis remains to be established. Most severely ischemic myocytes are dead in regional ischemia in the anesthetized open-chest dog heart after only 60 minutes of ischemia. Less severely ischemic myocytes in the mid- and subepicardial myocardium survive for as long as six hours. Virtually all myocytes destined to die in a zone of ischemia are irreversibly injured after six hours of ischemia have passed. Certain changes exhibited by myocytes injured by severe ischemia and reperfused late in the reversible phase of injury do not return to the control conditions for a period of days, while others rebound in only seconds to minutes. The adenine nucleotide pool still is not fully restored after four days of reperfusion. Stunning disappears after one to two days of reflow. The preconditioning effect is partially lost after two hours of reperfusion. The timing of its disappearance has not been fully established. Aerobic metabolism is restored after only a few minutes of reperfusion. Thus, reperfusion salvages injured myocardium and restores its structure and function to the control state at a variable rate.
Abstract: To determine the role of arterial O2 content on the mechanism of muscle O2 utilization, we studied the effect of 2, 11, and 20% carboxyhemoglobin (COHb) on O2 uptake (VO2), and CO2 output (VCO2) kinetics in response to 6 min of constant moderate- and heavy-intensity cycle exercise in 10 subjects. Increased COHb did not affect resting heart rate, VO2 or VCO2. Also, the COHb did not affect the asymptotic VO2 in response to exercise. However, VO2 and VCO2 kinetics were affected differently. The time constant (TC) of VO2 significantly increased with increased COHb for both moderate and heavy work intensities. VO2 TC was positively correlated with blood lactate. In contrast, VCO2 TC was negatively correlated with increased COHb for the moderate but unchanged for the heavy work intensity. The gas exchange ratio reflected a smaller increase in CO2 stores and faster VCO2 kinetics relative to VO2 with increased COHb. These changes can be explained by compensatory cardiac output (heart rate) increase in response to reduced arterial O2 content. The selective slowing of VO2 kinetics, with decreased blood O2 content and increased cardiac output, suggests that O2 is diffusion limited at the levels of exercise studied.
Abstract: We have reported oscillations in proximal tubular pressure and flow and in distal tubular pressure and chloride concentration in halothane-anesthetized Sprague-Dawley rats. These variables oscillated at the same frequency in each animal, approximately 35 mHz, but were out of phase with each other. We suggested that the oscillation arises within the tubuloglomerular feedback (TGF) system. As a test of this hypothesis, we have now developed a dynamic model to determine whether it can simulate the measured frequency and phase relationships with a realistic set of parameters. The model includes a detailed representation of pressure and flow in the tubules based on a reduced version of the Navier-Stokes equations. The NaCl concentration at the macula densa was used as the signal to the TGF mechanism. The tubular NaCl concentration was modeled by a partial differential equation based on conservation of mass. For a realistic set of parameter values the model accurately predicted oscillations with the same frequency and phase relationships among the oscillating variables as was found experimentally. Moreover, tubular NaCl handling significantly influenced the dynamic properties of the TGF system. Thus the model predicted a substantial phase shift of the NaCl concentration relative to the flow oscillation at the macula densa. The results are consistent with the hypothesis that the oscillations are caused by the TGF mechanism. The results further support the notion that the delays and damping caused by the tubule are responsible for the limited high-frequency response of renal autoregulation.
Abstract: Renal electrolyte and net acid excretion were characterized during generation and maintenance of hypochloremic metabolic alkalosis in a ruminant model. Two phases of renal response with regard to sodium and net acid excretion were documented. An initial decrease in net acid excretion was attributable to increase in bicarbonate excretion with associated increase in sodium excretion. As the metabolic disturbance became more advanced, a second phase of renal excretion was observed in which sodium and bicarbonate excretion were markedly decreased, leading to increase in net acid excretion and development of aciduria. Throughout the metabolic disturbance, chloride excretion was markedly decreased; potassium excretion also decreased. These changes were accompanied by increase in plasma renin and aldosterone concentrations. There was apparent failure to concentrate the urine optimally during the course of the metabolic disturbance, despite increasing plasma concentration of antidiuretic hormone.
Abstract: The present study was undertaken to evaluate some pathophysiological mechanisms of edema formation in diabetic nephropathy. Sixty-three subjects were investigated: 9 normal subjects (I), 9 normoalbuminuric Type 1 (insulin-dependent) diabetic patients (II), 15 microalbuminuric Type 1 diabetic patients (III), 16 Type 1 diabetic patients with nephropathy without edema (IV), and 14 Type 1 diabetic patients with nephropathy and edema (V). Plasma volume (125I-albumin), glomerular filtration rate and extracellular fluid volume (51Cr-EDTA) were measured. Colloid osmotic pressure and albumin concentration were measured in plasma and in subcutaneous interstitial fluid (suction blister technique). The ratio between plasma volume and interstitial fluid volume was reduced in patients with edema compared with group 1 (P less than 0.05). The interstitial colloid osmotic pressure (mm Hg) was significantly reduced (P less than 0.05) in group V compared with the other groups (V: 4.3 +/- 1.1, I: 7.9 +/- 1.7, II: 7.5 +/- 1.8, III: 6.6 +/- 1.5, IV: 6.6 +/- 1.1), but the transcapillary colloid osmotic gradient in patients with edema was comparable with the remaining subjects. The ratio between interstitial and plasma albumin concentration was significantly reduced in group V compared with groups I and II (V: 0.31 +/- 0.1, I: 0.43 +/- 0.06, II: 0.44 +/- 0.06; P less than 0.01; III: 0.41 +/- 0.07, IV: 0.41 +/- 0.08). This reduction was mainly due to enhanced lymph flow. The wash-down of subcutaneous interstitial protein indicated increased capillary filtration, but at the same time limited the increase in net filtration pressure and thereby prevented progressive edema formation in diabetic nephropathy.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: In the present study we investigated the effects of carboxyhemoglobinemia (HbCO) on muscle maximal O2 uptake (VO2max) during hypoxia. O2 uptake (VO2) was measured in isolated in situ canine gastrocnemius (n = 12) working maximally (isometric twitch contractions at 5 Hz for 3 min). The muscles were pump perfused at identical blood flow, arterial PO2 (PaO2) and total hemoglobin concentration [( Hb]) with blood containing either 1% (control) or 30% HbCO. In both conditions PaO2 was set at 30 Torr, which produced the same arterial O2 contents, and muscle blood flow was set at 120 ml.100 g-1.min-1, so that O2 delivery in both conditions was the same. To minimize CO diffusion into the tissues, perfusion with HbCO-containing blood was limited to the time of the contraction period. VO2max was 8.8 +/- 0.6 (SE) ml.min-1.100 g-1 (n = 12) with hypoxemia alone and was reduced by 26% to 6.5 +/- 0.4 ml.min-1.100 g-1 when HbCO was present (n = 12; P less than 0.01). In both cases, mean muscle effluent venous PO2 (PVO2) was the same (16 +/- 1 Torr). Because PaO2 and PVO2 were the same for both conditions, the mean capillary PO2 (estimate of mean O2 driving pressure) was probably not much different for the two conditions, even though the O2 dissociation curve was shifted to the left by HbCO. Consequently the blood-to-mitochondria O2 diffusive conductance was likely reduced by HbCO.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: In rat cremaster muscle, utilizing parallel arteriolar occlusion, we found that an increase in red blood cell (RBC) velocity (3.5-26.5 mm/s) per se induced an increase in diameter (1.5-9.4 microns) of arterioles (mean control diam 21.5 +/- 0.6 microns; n = 25). The dilation of arterioles appeared only when RBC velocity increased and started always with a delay (mean 8.4 +/- 0.5 s) after the increase in flow velocity. A positive linear correlation was found between peak changes in RBC velocity and diameter (r = 0.87, P less than 0.05). The velocity sensor as well as the mechanism(s) that mediates this response is likely to be located in endothelial cells, because the dilation to increased RBC velocity was completely eliminated after impairment of arteriolar endothelium with light-dye (L-D) treatment. The in vivo demonstration of this phenomenon in arterioles suggests the existence of a new endothelium-dependent, flow velocity-sensitive mechanism for the regulation of blood flow in the microcirculation.
Abstract: 1. Glucose uptake and transport, muscle glycogen, free glucose and glucose-6-phosphate concentrations were studied in perfused resting and contracting rat skeletal muscle with different pre-contraction glycogen concentrations. Rats were pre-conditioned by a combination of swimming exercise and diet, resulting in either low (glycogen-depleted rats), normal (control rats) or high (supercompensated rats) muscle glycogen concentrations at the time their hindlimbs were perfused. 2. Compared with control rats, pre-contraction muscle glycogen concentration was approximately 40% lower in glycogen-depleted rats, whereas it was 40% higher in supercompensated rats. Muscle glycogen break-down correlated positively (r = 0.76; P less than 0.001) with pre-contraction muscle glycogen concentration. 3. Glucose uptake during contractions was approximately 50% higher in glycogen-depleted hindquarters than in control hindquarters; in supercompensated hindquarters it was 30% lower. When rats with similar muscle glycogen concentrations were compared, glucose uptake in hindquarters from rats that had exercised on the preceding day was approximately 20% higher than in hindquarters from rats that had not exercised on the preceding day. 4. Muscle membrane glucose transport, as measured by the rate of accumulation of 14C-3-O-methylglucose in the contracting muscles, was 25% lower in supercompensated than in glycogen-depleted muscles at the onset as well as at the end of the 15 min contraction period. 5. Intracellular concentrations of free glucose and glucose-6-phosphate were higher at rest and during the entire 15-min stimulation period in supercompensated muscles than in glycogen-depleted muscles, and glucose uptake during contractions correlated negatively with free glucose (r = -0.52; P less than 0.01) as well as with glucose-6-phosphate (r = -0.49; P less than 0.01) concentrations. 6. It is concluded that: (a) The rate of glucose uptake in contracting skeletal muscle is dependent on the pre-contraction muscle glycogen concentration. Regulating mechanisms include limitations of membrane glucose transport as well as of glucose metabolism. (b) Contractions on the preceding day have a stimulating effect on glucose uptake during contractions of the same muscles on the next day.
Abstract: The effects of free fatty acids (FFA) on insulin receptor binding and processing (internalization, degradation, dissociation, and release) were examined in hepatocytes isolated from 12-week-old female rats. Animals were fasted for 24 h to deplete liver glycogen and lipid content. Cells were preincubated for 30 min or 3 h at 37 degrees C in media containing 10 mM lactate, 1 mM pyruvate, and 3.5 percent albumin with increasing concentrations of palmitate (0.00, 0.05, 0.2, 0.5, 1.0 and 2.0 mM). Under these conditions palmitate is the primary substrate for cellular metabolism, and its major fate is oxidation. Equilibrium binding was determined after 18-20 h of incubation at 4 degrees C with radiolabeled insulin and increasing concentrations of unlabeled hormone. With increasing palmitate concentration, a dose-dependent decline in cell-surface insulin receptor binding was observed. Binding decreased by 35 percent and 44 percent after 30 min and 3 h of preincubation with 2 mM palmitate, respectively. This decrease was due to a reduction in insulin receptor number. Receptor-mediated insulin processing was evaluated in cells prelabeled at 4 degrees C with 125I (A14)-monoiodoinsulin at an insulin concentration of 100 pM and reincubated at 37 degrees C for up to 30 min. The amount of internalized insulin was decreased by preincubation of hepatocytes with palmitate. This decrease was proportional to the reduction in cell-surface insulin receptor density at palmitate concentrations of 0.05-0.5 mM, but was disproportionally greater at higher fatty acid concentrations. Receptor-mediated insulin degradation decreased at palmitate concentrations between 0.05 and 1.0 mM. At 2 mM, however, insulin degradation was enhanced. This enhancement was observed after 30 min or 3 h of exposure to the fatty acid. Dissociation and/or release of cell-associated internalized insulin was not influenced by the FFA exposure. The effects of FFA on hepatocyte insulin binding and processing were contingent upon cellular metabolism, since no changes were noted when cells were preincubated with palmitate at 4 degrees C under otherwise similar conditions. Thus the in vitro exposure of hepatocytes to FFA influences both receptor and postreceptor events mediating insulin metabolism. These effects may account for the altered hepatic insulin extraction and sensitivity that accompany abdominal obesity and its progression to diabetes.
Abstract: 1. Multiwire surface electrodes were used to measure local hydrogen clearance curves and tissue PO2 in vivo. Evaluation of the initial slopes of the hydrogen clearance curves enabled the measurement of capillary blood flow and its distribution. 2. Capillary blood flow and tissue PO2 frequency distribution histograms were measured in the m. sartorius of anaesthetized, relaxed mongrel dogs under conditions of normoxic (Fi, O2 = 0.3) and hypoxic (Fi, O2 = 0.15 and 0.1) artificial ventilation. 3. Stepwise hypoxaemia (hypoxic hypoxia) induced an increasing discrepancy between capillary blood flow and arterial blood flow. The former decreased by 6% whereas the latter increased by 86%. 4. PO2 histograms provided no evidence of cellular anoxia even at Fi,O2 = 0.1. Capillary blood flow histograms suggested a redistribution of the local pattern of flow. 5. A 34.7% reduction of O2 consumption was observed as the result of severe hypoxaemia. 6. The concept of heterogeneity of capillary blood flow as a functional O2 reserve is presented, together with evidence for oxygen-dependent regulation of capillary blood flow and oxygen consumption.
Abstract: The half-life (t1/2) and metabolic clearance rate (MCR) of exogenous natural porcine oxyntomodulin (porcine OXM) and the synthetic analog of rat oxyntomodulin, [Nle27]-OXM (rat OXM), were compared with that of glucagon in control, sham-operated and acutely nephrectomized rats using the primed-continuous infusion technique. The half-disappearance times for porcine OXM (8.2 +/- 0.5 min) and rat OXM (6.4 +/- 0.5 min) were 3-fold slower than that of glucagon (1.9 +/- 0.1 min). Acute bilateral nephrectomy significantly prolonged the half-disappearance time of rat OXM (8.2 +/- 0.7 min) and glucagon (3.6 +/- 0.4 min) compared with that of sham-operated animals (6.5 +/- 0.8 min and 2.5 +/- 0.2 min, respectively). The mean MCRs were similar for porcine and rat OXM (11.3 +/- 0.7 and 11.9 +/- 0.5 ml.kg-1.min-1) but were 3 times lower than that measured with glucagon (36 +/- 5 ml.kg-1.min-1). Bilateral nephrectomy reduced the MCR of OXM and glucagon by 38% and 34%, respectively. No significant increase in C-terminal glucagon immunoreactivity was noticed during infusion of either porcine or rat OXM, measured directly in plasma, with a specific C-terminal glucagon antiserum or after HPLC. In the course of the glucagon infusion, blood glucose was increased 2-fold, while the same dose of porcine OXM or of rat OXM induced only a small increase over the values in phosphate buffer-infused rats. 10 times higher doses of rat OXM were necessary to obtain a similar hyperglycemic effect. These results indicate that: (1) the metabolism of OXM is 3-fold slower than that of glucagon, (2) renal clearance contributed close to 35% of the overall metabolic plasma extraction for OXM and glucagon and (3) OXM, although effective at a higher dose, when compared with glucagon, displays a hyperglycemic effect probably through the glucagon receptors.
Abstract: We demonstrated previously that intravenous administration of exogenous atrial natriuretic peptide (ANP) lowers mean pulmonary arterial pressure (MPAP) in hypoxia-adapted rats. To test the hypothesis that endogenous ANP may also lower MPAP in this model, C-ANP-(4-23), a ring-deleted analogue of ANP that binds to the biologically silent ANP clearance receptor (C-ANP receptor) but not to the ANP biological receptor (B-ANP receptor), was administered intravenously as a bolus injection (10 micrograms/kg) followed by an infusion (1 micrograms.kg-1.min-1 for 60 min) to rats adapted to hypoxia (10% O2) for 4 wk and to air control rats. C-ANP-(4-23) significantly lowered MPAP in hypoxic rats but not in air controls. A statistically insignificant reduction in mean systemic arterial pressure was found in both groups after C-ANP-(4-23) administration. C-ANP-(4-23) significantly (two- to threefold) increased endogenous plasma ANP levels in both groups; the increase was not significantly different between groups. Both basal and post-C-ANP-(4-23) levels of plasma ANP were greater in hypoxia-adapted animals than in air controls; the C-ANP-induced increase in plasma ANP was not significantly different between groups. These results suggest that the endogenous ANP may modulate pulmonary vascular tone in rats with hypoxic pulmonary hypertension.
Abstract: We investigated the effects of carbon dioxide-producing and carbon dioxide-consuming buffers on intramyocardial pH and on cardiac resuscitability. In 29 pigs, intramyocardial pH was continuously measured with a glass electrode advanced into the midmyocardium of the posterior left ventricle through a diaphragmatic window. Ventricular fibrillation (VF) was electrically induced by alternating current applied to the epicardium of the left ventricle. After 3 minutes of VF, precordial compression was begun and continued for an interval of 8 minutes. Sodium bicarbonate (a carbon dioxide-generating buffer), Carbicarb (a carbon dioxide-consuming buffer), and hypertonic sodium chloride (control solution) were infused into the right atrium during cardiac resuscitation. Defibrillation was attempted by transthoracic direct-current shock after 11 minutes of VF. Intramyocardial pH progressively decreased from an average value of 7.26 before VF to 6.87 before infusion of buffers. Systemic circulation and great cardiac vein pH significantly increased after administration of the two buffer agents. However, intramyocardial pH continued to decline to an average of 6.62 after 11 minutes of VF, and this decline was not altered by either buffer solution or by the saline control. As in previous studies, resuscitability was closely related to coronary perfusion pressure at the time of direct-current countershock but not to pH. Accordingly, the rationale of reversing acidosis by the administration of these buffer agents is not supported. Even more important, neither carbon dioxide-consuming nor carbon dioxide-producing buffers altered myocardial acidosis or improved myocardial resuscitability under controlled experimental conditions of cardiac arrest.
Abstract: In subjects without coronary disease, coronary perfusion pressure generated with closed-chest cardiopulmonary resuscitation (CPR) bears a direct relationship to myocardial blood flow. The effect of coronary lesions on this relationship was studied in an experimental porcine model not requiring thoracotomy. Coronary stenoses (a 50% reduction in coronary cross-sectional area) or total coronary occlusions were created by percutaneous, transarterial catheter placement of a Teflon cylinder in the left anterior descending artery of 21 swine (30 to 60 kg). Coronary perfusion pressure, defined as the aortic diastolic pressure minus right atrial diastolic pressure, was correlated with myocardial blood flow measured with nonradioactive, colored microspheres during external chest compression CPR. Complete occlusion of the left anterior coronary artery resulted in essentially no CPR-generated blood flow to the anterior myocardium distal to the site of occlusion. Coronary perfusion pressure showed a positive correlation with myocardial blood flow above the area of occlusion (r = 0.783; p less than 0.01) but did not correlate with myocardial blood flow below the occlusion site (r = 0.239). In the presence of a patent coronary artery stenosis, coronary perfusion pressure correlated with myocardial blood flow both above (r = 0.841; p less than 0.001) and below (r = 0.508; p less than 0.05) the stenosis. During closed-chest CPR producing coronary perfusion pressures between 30 and 60 mm Hg, anterior myocardial blood flow was 109 +/- 16 ml/min/100 gm above a patent stenosis and 66 +/- 13 ml/min/100 gm below the stenosis (p less than 0.005). Over a wide range of coronary perfusion pressures, myocardial blood flow below a coronary lesion was significantly less than that above the lesion. Coronary occlusions and stenoses can substantially affect the amount of CPR-generated coronary perfusion pressure needed to produce distal myocardial blood flow.
Abstract: The purpose of this study was to examine the effects of the increased sympathetic activity elicited by the upright posture on blood flow to exercising human forearm muscles. Six subjects performed light and heavy rhythmic forearm exercise. Trials were conducted with the subjects supine and standing. Forearm blood flow (FBF, plethysmography) and skin blood flow (laser Doppler) were measured during brief pauses in the contractions. Arterial blood pressure and heart rate were also measured. During the first 6 min of light exercise, blood flow was similar in the supine and standing positions (approximately 15 ml.min-1.100 ml-1); from minutes 7 to 20 FBF was approximately 3-7 ml.min-1.100 ml-1 less in the standing position (P less than 0.05). When 5 min of heavy exercise immediately followed the light exercise, FBF was approximately 30-35 ml.min-1.100 ml-1 in the supine position. These values were approximately 8-12 ml.min-1.100 ml-1 greater than those observed in the upright position (P less than 0.05). When light exercise did not precede 8 min of heavy exercise, the blood flow at the end of minute 1 was similar in the supine and standing positions but was approximately 6-9 ml.min-1.100 ml-1 lower in the standing position during minutes 2-8. Heart rate was always approximately 10-20 beats higher in the upright position (P less than 0.05). Forearm skin blood flow and mean arterial pressure were similar in the two positions, indicating that the changes in FBF resulted from differences in the caliber of the resistance vessels in the forearm muscles.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: We sought to determine whether tubuloglomerular feedback (TGF), activated from one nephron, affects other arterioles derived from the same cortical radial artery. Surface nephrons supplied by a single cortical radial artery were identified by injecting Ringer solution containing Fast Green from a narrow-gauge polyethylene catheter inserted via a lumbar artery into a renal artery. Stop-flow pressure was measured in an identified nephron from such a grouping. In one series, increasing end-proximal flow rate from 0 to 50 nl/min of synthetic tubular fluid in one member of an identified pair of nephrons reduced stop-flow pressure by 1.3 +/- 0.2 mmHg in the other member. When the nephrons were derived from different cortical radial arteries, the stop-flow pressure changed -0.2 +/- 0.1 mmHg. In another series, increasing flow in the adjacent nephron from 0 to 50 nl/min decreased stop-flow pressure 3.9 +/- 0.9 mmHg, and increasing flow in the adjacent nephron by the same amount when flow in the first nephron was 50 nl/min decreased stop-flow pressure 3.4 +/- 0.7 mmHg. These results indicate the operation of an interaction among nephrons derived from a common cortical radial artery. Such an interaction could produce a cooperative effect larger than that predicted from measured single-nephron responses when systemic arterial pressure changes.
Abstract: We studied the effects of varying degrees and durations of hypernatremia on the brain concentrations of organic compounds believed to be important, so-called "idiogenic" osmoles in rats by means of conventional biochemical assays, nuclear magnetic resonance spectroscopy, and high-performance liquid chromatography. There were no changes in the concentrations of these osmoles (specifically myoinositol, sorbitol, betaine, glycerophosphorylcholine [GPC], phosphocreatine, glutamine, glutamate, and taurine) in rats with acute (2 h) hypernatremia (serum Na 194 +/- 5 meq/liter). With severe (serum Na 180 +/- 4 meq/liter) chronic (7 d) hypernatremia, the concentrations of each of these osmoles except sorbitol increased significantly: myoinositol (65%), betaine (54%), GPC (132%), phosphocreatine (73%), glutamine (143%), glutamate (84%), taurine (78%), and urea (191%). Together, these changes account for 35% of the change in total brain osmolality. With moderate (serum Na 159 +/- 3 meq/liter) hypernatremia, more modest but significant increases in the concentrations of each of these osmoles except betaine and sorbitol were noted. When rats with severe chronic hypernatremia were allowed to drink water freely, their serum sodium as well as the brain concentrations of all of these organic osmoles except myoinositol returned to normal within 2 d. It is concluded that: idiogenic osmoles play an important role in osmoregulation in the brain of rats subjected to hypernatremia; the development of these substances occur more slowly than changes in serum sodium; and the decrease in concentration of myoinositol occurs significantly more slowly than the decrease in serum sodium which occurs when animals are allowed free access to water. These observations may be relevant to the clinical management of patients with hypernatremia.
Abstract: This study examines lactate and K+ fluxes from muscle to blood during and after intense exercise. Ten men performed exhaustive dynamic exercise (mean load 65 W, mean duration 3.18 min) with the knee extensors of one leg. The mean lactate efflux was 15.5 (range 8.9-24.0) mmol min-1 at exhaustion, and it was linearly related to the lactate gradient. A linear relationship was also obtained if the H+ gradient was taken into account. Muscle pH decreased from 7.14 at rest to 6.71 (range 6.50-6.87) at exhaustion. At rest and during late recovery blood lactate was distributed across the erythrocyte membrane according to the membrane potential (intra-/extracellular ratio of 0.5), but during rapid lactate release this ratio decreased to 0.2. In-vitro experiments demonstrated a time constant of 1.2 min for lactate efflux from the erythrocytes. Approximately 70% of the K+ ions released from the muscle to the blood accumulated in the plasma; the rest were taken up by other tissues. However, erythrocytes were not involved as a dilution space. The small change in erythrocyte K+ concentration was due to cellular volume changes. During recovery the kinetics of K+ reuptake by the muscle were described by a very fast (less than 1 min) and a slow component (greater than 1 min): the magnitude of the former was equivalent to what had accumulated in the plasma. Individuals displayed a wide range of intramuscular lactate concentrations and pH values at exhaustion. Further, the pH changes were not as extreme as previously reported, suggesting that pH may not be the only factor involved in the fatigue process. A possible role for the potassium shifts as a limiting factor for muscle function is discussed.
Abstract: Death from accidental electrocution is generally thought to be due to an arrhythmia, but little is known of the anatomic changes in the heart and almost nothing is known about the conduction system itself. We have studied the hearts of four men who died from electrical accidents and directed particular attention to the coronary arteries, conduction system, and neural structures of the heart. In every heart there was widespread focal necrosis involving all the myocardium and including the specialized tissue of the sinus and atrioventricular nodes. In all four hearts there was contraction band necrosis of smooth muscle cells in the tunica media of the coronary arteries. Cells in the His bundle and bundle branches were less affected. Neural structures of the heart were minimally involved. We also sought any cardiac changes of a chronic nature that may have predisposed to a fatal arrhythmia. Two of the four hearts were slightly enlarged, and increased myocardial mass predisposes to ventricular fibrillation and makes it more difficult to revert. One heart exhibited focal fibromuscular dysplastic narrowing of small coronary arteries, including that artery supplying the coronary chemoreceptor. Another heart had fatty deposition extensively present within and around the sinus and atrioventricular nodes. Thus numerous abnormalities specifically attributable to the electrocution help explain the pathogenesis of the electrical instability known to occur. But in three of the four hearts there were also chronic abnormalities favoring electrical instability but predating the electrocution.
Abstract: We studied urinary acidification daily during the hospital course of 16 infants with acute gastroenteritis and metabolic acidosis. Urine pH value on admission was higher than 5.5 in 14 (87%) patients. We hypothesized that inappropriate urinary acidification was due to sodium deficiency and inadequate sodium delivery to the distal nephron. Forty-one urinary samples were collected during metabolic acidosis. The mean pH of 24 urine samples with sodium concentration less than 10 mmol/L was significantly higher than the pH of 17 samples with sodium concentration greater than 10 mmol/L (6.04 +/- 0.06 vs 5.19 +/- 0.1; p less than 0.001). The urine ratios of titratable acid to creatinine and of total acidity to creatinine were significantly higher in urine samples containing more sodium (p less than 0.02), whereas the ammonium/creatinine ratio was not. After administration of furosemide or correction of the sodium deficit, appropriate acidification was observed. We conclude that impaired urinary acidification is frequently found during metabolic acidosis in infants with acute gastroenteritis and results from a sodium deficit rather than from transient distal renal tubular acidosis.
Abstract: The rate of increase in oxygen uptake (VO2) at the onset of a step change in work rate can be studied to provide information about the physiological mechanisms that control this process. Several systems must interact to produce the total response. These can be grouped into oxygen transport and oxygen utilization mechanisms. In this paper, the hypothesis that one or the other of these mechanisms limits the adaptation of VO2 to a change in work rate will be examined. In addition to the traditional approach with step changes in work rate, the responses to other work rate forcing functions will be reported. These include ramp, impulse, and pseudorandom binary sequence work rate changes. The evidence that is accumulating from studies involving transitions from different baseline levels of exercise, as well as studies of the effects of hypoxia and beta-adrenergic receptor blockade, has led to the conclusion that oxygen transport mechanisms limit the rate of increase in VO2. However, the dynamic response of VO2 in the presence of adequate oxygen is not much different from that of oxygen limited conditions.
Abstract: These studies utilize the isolated perfused rabbit juxtaglomerular apparatus (JGA) to study the macula densa signal for renin secretion in the absence of the confounding influences of intravascular pressure and renal nerve activity. In the first experimental series, JGAs were perfused alternately with high- and low-NaCl solutions to determine the reversibility of the renin response to changes in NaCl concentration. Compared with high-NaCl controls, perfusion with a low-NaCl solution resulted in a fivefold increase in renin secretion rate (RSR) [2.1-10.0 nano-Goldblatt hog units (nGU)/min], and this response was largely reversible. When the solutions were presented in the reverse order, a similar inhibition by high NaCl was observed. In the second series, JGAs were perfused with high-, medium-, and low-NaCl solutions to determine the sensitive range of the renin response to NaCl concentration changes. The full renin response (3.2-16.6 nGU/min), similar in magnitude to that seen in series 1, was found to occur between 80 and 24 mM for Na+ and 61 and 7 mM for Cl-. In the third series, the NaCl concentration and flow rate of the perfusate were altered independently to separate the effects of flow rate, NaCl delivery, and NaCl concentration on RSR. Although a decrease in perfusate flow rate slightly increased RSR (3.4-8.1 nGU/min), a comparable decrease in NaCl concentration resulted in a much higher RSR (26.3 nGU/min). We conclude that in this preparation 1) RSR responds equally to both increases and decreases in macula densa NaCl concentration, and these changes are rapid and largely reversible, 2) the full renin response occurs within the concentration range normally occurring at the macula densa, i.e., below 80 mM Na+ and 61 mM Cl-, and 3) RSR responds with a larger change to alterations in NaCl concentration than in NaCl delivery or fluid flow rate.
Abstract: To determine the long-term effects of a physiological dose of atrial natriuretic peptide (ANP) on renin release, the renin response to reductions in renal arterial pressure (RAP) was studied during 1) control conditions and 2) acute and 3) chronic (5 days) intravenous infusion (5 ng.kg-1.min-1) of alpha-human ANP in conscious dogs maintained on a normal sodium intake. Renal perfusion pressure was servo controlled at reduced levels with an inflatable occluder placed around the abdominal aorta just above the renal arteries. Under control conditions, reducing RAP by 30 and 40 mmHg increased plasma renin activity (PRA) 4- to 5- and 9- to 10-fold, respectively. Acute ANP infusion had no significant effect on either basal levels of PRA or the PRA response to reduced RAP. During chronic ANP infusion there was a two- to threefold increment in plasma ANP concentration and approximately a twofold increase in urinary sodium excretion on day 1; however, there were no significant long-term changes in mean arterial pressure, basal PRA, or the levels of PRA achieved during reductions in RAP. These findings indicate that the changes in plasma ANP concentration that occur under normal physiological conditions do not appreciably alter either basal PRA or renin release in response to renal hypotension in conscious sodium-replete dogs studied under resting conditions.
Abstract: When a large inorganic acid load is ingested by normals, the proton load is eliminated because the rate of excretion of ammonium can rise to 200 to 300 mmol/day. In subjects with ketoacidosis of chronic fasting, such a large increase in the rate of excretion of ammonium might not be possible because of ATP balance considerations in proximal cells. Subjects with ketoacidosis of chronic fasting excreted less net acid as defined in the conventional way when they consumed a large inorganic acid load (136 +/- 6 vs. 176 +/- 26 mmol/day in control fasted subjects). Nevertheless, the vast majority of this inorganic acid load was eliminated because they were in steady state and had only a slightly lower concentration of bicarbonate (13 +/- 0.6 vs. 15 +/- 0.5 mmol/liter) and ketoacid anions (3.3 +/- 0.2 vs. 5.5 +/- 0.2 mmol/liter) in their blood. Using a definition of net acid excretion where the component of bicarbonate loss was expanded to include "potential bicarbonate" (ketoacid anions) in the urine, the rate of excretion of net acid was higher in subjects who ingested the inorganic acid load, owing to a much lower rate of excretion of ketoacid anions (9 +/- 2 vs. 120 +/- 7 mmol/day). This lower rate of excretion was not only due to a lower filtered load, but also to a higher fractional reabsorption of ketoacid anions during acidosis (97 +/- 0.1 vs. 77 +/- 0.2%). This higher fractional reabsorption could not be explained by a lower filtered load of ketoacid anions or to a restricted intake of sodium.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Pharmacological evidence indicates that angiotensin (Ang II) converting enzyme inhibitors attenuate cardiovascular responses to sympathetic stimulation. To investigate the physiological significance of this attenuation, the pressor and heart rate responses to bilateral carotid occlusion (BCO) were studied before and after administration of captopril and again during Ang II replacement in conscious, aortic nerve-sectioned rabbits with chronically implanted carotid occluders. In the control period, BCO produced increases (p less than 0.05) in mean arterial pressure (MAP) and heart rate (HR) of 37.3 +/- 3.0 mm Hg and 21.7 +/- 5.4 beats/min from baseline values of 79.1 +/- 2.5 mm Hg and 255.4 +/- 16.7 beats/min. Captopril (5 mg/kg i.v.) markedly reduced (p less than 0.05) both the pressor (10.2 +/- 2.6 mm Hg) and HR (5.0 +/- 4.0 beats/min) responses to BCO, in parallel with a decrease in plasma Ang II of 75%. Infusion of a subpressor dose of Ang II (5-25 ng/kg/min i.v.) increased plasma Ang II to precaptopril levels and fully restored (p less than 0.05) the pressor (33.0 +/- 5.7 mm Hg) and HR (19.8 +/- 7.7 beats/min) responses to BCO. In two additional series of experiments, the mechanism of the effects of captopril and Ang II were investigated. In the first series, cardiac baroreflex curves (pulse interval versus MAP) were generated by increasing or decreasing blood pressure with phenylephrine or nitroprusside (5-20 micrograms/kg/min i.v.). The slope of the linear region of the curve (2.9 msec/mm Hg) was not changed significantly by captopril treatment (3.1 msec/mm Hg) or Ang II replacement (3.2 msec/mm Hg), indicating that cardiac baroreflex sensitivity was not altered by blockade of the renin-angiotensin system. In the second series, the effect of captopril on the pressor response to exogenous norepinephrine (0.1-2.5 micrograms/kg/min i.v.) was tested. The response was reduced by less than 40%, indicating only a modest postsynaptic component to the action of captopril. These results provide physiological evidence for an important action of endogenous Ang II in facilitating the cardiovascular responses to sympathetic stimulation in conscious rabbits. This facilitation is not due to an action upon the baroreflex per se but results, at least in part, from a presynaptic action of Ang II.
Abstract: The mature, healthy, non-starved mammalian brain uses glucose only as a source of energy in the form of ATP, which is necessary for several metabolic processes, such as the maintenance of cellular homeostasis via ion homeostasis, maintenance of the integrity of cellular compartments, and intracellular transportation processes for the formation of several neurotransmitters, neurotransmission itself and a few anabolic reactions. Glucose breakdown contributes to the formation of the neurotransmitters: acetylcholine, glutamate, aspartate, gamma-aminobutyrate, and glycine. Normal cerebral aging is associated with an incipient perturbation in both cerebral glucose and related metabolism, that determines an energy deficit and thus an imbalance in cell homeostasis after the 7th or 8th decade of human life, indicating a threshold phenomenon. This is evidenced by morphological/morphobiological abnormalities comprising neuronal loss and structural changes. These events are thought to cause a marked reduction in the biological plasticity of the brain, which may be severely involved after additional stress situations such as ischemia, hypoxia or hypoglycemia. The age-related increasing perturbation of neuronal homeostasis may represent a stress situation capable of inducing heat shock proteins effecting gene activity. Thus, several age-related metabolic abnormalities at the cellular level, starting with a deficient neuronal glucose and energy metabolism, can be regarded as risk factors for neuronal damage and death, and hence reduced mental capacity.
Abstract: Norepinephrine, an alpha 1,2-beta 1,2-adrenergic agonist, seems to be an alternative to epinephrine, an alpha 1,2-beta 1,2-agonist, for restoration of spontaneous circulation in VF. We therefore studied the effect of epinephrine and norepinephrine on MDO2 and MVO2 using OCCM after five minutes of cardiopulmonary arrest in 21 pigs. After OCCM of three minutes, seven animals each received placebo (controls) or epinephrine (45 micrograms/kg) or norepinephrine (45 micrograms/kg). All drugs were given blindly. At 90 seconds after epinephrine or norepinephrine, mean arterial blood pressure was significantly higher than in the control group. Prior to cardiac arrest, MBF, measured with radioactive microspheres, was 193 +/- 30 ml/min/100 g. During CPR but before drug administration, MBF was 51 +/- 23 in the control group, 71 +/- 10 in the group with epinephrine, and 74 +/- 11 ml/min/100 g in the group with norepinephrine. At 90 seconds after epinephrine, MBF increased to 126 +/- 18 and after norepinephrine to 107 +/- 30 ml/min/100 g (p less than 0.05). Compared to OCCM alone, MDO2 increased from 9.6 +/- 1.7 to 17.1 +/- 3.2 ml/min/100 g after epinephrine and from 9.4 +/- 1.8 to 13.6 +/- 4.2 ml/min/100 g after norepinephrine (p less than 0.05). There was an increase in MVO2 from 4.0 +/- 1.5 to 9.4 +/- 3.0 ml/min/100 g after epinephrine (p less than 0.05), whereas MVO2 increased only from 4.2 +/- 0.8 to 5.1 +/- 2.0 ml/min/100 g after norepinephrine. Because epinephrine led to a greater increase in MVO2 than norepinephrine, the myocardial oxygen ER remained unchanged. The oxygen requirements of the fibrillating heart seemed to be increased via beta 2-adrenergic stimulation. In both the control and epinephrine-treated groups, only three of the seven animals could be successfully resuscitated, whereas all of the animals in the group with norepinephrine survived the 15-minute period of observation. In this model, norepinephrine, in contrast to epinephrine, improves the balance between MDO2 and MVO2 and eases restoration of spontaneous circulation.
Abstract: The purpose of this study was to investigate if myogenic responses of isolated coronary arterioles were dependent on an intact, functional endothelium. Arterioles were located in situ by intracoronary perfusion with india ink-gelatin solution and then dissected and cannulated at both ends with glass micropipettes. Intraluminal pressure was initially set at 60 cm H2O; then the pressure was altered in steps of 20 cm H2O over a range of 20-140 cm H2O. Arterioles developed spontaneous tone and exhibited a significant myogenic response in physiological saline solution (36 degrees -37 degrees C). Arteriolar dilation and constriction were observed at lower (20-60 cm H2O) and higher (60-140 cm H2O) pressures, respectively. The presence of a functional and automatically intact endothelium was confirmed by relaxation to the endothelium-dependent vasodilator bradykinin and by transmission electron microscopy, respectively. After mechanical denudation of the endothelium with a specially designed abrasive micropipette, spontaneous tone and myogenic responses were preserved. Denudation of the endothelium was verified functionally (no response to bradykinin) and with transmission electron microscopy. Moreover, the mechanical denudation technique did not deleteriously affect smooth muscle because vasoconstrictor and vasodilator responses to nonendothelial-dependent drugs were the same before and after denudation. In summary, the present study demonstrates that pressure-dependent responses occur in isolated coronary arterioles and that this response is not dependent on the endothelium. Therefore, pressure-induced changes in coronary arteriolar tone are a true myogenic response in that they originate from smooth muscle.
Abstract: The chemosensitive area on the ventral surface of the brain stem responds to local acidosis by eliciting hyperventilation and to local alkalosis by hypoventilation. The stimulus is conventionally thought to be the hydrogen ion concentration in the area’s extracellular fluid. It is pointed out, however, that the elegant studies by Loeschcke & Ahmad have demonstrated that [pH]e and [pH]i are normally tightly and rapidly coupled (Loeschcke & Ahmad, 1980). For this reason, the stimulus might just as well be the intracellular hydrogen ion concentration in the chemoreceptor area. The administration of acetazolamide allows the dissociation of [pH]e from [pH]i. With acetazolamide a sharp acid shift of CSF pH [( pH]c) is measured and in two consonance with this shift a marked increase in CBF is seen. Comparing these two reactions to that obtained with CO2 breathing, it is apparent that 7% CO2 causes about the same decrease in [pH]e and the same increase in CBF. In other words CBF acidosis can quantitatively account for the CBF increase induced by acetazolamide. But CO2 and acetazolamide influence [pH]i quite differently, as CO2 drops [pH]i to almost the same extent as [pH]c, while two recent studies by MR spectroscopy have shown that acetazolamide does not drop [pH]i measurably, if tissue hypercapnia is prevented in artificially ventilated rabbits or by the mild spontaneous hyperventilation caused by acetazolamide in normal man.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: An automated servo-control system to maintain total body weight constant was used to investigate the role of fluid volume expansion in the development of salt-dependent hypertension in dogs continuously infused with subpressor doses of angiotensin II. Dogs maintained on a fixed salt and water intake were studied in metabolic scale cages, which enabled continuous 24 h/day monitoring of changes in body weight as an index of changes in total body water. Beat-by-beat hemodynamics were determined 24 h/day. Daily fluid and electrolyte balances and hormonal profile were determined. Blood volume was periodically measured by injection of 51Cr red blood cells. After a 3-day control period, salt intake was increased from 8 to 120 meq/day. In contrast to the rise of arterial pressure that was observed in our previous nonservo-controlled volume studies, average 24-h mean arterial pressure, cardiac output, and total peripheral resistance remained unchanged during a 4-day high-salt period. Total body weight was maintained within 7 +/- 17 g of the original weight. Blood volume was unchanged by day 2 as indicated by direct measurement (51Cr red blood cells) or by analysis of plasma protein concentration. There was a retention of 82 +/- 5 meq (P less than 0.05) of sodium on day 1 of high-salt period. Plasma sodium concentration increased approximately 7 meq/l (P less than 0.05) above control levels. Plasma renin activity and aldosterone decreased to undetectable values, whereas vasopressin and atrial natriuretic peptide increased significantly. These results confirm that elevations of blood volume and cardiac output normally observed when salt intake was increased in dogs infused with angiotensin II are secondary to water retention and that this salt-dependent model of hypertension is dependent on fluid volume expansion.
Abstract: The mechanism by which erythropoietin controls mammalian erythrocyte production is unknown. Labeling experiments in vitro with [3H]thymidine demonstrated DNA cleavage in erythroid progenitor cells that was accompanied by DNA repair and synthesis. Erythropoietin reduced DNA cleavage by a factor of 2.6. In the absence of erythropoietin, erythroid progenitor cells accumulated DNA cleavage fragments characteristic of those found in programmed cell death (apoptosis) by 2 to 4 hours and began dying by 16 hours. In the presence of erythropoietin, the progenitor cells survived and differentiated into reticulocytes. Thus, apoptosis is a major component of normal erythropoiesis, and erythropoietin controls erythrocyte production by retarding DNA breakdown and preventing apoptosis in erythroid progenitor cells.
Abstract: The purpose of this work was to determine the rate and extent of bone loss and recovery from long-term disuse and in particular from disuse after exposure to weightlessness. For this purpose, bed rest is used to simulate the reduced stress and strain on the skeleton. This study reports on the bone loss and recovery after 17 weeks of continuous bed rest and 6 months of reambulation in six normal male volunteers. Bone regions measured were the lumbar spine, hip, tibia, forearm, calcaneus, total body, and segmental regions from the total-body scan. The total body, lumbar spine, femoral neck, trochanter, tibia, and calcaneus demonstrated significant loss, p less than 0.05. Expressed as the percentage change from baseline, these were 1.4, 3.9, 3.6, 4.6, 2.2, and 10.4, respectively. Although several areas showed positive slopes during reambulation, only the calcaneus was significant (p less than 0.05), with nearly 100% recovery. Segmental analysis of the total-body scans showed significant loss (p less than 0.05) in the lumbar spine, total spine, pelvis, trunk, and legs. During reambulation, the majority of the regions demonstrated positive slopes, although only the pelvis and trunk were significant (p less than 0.05). Potential redistribution of bone mineral was observed: during bed rest the bone mineral increased in the skull of all subjects. The change in total BMD and calcium from calcium balance were significantly (p less than 0.05) correlated, R = 0.88.
Abstract: Traditionally, the renal collecting duct has been assigned the dual role of (1) secreting protons derived from dietary metabolism to form luminal NH4+ and titratable acid and (2) generating new HCO3-. This view has recently been challenged. According to current concepts, whole body proton balance is maintained predominantly by the lungs which excrete protons derived from dietary metabolism as the acid anhydride CO2. In the process of excreting CO2, HCO3- is also lost from the body. It is the function of the kidney to generate new HCO3- to replenish this loss. The major site of new HCO3- generation is the proximal tubule rather than the collecting duct. New HCO3- is generated predominantly via the metabolism of organic anions, i.e. alpha-ketoglutarate, citrate, lactate, fatty acids. In the process of generating alpha-ketoglutarate from glutamine, NH4+ is formed. Under normal acid-base conditions, 50% of the NH4+ produced is excreted in the urine, and the remaining 50% is delivered to the renal veins. NH4+ delivered to the renal veins consumes HCO3- during ureagenesis. In the discussion which follows, these new concepts are reviewed and applied to an analysis of the pathophysiology of renal tubular acidosis.
Abstract: Blood pressure was evaluated in adult patients (n = 9) and children (n = 57) with nephrotic syndrome and minimal change glomerulonephritis (GN). Prior to steroid treatment in the edematous phase, hypertension was found in 78% of adults (BP greater than or equal to 140/90 mm Hg or antihypertensive treatment other than diuretics) and 95% of children (BP greater than 95 percentile of age). After complete remission, the prevalence of hypertension decreased to 33% in adults and 19% in children. In 21 children with early focal segmental glomerulosclerosis, the prevalence of hypertension (BP greater than 95th percentile) was 91% and 24% after complete remission. In 20 adult patients with membranous GN, the prevalence of hypertension in the edematous phase was 89% and 30% after complete or partial remission. It is concluded that, irrespective of age, hypertension is a common feature of the nephrotic syndrome unrelated to steroid therapy or renal failure.
Abstract: The effects of near-maximal coronary vasodilation were examined in conscious dogs with left ventricular (LV) failure after pressure overload hypertrophy induced by either aortic banding alone or aortic banding plus a peripheral arteriovenous shunt. The findings were compared with results in littermates with compensated LV hypertrophy and with a third group of normal dogs. At rest, there was a marked difference in the intramyocardial distribution of coronary flow, measured with radiolabeled microspheres. The endocardial/epicardial (endo/epi) flow ratio in the LV failure dogs was 0.96 +/- 0.08 as compared with control dogs (1.28 +/- 0.06, p less than 0.05) or dogs with compensated LV hypertrophy (1.23 +/- 0.08, p less than 0.05). During near-maximal coronary vasodilation with adenosine, all groups showed similar increases in subepimyocardial (epi) flow. While significant increases in subendomyocardial (endo) flow during adenosine infusion were seen in the control group (0.88 +/- 0.10 to 3.53 +/- 0.24 ml/min/g) and in dogs with compensated LV hypertrophy (1.12 +/- 0.14 to 3.60 +/- 0.16 ml/min/g), there was no change in endo flow in the LV failure dogs (1.55 +/- 0.20 to 1.71 +/- 0.47 ml/min/g) and a further significant reduction in the endo/epi flow ratio was observed (0.30 +/- 0.06, p less than 0.01). These hemodynamic changes were associated with chronic multifocal interstitial or discrete areas of fibrosis observed preferentially in endo layers. Thus, endo flow reserve is nearly exhausted in dogs with decompensated pressure overload LV hypertrophy, which may induced periodic episodes of endo ischemia resulting in myocyte necrosis and fibrosis, which in turn results in exacerbation of LV failure.
Abstract: Previous experiments have shown oscillations in proximal tubular pressure in halothane-anesthetized rats. Such oscillations should be due to oscillations in flow rate and should cause periodic oscillations in both distal tubular chloride concentration and distal tubular pressure. The purpose of the study was to test these predictions. In halothane-anesthetized Sprague-Dawley rats, distal tubular chloride activity was measured with Cl- -sensitive electrodes, and late proximal flow rate was measured by pulse injection of boluses of solutions containing rhodamine dextran. Bolus velocity was detected by videomicroscopy. The time resolution was 2 s. All four variables oscillated with the same frequency, approximately 35 mHz. The amplitude of the flow and the chloride oscillations were 28 and 10%, respectively, of the mean values. Proximal fluid velocity led proximal pressure by 1.5 +/- 0.4 s, whereas distal chloride activity lagged proximal pressure by 8.9 +/- 0.8 s. The distal pressure lagged the proximal pressure by 1.05 +/- 0.38 s. It is concluded that there is a significant variation in distal chloride activity, the magnitude of which appears to be sufficient to account for the observed flow variations through the operation of the tubuloglomerular feedback mechanism.
Abstract: The present study was designed to determine the extent to which the brain stem neural networks, normally capable of synchronizing the sympathetic nerve discharge (SND) into 2- to 6- and 10-Hz rhythmic fluctuations, contribute to the control of autonomic reactions during brain hypoxia and/or hypercapnia. Vertebral, cardiac, and renal nerve discharges were recorded electrophysiologically in 34 anesthetized, curarized, and artificially ventilated cats. The sympathetic nerve responses to cerebral ischemia (elicited by reducing the blood supply to the brain), intracranial pressure elevation (Cushing reaction), and systemic asphyxia were tested with special focus on the rhythmic structure of the SND. It has been found that there are two phases of SND changes during cerebral ischemia differing mainly in the frequency content of the signals and less in the compound action potential amplitude. During the first phase the rhythmic generators controlling the tonic sympathetic outflow are more strongly activated, which is reflected in a stronger, more regular, and more widespread manifestation of these rhythms on the efferent neurograms. After some time the normal SND structure abruptly changes to a desynchronized activity with loss of the three main sympathetic rhythms and responsiveness to baroreceptor reflex activation. The same stereotyped changes can be observed regardless of the way in which the brain hypoxia and/or hypercapnia has been produced. Nor does the denervation of peripheral baro- and chemoreceptors substantially alter the general pattern of the responses.
Abstract: Experiments were performed to study the effect of chemical medullectomy on the renal retention of sodium in rats with an experimental nephrotic syndrome. Nephrosis was induced in rats by a single injection of puromycin aminonucleoside (PAN) and the renal excretion of water and electrolytes was monitored for 11 days. Sodium output in nephrotic rats fell to approximately 10% of control levels and exchangeable body sodium increased to 54.6 +/- 2.7 mM/kg compared with 41.5 +/- 0.8 mM/kg in controls. The animals had edema and ascites and there was a 35% increase in plasma volume and a corresponding fall in hematocrit. Severe structural and functional damage to the inner renal medulla induced by the injection of bromoethylamine hydrobromide (BEA) resulted in little change in the pattern of sodium and water retention caused by PAN alone. Exchangeable body sodium in rats treated with PAN and BEA was 51.5 +/- 3.8 mM/kg. It is concluded that an intact inner renal medulla is not necessary for sodium retention to occur in PAN nephrosis in rats.
Abstract: The effects of iv sodium bicarbonate (NaHCO3) and Carbicarb, an experimental buffer, were compared in a rat model of lactic acidosis induced by controlled hemorrhage and asphyxia. Although both NaHCO3 and Carbicarb were effective at alkalinizing the arterial blood in this model, NaHCO3 administration resulted in a rise in PaCO2 where Carbicarb did not (+9 +/- 2 vs. +2 +/- 2 torr at 2 min after infusion, p less than .01). Moreover, NaHCO3 resulted in a small decrease in intracellular brain pH as measured with P-31 nuclear magnetic resonance where Carbicarb afforded intracellular brain alkalinization (-0.03 +/- 0.01 vs. +0.08 +/- 0.02 pH units at 2 min, p less than .01). If these data are confirmed clinically, Carbicarb may offer advantages over NaHCO3 under conditions of fixed or limited ventilation.
Abstract: We determined how alterations in systemic hemodynamics, characteristic of the Cushing response, are related to changes in cerebral blood flow (CBF), cerebral metabolic rate of O2 (CMRO2), and brain electrical conductive function, as assessed by somatosensory-evoked potentials (SEP) and brain stem auditory-evoked responses (BAER). In three groups of eight pentobarbital-anesthetized sheep, intracranial pressure was gradually elevated to within 50, 25, or 0 mmHg of base-line mean arterial pressure and then held constant for 40 min by intraventricular infusion of mock cerebrospinal fluid. Microsphere-determined CBF fell when cerebral perfusion pressure was less than 50 mmHg. CMRO2 fell when CBF fell greater than 30-40%. Mean aortic pressure and cardiac output increased when CBF fell greater than 40%, i.e., at approximately the level at which CMRO2 fell. Furthermore, the magnitude of the increase in arterial pressure and cardiac output correlated with the reduction of CMRO2. SEP latency did not increase unless CBF fell greater than 55-65%, corresponding to a 20-30% reduction of CMRO2. Increased latency of BAER wave V was associated with a fall in midbrain blood flow of greater than 65-70%. Thus increase in SEP and BAER latencies required reductions of flow greater than those required to elicit a systemic response. This demonstrates that there is a range of intracranial pressure over which the increase in arterial pressure preserves sufficient CBF to sustain minimal electrical conductive function. The best predictor of the onset and magnitude of the Cushing response in adult sheep is the decrease in CMRO2.
Abstract: Atrial natriuretic factor was infused in a low dose (0.2 microgram/min) during 5 days in six patients with essential hypertension. Atrial natriuretic factor infusion caused plasma levels of atrial natriuretic factor to increase from 49 +/- 10 to 106 +/- 19 pg/ml. Within 4 hours after the start of the atrial natriuretic factor infusion, urinary sodium excretion increased in all subjects. Sodium balance was regained after 24 hours with a net loss of 72.3 +/- 14.6 mmol. However, systolic as well as diastolic blood pressure started to decrease gradually in all subjects only after 12 hours of atrial natriuretic factor infusion, reaching a stable level after 36 hours with a decrease of 11.5 +/- 1.5% and 10.3 +/- 0.8%, respectively. Heart rate increased in parallel by 12.6 +/- 3.1%. Hematocrit rose 7.1 +/- 2.3%. After cessation of atrial natriuretic factor infusion, plasma atrial natriuretic factor levels, sodium balance, and hematocrit returned to baseline within 24 hours, whereas blood pressure slowly returned toward baseline values over 3 days. These data show that chronic atrial natriuretic factor infusion in patients with essential hypertension causes a negative sodium balance and a rise in hematocrit, followed by a smooth decrease in blood pressure with a rise in heart rate until a new equilibrium is reached after approximately 2 days. Thus, atrial natriuretic factor in low doses appears intimately involved in the regulation of sodium balance and blood pressure in humans. Moreover, these data suggest that atrial natriuretic factor-like substances will eventually become useful antihypertensive drugs.
Abstract: 1. Isovolumic left ventricular pressure was measured at various coronary arterial pressures in Langendorff-perfused ferret hearts. The concentrations of phosphorus-containing metabolites were measured using 31P nuclear magnetic resonance (NMR). Intracellular free calcium concentration ([Ca2+]i), was measured with 19F NMR in a group of hearts that were loaded with the calcium indicator 5F-BAPTA. 2. Developed pressure increased when coronary arterial pressure was raised from the control value of 80 to 100-160 mmHg and decreased when coronary pressure was lowered to 40-70 mmHg. The changes were reversible. 3. Coronary flow varied directly with coronary pressure over the entire range from 40 to 160 mmHg. 4. The concentrations of phosphorus-containing metabolites and the efflux of lactate from the heart remained unchanged at coronary pressures of 60 mmHg or higher. Below 60 mmHg, intracellular pH decreased, while inorganic phosphate concentration and lactate efflux increased. 5. In contrast to the developed pressure during twitch contractions, maximal Ca2+-activated pressure remained constant at coronary pressures of 60-160 mmHg. Only below a coronary pressure of 60 mmHg did maximal Ca2+-activated pressure decline. 6. An increase in coronary pressure produced an increase in developed pressure even in hearts stretched to the peak of the Frank-Starling relation. 7. When coronary pressure was lowered from 80 to 60 mmHg, [Ca2+]i decreased during systole; the opposite effect was apparent when coronary pressure was raised from 80 to 120 mmHg. 8. We conclude that coronary perfusion (pressure or flow) modulates intracellular calcium and, consequently, contractile force. Ischaemia cannot fully explain this phenomenon, nor can changes in sarcomere length.
Abstract: The objective of this study was to investigate the possible causal role of renal interstitial hydrostatic pressure (RIHP) in the natriuretic and diuretic responses of the Wistar rat. The relationship between renal perfusion pressure (RPP), RIHP, and fractional excretion of sodium (FENa) was established in the acutely decapsulated kidney and the contralateral control kidney of the same rat. The renal response to acute saline volume expansion was also studied in control and decapsulated kidney. When RPP was allowed to increase from 100 +/- 1.2 to 123 +/- 1.3 mmHg in male Wistar rats (n = 10), RIHP and FENa increased significantly from 3.3 +/- 0.4 mmHg and 0.57 +/- 0.15% to 4.3 +/- 0.4 mmHg and 1.77 +/- 0.41% in the decapsulated kidney and from 4.1 +/- 0.4 mmHg and 0.86 +/- 0.17% to 6.9 +/- 0.5 mmHg and 2.56 +/- 0.38% in control kidney. During saline volume expansion, RIHP and FENa increased significantly from 6.3 +/- 0.5 mmHg and 1.30 +/- 0.43% to 9.8 +/- 0.5 mmHg and 7.53 +/- 0.88% in the decapsulated kidney. In the control kidney, RIHP and FENa were 8.3 +/- 0.6 mmHg and 1.81 +/- 0.35% during control period and increased significantly to 12.7 +/- 0.4 mmHg and 9.31 +/- 0.50% during acute saline volume expansion. We conclude that the renal capsule is essential for the full increase in RIHP and for the full expression of the natriuretic and diuretic responses of pressure natriuresis and acute volume expansion of Wistar rats.
Abstract: 1. The cardiovascular effects of bolus intravenous injections of vasopressin, angiotensin II and noradrenaline were studied in 6-hydroxydopamine pretreated, anaesthetized Brattleboro rats with hereditary diabetes insipidus and normal rats of the parent Long Evans strain. 2. Pretreatment with 6-hydroxydopamine did not significantly affect control values for mean arterial blood pressure, cardiac output or total peripheral resistance in either Brattleboro or Long Evans rats but the pressor response to haemorrhage was reduced in both strains compared to the control animals. 3. The pressor responses of the untreated Brattleboro rats to 250 mu kg-1 vasopressin were significantly greater and more prolonged than in control rats of the Long Evans strain. 4. Pretreatment with 6-hydroxydopamine significantly enhanced the peak pressor response to vasopressin, but not to angiotensin II (1 microgram kg-1), in Brattleboro and Long Evans rats. 5. Pretreatment with 6-hydroxydopamine resulted in an enhanced pressor response to 1 microgram kg-1 noradrenaline in both Brattleboro and Long Evans rats, but the effect was significantly greater in the vasopressin-deficient animals. 6. These results indicate differences in the pressor responsiveness of Brattleboro rats to vasopressin and noradrenaline, but not to angiotensin II, compared with control Long Evans rats and provide evidence for important interactions between the sympathetic nervous system and these pressor hormones.
Abstract: The objectives of this study were to determine the hemodynamic and microcirculatory changes that occur during reduced renal mass hypertension in rats. In conscious animals with 75% reduction of total renal mass, mean arterial pressure was initially (4-8 hours) elevated by 15-20 mm Hg during intravenous infusion with isonatremic (145.4 mM) NaCl. Cardiac index was elevated by 15-20%, and total peripheral resistance index was normal or reduced. Cardiac index subsequently returned toward normal, but mean arterial pressure remained elevated (20-40 mm Hg), presumably because of an elevated total peripheral resistance. Cremasteric arterioles were actively constricted (35-50%) in rats with short-term (36 hours), but not chronic (5-6 weeks) reduced renal mass hypertension. Total microvessel density was approximately 15% lower in maximally dilated cremaster muscles of chronically hypertensive rats versus sham-operated controls, which suggests that arterioles are lost during sustained reduced renal mass hypertension. Arteriolar constriction in response to increased superfusate PO2 (0% to 5% O2) was 2-4 times greater in rats with both short-term and chronic reduced renal mass hypertension than in normotensive controls, which suggests that oxygen-dependent autoregulatory mechanisms are altered. The hemodynamic and microcirculatory alterations observed in these experiments suggest that classic short-term autoregulatory mechanisms and an enhanced response of arterioles to increased oxygen availability contribute to the elevated total peripheral resistance in short-term reduced renal mass hypertension, whereas structural changes and altered vascular oxygen responses contribute to an elevated microvascular resistance in chronic reduced renal mass hypertension.
Abstract: Previous studies have indicated that motor center ("feedforward") activity is important for hormonal and metabolic responses to exercise. Now, epidural blockade at vertebrae L3-L4 was used to evaluate the importance of afferent neural feedback from working muscles. Six healthy, young males cycled for 20 min at 55 +/- 4% (mean +/- SE) of maximal oxygen uptake with, as well as without, epidural anesthesia. During anesthesia cutaneous sensory blockade was present below segment T11-12, the postexercise ischemic pressor response was attenuated from 34 +/- 9 to 14 +/- 4 mmHg, muscle strength reduced to 80 +/- 5% of control, and perceived exertion (Borg scale) was increased. At rest hormonal and metabolic parameters did not change in response to epidural anesthesia. During exercise, responses of catecholamines, insulin, glucagon, and growth hormone (GH) in plasma as well as glucose production and utilization, plasma free fatty acids, and plasma glycerol were similar in epidural and control experiments (P greater than 0.05). In contrast during submaximal exercise, plasma concentrations of adrenocorticotropin (ACTH) and beta-endorphin increased only in experiments without epidural anesthesia. The data indicate that impulses in afferent nerves from the working muscles are essential for the ACTH and beta-endorphin responses to submaximal dynamic exercise in humans. Afferent nervous activity is probably less important than efferent activity from motor centers for responses of GH, catecholamines and insulin, and, in turn, extramuscular fuel mobilization in exercise.
Abstract: The purpose of this study was to investigate the hypothesis that changes in renal perfusion pressure may be transmitted to the renal interstitium and cause alterations in renal interstitial hydrostatic pressure and sodium excretion. A method that utilizes a chronically implanted polyethylene matrix that allows for direct continuous measurement of renal interstitial hydrostatic pressure, and agrees well with subcapsular measurement in rats, was developed. Renal interstitial hydrostatic pressure, fractional excretion of sodium, and urine flow rate were 3.0 +/- 0.3 mmHg, 0.35 +/- 0.13%, and 19.44 +/- 3.00 microliter/min, respectively, when renal perfusion pressure was 101 +/- 0.8 mmHg. When renal perfusion pressure was increased to 123 +/- 0.9 mmHg renal interstitial hydrostatic pressure, fractional excretion of sodium, and urine flow rate increased significantly to 5.8 +/- 0.6 mmHg, 1.29 +/- 0.29%, and 50.76 +/- 8.83 microliter/min, respectively, in anesthetized male Sprague-Dawley rats. These changes occur despite a well-autoregulated glomerular filtration rate and renal blood flow. In conclusion, increasing renal perfusion pressure caused a significant increase in renal interstitial hydrostatic pressure as measured directly by the implanted polyethylene matrix method and was associated with a significant increase in sodium excretion.
Abstract: Previous studies have shown that the elevation of renal interstitial hydrostatic pressure by the direct expansion of renal interstitial volume increases urinary sodium excretion. The objective of the present study was to investigate whether proximal tubules respond to the elevated renal interstitial hydrostatic pressure and whether the inhibition of prostaglandin synthesis would alter the effect of elevated renal interstitial hydrostatic pressure on proximal sodium reabsorption. Expansion of renal interstitial volume by injecting 100 microliters of 2.5% albumin solution through a chronically implanted matrix increased renal interstitial hydrostatic pressure similarly in control rats (n = 8) and in indomethacin (n = 8) or meclofenamate-treated (n = 7) rats. In the absence of prostaglandin synthesis inhibition, renal interstitial volume expansion significantly increased the fractional delivery of sodium at the superficial late proximal tubules from 56.5 +/- 6.1 to 67.0 +/- 6.5% (p less than 0.01) with an accompanying increase in fractional excretion of sodium from 2.1 +/- 0.5 to 3.0 +/- 0.4% (p less than 0.01). In the presence of indomethacin or meclofenamate, renal interstitial volume expansion failed to augment the fractional delivery of sodium and the fractional excretion of sodium. In summary, these studies demonstrate that the synthesis of prostaglandins plays a role in the regulation of sodium reabsorption by the proximal tubules in response to elevated renal interstitial hydrostatic pressure.
Abstract: It has long been appreciated that renal nerves influence renal hemodynamics. Direct or reflex activation of renal nerves causes vasoconstriction, with the degree of vasoconstriction being proportional to the magnitude of stimulation. Conversely, removal of enhanced nerve activity ameliorates renal vasoconstriction. The effector loci within the renal microcirculation have been identified and include afferent and efferent arterioles as well as the glomerular capillary bed itself. The hemodynamic changes have been corroborated by morphological studies which reveal that the lumen of arterioles constrict and the glomerular capillary tuft contracts following an increase in neural activity. Moreover, mesangial cells, which are the putative vectors of regulation of hemodynamics within the glomerular capillary bed, constrict in response to the neurotransmitter, norepinephrine.
Abstract: We determined human and canine plasma clearance of atrial natriuretic factor (ANF) by lung, liver, and kidney from arteriovenous differences in plasma ANF and measured organ plasma flow. Human subjects had lower plasma ANF concentrations in the pulmonary vein or the pulmonary capillary wedge position when compared with the pulmonary artery, and both sites yielded pulmonary ANF extraction ratios of 24%. Canine lung ANF extraction was 19 +/- 3% and pulmonary ANF clearance was 328 +/- 78 ml/min per m2 vs. 357 +/- 53 ml/min per m2 in man. Hepatic plasma ANF clearance was 216 +/- 26 ml/min with an extraction ratio of 30 +/- 3% in humans and 199 +/- 89 ml/min and 36 +/- 6% in the dog. Renal plasma ANF clearance in human subjects was 78 +/- 12 ml/min per kidney and correlated well with each kidney’s creatinine clearance (r = 0.58, P less than 0.05). The mean renal ANF extraction ratio was 35 +/- 4% in human subjects and 42 +/- 6% in the dog. These data quantitate the specific organ ANF clearances by lung, liver, and kidney in human subjects and in dogs and provide a rationale for elevated plasma ANF levels in cirrhosis, renal failure, and diseases accompanied by reduced perfusion of these organs. These findings support the conclusion that plasma ANF concentrations are dependent upon both the stimuli for ANF secretion as well as the specific organ clearances of ANF.
Abstract: Although the brain has no formal lymphatic system, a substantial quantity of cerebrospinal fluid (CSF) has nonetheless been shown to drain via cervical lymphatics. To pursue further the issue of alternative drainage pathways for CSF, we infused a solution of Ringer’s lactate (RL) into the cisterna magna of the dog brain and monitored both the flow and concentration of total protein of cervical lymph. This maneuver promoted a nearly three-fold rise in intracranial pressure and was accompanied by a rise in cervical lymph flow and fall in its protein content. In addition, a profuse nasal discharge (11.4 ml/hr) developed with a moderately high protein content of the rhinorrhea fluid (1.8 g/dl), along with similar appearance times of Evans blue dye (instilled in the cisterna magna) in both cervical lymph and the rhinorrhea fluid (48-70 minutes after infusion). These findings suggest alternative drainage pathways for CSF besides the arachnoid villi (Pacchionian bodies) including connections with lymphatics in the neck and along the olfactory nerve, and around the cribiform plate to the nasal submucosa, and with proptosis, perhaps also through the aqueous humor-canal of Schlemm and nasolacrimal duct.
Abstract: Diabetic ketoacidosis and hyperosmolar hyperglycemic nonketotic coma are two of the most common acute complications of diabetes. The pathophysiologic changes that occur in both disease states represent an extreme example of the super-fasted state. The physiology of the fed and fasted state, evaluation, therapeutic issues, recommendations for therapy, immediate follow up care, and complications of therapy are reviewed for both syndromes.
Abstract: Because glucose metabolism and functional activity in brain regions are normally coupled, knowledge of regional brain glucose use can yield insights into regional functional activity. The deoxyglucose (DG) method is widely used for this purpose in experimental animals and humans but questions have arisen regarding its limits and accuracy. Therefore an experiment was designed to compare the DG method on a structure-by-structure basis with another tracer of glucose use, [6-14C]glucose, in normal rats. The cerebral metabolic rates obtained using the two tracers were similar in the telencephalon, but the results using DG were substantially lower in the midbrain and hindbrain (diencephalon, 18%; mesencephalon, 20%; metencephalon, 29%; and myelencephalon, 35%). The primary DG metabolite, DG 6-phosphate (DG-6-P) was found to disappear in a non-uniform manner from the major brain structures: telencephalon less than diencephalon less than mesencephalon = metencephalon less than myelencephalon. Thus a correlation was found between the rate of DG-6-P loss and the extent to which the DG method gave lower values of glucose use. Thus this may explain, at least in part, the discrepancies between the two methods.
Abstract: Under control conditions a primary culture containing about 80-90% of granular juxtaglomerular (JG) cells prepared from rat kidneys continuously released renin into the culture medium at a rate of 17.9 +/- 1.4 ng angiotensin I/h per mg of cell proteins per 30 min (n = 14). Dopamine (1.0 microM), the DA-1 dopamine receptor agonist fenoldopam (0.5 microM), and isoproterenol (1.0 microM) increased renin secretion markedly (130-200%). Propranolol (0.1 microM) reduced the effects of isoproterenol significantly (80%), but not those of dopamine or fenoldopam. In contrast, SCH 23390 (0.01 microM), a DA-1 dopamine receptor antagonist, inhibited markedly only the renin release evoked by the latter two agonists, whereas S-sulpiride (10 microM), a DA-2 dopamine receptor antagonist, and phentolamine (10 microM), a nonselective alpha-adrenoceptor antagonist, did not modify the effects of either dopamine or fenoldopam. In rats, pithed to eliminate reflexogenic mechanisms regulating renin release, at the end of a 15 min i.v. infusion of fenoldopam (20 micrograms/kg per min) there was a significant increase in plasma renin activity. This effect was completely prevented by SCH 23390 (0.1 mg/kg i.v.) but not significantly changed by S-sulpiride (0.3 mg/kg i.v.) or phentolamine (3.0 mg/kg i.v.) plus propranolol (0.75 mg/kg i.v.). In conclusion, these results indicate that DA-1 dopamine receptors are present in rat kidney JG cells and that pharmacological stimulation of these receptors with dopamine or fenoldopam leads to renin secretion.
Abstract: The intracellular pH recovery after stimulation of mouse soleus muscles in vitro was studied by means of intracellular pH-sensitive microelectrodes. The lactate efflux and the total lactate content were measured by means of an enzymic method. During electrical stimulation for 2 min in a CO2/HCO3- -buffered Ringer’s solution, pHi decreased by 0.5 units. The rate of pHi-recovery was independent of external bicarbonate, but dependent on the buffer concentration. The rate of intracellular pH recovery was reduced by the lactate transport inhibitors PCMBS and cinnamate, whereas the inhibitors of inorganic anion-exchange SITS and DIDS had no effect. The Na+/H+ exchange inhibitor amiloride reduced the rate of pHi recovery. The pHi recovery was faster than the lactate efflux, which could be accounted for by an Na+/H+ exchange. A number of inhibitor compounds were used in order to discriminate between the three possible lactate efflux pathways: the monocarboxylate carrier mechanism, the inorganic anion exchange, and the molecular (non-ionic) diffusion of lactic acid. The lactate efflux was partly inhibited by cinnamate, PCMBS and phloretin, but was unaffected by DIDS and tetrathionate. These experiments demonstrate the existence of a lactate carrier in mammalian skeletal muscles. The lactate carrier is responsible for more than half of the lactate efflux after muscle activity. Both the pHi recovery studies and the lactate efflux measurements showed that, under the given conditions, the inorganic anion-exchange mechanism is not essentially involved in the recovery processes after muscle activity.
Abstract: We measured ventilation in nine young adults while they breathed pure O2 after breathing room air and after 5 and 25 min of hypoxia. With isocapnic hypoxia (arterial O2 saturation 80 +/- 2%) mean ventilation increased at 5 min and then declined, so that at 25 min values did not differ from those on room air. After 3 min of O2 breathing, ventilation was greater than that on room air or after 25 min of isocapnic hypoxia, whether the hyperoxia had been preceded by hypoxia or normoxia. During transitions to pure O2 breathing, ventilation was analyzed breath by breath with a moving average technique, searching for nadirs before and after increases in PO2. After both 5 and 25 min of hypoxia, O2 breathing was associated with transient depressions of ventilation, which were greater after 25 min than after 5 min. Significant depressions were not observed when hyperoxia followed room air breathing, and O2-induced nadirs after hypoxia were lower than those observed during room air breathing. O2 transiently depressed ventilation after hypoxia but not after room air breathing. These results suggest that the normal ventilatory response to isocapnic hypoxia has two components, an excitatory one from peripheral chemoreceptors, which is turned off by O2 breathing, and a slower inhibitory one, probably of central origin, which is affected less promptly by O2 breathing.
Abstract: The objective of this study was to test the hypothesis that changes in renal perfusion pressure (RPP) are not fully transmitted to the renal interstitium in spontaneous hypertension in comparison with normotensive states. Okamoto spontaneously hypertensive and normotensive Wistar-Kyoto rats were used in this study. Renal interstitial hydrostatic pressure (RIHP) was measured directly and continuously via a polyethylene matrix that was implanted chronically in the left kidney 3 wk before RIHP measurement. When RPP was allowed to increase from 136 +/- 0.5 to 162 +/- 1.3 mmHg in male spontaneously hypertensive rats, RIHP was not significantly changed from 3.7 +/- 0.9 to 4.6 +/- 1.1 mmHg, and fractional excretion of sodium (FENa) increased significantly from 0.26 +/- 0.12 to 0.65 +/- 0.15% (P less than 0.05). When RPP was allowed to change from 104 +/- 0.9 to 127 +/- 1.3 mmHg in male Wistar-Kyoto rats, RIHP increased markedly from 4.0 +/- 0.3 to 7.2 +/- 0.4 mmHg (P less than 0.05), and FENa was significantly elevated from 0.27 +/- 0.08 to 2.02 +/- 0.55% (P less than 0.05). In conclusion, spontaneously hypertensive rats have a blunted increase in RIHP and pressure natriuresis response in comparison with Wistar-Kyoto rats. Thus, in Okamoto spontaneously hypertensive rats, the effect of RPP on RIHP is attenuated, leading to a blunted pressure natriuresis response.
Abstract: The purposes of this study were two. First, we wanted to evaluate in patients a technique for automated adjustment of selected energy for defibrillation or cardioversion based on transthoracic impedance. Second, we wanted to define the relationship of peak current and shock success in various arrhythmias. Applying a previously validated method of predicting transthoracic impedance in advance of any shock, we modified defibrillators to automatically double the operator-selected energy if the predicted impedance exceeded 70 omega. Success rates of shocks given for ventricular and atrial arrhythmias from these modified energy-adjusting defibrillators were compared with success rates for shocks given from standard defibrillators. We prospectively collected data on 347 patients who received a total of 1009 shocks. Low-energy (100 J) shocks given to high-impedance (greater than or equal to 70 omega) patients had a poor success rate; in such high-impedance patients significant improvement in shock success rate was achieved by the energy-adjusting defibrillators. For example, when 100 J shocks were selected for high-impedance patients in ventricular fibrillation the energy-adjusting defibrillators achieved a shock success rate of 75%, whereas standard defibrillators achieved a shock success rate of only 36% (p less than .01). Similar improvements were seen for ventricular tachycardia and atrial fibrillation. Thus, automated energy adjustment based on transthoracic impedance is a beneficial approach to defibrillation and cardioversion. For ventricular fibrillation, atrial fibrillation, and atrial flutter there was a clear relationship between peak current and shock success.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: The stereochemical course of the reduction of acetaldehyde to ethanol was investigated by evaluating, with the enzymic system yeast alcohol dehydrogenase/diaphorase and g.c.-m.s., the configuration of [1-2H]ethanol obtained from [1-2H]acetaldehyde with different micro-organisms. Although only S-[1-2H]ethanol was formed, all the micro-organisms showed evidence of the existence of alcohol dehydrogenases with opposite stereospecificity.
Abstract: In young anesthetized Munich-Wistar rats, red cell flux (Qrbc) was measured in the vasa recta of the exposed renal papilla by means of fluorescently labeled erythrocytes. To study the vasoreactivity of the juxtamedullary vasculature and its sensitivity to converting-enzyme inhibition, measurements of Qrbc were made before and after continuous intravenous infusion of the angiotensin I converting-enzyme inhibitor captopril (3 mg.h-1.kg body wt-1). A time control group that received vehicle alone was studied in parallel. Captopril acts as a vasodilator and reduces systemic arterial pressure. Captopril treatment increased Qrbc by 40 +/- 4% (n = 9, P less than 0.001) and decreased blood pressure by 9% (P less than 0.001). In the time control group no statistically significant change occurred in either Qrbc (+6 +/- 8%, n = 10) or blood pressure (-1%). Urine samples were taken from the papillary tip. In neither of the groups did the urine osmolality show a statistically significant change. In the time control group the values before and after intravenous infusion were 1,006 +/- 61 and 1,091 +/- 70 mosmol/kg H2O, respectively, and in the captopril-treated animals the corresponding values were 1,150 +/- 85 and 1,210 +/- 60 mosmol/kg H2O, respectively. These results confirm the suggestion that there is high vasoreactivity in the juxtamedullary vasculature and that this region is sensitive to inhibition of angiotensin I-converting enzyme, the latter sensitivity implying that angiotensin II plays a role in the regulation of juxtamedullary vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Different non-hypotensive hypovolemic stimuli were applied to 21 healthy and 20 uremic dialysis patients. The purpose was to study the effect on plasma arginine-vasopressin concentration, using orthostasis as a reference model. Orthostasis increased the plasma AVP level in healthy subjects as well as in uremic dialysis patients. In healthy subjects plasma AVP increased both when they were normohydrated and after they had been water-depleted. Lower body negative pressure (LBNP, -40 mmHg) was applied to 11 healthy males to induce a central blood volume decrease, equal to that induced by orthostasis. The plasma AVP increased in two subjects only who became hypotensive during the investigations. Ten hemodialysis patients were volume-depleted by isolated ultrafiltration. A flow directed Swan-Ganz catheter was used to measure the central intravascular pressures. Pulmonary capillary wedge pressure was reduced to normal or subnormal values during 1-2 h of ultrafiltration, without any significant changes in plasma AVP. Plasma AVP increased only in 2 patients, who became hypotensive during the investigations. Thus, of the present non-hypotensive volume stimuli only orthostasis was able to stimulate AVP secretion. Equal or even greater reductions in central blood volumes by other stimuli had no effect on AVP secretion. The results demonstrate that isolated stimulation of low-pressure volume receptors has no effect on the secretion of AVP in humans.
Abstract: The effects of halothane, enflurane, and isoflurane on myocardial contractility were compared in papillary muscles of the right ventricle of adult male ferrets at 30 degrees C. Isotonic and isometric variables of contractility were measured before, during, and after exposure to incremental concentrations of halothane (n = 9 muscles), enflurane (n = 9 muscles), and isoflurane (n = 9 muscles), in steps of 0.25 MAC up to 1.5 MAC of halothane and of enflurane, and up to 2.0 MAC of isoflurane. Each of the three anesthetics caused a dose-dependent reversible decrease in contractility. The onset of maximal myofibrillar activation was delayed in a dose-dependent manner, and time to peak shortening of the isotonic preloaded twitch was unchanged, except for a slight decrease at greater than 1 MAC of enflurane. Isoflurane’s negative inotropic effects were clearly less than those of either halothane or enflurane. Comparison of the time course of contraction and relaxation in both isometric and isotonic twitches suggests that, in addition to effects on intracellular calcium availability, these anesthetics decrease the myofibrillar responsiveness to calcium and/or the calcium sensitivity of the contractile proteins.
Abstract: To assess the importance of factors influencing the resolution of exercise-associated acidosis, measurements of acid-base variables were made in nine healthy subjects after 30 s of maximal exercise on an isokinetic cycle ergometer. Quadriceps muscle biopsies (n = 6) were taken at rest, immediately after exercise, and at 3.5 and 9.5 min of recovery; arterial and femoral venous blood were sampled (n = 3) over the same time. Intracellular and plasma inorganic strong ions were measured by neutron activation and ion-selective electrodes, respectively; lactate concentration ([La-]) was measured enzymatically, and plasma PCO2 and pH were measured by electrodes. Immediately after exercise, intracellular [La-] increased to 47 meq/l, almost fully accounting for a reduction in intracellular strong ion difference ([SID]) from 154 to 106 meq/l. At the same time, femoral venous PCO2 increased to 100 Torr and plasma [La-] to 9.7 meq/l; however, plasma [SID] did not change because of a concomitant increase in inorganic [SID] secondary to increases in [K+], [Na+], and [Ca2+]. During recovery, muscle [La-] fell to 26 meq/l by 9.5 min; [SID] remained low (101 and 114 meq/l at 3.5 and 9.5 min, respectively) due almost equally to the elevated [La-] (30 and 26 meq/l) and reductions in [K+] (from 142 meq/l at rest to 123 and 128 meq/l). Femoral venous PCO2 rose to 106 Torr at 0.5 min postexercise and fell to resting values at 9.5 min.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Flow cytometry (FC) T and B cell crossmatches were done retrospectively for 38 cadaver renal transplant recipients (29 first and 9 retransplants–minimum follow-up 12 months) using both current pretransplant serum and peak-reactive sera. An increase in median fluorescence intensity (channel shift) and/or an increase in the number of donor T and/or B cells binding antibody in test sera occurred in 23 cases. These 23 patients experienced a greater number of reversible rejection episodes as compared with patients with negative FC crossmatches (65% vs. 33%), P = 0.031. Graft outcome, however, was not different in the two groups. Thus, a positive FC crossmatch allows for the detection of subliminal levels of donor presensitization and is associated with a greater number of rejection episodes. A positive FC crossmatch is not predictive of ultimate graft loss.
Abstract: Time of useful consciousness (TUC) was determined in 17 subjects exposed twice to 25,000 ft (7,620 m) in an altitude chamber. The criterion for TUC determination was inability to add two-digit numbers correctly. Median values of TUC were 267.5 seconds (s) in the first exposure and 240 s in the second. The intraindividual variability between the two exposures was 40.6 s. The probability of remaining in "useful" consciousness as a function of time at 25,000 ft (7,620 m) was similar in both exposures. The need for a more scientific approach towards the determination of time of useful consciousness in simulated high altitudes is raised.
Abstract: The tubuloglomerular feedback (TGF) mechanism was evaluated in the nonclipped kidney of Goldblatt hypertensive rats from both stop flow pressure (SFP) and single nephron glomerular filtration rate (SNGFR) responses to step increases in late proximal perfusion rate from 0 to 40 nl/min. During control conditions, increases in late proximal perfusion rate produced flow dependent decreases in SFP and SNGFR with maximal values of 10.2 +/- 1.0 mm Hg and 12.9 +/- 2.5 nl/min, values similar to those obtained in normal rats. During ACE inhibition (MK 422; 0.6 mg/kg/hr), arterial pressure decreased from 168 +/- 8 to 137 +/- 7 mm Hg and there was a marked attenuation in the magnitude of SFP feedback responses (delta = 2.5 +/- 0.3 mm Hg). SNGFR feedback responses, however, were not significantly impaired. Direct decreases in renal arterial pressure reduced control SFP but SFP feedback responses were maintained, indicating that the attenuated SFP feedback responses during ACE inhibition were not due to decreased arterial pressure. Superimposed infusion of angiotensin II during ACE inhibition partially restored SFP feedback responses. In contrast, norepinephrine infusion did not result in a similar restoration of SFP feedback sensitivity. These results indicate that the nonclipped kidney of Goldblatt hypertensive rats has an intact TGF mechanism as assessed from SFP and SNGFR feedback responses. Furthermore, ACE inhibition attenuates SFP but not SNGFR feedback responses, and systemic angiotensin II infusions can restore SFP feedback responsiveness towards normal.
Abstract: In six healthy males on a fixed sodium/potassium (Na/K) intake, we studied the relation between plasma K and urine K and Na excretion after an oral K load. Studies were repeated during fludrocortisone (0.5 mg bid) or spironolactone (50 mg qid), that is, after escape from the Na-retaining and Na-excreting effects of these drugs. A steep positive relation between plasma K (ordinate) and urine K or Na (abscissa) was found, compatible with a strong influence of changes in plasma K on K and Na excretion. Fludrocortisone reset the relation to a lower level of plasma K. Spironolactone, on the other hand, had little effect on these relations, although a tendency towards a higher plasma K could be recognized. Paradoxically, the K load was excreted less efficiently during fludrocortisone, probably due to enhanced cellular K deposition. Prolonged kaliuresis relative to the transient rise in plasma K and natriuresis was found only without medication. Only in this situation aldosterone rose and fell parallel to plasma K. We conclude that: 1) chronic mineralocorticoid increase shifts the set point of both K and Na excretion following a K load to a lower plasma K, compatible with resetting of the positive influence of plasma K on distal solute delivery towards a lower plasma K; 2) total kaliuresis is paradoxically low due to enhanced cellular K uptake; 3) blockade of endogenous aldosterone action has relatively little influence on these relations between plasma K and urine K or Na; 4) the contribution of acute aldosterone stimulation to the excretion of a single oral K load can be recognized as a delayed kaliuresis extending beyond the peak in plasma K.
Abstract: The pulmonary responses and changes in plasma acid-base status occurring across the inactive forearm muscle were examined after 30 s of intense exercise in six male subjects exercising on an isokinetic cycle ergometer. Arterial and deep forearm venous blood were sampled at rest and during 10 min after exercise; ventilation and pulmonary gas exchange variables were measured breath by breath during exercise and recovery. Immediately after exercise, ventilation and CO2 output increased to 124 +/- 17 1/min and 3.24 +/- 0.195 l/min, respectively. The subsequent decrease in CO2 output was slower than the decrease in O2 intake (half time of 105 +/- 15 and 47 +/- 4 s, respectively); the respiratory exchange ratio was greater than 1.0 throughout the 10 min of recovery. Arterial plasma concentrations of Na+, K+, and Ca2+ increased transiently after exercise. Arterial lactate ion concentration ([La-]) increased to 14-15 meq/l within 1.5 min and remained at this level for the rest of the study. Throughout recovery there was a positive arteriovenous [La-] difference of 4-5 meq/l, associated with an increase in the arteriovenous strong ion difference ([SID]) and by a large increase in the venous Pco2 and [HCO3-]. These findings were interpreted as indicating uptake of La- by the inactive muscle, leading to a fall in the muscle [SID] and increase in plasma [SID], associated with an increase in muscle PCO2. The venoarterial CO2 content difference was 38% greater than could be accounted for by metabolism of La- alone, suggesting liberation of CO2 stored in muscle, possibly as carbamate.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Although extensive evidence indicates that free fatty acids can decrease glucose utilization in vitro, it is still controversial how an increase in lipolysis affects glucose metabolism in man. To test the hypothesis that an increase in lipolysis is related to insulin resistance, we examined the effect of lipid-heparin infusion on glucose metabolism in ten normal subjects by the euglycaemic glucose clamp technique and isotopic determination of glucose turnover. In the control euglycaemic clamp studies with insulin infusion at 0.2 and 1.0 mU.kg-1.min-1, endogenous glucose production was suppressed from the basal rate of 2.0 +/- 0.3 mg.kg-1min-1 to 1.1 +/- 0.7 mg.kg-1.min-1 and -0.4 +/- 0.7 mg.kg-1min-1 respectively. Glucose utilization increased from the basal rate of 2.0 +/- 0.3 mg.kg-1min-1 to 2.3 +/- 0.5 mg.kg-1min-1 and 5.9 +/- 1.8 mg.kg-1min-1 respectively. When the euglycaemic clamp studies were coupled with lipid-heparin infusion at comparable low and high rates of insulin infusion, endogenous glucose production increased (1.8 +/- 0.7 mg.kg-1.min-1, p less than 0.001, and 0.3 +/- 0.6 mg.kg-1.min-1, p less than 0.05, respectively), and glucose utilization decreased (2.1 +/- 0.3 mg.kg-1.min-1, not significant, and 3.2 +/- 0.7 mg.kg-1.min-1, p less than 0.001 respectively). These data suggest that the artificial induction of intravascular lipolysis by lipid-heparin infusion leads to a state of insulin resistance in man.
Abstract: During external cardiac massage and after restoration of spontaneous circulation, the arterial and central venous blood gas status of ten patients was determined. During cardiopulmonary resuscitation the median arterial pH value was 7.29 and the median central-venous pH value was 7.16. The low central-venous pH during resuscitation was probably caused by the high partial pressure of carbon dioxide, because no significant difference between arterial and central-venous base deficit was found. The arteriovenous pH and carbon dioxide gradients were significantly lower after spontaneous circulation had been restored. The arterial pH does not parallel the marked fall in central venous pH, and therefore only partly indicates acid-base changes during resuscitation. On the other hand, a central-venous blood gas status not only indicates the degree of metabolic acidosis present, but also the "respiratory" acidosis that in turn is a measure of the severity of intracellular acidosis.
Abstract: To determine whether increased glucose transport following exercise is associated with an increased number of glucose transporters in muscle plasma membranes, the D-glucose inhibitable cytochalasin B binding technique was used to measure glucose transporters in red gastrocnemius muscle from exercised (1 h treadmill) or sedentary rats. Immediately following exercise there was a 2-fold increase in cytochalasin B binding sites, measured in purified plasma membranes enriched 30-fold in 5’-nucleotidase activity. This increase in glucose transporters in the plasma membrane may explain in part, the increase in glucose transport rate which persists in skeletal muscle following exercise. Where these transporters originate, remains to be elucidated.
Abstract: To study the regulation of cell pH by ambient pH, carbon dioxide tension (PCO2), and bicarbonate (HCO3), cell pH was measured in the isolated, in vitro microperfused rabbit proximal convoluted tubule using the fluorescent dye (2’,7’)-bis-(carboxyethyl)-(5,6)-carboxyfluorescein. For the same changes in external pH, changes in [HCO3] and PCO2 affected cell pH similarly ([HCO3]: pHi/pHe = 0.67, PCO2: pHi/pHe = 0.64, NS). Isohydric changes in extracellular [HCO3] and PCO2 did not change cell pH significantly. Changes in peritubular [HCO3] elicited larger changes in cell pH than changes in luminal [HCO3], which were enhanced by peritubular 4-acetamido-4’-isothiocyanostilbene-2,2’-disulfonate (SITS). The cell pH defense against acute increases and decreases in PCO2 was inhibited by sodium, but not by chloride removal. Peritubular SITS inhibited the cell pH defense against increases and decreases of PCO2, whereas luminal amiloride inhibited cell pH defense against increases in PCO2. Conclusions: (a) Steady-state cell pH changes in response to changes in extracellular [HCO3] and PCO2 are quantitatively similar for a given change in extracellular pH; (b) the rate of the basolateral Na/(HCO3)3 cotransporter is a more important determinant of cell pH than the rate of the apical membrane mechanism(s); (c) cell pH defense against acute changes in PCO2 depends on the basolateral Na/(HCO3)3 cotransporter (acid and alkaline loads) and the luminal Na/H antiporter (acid loads).
Abstract: The purpose of these investigations was to describe the mechanisms responsible for the change in the plasma [K] during the development and maintenance of hyperchloremic metabolic acidosis. Acute metabolic acidosis produced by HCI infusion resulted in a prompt rise in the plasma [K], whereas no change was observed during acute respiratory acidosis in the dog. After 3 to 5 days of acidosis due to NH4Cl feeding, dogs became hypokalemic; this fall in the plasma [K] was due largely to increased urine K excretion. Despite hypokalemia, aldosterone levels were not low, and the calculated transtubular [K] gradient was relatively high, suggesting renal aldosterone action. Thus, rather than anticipating hyperkalemia in patients with chronic metabolic acidosis due to a HCl load, the finding of hyperkalemia should suggest that the rate of urinary K excretion is lower than expected (ie, there are low aldosterone levels or failure of the kidney to respond to this hormone).
Abstract: In young anesthetized Munich-Wistar rats, red cell flux (Qrbc) was measured in the vasa recta of the exposed renal papilla by means of fluorescently labeled erythrocytes. To study the vasoreactivity of the juxtamedullary vasculature and its sensitivity to converting-enzyme inhibition, measurements of Qrbc were made before and after continuous intravenous infusion of the angiotensin I converting-enzyme inhibitor captopril (3 mg.h-1.kg body wt-1). A time control group that received vehicle alone was studied in parallel. Captopril acts as a vasodilator and reduces systemic arterial pressure. Captopril treatment increased Qrbc by 40 +/- 4% (n = 9, P less than 0.001) and decreased blood pressure by 9% (P less than 0.001). In the time control group no statistically significant change occurred in either Qrbc (+6 +/- 8%, n = 10) or blood pressure (-1%). Urine samples were taken from the papillary tip. In neither of the groups did the urine osmolality show a statistically significant change. In the time control group the values before and after intravenous infusion were 1,006 +/- 61 and 1,091 +/- 70 mosmol/kg H2O, respectively, and in the captopril-treated animals the corresponding values were 1,150 +/- 85 and 1,210 +/- 60 mosmol/kg H2O, respectively. These results confirm the suggestion that there is high vasoreactivity in the juxtamedullary vasculature and that this region is sensitive to inhibition of angiotensin I-converting enzyme, the latter sensitivity implying that angiotensin II plays a role in the regulation of juxtamedullary vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: The ventricular systolic pressure-volume area correlates well with myocardial oxygen consumption. However, in isolated muscle preparations, there are experimental data based on both mechanical and energetic measurements that suggest that the pressure-volume area concept may not obtain. In the present study, force-length area, the analog of pressure-volume area for a linear muscle, was examined in the ferret papillary muscle preparation under a wide range of loading conditions. There were two major findings: first, force-length area is closely correlated with oxygen consumption (r = 0.94-0.98); this correlation is better than those for such other indexes as peak force and force-time integral. Furthermore, this relation of oxygen consumption with force-length area is independent of the mode of contraction (isometric or shortening), while the relations with the other indexes are not. Second, quick release imposed after end-systole during isometric contraction was found to curtail oxygen consumption. The first finding, the optimal correlation of force-length area with oxygen consumption, suggests both that the correlation of pressure-volume area with oxygen consumption on the ventricular level arises from a basic property of cardiac muscle and that force-length area may be the best mechanical index to use in calculating regional oxygen consumption for a ventricular segment. The second finding, however, suggests that the time-varying elastance model, on which the concepts of pressure-volume area and force-length area are based, may not provide a complete description of the mechanical basis of cardiac muscle energetics, especially during the isometric contraction.
Abstract: The discovery that atrial extracts have potent diuretic and natriuretic properties revealed a possible endocrine function of the heart in the regulation of extracellular fluid volume. Since that first report intense research activity has been directed towards determining the mechanism of action of the active atrial natriuretic polypeptides (ANP) found in these extracts. Despite these efforts it remains controversial whether the renal actions of ANP are exerted solely on the process of glomerular filtration or involve additional direct actions on tubular transport. We have investigated the possibility that atrial natriuretic polypeptides may induce natriuresis by suppression of proximal tubular sodium and water reabsorption. Using shrinking split-drop micropuncture combined with simultaneous capillary perfusion in anaesthetized rats we report that 20 nanomolar alpha-rANP (the main component of ANP in rat plasma) added to the peritubular fluid had no direct effect on proximal fluid uptake whereas picomolar angiotensin II had a marked stimulatory action as reported. The stimulatory effect of angiotensin II on fluid reabsorption was inhibited by peritubular ANP at physiological concentrations and abolished by higher concentrations of ANP. Thus at physiological concentrations ANP acts within the kidney to decrease proximal reabsorption by inhibition of angiotensin-stimulated sodium and water transport.
Abstract: The physiological role of glucagon-like peptide-1 7-36 amide (GLP-1 7-36) in man was investigated. GLP-1 7-36-like immunoreactivity was found in the human bowel; its circulating level rose after oral glucose and after a test breakfast. When it was infused into seven volunteers at a rate to mimic its postprandial plasma concentration in the fasting state, plasma insulin levels rose significantly and glucose and glucagon concentrations fell. During an intravenous glucose load, it greatly enhanced insulin release and significantly reduced peak plasma glucose concentrations, compared with a control saline infusion, even inducing postinfusion reactive hypoglycaemia. By comparison, infusion of glucose-dependent insulinotropic peptide (GIP) to physiological levels was less effective in stimulating insulin release. These observations suggest that GLP-1 7-36 is a physiological incretin and that it is more powerful than GIP. The observation of greatly increased postprandial plasma GLP-1 7-36 levels in patients with postgastrectomy dumping syndrome suggests that it may mediate the hyperinsulinaemia and reactive hypoglycaemia of this disorder.
Abstract: Patterns of in vitro renal renin release and the ability of atriopeptin to directly inhibit renin release have been examined in the rat, rabbit, and dog, but have been unstudied in the primate kidney. Accordingly, we examined renin release from superficial renal cortical slices of the squirrel monkey (Samiri sciuresus). The average age of the 5 animals was 10.2 +/- 2.5 yr at the time of study. Renin release was stimulated significantly by the beta-adrenergic agonist isoproterenol in concentrations of 10(-5) M (1.67-fold) and 10(-4) M (1.84-fold). Isoproterenol-induced renin release was inhibited by atriopeptin III (ANP, 2 X 10(-8) M) and the adenylate cyclase inhibitor dideoxadenosine (DDA, 10(-5) M). Similarly, the incubation of the superficial cortical slices with arachidonic acid (10(-3) M) resulted in a 4-fold increase in tissue renin release which was blocked by the calcium ionophore A23187 (17 X 10(-6) M) and ANP; interestingly, DDA did not block arachidonic acid-induced renin release. These results suggest that ANP exerts a direct inhibitory effect on B-adrenergic and arachidonic acid-induced renin release in the primate kidney. Further, the inhibitory action of A23187 on renin release suggests, as in other species, an integral role for intracellular calcium in the renin release process. These patterns of renin release in primate kidney are similar to those observed in the rodent kidney in vitro.
Abstract: To determine whether synthetic atrial natriuretic peptide (ANP) increases renal medullary blood flow and if so whether the increase mediates the diuresis and natriuresis induced by ANP, inner medullary vasa recta blood flow in the exposed left renal papilla of anesthetized Munich Wistar rats weighing between 102 and 161 g was measured by fluorescence videomicroscopy. The rats were maintained in a euvolemic state by the infusion of albumin. Synthetic ANP (Auriculin B) was administered intravenously as 2.5 micrograms/kg body wt prime and as a continuous infusion of 0.2 microgram X min-1 X kg body wt-1 to the experimental group (n = 7). Within 2 min after ANP was given, urine flow and sodium excretion increased (29.4 +/- 3.8 to 50.4 +/- 5.8 microliter X min-1 X kidney wt-1, P less than 0.01, and 3.39 +/- 0.57 to 6.05 +/- 0.95 mueq X min-1 X g kidney wt-1, P less than 0.01, respectively), but vasa recta blood flow in descending (DVR) or ascending (AVR) vasa recta did not change significantly (9.5 +/- 2.3 to 10.0 +/- 2.8 nl/min in DVR and 5.3 +/- 1.0 to 6.1 +/- 1.2 nl/min in AVR). Forty-five minutes after ANP was begun, urine flow and sodium excretion increased further (77.1 +/- 11.1 microliter X min-1 X g kidney wt-1 and 12.0 +/- 2.15 mueq X min-1 X g kidney wt-1, respectively), and by this time vasa recta blood flow had increased significantly to 14.0 +/- 2.6 in DVR, P less than 0.01, and 9.8 +/- 1.2 in AVR, P less than 0.01.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Osmotic diuresis occurs, if nonreabsorbed solutes such as mannitol impair the reabsorption of water. The reduced reabsorption of volume affects in turn the reabsorption and excretion of solutes. Thus, mannitol leads to modest impairment of proximal tubular reabsorption not only of water, but as well of electrolytes (Na, Cl, K, Pi, Ca, but not Mg), urea, and uric acid. Infusion of hypertonic mannitol increases renal blood flow and the glomerular filtration rate of superficial nephrons. The increased perfusion of medulla leads to wash out of medullary hypertonicity. The decline of medullary osmolarity leads to a marked impairment of water reabsorption in descending limbs and possibly to moderate impairment of NaCl, Ca, and Mg reabsorption in the ascending limbs of Henle’s loop. In the collecting duct, inhibition is marked of water and urea reabsorption and modest of NaCl reabsorption. A number of open questions remain, such as the mechanisms underlying decrease of renal vascular resistance, increased proximal tubular reabsorption of magnesium, or impaired NaCl reabsorption in thick ascending limbs.
Abstract: Portal venous pressure was controlled by resistance localized to specific sites in hepatic lobar veins in cats. All of the pressure drop from the portal vein to the vena cava occurred across postsinusoidal vessels; portal pressure, lobar venous pressure, and, therefore, sinusoidal pressure were not significantly different. Norepinephrine and angiotensin infusions (intraportal) caused elevation in portal pressure due to constriction of hepatic venous resistance sites as well as some constriction of presinusoidal (portal or sinusoidal) resistance sites. At low doses of norepinephrine presinusoidal constriction dominated whereas at higher doses the postsinusoidal constriction increased proportionately more. Hepatic nerve stimulation produced a similar response measured at an early time (1 min), but by 3 min the presinusoidal constriction showed complete escape so that elevated portal pressure was entirely due to hepatic venous constriction. The same site that provided basal vascular resistance also provided the increased hepatic venous resistance with nerve stimulation and infusion of angiotensin and norepinephrine. Rapid elevation of central venous pressure (CVP) caused elevated sinusoidal pressure. At high CVP (16 mm Hg), 75% of a rise in CVP was transmitted whereas at normal CVP (less than 4.5 mm Hg) less than 20% transmission occurred. The presence of a high resistance in the hepatic veins protected intrahepatic pressure from the effects of normal fluctuation of CVP.
Abstract: It is uncertain whether, in humans, potassium depletion can cause or sustain metabolic alkalosis of clinically important degree in the absence of coexisting known alkalosis-producing conditions. Previously we found, in normal humans ingesting abundant NaCl, that dietary K+ depletion alone can induce and sustain a small decrease in blood acidity and increase in plasma bicarbonate concentration; we hypothesized that more severe alkalosis was prevented by mitigating mechanisms initiated by renal retention of dietary NaCl that was induced by K+ depletion. To ascertain the acid-base response to dietary K+ depletion under conditions in which the availability of NaCl for retention is greatly limited, in the present study of six normal men we restricted dietary K+ as in the previous study except that intake of NaCl was maintained low (2 to 7 mEq/day, Low NaCl Group) instead of high (126 mEq/day, High NaCl Group). Plasma acid-base composition and renal net-acid excretion (NAE) did not differ significantly between groups during the control period. In the steady state of K+ depletion (days 11 to 15 of K+ restriction), neither plasma K+ concentration (2.9 +/- 0.9 mEq/liter vs. 3.0 +/- 0.1 mEq/liter) nor cumulative K+ deficit (399 +/- 59 mEq vs. 466 +/- 48 mEq) differed significantly between groups. During K+ restriction, persisting metabolic alkalosis developed in both groups, which was more severe in the Low NaCl Group: increment in [HCO3-]p, 7.5 +/- 1.0 mEq/liter versus 2.0 +/- 0.3 mEq/liter, P less than 0.001; decrement in [H+]p, 5.5 +/- 0.6 nEq/liter versus 2.9 +/- 0.4 nEq/liter, P less than 0.003. A significantly more severe alkalosis in the Low NaCl Group was evident at all degrees of K+ deficiency achieved during the course of the 15 days of K+ restriction, and the severity of alkalosis in the Low NaCl Group correlated with the degree of K+ deficiency. During the generation of alkalosis (days 1 to 7 of K+ restriction), NAE increased in the Low NaCl Group whereas it decreased in the High NaCl Group. During the maintenance of alkalosis (days 11 to 15), NAE stabilized in both groups after it returned to values approximating the control values. In both groups, urine Cl- excretion decreased during K+ restriction even though Cl- intake had not been changed, with the result that body Cl- content increased negligibly in the Low NaCl Group (28 +/- 6 mEq) and substantially in the High NaCl Group (355 +/- 64 mEq).(ABSTRACT TRUNCATED AT 400 WORDS)
Abstract: Pressure in the distal third of the interlobular arteries (Pila) was measured in anesthetized rats by micropuncture through corticotomy. Control Pila was 83.9 (SD 11.9) mm Hg at a renal arterial pressure (RAP) of 113.1 (SD 12.8) mm Hg. Reduction of RAP by 20 mm Hg caused no consistent change of total renal blood flow (RBF) or Pila. Relative interlobular arterial resistance, Rila = (RAP - Pila)/RBF, fell by 40 to 50%, and then remained practically unchanged at further reduction of RAP. Blood flow measured by radiolabeled microspheres (10.7 micron) showed similar values in intact cortex and in the tissue beneath the corticotomy, both varying in proportion to RBF. Intravenous infusion of angiotensin II (AII) 40 to 90 ng/min reduced RBF by 29% and increased RAP by 19 mm Hg. Pila rose by only 8 mm Hg and Rila increased to 209% of control. Reduction of RAP to control level during continued AII infusion did not change RBF, while Rila fell to 131% of control. We conclude that: dilatation and constriction of the interlobular arteries contribute importantly to autoregulation of outer cortical blood flow, probably through a myogenic mechanism (Bayliss); the constriction of interlobular arteries elicited by i.v. AII reflects mainly an autoregulatory response to increased arterial pressure, and to a smaller extent, a direct constrictor effect of AII.
Abstract: We have previously shown that arginine vasopressin (AVP) in physiological amounts reduces inner medullary blood flow and that the mechanism of this decrease is at least in part mediated by the vasopressor (V1-receptor) action of AVP. To determine whether the antidiuretic action of AVP (V2-receptor) also contributes to the reduction in inner medullary blood flow, we determined capillary blood flow (QVR) in individual descending vasa recta (DVR) and ascending vasa recta (AVR) using fluorescence videomicroscopy in the exposed renal papilla of the anesthetized rat. Three groups of chronically water-diuretic rats were studied in three consecutive periods: control (period 1), experimental (period 2), and recovery (period 3). Group I rats (designated the AVP group) received AVP, 45 ng X h-1 X kg body wt-1; group II (AVP + V2-inhibitor), AVP plus its specific antidiuretic antagonist d(CH2)5[D-Ile2,Thr4]AVP; and group III (V2-inhibitor), the antagonist alone, respectively, in the experimental period 2. Only group I rats concentrated their urine, urine osmolality (Uosmol) = 499 +/- 48 mosmol/kgH2O, whereas urine remained hypotonic throughout in groups II and III. In group I, QVR in DVR and AVR decreased in period 2; but in groups II and III, QVR tended to increase. These results suggest that the AVP-induced decrease in papillary vasa recta blood flow is in part mediated by its antidiuretic V2-receptor as well as by its vasopressor (V1-receptor). They also suggest that the rate of urinary flow in the medullary collecting ducts is a determinant of inner medullary blood flow.
Abstract: Patients put at bedrest for medical reasons lose 1-2% of spinal bone mineral per week. Losses of this magnitude during even short-term space flights of a few months would pose a serious limitation and require countermeasures. The spinal bone mineral (L2-L4) was determined in 6 healthy males (precision = 2%) before and after 5 weeks of complete bed rest. Only one individual had a significant loss (3%) and the -0.9% mean change for the 6, was not significant (P = 0.06). The average negative calcium balance during the 5 weeks was 4 g or 0.36% of total body calcium, similar to that reported in other bed-rest studies. Spinal bone loss, however, in healthy bed-rested males is significantly less than reported for bed-rested patients, suggesting that a large loss of spinal bone mineral does not occur during space flight missions lasting 5 weeks or less.
Abstract: Although severe potassium depletion has been shown to cause sodium retention, the effect of small potassium losses on sodium excretion is unknown. Seven healthy male volunteers were given a diet containing 35 mEq sodium and either low (10 mEq) or normal (90 mEq) potassium intake for 9 days. With the low potassium diet plasma potassium concentration decreased by 0.60 +/- 0.15 mEq/L. The cumulative potassium balance with this diet was negative (-124 +/- 22 mEq). Cumulative sodium balance was -82 +/- 43 mEq with the normal potassium diet but was positive (20 +/- 22 mEq) when the same subjects ingested a low potassium diet (P less than 0.05). A significant difference in sodium excretion could be detected as early as day 1 of potassium restriction. To study the effect of potassium depletion on the renal ability to handle a short-term sodium load, on day 10 each subject received a 2 L isotonic saline infusion over a period of 4 hours. Subjects while ingesting a normal potassium diet excreted 20% +/- 4% of the administered load. The same subjects while ingesting a low potassium diet excreted only 9% +/- 3% of the administered load (P less than 0.001). The difference in sodium excretion was not dependent on changes in glomerular filtration rate, renal plasma flow, plasma renin activity, plasma aldosterone, or plasma and urinary catecholamines. We conclude that variations in dietary potassium strikingly modify sodium excretion. Even mild potassium depletion impairs the renal ability to handle a short-term sodium load.
Abstract: We previously reported that the very act of cannulating a lung lymph vessel could alter the unique flow characteristics that existed within the lymphatic before cannulation. We postulated that this phenomenon could hold true for lymphatics draining any organ within the body. Since it is frequently important to know the relationship between the transmicrovascular fluid flux and true lymph flow rate, it would be critical that a cannulated lymphatic vessel have the same flow characteristics as those uncannulated vessels draining the same organ. In order to test our hypothesis we cannulated lymph vessels draining the heart, liver, small intestine, kidney, and skeletal muscle. By altering the lymphatic outflow pressure (normally related to systemic venous pressure) and by using lymphatic cannulas of various resistance, we were able to demonstrate that lymph flow varied linearly with lymphatic outflow pressure in every organ. By increasing transmicrovascular fluid flux and lymph flow rate in each organ we were also able to demonstrate that effective resistance of the lymphatic vessels and the effective pressure driving lymph flow varied as a function of the physical characteristics of the organ under investigation. Characteristic effective resistances of the heart, liver, skeletal muscle, kidney, and small intestine lymphatics decreased by 83, 40, 61, 36, and 50%, respectively. Along with these changes in effective resistance, the effective lymph driving pressure in the same organs varied by 49, 0, 257, 0, and 63%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Plasma erythropoietin titers (Ep) were compared in rats subjected to different kinds of systemic hypoxia. Ep increased exponentially, when hypoxia was induced by exposure to simulated altitude (from less than 0.025 IU Ep/ml plasma at sea-level up to 3.65 IU Ep/ml at 7000 m). An acute increase in the O2 affinity of blood augmented Ep production in normal rats but not in rats exposed to hypobaria. Ep also rose exponentially when isovolemic anemia was induced (e.g., 0.5 IU Ep/ml plasma were found at 7 g Hb/dl blood). When the same reduction in blood O2 carrying capacity was produced by CO-inhalation (0.1% CO in air), Ep increased to 5.57 IU/ml plasma. This very high value was considered to be partly due to the very high O2 affinity of carboxyhemoglobin. These results indicate that a left shift in the hemoglobin-O2 dissociation curve produces a stimulation of Ep production, particularly, when the O2-carrying capacity of blood is lowered.
Abstract: Recent studies of cerebral metabolism have suggested that although cerebral blood flow is reduced during rest in the healthy aged brain, there is little or no decline in resting glucose consumption. Intercorrelations between resting regional cerebral rates for glucose (rCMRglc), as determined by positron emission tomography using [18F]fluorodeoxyglucose, were shown to provide a measure of the functional associativity of brain regions. Partial correlation coefficients, controlling for whole brain glucose metabolism, were used in the analysis. Dividing the brain into 59 regions, we found, for 40 healthy males (21-83 years in age) in a state of reduced sensory input, that the strongest correlations generally were between bilaterally symmetric brain regions, and that there were many statistically significant correlations (P less than 0.01) among frontal and parietal lobe regions and also among temporal and occipital lobe areas, but few significant correlations between these two domains. The correlation analysis then was applied to two groups (15 healthy males each) of young (20-32 years old) and elderly (64-83 years old) subjects in the same resting state. Compared with the young group, we found that the elderly subjects have fewer statistically significant (P less than 0.01) correlations, with the most noteworthy reductions being between parietal and frontal lobe regions, and among parietal lobe areas. These findings indicated that cerebral functional interactions were reduced in the healthy elderly. The same analysis, applied to 21 mainly mildly-to-moderately impaired presumed Alzheimer subjects (and 21 age-matched controls), revealed fewer significant correlations between homologous brain regions which correspond to metabolic asymmetries linked to neuropsychological deficiencies.
Abstract: Cerebral glucose metabolic rates were measured in 80 normal volunteers by studying the uptake of [18F]deoxyglucose with positron emission tomography (PET), using three PET scanners. A brain size index was determined from the PET images using either length-width or area measurements of the brain at a standard level. There was a significant negative correlation between glucose metabolism per unit volume and brain size that was well described by an inverse functional relationship, implying that the total glucose consumption of the brain is approximately constant. Analyses of men versus women revealed no sex differences in total brain glucose consumption, although there were differences in brain size and in glucose metabolism per unit volume. Similarly there was no significant correlation of total brain glucose consumption with age. The variation with brain size accounted for 46% of the logarithmic intersubject metabolic variance. When comparing global metabolic rates in different subjects, multiplying the rates by a brain size index has the dual advantage of correcting for differences related to brain size and correcting for differences in cerebrospinal fluid volume.
Abstract: Dangerous or long lasting ventricular arrhythmias developed in three patients who had sustained an electrical injury in which current passed through the thorax. In all three cases there was a delay of 8-12 hours between the injury and the onset of symptoms. The ventricular arrhythmias were severe and long lasting. In two of the three patients, ventricular tachycardia or ventricular fibrillation or both occurred and in one patient ventricular parasystole developed. No enzymatic evidence of myocardial necrosis was found but the results of an endomyocardial biopsy carried out in two of the three patients showed focal myocardial fibrosis and increased numbers of Na, K-pumps. The two patients with ventricular tachycardia became symptom free after appropriate antiarrhythmic treatment and in the third patient ventricular parasystole disappeared spontaneously within two years. Patients sustaining electrical injury in which current passes through the thorax should be monitored electrocardiographically for at least 24 hours, and patients with unexpected arrhythmias should be questioned about previous electrical injury.
Abstract: To investigate the sites of action of aldosterone (Aldo) and chronic potassium loading (high K) and to determine whether dietary K can modulate collecting duct structure independent of Aldo, a morphometric study of the structure of the initial collecting tubule (ICT), the cortical collecting tubule (CCT), the medullary collecting duct in the outer stripe (MCDOS) and the inner stripe (MCDIS), and the papillary collecting duct (PCD) was carried out in a rat model in which plasma levels of Aldo were clamped at basal or physiologically elevated levels and high K could be induced without concomitant hyperaldosteronism. Elevated levels of Aldo increased cell area (Ac) and basolateral membrane surface (BLM) from control values in the ICT, CCT, and MCDOS but not in the MCDIS or PCD. High K with normal physiological levels of Aldo increased BLM in the ICT and CCT without a concomitant change in AC. No response was seen in MCDOS, MCDIS, or PCD. It is concluded that Aldo can modulate principal cell structure in the collecting duct system in segments extending from the ICT through the MCDOS in the rat and that high K independent of Aldo can influence collecting duct structure only in the ICT and CCT.
Abstract: In vivo microperfusion was used to assess the changes in the active and passive components of bicarbonate absorption in the rat late proximal tubule during chronic metabolic alkalosis. In tubules perfused with 40 mM bicarbonate, net bicarbonate absorption was inhibited and normal flow dependence was attenuated during alkalosis, compared with values in normal tubules perfused with 40 or even 25 mM bicarbonate concentrations. Under all conditions, bicarbonate back leak was small and contributed little to alterations in net bicarbonate transport, even though bicarbonate permeability was reduced by approximately 75% during chronic metabolic alkalosis and was flow dependent. Suppression of net bicarbonate absorption during chronic metabolic alkalosis was instead attributable to inhibition of proton secretion as a function of both luminal bicarbonate concentration and flow rate. At the highest level of bicarbonate delivery to yield maximal acidification rates, proton secretion during alkalosis was diminished by 38% (from 216 +/- 15 to 133 +/- 10 peq X mm-1 X min-1, P less than 0.001). In conclusion, despite extracellular volume contraction, potassium deficiency, and reduction in bicarbonate permeability during chronic metabolic alkalosis, net bicarbonate absorption in the late proximal convoluted tubule is depressed as a function of luminal bicarbonate concentration and flow rate because acidification is inhibited by hyperbicarbonatemia/alkalemia.
Abstract: Substrate utilization during exercise at 65% of maximal O2 uptake (VO2 max) and biochemical characteristics of vastus lateralis were compared between five endurance-trained (T) and five untrained subjects (U). The oxidative enzyme activities were 100% greater in T than in U, and VO2 max was 50% higher. A greater proportion of ATP regeneration occurred through oxidative processes in T than in U (smaller leg lactate release and smaller muscle lactate accumulation). The respiratory exchange ratio together with the local leg respiratory quotient indicated a greater contribution of fat to oxidative metabolism in T than U (53 vs. 33%). No difference, however, in the ratio of plasma free fatty acid extraction to O2 extraction by the working legs was found between T and U. Thus it could be calculated that a greater fraction of fat oxidation would have been covered by intramuscular triglycerides in T than in U (34 vs. 15%, P less than 0.05). T in comparison to U were further characterized by a smaller glycogen breakdown and a smaller glucose uptake, which may have been one contributing factor that prevented the blood glucose level from falling in T. The greater leg muscle citrate concentration in T could have been one factor mediating a lower carbohydrate utilization as a response to an increase in the relative proportion of fat oxidation.
Abstract: Previous studies in rat kidneys have demonstrated that oscillations in the proximal intratubular pressure are a prominent feature of the tubulo-glomerular feedback mechanism (TGF) operating during free flow conditions. The purpose of the present study was to investigate whether a subpopulation of synchronized, interacting nephrons could be detected. In group A nephrons, i.e., nephrons with a high probability of having their afferent arterioles arising from the same interlobular artery, 29 out of 33 pairs of nephrons were found to show synchronized pressure oscillations. In group B nephrons, not expected to have this common origin of their afferent arterioles, only 1 out of 23 pairs was found to be synchronized. The standard deviation of the frequency differences was 0.063 cycles per minute in group A nephron pairs and 0.202 cycles per minute in group B pairs (p less than 0.05), showing the greater homogeneity in frequency in group A. Furthermore, nephrons having synchronized pressure oscillations were found to interact with each other. Thus, perturbation of the proximal tubular pressure oscillations in one nephron by loop microperfusion affected the amplitude of the pressure oscillations in the non-perfused nephron; and reactivation of pressure oscillations in one nephron was followed by reactivation of oscillations in the non-perfused nephron. Thus, the present results show that there exists a well defined subpopulation of nephrons, in which the TGF-mediated proximal pressure oscillations are synchronized. This synchronization is a result of interaction between the different nephrons.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: To investigate the relative influence of pericardial and intrathoracic pressures on left and right ventricular diastolic and systolic pressures two experimental groups were studied: group 1-10 open chest dogs with a controlled pericardial effusion; and group 2 - five closed chest dogs with a controlled pneumothorax at constant transpulmonary pressure and lung volume. In both groups right and left ventricular diastolic pressures were linear functions of external pressure with respective slopes of 0.71 and 0.39 for group 1 and 0.80 and 0.78 for group 2. The left ventricular slope of 0.39 indicates that left ventricular volume decreased more with increments in pericardial pressure since a slope of approximately 1.00 would be expected if the filling volume was invariant. Accordingly, the fall in left ventricular systolic pressure that occurred in both groups was two to three times greater in group 1. Right ventricular systolic pressure fell in group 1 whereas it increased in group 2. It is concluded that there are no major differences between the influence of either type of external pressure on right ventricular filing. In contrast, the left ventricle, and in particular the filling pressure gradient between the pulmonary circulation and the left ventricle, is more sensitive to pericardial pressure.
Abstract: Noradrenaline preconstricted pulmonary and renal artery segments from 20 large White pigs were examined in vitro for their responses to alpha-human atrial natriuretic peptide (alpha-hANP), rat-atriopeptin I (AP I) or rat-atriopeptin III (AP III) added in a cumulative manner. The role of the vascular endothelium in atrial peptide-induced relaxation was examined in the presence of indomethacin and propranolol by removal of the endothelium in one of a pair of arterial segments. Pulmonary artery was significantly (P less than 0.001) more sensitive than renal artery to alpha-hANP with a potency ratio of approximately 10. alpha-hANP appeared to be a more potent relaxant than AP III and AP I in pulmonary artery. Potency ratios were approximately 2 (AP III vs alpha-hANP; P less than 0.05) and 30 (API vs alpha-ANP; P less than 0.001). Removal of the endothelium increased the sensitivity of renal artery to a alpha-hANP, but made no difference to the pulmonary arterial relaxations. In man the highest circulating concentrations of ANP are found in the pulmonary artery. The demonstration of its potent relaxant effects at this site in the pig indicates a possible role in the modulation of pulmonary arterial tone.
Abstract: This study presents a dynamic continuous time model of the regulation of the renal proximal intratubular pressure in the rat. The model integrates a functional model of the glomerulus, a tubular model, a feedback model, and an afferent arteriolar model. The model has one equilibrium solution for the dependent variables (equilibrium point) for each set of independent variables. An equilibrium point, chosen to be in accordance with experimental data from Sprague-Dawley rats, was used as the initial value for the dependent variables. The model is shown to have parameter ranges in which sustained stable oscillations in proximal pressure are present. For sustained oscillations to appear, it is necessary for the system’s operating point to be located on a sufficiently steep portion of the tubuloglomerular feedback curve. The model analyses are compared with various experimental recordings of the proximal intratubular pressure. The model simulations show both spontaneous and induced oscillations in the proximal pressure in close agreement with the experimental results; but the steady-state mean pressure regulation is found to be less efficient in the model than that apparent from the experimental recordings, suggesting the involvement of additional pressure-regulating mechanisms other than those included in the present model. It is concluded that the dynamic systems approach used in the present study yields new insight into the mechanisms underlying the proximal intratubular pressure oscillations and that it can be of further value for the study of the factors regulating the proximal intratubular pressure.
Abstract: Muscle ATP, creatine phosphate and lactate, and blood pH and lactate were measured in 7 male sprinters before and after running 40, 60, 80 and 100 m at maximal speed. The sprinters were divided into two groups, group 1 being sprinters who achieved a higher maximal speed (10.07 +/- 0.13 m X s-1) than group 2 (9.75 +/- 0.10 m X s-1), and who also maintained the speed for a longer time. The breakdown of high-energy phosphate stores was significantly greater for group 1 than for group 2 for all distances other than 100 m; the breakdown of creatine phosphate for group 1 was almost the same for 40 m as for 100 m. Muscle and blood lactate began to accumulate during the 40 m exercise. The accumulation of blood lactate was linear (0.55 +/- 0.02 mmol X s-1 X l-1) for all distances, and there were no differences between the groups. With 100 m sprints the end-levels of blood and muscle lactate were not high enough and the change in blood pH was not great enough for one to accept that lactate accumulation is responsible for the decrease in running speed over this distance. We concluded that in short-term maximal exercise, performance depends on the capacity for using high-energy phosphates at the beginning of the exercise, and the decrease in running speed begins when the high-energy phosphate stores are depleted and most of the energy must then be produced by glycolysis.
Abstract: The following picture emerges from the relatively small literature concerned with pHi regulation in the stomach. Oxyntic cells have a H,K-ATPase at the luminal membrane and both Na+-H+ and Cl(-)-HCO3 exchangers at the serosal membrane. The intrinsic buffer capacity is 40-50 mM/pH. In the resting state, when the H, K-ATPase is inactive, pHi is 7.1. The Na+-H+ exchanger prevents acidic shifts of pHi, and the Cl(-)-HCO3 exchanger prevents alkaline shifts. The combined operation of the two appears to contribute directly to the net Cl- secretion (and short-circuit current) generated by resting OC. In the stimulated state, H+ secretion into the gland lumen via the H,K-ATPase increases, and Cl- movement across the serosal membrane via exchange for HCO3 doubles or triples; however, pHi remains roughly constant (delta pHi less than or equal to 0.1 units). The large increase in Cl- and HCO3 movement across the serosal membrane requires one (or all) of the following events: The anion exchanger changes its characteristics (Km or Vmax); [Cl-]i decreases; or other membrane mechanisms must be activated. Chief cells also have a pHi of 7.1 and a Bi of 40-50 mM/pH. They exhibit Na+-dependent and Cl(-)-dependent changes of pHi that are consistent with the presence of both Na+-H+ and Cl(-)-HCO3 exchangers. The Na+-dependent changes of pHi are larger and the Cl(-)-dependent changes are smaller in CC than in OC. Surface cells exhibit changes of AO fluorescence that indicate that there is a Na+-H+ exchanger and a HCO3 conductance. The H+ permeability of the luminal membranes of all cells is very low, while that of the serosal membrane (via the cation and anion exchangers) is high.
Abstract: This study evaluated the possibility that during skeletal muscle contractions tissue O2 tension (Po2) around arterioles and venules decreases substantially more than in the middle of the capillary bed and thereby influences functional hyperemia. Periarteriolar [H+] and [K+] were also measured because most large arterioles are in close proximity to venules such that the biochemical status of the periarteriolar tissue could be influenced by a large decrease in O2 availability in the annulet of tissue surrounding the venules. Stimulation frequencies in the range of 2-12 Hz were used to activate the rat spinotrapezius muscle. Periarteriolar and capillary bed Po2, [H+], and [K+] changed during the first few minutes of stimulation but were restored to near resting concentrations as the functional hyperemia developed. However, perivenular Po2 decreased rapidly to approximately 50-60% of the resting gas tension as contractions began, and only minor recovery occurred. Elevation of tissue and periarteriolar Po2 with an O2-enriched superfusion solution did not prevent dilation during contractions to the same diameter as during the response at very low superfusion Po2. Therefore, the extent to which O2 influences arteriolar dilation and exercise hyperemia in the spinotrapezius muscle of the rat may depend less on periarteriolar and capillary bed Po2 than on the release of vasoactive materials from the nearby perivenular tissues as the availability of O2 decreases.
Abstract: Elevation of brain glucose before the onset of nearly complete ischemia leads to increased lactic acid within brain. When excessive, such acidosis may be a necessary factor for converting selective neuronal loss to brain infarction from nearly complete ischemia. To examine the potential neurotoxicity of excessive lactic acid concentrations, we microinjected (0.5 microliter/min) 150 mM sodium lactate solutions (adjusted to 6.50-4.00 pH) for 20 min into parietal cortex of anesthetized rats. Interstitial pH (pH0) was monitored with hydrogen ion-selective microelectrodes. Animals were allowed to recover for 24 h before injection zones were examined with the light microscope. Injectants produced brain necrosis in a histological pattern resembling ischemic infarction only when pH0 was less than or equal to 5.30. Nonlethal injections showed only needle tract injuries. Abrupt deterioration of brain acid-base homeostatic mechanisms correlated with necrosis since pH0 returned to baseline more slowly after lethal tissue injections than after nonlethal ones. The slowed return of pH0 to baseline after the severely acidic injections may reflect altered function of plasma membrane antiport systems for pH regulation and loss of brain hydrogen ion buffers.
Abstract: We followed renal function through the natriuretic phase of 6 occasions of drug-induced recovery from minimal lesions nephrotic syndrome (MLNS). Protein excretion started to fall 1-3 days prior to the start of the natriuresis. The natriuresis was accompanied by a rise in glomerular filtration rate (GFR, inulin clearance). The filtration fraction, calculated from the GFR and the p-aminohippurate clearance, rose steadily in 5 subjects in whom it was low before therapy. Proximal and distal sodium reabsorption fractions, estimated from the changes in maximum free water clearance, fell, and fractional sodium, lithium, uric acid and free water clearance rose. At the time of these changes plasma protein had hardly risen, whereas renin activity was down. These results are in agreement with the notion that the sodium retention of MLNS is due to a renal defect. Repair of the glomerular filter, evident from the disappearance of proteinuria and the rise in filtration fraction, apparently normalizes the elevated tubular sodium reabsorption proximal to the macula densa, which leads to a fall in renin release.
Abstract: Insulin causes a translocation of glucose transporters from intracellular microsomes to the plasma membrane in adipocytes. To determine whether insulin has a similar effect in rat hindlimb muscles, we used glucose-inhibitable cytochalasin B binding to estimate the number of glucose transporters in membrane fractions from insulinized and control muscles. Insulin treatment caused an approx. 2-fold increase in cytochalasin B-binding sites in a plasma membrane fraction and an approx. 70% decrease in cytochalasin B-binding sites in an intracellular membrane fraction. In order to detect this effect of insulin, it was necessary to develop a procedure for isolating a plasma membrane fraction and an intracellular membrane fraction that were not contaminated with sarcoplasmic reticulum. Our results show that, as in adipocytes, insulin stimulates translocation of glucose transporters from an intracellular membrane pool to the plasma membrane in hindlimb skeletal muscles.
Abstract: The two-dimensional mechanical properties of human pericardium from seven males undergoing coronary artery bypass surgery were studied. A 25-mm square piece of parietal pericardium overlying the right ventricle was excised. An approximately 8-mm square target was marked at the center, and its dimension was measured electrooptically. When immersed in physiological saline at 37 degrees C, the specimen was subjected to biaxial isotropic loading. Large deformations developed in the beginning of the loading; the pericardium became increasingly stiffer when load was increased, and then became almost inextensible. As in canine pericardium [Lee et al., Am. J. Physiol. 249 (Heart Circ. Physiol. 18): H222-H230, 1985], hysteresis was present and tension-stretch relationship was insensitive to loading frequency during cyclic loading, relaxation of tension was substantial, and creep was insignificant. Unlike canine specimens, however, human pericardium was nearly isotropic and almost three times as thick [mean 0.55 +/- 0.02 mm (SD)]. The human tension-area relation for isotropic loading could be described by an exponential function and was found to shift significantly to the left of the canine. Therefore, human pericardium is less extensible than canine.
Abstract: The geometry of the arteriolar network is one of the major determinants of blood flow distribution within a tissue. The purpose of this study was to describe the distribution of geometrical variables (lengths, diameters) as well as the pattern of branching in the nonarcading portion of the arteriolar network in skeletal muscle. The exteriorized cat sartorius muscle was used as the experimental model. The intravascular fluorescence of fluorescein isothiocyanate (FITC)-labeled Dextran 150 was observed with a low-light-level video camera, and the vascular networks were mapped. Arteriolar lengths and diameters were measured, and vessel position in the network was characterized by Strahler’s method of ordering, in which the first-order arterioles give rise to most of the capillaries. Typically, the nonarcading, terminal networks contain three or four arteriolar orders. The sequences of the number of vessels, mean diameter, and mean length for each order are accurately described by geometric progressions (Horton’s law). The distribution of diameters within each order was rather narrow: typically two-thirds of the vessels fell within 20% of the mean value. The spread was reduced by half when vessels within a single network were considered. During vasodilation to a standard stimulus the relative dispersion of diameters increased modestly. The distribution of vessel lengths was broader than for diameters. Two-thirds of vessels of a single order fell within 50-75% of the mean. The spread was less within individual networks. The variability of vessel geometry and branching patterns was substantially less within a single network than for a population drawn from a group of networks.
Abstract: An appreciation for the potential of skeletal muscle vascular beds for blood flow (blood flow capacity) is required if one is to understand the limits of the cardiorespiratory system in exercise. To assess this potential, an index of blood flow capacity that can be objectively measured is required. One obvious index would be to measure maximal muscle blood flow (MBF). However, a unique value for maximal MBF cannot be measured, since once maximal vasodilation is attained MBF is a function of perfusion pressure. Another approach would be to measure maximal or peak vascular conductance. However, peak vascular conductance is different among skeletal muscles composed of different fiber types and is a function of perfusion pressure during peak vasodilation within muscle composed of a given fiber type. Also, muscle contraction can increase or decrease blood flow and/or the apparent peak vascular conductance depending on the experimental preparation and the type of muscle contraction. Blood flows and calculated values of conductance appear to be greater during rhythmic contractions (with the appropriate frequency and duration) than observed in resting muscle during what is called "maximal" vasodilation. Moreover, dynamic exercise in conscious subjects produces the greatest skeletal muscle blood flows. The purpose of this review is to consider the interaction of the determinants of muscle blood flow during locomotory exercise. Emphasis is directed toward the hypothesis that the "muscle pump" is an important determinant of perfusion of active skeletal muscle. It is concluded that, during normal dynamic exercise, MBF is determined by skeletal muscle vascular conductance, the perfusion pressure gradient, and the efficacy of the muscle pump.
Abstract: Factors determining the symptoms of breathlessness and fatigue in patients with congestive heart failure were investigated by comparing the response to slow and fast exercise. Symptom limited oxygen consumption (maximal); minute ventilation, mean pulmonary capillary wedge pressure; and arterial blood gases, pH, and lactate concentrations were measured during treadmill exercise using a slow protocol in 25 men (age 34-67 years) with congestive heart failure (New York Heart Association class II-III). Ten of these patients were also exercised according to a rapid protocol. Exercise was terminated by fatigue in 23/25 patients after the slow test and by breathlessness in all patients after the rapid test. Exercise capacity (maximal oxygen consumption and exercise duration) was not related to resting or exercise pulmonary capillary wedge pressure or the change in pulmonary capillary wedge pressure during exercise, nor was there any difference in pulmonary capillary wedge pressure at the end of exercise within individuals between the fast and slow tests. Minute ventilation was greater (51 vs 43 1/min), peak exercise lactate concentration higher (3.7 vs 2.2 mmol/l), and the change in pH from the resting state was greater (0.06 vs 0.02) during the rapid test than during the slow test. The sensation of breathlessness in congestive heart failure is not simply related to raised pulmonary capillary wedge pressure, but may in part be due to stimulation of peripheral chemoreceptors in response to metabolic acidosis.
Abstract: The respiratory exchange ratio (RER) is lower during exercise of the same intensity in the trained compared with the untrained state, even though plasma free fatty acids (FFA) and glycerol levels are lower, suggesting reduced availability of plasma FFA. In this context, we evaluated the possibility that lipolysis of muscle triglycerides might be higher in the trained state. Nine adult male subjects performed a prolonged bout of exercise of the same absolute intensity before and after adapting to a strenuous 12-wk program of endurance exercise. The exercise test required 64% of maximum O2 uptake before training. Plasma FFA and glycerol concentrations and RER during the exercise test were lower in the trained than in the untrained state. The proportion of the caloric expenditure derived from fat, calculated from the RER, during the exercise test increased from 35% before training to 57% after training. Muscle glycogen utilization was 41% lower, whereas the decrease in quadriceps muscle triglyceride concentration was roughly twice as great (12.7 +/- 5.5 vs. 26.1 +/- 9.3 mmol/kg dry wt, P less than 0.001) in the trained state. These results suggest that the greater utilization of FFA in the trained state is fueled by increased lipolysis of muscle triglyceride.
Abstract: Adult normothermic monkeys were submitted to 1 h of total cerebral ischemia, followed by blood recirculation for 1.5-24 h. During ischemia EEG and evoked potentials were suppressed within 12 s and 3 min, respectively. Upon recirculation, high-voltage EEG bursts began to reappear after 82-125 min, followed by gradual return of continuous background activity and near normalization of EEG frequency pattern within 24 h. Somatically evoked potentials, in contrast, exhibited only partial recovery, and consciousness did not return during the observation period. At the end of the experiments, tissue contents of sodium, potassium, calcium, and magnesium were measured in the gray and white matter of parietal lobe by atomic absorption spectroscopy. Gray matter sodium content gradually increased by approximately 50% from 41.0 to 59.8 mumol/g wet wt during 24 h of recirculation. The other electrolytes including calcium did not change during the observation period. Postischemic recovery reported in this and the accompanying article is attributed to careful control of postischemic general physiological state and prevention or treatment of postischemic complicating side effects such as postischemic brain edema, hypotension, acidosis, pulmonary distress, and anuria. No specific drug treatment such as application of calcium antagonists or metabolic inhibitors was necessary to achieve this effect.
Abstract: The present study examines the effect in free flow microperfusion experiments of various diuretics with different sites of action on an oscillating tubular pressure response to changes in Henle loop flow rate. Amiloride (1 mM) and bendroflumethiazide (0.1 mM) had no effect outside the stimulation caused by the solvent (Ringer solution). Acetazolamide (0.5 mM) stimulated a slow (30 mHz) oscillation and often activated a fast (130-190 mHz) rhythm. Furosemide (FUR) (0.1-2.0 mM) abolished the slow oscillation and caused the intratubular pressure to rise by 2-3 mm Hg. FUR (0.05 mM) caused partial inhibition of the slow rhythm, which usually became irregular. Bumetanide (BUM) (0.05 mM) elicited a biphasic response. Initially the pressure decreased, while the slow rhythm was amplified; then the fast oscillation was activated; after 4-6 min the oscillations disappeared, while the pressure increased. In the recovery period the oscillations often became irregular. The results confirm that the oscillating pressure response is mediated by a transport function of the macula densa (MD); and, thus, has the character of a tubulo-glomerular feedback (TGF) response. The data suggest 1. that BUM inhibition of NaCl co-transport in the cortical thick ascending limb of Henle (TAL) is delayed as compared to the medullary TAL; and 2. that FUR action at the MD interferes with more than one carrier mechanism. Partial inhibition gives rise to irregular oscillations.
Abstract: The present study was undertaken to evaluate the metabolic response of the kidney to lactic acidosis. Four types of lactic acidosis were induced in the dog: infusion of lactic acid, infusion of lactic acid with phenformin, administration of phenformin alone, and hypoxia by breathing 95% nitrogen. In all groups of animals, the same degree of acidosis was observed with plasma bicarbonate ranging from 12.8 to 14.9 mM. Plasma lactate concentration ranged from 3.0 to 8.1 mumol/mL. Renal ammoniagenesis failed to be influenced by lactic acidosis. As a matter of fact, it fell during anoxia. The extraction of glutamine by the kidney rose except during anoxia where it fell. The renal production of alanine rose during the infusion of lactic acid with and without phenformin. This coincided with the extraction of glutamine. The renal extraction of lactate rose in all forms of acidosis as well as the production of pyruvate. In the renal cortical tissue, the concentration of malate, pyruvate, and lactate rose. Alanine also rose except during anoxia. An important fall in cytosolic redox potential (NAD+/NADH lactate dehydrogenase) was observed, as well as a fall in mitochondrial redox (NAD+/NADH beta-hydroxybutyrate dehydrogenase). Lactate also accumulated in the liver and in the muscle. We propose that the kidney is unable to respond to lactic acidosis in terms of ammonia production and that this phenomenon is explained by transamination of pyruvate and glutamate into alanine and also by the observed fall in cytosolic redox potential. It is likely that renal gluconeogenesis is also inhibited and this is reflected by the rise in the concentration of malate in the kidney.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Simultaneous measurements of tissue PCO2 (PtCO2), interstitial H+ concentration ([H+]o), and tissue lactate content were used to examine changes in interstitial HCO3- concentration ([HCO3-]o) during complete ischemia. In normoglycemic rats (blood glucose of 6-8 mM; neocortical ischemic-induced lactate content 8-12 mmol/kg) [H+]o increased from 7.22 +/- 0.02 to 6.79 +/- 0.02 pH (n = 3). By contrast, in hyperglycemic rats (blood glucose 18-75 mM; ischemic-induced lactate content 19-31 mmol/kg) [H+]o rose by a significantly larger amount to 6.19 +/- 0.02 pH (n = 7). Given that HCO3- is the predominant interstitial H+ buffer, changes in peak PtCO2 show why peak [H+]o were bimodally distributed compared with lactate content. Between 8 and 12 mmol/kg lactate, when peak PtCO2 rose from 99 to 186 Torr but [H+]o was constant at 6.79 pH, calculated [HCO3-]o increased from 11.9 to 21.9 mM. Then after transitional changes, peak PtCO2 and [H+]o remained constant at 389 +/- 9 Torr (n = 7) and 6.19 pH despite the fact that tissue lactate ranged from 19 to 31 mmol/kg lactate, respectively; [HCO3-]o must have remained constant at 12.3 +/- 0.7 mM (n = 7). Since ischemic brain continued to produce another 12 more mmol/kg of lactic acid above 19 mmol/kg lactate without further changes in PtCO2 or [H+]o, H+ and HCO3- must have been heterogeneously compartmented. The continued lactic acid production occurred in a compartment that occupied 36% of neocortical space. This compartment is likely to represent glial cells.
Abstract: The glomerulus is a complex structure containing a remarkable capillary bed which is freely permeable to water and solutes up to the size of inulin. Many small proteins are filtered, reabsorbed, and catabolized by the kidney; but most large proteins, such as albumin or immunoglobulins, are almost entirely excluded from the glomerular ultrafiltrate due to the charge-size permselectivity of the glomerular capillary basement membrane. These large proteins appear in the urine when diseases reduce the charge selectivity or result in the development of large pores in this membrane. The reabsorptive capacity of the renal tubules for these proteins is overwhelmed. Hypoalbuminemia results when increased synthetic and decreased catabolic rates of albumin fail to compensate for the urinary loss of the protein. The resulting decrease in serum oncotic pressure increases the flux of fluid out of systemic capillaries into the interstitial space, a process that increases lymphatic flow and returns the relatively protein-poor ultrafiltrate to the plasma compartment. Interstitial proteins are swept into the plasma by the increased lymphatic flow, leading to a depletion of the extravascular pool of albumin even more severe than the depletion of albumin in the plasma compartment. The rate of albumin synthesis is increased but not sufficiently to replace losses and restore the serum concentration to normal. The rate of albumin catabolism is decreased. This decrease from the normal catabolic rate is as important as the increased rate of albumin synthesis in maintenance of albumin homeostasis in nephrosis. Whereas the reduced serum oncotic pressure certainly contributes to edema formation, sodium retention may result from processes intrinsic to the kidney itself; and plasma volume may actually be expanded despite hypoalbuminemia. The hyperlipemia that occurs in nephrosis is due to a combined defect in lipoprotein metabolism: increased hepatic synthesis of VLDL and decreased removal of TG and highly atherogenic remnants of incompletely metabolized CMs. The defects in lipoprotein metabolism may in part be the end result of the urinary loss of highly negative-charged macromolecules of the mucopolysaccharide called orosomucoid, which carries with it heparan sulfate, and important cofactor for LPL.
Abstract: Lymph pressure (PL) in the main intestinal lymph duct with obstruction of lymph flow was determined. Under various conditions, the rate of lymph flow (JL) was essentially the same in either A rats (with communications between hepatic and intestinal lymphatics) or B rats (without such communications), but PL of A rats was significantly lower (P less than 0.01) than that of B rats. When the intestine was in the basal state, JL of A and B rats was 0.2-0.3 ml/h per rat, and PL was 1.5 +/- 0.2 and 3.3 +/- 0.2 mm/Hg, respectively. During fluid absorption, JL of A and B rats increased to 0.8-0.9 ml/h, and PL was 2.1 +/- 0.4 and 6.4 +/- 0.7 mmHg, respectively. During intravenous saline infusion, JL of A and B rats increased greatly to approximately 14 ml/h, and PL was 3.1 +/- 0.3 and 10.4 +/- 1.1 mmHg, respectively. The lower PL in A rats is apparently due to the possibility that during lymphatic obstruction most lymph could be drained off by the hepatic lymphatics. In A rats, luminal distension pressure had no effect on PL but in B rats PL decreased when distension pressure was 20 mmHg or higher. Furthermore, lymph pressure waves indicate the occurrence of rhythmical contractions of the lymph duct or its surrounding tissues, which may play a role in the propulsion of lymph.
Abstract: Fifteen patients with symptomatic mild-to-moderate and severe chronic aortic regurgitation (AR) performed supine bicycle exercise while measurements of rest and exercise hemodynamics and left ventricular function were obtained. A continuous Doppler method was used to determine the change in distribution of total left ventricular stroke volume between forward stroke volume and regurgitant volume (RgV) with exercise. The pulmonary arterial wedge pressure (PAWP) was lower in the mild-to-moderate AR group than in the severe AR group at rest (8 +/- 1.2 vs 19 +/- 3.6 mm Hg, p = 0.01) and during exercise (15 +/- 3.9 vs 30 +/- 4.3 mm Hg, p = .02). In all patients there were increases in heart rate (78 +/- 4 to 96 +/- 5 beats/min, p less than .001), forward stroke volume (41 +/- 2 to 46 +/- 2 ml/m2), and the cardiac index (3.1 +/- 0.2 to 4.4 +/- 0.3 liters/min-m2, p less than .001), despite a fall in total left ventricular stroke volume index from 84 +/- 5 to 76 +/- 5 ml/m2 (p = .03). The systemic vascular resistance (SVR) decreased with exercise from 1277 +/- 72 to 1031 +/- 64 dynes-sec/cm5 (p less than .001), and the RgV and regurgitant fraction (RgF) both decreased with exercise from 43 +/- 5 ml/m2 to 30 +/- 4 ml/m2 (p = .002) and 0.50 +/- 0.03 to 0.37 +/- 0.03 (p less than .001), respectively. Left ventricular ejection fraction increased on exercise from 0.51 +/- 0.03 to 0.55 +/- 0.03 (p = .02) for the group, but it either decreased or failed to increase by at least 0.05 in seven of 13 patients. The change in ejection fraction on exercise was directly related to the change in SVR (r = .80, p less than .001). We conclude that: in patients with mild-to-moderate AR, the PAWP is generally normal at rest and exercise, in most of those with severe AR, the PAWP is elevated at rest and increases significantly with exercise, which is the likely mechanism for dyspnea on exertion in these patients, the cardiac index in both groups is normal at rest and increases on exercise, the increase in cardiac output results from both an increased heart rate and forward stroke volume, the increase in forward stroke volume results from reductions of RgV and RgF, the RgV and RgF are decreased due to a decreased SVR, and the ejection fraction response to exercise is variable and correlates best with changes in SVR with exercise.
Abstract: Leg glucose uptake (LGU) during submaximal (50% maximal O2 uptake) and maximal dynamic exercise (97%) has been quantified from the product of the leg blood flow and the arterial minus femoral venous glucose concentration. Muscle biopsies were also obtained. During 15 min of submaximal exercise the mean LGU values ranged from 1.07 to 1.25 mmol/min, which demonstrates that LGU was stable under this condition. In contrast, during maximal exercise LGU increased continuously, reaching 2.38 +/- 0.22, 2.95 +/- 0.32, and 3.82 +/- 0.34 mmol/min after 2, 4, and 5.2 min (fatigue), respectively. The mean LGU was negatively related to the mean muscle phosphocreatine content (r = -1.00;P less than 0.01). Intracellular glucose-6-phosphate (G-6-P) and glucose were very low at rest and did not change significantly during submaximal exercise (P greater than 0.05). However, at fatigue G-6-P and glucose increased substantially and were both 8.5 mmol/kg dry muscle (P less than 0.001). These findings demonstrate that during heavy exercise glucose accumulates in the cell probably due to hexokinase inhibition by G-6-P, and thus the rate of glucose utilization appears to be lower than the rate of glucose uptake. It is suggested that 1) LGU during short-term exercise is dependent on the energy state of the muscle and 2) LGU is equal to leg glucose utilization during submaximal exercise but is in excess of utilization during heavy exercise.
Abstract: It has been widely held that systemic acidemia represents the proximate event signaling the kidney to elicit its acidification response to chronic metabolic acidosis. However, a previous study from this laboratory has cast serious doubt on the validity of this conventional viewpoint. When a large acid load (7 mEq/kg/day) was fed chronically to dogs as HCl, H2SO4 or HNO3, net acid excretion increased similarly in all three groups of animals despite wide variability in the prevailing systemic acid-base composition. Marked or moderate hypobicarbonatemia and acidemia were observed in the HCl- or H2SO4-fed animals respectively, but strikingly, plasma [HCO3-] and pH did not change significantly from the control in the HNO3-fed animals. That study concluded that the renal response to chronic mineral acid feeding appears to be triggered, not by acidemia, but by the interplay of sodium delivery to and sodium avidity of the distal nephron as modulated by the reabsorbability of the "acid" anion. We have re-examined the above provocative conclusion in the light of the observation that the only evidence for a dissociation of the renal response from systemic acidemia in that study was derived from preprandial (8:00 a.m.) blood samples obtained some 23 hr after the ingestion of the daily acid load (administered at 9:00 a.m.). We investigated the diurnal variation of plasma acid-base composition in two groups of dogs fed chronically a large acid load (7 mEq/kg/day) as either HCl or HNO3. Both groups exhibited significant diurnal oscillations of plasma acid-base composition.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Much has been learned about the formation of the active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3. Information concerning its formation and catabolism has allowed a clear understanding of factors involved in the maintenance of plasma concentrations of the hormone. The effects of 1,25-dihydroxyvitamin D3 on calcium transporting cells in the intestine are marked and well defined. The tissue (intestinal tissue) is easily isolated and manipulated and hence, this is an ideal tissue in which to examine the mechanism of divalent cation transport. The mechanism by which 1,25-dihydroxyvitamin D3 brings about this effect should help in understanding sterol hormone action.
Abstract: In vivo renin release from single nephrons microperfused with artificial tubular fluid was studied in recollection experiments. Renin concentration was measured in systemic arterial plasma (A-PRC) and in either early proximal tubular fluid (TFR), or in plasma from the welling point of the efferent arteriole (SV-PRC) belonging to the microperfused nephron. Micropuncture collections were controlled to maintain the proximal intratubular pressure equal to the control free-flow pressure. Increasing the Henle loop flow rate from 12 to 18, or to 34 nl/min, was followed by a significant decrease in TFR, while reducing the flow rate from 12 to 6 nl/min caused a significant increase in TFR. Similarly, increasing the Henle loop free-flow rate by 6 to 8 nl/min depressed SV-PRC, while reducing the flow rate by fluid aspiration at 8 to 10 nl/min caused a significant increase in SV-PRC. These data indicate: that renin release, to a significant part at least, occurs into the vascular lumen of the afferent arteriole: that modest changes in early distal flow rate may control renin release from the JG-cells; and that increasing the flow rate depresses renin release, and vice versa. It is suggested that the renin system is directly involved in an additional TGF mechanism controlling postglomerular vascular resistances.
Abstract: A highly sensitive oscillatory tubulo-glomerular feedback (TGF) response has previously been demonstrated in normotensive Sprague-Dawley rats. The purpose of the present study was to examine whether such as oscillating TGF-response could be elicited in Wistar-Kyoto rats (WKY) and genetically hypertensive rats (SHR) and furthermore if any differences in the TGF-response characteristics between SHR and WKY rats could be detected. The closed loop function of the TGF-system was studied. In 12-18-week-old WKY rats regular oscillations in the intratubular pressure occurred spontaneously. The median frequency were 29.7 mHz (range 20-46.7 mHz). In SHR rats, spontaneous oscillations also occurred, but these were highly irregular. Spontaneous oscillations were more frequent in WKY than in SHR (88% vs. 54%). In both strains, oscillations could be elicited by free flow microperfusion with artificial tubular fluid (ATF). When furosemide was added to the ATF in a concentration of 0.1 mM, the oscillations were abolished in both strains of rats. It is concluded that, in both strains of rats the oscillatory phenomena depend upon TGF activity. It is suggested that the irregular pattern of the oscillations observed only in SHR rats may represent a chaotic process.
Abstract: To determine the effect of age on the solubility of volatile anesthetics in human tissues, the authors measured the solubilities of isoflurane, enflurane, halothane, and methoxyflurane in vitro at 37 degrees C in 35 postmortem human tissue specimens. Specimens were taken from neonates, and young (20-50 yr), middle-aged (50-70 yr), and elderly adults (greater than 70 yr). Brain/gas, heart/gas, and liver/gas partition coefficients for all four anesthetics increased significantly (P less than 0.05) between birth and adulthood, although brain/gas partition coefficients in young adults tended to be higher than those in middle-aged and elderly adults. Heart/gas and liver/gas partition coefficients tended to increase with aging. Muscle/gas partition coefficients for the four anesthetics increased linearly with age. Fat/gas partition coefficients did not change significantly with age. Tissue/blood solubilities for the four anesthetics were of the same order of magnitude for a given tissue and age group. Tissue/blood solubilities for enflurane were 30% lower than those for isoflurane in the same tissue and age group. In summary: the solubility of volatile anesthetics in human tissues increases with age; the lower solubility of anesthetics in neonates partially explains the more rapid increase of alveolar and tissue anesthetic partial pressures in neonates; despite the higher blood solubility of enflurane, its lower tissue solubility may explain a rate of recovery comparable with that of isoflurane.
Abstract: If plasma vasopressin (PVP), plasma renin (PRA), and plasma aldosterone (PA) responses to change in posture are mediated only by alterations in intrathoracic baroreceptor activity, hydration status should have minimal influence on these responses. To test this hypothesis, six male subjects underwent 45 min of 70 degree head-up tilt (HUT) following 26 h dehydration, and again, 105 min later, following rehydration. Compared with preceding supine hydrated control values, PVP, PRA, and PA increased (p less than 0.001) during dehydrated HUT, but only PVP and PRA increased during rehydrated HUT (p less than 0.001). The dissociation during rehydrated HUT of PRA and PA may have been related more to the reduction (p less than 0.001) in plasma potassium concentration than to the accompanying decrease (p less than 0.001) in plasma osmolality and sodium concentration. Although increases in PVP and PRA during HUT were attenuated (p less than 0.01) following rehydration, this attenuation was associated with the absence of symptoms of overt hypotension following rehydration. However, since rehydration did not abolish the increases in PVP and PRA induced by HUT, it is concluded that the present observations support the concept of intrathoracic baroreceptor involvement in the regulation of vasopressin secretion and renin release.
Abstract: The ability of atriopeptin III (AP) to directly inhibit renal renin release has not been resolved. This issue was examined in a series of experiments performed in a system of rat renal cortical slices (dry weight 1.91 mg) in which the goal was to explore the effects of AP on renin release induced by cyclic AMP (cAMP)-coupled stimuli or by agents which are believed to decrease intracellular calcium (Cai). Concentration response relationships were initially established for all test agents. The cAMP stimuli utilized were isoproterenol (10(-5) M), forskolin (10(-5) M), and dibutyryl cAMP (3 X 10(-4) M); each of these agents produced a significant increase in renin release in the system (with isoproterenol a 59% increase, with forskolin 37%, and with dibutyryl cAMP 52%). The addition of AP (2.09 X 10(-8) M, a minimum inhibitory concentration derived from preliminary studies) significantly blunted these increases; in the case of the dibutyryl cAMP-stimulated renin release, the inhibition was partial as a significant 25% increase in renin occurred in the presence of AP. The addition of the calcium channel blocking agent diltiazem (10(-4) M) resulted in a significant increase in renin release (364 to 567 ng X mg-1, p less than .05) which was not blocked by the addition of AP. Similarly, TMB-8 (0.6 X 10(-4) M), another agent thought to lower Cai, also resulted in increased renin release (455 to 810 ng X mg-1), p less than .01) which was also unaffected by the addition of the AP. In summary, these results show that AP is capable of partially inhibiting renin release in vitro, particularly renin release coupled to cAMP action. In contrast, renin release induced by a decline in Cai appears to be unaffected by the addition of AP.
Abstract: To evaluate the influence of plasma protein concentration and colloid osmotic pressure (COP) on blood volume and blood pressure, we studied 40 patients with the nephrotic syndrome (plasma protein 41.1 +/- 5.3 g/liter, COP 10.9 +/- 2.2 mm Hg) and 43 patients with chronic renal failure (plasma protein 65.0 +/- 5.8 g/liter, COP 22.4 +/- 3.0 mm Hg) at overhydration, during gradual edema removal to normal hydration, and occasionally, to mild dehydration. The number of measure points was 113 in the nephrotic syndrome and 92 in renal failure. In both groups blood volume was normal at normal extracellular fluid volume (ECFV). Elevation of ECFV to 300% of normal in the nephrotic syndrome occurred with only a modest elevation of blood volume (NS). Elevation of ECFV to 200% of normal in the patients with renal failure was attended by a major elevation of blood volume (P less than 0.01). Reduction of ECFV to about 10% below normal was accompanied by parallel blood volume reduction in both groups. Blood pressure was comparable at normohydration, and increased to clearly hypertensive levels only in the renal failure group with increasing ECFV and blood volume (P less than 0.01). No major blood pressure difference was observed between normal and subnormal hydration, but hypotension was observed twice in the nephrotic group. Apparently, patients with severe hypoproteinemia due to the nephrotic syndrome are generally able to preserve their blood volume even when free of edema. However, their blood volume is not elevated in overhydration, in contrast to patients with renal failure who are normoproteinemic. This difference in regulation of extracellular fluid distribution is probably related to the hypoproteinemia, and its effect to reduce tissue-fluid protein.
Abstract: Depressant effects of halothane and isoflurane on isolated right ventricular guinea pig papillary muscle bathed in Tyrode’s solution at 37 degrees C were examined. Contractions were elicited by stimulation through external field electrodes while tension was recorded continuously and the intracellular cardiac action potential (AP) was monitored simultaneously by microelectrodes. The time differential of tension (dT/dt) and of membrane potential (V) was determined electronically and recorded also. Contractions after rest and at stimulation rates of 0.1, 0.25, 0.5, 1, 2, and 3 Hz were studied. With normal APs, isoflurane (1.3 and 2.5%) depressed peak tension significantly less at high frequencies than did equivalent doses of halothane (0.75 or 1.5%). Isoflurane depressed dT/dt max less than halothane at all frequencies. At 0.3 Hz stimulation, isoflurane (1-4%) significantly increased the normal AP duration by 7-11%. Slow calcium-dependent APs and accompanying contractions were studied in partially depolarized muscles (-40 to -45 mV resting potential in 26 mM K+ Tyrode’s solution) stimulated with 0.1 microM isoproterenol. Following rest and at 0.1, 0.25, 0.5, 1, 2, and 3 Hz, both isoflurane (1.3% or 2.5%) and enflurane (1.7% or 3.5%) markedly depressed the late-peaking slow AP contraction observed with low-frequency stimulation. Halothane (0.75% or 1.5%) caused a similar contractile depression (40-60%) at all frequencies. In contrast, isoflurane depressed early peaking tension and the dT/dt max at frequencies greater than 1 Hz significantly less than did halothane or enflurane. At 0.3 Hz, 2% and 4% isoflurane caused 9% and 17% depression of slow AP maximum rate of depolarization (Vmax), but significantly prolonged the AP duration. Isoflurane altered the pattern of tension development in a different manner than halothane, suggesting differing mechanisms of myocardial depression by these anesthetics.
Abstract: Muscle phosphorylase deficiency (McArdle’s disease) has conventionally been considered a disorder of glycogenolysis, and the associated impairment in oxidative metabolism has been largely overlooked. Muscle glycogen normally is the primary oxidative fuel at exercise work loads requiring more than 75-80% of maximal O2 uptake (VO2max). Evidence is presented to support the hypothesis that a limited flux through the Embden-Myerhof pathway in McArdle’s disease reduces the capacity to generate NADH required to support a normal VO2max. The extent of the oxidative defect is substrate dependent; i.e., it can be partially corrected by increasing the availability of alternative oxidative substrates (e.g., glucose, free fatty acids) to working muscle. Experiments employing modification of substrate availability closely link the hyperkinetic circulatory response to exercise (i.e., an abnormally large increase in O2 transport to skeletal muscle) and the premature muscle fatigue and cramping of McArdle patients with their oxidative impairment and suggest that a metabolic common denominator in these abnormal responses may be a pronounced decline in the muscle phosphorylation potential ([ATP]/[ADP][Pi]). The hyperkinetic circulation likely is mediated by the local effects on metabolically sensitive skeletal muscle afferents and vascular smooth muscle of K+, Pi, or adenosine or a combination of these substances released excessively from working skeletal muscle. The premature muscle fatigue and cramping of McArdle patients does not appear to be due to depletion of ATP but is associated with an increased accumulation of Pi and probably ADP in skeletal muscle. Accumulations of Pi and ADP are known to inhibit the myofibrillar, Ca2+, and Na+-K+-ATPase reactions.
Abstract: The pressure drop from the portal vein to the vena cava occurs primarily across a postsinusoidal site localized to a narrow segment (less than 0.5 cm) of hepatic veins (roughly 1.5 mm diam) in the anesthetized cat. Portal venous pressure (PVP = 8.9 +/- 0.3 mmHg) and lobar hepatic venous pressure (LVP = 8.7 +/- 0.4 mmHg) are insignificantly different, and pressure changes imposed from the presinusoidal or postsinusoidal side are equally transmitted to both pressure sites. Several types of experiments were done to validate the LVP measurement. The portal vein, hepatic sinusoids, and hepatic veins proximal to the resistance site are all under a similar pressure. Previously reported calculations of hepatic vascular resistance are in error because of incorrect assumptions of sinusoidal pressure and localization of the portal resistance site as presinusoidal. Stimulation of hepatic sympathetic nerves for 3 min caused LVP and PVP to increase equally, showing that the increased "portal" resistance is postsinusoidal across the same region of the hepatic veins that was previously localized as the site of resistance in the basal state.
Abstract: Studies were conducted to evaluate the role of water-sodium metabolism on the hypertensive mechanisms in obese patients with essential hypertension (EHT). The obesity index correlated positively with the mean arterial pressure, plasma volume, extracellular fluid volume or total exchangeable sodium, and negatively with plasma noradrenaline concentration or plasma renin activity in EHT. Hypotensive effects of sodium restriction (Na 35 mEq, K 75 mEq) or the natriuretic response to infused dopamine (3 micrograms/kg/min) was remarkable in obese EHT. Fractional excretion of sodium (FENa), which reflects the renal tubular reabsorption of sodium, was significantly lower in obese EHT than that in non-obese or mildly obese EHT. Urinary excretion of free dopamine (UDA) had a positive relationship with simultaneously measured urinary excretion of sodium or FENa. In addition, UDA correlated positively with the obesity index in patients whose weight was under 115% of the ideal weight. On the contrary, the relation between the two parameters was significantly negative in patients whose weight was over 115% of the ideal weight. These findings suggest that the expansion of body fluid volume and sodium, which might result from the blunted natriuretic ability, at least in part, due to an attenuation of the renal dopaminergic activity, play an important role of the hypertensive mechanisms in obese EHT.
Abstract: The goal of this study was to assess the possible role of O2-related local control mechanisms in contributing to an elevated skeletal muscle resistance during the development of hypertension in the spontaneously hypertensive rat (SHR). Diameters of first- (1A), second- (2A), third- (3A), and fourth-order (4A) arterioles were measured by television microscopy in the cremaster muscle of SHR in the early (4- to 6-wk-old) and rapidly developing (8- to 9-wk-old) stages of hypertension and in age-matched normotensive Wistar-Kyoto (WKY) controls. Active neurogenic tone was blocked by superfusing the tissue with 0.1 microgram/ml tetrodotoxin. When superfusion solution PO2 was elevated by changing the gas equilibration mixture from 0 to 5% O2, neurally blocked 3A and 4A of SHR exhibited a significantly greater constriction and a higher incidence of complete closure than those of their age-matched WKY controls. However, there were no significant differences in the constriction of larger arterioles (1A and 2A) in response to elevated superfusion solution PO2. The results suggest that O2-related local control mechanisms could contribute to constriction and closure of small arterioles and to an elevated skeletal muscle vascular resistance early in the development of hypertension in SHR.
Abstract: Plasma and urine fibrinopeptide-A (FPA) levels were investigated in type I and II diabetic patients. Plasma FPA and 24-h urinary excretion of FPA were significantly elevated in diabetic patients compared with normal volunteers, indicating augmented thrombin activity in diabetes. Plasma and urine FPA did not differ between type I and type II diabetic subjects. Comparison of plasma FPA with blood glucose and hemoglobin A1 (HbA1) indicated that elevation of FPA is rapidly reversible and intermittent during hypo- and hyperglycemia. Although elevated plasma FPA was seen in patients of short as well as long duration of diabetes, plasma and urine FPA correlated with duration of diabetes in type I patients. In type I diabetic patients with vascular complications, hyperglycemia induced by an oral glucose challenge was accompanied by elevation of plasma FPA and acceleration of fibrinogen disappearance. These responses were not seen when the patients were treated with intravenous (i.v.) heparin before the glucose challenge. In patients without vascular complications, there was also an acceleration of fibrinogen disappearance and a marginal (not statistically significant) elevation of plasma FPA seen after the FPA response observed in vascular disease patients. In all patients, induced hyperglycemia resulted in a decrease in hematocrit and hemoglobin (blood volume expansion) and an increase in pulse pressure indicating hemodynamic changes. The association of hyperglycemia and hemodynamic changes with augmented thrombin activity is consistent with a mechanism for fibrin formation and deposition based on endothelial injury and/or increased vascular permeability. Fibrin deposition due to such a mechanism may participate in the development of the vascular complications of diabetes.
Abstract: Clinically apparent cerebral edema is a rare and often fatal complication of diabetic ketoacidosis. To determine whether subclinical brain swelling occurs more commonly, we obtained cranial CT scans in six children with diabetic ketoacidosis treated with fluid resuscitation and continuous low-dose insulin therapy. Control scans were obtained before hospital discharge. Compared with the scans during convalescence, the early scans of all six children showed a narrowing of the brain’s ventricular system, compatible with brain swelling. Average changes in diameter were 1.3 +/- 0.1 mm for the third ventricle and 3.7 +/- 0.8 mm for the lateral ventricles (P less than 0.01). In addition, a narrowing of the subarachnoid spaces was subjectively noted during a blind reading of the early scans. Although no single scan was overtly indicative of cerebral edema, the data suggest that subclinical brain swelling may be a common occurrence during treatment of diabetic ketoacidosis in children. Sequential CT scans of the brain may provide a means of evaluating modifications of standard therapy aimed at preventing cerebral edema.
Abstract: The reactions of the mean systemic arterial blood pressure, arterial acid-base balance kidney function (clearance-technique), and plasma aldosterone concentration (radio-immunoassay) elicited by stimulation of the peripheral arterial chemoreceptors with almitrine bismesylate were determined in chloralosed, non-vagotomized, spontaneously breathing cats in moderate mannitol-saline diuresis. The left renal nerves were cut; urine was collected separately from both the innervated and denervated kidneys. Intravenous injection of 0.2 mg/kg of the drug caused the expected long-lasting increase of the pO2 and pH and a decrease of pCO2 in the arterial blood, whereas the mean systemic arterial blood pressure slightly rose by an average of 2-4 mm Hg in the first hour of chemoreceptor stimulation but afterwards considerably decreased below the pre-injection values. The renal responses were characterized by a moderate vasoconstriction particularly in the innervated kidneys and a pronounced increase of sodium and urine excretion especially in the denervated kidneys. The inhibition of renal tubular sodium reabsorption underlying these natriuretic and diuretic reactions was fully demonstrable even at the end of the experiments, i. e. 4 h after the administration of the agent. Plasma aldosterone increased with the time of the experiments but did not show any clear relationships to the activity of the arterial chemoreceptors. The results show that the intravenous injection of almitrine bismesylate is connected with a renal response pattern which is typical for an excitation of the peripheral arterial chemoreceptors, i. e. moderate vasoconstriction (efferently mediated by the renal nerves) and an inhibition of renal tubular sodium reabsorption (efferently mediated by hormonal mechanisms). Furthermore, the data suggest that, on the one hand, under certain conditions these reactions of the kidney function could play the role of undesirable side effects but, on the other hand, the inhibition of renal tubular sodium reabsorption caused by almitrine bismesylate might possibly be used to treat diseases that are connected with a reduced ability of the kidneys to sufficiently excrete sodium.
Abstract: Effects of intrarenal infusions of prazosin (0.7 microgram/kg/min), yohimbine (1 microgram/kg/min), propranolol (4 micrograms/kg/min) and sulpiride (20 micrograms/kg/min) on renal prostaglandin (PG) E2 and renin release in response to renal nerve stimulation (RNS) were examined in anesthetized dogs. RNS (2.5-5 Hz, for 10 min) decreased renal blood flow and increased both PGE2 and renin secretion rates. The blood flow response was inhibited by prazosin but not by other antagonists. Prazosin and propranolol, but not yohimbine or sulpiride, attenuated the renin response. However, none of these antagonists affected the PGE2 response. The results suggest that the RNS-induced renin release is mediated by alpha adrenoceptors, which seem to be alpha-1 type, and beta adrenoceptors, but the RNS-induced PGE2 release is not mediated by these adrenoceptors. Renal dopaminergic component may play no significant role in the RNS-induced PGE2 or renin release.
Abstract: To provide a description of the metabolic changes in muscle during maximal dynamic exercise, muscle biopsies were obtained in five healthy subjects before and after 30 s of isokinetic exercise at two pedaling frequencies (60 and 140 rpm) associated with contrasting fatigue characteristics. Higher peak power was attained at 140 rpm (1,473 + 185 W) (mean +/- SE) than at 60 rpm (1,122 +/- 70 W), but the decline in power during 30 s (fatigue index) was greater at 140 rpm (61.6 +/- 3.2 vs. 21.5 +/- 2.4%), total work in 30 s being similar (18.1 +/- 1.10 vs. 20.1 +/- 1.10 kJ). Changes in the concentration of muscle metabolites were similar; creatine phosphate concentration fell to approximately 50% of resting values, and the glycolytic intermediates glucose 6-phosphate, fructose 6-phosphate, and fructose 1,6-biphosphate increased up to 30-fold. Muscle lactate concentration ([La-]) was 29.0 +/- 3.98 and 31.0 +/- 4.31 mmol/kg wet wt immediately postexercise at 140 and 60 rpm, respectively. Even after only 10 s exercise (n = 2), large increases were measured in glycolytic intermediates and [La-]. In the two subjects, muscle [La-] increased to 17.2 and 15.1 mmol/kg at 140 rpm and to 14.3 and 14.2 mmol/kg at 60 rpm. In this type of exercise, glycogenolysis is activated very rapidly at both pedal speeds; the changes in glycolytic intermediates were consistent with rate-limiting steps at the phosphofructokinase and pyruvate dehydrogenase reactions. The greater fatigue at the higher speed is not accompanied by different biochemical changes than at 60 rpm.
Abstract: A model of lymphatic conductivity (i.e. flow rate per unit pressure difference = conductance) based on protein-kinetic and haemodynamic measurements is described. The model is applied to data from patients with cirrhosis and from pigs with different haemodynamic abnormalities in the hepatosplanchnic system. In cirrhotic patients without ascites the estimated thoracic duct conductance (gthd) was three times higher than normal whereas this value was close to normal in patients with tense ascites. The estimated conductance of the right lymphatic duct was ten times below that of the thoracic duct in patients with ascites. In pigs gthd was similar to that in normal humans and no change was seen during acute congestion of the liver. In ascitic pigs gthd was low. The estimated conductance of the liver blood-lymph barrier was similar in normal humans and pigs, but decreased in cirrhosis and was thus compatible with increased sinusoidal wall tightening and fibrosis in the interstitial space of the liver. The model presented supports the so-called ’lymph-imbalance’ theory of ascites formation according to which a relatively insufficient lymph drainage is important in the pathogenesis of hepatic ascites.
Abstract: The cardiocytes of mammalian cardiac atria contain granules very similar to those in endocrine cells. The number of these atrial granules is related directly to salt loading and blood volume. Furthermore, crude extracts of rat atria and granule preparations have powerful natriuretic and diuretic effects. These effects are mediated by peptides identified previously as atrial natriuretic factor (ANF). The peptides are derived from a common precursor, whose structure has been elucidated recently. Although there is indirect evidence from morphological studies that at least some of these peptides may be released into the blood and function as hormones, their presence in the blood has not yet been demonstrated. Here we describe a sensitive and specific radioimmunoassay for ANF and its stimulation on volume loading.
Abstract: Plasma volume (PV), plasma renin activity (PRA) and plasma aldosterone (PA) were examined serially at the edema forming stage, the stage of diuresis, and the stage of remission in 11 patients. These patients were steroid responsive, minimal change nephrotic syndrome with normal kidney function. PV was expressed as a percentage of the normal reference value, which was obtained from PV and body height in 44 normal volunteers. PV decreased significantly at the edema-forming stage and increased at the stage of the diuresis. A significant inverse correlation was obtained between PV and PRA. PRA correlated significantly with PA. The amount of 24 hour urinary sodium excretion severely reduced at the edema-forming stage and increased at the stage of diuresis: thus showing a significant inverse correlation with PA. In conclusion, renin-angiotensin-aldosterone system plays a role as a compensatory mechanism to the intravascular volume status in minimal change nephrotic syndrome, but, its’ contribution to the genesis of edema is unsusceptible.
Abstract: Edema formation in nephrotic syndrome has been attributed to intravascular volume depletion resulting from leakage of plasma water into the interstitial space and activating secondary renal sodium retention. However, clinical studies indicate that edematous patients with nephrotic syndrome may have normal or expanded plasma volumes. We evaluated the relationship between plasma volume and edema formation in control rats and rats with chronic renal failure (CRF) produced by 7/8 nephrectomy. In each group, plasma volume and 22Na space were measured during the control period and after induction of hypoalbuminemia from passive Heymann nephritis. Rats with CRF had expanded plasma volume during the initial period (4.23 +/- 0.46 vs. 3.32 +/- 0.68 ml/100 g body wt) that became significantly more expanded (to 5.44 +/- 1.16 ml/100 g body wt) when they became nephrotic as 22Na space also increased. Plasma volume and 22Na space did not change in the sham-operated rats when nephrosis was produced. Plasma renin activity was lower in the CRF rats during the control period than in the sham-operated rats and fell significantly during the nephrotic period when edema developed. Nonnephrotic rats had a plasma colloid osmotic pressure (COP) of 17.8 +/- 4.3 mmHg compared with 8.5 +/- 2.9 mmHg when nephrotic. Despite this large difference in COP, both nephrotic and nonnephrotic rats exhibited the same relationship between plasma volume and extravascular sodium space, a measure of edema formation. Hypoproteinemia is not sufficient for edema formation in the rat with passive Heymann nephritis; concomitant plasma volume expansion resulting from CRF is a necessary additional component.
Abstract: Stimulus-response curves relating renal-venous-arterial plasma renin activity difference (P.R.A.-difference) to mean renal artery pressure (R.A.P.) were studied in seven chronically instrumented conscious foxhounds with a daily sodium intake of 6.1 mmol/kg. R.A.P. was reduced in steps and maintained constant for 5 min using an inflatable renal artery cuff and a pressure control system. The stimulus-response curve obtained during control conditions (C) or during common carotid artery occlusion (C.C.O.) could be approximated by two linear sections: a rather flat section or plateau-level of P.R.A.-difference at normal blood pressure or above, and a very steep section between a distinct threshold pressure and 65-70 mm Hg. While the parameters of the curves varied from dog to dog, the curves kept their unique shape in the individual dog for at least 1 week. C.C.O. had no effect on the plateau-level of the P.R.A.-difference (C:0.98 +/- 0.14, C.C.O:0.99 +/- 0.14 ng AI . ml-1 . h-1) and on the slope of the curve below threshold pressure (C:-0.379 +/- 0.041, C.C.O:-0.416 +/- 0.082 ng AI . ml-1 . h-1 . mm Hg-1) but shifted the stimulus-response curve to the right and increased threshold pressure (C:92.7 +/- 2.8, C.C.O:109.7 +/- 4.1 mm Hg; P less than 0.05). Renal blood flow, which was measured simultaneously in three of the dogs, showed good autoregulation down to 70 mm Hg under resting conditions and was not affected by C.C.O. except for a 30% reduction of renal blood flow at the lowest pressure step (70 mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: To assess the possible effects of lipid metabolism on insulin-mediated glucose disposal, 18 nondiabetic Pima Indian women (age 18-35 yr) were studied using 1-14C-palmitate infusion to measure free fatty acid turnover rate followed by a euglycemic clamp (clamp) to measure in vivo insulin-mediated glucose disposal (M). Indirect calorimetry was performed in the basal state and during the clamp. This was used to assess glucose oxidation rate, lipid oxidation rate, and to calculate nonoxidative glucose disposal (storage). Basal and clamp lipid oxidation rate correlated with basal plasma free fatty acid concentration (r = 0.81, P less than or equal to 0.0001, r = 0.67, P less than 0.003, respectively). The fall in lipid oxidation was highly correlated with the increase in glucose oxidation during the insulin infusion (r = 0.96, P less than or equal to 0.0001). The clamp lipid oxidation rate negatively correlated with the glucose oxidation rate (r = -0.85, P less than 0.0001) and with the M value (r = -0.60, P less than 0.01) but was not correlated with the clamp glucose storage (r = -0.2, P = 0.4). On the other hand, glucose storage appeared to make a greater contribution to the difference in M value between the upper and lower extremes of M than did glucose oxidation, as evidenced by an increase in glucose storage of 0.59 mg/kg fat-free mass times minute per 1 mg/kg fat-free mass times minute increase in glucose disposal. The M value was negatively correlated with obesity as measured by percent body fat (r = -0.64, P less than 0.004), but neither basal free fatty acid concentration, basal free fatty acid turnover, basal lipid oxidation, nor clamp lipid oxidation correlated with percent body fat. We conclude that an interaction of lipid and glucose metabolism in a glucose fatty acid cycle, as proposed by Randle et al. (1), may be operative in the regulation of glucose oxidation in man. The disposal of glucose however has two components. The storage component does not appear to be associated with lipid oxidation in the way that the oxidative component is and may be regulated by a different mechanism. Since the results show that the glucose storage component plays a significant role in distinguishing between those with low and high M values, we suggest that the glucose fatty acid cycle can, at best, only partially explain impaired in vivo insulin-mediated glucose disposal. Furthermore, the data suggest that the impact of obesity on in vivo insulin resistance appears to be mediated by factors other than changes in lipid availability or metabolism.
Abstract: Cardiorespiratory function was assessed in 22 mechanically ventilated patients who underwent surgery within an average of 4.8 days following traumatic spinal cord injury at C3-7. A fluid challenge technique was used to derive right and left ventricular function curves and to assist in choice of therapy from four possible outcome responses. Both right and left ventricular stroke work increased but left ventricular stroke work was still lower than normal in six (27%) of 22 patients despite elevation of cardiac filling pressures. Pulmonary vascular resistance fell, but systemic vascular resistance was unchanged following fluid challenge. Respiratory function, including intrapulmonary shunt, lung/thorax compliance, dead space, and arterial pO2 and pCO2, were unchanged by fluid administration averaging 520 ml of plasma protein fraction in 12 minutes. The Bainbridge reflex was inoperative. There was no correlation between anesthetic agent, level or type of neurological deficit, and cardiorespiratory function. Left ventricular function was impaired so the use of peripheral vasoconstrictors that elevate systemic vascular resistance should be avoided in the management of spinal shock. Instead, myocardial depressants should be reduced and fluid replacement used to optimize cardiac function. Elevation of central venous or pulmonary capillary wedge pressures to 18 mm Hg should be used to reverse hypotension, acidosis, low venous pO2, or oliguria before institution of centrally acting inotropic therapy in the management of acute spinal cord injury.
Abstract: Control of ventilation at rest and in exercise was studied in subjects whose carotid bodies were bilaterally resected (BR) for the treatment of bronchial asthma some 30 years ago. Ventilatory activities of the carotid body were estimated to be responsible for about 90% and about 30% of the hypoxic and hypercapnic responses, respectively. The BR subjects still revealed a weak hypoxic chemosensitivity, called residual hypoxic response (RHR). The nature of RHR was discussed in detail. Exercise hyperpnea was found to be depressed in the BR subjects when compared with the subjects with similarly impared pulmonary function. This result appears to support the oscillation hypothesis in explaining exercise hyperpnea.
Abstract: As a first step to quantify [H+] changes in brain during ischemia we used H+-selective microelectrodes and enzyme fluorometric techniques to describe the relationship between interstitial [H+] ([H+]o) and peak tissue lactate after cardiac arrest. We found a step function relationship between [H+]o and tissue lactate rather than the linear titration expected in a homogeneous protein solution. Within a blood glucose range from 3-7 mM, brain lactate rose from 8-13 mmol/kg along with a rise in [H+]o of 99 +/- 6 nM(0.44 +/- 0.02 pH). At higher blood glucose levels (17-80 mM), brain lactate accumulated to levels of 16-31 mmol/kg; concurrently [H+]o rose by 608 +/- 16 nM (1.07 +/- 0.02 pH). The unchanging level of [H+]o between 8-13 and 16-31 mmol/kg lactate implies that [H+]o is at a steady-state, but not equilibrium with respect to [H+] in other brain compartments. We propose that ion-transport characteristics of astroglia account for the observed relationship of [H+]o to tissue lactate during complete ischemia and suggest that brain infarction develops after plasma membranes in brain cells can no longer transport ions to regulate [H+].
Abstract: Five volunteers were studied before and after oral administration of NH4Cl (0.3 g/kg body wt.) given in order to create a moderate acidosis. The quadriceps femoris muscles were stimulated electrically for 75 s and muscle biopsies for determination of pH and metabolite content were taken before, at the end of contraction and after 10 min in the recovery period. Muscle pH at rest (mean 7.04) was not significantly decreased after acidification despite an extracellular pH decrease of 0.15 unit. After contraction muscle pH was significantly lower after NH4Cl. Mean values before and after acidification were 6.70 and 6.54 respectively. The buffer capacity calculated as the total capacity of the muscle to buffer H+ produced during the isometric contraction before and after NH4Cl ingestion was reduced from 68.6 sl to 54.5 sl. The force produced by contracting muscle was significantly lower at the end of the contraction period after NH4Cl ingestion, 44.6% of initial compared with 55.4% without NH4Cl.
Abstract: Previous studies from this laboratory have demonstrated that the decreased renal bicarbonate reabsorption prevailing during chronic hypocapnia is not mediated by the alkalemia that normally accompanies this acid-base disturbance but by some direct consequence of the change in PaCO2 itself. Based on the reasonable expectation that the mechanisms underlying the kidney’s response to primary respiratory disturbances would be similar over the entire spectrum of physiologic carbon dioxide tensions, the present study was designed to assess whether an acidic change in systemic pH is a critical factor in the renal response to chronic hypercapnia. For this purpose, the plasma and renal responses to chronic respiratory acidosis in normal dogs were compared to those in dogs chronically fed a large hydrochloric acid (HCl) load (7 mmoles/kg/day). Exposure to 6% carbon dioxide for 7 days in a large environmental chamber induced a stable increment in PaCO2 which averaged 17 +/- 0.5 and 22 +/- 1.3 mm Hg in normal and HCl-fed animals, respectively. Steady-state plasma bicarbonate concentration rose from 22.0 +/- 0.4 to 27.1 +/- 0.5 mEq/liter in normals and from 14.7 +/- 0.7 to 24.2 +/- 0.8 mEq/liter in the HCl-fed group. As a result of these changes in PaCO2 and plasma bicarbonate, steady-state plasma hydrogen ion concentration rose in normals from 41 +/- 0.8 to 49 +/- 0.9 nEq/liter (pH 7.39 +/- 0.01 vs. 7.31 +/- 0.01) but did not change significantly in the HCl-fed group (55 +/- 1.4 vs. 56 +/- 1.4 nEq/liter; pH 7.26 +/- 0.01 vs. 7.25 +/- 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Whereas most experiments on the mechanical function of the pericardium have been performed on dogs, very little is known about the applicability of those data to humans. To examine the tensile viscoelastic properties of fresh human pericardium, we have used the methods from our previous study of canine pericardium. Although the mechanical responses of canine and human pericardium were qualitatively similar, human pericardium displayed a significantly greater viscous character. Human pericardium was 7.3 times thicker than canine pericardium, but was more extensible in stress-strain tests, with lower stiffness at a given strain. The static (elastic) stiffness of human pericardium seems identical to that of canine pericardium; lower stiffness per unit thickness of the human tissue at predicted physiological stresses was almost exactly compensated by the greater wall thickness. This effect was also seen in data on fracture strength and stiffness. However, human pericardium displayed greater viscous responses than the canine tissue. This was seen in doubled cyclic hysteresis losses, and greater stress relaxation and creep. Our results suggest that experiments on the viscoelastic properties of canine pericardium may not be directly applicable to humans, especially where dynamic mechanical properties are most important: i.e., in studies of ventricular function and the time-course of pericardial effusions.
Abstract: To find out why most patients with the nephrotic syndrome maintain a normal blood volume despite a reduced plasma colloid osmotic pressure (COP), we measured the transcapillary (plasma-tissue fluid) COP difference in 12 patients with the nephrotic syndrome, as well as in 6 patients during complete (n = 3) and partial (n = 3) recovery. Subcutaneous nylon wicks were used to collect tissue fluid. The albumin content was also measured. The albumin content and COP were lowered in both plasma and tissue fluid in the nephrotic phase, and rose gradually during recovery. During these changes the transcapillary COP difference only rose slightly: from 6.2 +/- 1.7 mm Hg when the plasma COP was below 10 mm Hg (n = 11) to 8.7 +/- 1.5 mm Hg when the plasma COP exceeded 20 mm Hg (n = 12). These observations indicate that in hypoproteinemia preservation of the intravascular volume is strongly dependent on maintenance of the difference in oncotic pressure across the capillary wall.
Abstract: The two-dimensional mechanical properties of the pericardium from dogs with a normal or chronically enlarged heart were studied in vitro. A 3.0-cm-square piece of the pericardium overlying the right and/or left ventricle was excised. An approximately 1.0-cm-square target was marked at the center, and its dimension was measured electrooptically. When immersed in physiological saline at 37 degrees C, the specimen was stretched and unloaded sinusoidally in one direction while force in the transverse direction was held constant. The tension-stretch relationship was highly reproducible and was insensitive to strain rate in the range of 0.002-0.1 Hz. Hysteresis was present. The pericardium was mostly anisotropic; however, the direction of maximal compliance varied among dogs. The elastic properties of the pericardium overlying the left and right ventricles were the same in most cases. Substantial stress relaxation was observed; in contrast, insignificant creep developed over 30 min. In five dogs with chronic cardiac dilatation due to an infrarenal aortocaval shunt, the tension-stretch curves were shifted significantly to the right (i.e., greater deformation at the same tension level). However, the pericardial viscoelastic properties and thickness were unchanged. In other words, chronic cardiac dilatation resulted in a more compliant pericardium.
Abstract: In muscle phosphorylase deficiency (McArdle’s disease) there is an abnormally rapid fatigue during strenuous exercise. Increasing substrate availability to working muscle can improve exercise tolerance but the effect on muscle energy metabolism has not been studied. Using phosphorus-31 nuclear magnetic resonance (31P-NMR) we examined forearm muscle ATP, phosphocreatine (PCr), inorganic phosphate (Pi) and pH in a McArdle patient (MP) and two healthy subjects (HS) at rest and during intermittent maximal effort handgrip contractions under control conditions (CC) and during intravenous glucose infusion (GI). Under CC, MP gripped to impending forearm muscle contracture in 130 s with a marked decline in muscle PCr and a dramatic elevation in Pi. During GI, MP exercised easily for greater than 420 s at higher tensions and with attenuated PCr depletion and Pi accumulation. In HS, muscle PCr and Pi changed more modestly and were not affected by GI. In MP and HS, ATP changed little or not at all with exercise. The results suggest that alterations in the levels of muscle PCr and Pi but not ATP are involved in the muscle fatigue in McArdle’s disease and the improved exercise performance during glucose infusion.
Abstract: We describe here a technique using bolus 2-[3H]deoxyglucose (2-[3H]DG) administration for estimating the glucose metabolic rate (R’g) in individual tissues of the rat during exercise. After 50 min of treadmill running at a moderate work load various tissues were analyzed for accumulation of phosphorylated 2-[3H]DG and/or glycogen mass. There was considerable heterogeneity in R’g in response to exercise among different muscles, despite similar basal values. R’g increased 32-fold above basal in soleus (to 90.4 +/- 5.7 mumol X 100 g-1 X min-1), 42-fold in red gastrocnemius (to 71.2 +/- 1.6), 5-fold in white gastrocnemius (to 7.0 +/- 0.8), and 2-fold in extensor digitorum longus (to 4.1 +/- 1.0) during exercise. There was a close relationship between muscle glycogen depletion and R’g within different muscles. In view of the magnitude of the increase in R’g during exercise, this method provides a very sensitive index of muscle fiber recruitment during exercise. The pattern of exercise-stimulated R’g in muscles of different fiber composition was similar to that seen with insulin stimulation. However, moderate exercise alone produced increments in R’g (soleus and red gastrocnemius) that were significantly higher (P less than 0.005) than that observed during maximal insulin stimulation even though whole body glucose utilization was slightly higher during maximal insulin stimulation. These data emphasize the heterogeneity of the response in different muscles during exercise and suggest that intracellular events beyond glucose transport may be rate limiting under the influence of one or both of these stimuli.
Abstract: Control of transmicrovascular fluid exchange in the heart is of critical importance in the prevention of myocardial edema formation. To quantify the absolute values for, and the interrelationships between, the forces and flows governing fluid balance within the normal heart, the following variables were measured: arterial pressure (Pa), coronary sinus pressure (Pcs), myocardial interstitial fluid pressure (Pint), plasma protein concentration (Cp), and oncotic pressure (tau cap) along with interstitial protein concentration (CL), interstitial oncotic pressure (tau int), and left ventricular lymph flow rate (Jv). All parameters were recorded under control conditions and during graded venous pressure elevations. Control values were Pa, 125 +/- 21 mmHg; Pcs, 7.3 +/- 1.3 mmHg; Pint, 14.9 +/- 3.1 mmHg; CL/Cp, 0.82 +/- 0.12; and Jv, 7.0 +/- 2.7 ml/h. As Pcs was elevated to eight times control, Pint increased from 15 to 50 mmHg and lymph flow rose sixfold. A filtration-independent value for CL/Cp could not be obtained for total plasma protein, although a washdown CL/Cp value for beta-lipoprotein of 0.04 was obtained. Our data indicate that a large surface area of myocardial exchange vessels coupled with lymphatics of relatively low sensitivity to extravascular volume expansion produce a system that relies on a large increase in interstitial hydrostatic pressure to limit edema formation.
Abstract: To examine the role of the macula densa in renin release, afferent arterioles alone or afferent arterioles with the macula densa attached were microdissected from rabbit kidney and incubated in Medium 199 for two consecutive 30-minute periods. Renin concentration in the medium was measured using partially purified rabbit angiotensinogen. Renin release rate over 1 hour from a single arteriole (or an arteriole with macula densa) was calculated and expressed as nanograms of angiotensin I generated per hour per arteriole (or arteriole with macula densa) per hour incubation (ng of ANG I X hr-1 X Af-1/hour). Basal renin release rate from afferent arterioles was 0.69 +/- 0.13 ng of ANG I X hr-1 X Af-1/hour (mean +/- SEM, n = 9) and remained stable for 60 minutes. Basal renin release rate from arterioles with macula densa was 0.25 +/- 0.03 ng of ANG I X hr-1 X Af + MD-1/hour (n = 9), which was significantly lower (p less than 0.025) than that from afferent arterioles alone. When furosemide (1.5 X 10(-3) M) was added to afferent arterioles alone, no significant change in renin release was observed (percent change from control; 24.8 +/- 29.9%; p greater than 0.05, n = 6). When furosemide was added to arterioles with macula densa attached, however, renin release increased by 387 +/- 46% (n = 7; p less than 0.001). After pretreatment with indomethacin, a cyclooxygenase inhibitor, furosemide still increased renin release from 0.17 +/- 0.03 to 0.60 +/- 0.10 ng of ANG I X hr-1 X Af + MD-1/hour (n = 4; p less than 0.05); however, indomethacin pretreatment reduced both the basal renin release rate and the absolute change in renin release induced by furosemide. We conclude that (1) the macula densa inhibits renin release in this preparation, (2) the macula densa plays a central role in furosemide-induced renin release, and (3) while the prostaglandin system is not essential for furosemide-induced renin release, it may be a modulating factor.
Abstract: Potassium transport in the isolated proximal convoluted tubule (PCT) of the rabbit was studied to determine the importance of concentration-dependent passive processes in potassium reabsorption. Net potassium flux was measured with an initial perfusate potassium concentration of 4 mM and bath potassium concentration of 2, 4, or 6 mM. When bath concentration was 6 mM, there was net potassium secretion in both superficial (SF) and juxtamedullary (JM) PCT. When bath concentration was 2 mM, there was net reabsorption in both groups of tubules. The apparent permeability coefficients were found to be significantly higher in JMPCT (2.96 +/- 0.37 pmol X mm-1 X min-1 X mM-1) than in SFPCT (1.94 +/- 0.34 pmol X mm-1 X min-1 X mM-1). We also attempted to uncover an active potassium reabsorption process by inhibiting water flux, but not other transport processes, by the imposition of a transtubular osmotic gradient. When the perfusate was made 30 mosmol/kg H2O hypertonic to the bath, there was net fluid entry of 0.38 +/- 0.09 nl/min, accompanied by a significant decline in net potassium flux. The collected fluid-to-perfusate potassium concentration ratio was not significantly less than zero, thereby not providing evidence for active potassium reabsorption. These studies suggest that a primary mode of potassium reabsorption in this segment is due to its movement along a transepithelial gradient established by fluid reabsorption. We have been unable to identify an active component of potassium reabsorption.
Abstract: In 10 patients with the nephrotic syndrome (NS) and edema persisting despite a NaCl-poor diet, the effect of a single infusion of hyperoncotic albumin (75 g) on NaCl excretion was studied. 6 patients had minimal lesions, and 2 patients were studied twice. On half of the occasions the glomerular filtration rate was reduced. Blood volume (BV), calculated from plasma volume and hematocrit, was slightly elevated before infusion, and increased to 136 and 120% of normal at 4 and 20 h after it, respectively. Plasma renin activity (PRA) and plasma aldosterone (PA) both decreased to suppressed levels at 20 h after infusion. Sodium excretion increased from 9.2 +/- 7.6 muEq/min before, to 3.10 +/- 22.4 (0-4 h) and 43.1 +/- 36.3 muEq/min (4-20 h) after infusion. In 6 of these patients clearance studies were done before and after the infusion, maximal free water clearance being used as marker for distal NaCl reabsorption. Proximal fractional NaCl reabsorption was elevated before (94.9 +/- 1.4%) and decreased after the infusion (92.8 +/- 1.7%). Distal fractional NaCl reabsorption was also elevated before (93.0 +/- 6.4%), but unaltered after infusion (93.0 +/- 5.6%). Thus, after marked expansion of BV and suppression of PRA and PA, sodium excretion remained low despite the present edema. The results indicate that in many patients with the NS, including minimal lesion NS, intravascular hypovolemia is not the sole cause of sodium retention.
Abstract: Auriculin is a potent vasoactive and natriuretic peptide that was recently isolated and purified from rat atrial tissue. Since this peptide could be of great importance for renal, cardiovascular, and volume homeostasis, its functional properties have been characterized in dogs. The effects of synthetic auriculin on renal function, mean blood pressure, plasma renin activity, renin secretory rate, and plasma aldosterone levels were determined. Auriculin was administered intravenously as a prime (1.0 microgram/kg body weight) and constant infusion (0.1 microgram per minute/kg body weight for one hour) to five anesthetized dogs. In addition, two conscious dogs were used to verify some of the results obtained in anesthetized dogs. Auriculin decreased mean blood pressure from 134 +/- 5 to 122 +/- 4 mm Hg (p less than 0.05, paired t test) and increased glomerular filtration rate (25.5 +/- 2.7 to 32.4 +/- 4.1 ml per minute per kidney, p less than 0.05), diuresis (0.21 +/- 0.03 to 1.06 +/- 0.14 ml per minute per kidney, p less than 0.05), natriuresis (38 +/- 0.6 to 187 +/- 35 mueq per minute per kidney, p less than 0.05), and kaliuresis (14.8 +/- 1.6 to 35.7 +/- 6.3 mueq per minute per kidney, p less than 0.05). These effects were sustained throughout the infusion of auriculin and were entirely reversible. Renal plasma flow increased transiently for one to two minutes, and then returned to or below control levels. Urine osmolality decreased by 40 percent (p less than 0.05) whereas free water clearance remained unchanged (p less than 0.05). Auriculin reversibly decreased plasma renin activity (11.6 +/- 2.3 to 3.6 +/- 1.2 ng/ml per hour, p less than 0.05), renin secretory rate (895 +/- 313 to 255 +/- 28 ng per hour per minute, p less than 0.05), and plasma aldosterone levels (8.4 +/- 1.6 to 3.6 +/- 0.7 ng/dl, p less than 0.05), whereas plasma cortisol levels remained unchanged. These results demonstrate that auriculin has a unique combination of functional properties, increasing glomerular filtration rate, diuresis, and natriuresis, without a sustained increase in total renal blood flow, and lowering blood pressure, plasma renin levels, renin secretory rate, and plasma aldosterone levels. These properties suggest an important potential role for atrial natriuretic peptides in the regulation of renal function, extracellular volume, and blood pressure.
Abstract: Vasopressin has been shown to elicit vasoconstriction in unanaesthetized animals at plasma concentrations similar to those associated with its renal antidiuretic effect. The vasconstrictor effects of vasopressin do not normally translate into pressor responses until relatively high plasma concentrations are reached. This appears to be related to very effective buffering by the baroreceptor reflex. In the absence of afferent signals from the baroreceptors (surgical denervation, but more importantly, low arterial pressure), the vasoconstriction elicited by vasopressin represents a significant part of the mechanisms that determine blood pressure. Vasopressin is clearly involved in the short-term control of blood pressure in situations such as haemorrhage, other volume-depleted states and dehydration. However, it is only one of several short-acting mechanisms which complement each other in the defence against hypotensive stresses. Under different conditions, the cardiovascular effects of vasopressin seem to have a component related to the central nervous system control of the circulation. Whether or not circulating vasopressin interacts with the newly described network of extrahypothalamic projections from the paraventricular nucleus is yet conjectural. However, the presence in the brain of vasopressin-containing pathways and of various types of receptors to vasopressin, as well as the existence of cardiovascular effects elicited by central administration of antidiuretic hormone, suggests a role for cerebral vasopressin in the control of autonomic function. Slightly elevated levels of vasopressin have been found in various forms of hypertension. Yet, the role of vasopressin, when present, may be more related to its antidiuretic than to its vasoconstrictor properties.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: The capillary is the principal barrier at high Vo2. Mathematical modelling indicates that at high flow and Vo2 the time required for release of O2 is greater than red cell transit time in some capillaries. This convective shunting appears to be particularly important in the myocardium. The Mb acts to buffer Po2 below 5 Torr during muscle contraction. This greatly increases the transcapillary O2 gradient and promotes O2 delivery. During voluntary movements, Mb should act as a major O2 source in parallel with capillaries. The Kroghian model of the capillary as a "low-resistance" point source of O2 supplying a spatially uniform sink appears to be the reverse of the actual geometry of O2 supply to working red muscle.
Abstract: This chapter reviews the current concepts concerning the pathogenesis and treatment of lactic acidosis. The biochemistry of lactic acidosis and the physiology of lactate homeostasis, particularly as it relates to interorgan lactate flux and the role of the liver, are stressed. Limitations of bicarbonate therapy and the potential benefits of a new drug, dichloroacetate, in the treatment of lactic acidosis are discussed.
Abstract: We estimated vascular neuroeffector junctional norepinephrine concentrations and their relation to pressor responses by measuring plasma norepinephrine levels and blood pressure during sympathetic stimulation or norepinephrine infusion in pithed, vagotomized, alpha 2-adrenoceptor blocked, adrenal-demedullated rats with and without uptake1 blockade by desipramine. For an increment in mean arterial pressure of 50 mm Hg, the estimated mean junctional norepinephrine concentration ( ES50m ) was about 7 nmol/l. Norepinephrine concentration gradients between the site of norepinephrine release and plasma appeared to be equal and reciprocal for sympathetic stimulation and for norepinephrine infusion. These gradients were reduced equally (by about two-thirds) after desipramine treatment, indicating that removal of both released and infused norepinephrine is mainly by neuronal uptake.
Abstract: The influence of renal nerve stimulation on the tubuloglomerular feedback mechanism was studied on anaesthetized rats. The analyses was made by comparing the single-glomerular filtration rate (SNGFR) measured from late proximal tubules with SNGFR measured from distal tubules in the same nephron. In the former situation the flow to the macula densa cells is interrupted and in the latter the macula densa is influenced by the flow passing by. In the control situation the SNGFR measured proximally was 47.7 +/- 2.2 nl . min-1 (mean +/- SE) and 40.1 +/- 1.8 measured distally indicating an activated tubuloglomerular feedback. During renal nerve stimulation (2-3 Hz), the SNGFR fell to 38.5 +/- 2.3 and 33.5 4/- 1.7 when measured proximally and distally, respectively. The results indicate that the tubuloglomerular feedback mechanism is unaffected by renal nerve stimulation.
Abstract: The collecting duct system is a major site of ammonia addition to the tubule fluid. To study the mechanisms involved, we measured total ammonia and total CO2 transport in isolated, perfused cortical collecting ducts (CCD) from deoxycorticosterone-(DOC) treated rabbits. Perfusate and bath solutions contained 25 meq/liter HCO3 and 4 mM total ammonia. Net fluid transport was not significantly different from zero. Net secretion of total CO2 occurred in all tubules (mean collected concentration, 44.2 mM). Despite bicarbonate secretion, there was net secretion of total ammonia (mean collected concentration, 6.4 mM). There was no detectable ammonia addition to the collected fluid when ammonia was excluded from the perfusate and bath, ruling out a major contribution from synthesis. Ouabain did not significantly affect net transport of total ammonia or total CO2. To test the hypothesis that an acid pH disequilibrium may lower the luminal pH enough to drive ammonia secretion by nonionic diffusion, we perfused CCD from DOC-treated rabbits with carbonic anhydrase (CA) (0.1 mg/ml). Without CA, there was net total ammonia secretion (-2.2 pmol X min-1 X mm-1) and net total CO2 secretion (-16.6 pmol X min-1 X mm-1). Luminal CA converted the net total ammonia secretion to net absorption (1.0 pmol X min-1 X mm-1) while the bicarbonate secretion persisted (-11.2 pmol X min X mm-1). We conclude that total ammonia secretion in these tubules occurs primarily by diffusion of NH3 and is dependent on a luminal acid pH disequilibrium.
Abstract: During dynamic exercise cardiac output (Q) normally increases approximately 5 liters per liter of increase in O2 uptake (Vo2) (i.e., delta Q/delta Vo2 approximately equal to 5), indicative of a tight coupling between systemic O2 transport and utilization. We studied four patients with muscle phosphorylase deficiency (McArdle’s disease) in whom Q was normal at rest, but delta Q/delta Vo2 was 14.1 +/- 1.3 during bicycle exercise. Procedures designed to alter the availability of substrates were employed to test the hypothesis that the increased delta Q/delta Vo2 is linked to the abnormal metabolic state of skeletal muscle. Fasting plus prolonged moderate exercise was used to increase the availability of plasma free fatty acid (FFA) and resulted in a normalization of delta Q/delta Vo2 (5.3 +/- 0.4). Hyperglycemia (70% above control levels) partially normalized delta Q/delta Vo2. Nicotinic acid lowered plasma FFA concentration and dramatically increased delta Q/delta Vo2 (4.6 to 13.7) when administered after fasting plus prolonged exercise in one patient. Glucose infusion after nicotinic acid administration markedly lowered delta Q/delta Vo2. The results support the hypothesis and suggest that the metabolic state of skeletal muscle, possibly via activation of muscle afferents, participates in the regulation of systemic O2 transport.
Abstract: This study sought to determine if neural influences and/or alterations in arteriolar responses to oxygen could contribute to an elevated microvascular resistance in spontaneously hypertensive rats (SHR). Diameters of third-order arterioles (3A) and fourth-order arterioles (4A) were measured in the cremaster muscle of 12- to 15-week-old SHR and normotensive Wistar-Kyoto (WKY) controls anesthetized with pentobarbital. The preparation was suffused with physiological salt solution (PSS) equilibrated with various concentrations of oxygen (0% O2, 5% O2, or 10% O2) with and without local neural blockade with 10(-7) g/ml tetrodotoxin (TTX). Total active tone was assessed with 10(-4) M adenosine. SHR 3A (but not 4A) exhibited a smaller resting diameter than WKY, and larger dilations in response to TTX and adenosine. When suffusion solution PO2 was elevated in the presence or absence of TTX, SHR arterioles constricted more than did those of WKY, and SHR 4A exhibited a higher incidence of complete closure. Therefore, both neural influences and local vascular control mechanisms may contribute to an elevated microvascular resistance in SHR.
Abstract: The effects of captopril on mean arterial blood pressure and proximal tubular fluid reabsorption (JV) were examined in anaesthetized normotensive rats and in the non-clipped kidneys of two-kidney, one-clip Goldblatt hypertensive rats. In the normotensive animals, captopril reduced arterial blood pressure from 121 +/- SD 9 to 106 +/- 10 mmHg and JV decreased from 3.78 +/- 0.45 to 2.57 +/- 0.58 X 10(-4) mm3 mm-2 s-1. Captopril had a greater effect on blood pressure in the hypertensive animals (172 +/- 17 reduced to 133 +/- 23 mmHg) although the decrease in JV from 3.62 +/- 0.12 to 2.40 +/- 0.40 was similar to that observed in normotensive animals. These results provide evidence that, in the anaesthetized rat, angiotensin II contributes to the maintenance of the rate of proximal fluid reabsorption. The magnitude of the angiotensin-stimulated component of proximal fluid absorption is similar in normotensive and two-kidney, one-clip Goldblatt hypertensive rats.
Abstract: We studied the effect of chronic right ventricular pressure overload on diastolic ventricular interdependence in dogs without pericardia, instrumented to measure left ventricular pressure, right ventricular pressure, and 3 left ventricular dimensions. We studied 12 dogs before (control) and nine dogs after 6 weeks of pulmonary artery constriction producing systolic right ventricular pressure greater than or equal to 70 mm Hg. Compared to control, following pulmonary artery band there was greater (P less than 0.01) interventricular septal mass (53 +/- 15 vs. 35 +/- 7 mg, mean +/- SD), thickness (15 +/- 2 vs. 10 +/- 1 mm), and ratio of the surface area of the interventricular septal to total left ventricular surface area (0.38 +/- 0.03 vs. 0.33 +/- 0.02), but unchanged left ventricular free wall mass (81 +/- 12 vs. 84 +/- 14 mg) and thickness (11 +/- 2 vs. 11 +/- 2 mm). End-diastolic right and left ventricular pressures and left ventricular volume were varied by vena cava and pulmonary artery occlusions and releases. Volume was calculated as an ellipsoid and the data in each dog fit to: left ventricular pressure = a0 + a1V + a2V2 + a3V3 + a4V4 + bPRV, r greater than or equal to 0.91 in each dog. During control, b was similar, whether calculated from both pulmonary artery and vena cava occlusions (0.47 +/- 0.09) or from vena cava occlusions alone (0.43 +/- 0.11), and was greater than the ratio of the interventricular septal surface area to left ventricular surface area (0.33 +/- 0.02, P less than 0.05). Following the pulmonary artery band, b decreased to 0.21 +/- 0.10 (P less than 0.05) and was less than the ratio of interventricular septal surface area to the left ventricular surface area which increased to 0.38 +/- 0.03 (P less than 0.05). We conclude that the effect of alterations in right ventricular pressure on the end-diastolic left ventricular pressure volume relationship, independent of the pericardium, is reduced following the pulmonary artery band that produces interventricular septal hypertrophy. These results are consistent with the hypothesis that the effect of alterations of right ventricular pressure on the diastolic left ventricular pressure-volume relationship depends on the relative elastance of the interventricular septum and left ventricular free wall, and not simply on the ratio of the interventricular septal surface area to the left ventricular surface area.
Abstract: The gross energy cost of treadmill and track running is re-investigated from data published in the literature. An average equation, weighted for the number of subjects in each study, was found: VO2 (ml/kg/min) = 2.209 + 3.163 speed (km/h) for 130 subjects (trained and untrained males and females) and 10 treadmill studies. On the track, wind resistance as predicted by Pugh (1970) was added to the treadmill cost of running and yielded the following equation for adults of average weight and height: VO2 = 2.209 + 3.163 speed + 0.000525542 speed. Between 8 and 25 km/h, the following linear equation: VO2 = 3.5 speed (or met = km/h) was very close to the cubic equation. This linear equation for track running is, however different from the treadmill linear equation, particularly for speeds over 15 km/h. This equation is also slightly different from the one published by Pugh (1970) for track running from 7 trained subjects only.
Abstract: Passive diastolic properties were determined in 10 control patients and 21 patients with aortic valve disease before and 17.5 months after successful valve replacement. Ten patients had severe aortic stenoses (AS), five had combined aortic valve lesions (AS + aortic insufficiency [AI]), and six patients had severe AI. Left ventricular endomyocardial biopsies were obtained before and after surgery in patients with AS, AS + AI, and AI. Simultaneous echocardiographic and high-fidelity pressure measurements were made in all patients, and left ventricular chamber stiffness was calculated from a viscoelastic pressure-circumference relationship and left ventricular myocardial stiffness from a viscoelastic stress-strain relationship. The constant of chamber stiffness, beta’, was slightly although not significantly increased in patients with AS (0.27 before and 0.24 after surgery), but was normal in those with AS + AI (0.22 before and 0.17 after surgery) and slightly decreased in those with AI (0.18 before and 0.16 after surgery) when compared with in control subjects (0.21). The constant of myocardial stiffness beta was normal in patients with AS (13.2), AS + AI (11.5), and AI (11.7) before surgery compared with in the control group (12.5). beta increased, however, significantly in those with AS (25.2; p less than .02), but not in those with AS + AI (16.3; NS) and AI (12.8; NS) after surgery. Myocardial morphologic characteristics showed a significant decrease in muscle fiber diameter in patients with AS, AS + AI, and AI, as well as a significant increase in interstitial fibrosis from 15% to 26% (p less than .05) in those with AS and a slight increase from 15% to 22% (NS) in those with AS + AI and from 19% to 24% (NS) in those with AI. Left ventricular fibrous content (left ventricular muscle mass index multiplied by interstitial fibrosis) remained, however, unchanged in all three groups after aortic valve replacement. In conclusion, left ventricular chamber stiffness is increased in AS but decreased in AI, whereas LV myocardial stiffness is normal in patients with aortic valve disease before surgery. After surgery, left ventricular myocardial stiffness increased significantly in AS patients but remained unchanged in those with AI. Postoperative changes in myocardial structure were characterized by a decrease in muscle fiber diameter and a relative increase in interstitial fibrosis, whereas fibrous content remained unchanged. Thus, regression of myocardial hypertrophy in aortic valve disease is accompanied by an increase of myocardial stiffness in concentric hypertrophy that is not seen in eccentric hypertrophy.
Abstract: We postulated an interaction between the osmoreceptor and baroreceptor regulation of arginine vasopressin (AVP) release in humans such that the modulating effects of the baroreceptors on AVP release may be undetectable unless the serum osmolality is elevated. We studied normal subjects in both a water-replete (WR, n = 9) and water-deplete (WD, n = 9) state. We monitored blood pressure, central venous pressure, and forearm blood flow. In both WR and WD subjects selective unloading of cardiac baroreceptors with lower body negative pressure (LBNP) -15 mmHg for 30 min did not increase AVP levels. Combined unloading of cardiac and arterial baroreceptors by LBNP -40 mmHg for 10 min significantly increased AVP levels in only the fluid-deplete group [3.54 +/- 0.40 to 8.09 +/- 1.40 (SE) microU/ml, control vs. LBNP -40 mmHg, P less than 0.05]. Mean arterial pressures did not decrease with LBNP -40 mmHg for 10 min. Further analysis of the data based on serum osmolalities (OSM) indicated that LBNP -40 mmHg significantly increased AVP levels (3.72 +/- 0.43 to 13.59 +/- 3.63 microU/ml; P less than 0.05; n = 9) during sessions with OSM greater than 294 mosmol/kg, but not during sessions with OSM less than 294 mosmol/kg (2.85 +/- 0.29 to 4.66 +/- 1.15 microU/ml; P = NS; n = 11). This study demonstrates that significant baroreflex-mediated regulation of vasopressin can occur in humans in the absence of overt hypotension. Second, it reveals an interaction between osmoreceptor and baroreceptor regulation of vasopressin levels in humans such that physiological unloading of cardiac and arterial baroreceptors significantly increases plasma vasopressin levels only when serum osmolality is increased.
Abstract: Although esophageal pressures have been substituted for direct pleural pressure measurement in humans, we have investigated the validity of this approach under circumstances when left and right pleural pressures are not equal. Esophageal and bilateral pleural pressures in awake sheep were compared by using matched balloon catheters in close proximity. In standing sheep, both end-expiratory pressures and inspiratory pressure swings were similar in all three catheter systems. However, when pleural pressures were made unequal, as during lateral recumbency or unilateral pneumothorax, the esophageal pressure reflected predominantly the right pleural pressure. These results suggest that esophageal pressures are useful estimates of pleural pressure under normal conditions when pleural pressures are equal bilaterally. However, the usefulness of esophageal pressures is limited in the presence of unilateral pneumothorax or other conditions where left and right pleural pressures are unequal. In the lateral decubitus position, positive end-expiratory pleural pressures were consistently observed. This was believed to be due to a combination of contraction of expiratory muscles, rapid respiratory rate resulting in insufficient expiratory time to reach an equilibrium pressure, and increased airways resistance resulting from compression of the dependent lung by the abdominal viscera. A single study in a paralyzed ventilated sheep showed less positive expiratory pressures, which were further reduced to zero or less when the respiratory rate was slowed to 10 breaths/min.
Abstract: To assess the role of hormonal factors in the pathogenesis of the dawn phenomenon, nocturnal (9:00 PM to 9 AM) concentrations of blood glucose, free insulin, and counterregulatory hormones were determined in eight insulin-dependent diabetic patients under feedback-controlled and continuous insulin infusions after previous blood glucose normalization. Under feedback control, mean insulin requirements, necessary for maintenance of euglycemia rose significantly in the early morning (11:00 PM to 3 AM: 8.4 +/- 1.4; 5 AM to 9 AM: 12.6 +/- 1.5 mU/kg/h; P less than 0.01). Mean free-insulin concentrations did not increase simultaneously. Correspondingly, mean insulin-clearance rates under continuous insulin infusion were higher in the morning (11:00 AM to 3 AM: 359 +/- 58; 5 AM to 9 AM: 459 +/- 72 mL/min/m2; P less than 0.05). Increases of insulin clearance rates were most marked (greater than 15%) in patients whose blood glucose rose during continuous insulin administration. Glucagon and norepinephrine concentrations were stable throughout both parts of the study. Cortisol and growth hormone exhibited the known nocturnal rhythms. Epinephrine levels were at the lower limit of detection at night and rose to normal basal concentrations at 9:00 AM. We conclude that increases of insulin clearance rates may be an important factor for the development of the dawn phenomenon while the role of most counter-regulatory hormones is still uncertain.
Abstract: The effect of (1) renal denervation and (2) stimulation of the renal nerve on the regional renal blood flow were determined by the Rb uptake method. Under control conditions the total renal blood flow was 3.64 +/- 0.09 ml X min-1 X g-1 tissue increasing significantly (p less than 0.02) to 4.39 +/- 0.28 ml X min-1 X g-1 after denervation. Upon stimulation of the peripheral portions of the sectioned renal nerves the blood flow decreased almost linearly with the frequency of stimulation reaching 0.99 +/- 0.24 ml X min-1 X g-1 at 10 Hz. Utilizing the relation between blood flow and stimulation frequency the control blood flow correspond to a spontaneous activity of 1.5 Hz. As expected the cortical blood flow responded in the same way as for the total renal blood flow. In the renal medulla denervation gave a much more pronounced response where e.g. the inner medullary flow increased from 0.88 +/- 0.09 to 1.30 +/- 0.16 ml X min-1 X g-1, i.e. a 50% increase (p less than 0.05). Stimulation with 2 Hz produced a steep fall in the blood flow, whereafter it decreased linearly with the stimulation frequency reaching 0.11 ml X min-1 X g-1 at 10 Hz stimulation. This demonstrates again that the renal medulla is sensitive to renal nerve activity primarily in the low level range. It should be remarked, however, that the 86-Rb uptake method reflects the effective blood flow, which might differ from the blood flow in absolute terms.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: To determine whether the body fluid shift from the lower limbs toward the head that occurs during spaceflight leads to lasting increases of venous pressure in the upper body, venous pressure and hematocrit measurements were made on four astronauts before flight and 1 and 12 hours after recovery and compared with measurements in space. During the mission the hematocrit was elevated and the venous pressure lowered by 1 to 8 centimeters of water as compared with the preflight data. One hour after landing the hematocrit decreased, indicating a hemodilution, venous pressures were unexpectedly high, and a body weight loss of 4 to 5 percent was observed. Twelve hours later the venous pressures were the lowest recorded during the study. The fluid shift apparently takes place during the first several hours of spaceflight. Thereafter, the pressure in the peripheral veins and the central circulation is lower than that measured before flight.
Abstract: A significant postflight reduction in the circulating red cell mass has been observed in both the American and Soviet manned programs. The mechanism and etiology of this loss were studied in blood samples from the four payload crewmen of Spacelab 1 taken before, during, and after flight. These samples and samples from control groups on the ground were analyzed for selected hematological and biochemical parameters, which were chosen on the basis of data previously collected, the restraints imposed by the use of human subjects, and the guidelines established for the first Spacelab mission. Twenty-two hours after weightless exposure, there was an increase in hemoglobin and hematocrit. On day 7 in flight, the hemoglobin and hematocrit remained high and there was a slight decrease in reticulocyte number. On landing, red cell mass, plasma volume, hematocrit, and reticulocyte number were decreased. Throughout the 2-week postflight sampling period, hemoglobin, hematocrit, and reticulocyte number remained below the preflight value. Since this crew was not exposed to 100 percent oxygen these results are viewed as evidence that other spaceflight factors cause the measured red cell mass reduction.
Abstract: Cerebral blood flow (CBF) responses to two types of isocapnic hypoxia, hypoxic hypoxia (HH) and carbon monoxide hypoxia (COH), were examined in seven unanesthetized adult sheep by the radiolabeled microsphere technique. Comparisons were made with newborn lambs (5-12 days old) previously studied under similar conditions. The arterial O2 content (CaO2) was reduced in a graded manner to 50-60% of the control value. During HH, CBF increased to maintain cerebral O2 delivery (CaO2 X CBF) in both adults and newborns; however, cerebral O2 uptake (CMRO2) did not change. Although CMRO2 was higher in newborns, the responses of CBF/CMRO2 to HH did not differ significantly in newborns and adults. In newborns, regional CBF showed that brainstem areas were particularly responsive to HH. In both age groups, CBF increased to a greater extent with COH than with HH for similar reductions in CaO2. This resulted in an increase in cerebral O2 delivery with COH. The degree to which COH differed from HH correlated with the magnitude of the leftward shift of the oxyhemoglobin dissociation curve that accompanies COH. In adults, CMRO2 fell by 16% with COH but was maintained in newborns. We conclude that maintenance of cerebral O2 delivery during acute, isocapnic HH is a property of CBF regulation common to both newborn and adult sheep. During COH, the position of the oxyhemoglobin dissociation curve is an additional factor that sets the level of O2 delivery. The fetal conditions of low CaO2 and a left-shifted oxyhemoglobin dissociation curve may have provided the newborn with a microcirculation better suited for maintaining CMRO2 during COH.
Abstract: A unilateral model of puromycin aminonucleoside (PAN)-induced albuminuria was produced in Munich-Wistar rats to examine the mechanisms responsible for renal salt retention. 2 wk after selective perfusion of left kidneys with PAN (n = 8 rats) or isotonic saline (control, n = 7 rats), increases in albumin excretion and decreases in sodium excretion were demonstrated in PAN-perfused but not in nonperfused kidneys of PAN-treated rats although systemic plasma protein concentration remained at control level. Total kidney glomerular filtration rate (GFR) and superficial single nephron (SN) GFR were also reduced selectively in PAN-perfused kidneys, on average by approximately 30%, due primarily to a marked decline in the glomerular capillary ultrafiltration coefficient (Kf), which was also confined to PAN-perfused kidneys. Values for absolute proximal reabsorption (APR) were also selectively depressed in PAN-perfused kidneys, in keeping with a similarly selective decline in peritubular capillary oncotic pressure measured in these kidneys, the latter also a consequence of the fall in Kf. In a separate group of seven PAN-treated rats, however, no differences were detected between PAN-perfused and nonperfused kidneys in the absolute amount of sodium reaching the early (0.77 +/- 0.09 neq/min vs. 0.74 +/- 0.08, P greater than 0.40) and late portions of superficial distal tubules (0.31 +/- 0.02) neq/min vs. 0.32 +/- 0.05, P greater than 0.50), despite the lesser filtered load of sodium in PAN-perfused kidneys. Suppressed sodium reabsorption in both proximal convoluted tubules and short loops of Henle of PAN-perfused kidneys contributed to this equalization of sodium delivery rates to the late distal tubule, as did comparable reabsorption along distal convolutions. In two additional groups of PAN-treated rats, infusion of saralasin (0.3 mg/kg per h, i.v.) led to substantial increases in total kidney GFR and SNGFR in PAN-perfused but not in nonperfused kidneys. Despite these increases in total and SNGFR, urinary sodium excretion by PAN-perfused kidneys remained at a level far below that for nonperfused kidneys, again indicating that the antinatriuresis characterizing the PAN-perfused kidney is due to alterations in sodium handling by the tubules rather than changes in GFR. These results therefore indicate (a) that reductions in Kf and depressed sodium reabsorption by proximal tubules and Henle’s loop segments in this model are brought about by intrarenal rather than circulating or systemic factors, and (b) assuming that superficial nephrons are representative of the entire nephron population, renal salt retention in this model is due primarily to intrarenal factor(s) acting beyond the distal convolution.
Abstract: The impact of hepatic blood flow on overall metabolism is not generally appreciated but is of major consequence for homeostasis. Endocrine glands produce and secrete hormones, but for effective and rapid control of hormonal levels, a rapid turnover is required. The liver is the principal organ of clearance for a wide variety of hormones and other endogenous substances. Altered total hepatic blood flow results in altered hepatic clearance rates. The main intrinsic control of hepatic blood flow is designed to hold total hepatic blood flow steady. The liver cannot control portal venous flow (which is simply the sum of outflows of the extrahepatic splanchnic organs); therefore, to hold total blood flow steady, the hepatic artery adjusts total flow in relation to alterations in portal blood flow. This control is referred to as the hepatic arterial buffer response and it functions to regulate blood flow per se rather than nutrient or oxygen regulation. The hepatic arterial flow does not change in response to altered hepatic metabolic activity as shown by the lack of expected vascular changes with altered oxygen content of blood, altered metabolic activity induced by enzyme induction or enzyme inhibition, and altered oxygen uptake or biliary secretion. The hepatic artery is not subservient to local metabolic needs of the liver but rather is controlled in a manner that subserves the homeostatic needs of the entire body. The mechanism of the arterial buffer response is not yet clear but various hypotheses are discussed.
Abstract: Oral glucose (92 g) was administered to 22 healthy, young volunteers undergoing hepatic vein catheterization, and net splanchnic glucose output (SGO) was measured during the basal period and for 4 h after glucose ingestion. In the basal state, SGO averaged 1.90 +/- 0.11 mg/min X kg. After glucose, SGO rose to a peak value of 6.65 +/- 0.83 mg/min X kg at 30 min and returned to baseline by 3 h. Total SGO over 4 h was 69 +/- 4 g; assuming complete absorption of the load, this amount represented 75% of the oral glucose. In a subgroup of six subjects, leg glucose uptake was simultaneously quantitated by femoral vein catheterization and leg blood flow measurement. In the postabsorptive state, glucose uptake by one leg was 24 +/- 8 mg/min and increased to a mean value of 76 +/- 7 mg/min during the 4 h after glucose ingestion. Overall, 18 +/- 2 g/4 h of glucose were taken up by one leg, which extrapolates to a total body muscle uptake of 65 +/- 4 g over 4 h. We conclude that in normal man, well over 2/3 of an oral glucose load escapes splanchnic removal, and that the peripheral tissues quantitatively play the dominant role in glucose disposal.
Abstract: To determine the effector loci for renal neural vasomotor control, we performed micropuncture measurements before or after renal nerve stimulation and during low- (0.5-1.5 Hz) (LFS) or high- (3-5 Hz) (HFS) frequency nerve stimulation in Munich-Wistar rats. In response to HFS, single nephron glomerular filtration rate decreased on average from 24.1 +/- 4.1 to 10.4 +/- 2.3 nl/min. Although mean glomerular transcapillary hydraulic pressure difference remained essentially constant, HFS led to a marked fall in glomerular plasma flow rate (71.3 +/- 0.9 to 44.1 +/- 10.4 nl/min). The latter was associated with significant increase in both afferent (RA) and efferent (RE) arteriolar resistance, on average by more than twofold. Because of this profound arteriolar constriction, early peritubular capillary hydraulic pressure (PEA) fell markedly during HFS (mean: 19.1 +/- 1.4 vs. 13.2 +/- 1.4 mmHg). The ultrafiltration coefficient (Kf) also decreased significantly, on average from 0.055 +/- 0.014 to 0.015 +/- 0.002 nl/(s . mmHg) with HFS. By contrast, LFS affected these indices to a much lesser and more variable degree although the marked decline in PEA was again demonstrated. Despite this decrease in postglomerular capillary hydraulic pressure, absolute proximal tubule fluid reabsorption (APR) failed to change in some animals and decreased slightly in others. Analysis of the Starling forces acting across the peritubular capillaries showed that due largely to a uniform decrease in mean peritubular capillary hydraulic pressure, mean net reabsorption pressure (Pr) rose substantially and significantly, on average by more than 5 mmHg.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: The composition of afferent lymph draining into the canine popliteal lymph node was compared with that of the efferent lymph leaving the node. Both the protein and cellular composition were studied. In twenty-five greyhounds the protein concentration of efferent lymph was greater than that of afferent lymph collected from the same limb. Although the absolute level of protein varied greatly between dogs, in a particular animal there was a constant ratio between the protein content of afferent and efferent lymph. The concentration of protein in efferent lymph was approximately double that of afferent lymph. Chromatographic analysis of lymph and the use of radio-iodinated canine albumin indicated that the reason for the increased level of protein in the efferent lymph is that the popliteal node concentrates the protein in afferent lymph. Afferent lymph contained less than 3 X 10(3) cells/ml; efferent lymph contained between 0.5 X 10(6) and 4.3 X 10(6) cells/ml, 98% of which were lymphocytes. In different dogs there was no correlation between efferent lymphocyte density and afferent or efferent protein concentration; however, when an afferent lymphatic was perfused with solutions of different protein concentration, the lymphocyte number in the efferent fluid became greater as protein concentration in the afferent perfusate was increased. The concentrating effect of the node is discussed in terms of its significance to both fluid balance and immunological surveillance.
Abstract: The purpose of this study was to evaluate the extent of anaerobic glycogenolysis, as indicated by intramuscular lactate concentration, after 10 and 30 s of supramaximal exercise and to compare male and female subjects in this regard. Fifteen males and seven females performed two cycle exercise bouts against a resistance which was standardized so that one pedal revolution resulted in 4.90 J work X kg body wt-1. A muscle biopsy was obtained after 10- and 30-s exercise bouts and analyzed for lactate concentration. The lactate concentrations averaged 36 and 61 mmol X kg dry wt-1 after the 10- and 30-s exercise bouts, respectively. The male subjects had higher (P less than 0.005) lactate concentrations and generated higher (P less than 0.001) power outputs for both exercise bouts. When the mean lactate concentrations were statistically adjusted after controlling for between-group variation in power output, no difference was evident between groups for the 10- or the 30-s lactate value. The results are evidence that pronounced lactate accumulation occurs during supramaximal exercise of a 10-s duration, suggesting that glycolysis can occur within this time frame. This is in contrast to the theory that glycolysis does not occur until endogenous phosphagen levels reach some critically low value, not thought to be obtainable within the first 10 s of supramaximal exercise.
Abstract: A reconstituted "open" system comprising respiring mitochondria and actively glycolyzing muscle extract was devised for studies of vectorially mediated interactions. Glycogen particles were the substrate for the glycolyzing enzymes. Purified soluble (F1) ATPase was added in varying quantities to establish a range of energetic steady states. The data generally confirm our recent conclusions (Wu and Davis, (1981) Arch. Biochem. Biophys. 208, 85-89) on the relative efficacy of the adenine nucleotides and their ratios, and of inorganic phosphate on flux through rate-controlling steps of glycolysis. When mitochondrial ATP synthesis was blocked, glycolytic flux was relatively rapid, and the lactate/pyruvate ratio increased with time to values up to greater than 300. If functional mitochondria were present, glycolytic flux was very strongly suppressed, provided the energy state (ATP/ADP) was high, and the phosphate concentration[Pi] was low. Adenine nucleotide control of glycolysis was to a large extent lost when the steady-state ATP/ADP was below about 10, or if [Pi] was elevated. In the two-phase system containing respiring mitochondria and components of the malate-aspartate shuttle, the ATP/ADP and both extra- and intramitochondrial NAD+/NADH ratios were maintained constant, and to various perturbable levels with varying energy load (ATPase). The gradient in reduction potentials attained values (delta Gredox) of up to about 2.5 kcal. The extramitochondrial redox state was not positively correlated with the external phosphorylation potential ([ATP]/[ADP] X [Pi]). The following conclusions are drawn on the basis of the present data, together with other reports (Davis, Bremer, and Akerman (1980) J. Biol. Chem. 255, 2277-2283) and (Klingenberg and Rottenberg (1977) Eur. J. Biochem. 73, 125-130): (a) the gradient in reduction potential is driven by the membrane potential (delta psi), mediated by the electrogenic glutamate-aspartate exchange, and the poise or set point of this gradient is a function of delta psi; and (b) the gradient of ATP/ADP ratios across the membrane is also driven principally by delta psi, mediated by the electrogenic ATP-ADP exchange. Hence, segregation of phosphorylation and reduction potentials is linked through a mutually shared electrical driving force.
Abstract: Dobutamine is a synthetic catecholamine developed as a relatively selective positive inotropic drug for short-term parenteral administration. Dobutamine’s effects are mediated by strong beta 1 adrenergic receptor stimulation and mild stimulation of beta 2 and alpha 1 receptors. Dobutamine should be used to improve ventricular function and cardiac performance in patients in whom ventricular dysfunction has caused a reduced stroke volume and cardiac output, a mild to moderate drop in systemic blood pressure, diminished organ and tissue perfusion, and elevated ventricular filling pressures. When guidelines for patient selection and dosing are adhered to, ventricular dysfunction and cardiac decompensation secondary to atherosclerotic occlusive coronary artery disease can be improved without adversely affecting the myocardial oxygen supply and demand balance. Dobutamine has less vasopressor activity than norepinephrine and dopamine, and should not be the primary treatment in conditions characterized by marked hypotension and shock.
Abstract: Recent studies have demonstrated that for the same chest compression force during mechanical cardiopulmonary resuscitation (CPR), the carotid artery-to-jugular vein pressure gradient and carotid blood flow are increased when the phasic rise of intrathoracic pressure is enhanced by abdominal binding and simultaneous ventilation at high airway pressure with each chest compression (SCV). The objective of the present study was to assess whether cerebral blood flow is also enhanced, since it is known that fluctuations in intrathoracic pressure are transmitted to the intracranial space and affect intracranial pressure (ICP). In two series of pentobarbital-anesthetized dogs, one of two CPR techniques was initiated immediately after inducing ventricular fibrillation. Brain blood flow was measured by the radiolabeled microsphere technique immediately before cardiac arrest and at 1 and 3 minutes after commencing CPR. Evidence of adequate mixing of spheres and lack of sedimentation under these low-flow conditions was verified by correlation with brain venous outflow, comparison of the arterial concentration-time profile of spheres and a nonsedimentary marker (thallium-201 in solution), and use of multiple arterial sampling sites. During SCV CPR with abdominal binding, mean carotid artery pressure (60 +/- 3 mm Hg) was higher than that during conventional CPR (25 +/- 2 mm HG). Pulsations of ICP occurred that were in phase with chest compression and greater than jugular venous pressure. Mean ICP was higher during SCV (46 +/- 2 mm Hg) than conventional CPR (20 +/- 2 mm Hg). However, the net brain perfusion pressure gradient (carotid artery pressure - ICP) was greater with SCV (14 +/- 3 mm Hg) than with conventional CPR (5 +/- 0.4 mm Hg). Cerebral blood flow was significantly greater during SCV CPR (32 +/- 7% of prearrest cerebral flow) than during conventional CPR (3 +/- 2%). We conclude that SCV CPR combined with abdominal binding substantially improved brain perfusion by enhancing cerebral perfusion pressure in this experimental model.
Abstract: The specific role of luminal carbonic anhydrase in bicarbonate reabsorption by the proximal tubule has not been established because it has been difficult to inhibit selectively the luminal enzyme without simultaneous inhibition of the cytoplasmic enzyme. The present experiments employed in vivo microperfusion, microcalorimetry, and microelectrode techniques to determine the effects of luminal application of a dextran-bound carbonic anhydrase inhibitor (DBI) on bicarbonate reabsorptive rate (JtCO2) and intraluminal pH in the rat proximal convoluted tubule. Tubules were perfused at 20 nl/min with an artificial ultrafiltrate. Aminoethyl dextran (AED) with no enzyme-inhibitor activity was added to the control perfusate, and the effects of the parent inhibitor STZ not bound to dextran were also determined. Both DBI and STZ significantly reduced JtCO2 from 138 +/- 10 pmol X mm-1 X min-1 (control) to 30 +/- 4 and 30 +/- 9, respectively. In contrast to the indistinguishable effects on JtCO2, intraluminal pH measured close to the site of perfusion was 6.80 +/- 0.02 during DBI perfusion, whereas with STZ perfusion the pH was 7.24 +/- 0.04 (P less than 0.001). Using the collected perfusate total CO2 concentration and a renal cortical PCO2 of 60 mmHg, the calculated equilibrium pH for this solution was 7.27. DBI inhibited only luminal carbonic anhydrase, therefore. We conclude that luminal carbonic anhydrase is in functional contact with proximal tubule fluid and is necessary for at least 80% of bicarbonate reabsorption by this segment.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Steady-state plasma and urine acid-base composition was assessed in 19 studies of 16 normal subjects who ingested constant amounts of one of three diets that resulted in different rates of endogenous noncarbonic acid production (EAP) within the normal range. Renal net acid excretion (NAE) was used to quantify EAP since the two variables are positively correlated in normal subjects. A significant positive correlation was observed between plasma [H+] and plasma PCO2, and between plasma [HCO3-] and plasma PCO2, among the subjects. Multiple correlation analysis revealed a significant interrelationship among plasma [H+], plasma PCO2, and NAE (r = 0.71, P less than 0.001), and among plasma [HCO3-], plasma PCO2, and NAE (r = 0.77, P less than 0.001). The partial correlation coefficients indicated a significant positive correlation between plasma [H+] and NAE, and a significant negative correlation between plasma [HCO3-] and NAE, when plasma PCO2 was held constant. These findings indicate that two factors influence the level at which plasma [H+] is maintained in normal subjects: (1) the steady-state rate of endogenous noncarbonic acid production, and (2) the setpoint at which plasma PCO2 is regulated by the respiratory system. Plasma [HCO3-] is also co-determined by these two factors. In disease states, therefore, both factors must be known before a disturbance in acid-base homeostasis can be excluded.
Abstract: Clinical and biochemical findings, obtained in 76 diabetic children aged 3 to 15 years, were analyzed. Osmolarity of the plasma and plasmic components (electrolytes, glucose and urine) as well as blood antidiuretic activity (ADA) were studied. Osmolarity and plasmic ADA indices increased and water-electrolyte balance deteriorated as metabolic disorders developed. No exact linear correlation between osmolarity and the blood ADA indices was observed in diabetes decompensation. A high blood ADA level is considered to be a manifestation of the pronounced organism dehydration. It was shown that blood coagulation, accumulation of active osmotic substances in the blood, i.e. glucose, urine and other products of the disordered metabolism, as well as a decrease in renal glomerular filtration cause the hyperosmolaric syndrome in diabetic children.
Abstract: A simple procedure is presented to describe accurately the whole blood CO2 dissociation curve on linear content (CCO2) and pressure (PCO2) coordinates with an exponential equation (CCO2 = K . PCO2b). A single coordinate and the hemoglobin concentration, Hb, are required. Whole blood CCO2 can be calculated from values for pH, PCO2, Hb and O2 saturation by empirically accurate equations. The mathematical description of the CO2 curve was employed to quantitate the in vivo Haldane factor (fH) from simultaneous arterial and mixed venous blood samples in 20 healthy exercising subjects. The mean +/- SE was 0.28 +/- 0.03 (vol. % delta CCO2/vol. % delta HbO2). In 20 patients with severe obstructive lung disease fH was 0.29 +/- 0.08 when calculated from arterial samples while breathing air and 100% O2. Values for fH were not related significantly to acid-base status or Hb as suggested by previous workers. By assuming these or other values for fH, the in vivo change in blood PCO2 resulting from a given change in oxygenation can be predicted.
Abstract: The purpose of these experiments was to follow blood flows (BF) within and among rat hindlimb skeletal muscles as a function of time during prolonged low-speed treadmill locomotion. Male Sprague-Dawley rats were chronically instrumented with two Silastic catheters, one in the ascending aorta via the right carotid artery for microsphere infusion and one in the left renal artery for arterial reference blood sample withdrawal. BFs were measured, using the radio-labeled microsphere technique, within and among 23 major skeletal muscles of rats before exercise and during treadmill locomotion at 15 m/min at 0.5, 1, 5, 15, 30, 54, and 71 min of exercise. During preexercise, BF was highest to deeply situated slow-twitch muscles (210 ml . min-1 . 100 g-1 in vastus intermedius) in the antigravity extensor muscle groups. During the 1st min of exercise each of the hindlimb muscles displayed one of four general BF patterns. 1) Many muscles had an "overshoot" in BF during the first 30 s of exercise; 2) some muscles attained steady-state exercise levels in the first 30 s of exercise; 3) others showed a decrease below preexercise levels; and 4) some muscles showed no change from preexercise. Most muscles showed a gradual increase in BF from 5 min through 54 min of exercise. The elevations in BF over preexercise were primarily directed to fast-twitch oxidative muscle fibers in the antigravity extensor muscles, and BFs to extensor muscle groups were generally higher than those to flexor muscle groups. The data demonstrate that BFs within and among rat muscles are heterogeneous, both before exercise and during prolonged low-intensity treadmill walking to fatigue. Mechanisms regulating the distribution of flow to the muscles remain to be elucidated.
Abstract: Despite the clinical prevalence of paradoxic interventricular septal (IVS) motion, its pathogenesis remains unclear. To assess the influence of the end-diastolic transseptal pressure gradient, we studied eight open-chest dogs during right ventricular (RV) volume loading (induced by opening a Dacron shunt between the pulmonary artery [PA] and right atrium), RV pressure loading (constriction of PA), and left bundle branch block (RV pacing). Ultrasonic crystals in the IVS and on the RV and left ventricular (LV) free walls (FW) allowed measurement of RV septal-to-free wall (S-FW) and LVS-FW diameters. Another set measured the anteroposterior (AP) diameter of the LV (LVAP). Two-dimensional and M mode echocardiograms confirmed IVS shape and motion pattern, respectively. RV volume load caused a reduction in mean transseptal end-diastolic pressure gradient from 2.1 to -2.6 mm Hg (p less than .001), with a concomitant increase in mean end-diastolic RVS-FW diameter of 2.5 mm (p less than .001) and a decrease in LVS-FW diameter of 2.8 mm (p less than .001). LVAP was unchanged. Echocardiograms confirmed a leftward IVS shift during diastole with paradoxic systolic motion. PA constriction and RV pacing caused similar directional changes in transseptal end-diastolic pressure gradients and diameters. Compared with control values, shunt opening and PA constriction also caused a small leftward shift of IVS at end-systole. Normalized data from all eight dogs revealed significant (p less than .001) correlations between reduction in LV-RV end-diastolic pressure gradients and increases in RVS-FW (r = .85) and decreases in LVS-FW (r = .80) diameters.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: To simulate weightlessness in a normal-gravity environment, eight male subjects were tilted 5 degrees head-down for 8 h to determine vascular and extravascular shifts of fluid. Most of the initial loss of leg volume during head-down tilt represented a passive shift of venous blood toward the head. Facial edema, headache, nasal congestion, and a pronounced diuresis were associated with this redistribution of blood volume. As measured by the wick-catheter technique during head-down tilt, interstitial fluid pressure in lower-leg muscle and overlying subcutaneous tissues decreased by 7.4 and 4.4 mmHg, respectively. Interstitial fluid was shifted from the lower legs at a rate of 12 ml X h-1. Dehydration of lower-leg tissues probably resulted from decreased capillary blood pressure within these tissues during tilt. Other transcapillary pressures were unchanged. The abrupt alterations in local blood pressure upon changes in body posture were probably sufficient to explain all shifts of vascular and extravascular fluid. In this regard, countermeasures may be necessary to maintain precapillary-muscle tone during long space flights in order to prevent swelling of lower-leg tissues upon readjustment to Earth’s gravity.
Abstract: In a recent study of 50-year-old men with long-standing, untreated essential hypertension we found increased arterial and venous plasma concentrations and arterial-venous differences of adrenaline (a-v) and noradrenaline (v-a) as compared to a matching normotensive control group. The aim of the present study was to investigate whether men of this age with hypertension of shorter duration and less severity than in the first study might also have increased plasma catecholamines. Twenty-three hypertensive and 17 age-matched normotensive control men were studied. The hypertensive ones had increased supine heart rate (P less than 0.05), arterial noradrenaline (P less than 0.01) and adrenaline (P less than 0.02) whereas venous catecholamines did not differ between the two groups. The a-v differences (means +/- SE) of adrenaline (78 +/- 14 vs 42 +/- 6 ng/l, P less than 0.05) were increased in the hypertensive compared to the normotensive group. In the hypertensive, the arterial plasma concentrations of the two catecholamines correlated positively (r = 0.71, P less than 0.001) as did the a-v differences (r = 0.54, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: A noninvasive method is described for assessing the disposition of NE produced by peripheral sympathetic neurons. Total NE production is estimated from integrated NE metabolite excretion. The rate at which NE enters the bloodstream (apparent NE secretion) is estimated by isotope dilution analysis. The rate at which NE is metabolized locally is calculated by subtracting apparent NE secretion from NE production. In 10 normal volunteers, basal NE production by the peripheral sympathetic nervous system was 11.1 +/- 1.0 nmol/m2/min. Apparent NE secretion, by contrast, was only 2.4 +/- 0.18 nmol/m2/min. Our data thus demonstrate that in normal individuals under basal conditions, at least 78% of the NE produced by the sympathetic nervous system undergoes local metabolism and that no more than 22% of NE diffuses into the circulation.
Abstract: We describe in gas anesthetized rats an oscillating intratubular pressure response, probably of vascular origin, sensitive to small physiological changes in fluid delivery to the distal tubule. The oscillation apparently indicates that an adjustment of vascular resistance is in operation, but at present it reveals neither the effector site (afferent and/or efferent arteriole) nor the effector mechanism (vasoconstriction and/or dilatation). The renin-angiotensin system seems to be involved in this phenomenon.
Abstract: The release of newly synthesized renin by dog renal cortical slices was investigated. A radioactive protein believed to be renin was secreted from cortical slices into an incubation medium containing radioactive leucine. The nature of the radioactive protein was established by dialyzing the incubation medium after the cortical slices were removed, and subsequently applying the dialysate to 15% discontinuous polyacrylamide gels. Renin activity in the gels comigrated with the labeled protein. The labeled protein, as evidenced by a peak in 3H or 14C disintegrations per min, also comigrated with renin activity in isoelectric focusing gels. The molecular weight of the labeled protein was found to be the same as renin, approximately 40,000. Cortical or medullary slices possessing little or no renin activity did not secrete the labeled protein into the incubation medium. Isoproterenol significantly increased total renin secretion from the slices, but not the secretion of newly synthesized renin. The data support the hypothesis that two or more pools of renin are available for release. One pool releases newly synthesized renin, while another pool releases older, possibly stored renin, dependent in part on the stimuli available for renin release.
Abstract: To understand the basis of hypothalamic neuronal thermosensitivity, single-unit activity was recorded in vitro, from constantly perfused tissue slices of rat preoptic area and anterior hypothalamus, PO/AH. The firing rate and thermosensitivity of individual PO/AH neurons was determined before, during, and after tissue perfusion with a synaptic blocking medium, containing elevated magnesium and decreased calcium concentrations. During synaptic blockade, thermosensitivity was retained in nearly all of the warm-sensitive neurons, and some temperature-insensitive neurons showed increased warm sensitivity. The thermosensitivity of all cold-sensitive neurons was lost during synaptic blockade. These results support the hypothesis that PO/AH cold-sensitive neurons depend on synapses from nearby warm-sensitive neurons for their temperature sensitivity; whereas warm sensitivity is an independent property of certain PO/AH neurons.
Abstract: Inflatable suits were constructed for lower body compression in pigs and dogs. The suit for pigs encompassed hindquarters and part of the abdomen, and the smaller suit for dogs compressed only the hindquarters, leaving free the abdominal cavity. In conscious, diazepam-pretreated pigs, the compression lasted 30 minutes; during that period the blood pressure increased 50/38 mm Hg over the baseline. In chloralose-anesthetized dogs, the compression was extended to 3 hours; the blood pressure increase was 44/53 mm Hg. Blood pressure fell to the baseline immediately after decompression in both animals. In both species the substantial blood pressure increase was due to an increase of vascular resistance; this did not induced the expected baroreceptor-mediated bradycardia. In dogs, the blood pressure increase was accompanied by a large increase of plasma norepinephrine (from 179 to 975 pg/ml). To test whether the increase of vascular resistance reflected the mechanical compression of the vessels under the suit, animals were pretreated with trimethaphan. In pigs the trimethaphan substantially decreased the vascular resistance and the blood pressure response. This indicated that a portion of the vasoconstriction occurred in areas outside the suit. Lower body compression is a new model to cause prolonged blood pressure elevation by noninvasive and nonpharmacologic means. The mechanism of the blood pressure elevation requires further investigation.
Abstract: The left ventricular (LV) and coronary vascular effects of prazosin, a drug that reduces peripheral vascular resistance by blocking postsynaptic alpha receptors, were examined in conscious dogs. Prazosin, 0.07 mg/kg/min i.v. for 7 minutes, induced sustained hypotensive effects for more than 12 hours. The peak effects occurred 30-45 minutes after administration. Prazosin increased heart rate by 28 +/- 9%, did not change mean coronary blood flow significantly, decreased mean arterial pressure by 15 +/- 4%, LV end-diastolic diameter by 10 +/- 2%, LV end-systolic diameter by 8 +/- 2%, late diastolic coronary resistance by 22 +/- 7%, and LV dP/dt by 9 +/- 4%. These effects of prazosin were not altered substantially by maintaining heart rate constant with electrical pacing or by pretreatment with beta-adrenergic blockade. However, after chronic reserpine treatment, prazosin did not reduce either mean arterial pressure or late diastolic coronary resistance. The alpha-blocking properties of the drug were established when prazosin attenuated pressure responses to phenylephrine, norepinephrine and bilateral carotid occlusion. Thus, in conscious dogs with heart rate constant, prazosin, by blocking alpha-adrenergic receptors, induces prolonged coronary vasodilation associated with reductions in the major determinants of myocardial oxygen consumption, e.g., arterial and LV pressures, LV end-diastolic diameter and LV dP/dt. However, the coronary vasodilation was not intense enough to increase coronary blood flow above control levels.
Abstract: Although chronic potassium deficiency is a common clinical problem, the hemodynamic consequences of chronic sustained potassium depletion have not been clearly delineated. In this study, the hemodynamic consequences of chronic potassium depletion were evaluated in the conscious rat. Potassium-depleted rats had a decrease in mean arterial pressure which was caused by a decrease in systemic vascular resistance. In association with these changes in systemic hemodynamics, renal blood flow (RBF) was also decreased. The decreased renal blood flow was caused by an increased renal vascular resistance (RVR). Because plasma renin activity was increased the role of angiotensin II as a renal vasoconstrictor was evaluated by utilizing two angiotensin antagonists. Although the administration of saralasin to potassium-depleted rats did not alter systemic hemodynamics, RVR was decreased and RBF was increased. Similar results were obtained with the converting enzyme inhibitor teprotide. Because products of endoperoxide metabolism may cause renal vasoconstriction, the role of prostaglandins and thromboxanes as renal vasoconstrictors were evaluated by utilizing cyclo-oxygenase and thromboxane synthetase inhibitors. None of these agents altered systemic hemodynamics. Following the administration of indomethacin, RVR was decreased and RBF was increased in potassium-depleted rats. Similar results were obtained with another cyclo-oxygenase inhibitor, meclofenamate, and with imidazole, an inhibitor of thromboxane synthetase. Because neither angiotensin II nor products of endoperoxide metabolism could alone account for the increased renal vascular resistance of potassium depletion, studies were performed in potassium-depleted rats treated with indomethacin plus either saralasin or teprotide. In these potassium-depleted animals, renal blood flow was restored to normal. In conclusion, the decrease in renal blood flow and the increase in renal vascular resistance in potassium depletion is mediated by angiotensin II and a product of prostaglandin endoperoxide metabolism, most likely, thromboxane.
Abstract: Nine male subjects performed continuous incremental exercise on a bicycle ergometer pedaling at 50 and 90 rpm in a normal glycogen state (NG) and at 50 rpm in a glycogen-depleted state (GD) to determine if alterations in pedaling frequency and muscle glycogen content would affect their "anaerobic thresholds." Ventilatory [T(vent)] and lactate [T(lac)] thresholds were identified as the points after which expired minute volume and blood lactate began to increase nonlinearly as a function of work rate. The GD protocol elicited a significant divergence between the two thresholds shifting the T(vent) to a lesser and the T(lac) to a greater work rate relative to the NG state. When the pedaling frequency was increased to 90 rpm in the NG condition, the T(lac) was shifted to a lesser work rate relative to the 50-rpm NG condition. A correlation of only 0.71 was obtained between subjects’ T(vent) and T(lac). In subjects of less than 70 kg body wt, the T(lac) came at a work rate 400 kg.m.min-1 less than in subjects of greater than 80 kg body wt despite equivalent O2 uptake. The observation that the T(vent) and T(lac) could be manipulated independently of each other reveals limitations in using the T(vent) to estimate the so-called anaerobic threshold.
Abstract: In 14 unanesthetized newborn lambs the relationship between cerebral blood flow (measured by radiolabeled microspheres) and arterial O2 saturation (SaO2) was compared during two types of hypoxia: hypoxic hypoxia and carbon monoxide (CO) hypoxia. Cerebral venous samples were obtained from the sagittal sinus. The Increase in blood flow was 47% greater during CO than during hypoxic hypoxia. Cerebral O2 consumption and O2 delivery were constant during hypoxic hypoxia. Thus fractional O2 extraction, which equals O2 consumption/O2 delivery, remained constant with hypoxic hypoxia. During CO hypoxia, although O2 consumption remained constant, O2 delivery increased and fractional O2 extraction decreased. This decline in fractional O2 extraction was correlated with the leftward shift of the oxyhemoglobin dissociation curve that accompanied CO hypoxia. We suggest that cerebral blood flow depends on both SaO2 and the position of the oxyhemoglobin dissociation curve in the newborn lamb. However, this correlation does not exclude other potential histotoxic effects contributing to the relative overperfusion with CO hypoxia.
Abstract: The distribution pattern of CPP-containing neurons and fibers in the human pituitary and hypothalamus was studied with a specific antiserum to human CPP and the unlabeled antibody technique. Immunoreactive CPP was found in the magnocellular neurons of the supraoptic nucleus (SON), the paraventricular nucleus (PVN) and in neurons scattered in the supraoptic hypophyseal tract. CPP-containing parvocellular neurons were found in the suprachiasmatic nucleus (SCN). The CPP-containing fibers from the magnocellular neurons formed a tract coursing through the median eminence and the pituitary stalk to the posterior lobe of the hypophysis. In contrast, no such fibers from the SCN projected to SON, PVN and the median eminence. This pattern is identical to that of vasopressin and its associated neurophysin-containing neurons and fibers and strongly supports the concept that CPP is a part of the common precursor for vasopressin and neurophysin II. The biological importance of human CPP other than being a precursor fragment remains to be elucidated.
Abstract: We have found an appreciable number of pheochromocytomas in patients with neurofibromatosis and concurrent hypertension (ten of 18 cases). At diagnosis, the patient age range was 15 to 62 years, the clinical appearance of the neurofibromatosis did not predict who would and who would not have pheochromocytomas, but the age at diagnosis was helpful in that our younger patients tended to have causes of hypertension other than pheochromocytoma. However, several causes of hypertension may coexist. The biochemical findings were highly diagnostic. The pheochromocytomas secreted epinephrine as well as norepinephrine and resided in or next to the adrenal gland. Where pheochromocytoma is the cause of hypertension, its resection generally results in a better control of hypertension than that obtained in patients whose BPs were elevated from other unknown causes.
Abstract: The biological half-life of synthetic, radiochemically pure, biologically active [3H]8-arginine-vasopressin ([3H]AVP), the distribution of radioactivity among the organs and the in-vivo metabolism of the hormone were studied in the rat. The half-life calculated from the [3H]AVP radioactivities isolated from the blood was found to be 1.74 +/- 0.22 (S.D.) min in the fast phase, and 16.98 +/- 1.01 min in the slow phase. The half-lives of total radioactivity were longer in both phases. The radioactivity accumulated to the greatest extents in the adenohypophysis and small intestine. The radioactive substance was accumulated more by the kidney than by the liver, but the hormone underwent inactivation more quickly in the liver.
Abstract: During a total fast in obese subjects, the daily rate of nitrogen excretion undergoes only a small further decline after 2 wk, the excretion rate being about 5 g N/day. At this time, ammonium and urea each constitute about one-half of this excretion. The purpose of this study was to consider two alternative hypotheses: first, that the near plateau in nitrogen excretion represents an irreducible minimum rate of net protein breakdown in order to supply essential organs with calories in the form of glucose; second, that protein breakdown could be further reduced by minimizing the requirement to provide nitrogen for ammonium excretion during the ketoacidosis of fasting. Because ammonium excretion is largely controlled by acid-base balance, 150 mmol of sodium bicarbonate plus 60 mmol of potassium chloride were administered daily to decrease ammonium excretion in eight obese subjects who were totally fasting for more than 14 days. Urine ammonium nitrogen fell with this treatment (from 3.8 +/- 0.4 to 2.0 +/- 0.4 g N/g creatinine). In addition, there was a smaller fall in the rate of urea excretion (from 2.5 +/- 0.2 to 2.1 +/- 0.3 g N/g creatinine) together with a fall in the blood urea nitrogen. Therefore, it appears that ammonium excretion contributes to the negative nitrogen balance of a prolonged total fast, as assessed over a 3-day period of observation, is responsible for about one-third of the net lean body mass loss.
Abstract: Reported is a case of myocardial infarction following electrical injury in a previously healthy 57-year-old man. After coming into contact with high tension electrical current, the patient noted chest pain and electrical burns to his extremities. An electrocardiographic diagnosis of inferior wall myocardial infarction was made in the emergency department and was later substantiated by cardiac enzyme and angiographic studies. Although myocardial infarction following electrical injury has rarely been reported in the literature, most cases of severe electrical injury probably warrant cardiac monitoring.
Abstract: Plasma renin activity (PRA) was measured in conscious Brattleboro strain, vasopressin (AVP)-deficient diabetes insipidus (DI) and heterozygous rats with the aid of chronically implanted catheters. Baseline, dehydration-stimulated, and hemorrhage-stimulated levels of PRA were elevated in DI rats, as compared to levels in heterozygous controls. Replacement therapy with either AVP or the nonpressor AVP analog dDAVP reduced PRA to control levels. The high level of PRA in DI rats was associated with the lack of endogenous antidiuretic activity per se and not the pressor activity associated with the vasopressin molecule. Thus, elevated PRA in the chronic absence of AVP (in DI rats) most probably results indirectly from the chronically reduced plasma volume reported associated with hypothalamic diabetes insipidus.
Abstract: This investigation was undertaken to determine whether a Starling resistor or venous waterfall effect exists between the sagittal sinus and the cerebral veins such that increases in sagittal sinus pressure (Pss) do not abolish cerebral venous outflow and to examine two possible contributions of extracranial venous valves in regulating outflow. Anesthetized dogs were subjected to positive end-expiratory pressure (PEEP) before and after intracranial pressure (Pic) was elevated by inflation of an epidural balloon. PEEP raised Pss equally in all animals, but Pic and cerebral venous pressure (Pcv) increased less in the presence of intracranial hypertension. When Pss was low, passage of a catheter in the cerebral vein in and out of the sagittal sinus demonstrated an abrupt drop in pressure as the sinus was entered. When Pss was raised and lowered independently of superior vena caval pressure (Psvc) the changes in Pic and Pcv were less when Pss was decreased than when it was increased. Sustained increases and decreases in Psvc caused increases and decreases in Pcv, Pic, Pss, and external jugular venous pressure (Pejv) regardless of whether external jugular venous valves were present or absent. We conclude that a Starling resistor between the sagittal sinus and the cerebral veins regulates cerebral venous outflow when Pss is increased by PEEP and other maneuvers that raise Psvc. The waterfall maintains Pcv and Pic at normal levels when Psvc and Pss are reduced. Extracranial venous valves are not essential to this mechanism.
Abstract: To better understand the role of arginine vasopressin in cardiovascular regulation, we measured in unanesthetized dogs regional blood flows with radioactive microspheres before and during 1-h vasopressin infusions that increased the vasopressin concentration of plasma by 11 +/- 0.6 pg/ml. Cardiac output measured by an electromagnetic flowmeter decreased by 13%. Blood flows to the skeletal muscle and skin, the areas most affected, decreased by 30.8 and 34.3%, respectively. In the same group of dogs a period of 48-h water restriction increased plasma vasopressin by 6.9 +/- 1.3 pg/ml and reduced cardiac output by 14.4%. Skeletal muscle blood flow decreased by 32.8%, a pattern strikingly similar to that following vasopressin infusion. Obvious differences between vasopressin infusion and dehydration were also noted, in particular in the skin and splanchnic areas. However, the possibility that vasopressin contributed to the cardiovascular adjustments to dehydration must be considered. The use of an antagonist of the vascular effects of vasopressin, [1-deaminopenicillamine, 2-(O-methyl)tyrosine]arginine-vasopressin ([dPTyr(Me)]AVP), did not permit us to clarify this issue, because this analogue given alone exerted pronounced systemic and regional cardiovascular effects that resembled those of vasopressin.
Abstract: The suppression of renin release by angiotensin II (AII) (the so-called short feedback loop) is blunted in essential hypertension. To determine whether this abnormality is reversible, renin release was assessed in sodium-restricted essential hypertensives and normal controls: (a) during the administration of captopril for varying intervals and (b) following the infusion of graded doses of AII (0.3-3 ng/kg per min) before and after plasma levels of AII had been chronically reduced with captopril (25-50 mg every 6 h) for 70 h. In control subjects, the maximal increment above control in plasma renin activity (PRA) after a single dose of captopril (11.9+/-3 ng/ml per h) was significantly (P \textless 0.02) greater than in hypertensives (8.1+/-1.7 ng/ml per h) despite similar reductions in AII levels and significantly greater decrements in diastolic blood pressure in the hypertensives. When captopril was continued for 70 h, the PRA increments above base line in hypertensive subjects (11.4+/-2.9 ng/ml per h) rose to levels seen in the controls (11+/-2.6 ng/ml per h); there were no significant differences in the AII or diastolic blood pressure decrements between the two groups. Compared with normotensive subjects, AII failed to suppress renin release in hypertensive subjects despite significantly greater diastolic blood increments and comparable AII levels achieved at each AII dose. After captopril treatment, AII now produced significant declines in PRA in the hypertensives; moreover, comparing declines pre- and postcaptopril, greater PRA decrements were seen either at comparable rises in levels of AII or diastolic blood pressure. Finally, the suppression of PRA by AII postcaptopril in hypertensives was now indistinguishable from that seen in normal controls. Thus, the impaired regulation of renin by AII is reversible with prolonged captopril treatment, suggesting that this abnormality is not due to a fixed structural defect but to a reversible lesion.
Abstract: Phosphorus nuclear magnetic resonance spectroscopy (P-31 NMR) has been used to assess dynamic aspects of the metabolism of phosphorus-containing compounds in intact cells, organs, and animals. This review describes the NMR experiment and the kinds of information the P-31 NMR spectrum provides for intact, functioning cardiac and skeletal muscles. The P-31 NMR spectrum not only identifies which phosphorus-containing compounds are present in high concentration, namely adenosine 5’-triphosphate (ATP) and creatine phosphate, but also provides information about their chemical environment (including pH) and intracellular distribution. The method is quantitative and nondestructive and permits repetitive measurements in an intact functioning organ. For the perfused heart, it is possible to manipulate the chemical and gaseous composition of the perfusate and to define the effects of, for example, ischemia and reperfusion on the metabolism of ATP and creatine phosphate in the same sample. Using saturation-transfer NMR techniques, it is also possible to measure rates of certain reactions, including creatine kinase and adenylate kinase, in the intact cell. NMR can also be used as an imaging modality.
Abstract: Rat renal cortical slices incubated in vitro released 7.0 +/- 0.5% (mean +/- SE, n=30) of their total renin content into the incubation medium in 1 h. Isoproterenol (10-6 M), a beta-adrenergic agonist, caused a 75 +/- 17% (n=7) increase in renin release from the cortical slices. Treatment of the cortical slices with either cycloheximide or puromycin caused a significant 96.2 +/- 0.34 (n=8) or 98.5 +/- 0.3% (n=5), respectively, inhibition of protein synthesis. After protein synthesis and presumably renin synthesis was blocked with either cycloheximide or puromycin, isoproterenol was still able to increase significantly renin release from the cortical slices despite almost total blockade of protein synthesis. We conclude that a storage pool of renin content is released may exist, since 1) only 7.0 +/- 0.5% of the cortical slice renin content is released each hour, and 2) isoproterenol stimulation of renin release is not acutely dependent on renin synthesis. It is hypothesized that beta-adrenergic stimulation of renin release is elicited from a storage pool of previously synthesized renin.
Abstract: alpha-Adrenergic control of the oxygen delivery to the myocardium during exercise was investigated in eight conscious dogs instrumented for chronic measurements of coronary blood flow, left ventricular (LV) pressure, aortic blood pressure, and heart rate and sampling of arterial and coronary sinus blood. After alpha-adrenergic receptor blockade a standard exercise load elicited a significantly greater increase in heart rate, rate of change of LV pressure (LV dP/dt), LV dP/dt/P, and coronary blood flow than was elicited in the unblocked state. In contrast to the response pattern during control exercise, there was no significant change in coronary sinus oxygen tension (PO2), myocardial arteriovenous oxygen difference, and myocardial oxygen delivery-to-oxygen consumption ratio. It is concluded that the normal relationship between myocardial oxygen supply and oxygen demand is modified during exercise after alpha-adrenergic blockade, whereby oxygen delivery is better matched to oxygen consumption. These results indicate that the increase in coronary blood flow and oxygen delivery to the myocardium during normal exercise is limited by alpha-adrenergic vasoconstriction.
Abstract: The purpose of this study was to quantify the changes in selected intramuscular metabolites associated with non-oxidative energy metabolism after performance of the Wingate Test (WT), a widely used, exhaustive, 30-s cycle test of short-time muscular power. Muscle biopsies were taken from the m. vastus lateralis of nine female physical education students at rest and immediately after performance of the WT. The concentrations of adenosine triphosphate (ATP), creatine phosphate (CP), lactate, and glycogen were determined. The ATP decreased from 20.9 to 13.8; CP decreased from 62.7 to 25.1; lactate increased from 9.0 to 60.5; and glycogen decreased from 360 to 278 (all concentrations are mmol X kg-1 dry muscle). The absolute changes in CP and lactate were not as large as those reported in other exercise studies. Based on the metabolite changes, it was concluded that the WT is a satisfactory test of the maximal muscular power that can be generated from non-oxidative metabolism, but that the 30-s duration of the test probably does not tax the maximal capacity of such energy metabolism.
Abstract: Patients with classical heat stroke are different in many ways from those with exertional injury; contrasts included difference in demographic factors, prior general health, in-hospital complications and laboratory abnormalities (lactate, liver enzymes, pH, electrolytes). Severe hyperkalemia, acute renal failure, rhabdomyolysis and disseminated intravascular coagulation often dominate the course of patients with exertional heat stroke but are uncommon in those with classical heat stroke (Table 4). While lactic acidosis is the rule in exertional injury, it is somewhat unusual in patients with classical heat stroke and when above 3 mmoles/L predicts a poor outcome or death. In spite of the advanced age and multiple medical problems of the patients with classical heat stroke, careful attention to early and aggressive cooling and scrutiny for potential complications can result in salvage of most patients.
Abstract: Sections of the hypothalami and pituitary glands of normal (Sprague-Dawley) and homozygous diabetes insipidus (Brattleboro) rats were stained with antiserum to a human pituitary glycopeptide (HPGP) by using the immunohistochemical peroxidase-antiperoxidase method at the light microscopic level. Our results show in normal rats that immunoreactive HPGP was localized in the perikarya of the magnocellular neurons of the hypothalamus, in the posterior pituitary, and in the nerve fibers distributed in the median eminence (ME) and in the areas between the supraoptic nuclei (SON), paraventricular nuclei (PVN), and median eminence and also in the suprachiasmatic nuclei (SCN), a part of the parvocellular system. In the Brattleboro rats, however, no staining was found either in the hypothalami or pituitary glands. The present data strongly support our previous hypothesis that HPGP, a 39 residue glycopeptide isolated from human neurohypophysis, may be part of the precursor of arginine-vasopressin and its neurophysin II (Pro-NP-AVP).
Abstract: Increased renal blood flow and increased renal interstitial pressure have been proposed as mechanisms for the natriuresis caused by vasodilation with acetylcholine. We tested the hypothesis that the natriuresis due to acetylcholine is associated with the increase in interstitial pressure rather than with the increase in blood flow. Experiments were performed in decapsulated kidneys that, along with partial aortic clamping, allowed dissociation of the increases in renal interstitial pressure and blood flow. At the beginning of intrarenal acetylcholine infusion (2 micrograms . kg-1 . min-1), the aorta was clamped so that a vasodilation occurred without an increase in interstitial pressure. A response to acetylcholine was also obtained when interstitial pressure was allowed to increase. During this response, renal blood flow, interstitial pressure, and fractional sodium excretion increased. During control of interstitial pressure, renal blood flow increased, but fractional sodium excretion did not change. Thus, when interstitial pressure was controlled, the acetylcholine-induced vasodilation did not result in an increase in fractional sodium excretion. These results demonstrate that an increase in renal interstitial pressure is required for the natriuresis associated with acetylcholine-induced vasodilation.
Abstract: Equilibrium dialysis of fresh human plasma revealed that aldosterone was bound to plasma proteins other than albumin. The apparent association constant of aldosterone to nonalbumin plasma proteins was one order of magnitude larger than that reported for aldosterone to corticosteroid-binding globulin (CBG), while its binding capacity was smaller than that of CBG. Bound aldosterone was not completely dissociated when the binding capacity of CBG was saturated with a large amount of cortisol. The addition of aldosterone under these experimental conditions further displaced its binding to nonalbumin plasma proteins. Progesterone inhibited binding of aldosterone but not to the same extent as cortisol did. Column electrophoresis of dialyzed plasma demonstrated, in addition to the peak of aldosterone binding to CBG and albumin, a peak of aldosterone comigrating with alpha 1-globulin. When the fractions containing this peak were pooled and subjected to equilibrium gel filtration on Sephadex G-200, bound aldosterone was eluted between CBG and albumin. Desialylated plasma also showed a peak of aldosterone binding different from the peaks corresponding to CBG and albumin on gel filtration. This aldosterone-binding protein was a glycoprotein precipitable with 60% saturation of ammonium sulfate and completely inactivated by heating at 60 degrees C for 30 min. These results suggest the existence of an aldosterone-binding protein in human plasma different from CBG, albumin and alpha 1-acid glycoprotein.
Abstract: The role of prostaglandins in the renin release response to renal nerve stimulation (RNS) at different intensities was examined in the anaesthetized dog. The animals were divided into two groups receiving either low or high level RNS, defined by the frequencies of stimulation producing reduction in renal blood flow by 5% or less and 50%. Indomethacin or diclofenac sodium (5 mg/kg i.v.), prostaglandin synthesis inhibitors, did not affect the renin release response to low level RNS but decreased the renin release response to high level RNS by 31 +/- 8% (P less than 0.01). Addition of metoprolol, (0.5 mg/kg i.v.) beta-1-adrenoceptor antagonist, to indomethacin or diclofenac sodium resulted in a greater reduction (68 +/- 6% P less than 0.01) of the renin release response to high level RNS compared to that produced by either drug alone. Metoprolol, alone, reduced the renin release response to high level RNS by 37 +/- 14% (P less than 0.05). Phenoxybenzamine (0.6 microgram . kg-1 . min-1), alpha-adrenoceptor antagonist, into the renal artery practically abolished the renal vasoconstrictor response to high level RNS and reduced the renin release response by 50 +/- 7% (P less than 0.01). Addition of metoprolol to phenoxybenzamine practically abolished the renal vasoconstrictor response and the renin release response to high level RNS; 94 +/- 4% (P less than 0.01). Addition of phenoxybenzamine to indomethacin or diclofenac sodium practically abolished the renal vasoconstrictor response to high level RNS but did not produce any greater reduction of the renin release response than that produced by either drug alone. These findings suggest that low level RNS results in renin release which is not dependent on prostaglandins. High level RNS results in renin release which is partly mediated by beta-1-adrenoceptors and partly related to alpha-adrenoceptors mediated renal vasoconstriction. Prostaglandins are not involved in the renin release deriving from alpha-adrenoceptor mediated renal vasoconstriction.
Abstract: In anaesthetized 300 g rats, the influence of sympathetic nerve activity on the renal hemodynamics, glomerular filtration and fluid reabsorption was studied with direct stimulation at frequencies of 2 Hz and 5 Hz. The single nephron plasma flow at control conditions was 164 nl/min decreasing to 138 nl/min during 2 Hz and 68 nl/min during 5 Hz, reaching complete glomerular ischemia at about 10 Hz. At 2 Hz, the pressure drop over the two arterioles remained essentially unchanged, indicating an equal response to sympathetic discharge. At higher frequencies the afferent tone showed a more marked increase. The glomerular ultrafiltration decreased in parallel to the blood flow. The filtration fraction remained thereby constant at about 0.33. The fractional proximal fluid reabsorption up to the puncture site in early distal tubules showed a clear increase; the Tf/P-Inulin increasing from 6.0 to 7.1 and 7.2 for 2 Hz and 5 Hz, respectively. The absolute reabsorption decreased, however, and indeed not far from the decrement in glomerular filtration. It is concluded that sympathetic nerve activity acts in the direction of fluid conservation, by reducing the glomerular filtration and increasing the fractional reabsorption. The hemodynamic effects will play the dominant role even at 2 Hz stimulation.
Abstract: The influence of severe tissue lactic acidosis during incomplete brain ischemia (30 min) on cortex morphology was studied in fasted rats. Production of lactate in the ischemic tissue was varied by preischemic infusions (i.v.) of either a saline or a glucose solution. The brains were fixed by perfusion with glutaraldehyde at 0, 5, or 90 min of recirculation. In saline-infused animals (tissue lactate about 15 mumol g-1), changes observed at 0 and 5 min of recirculation were strikingly discrete: slight condensation of nuclear chromatin, mild to moderate mitochondrial swelling, and only slight astrocyte edema. These changes had virtually disappeared after 90 min recirculation and, at this time, only discrete ribosomal changes were observed. In contrast, glucose-infused rats (tissue lactate about 35 mumol g-1) showed severe changes: marked clumping of nuclear chromatin and cell sap in all cells was already evident at 0 and 5 min recirculation, while mitochondrial swelling was mild to moderate. Although tissue fixation was inadequate at 90 min, the ultrastructural appearance indicated extensive damage. It is concluded that excessive tissue lactic acidosis during brain ischemia exaggerates structural alterations and leads to irreversible cellular damage. A tentative explanation is offered for the paucity (less than 0.2%) of condensed neurons with grossly swollen mitochondria, previously considered a hallmark of ischemic cell injury.
Abstract: Water intake was reduced during the 1st day of hypobaric hypoxia (inspired O2 pressure of 75 Torr) to 35-40% of the normoxic level in both normal rats (N) and rats with diabetes insipidus (DI). Analysis of water intake under graded saline loads at several inspired O2 levels (inspired O2 fractional concentrations of 0.105, 0.120, and 0.2095) indicated that hypoxia increased the threshold for osmotic stimulation of drinking without changing the sensitivity of the response in both N and DI rats. Nephrectomized N rats reduced water intake during hypoxia to 33% of the nephrectomized normoxic level of intake, and nephrectomized DI rats reduced intake to 47% of the nephrectomized normoxic intake. From these results it is concluded that reduced angiotensin II formation was not the factor responsible for reduced water intake during hypoxia. Polyethylene glycol-induced hypovolemia resulted in increased water intake during normoxia, but during hypoxia it was reduced to 29% of the normoxic rate. Reduced body temperature and hyperventilation were not the source of hypoxic attenuation of thirst. The mechanism may reside beyond the central integration of osmotic and nonosmotic information, or at the osmotic sensing mechanism itself.
Abstract: An awake-primate model has been developed which permits reversible middle cerebral artery (MCA) occlusion during physiological monitoring. This method eliminates the ischemia-modifying effects of anesthesia, and permits correlation of neurological function with cerebral blood flow (CBF) and neuropathology. The model was used to assess the brain’s tolerance to focal cerebral ischemia. The MCA was occluded for 15 or 30 minutes, 2 to 3 hours, or permanently. Serial monitoring evaluated neurological function, local CBF (hydrogen clearance), and other physiological parameters (blood pressure, blood gases, and intracranial pressure). After 2 weeks, neuropathological evaluation identified infarcts and their relation to blood flow recording sites. Middle cerebral artery occlusion usually caused substantial decreases in local CBF. Variable reduction in flow correlated directly with the variable severity of deficit. Release of occlusion at up to 3 hours led to clinical improvement. Pathological examination showed microscopic foci of infarction after 15 to 30 minutes of ischemia, moderate to large infarcts after 2 to 3 hours of ischemia, and in most cases large infarcts after permanent MCA occlusion. Local CBF appeared to define thresholds for paralysis and infarction. When local flow dropped below about 23 cc/100 gm/min, reversible paralysis occurred. When local flow fell below 10 to 12 cc/100 gm/min for 2 to 3 hours or below 17 to 18 cc/100 gm/min during permanent occlusion, irreversible local damage was observed. These studies imply that some cases of acute hemiplegia, with blood flow in the paralysis range, might be improved by surgical revascularization. Studies of local CBF might help identify suitable cases for emergency revascularization.
Abstract: An equation that will represent blood O2 dissociation relations over the saturation range of 0-100% and be invertible is presented. The Hill equation is contained as a special case of this form. Determination of the four parameters of the equations by standard dissociation curves presented by Severinghaus gives an equation of improved accuracy when contrasted to previous treatments. A program for use of this equation with certain hand-held calculators is available.
Abstract: This study was designed to determine whether angiotensin II of renal origin physiologically mediates free water production by the kidney. The effect of renal arterial infusion of the angiotensin-converting enzyme inhibitor, teprotide, on renal function was studied under conditions of hydropenia and hydration in uninephrectomized conscious dogs after 5 days of equilibration on a normal or low sodium diet. In low sodium animals, intrarenal infusion of teprotide (0.25 microgram/kg.min) after 12 h of water restriction elicited marked increases in the glomerular filtration rate (GFR) and free water formation. After 24 h of water restriction, vasopressin (10 microU/min) was infused iv to achieve an effective maximal urine concentration. Under these conditions, the inhibitor again increased the GFR and free water formation. After the production of a state of stable hydration, intrarenal infusion of teprotide also increased the GFR and free water formation. In the normal sodium animals, intrarenal infusion of the converting enzyme inhibitor (2.5 microgram/kg.min) in 12-h hydropenic dogs failed to change the GFR but increased free water formation, while the inhibitor decreased effective renal plasma flow and free water formation in normal sodium, hydrated animals. These data suggest that angiotensin II of renal origin plays an important role in the control of free water production by the kidney.
Abstract: Dopamine is widely used in the treatment of hypotensive conditions and/or impending renal failure, but the plasma levels of dopamine and other catecholamines in association with dopamine infusion are not known. Plasma catecholamines and dopamine pharmacokinetics during and after dopamine infusion were therefore studied in man. Two and 5 micrograms x kg-1 x min-1 of dopamine were infused for 30 min in two groups of five patients. Dose-dependent mean steady state levels with fairly large interindividual variations were reached within 5 min. Elimination of dopamine from plasma after termination of infusion had a biphasic course with t 1/2 alpha around 1 min and t 1/2 beta about 9 min in both groups. Noradrenaline plasma levels and blood pressure increased significantly in the 5 micrograms group. It is suggested that the vasoconstriction with deleterious effects on tissue perfusion, seen in conjunction with high-dose dopamine infusion, may be due to increased noradrenaline levels.
Abstract: The renal medulla develops very differently among species, being more prominent in those with a high urinary concentrating capacity. Attempts to correlate structure and function must consider loops of Henle, collecting ducts, vessels, interstitium, and pelvis. Two types of loops of Henle, long and short, are distinguished. Numerical relationships between both differ among species. Based on the epithelial lining a short loop consists of a thick descending limb (pars recta of proximal tubule), a thin descending limb, and a thick ascending limb. Long loops, in addition, have a thin ascending limb; their descending thin limbs are different from those of short loops and are site of considerable interspecies differences. Collecting ducts form in the cortex by joining several nephrons. Patterns with and without arcade formation are distinguished. On entering inner medulla, collecting ducts fuse successively. Collecting duct epithelium consists of principal and intercalated cells whose individual functions are subject to debate. Blood vessels are arranged in a very strict pattern reflecting that, in addition to nourishment, unique requirements in maintaining the corticomedullary osmotic gradient are to be met. Ultrastructural organization of medullary vessels is less specific compared to cortical vessels. Two types of renal medulla are distinguished. The simple type has vascular bundles consisting only of de- and ascending vasa recta; in the complex type, descending thin limbs of short loops are also integrated into vascular bundles. Functional implications of this difference are considerable. Striking interspecies differences also occur in the renal pelvis.
Abstract: Although left ventricular dysfunction is common during ventilatory support with positive end-expiratory pressure (PEEP), the mechanism of this disorder remains unclear. In 10 patients with the adult respiratory-distress syndrome we studied the effects of a stepwise increase in PEEP from 0.to 30 cm H2O on left ventricular output, intracardiac transmural pressures, and two-dimensional echocardiographic measurements of left ventricular cross-sectional area at end-systole and at end-diastole. Increasing PEEP was associated with progressive declines in cardiac output, mean blood pressure, and left ventricular dimensions and with equalization of right and left ventricular filling pressures. The radius of septal curvature decreased at both end-diastole and end-systole, implying a leftward shift of the interventricular septum. At the highest PEEP, blood-volume expansion did not restore cardiac output, although left ventricular transmural filling pressures had returned to base-line values. We conclude that decreased cardiac output during PEEP is mediated by a leftward displacement of the interventricular septum, which restricts left ventricular filling.
Abstract: The hepatic extraction (HE) of glucagon (G) and insulin (I) was measured in 27 dogs, using peripheral infusion of the hormones following elimination of endogenous secretion by pancreatectomy (Px) or somatostatin (S) infusion. HE(G) was 22.5 +/- 1.7%, and HE(I) was 45.1 +/- 3%. HE(G) in seven Px dogs was 27.9 +/- 4.2%, not significantly different from the value of 20.6 +/- 1.6% in 20 S-infused dogs, with corresponding values for HE(I) being 44.9 +/- 6 and 46.0 +/- 3.6%, respectively, suggesting that S does not affect HE of either hormone. HE of endogenous G (22.1 +/- 2.8%) was similar to that of exogenously infused G (19.1 +/- 1.9). HE(G) was nonsaturable in the physiologic and pathophysiologic range of plasma G levels, but there was evidence of saturability in the pharmacologic range. Comparison of simultaneously measured parameters of I and G metabolism indicated independence of the metabolic processes of these two islet hormones, despite distinct similarities in their overall patterns of metabolic disposal. Metabolic clearance rates (MCR) for G and I were 12.6 +/- 0.8 and 19.5 +/- 1.0 ml . kg-1 . min-1, while simultaneously measured hepatic HE rates were 4.2 +/- 0.3 and 8.1 +/- 0.6 ml . kg-1 . min-1, respectively. MCR(G) was independent of arterial G levels. Half-life of infused G and I was 5.5 +/- 0.5 and 4.1 +/- 0.3 min, respectively. The liver accounted for 34.7 +/- 2.4% of the MCR(G) and 42.0 +/- 2.9% of MCR(I). The liver is thus an important site for G removal. However, HE(G) varies widely in different animals, and it is therefore not possible to predict portal vein G concentrations or G secretion rates from G levels in peripheral vessels.
Abstract: Thiazide diuretics are widely accepted as the cornerstone of antihypertensive treatment programs. Hypokalemia is a commonly encountered metabolic consequence of chronic thiazide therapy. We treated 38 patients (22 low renin, 16 normal renin) with moderate diastolic hypertension with hydrochlorothiazide (HCTC) administered on a twice daily schedule. Initial dose was 50 mg and the dose was increased at monthly intervals to 100 mg, 150 mg and 200 mg daily until blood pressure normalized. The serum K during the control period was 4.5 +/- 0.2 mEq/l an on 50, 100, 150 and 200 mg HCTZ daily 3.9 +/- 0.3, 3.4 +/- 0.2, 2.9 +/- 0.2, and 2.4 +/- 0.3 mEq/l, respectively. Corresponding figures for whole body K were 4107 +/- 208, 3722 +/- 319, 3628 +/- 257, 3551 +/- 336, and 3269 +/- 380 mEq, respectively. In 13 patients we observed the effects of HCTZ therapy (100 mg daily) on the occurrence of PVC’s during rest as well as during static and dynamic exercise. During rest we observed 0.6 +/- 0.08 PVC beats/min +/- SEM and during static and dynamic exercise 0.6 +/- 0.06 and 0.8 +/- 0.15, respectively. Corresponding figures during HCTZ therapy 100 mg daily were 1.4 +/- 0.1, 3.6 +/- 0.7 and 5.7 4/- 0.8, respectively. The occurrence of PVC’s correlated significantly with the fall in serum K+ observed r = 0.72, p less than 0.001. In conclusion we found that thiazide diuretics cause hypokalemia and depletion of body potassium. The more profound hypokalemia, the greater the propensity for the occurrence of PVC’s.
Abstract: Normal rats (N) and rats with hereditary hypothalamic diabetes insipidus (DI) were employed to examine the role of arginine vasopressin (AVP) in the reduction of water intake and urine output during hypoxic exposure. The pattern of reduced water intake followed by recovery was similar in both N and DI rats during 7 days of hypobaric hypoxia (inspired O2 pressure of 75 Torr). Water intake was markedly reduced during the first 6 h of hypoxic exposure in both groups, whereas urine output did not decrease significantly until after 6 h in DI rats and after 18 h in N rats. Total urinary excretion of AVP in N rats decreased and remained depressed during 7 days of hypoxia. (AVP excretion corrected for osmolar clearance was unchanged.) Plasma AVP of conscious N rats was 2.7 +/- 0.40 pg/ml plasma during normoxia and 2.4 +/- 0.74 pg/ml plasma after 2 h of exposure to inspired O2 fractional concentrations of 0.105 (paired samples). We conclude that AVP is not a major factor in the decreased water intake and urine output observed during hypoxia, and that the initial disturbance is a reduced water intake that leads to negative water balance, reduced urine volume, increased urine concentration, and hyperosmotic volume contraction. The reduced or unchanged AVP release in normal rats during hypoxia appears to be inappropriate.
Abstract: The effects of hypoxemia on inspiratory muscle fatigue were assessed in 4 normal subjects. They breathed to exhaustion through high inspiratory resistances producing an inspiratory mouth pressure (Pm) of about 80% of maximal mouth pressure. The endurance time (tlim) during hypoxia (13% O2) was found to be shorter than that while breathing room air at equal inspiratory mouth pressures. Endurance time during hypoxia was also compared with that while breathing room air at equal rates of energy consumption (C), assuming that C is proportional to: Formula: (See Text). At these equal rates, endurance time during hypoxia still remained shorter than that during normoxia. Fatigue was also assessed by measuring the electromyographic power spectrum of the diaphragm and the parasternal intercostals. The power spectrum shifted towards low frequencies during fatigue and a greater rate of shift was observed under hypoxic conditions. The rate of lactate production during hypoxemia was greater than that during normoxia; however, blood lactate concentrations at the end of the tests were similar under both conditions. It was concluded that respiratory muscles, working against high inspiratory resistances, fall as pressure generators sooner during low oxygen breathing. The effect of low oxygen breathing on inspiratory muscle fatigue resulted in a shorter endurance time, a faster rate in the shift of the electromyographic power spectrum, and a greater rate of increase in blood lactate concentrations.
Abstract: To generate quantitative data relating to the potential hypertensive activity of arginine vasopressin (AVP), 140 and 560 microunits AVP/kg/min were infused chronically in both normotensive dogs and dogs made hypertensive by chronic infusion of either angiotensin II (AII) or aldosterone. The lower rate of AVP infusion increased plasma AVP concentration from 0.4 +/- 0.1 microunits/ml. Mean arterial pressure (MAP) was recorded 24 hours per day, and all dogs were infused continuously with 800 ml of isotonic saline per day. During the initial days of AVP infusion in normotensive dogs, natriuresis, kaliuresis, and water retention were prominent and MAP increased progressively to a peak on Day 6 (30 mm Hg above control). Subsequently, diuresis ensued, net water retention decreased, and MAP fell progressively to only 13 mm Hg above control by Day 12 of AVP infusion. In contrast, in AII or aldosterone hypertensive dogs during AVP infusion, the natriuresis was greatly attenuated, water balance was unchanged or even negative, and MAP either did not increase or increased only transiently. When AVP infusion was terminated in dogs given only AVP, diuresis occurred, and MAP fell gradually over a period of hours to hypertensive levels. In marked contrast, cessation of AVP infusion in dogs with either AII or aldosterone hypertension was associated with a precipitous fall in MAP of 35 to 40 mm Hg within 1 hour: however, this reduction was only transient - over the subsequent hours, both salt and water retention occurred, and MAP returned to previous hypertensive levels. Thus, in the hypertensive models studied, high plasma levels of AVP had relatively weak hypertensive effects. Although variations in plasma AVP concentration were associated with rather pronounced acute effects on MAP, the long-term changes in MAP produced by AVP were either minimal or, in the case of the animals made hypertensive by other agents, nonexistent.
Abstract: The object of this paper was to evaluate the effect of a continuous dopamine infusion (10–12 micrograms/kg . min) on the estimated hepatic blood flow (EHBF) and cardiac output (CO) in man. Measurements were made in 3 periods: the initial control state, during dopamine infusion, and after the infusion. The CO (by thermodilution) and EHBF (by hepatic vein sampling after continuous indocyanine green (ICG) infusion) were measured during each phase. Ten subjects, with inapparent hepatic disease, hemorrhage, or hemodynamic anomalies, were studied. The results showed a 64% increase in the EHBF and a 49% increase in the CO. All subjects showed a return to the original baseline state after infusion. The EHBF/CO was 14% in the control period, 17.3% during infusion, and 13.4% after dopamine infusion. These changes were not statistically significant. Dopamine, therefore, increased both EHBF and CO, but the existence of intrahepatic dopaminergic receptors could not be established.
Abstract: Many suggestions have been made regarding protective methods against lightning, without any quantitative tests of safety. As a fundamental study on lightning protection, the lethal threshold energy for the artificial lightning impulse was investigated, using 14 rabbits. The voltage and current impulse had a 1 microsecond wave front and 40 microsecond wave tail. The imposed energy was measured by simultaneous photographic recording of both voltage and current waves on separate oscilloscopes. The impulse voltage was applied to head, neck, upper chest, and lower chest while the right hind limb was grounded. Artificial lightning current impulses were fed through the skin of the animals by making the surface flash over so that the surface flash was monitored carefully to delete the data of this case which gives an erroneous energy value from the statistical analysis. The lethal threshold energy was found to be 157.6 +/- 54.1 Joule (J), and the percentage of survival was 25% when 160 J impulse energy was given. Impulses of 160 J were then applied to the heads of 21 other rabbits maintained on an artificial respirator. Under these conditions the percentage of survival increased significantly to 47.6%.
Abstract: We measured serum concentrations of erythropoietin in 59 patients with polycythemia using a sensitive and specific radioimmunoassay. The mean concentration was 17.5 +/- 8.4 mU/mL (+/- SD) in 26 patients with polycythemia vera and 14.9 +/- 4.2 mU/mL in 26 normal persons. In contrast, the average concentration was 94.3 +/- 101.2 mU/mL in 33 patients with secondary polycythemia, representing a highly significant elevation (p \textless 0.0001) compared to both normal and polycythemia vera groups. The average hematocrit value did not differ between the polycythemia vera and the secondary polycythemia patients, and both groups had higher values (median, 55%) than the normal donors (median, 41%). Erythropoietin concentrations ascertained by radioimmunoassay helped discriminate between polycythemia vera and secondary polycythemia. Ninety-two percent of polycythemia vera patients had concentrations less than 30 mU/mL (the concentration used as a cut off point), and 94% of secondary polycythemia patients had concentrations greater than 30 mU/mL. This represents an overall correct classification of 93% of the patients. Serum erythropoietin levels as ascertained by radioimmunoassay can distinguish between most polycythemia vera and secondary polycythemia patients and should prove useful in the differential diagnosis of polycythemia.
Abstract: The need to avoid hypokalemia during diuretic therapy in nondigitalized patients has been questioned. Twenty-one patients with (1) mild essential hypertension, (2) plasma potassium of less than 3.5 meq/liter during previous diuretic treatment, and (3) normal findings [less than 6 unifocal ventricular premature beats/hour] on 24-hour ambulatory electrocardiographic monitoring and exercise testing were treated with hydrochlorothiazide (50 mg twice a day) for four weeks and then ambulatory electrocardiographic monitoring and exercise testing were repeated. Ambulatory electrocardiographic monitoring revealed that ventricular ectopic activity developed in seven patients and complex ventricular ectopic activity (multifocal ventricular premature beats, ventricular couplets and/or ventricular tachycardia) in four. Only two of these seven had ventricular ectopic activity during exercise testing while they were hypokalemic. Potassium repletion in these seven patients with spironolactone abolished complex ventricular ectopic activity and reduced unifocal ventricular premature beats significantly (p less than 0.01) from an average of 71.2 ventricular premature beats/hour/patient during hydrochlorothiazide treatment to 5.4 ventricular premature beats/hour/patient after potassium repletion. Although complex ventricular ectopic activity was more likely to occur with plasma potassium less than 3.0 meq/liter, restoration of normokalemia was required in several patients to abolish residual ventricular ectopic activity. Persistent ventricular ectopic activity in one patient suggested that myocardial injury sustained during hypokalemia may initiate chronic ventricular ectopic activity. Even in nondigitalized patients, the hazard of diuretic-induced ventricular ectopic activity warrants correction of hypokalemia.
Abstract: The effects of carbon monoxide inhalation and of consequent carboxyhemoglobinemia (HbCO) on the discharge rates of aortic body and carotid body chemoreceptor afferents were investigated in 18 anesthetized cats. In 10 experiments both aortic and carotid chemoreceptor activities were monitored simultaneously. Carbon monoxide inhalation during normoxia always stimulated aortic chemoreceptors before carotid chemoreceptors, and the steady-state response of aortic chemoreceptors to HbCO was greater than that of most carotid chemoreceptors. Only 2 of the 18 carotid chemoreceptor fibers tested showed a distinct increase in activity in response to moderate increases in HbCO%. Thus, oxyhemoglobin contributed substantially to maintain tissue PO2 of all aortic chemoreceptors and of a few carotid chemoreceptors. Hyperoxia diminished the response of both aortic and carotid chemoreceptors to HbCO, indicating a lowered tissue PO2 as the stimulus source. We hypothesize that the aortic bodies have a much lower perfusion relative to their O2 utilization compared to the carotid bodies. As a consequence, the aortic chemoreceptors are able to act as a sensitive monitor of O2 delivery and to generate a circulatory chemoreflex for O2 homeostasis. carotid chemoreceptors monitor O2 tension and initiate strong reflex effects on the level of ventilation.
Abstract: In rat parotid glands the uptake of 2-[1-14C]aminoisobutyric acid (AIB), in vitro, depends on a Na concentration gradient between the intra- and extracellular medium. Ouabain (1 mM) which inhibits the Na+-K+-ATPase and a Na+ ionophore, monensin (which dissipates the Na+ gradient), both suppress this amino acid uptake. Carbachol (5 microM) (through muscarinic receptors) evokes a decrease in AIB uptake, and in the presence of 0.1 mM ouabain the cholinergic effect is enhanced. Ouabain alone (0.1 mM) very slightly depresses the [14C]AIB uptake. Neither 1 microM isoproterenol, nor 1 microM Ca2+ ionophore A23187, which affect the membrane potential in rat parotid acinar cells, modifies the AIB uptake. When the Ca is removed from the incubation medium, carbachol still evokes a small decreasing effect on AIB uptake. From these data we can suggest that the reduced AIB uptake (induced by the cholinergic agonist) appears to be related to a process dependent on variation of intracellular Na concentration that may be triggered by the cholinergic agonist.
Abstract: Forty-year-old individuals with labile and with mild sustained essential hypertension, identified during a survey of a population born in 1936, were investigated. None had ever received antihypertensive treatment. In thirty-three individuals (26 M, 7F) with diastolic blood pressure (DBP) greater than or equal to 95 mmHg at the very first examination and in thirty-one (14 M, 17 F) randomly selected normotensive controls plasma noradrenaline concentration (PNAC) was measured at rest supine. In twenty-two patients (16 M, 6 F), with sustained diastolic hypertension (diastolic blood pressure greater than or equal to 95 mmHg on at least three different occasions) and in twenty-four (14 M, 10 F) normotensive controls PNAC and plasma renin concentration (PRC) were measured supine at rest and again 2 h after furosemide and ambulation. Basal and acutely stimulated values for PNAC and PRC were identical in hypertensive and normotensive individuals. A close correlation between PNAC and PRC after acute stimulation (r = 0.77, P \textless 0.001) as well as between the absolute changes from resting to acutely stimulated values (r = 0.72, P \textless 0.001) were found in the hypertensive individuals. It is concluded that sympathetic nerve activity, as defined from measurements of plasma noradrenaline concentration, is similar in young patients with mild hypertension and in normotensive controls. We propose that the discrepancies found in the literature might be related to a lack of comparability between hypertensive and normotensive individuals studied, as far as the source of study populations is concerned.
Abstract: The effects of alpha-adrenergic blockade with phentolamine or dibenamine on the cardiovascular response to pharmacological doses of vasopressin were studied in anesthetized dogs. Some observations were also made on the combined effects of vasopressin and norepinephrine. Changes in mean systemic arterial pressure, portal pressure, and resistance in the prehepatic splanchnic vasculature during vasopressin infusion were noted. A total of 97 dogs were used. alpha-Blockade appeared to enhance the response of arterial pressure to vasopressin, possibly because of loss of baroreceptor-mediated buffering action which normally attenuates its pressor action. Effects of vasopressin on mesenteric vascular resistance and portal pressure were unchanged or somewhat less after alpha-blockade, hence no evidence that its therapeutic effect would be improved by this combination. Vasopressin and norepinephrine when given together result in an additive pressor response with little or no evidence of potentiation.
Abstract: The activity of the sympathetic nervous system during the course of severe closed head injury has been evaluated in 15 patients by measuring plasma levels of epinephrine and norepinephrine. With the onset of the transition stage from midbrain syndrome to the apallic syndrome the plasma levels mainly of norepinephrine started to increase and remained high during the further course of the disease. During the remission from the apallic syndrome the elevated norepinephrine levels started to decline. The data indicate that a longlasting overactivity of the sympathetic nervous system is a characteristic feature in the course of severe head injury. As a rational therapy to protect the peripheral tissues against the consequences of a longlasting sympathetic overactivity we suggest the use of beta-adrenergic blocking agents and adrenergic neuron blocking drugs.
Abstract: 1. To investigate differences between the metabolic effects of light and heavy exercise, five healthy males (mean maximal oxygen intake 3.92 litres/min) exercised for 40 min at 36% maximum power (light work) and 70% maximum power (heavy work) on separate days, after an overnight fast. 2. A steady state was achieved in both studies between 20 and 40 min in: oxygen intake (1.42 and 2.64 litres/min respectively); respiratory exchange ratio (0.89 and 1.01); plasma lactate concentration (1.78 and 9.94 mmol/l). 3. Plasma palmitate turnover rate (14C) was unchanged from resting values in light work but was decreased by 40% (from 104 +/- 16 to 63 +/- 8 micronml/min) in heavy work. Heavy work was associated with falls in the plasma concentrations of all free fatty acids measured: palmitic acid (C16:0), oleic acid (C18:1), stearic acid (C18:0), linoleic acid (C18:2) and palmitoleic acid (C16:1). 4. In contrast to th fall in palmitate turnover the increase in plasma glycerol was greater in heavy exercise (0.054-0.229 mmol/l) than in light exercise (0.053-0.094 mmol/l), suggesting that lipolysis was occurring which did not lead to influx of free fatty acids into plasma. 5. In light exercise fat metabolism may be controlled to favour adipose tissue lipolysis and extraction of free fatty acids by muscle from the circulation, whereas in heavy exercise adipose tissue lipolysis is inhibited and hydrolysis of muscle triglycerides may play a more important part. 6. The finding of a high respiratory exchange ratio may not exclude the use of fat as a major fuel source in exercise associated with lactate production.
Abstract: Circulatory adjustments during hypoxia act to redistribute blood flow and maintain arterial pressure. Redistribution of blood flow is accomplished by a local effect of hypoxia, which produces dilatation in coronary and cerebral vessels, and the chemoreceptor reflex, which produces vasoconstriction in skeletal muscle and the splanchnic bed and dilatation in coronary vessels. Arterial pressure is maintained primarily by the chemoreceptor reflex. If the chemoreceptor reflex fails to maintain arterial pressure, hypoxia and hypotension together activate the central pressor response. Compensatory mechanisms usually are sufficient to maintain homeostasis during hypoxia. However, when a hypotensive stress is superimposed during hypoxia, compensatory mechanisms may fail to maintain arterial pressure. Thus, systemic hypoxia interferes with autonomic cardiovascular adjustments.
Abstract: A review of 102 cases of high-voltage electric injuries was performed. The average total body surface area was 15.2%. The average age was 32 years. The mortality was 2.1%. Advances in fluid therapy have virtually eliminated renal failure. Devitalized muscle was accurately identified preoperatively with the use of the technetium Tc 99m pyrophosphate muscle scan. Septic complications were reduced substantially by using the following therapeutic modalities: early excision of the burn eschar and necrotic muscle; quantitative wound biopsies to monitor the bacterial flora; allograft as a temporary coverage of open wounds; and early creation of local and distant flaps. Early institution of physical and occupational therapy are mandatory if the patient is to be restored to his or her maximum postinjury potential.
Abstract: The influence of a 48-h dopamine (DA) infusion (5-7.5 micrograms/kg.min) on serum PRL, TSH, LH, FSH, and GH values was determined in six normal adult males. Sustained suppression of serum PRL to 78% (P less than 0.01) below baseline levels during DA was followed by an acute rebound of 319% (P less than 0.01) 4 h after stopping DA. Similarly, TSH decreased by 44% during DA but had a more gradual and sustained rebound of 41% (P less than 0.01) over a 36-h period. While both serum LH and FSH initially dropped by 25% (P less than 0.001) and 10% (P less than 0.05), a gradual escape occurred during the DA infusion, followed by rebounds of 23% (P less than 0.01), respectively. A brief rise in serum GH levels occurred with DA treatment, followed by a return to baseline. Subsequently, oscillatory spikes continued throughout the DA infusion but were significantly decreased (P less than 0.01) after stopping DA. Thus, DA administration initially produced a reduction in serum PRL, TSH, LH and PSH while stimulating GH release. PRL and TSH showed a sustained inhibition, whereas LH and FSH progressively escaped after a lesser degree of suppression by DA. The rebound after DA withdrawal probably reflected the discharge of hormone synthesized and stored during DA administration. The inverse relationship between the nadir of inhibition and the peak rebound values (r = 0.92) supports this hypothesis. Clearly, the patterns of serum LH, FSH, and GH values differ with acute and chronic DA administration. These differences are of potential importance in interpreting dopaminergic influences on anterior pituitary function.
Abstract: The contribution of beta-adrenoceptor activation to renin release was examined in anaesthetized dogs using renal nerve stimulation (RNS) at different discharge rates in the presence of i.v. beta-adrenoceptor blockade. The animals were divided into 2 groups, which received either low or high level of RNS, defined by the frequency of stimulation producing decrease in renal blood flow of 5 and 50%, respectively. Low level RNS increased renin release tenfold. The renin release response was almost abolished by 0.5 mg/kg of metoprolol or dl-propranolol but unaffected by 0.5 mg/kg of d-propranolol. The increase in renin release to high level RNS was equally reduced by 33% by 0.5 mg/kg and 2.0 mg/kg of metoprolol. dl-propranolol, 0.5 mg/kg, reduced the renin release response to about the same extent, 44%, while 2.0 mg/kg reduced it somewhat more, 59%. This was probably due to its membrane stabilizing properties as d-propranolol, 2.0 mg/kg and lidocaine 2.0 mg/kg + 0.1 mg x kg-1 x min-1, also reduced the renin release response. These data suggest that the renin release response to low level RNS is almost completely mediated by beta-adrenoceptors which are of the beta-1 subtype. High level RNS results in a renin release, which is only partly mediated by beta-1-adrenoceptors. The remainder is apparently related to other mechanisms activated by high level RNS and is probably a consequence of the associated renal vasoconstriction.
Abstract: In the anesthetized, normally hydrated dog, the i. v. infusion of norepinephrine (NE; 0.5 microgram/kg/min) resulted in an increased blood pressure and a marked reduction in the plasma vasopressin (ADH) concentration (2.6 +/- 0.2 to 1.1 +/- 0.2 muU/ml). Urine flow and osmolar clearance, and urine osmolality fell. However, the negative free water clearance (TcH2O) increased, despite the reduction in plasma ADH levels. Thus, the NE-induced diuresis appeared to be due largely to the increased solute excretion, but the reduction in plasma ADH levels may also have been a factor. These data show that change in free water clearance is not a satisfactory index of change in the plasma ADH levels may also have been a factor. These data show that change in free water clearance is not a satisfactory index of change in the plasma ADH concentration when there are acute changes in renal hemodynamics and solute excretion. The norepinephrine-induced reduction in ADH secretion appeared to be due largely to increased activity of the arterial baroreceptors, but a central action cannot be ruled out.
Abstract: Acute oliguric renal failure previously was reported to develop in patients with preexisting idiopathic nephrotic syndrome in association with clinical evidence of vascular volume depletion. We describe an 81-year-old man without recent proteinuria or evidence of preexisting nephrotic syndrome in whom acute oliguric renal failure developed. Renal biopsy disclosed minimal change disease. Nephrotic range proteinuria without severe hypoalbuminemia was detected during the 25-day course of oliguric renal failure. Renal vein thrombosis was excluded. Urine sodium concentration and fractional sodium excretion were reduced, yet left ventricular filling pressure was not subnormal and could be increased to supernormal levels without improvement in glomerular filtration rate. Oliguria and azotemia were corrected following initiation of glucocorticoid therapy. This case suggests that lipoid nephrosis can appear as acute oliguric renal failure without historical or physical evidence of preexisting nephrotic syndrome.
Abstract: High dose barbiturate therapy is being used with increasing frequency in the management of a widening spectrum of neurological disorders. Accurate regulation of the barbiturate dose is essential to maximize cerebral vasoconstriction and reduce brain metabolism while avoiding the cardiovascular depressant side effects of the drug. The purpose of this study was to determine whether the electroencephalogram (EEG) could be used to regulate administration of the agent. In nine mongrel dogs cerebral blood flow (CBF) was determined using the radioactive microsphere technique. After the determination of control CBF, a slow infusion of sodium thiopental was begun. CBF determinations were repeated when the periods of burst suppression in the EEG over several minutes averaged 30, 60, 120, and 240 seconds. CBF and oxygen metabolism showed a nearly identical pattern of a precipituos drop from control levels reaching a plateau at burst suppression between 30 and 60 seconds. Changes in cerebrovascular resistance were of a similar but opposite nature. Significant increases in heart rate occurred with burst suppression of 30 seconds, whereas the arterial pressure and cardiac index decreased with burst suppression between 30 and 60 seconds. In this study cerebral metabolic depression and vasoconstriction from sodium thiopental reached a plateau when sufficient barbiturate was administered to produce EEG burst suppression of between 30 and 60 seconds. At this level there was no important cardiovascular depression. Administration of additional barbiturates significantly decreased systemic arterial pressure and cardiac output, but produced no further decrement in the cerebral metabolic rate of oxygen or the CBF. There was no predictable relationship between cerebral metabolism or cardiovascular function and blood levels of sodium thiopental.
Abstract: 1. Chronic sodium depletion in dogs is associated with a blunting of the pressor response to carotid occlusion. AFter section of the vagus nerves this pressor response reverts to normal although atropine is without effect, suggesting a possible role for increased activity of cardiopulmonary vagal afferents in suppressing sympathetic outflow. Since increases in central blood volume stimulate vagal afferents, cardiopulmonary haemodynamics were studied by radioisotope dilution before and after 3 and 4 weeks of dietary sodium restriction together with frusemide. 2. Sodium depletion was associated with significant decreases in cardiac output, ejection fraction and total blood volume; the cardiopulmonary blood volume increased but the change was not statistically significant (P \textless 0.2). These changes were accompanied by a significant increase in the ratio cardiopulmonary blood volume/total blood volume and a decrease in the ratio cardiac output/cardiopulmonary blood volume. 3. Results indicate that sodium depletion may be accompanied by a paradoxical translocation of blood to the cardiopulmonary region in part due to depressed ventricular performance.
Abstract: In many experimental models, acute increases in sympathetic nervous system activity produce disproportionately greater vasoconstriction in the renal vascular bed than occurs in most other vascular beds. Since increased sympathetic nervous system activity has been implicated in the pathogenesis of DOCA-salt hypertension in the rat, we hypothesized that an attenuation of renal sympathetic tone would delay the development of this form of hypertension. Renal denervation was carried out in 5-week-old uninephrectomized male Sprague-Dawley rats 1 week before beginning DOCA-salt treatment. Systolic blood pressures using the tailcuff method in 32 sham-operated rats were significantly (p less than 0.05) elevated above control by Day five (115 +/- 3 vs 128 +/- 3 mm Hg) of DOCA-salt administration and continued to rise, reaching a plateau by Day 21 (192 +/- 5 mm Hg). In contrast, DOCA-salt administration in 32 renal denervated rats did not result in a significant elevation of blood pressure above control until Day 17 (121 +/- 3 vs 135 +/- 3 mm Hg, p less than 0.05). During the first 2 weeks of DOCA-salt treatment, fractional urinary sodium excretion was significantly greater (p less than 0.05) in renal denervated rats than in sham animals. During the third week of DOCA-salt administration, renal denervated rats had a rapid rise in blood pressure and a fall in fractional urinary sodium excretion to the level of the sham-operated animals. Coincident with the development of hypertension was a threefold increase in renal norepinephrine content (5.3 +/- 0.4 ng/g on Day 14 vs 17.7 +/- 3.0 ng/g on Day 24, p less than 0.01), suggesting reinnervation. These data suggest that increased renal sympathetic tone in the DOCA-salt rat facilitates sodium retention and is necessary for the development of the hypertension.
Abstract: Plasma levels of norepinephrine reflect the rate of its release from sympathetic nerves. In patients with hypertension and in spontaneously hypertensive (SHR) rats basal plasma NE levels are normal. SHR rats are abnormally reactive to stress, as are the normotensive (WKY) strain from which they were derived. The amounts of NE released by sympathetic stimulation are similar in pithed SHR and WKY rats, but SHR rats have greater blood pressure responses. This may be due to diminished beta-adrenoceptor-mediated vasodilation in young SHR rats and structural changes in arterioles of older SHR rats. It is concluded that in SHR rats separate abnormalities of centrally-mediated responses to stress and of peripheral sensitivity to catecholamines contribute to the development and maintenance of elevated blood pressure.
Abstract: This report reviews a number of significant developments in the fields of noradrenergic transmission and adrenergic receptors which suggest that, in addition to the classical postsynaptic adrenoceptors, there are also presynaptic adrenoceptors that help modulate the release of norepinephrine (NE) from peripheral as well as central noradrenergic nerve endings during nerve stimulation. In particular, stimulation of presynaptic alpha-adrenoceptors reduces this release of transmitter and the reverse is observed after blockade of these receptors. Clearcut pharmacological differences exist between the postsynaptic alpha 1-adrenoceptors that mediate the responses of certain organs and the presynaptic alpha 2-adrenoceptors that modulate the NE release during nerve stimulation. Therefore, subclassification of alpha-adrenoceptors into alpha 1 and alpha 2 subtypes is warranted but must be considered to be independent of the anatomical location of these receptors. Some noradrenergic nerve endings have also been shown to possess beta-adrenergic receptors, the stimulation of which increases the quantity of transmitter released by nerve impulses. Physiologically, these receptors could be activated by circulating epinephrine (E) and be involved in essential hypertension. A third type of catecholamine receptor found at the noradrenergic nerve ending is the inhibitory dopamine (DA) receptor, which might be of significance in the development of new antihypertensive agents. Application of these new concepts of noradrenergic neurotransmission and the subclassification of alpha-adrenoceptors to the treatment of hypertension is presented. Clonidine, for example, appears to be a potent alpha 2-adrenoceptor agonist; the central receptor involved in its antihypertensive action is pharmacologically an alpha 2-type but located postsynaptically. Clonidine also induces activation of peripheral presynaptic alpha 2-adrenoceptors, which might contribute to its cardiovascular action. The antihypertensive effects of alpha-methyldopa are related to the formation of alpha-methylnorepinephrine, a preferential alpha 2-adrenoceptor agonist, which can stimulate peripheral presynaptic alpha 2-adrenoceptors leading to a decrease of NE release and a reduction in sympathetic tone. Prazosin is a new antihypertensive agent the mechanism of action of which involves a selective blockade of postsynaptic alpha 1-adrenoceptors. This drug does not antagonize several effects of clonidine that are mediated via alpha 2-adrenoceptors. The mechanisms presently considered to account for the antihypertensive activity of beta-adrenoceptor blocking agents are numerous. It is proposed that blockade of peripheral presynaptic facilitatory beta-adrenoceptors could be of significance in the antihypertensive action of these drugs.
Abstract: We examined the effect of hyperglycemia per se on net splanchnic glucose balance. In 2 groups of normal postabsorptive men who had undergone hepatic vein catheterization, somatostatin was administered to block endogenous insulin and glucagon secretion. Exogenous glucose was infused in both groups to maintain euglycemia for 2 h in one group (n = 7) and to induce hyperglycemia of 220-240 mg/dl after 30 minutes of euglycemia in the second group (n = 4). In both groups the induction of insulinopenia and glucagonopenia with euglycemia maintained resulted in an initial 75% fall in net splanchnic glucose production (NSGP). In the group in which euglycemia was maintained NSGP returned to basal rates (157 +/- 31 mg/min) within 2 h. However, in the group in which hyperglycemia was induced, NSGP did not return to basal rates but remained suppressed (28 +/- 4 mg/min) for the duration of the study. These data in normal man indicate that hyperglycemia per se with insulin and glucagon acutely withdrawn can suppress splanchnic glucose production but does not induce net splanchnic glucose storage.
Abstract: Uninephrectomized adult female dogs with chronic indwelling catheters were maintained on a low sodium diet and studied without anesthesia. Following hydration with 3% dextrose, an intravenous infusion of either arginine vasopressin (AVP) or of 1-desamino-8-D-arginine vasopressin (DDAVP) was begun. The dose was calculated to achieve a near maximal physiological plasma concentration of AVP, or an equimolar concentration of DDAVP. Both AVP and DDAVP increased urinary osmolality from less than 60 to over 800 mosmol/kg H2O within 1 h. AVP infusion increased mean arterial pressure and renal electrolyte excretion and decreased heart rate and plasma renin activity (PRA), while DDAVP was without effect on these parameters. AVP infused into the renal artery at doses which did not alter systemic pressure and heart rate caused kaliuresis and reduced PRA. We conclude that the AVP-induced inhibition of renin secretion and increase in renal electrolyte excretion are not secondary to increased tubular permeability to water, but must represent a more specific action of AVP which is not shared by DDAVP.
Abstract: The natriuresis and concomitant decline in absolute proximal reabsorption (APR) that occur in rats in response to saline loading are blunted markedly when renal perfusion pressure is reduced immediately before, but not after, the volume load. To ascertain the mechanism responsible for these differences between early clamp (EC) vs. late clamp (LC), intracapillary and interstitial determinants of peritubular capillary uptake of APR were measured in seven LC and seven EC Munich-Wistar rats before and after isotonic saline loading (80% body wt). With volume expansion in LC animals, we observed a marked decline in APR (averaging 11+/-1 nl/min), associated with large increases in urinary sodium excretion rate, which averaged 8+/-2 mueq/min. In EC, the changes in urinary sodium excretion rate (+1+/-0 mueq/min) and APR (-3+/-1 nl/min) with volume expansion were smaller in magnitude. Since peritubular capillary reabsorption coefficient and mean peritubular transcapillary hydraulic pressure difference did not change with saline loading in LC, the marked fall in APR was attributed primarily to a measured large decline in mean peritubular transcapillary oncotic pressure difference (deltapi). Despite an equivalent mean fall in deltapi with volume expansion in EC, near-constancy of APR was found to be associated with a simultaneous and equivalent decline in mean peritubular transcapillary hydraulic pressure difference (a consequence of decreased mean peritubular capillary hydraulic pressure), which effectively offset the fall in deltapi. These results demonstrate the importance of hydraulic pressure patterns of the peritubular capillaries in modulating APR and are consistent with the view that Starling forces across the postglomerular microcirculation play a fundamental role in determining APR.
Abstract: The importance of renal perfusion pressure (RPP), the sympathetic beta adrenergic nervous system and renal prostaglandins (PG) on renin release during a uniform 15-17% reduction in blood pressure by hemorrhage (HH) was studied systematically in anesthetized dogs. All groups of animals had similar decrements in systemic and renal hemodynamics with HH. In control dogs (n = 7), both plasma renin activity (PRA, 4.1-9.0 ng angiotensin I/ml per h, P \textless 0.05) and renin secretory rate (RSR, 26-228 ng/ml per h.min, P \textless 0.005) increased significantly with HH. This increase in renin release during HH was not abolished by any single maneuver alone including beta adrenergic blockade with d,l-propranolol (n = 6), renal PG inhibition with indomethacin (n = 7), or control of RPP (n = 6). However, when beta adrenergic blockade was combined with control of RPP (n = 7) during HH, neither PRA (1.9-2.7 ng/ml per h, NS) nor RSR (16-53 ng/ml per h.min, NS) increased significantly. Similarly, a combination of beta adrenergic blockade and PG inhibition (n = 6) also abolished the increase in PRA (1.5-1.4 ng/ml per h, NS) and RSR (14-55 ng/ml per h.min, NS) during HH despite significant decreases in sodium excretion. Finally, a combination of PG inhibition and RPP control was associated with significant increases in PRA and RSR during HH. These results support a multifactorial mechanism in renin release during HH and implicate both the beta adrenergic receptors, renal baroreceptors, and possibly the macula densa as constituting the primary pathways of renin release during HH of this magnitude. Because either constant RPP or PG inhibition blunted renin release during HH in the setting of beta adrenergic blockade, the present results strongly suggest that the renal baroreceptor, and probably the macula densa mechanism are PG mediated.
Abstract: Plasma concentrations of norepinephrine (NE) appear to reflect sympathetic nervous system (SNS) tone. Plasma NE increases substantially when the SNS is stressed by acute postural change or physical exercise. Standing up from the recumbent position elevates NE by about 90% in healthy normotensive and hypertensive subjects. Although a primary role of the SNS is the maintenance and stabilization of blood pressure, there does not seem to be a direct relationship between plasma levels of NE and blood pressure. Patients with essential hypertension cannot be differentiated from normotensive subjects of the same mean age on the basis of either basal plasma levels of NE nor increments in NE after a standard postural stress. Patients with syndromes affecting the autonomic nervous system who suffer from orthostatic hypotension may have striking abnormalities in SNS response to stress, and some subgroups may be distinguished on the basis of the plasma concentrations of NE and the changes in NE elicited by stress.
Abstract: Midodrine, i.v. or orally administered, causes a prolonged elevation of blood pressure and a reduction in heart rate. These cardiovascular changes are not correlated to the plasma levels of the intact drug. On administration of either midodrine or its metabolite, ST-1059, formed by cleavage of the glycine residue, the elevation of blood pressure and the reduction in heart rate were significantly correlated to the plasma level of ST-1059. The results are in agreement with the assumption that the pressor activity of midodrine is mainly exerted by its metabolite ST-1059.
Abstract: To determine whether the rate of fatty acid utilization, reflecting myocardial oxygen consumption under steady-state conditions, can be assessed noninvasively, we assayed positron emission from [11C]palmitate (100 muCi) in isolated rabbit hearts and after intra-atrial injection in vivo. In 11 isolated hearts, clearance of 11C-radioactivity during a monoexponential portion of residue detection curves correlated with tension-time index (TTI)(r = 0.86) and peak dP/dt (r = 0.89). Among 9 hearts prelabeled with [14C]palmitate, 14CO2 production from neutral lipid stores correlated with TTI (r = 0.83). In vivo the decline of 11C-radioactivity was 1st order and constant when physiological conditions were maintained constant (slope of the semilog plot = 0.099 +/- 0.002 (SE) in counts/min) (n = 2 animals, 7 injections). Decline of activity changed predictably when oxygen requirements were increased by administration of methoxamine. Thus, residue detection of [11C]palmitate 1) permits external assessment of global myocardial metabolism in vitro, and 2) reflects effects of interventions that alter the rate of substrate utilization in vivo, and should, therefore, permit comparison of rates of regional myocardial metabolism in patients with detection of radioactivity by positron-emission transaxial tomography.
Abstract: It has been shown recently that normal acid-base equilibrium in the dog is characterized by a strong positive correlation between plasma bicarbonate concentration and PCO2. The present study was undertaken to examine the possibility that a similar relationship between normal levels of PCO2 and plasma bicarbonate might be present in man. The results indicate that values for bicarbonate within the normal range are highly dependent upon the prevailing level of PCO2 ([HCO3-] = 0.36 PaVCO2 + 10.4; r = 0.73). Thus, approximately 50% of the normal variance in bicarbonate concentration is explained simply by the variance in PCO2. The joint confidence region for bicarbonate concentration and PCO2, that can be derived from these data provides a new and more rigorous definition of normal acid-base equilibrium in man.
Abstract: Plasma dobutamine concentrations and hemodynamic and noninvasive cardiac measurements were made during dobutamine infusions in eight patients with congestive cardiomyopathy and low output heart failure. Plasma concentrations correlated well with infusion rates (2.5, 5.0, 7.5 and 10 microgram/kg/min). Cardiac output and stroke volume increased linearly, whereas pulmonary capillary wedge pressure, and total pulmonary and systemic resistances decreased linearly with increasing dobutamine concentrations. No constant relationship existed between plasma dobutamine levels and changes in heart rate or mean arterial pressure. The noninvasive left ventricular function data (echocardiographic and systolic time intervals) correlated linearly with plasma concentrations and suggest that these noninvasive technics be employed in guiding the administration of this new inotropic agent.
Abstract: To define the factors influencing the success of emergency ventricular defibrillation, we identified 52 patients defibrillated at the University of Iowa Hospital during 1974–1976. Thirty-eight patients were successfully defibrillated at least once; 14 could not be defibrillated, despite multiple attempts. Comparisons between these groups revealed no significant differences in body weight, heart weight, energy per kilogram of body weight and energy per gram of heart weight. Factors that militated against successful defibrillation included a prolonged delay before the first defibrillatory shock (successful 7 +/- 7 minutes (SD); unsuccessful 17 +/- 13 minutes, p less than 0.001), acidosis (successful pH 7.36 +/- 0.22; unsuccessful pH 7.23 +/- 0.12, p = 0.05) and hypoxia (successful PO2 100 + 98 torr; unsuccessful PO2 40 +/- 67 torr; p = 0.06). These three conditions tended to occur together in individual patients. Metabolic factors are important in determining defibrillation success; however, the role of high-energy doses is uncertain.
Abstract: 1. Plasma noradrenaline concentrations were similar in normotensive and hypertensive outpatients, but were significantly lower in laboratory control subjects. 2. Standing plasma noradrenaline concentrations were similar in all three groups. 3. Urinary vanillyl mandelic acid, catecholamines and metanephrines were also similar in the normotensive and hypertensive groups. 4. Laboratory controls, possibly because of familiarity with the techniques of sphygmomanometry and blood sampling, may attain a ’basal’ resting level of sympathetic nervous discharge more readily and rapidly than subjects who are unfamiliar with such procedures. 5. After orthostatic stimulation by standing for 2 min, the activity of the sympathetic nervous system, as determined by pulse rate and plasma noradrenaline concentrations, was similar in the three groups, despite the lower starting values in the laboratory staff. 6. The absence of differences in plasma noradrenaline or urinary catecholamine and metabolite concentrations does not support the hypothesis of excessive sympathetic nervous activity in essential hypertension.
Abstract: Five mongrel dogs with chronically implanted catheters in the left atrium, mid-thoracic aorta, and right atrium were continuously infused with subhypertensive doses of norepinephrine for 3 months. Left ventricular cineangiography, determinations of aortic pressure, and cardiac output were performed in the conscious dog. After 3 months of continuous norepinephrine infusion, stroke volume increased from 38 +/- 3.0 to 67 +/- 8.0 ml. (p less than .01), the left ventricular end-diastolic volume increased from 72 +/- 6.4 to 89 +/- 12.9 ml. (p less than .05), and the ejection fraction increased from 52 +/- 3.6 to 76 +/- 3.6% (p less than .005). We postulate that norepinephrine results in an increased myocardial function by producing physiological myocardial hypertrophy.
Abstract: The extent to which bicarbonate reabsorption in the rat proximal convoluted tubule depends on carbonic anhydrase has been examined by in vivo microperfusion and the measurement of total CO2 concentration by microcalorimetry. Tubules were perfused with an ultrafiltrate-like solution at 13 nl/min, and volume reabsorptive rate (JV) was measured using [14C]inulin. Addition of either 800 or 100 microM acetazolamide to the perfusion solution completely inhibited the reabsorption of total CO2. The control total CO2 reabsorptive rate (JtCO2) was 147 +/- 23 pmol/mm.min, and acetazolamide reduced JtCO2 to -3 +/- 5 pmol/mm.min. Acetazolamide reduced JV by 65% from a control of 2.3 +/- 0.4 to 0.8 +/- 0.1 nl/mm.min. The dose-response curve for acetazolamide showed that the I50 for inhibition of JtCO2 was 4 microM. The inactive congener of acetazolamide, t-butyl acetazolamide, did not reduce JV or inhibit bicarbonate reabsorption, indicating that the effect of acetazolamide on JtCO2 was specific for carbonic anhydrase inhibition. Since bicarbonate reabsorption was completely blocked by carbonic anhydrase inhibition, there is no need to postulate either carbonic acid recycling or carbonic anhydrase-independent bicarbonate reabsorption.
Abstract: In four healthy volunteers, muscle lactate concentration and the release of lactate from the leg were determined at rest and at 4 and 12 min of sitting bicycle exercise at four intensities (30, 50, 70, and 90% of maximal oxygen uptake). The muscle biopsies were obtained by needle biopsy technique from m. vastus lateralis. The rate of lactate release was calculated from the femoral venous-arterial differences of lactate and the leg blood flow was determined by constant rate dye infusion. Both leg blood flow and leg oxygen consumption increased linearly with work intensity. The release of lactate rose approximately linearly with the muscle lactate concentration up to about 4-5 mmol/min but then the relationship revealed a clear leveling off. These results indicate a maximal level for the lactate release from the exercising muscles with a translocation hindrance for lactate within the muscles.
Abstract: The free triiodothyronine index (FT3I) was significantly correlated to basal metabolic rate (BMR) in hyperthyroid (r=+0.63, p less than 0.01) and hypothyroid patients (r=+0.61, p less than 0.05). Elimination of the effect of the free thyroxine index (FT4I) on the total correlation between BMR and FT3I by partial correlation analysis gave partial r=+0.60, p less than 0.01 in hyperthyroid patients and partial r=+0.43, p less than 0.1 in hypothyroid patients. The FT4I did not correlate to BMR in either hyper- or hypothyroid patients. These results point to triiodothyronine as the major regulator of BMR in hyper- and hypothyroidism.
Abstract: 1. Direct measurements of the capillary pressure (P(c)) were made in capillaries at the base of the nails of the fingers and toes of two subjects (the authors of this paper).2. With the hand or foot at heart level, P(c) varied over the range of 7-70 cm H(2)O with mean values of 43 cm H(2)O in both the fingers and the toes. P(c) was higher in the arterial limb (mean 49 cm H(2)O) than in the venous limb (mean 34 cm H(2)O) of the capillary loops. The plasma colloid osmotic pressures for the two subjects were 33 and 34 cm H(2)O.3. For capillaries at heart level there was a strong positive correlation between P(c) and skin temperature when the latter was varied over the range 23-36 degrees C.4. When the hand or foot was lowered, P(c) increased less than the local arterial (P(a)) and venous pressures (P(v)). Furthermore the variation in P(c) was reduced. In fourteen measurements of P(c) made on capillaries in the toes of standing subjects, P(c) was no more than 10 cm H(2)O greater than P(v). It is argued that the increase in the ratio (P(a) - P(c))/(P(c) - P(v)) with hydrostatic load represents an increase in the ratio of pre- to post-capillary resistance.5. When P(v) was increased by inflating a sphygmomanometer cuff around the upper arm, (P(a) - P(c))/(P(c) - P(v)) increased in the hand held at heart level. These changes were similar to those seen with changes in position.6. The implications of the results are discussed with respect to fluid balance between the blood and tissues. It is argued that since P(c) in the warm hand was never less than the plasma colloid osmotic pressure, fluid is not reabsorbed from the tissues into the capillaries of the warm skin of the hand even at heart level. Compensatory changes in the circulation appear to minimise the filtration of fluid into the feet of the standing subject but the mechanism of these changes remains obscure.
Abstract: Both vasodilator and inotropic agents improve cardiac function in ischemic heart failure. However, since vasodilators may reduce coronary perfusion pressure and inotropic interventions may increase myocardial oxygen consumption (MVO2), both may increase myocardial ischemia. Accordingly, we determined myocardial blood flow and MVO2 in a canine model of failure induced by propranolol and volume load combined with acute coronary ligation. Both nitroprusside and digitalis reduced ventricular diastolic pressure (LVDP) and increased myocardial blood flow in the ischemic subendocardium. Decreased systolic wall tension also caused a significant reduction MVO2. The benefit of nitroprusside in failing hearts was obtained even with the addition of critical obstruction of the main left coronary artery (LCA). The role of preload reduction is emphasized by the contrasting results with nitroprusside in hearts with low LVDP: (1) decreased myocardial blood flow in ischemic subendocardium, and (2) left ventricular decompensation in animals with critical LCA obstruction. Thus, reduction of LVDP, which decreases subendocardial ischemia, is essential for the beneficial effects of vasodilators and inotropic interventions in ischemic heart failure. Decreased MVO2 caused by reduced heart size may also have a salutary role.
Abstract: Intravenous infusion of two separate doses of angiotensin II in pentobarbital-anesthetized, desipramine-treated animals produced dose-related increases in arterial blood pressure and caused significant potentiation of the cardioacceleration observed during the stimulation of the right postganglionic cardiac sympathetic nerve fibers. Positive chronotropic effects of intravenous norepinephrine were not altered during angiotensin II infusion. Prior administration of Saralasin, an angiotensin receptor antagonist, caused significant attenuation of the pressor action of angiotensin II, and also significantly antagonized the facilitatory effect of angiotensin II on sympathetic transmission to the myocardium. These results suggest that angiotensin II can cause facilitation of sympathetic nerve function to the myocardium via an action on angiotensin receptors which may be located on sympathetic nerve terminals.
Abstract: Dobutamine pharmacokinetics was investigated in 7 patients with severe cardiac failure. Dobutamine was administered by a constant intravenous infusion at rates of 2.5, 5.0, 7.5, and 10.0 microgram/kg/min. Steady-state plasma levels increased in proportion to the infusion rate, indicating that there was no saturation of the disposition processes. The average total body clearance was found to be 2.35 +/- 1.01 L/min/m2. After termination of the final infusion, plasma levels of dobutamine were monitored to determine the elimination half-life. The disappearance half-life of dobutamine was calculated to be 2.37 +/- 0.7 min and the distribution volume was 0.202 +/- 0.084 L/kg. The limited data suggest that the volume of distribution of dobutamine was related to the extent of edema.
Abstract: Plasma norepinephrine derives from sympathetic nerves, but the proportion reaching the circulation before being metabolized varies with the type of nerve ending-effector junctions in the tissue. Plasma levels of norepinephrine also will fluctuate because of rapid metabolism rates and environmental, emotional, and endogenous stimuli provoking a sympathetic response. The responses of plasma catecholamines in spontaneously hypertensive rats and in normotensive rats of the same strain were compared after exposure to a variety of stressors. Drugs that inhibit monoamine oxidase, catechol-O-methyl transferase, or neuronal uptake were administered to show the effects of metabolic enzymes and neuronal uptake on the amounts of catecholamines reaching the circulation. Sympathetic nervous activity and the ability of the sympathetic nervous system to respond to a uniform stimulus are studied in hypertensive and normotensive subjects. A survey of the plasma levels of norepinephrine in a variety of neurologic disorders is given.
Abstract: In humans, there is still considerable controversy concerning the tolerance of the liver to warm ischemia. To avoid anoxic hepatocellular damage, chilled intraportal and intra-arterial infusion has been advised as an adjunct to hepatic vascular isolation. Fourteen patients with hepatic tumors underwent extensive hepatic resection, complete hepatic vascular exclusion being used but without the use of refrigeration. This procedure may considerably reduce blood loss during resection of large and hypervascular hepatic tumors and increase the safety of hazardous lobectomies. Careful hemodynamic monitoring including pulmonary artery pressure is necessary. Hepatic tolerance to prolonged warm ischemia up to 65 minutes is surprisingly good, in the absence of preoperative, extensive hepatic dysfunction. The use of this procedure is advised for resection of large hepatic tumors when the technical risks appear to be high. It is suggested that the classical delay of 15 to 20 minutes of normothermic hepatic ischemia may be safely extended to about one hour when necessary.
Abstract: New concepts concerning the pathogenesis and therapy of diabetic ketoacidosis are reviewed. The regulation of ketogenesis by intrahepatic enzymic processes and the roles of insulin deficiency or glucagon or other counterregulatory hormone excess are summarized. Major emphasis is placed on an analysis of the use of low-dose insulin regimens for the treatment of ketoacidosis. Most patients with diabetic ketoacidosis will respond to low-dose, hourly, intravenous or intramuscular regular insulin. Low doses of insulin are as effective as high doses and have fewer associated complications of hypoglycemia and hypokalemia. Phosphorus deficiency is common in diabetic ketoacidosis and hypophosphatemia usually becomes manifest within 4 to 12 h of institution of therapy. Phosphorus supplementation is now generally recommended to replete erythrocyte 2,3-diphosphoglycerate and improve oxygen delivery to tissues. Coexistent and biochemically significant lactic acidosis is a relatively infrequent complication of diabetic ketoacidosis and when present is usually due to underlying disorders associated with poor tissue perfusion.
Abstract: The influence of the prevailing PaCO2 on the water-retaining effects of sustained elevations in ADH was assessed by administering vasopressin (5 U in oil, twice daily) and a fixed water intake to dogs with eucapnia (n, 7), chronic hypercapnia (n, 6), and chronic hypocapnia (n, 8). Although water excretion initially fell to a similar extent in all three groups, cumulative water retention by day 4 of vasopressin administration was 77 mg/kg in the hypocapnic group, 46 ml/kg in the eucapnic group, and only 14 ml/kg in the hypercapnic group. These differences were reflected in a marked disparity in the degree of hyposmolality of body fluids, plasma osmolality falling by day 4 to an average value of 223, 237, and 268 mosmol/kg in the hypocapnic, eucapnic, and hypercapnic animals, respectively. In a separate group of dogs, water deprivation and water loading studies revealed that sustained hypercapnia does not affect the maximal concentrating or diluting ability of the kidney. We conclude, therefore, that the striking influence of the prevailing PaCO2 on the water-retaining effects of administered vasopressin cannot be ascribed to an altered responsiveness of the nephron per se, but that this influence reflects an alteration in the ease with which the kidney can escape from the antidiuretic effects of this substance.
Abstract: Cerebral metabolic and vascular effects of hypothermia (30 C) and deep pentobarbital anesthesia, separately and combined, were evaluated in 15 mongrel dogs. External cardiovascular support was not used, and mean arterial blood pressures remained greater than 60 torr. Normothermic deep pentobarbital anesthesia, characterized by an electroencephalographic (EEG) frequency of less than 1 Hz, was associated with 30% decreases in cerebral metabolic rates for oxygen (CMRO2) and glucose (CMRG) from lightly anesthetized control values. Hypothermia (30 C) alone caused similar decreases in CMRO2 and CMRG in the presence of an active EEG. The use of pentobarbital anesthesia and hypothermia combined achieved significantly greater (P less than 0.05) decreases in CMRO2 (70%) and CMRG (72%) from the control state. Cerebral vascular resistance (CVR) increased by 70% (P less than 0.05) during hypothermia and about 20% when pentobarbital was administered to normothermic dogs. In hypothermic animals the addition of pentobarbital had a minimal effect on CVR. No alteration in the oxygen-glucose or lactate-glucose index indicative of cerebral hypoxia occurred in any experimental group. This study indicates that barbiturates combined with hypothermia decrease cerebral metabolism to a greater extent than hypothermia or barbiturate alone. When cerebral hypometabolism is therapeutically necessary, barbiturates may be indicated as an adjunct to moderate hypothermia.
Abstract: The clinical manifestations in thyrotoxic and myxoedematous subjects were assessed by clinical diagnostic score indices and related to the free thyroxine index (FT4I) and the free triiodothyronine index (FT3I), basal metabolic rate (BMR) and in the hypothyroid patients to serum thyrotropin (TSH) level. The clinical score index was significantly correlated to both FT4I and FT3I in both groups of patients. No difference existed in degree of correlation between the clinical score index, on the one hand, and FT3I and FT4I, on the other, in either thyrotoxic or myxoedematous subjects. The degree of correlation between clinical score index and FT3I and FT4I was higher than that between the thyroid hormones and BMR. The clinical score index thus appears to be a better indicator of severity of hyper- and hypothyroidism than BMR. Serum TSH concentration was not correlated to the clinical state.
Abstract: Myocardial blood flow (MBF) per unit mass was measured in 10 patients (pts) with severe aortic stenosis (AS) and no significant aortic insufficiency, normal ejection fractions, and normal coronary arteriograms, using xenon-133 and a multiple crystal scintillation camera. MBF per unit mass was reduced in AS (53 +/- 13 mg/100g.min) in comparison to a group of seven normal control patients (69 +/- 12 ml/100g.min) (P less than 0.05). When normalized for heart rate. MBF remained depressed in aortic stenosis (0.65 +/- 0.11 ml/100 g.beat). MBF/beat was strongly related to peak left ventricular wall stress in both groups (r = 0.97). Individual values of MBF/beat were normalized for peak stress using an analysis of covarience; the adjusted mean values were 0.62 +/- 0.03 ml/100g.beat for the AS patients and 0.84 +/- 0.03 ml/100 g.beat for the control patients. There was no overlap between groups in adjusted MBF per beat. Values of MBF per beat and peak stress for a group of ten cardiomyopathy patients with depressed contractility were observed to fall close to the regression line for AS patients. The results suggest that variability in resting MBF in these AS patients is due primarily to differences in LV stress and that reduction in MBF per beat in this group may be due to reduced contractility.
Abstract: Studies were undertaken to examine the mechanism whereby changes in intraluminal flow rates after reabsorption in the isolated perfused proximal tubule of the rabbit. All protocols employed the technique of in vitro perfusion of isolated segments of the proximal convoluted tubule. Stepwise elimination of d-glucose and l-alanine from an artifical perfusate stimulating ultrafiltrate decreased the unidirectional flux of sodium, transtubular potential difference, and net water absorption. Using isosmolal ultrafiltrate as the perfusate, net fluid reabsorption and the unidirectional lumen-to-bath flux of sodium and chloride decreased with a decrease in flow rate below 11 nl/min, but neither net fluid reabsorption nor the unidirectional fluxes of sodium and chloride increased further as the perfusion rate was increased above 11 nl/min. The unidirectional flux of 14C-urea was not affected by changes of perfusion rate from 1.6 to 44 nl/min. The dependence of net fluid reabsorption and unidirectional fluxes of sodium and chloride on flow rate per se, and not on intraluminal hydrostatic pressure or geometry, was established by demonstrating their decrease despite a rise in intraluminal pressure and inside diameter produced by counterpressure at the collecting end of the tubule, while flow was decreased. Ouabain decreased net fluid reabsorption to near zero at all flow rates, but ouabain had no effect on the flow-dependency of unidirectional sodium anf sodium was eliminated with a decrease in bicarbonate concentration and removal of d-glucose and l-alanine from the perfusate. Thus, the present studies demonstrate that net water and unidirectional sodium and chloride fluxes are flow-dependent. At flow rates somewhere below 11 nl/min, unidirectional fluxes decreased with decreasing perfusion rates; however, at perfusion rates greater than 11 nl/min, there was no further effect of perfusion rate on either net water absorption or the unidirectional fluxes of sodium or chloride. These effects may be partly mediated through the flow-dependent changes in the intraluminal concentration of bicarbonate, d-glucose, and 1-alanine.
Abstract: The effect of local hypercapnic acidosis or local hypocapnic alkalosis on pial arterioles were studied in anesthetized cats equipped with a cranial window for the direct observation of the pial microcirculation of the parietal cortex. Changes in PCO2 and pH of the extracellular fluid were induced by perfusing the space under the cranial window with artificial cerebrospinal fluid equilibrated with different concentrations of CO2, while PaCO2 was maintained constant. Hypercapnic acidosis dilated and hypocapnic alkalosis constricted pial arteioles markedly. The results indicate that a basis exists for considering CO2 as a mediator for local regulation of brain blood flow. The vasodilation associated with arterial hypercapnia was abolished by a reduction in CSF PCO2 equal in magnitude to the rise in arterial blood PCO2, suggesting that the action of CO2 is entirely local.
Abstract: The mechanism by which the local effect of CO2ON pial arterioles is exerted was examined in anesthetized cats equipped with a cranial window for the direct observation of the microcirculation of the parietal cortex. The dilation of pial arterioles in response to application of artificial cerebrospinal fluid with low pH was the same whether or not the PCO2 of the solution was maintained in the normal range or markedly increased. The constriction of pial arterioles in response to application of artificial cerebrospinal fluid with high pH was the same whether or not the PCO2 of the solution was maintained in the normal range or markedly decreased. Finally, pial arterioles did not change their caliber in response to application of cerebrospinal fluid with unchanged pH but markedly increased or decreased Pco, or bicarbonate ion concentration. These results show that the action of CO2 on cerebral vessels is exerted via changes in extracellular fluid pH and that molecular CO2 and bicarbonate ions do not have independent vasoactivity on these vessels.
Abstract: The effect of ouabain on left ventricular function in nonfailing hearts was assessed in 14 chronically instrumented dogs during graded treadmill exercise. At rest, ouabain increased the maximum first derivative of the left ventricular pressure (dp/dtmax) and stroke volume by 38% and 16%, respectively. No change occurred in end-diastolic left ventricular diameter or peak systolic left ventricular pressure. During exercise, ouabain reduced maximum running speed and limited the increments in heart rate and systolic pressure but did not alter dp/dtmax, stroke volume, or end-diastolic diameter. When atropine and ouabain were given and severe exercise was performed, there were no differences from controls in running speed, heart rate, dp/dtmax, or other parameters. When ouabain and propranolol were given dp/dtmax increased at rest and during exercise, compared with results with propranolol alone. It is concluded that the inotropic effect of ouabain is negligible during strenuous physical activity because of the presence of high levels of sympathetic stimulation. However, during exercise in the presence of beta-adrenergic blockade, increases in myocardial contractility do occur in response to ouabain.
Abstract: A boy, injured by lightning, had cardiopulmonary arrest. Following resuscitation and during the course of hospitalization, he developed further cardiac arrhythmia, cerebral edema, generalized seizures, and upper gastrointestinal bleeding. Despite efforts to combat these complications, the patient’s condition deteriorated, and he died on the tenth day of hospitalization. The pathologic findings are described and the treatment discussed.
Abstract: We assessed the role of the renin-angiotensin system in the response of the renal circulation to restriction of sodium intake in 38 normal patients. Both saralasin (10 to 30 ng/kg/min), an angiotensin antagonist, and SQ 20881 (30 to 300microgram/kg), a converting enzyme inhibitor, induced a dose-related increase in renal blood flow (xenon 133 washout) only when the resin-angiotension system was activated by restriction of sodium intake to 10 MEq/day. Increasing doses of saralasin (100 to 1,000 ng/kg/min) reduced renal blood flow, presumably due to the angiotensin-like action of this partial agonist. The renal vascular response to SQ 20881 paralleled the endocrine response: An identical threshold dose (30 microgram/kg) increased renal blood flow and reduced plasma angiotensin II concentration, which fell despite a progressive rise of plasma renin activity. Plasma bradykinin concentration did not change in response to SQ 20881, which also blocks kininase II. Both agents also induced a small but consistent and statistically significant reduction in arterial blood pressure, which will be important in assessing the pathogenetic significance of a blood pressure reduction in patients with hypertension. This study indicates that angiotensin mediates the renal vascular response to restriction of salt intake in normal man and provides an approach to assessing the role played by angiotensin in the pathogenesis of functional renal disease.
Abstract: 5 conscious, well trained, female dogs kept on a high sodium intake (14 meq Na/kg bw) were used to measure left atrial pressure (LAP), urine volume (V), sodium and potassium excretion (UNaV, UKV) as well as plasma osmolality (Posm) before and up to 180 min after food intake. The dogs were fitted with a catheter in the left atrium (thoracotomy). In all experiments (n=23) LAP increased postprandially (pp) above fasting controls. The mean peak increase ranged from 4 to 6 cm H2O and was observed as early as 61-80 and as late as 161-180 min pp. Increase in LAP was closely correlated to V which rose from 36+28 to 160+51/ul/min. kg. pp V was also correlated to pp UNa V, which increased from 4.8 +/- 3.3 to 34.O+/-8.5/ueq/min-kg. The pp increase in LAP and its close relation to pp V and pp UNav emphasize the assumption that intrathoracic receptors are involved in the regulation of body fluids.
Abstract: 1. Ten patients on maintenance diuretic treatment received an intravenous infusion of antidiuretic hormone at a low rate for 1 hr. 2. A gradual reduction in mean plasma renin activity was observed and this was significant at 60 min. 3. There was a significant correlation between the initial value and the extent of the fall in plasma renin activity. There was no consistent change in blood pressure, heart rate and blood volume. 4. The results point to an intrarenal site of action of antidiuretic hormone.
Abstract: 71 patients with traumatic splenic rupture are reported. Most had severe associated injuries. In 44 patients the mechanism of trauma was blunt, in 10 penetrating, and in 17 iatrogenic, occurring most commonly (11/17) during operations for peptic ulcer. Splenectomy gave use to thrombocytosis which reached its peak about 2 weeks and returned to normal within one month after operation. Postoperative complications occurred in 24 of the 60 surviving patients (40%) of which most, 17 patients (30%) were infectious in origin. One patient developed deep venous thrombosis. Mortality was 16%. Associated injuries were the main cause of death in most patients (9/11), the ruptured spleen being responsible for only 2 deaths. None of the 17 patients with injury to the spleen alone died, whether associated with fractures of the left lower ribs or not. Primary unconsciousness, shock on admission, and multiple injuries, especially renal and hepatic, increased the mortality rate markedly. The necessity of drainage, the possibility of increased susceptibility of splenectomized patients to infection and thromboembolic complications and their prevention are briefly discussed.
Abstract: The cardiovascular effects of ketamine hydrochloride and thiopental sodium were studied in 11 dogs. During anesthesia, mean heart rate rose to 185 beats/min with ketamine and 147 beats/min with thiopental. Cardiac output was increased with ketamine but unchanged by thiopental. The maximum first derivative of the left ventricular pressure (dP/dt max) fell by 14% with thiopental but did not change significantly with ketamine. Propranolol resulted in attenuation of the tachycardia and a fall of 10% in dP/dt max with ketamine but had little effect on the response to thiopental. Phentolamine had no consistent effects on either drug. With pentolinium both drugs decreased dP/dt max. Intracoronary injection of ketamine decreased dP/dt max. Adrenalectomy had little effect on the responses to either anesthetic. The results lead to the conclusion that both ketamine and thiopental have myocardial depressant effects, but, whereas thiopental does not alter sympathetic tone, the depressive effects of ketamine are obscured by stimulation of cardiac sympathetic nerves.
Abstract: Five male subjects performed exercise at 33, 66, and 95% of their maximum power output on three occasions in random order. Each study was preceded by a 3-h period in which capsules were taken by mouth, containing either CaCO3 (control, NH4Cl (acidosis), or NaHCO3 (alkalosis) in a dose of 0.3 g/kg body wt; preexercise blood pH was 7.38 +/- 0.015, 7.21 +/- 0.033, and 7.43 +/- 0.029, respectively. Exercise was continuous and maintained for 20 min at the two lower power outputs and for as long as possible at the highest. Compared with control (270 +/- 13 s), endurance time at the highest power output was reduced in acidosis (160 +/- 22 s) and increased in alkalosis (438 +/- 120 s). No differences were observed for central cardiovascular changes in exercise (cardiac output, frequency, or stroke volume). The respiratory changes expected from changes in blood pH were observed, with a higher alveolar ventilation in acidosis. At all power outputs arterialized venous lactate was lowest in acidosis and highest in alkalosis. Plasma glycerol and free fatty acids were lowest in acidosis. Changes in blood [HCO3-] and pH were shown to have major effects on metabolism in exercise which presumably were responsible for impaired endurance.
Abstract: While intensive physical exercise has been part of the conditioning of astronauts and consmonauts for spaceflights, its benefits have been questioned. After reviewing the pertinent literature, it is concluded that the morphological and functional changes obtained with athletic endurance training are rather specific and of no general advantage for the tolerance to space stresses. Particularly during gravitational loads, in the relaxed subject, these changes allow a more pronounced shift of fluid into the lower extremities, with the possible consequence of a reduced tolerance. This unfavourable response, obviously, is accentuated through immersion and weightlessness. The aerobic work capacity is also more impaired in athletes. Based on these conclusions, recommendations for crews and passengers of future Spacelab missions are given with respect to selection and pre-and in-flight physical exercise.
Abstract: The cerebral metabolic effects of 2.5, 5, 7.5, 10, 20, 30 and 60 min exposure to 1% CO were studied in lightly anesthetized rats by measurement of cerebral cortical contents of selected glycolytic and citric acid cylce intermediates, as well as tissue energy phosphates. The initial change in the glycolytic sequence occurred at 2.5 min with decreases in tissue glucose and glucose-6-phosphate and increases in fructose-1-6-diphosphate which indicated an activation of phosphofructokinase and hexokinase. The "crossover" pattern between glucose-6-phosphate and fructose-1,6-diphosphate was present at 5, 7.5 and 10 min, but not at 20, 30 and 60 min and thus confirmed previous observations that detection of phosphofructokinase activation in acute unifactorial cerebral hypoxia requires tissue study during the early phases of the experimental exposure. The initial activation of phosphofructokinase occurred in the absence of detectable changes in the tissue content of ATP, ADP, AMP or phosphocreatine and therefore suggested that an imbalance of tissue energy homeostasis is not a prerequisite for the activation of glycolysis in CO intoxication. One percent CO resulted in an increasing malate/oxaloacetate ratio at 5 min, followed by a decrease in alpha-ketoglutarate and aspartate at 7.5 min which suggested a shift in the aspartate aminotransferase reaction towards the replenishment of oxaloacetate removed via the malate dehydrogenase reaction. Subsequent increases in alpha-ketoglutarate at 10, 20, 30 and 60 min were associated with increases in alanine, indicating a contributing role for a secondary shift of the alanine aminotransferase reaction in the replenishment of alpha-ketoglutarate. A comparison of the CO induced changes in the glycolytic and citric acid cycle pathways with those seen in acute hypoxemia indicates no basic qualitative differences in the metabolic responses of brain tissue to the two conditions.
Abstract: Furosemide kinetics were studied in 4 normal subjects after single intravenous injections (1 mg/kg). One experiment was done after pretreatment with probenecid. The apparent volume of furosemide distribution was unchanged after probenecid (10.9 L). The mean plasma clearance fell from 155 to 85 ml/min and the mean plasma t1/2 rose from 36 to 61 min. Renal clearance of furosemide fell below 50% of control after probenecid, but the kidney remained the main route of its excretion (75% of the dose appeared in the urine). In another experiment in 4 subjects an infusion of furosemide was sustained following a loading dose to maintain a constant plasma level. After a control period, probenecid was given orally. This resulted in a decrease in renal excretion of furosemide with a simultaneous rise in its plasma concentration. Despite the rising plasma furosemide concentration, however, there was a diminution in both urine flow and the excreted fraction of filtered sodium, which suggested some reduction of diuretic action. In doses commonly used, probenecid reduces renal elimination of furosemide in man with only a mild impairment of its diuretic activity. This suggests that furosemide is eliminated predominantly by way of proximal tubular secretion and that tubular rather than plasma concentration is the main determinant of its diuretic effect.
Abstract: The purpose of this study was to determine whether increased sympathetic nervous system activity with proportionally greater stimulation to the kidney could result in sustained hypertension. This was simulated by continuous intrarenal norepinephrine infusion. Effects of chronic infusion of norepinephrine (0.285 microng/kg per min) into the renal artery and inferior vena cava were compared in uniephrectomized conscious dogs. Ten days of intrarenal norepinephrine infusion produced a sustained rise in mean arterial pressure (25 mm Hg), and a 32-mEg positive sodium balance occurred. Inferior vena caval infusion caused a transient rise, lasting 24 hours, in mean arterial pressure which was associated with a 54-mEq natriuresis. With renal artery infusion, peripheral plasma renin activity rose from 1.0 +/- 00.2 to 4.4 +/- 0.8 ng angiotensin I/ml per hour at 1 hour (P less than 0.002) and fell to 1.4 +/- 0.4 at 24 hours (not significant). Inferior vena caval infusion produced a similar result. [Sar1,ala8]angiotensin II (6 MICrong/kg per min) produced no significant change in arterial blood pressure. (alpha-Adrenergic blockade with phentolamine normalized the blood pressure. Renal plasma flow was chronically decreased by about 25% in dogs given intrarenal norepinephrine; no significant change in glomerular filtration rate occurred. The cardiac output decreased from a control of 7.2 +/- 0.6 to 4.8 +/- 0.1 liters/min (P less than 0.01) and total peripheral resistance was increased from a control of 13 +/- 1 to 26 +/- 1 resistance units (RU) (P less than 0.0005) in dogs given intrarenal norepinephrine. The data indicate that chronic intrarenal infusion of norepinephrine in uninephrectomized conscious dogs results in sustained hypertension characterized by decreased renal plasma flow, normal glomerular filtration rate, positive sodium balance, and increased total peripheral resistance due to norepinephrine-dependent vasoconstriction.
Abstract: The mean renal tubular diameters, number of tubules per unit of cross-sectional area, and fraction of the total volume occupied by each medullary structure were determined at various levels of the renal medulla of the rat and rabbit. Statistical estimates of anatomic variables were made using spatial sampling techniques on histologic sections. Osmotic diuresis and renal venous occlusion were used to allow fixation of renal tubules and blood vessels in an open state. The distribution of volume fractions of medullary structures are similar in rats and rabbits. Diameters of outer medullary tubular segments and inner medullary thin limbs of Henle are also similar in rats and rabbits. Marked differences between rats and rabbits, however, are seen in the size and number of collecting ducts in the inner medulla. Rabbit inner medullary collecting ducts increase in diameter and decrease in number in the papillary direction relatively closer to the cortex than do those of the rat. Luminal diameters of papillary collecting ducts are more than twice as great in the rabbit as in the rat. An additional finding was that short loops of Henle in the rabbit have their bends relatively closer to the cortex than those of the rat. The quantitative anatomic data derived in this study, when combined through mathematical modeling with knowledge of transport properties of renal tubular membranes, should lead to a clearer understanding of renal function.
Abstract: To investigate the role of glucagon in regulating hepatic glucose production in man, selective glucagon deficiency was produced in four normal men by infusing somatostatin (0.9 mg/h) and regular pork insulin (150-muU/kg per min) for 2 h. Exogenous glucose was infused to maintain euglycemia. Arterial plasma glucagon levels fell by greater than 50% whereas plasma insulin levels were maintained in the range of 10-14 muU/ml. In response to these hormonal changes, net splanchnic glucose production (NSGP) fell by 75% and remained suppressed for the duration of the study. In contrast, when somatostatin alone was administered to normal men, resulting in combined insulin and glucagon deficiency (euglycemia again maintained), NSGP fell markedly but only transiently, reaching its nadir at 15 min. Thereafter, NSGP rose progressively, reaching the basal rate at 105 min. These data indicate that the induction of selective glucagon deficiency in man (with basal insulin levels maintained) is associated with a marked and sustained fall in hepatic glucose production. We conclude, therefore, that basal glucagon plays an important role in the maintenance of basal hepatic glucose production in normal man.
Abstract: When a sea-level resident ascends to a high altitude, his breathing immediately increases because of hypoxic stimulation of the peripheral chemoreceptors. In many species the aortic bodies are relatively unimportant in this response compared to the carotid bodies. When the subject stays at that altitude, his breathing increases progressively in the next few hours and days in a process termed ventilatory acclimatization and does not immediately return to control levels when hypoxia is terminated. Evidence is summarized indicating that this chronic process does not depend on the peripheral chemoreceptors or an initial respiratory alkalosis. Historical review indicates that the process of ventilatory acclimatization was initially attributed to renal excretion of plasma bicarbonate with development of a metabolic acidosis; but subsequent measurements indicated this process did not lower the arterial pH sufficiently to account for the ventilatory stimulation. More recently, ventilatory acclimatization has been attributed to accelerated removal of bicarbonate from the cerebrospinal fluid (CSF), producing a metabolic acidosis in the region of the medullary chemoreceptors; but still more recent observations indicate that this process, contrary to earlier observations, does not lower the CSF pH sufficiently to account for the ventilatory stimulation, either. Some other mechanism should be sought.
Abstract: In the rat, infusion of a volume of isotonic saline equal to 2% of body weight resulted in an 82% increase in delivery of filtrate out of the proximal tubule but little or, in some animals, no change in the urinary excretion of sodium. By contrast, further degrees of volume expansion resulted in lesser increases in the distal delivery of filtrate, but were associated with a marked increase in the urinary excretion of sodium. Sixty minutes following completion of volume expansion, while the animals were still in positive sosium balance, the urinary excretion of sodium decreased 52% compared to a decrease of only 24% in the distal delivery of filtrate. During the course of progressive volume expansion and during the recovery phase, there was a dissociation between alterations in sodium reabosrption in the proximal convoluted tubule and in the whole kidney. These studies indicate that although the proximal tubule is more sensitive to changes in the extracellular fluid volume, distal nephron sites are ultimately responsible both for the natriuresis of volume expansion and the relative antinatriuresis of the recovery periods.
Abstract: Two aspects of the recovery period after endurance exercise were investigated: a) the fluid distribution between the intra- and extravascular parts of the extracellular fluid volume (ECFV) induced by exercise dehydration, b) the cardiovascular response pattern [blood pressure (BP), heart rate (HR), cardiac output (CO), total peripheral resistance (TPR), and central venous pressure (CVP)] to the heat load which results from the preceding exercise. Seven conscious dogs performed endurance exercise in a cool environment (16 degrees C) on a horizontal treadmill till 4% of the body weight was lost. It was found that about 70% of the total fluid loss of the body came from intracellular water. During exercise sodium and chloride concentrations rose by 6 mMol and 7 mMol respectively (P less than 0.005) and remained elevated throughout the early recovery period indicating a fluid loss of about 100-200 ml out of the ECFV. Direct measurements of the ECFV as sulfate space confirmed these values. Since the plasma volume remained unchanged, this fluid loss was carried totally by the interstitial fluid volume. Immediately after exercise body temperature was elevated by 1.5 degrees C and returned towards control within 90 min. Cardiac output was above control level for 2 h after the end of exercise, at first due to an increased HR and thereafter to an elevated stroke volume (SV) (P less than 0.02). CVP and TPR were below control levels for at least 2 h (P less than 0.01). A linear correlation was found between CVP and TPR. A close correlation existed between the body temperature and the cardiovascular parameters. It can be concluded that even long after exercise the cardiovascular system has to serve thermoregulatory needs.
Abstract: The effect of val5-angiotensin II on steady-state sodium concentration gradients (deltacNa) was studied in rat proximal tubules by stationary micro-perfusion combined with perfusion of the peritubular capillaries. Angiotensin added to the peritubular perfusion fluid had a biphasic action with stimulation of sodium reabsorption at low doses (10(-12)-10(-10)M) and inhibition at high doses (3 X 10(-7) - 3 X 10(-6)M). Stimulation of transport was also observed with intraluminal angiotensin but only at a dose of 10(-9)M. Transepithelial potential difference was calculated from the steady-state chloride distribution; no significant change was observed at low (10(-11)M) or high (10(-6)M) concentrations and a direct action on sodium transport is postulated. This biphasic effect is discussed in relation to the responses of the intact kidney to intra-renal infusion of angiotensin, and to the control of tubulo-glomerular feed-back.
Abstract: Blood flow was measured by the 133Xe technique in normal and corticosteroid-treated skin. Epicutaneous and intracutaneous methods of tracer application were compared in normal skin. The two labeling methods were equally suitable for measuring cutaneous blood flow provided calculations in both cases were based on a biexponential resolution of the wash-out curve in its cutaneous and subcutaneous components and provided the traumatic hyperemia phase was considered, when intracutaneous application of the tracer was used. Results were invalidated if calculations were based on initial slope of the wash-out curves.Topical application of beta-methasone valerate in a reduction in cutaneous blood flow as measured by the intracutaneous technique with curve resolution, whereas no effect could be demonstrated when calculations were based on the initial slopes of the curves. The 133Xe technique is a simple and reliable method for measuring cutaneous blood flow, which might prove useful in estimations of penetration ability and potency of topical corticosteroids.
Abstract: 1. Limited isovolaemic haemodilution was produced in cats by addition of dextran 75-Ringer solution to an extracorporeal blood reservoir connected in series with the cat. Total hepatic venous outflow was neasured using a hepatic venous long-circuit and hepatic arterial flow was measured with an electromagnetic flow probe. Oxygen uptake was monitored in the guts and liver. Na-pentobarbitone anaesthesia was used. 2. Following reduction of the haematocrit (from 31 to 22) the oxygen uptake of the gut segment and liver were maintained. Gut conductance increased to 125% of control while the oxygen extraction ratio increased to only 109%. The hepatic arterial conductance did not change in spite of a greatly reduced (to 68%) oxygen delivery. Hepatic extraction increased to 140% of control. 3. The hepatic artery did not dilate to maintain constant oxygen supply to the liver thus confirming our previous observation that blood flow is not coupled to hepatic metabolism. 4. Oxygen extraction in the gut correlated well with changes in portal blood flow but not with changes in vascular conductance, arterial blood pressure or oxygen delivery. 5. The blood flow of the gut (vascular beds draining into the portal vein in the splenectomized preparation) was controlled in a manner that prevented changes in portal venous PO2 in spite of a reduction in oxygen content. Local PO2 and perhaps pH, are suggested as the factors controlling gut blood flow following haemodilution. 6. Changes in portal blood flow correlated with changes in portal vascular (intrahepatic) conductance such that increased portal flow produced an increased portal conductance thereby maintaining portal venous pressure constant.
Abstract: 1. Antidiuretic hormone (ADH) was infused into normal male rats at a rate of 60 muu./min. 100 g body wt., to maintain an effectively constant maximal circulating level. Four groups of rats were used; they were water-loaded by receiving together with the ADH, I.V. infusions of hypotonic dextrose (2.5 g/100 ml.) at different rates (1.0, 4.5, 9.0 and 12 ml./hr, respectively), over an infusion period of 4 hr.2. Urine flow rate increased in all groups, the rate and extent of the increase being related to the volume rate of infusion. The differences in urine flow rates between the four groups were due almost entirely to increases in free water clearance, with no consistent differences in osmolal clearance between the groups. At the end of the 4 hr infusion period, osmolal clearances were closely similar in the four groups.3. Papillary and medullary tissue solute concentrations were progressively reduced at the higher rates of infusion. The changes were due to small increases in the water content, together with a profound decrease in urea concentration and a smaller decrease in sodium concentration. However, papillary osmolality was consistently higher than urine osmolality at the three highest rates of dextrose infusion.4. As urine flow rate increased, there was a progressive reduction in the degree of osmotic equilibration between the final urine and the papillary tip. For urea, however, the degree of equilibration remained high.5. It is concluded that, in the rat, the rate of flow per se, along the collecting duct, is an important determinant of final urine concentration; even if there is an osmotic driving force for water re-absorption in the renal medulla, and the collecting duct walls are permeable to water, osmotic equilibration is restricted by tubular flow rate.
Abstract: Single-unit activity was monitored extracellularly from medullary respiratory neurons and nonspecified neurons of decerebrate cats which were paralyzed, vagotomized, and artificially ventilated. Hypercapnia consistently resulted in increased discharge frequencies and decreased modal interspike intervals for respiratory units; peak integrated phrenic discharge heights increased concomitantly. Although isocapnic hypoxia usually resulted in comparable changes, the firing frequency of some respiratory units was depressed. Moreover, this depression was frequently observed simultaneously with a hypoxia-induced increase in phrenic discharge. Nonrespiratory unit discharge was mainly unaltered by hypercapnia or hypoxia. Following bilateral carotid sinus nerve section, hypercapnia-induced increases in respiratory neuronal and phrenic activities were still obtained; hypoxia depressed these activities. It is concluded that central chemoreceptor afferent influences are ubiquitously distributed to the medullary respiratory complex whereas peripheral chemoreceptor afferents produce only a discrete and unequal excitation of respiratory units. Hypoxia-induced ventilatory changes are further concluded to be the net result of peripheral chemoreceptor excitation of respiratory units and a direct depression of the brain stem respiratory complex by hypoxia.
Abstract: The pressor-response to norepinephrine was determined in the whole body circulation of 15 normal subjects and 86 untreated essential hypertensive patients. The slope, the threshold-dose and the critical-dose were calculated from the log dose-response curve. In the overall population (101 subjects) a slight correlation (r = +0.20 less than 0.05) was observed between the basal diastolic arterial pressure and the threshold-dose. In contrast, highly significant parabolic correlations (r = +0.46 less than 0.00001) were observed between the diastolic arterial pressure and the slope or the critical dose. When diastolic arterial pressure was above 100 mmHg, the slope increased while the blood pressure increased. This result suggests either a decreased sympathetic tone or an adaptative structural change of the arterial wall. When diastolic arterial pressure was under 100 mmHg, the slope decreased while the blood pressure increased. This observation points to an enhanced sympathetic activity in mild blood pressure.
Abstract: Maximal oxygen consumption (VO2 max) and muscle blood flow (Q max) were measured in an isolated gracilis muscle preparation before and after alteration in perfusion pressure (BP), arterial oxygen saturation (SaO2), and hemoglobin concentration (Hb). Q varied directly with BP and inversely with Hb (viscosity) but was unaffected by changes in arterial SaO2. VO2 max varied directly with oxygen delivery under all conditions. These results indicate that VO2 max is normally limited by oxygen delivery rather than any intrinsic limiting of oxygen consumption of the muscle.
Abstract: The cause of the sudden infant death syndrome (SIDS, crib death, or cot death) is unknown. Current hypotheses include lability of heart rate and/or rhythm as a pathogenetic factor. The conduction system of 50 infants coming to autopsy were examined by serial sections; the infants were from newborn to two years of age. Twenty-six were SIDS deaths and 24 were explained deaths (ED). The frequency of histologic abnormalities of the specialized tissue was almost identical in both groups of infants. Hemorrhage in or around different parts of the conduction system was present in 27% SIDS and 29% ED. There was no evidence of cell death or degeneration of conduction fibers, nor obstructive lesions of the atrioventricular (A-V) arteries. Apparent moulding of A-V node and His bundle was a universal finding in both SIDS and ED, and consisted of irregular interdigitation of A-V node and His bundle fibers with the myxoid central fibrous body (CFB). Isolated bundles of conduction fibers residing in CFB and membranous ventricular septum were seen in two SIDS, but no direct contact between these fibers and the working myocardium could be identified in serial sections in either case. Without corroborating antemortem electrophysiologic data, the functional significance of morphologic findings in the conduction system of SIDS must remain conjectural.
Abstract: The relative influence of presence and flow on dilation of arterioles with pressure reduction was examined in preparations of cat mesentery. Erythrocyte velocity and diameter were measured in individual arterioles during stepwise reduction in mesenteric arterial pressure. Volume flow was calculated from velocity and diameter data. Approximately half of the arterioles which dilated with pressure reduction also showed an increase in volume flow. In a second series of experiments, a graded reduction of flow in single arterioles was produced by local downstream occlusion. Graded occlusion caused dilation. In a third series, flow in single arterioles was completely stopped by downstream occlusion, and arterial pressure was then lowered. Most arterioles dilated with pressure reduction. In a fourth series, flow in the total preparation was completely stopped and static intravascular pressure set by a reservoir. Elevation of static pressure typically produced arteriolar constriction. We conclude from these studies that the mesenteric arteriole is sensitive both to intravascular pressure and flow, with the former probably more important than the latter in the phenomenon of autoregulation.
Abstract: The major factor that controls glycogen metabolism in the liver is the concentration of phorphorylase alpha. Indeed, this enzyme catalyzes the limiting step of glycogen breakdown and, by controlling the activity of synthetase phosphatase, also regulates glycogen synthesis. The formation of phosphorylase alpha is stimulated by cAMP, by glycogen, and presumably also by some still ill-defined ionic changes. The ininactivation of phosphorylase is greatly stimulated by glucose and inhibited by AMP and glycogen. Glycogen synthesis is proportional to the concentration of synthetase alpha, which in normally fed animals is formed only when most of the phosphorylase is in the beta form. The inactivation of glycogen synthetase is stimulated by cAMP, an elevated concentration of which puts a double lock on glycogen synthetase by activating phosphorylase alpha (and thereby preventing synthetase activation) and by inactivating glycogen synthetase. The effect of cAMP, 5’-AMP, glucose, and glycogen can presently be explained in molecular terms. The main missing link is in the ionic effect whose elucidation might lead to the understanding of the mode of action of insulin.
Abstract: A comparison was made of the effects of vasopressin (ADH), methoxamine (MX), and angiotensin II (AN) on coronary and left ventricular dynamics, cardiac output, and regional blood flow distribution in intact, consci9us dogs. At an equal percent pressure elevation, ADH reduced cardiac output and cardiac rate the most, while AN had the least effect. After denervation of arterial baroreceptors, ADH still reduced heart rate, while AN increased it, suggesting nonbaroreceptor negative and positive chronotropic effects, respectively. A differential pattern on peak dP/dt was also observed, with ACH causing a greater reduction than MX while AN did not decrease dP/dt. With heart rate held constant, AN did not reduce dP/dt, suggesting a direct positive inotropic effect since dP/dt should have fallen slightly due to reflex mechanisms, as was observed with MX and ADH. ADH induced the greatest increase in coronary resistance (140%), while the least (46%) was observed with AN, which could be explained, in part, by the differential effects observed on cardiac rate and contractility. The greatest increase in resistance in the iliac bed occurred with ADH (30%), and the least with AN (34%). Conversely, the greatest constriction in the renal bed occurred with AN (95%), and lesser amounts were observed with ADH (36%) and MX (35%). Thus ADH, MX, and AN exert potent yet differential vasoconstricting actions on peripheral beds. In addition, while all three agents elicited coronary vasoconstriction, the differential effects on coronary vascular resistance appeared to be due predominantly to a difference in chronotropic and inotropic actions.
Abstract: This study describes absorption, excretion, and metabolism of[20(-3)H]-spironolactone (SP) in 5 healthy men. After a single oral dose (200 mg + 200 muCi) of the drug given in alcoholic solution, the peak serum levels of the ethyl acetate-extractable tritium and the dethioacetylated metabolite canrenone were 763 +/- 400 ng/ml (mean +/- SD) and 415 +/- 145 ng/ml, respectively. These levels occurred within 3 hr. The serum half-life (T1/2) of the extractable materials was 37.3 +/- 6.53 hr. Canrenone levels declined in two phases. The T1/2 from 2.5 to 12 hr was 4.42 +/- 1.07 hr and from 12 to 72 hr was 16.8 +/- 2.75 hr. In the blood both SP and canrenone were confined largely in the plasma, and their protein binding exceeded 89% at concentrations of 550 and 710 ng/ml, respectively. In 5 days 31.6 +/- 5.87% of the radioactivity was excreted in the urine and 22.7 +/- 14.1% in the feces. Unchanged SP was not detected in the urine. The major urinary metabolites were canrenone (5.04 +/- 2.83% of dose), 6beta-OH-sulfoxide (5.21 +/- 0.93% of dose), and canrenoate ester glucuronide (6.2% of dose).
Abstract: The effect on plasma renin activity of intravenous furosemide combined with saline replacement of the volume depletion was studied in twelve patients with insignificant heart disease. In ten of the patients the investigation was repeated without saline replacement. It was found that saline infusion, reducing or eliminating hemoconcentration, had no significant influence on the marked plasma renin increase. In eight of the patients the combined furosemide-saline study was performed during right-hear catheterization. Decrease in atrial pressures, known to occur within 15 min after furosemide intravenously, was virtually absent with the saline replacement. It is concluded that plasma volume reduction after intravenous furosemide is responsible for decreased filling pressures of the ventricles but not for plasma renin increase.
Abstract: We have assessed the capacity of an analogue of angiotensin II (A II), 1-Sar, 8-Ala A II (P113) in normal man to stimulate and block responses to A II in four systems: blood pressure was monitored directly from an arterial catheter, and renal blood flow was measured with 133Xe and arterial renin and aldosterone concentrations by radioimmunoassay. The 31 normal subjects were in balance on a daily intake of 200 meg sodium and 100 meq potassium to suppress endogenous renin. P113 administered intravenously induced a dose-related renal blood flow reduction, with a threshold dose of 0.1 mug/kg/min. This dose also induced a small but significant increase in arterial blood pressure and plasma aldosterone as well as a reduction in plasma renin activity. In contrast to its effect on the renal vasculature, no tendency to a progressive response in the latter three parameters was noted as the P113 dose was increased 30-fold, to 3.0 mug/kg/min. P113 also reduced the clearance of para-aminohippurate, creatinine, sodium, and potassium, a pattern similar to that induced by A II. P113 at 0.1 mug/kg/min reduced significantly the blood pressure and renal vascular and aldosterone responses to graded doses of A II. Higher P113 doses totally obliterated all three responses to A II infused at 10 ng/kg/min, a dose that provides arterial A II concentrations in the range found in angiotensin-mediated hypertension. When A II was infused first, to induce a pressor, renal vascular, and aldosterone response, P113 induced a dose-related reversal of the response in each system. In conclusion, P113 is a partial agonist in normal man, inducing an angiotensin-like response in settings in which endogenous A II is not playing a tonic role, and displaying dominant antagonist activity in settings in which A II is active. Moreover, the studies suggest that the receptors mediating the responses to A II are different in the renal vasculature and other systemic vascular beds. The adrenal receptor must also differ. This agent should be useful in dissecting the role of A II in diseases characterized by hypertension or abnormalities of renal and adrenal function.
Abstract: To study the effect of prolonged recumbency on plasma vasopressin and renin activity, eight women (23-34 yr) were subjected to 17 days of absolute bed rest. The +3 Gz tolerance of the subjects was tested before and after 14 days of bed rest. From day 2 and through day 17 of bed rest, plasma arginine vasopressin (AVP) levels were reduced 33%. Plasma renin activity (PRA) increased 91% (P less than 0.05) above ambulatory control values from days 10 through 15 of bed rest. When compared to precentrifuge values, exposure to +3 Gz prior to bed rest provoked a 20-fold rise (P less than 0.05) in mean plasma AVP but resulted in only a slight increase in PRA. After bed rest, acceleration increased plasma AVP 7-fold (P less than 0.02); however, the magnitude of this increase was less than the post +3Gz value obtained prior to bed rest. After bed rest, no significant rise was noted in PRA following +3 Gz. This study demonstrates that prolonged bed rest leads to a significant rise in the PRA of female subjects, while exposure to +Gz acceleration provokes a marked rise in plasma AVP.
Abstract: The time course of phosphorylcreatine (PC) resynthesis in the human m. quadriceps femoris was studied during recovery from exhaustive dynamic exercise and from isometric contraction sustained to fatigue. The immediate postexercise muscle PC content after either form of exercise was 15-16% of the resting muscle content. The time course of PC resynthesis during recovery was biphasic exhibiting a fast and slow recovery component. The half-time for the fast component was 21-22s but this accounted for a smaller fraction of the total PC restored during recovery from the isometric contraction than after the dynamic exercise. The half-time for the slow component was in each case more than 170 s. After 2 and 4 min recovery the total amount of PC resynthesized after the isometric exercise were significantly lower than from the dynamic exercise. Occlusion of the circulation of the quadriceps completely abolished the resynthesis of PC. Restoration of resynthesis occurred only after release of occlusion.
Abstract: The cardiopulmonary effects of 2 new inhalant anesthetics, enflurane and isoflurane, were studied in nonsedated, previously instrumented, awake dogs. Base line values were determined, and anesthesia was induced and maintained with the drug being studied. Enflurane depressed cardiopulmonary function to a greater extent than isoflurane. The depression of cardiopulmonary function from both agents increased with increasing depth of anesthesia. Enflurance produced muslce twitching, but isoflurane did not.
Abstract: Para-aminohippurate (PAH) transport and fluid absorption were studied in isolated perfused frog (Rana catesbeiana) proximal renal tubules. With 2 X 10(-5) M PAH in the bath, tubule fluid-to-bath (TF/B) concentration ratios averaged 3.0 and net secretion averaged 746 X 10(-15) mol min(-1) mm(-1) in the proximal tubule. Net PAH secretion did not vary with perfusion rate. During PAH secretion, cell water PAH concentration exceeded that in the tubular fluid or bath, suggesting active transport into cells and subsequent diffusion into lumen. In accordance with this concept, luminal membrane permeability (3.8 X 10(-5) cm s(-1) calculated from perfusion studies was about 6 times greater than peritubular membrane permeability (0.66 X 10(-5) cm s(-1)) determined from studies of PAH efflux from tubules with oil-filled lumens. Net transepithelial PAH transport saturated at bath concentration of about 6 X 10(-5) M. Addition of 20 mM urea to PAH bath concentration of 2 X 10(-5) M reduced net PAH secretion by 32%. Fluid absorption in proximal tubules averaged 0.34 nl min(-1) mm(-1). Ouabain (10(-4), 10(-5), or 10(-6) M) added to bath blocked fluid absorption. Fluid absorption was partially restored following removal of ouabain.
Abstract: In an attempt to examine the effects of mild and severe chronic metabolic acidosis on proximal tubule sodium reabsorption, 6 dogs were given 10 mEq. per kilogram per day and 5 dogs were given 20mEq. per kilogram per day of ammonium chloride for 3 days and compared to 12 normal dogs during a steady-state water diuresis and following the administration of ethacrynic acid (EA) intravenously (2 mg. per kilogram) utilizing standard clearance methodology, In the severely acidotic group (pH decrease is greater tthan 0.2) plasma pH was 7.08 +/- 0.06 and plasma bicarbonate was 6.3 +/- 1.0 Eq. per liter compared to a pH of 7.33 +/-0.02 and bicarbonate of 13.4 +/- 0.7 in mild acidosis (pH decrease is less than 0.2). During a steady-state water diuresis urine flow was 14.2 +/- 0.9 in severely acidotic compared to 10.5 +/-0.7 ml. per minute per 100 ml. glomerular filtration rate (GFR) in normal dogs (p is less than 0.01). Following EA sodium clearance increased 38.4 +/- 3.5 in severely acidotic dogs and 27.6 +/- 2.0 ml. per minute per 100 ml. GFR in normal dogs (p is less than 0.02). In mild acidosis, steady-state fractional urine flow and the increase in fractional sodium clearance following EA were not significantly different than normal dogs. We conclude that chronic metabolic acidosis leads to an increase in distal solute load and enhanced natriuretic effect of EA secondary to a decrease in proximal tubule sodium reabsorption which may be dependent upon the degree of reduction in the plasma bicarbonate level.
Abstract: In conclusion, the reviewed results clearly suggest that vital functions of the brain -in spite of the well-developed autoregulatory mechanisms-are impaired during long-lasting hypovolemic and other shock conditions. The insufficiency of the cerebrocortical and hypothalamic regulatory mechanisms can contribute to the development of the irreversible shock. In other words, failure of the body suffering from shock to restore the homeostatic equilibrium can be attributed to the inadequacy of the central nervous servocontrol system. According to the available results, the regional cerebral microcirculatory defect develops through sludge formation. The unevenly distributed local brain damage could be the background of the functional impairment. The focal appearance suggest that, in addition to generalized (bloody borne) changes, local factors play an important role in the production of patchy ischemic areas in the brain.
Abstract: 1. Arginine vasopressin was infused into seven healthy young male volunteers at 12-5 and 25 units/min for 1 h at each dose. Plasma renin activity fell sharply and progressively in each subject. The mean fall was 47% and 66% of the initial value at the end of the lower and higher rates of arginine vasopressin infusion respectively; over 70% of the observed fall in plasma renin activity occurred at the end of the first infusion period. 2. The majority of the plasma arginine vasopressin concentrations achieved were within the physiological range observed after fluid deprivation and orthostatic stress in man, particularly at the lower rate of infusion. 3. There was no change of arterial pressure, despite a slight bradycardia at the lower rate of infusion; at the higher rate of infusion, there was only a very slight pressor response. 4. There was a concomitant and significant fall of plasma protein concentration and peripheral venous packed cell volume without any significant change of plasma sodium concentration or plasma osmolality, implying an expansion of plasma volume. 5. The results indicate that, in man, physiologically relevant amounts of arginine vasopressin suppress the rate of renin secretion indirectly by increasing the plasma volume at the expense of the extravascular fluid volume.
Abstract: 1. Nine paatients with clinically unimportant heart disease or benign essential hypertension were given frusemide intravenously during right-heart catheterization. 2. Pressures in both atria decreased rapidly and in parallel. The magnitude of the pressure decrease was clearly related to decrease in plasma volume loss. 3. Plasma renin activity increased significantly after 5 min (P less than 0-01), but did not correlate with plasma volume loss. 4. Venous tone in the forearm was unchanged. 5. It is concluded that the pressure reduction was secondary to plasma volume depletion through diuresis and that increased plasma renin activity was mainly caused by intrarenal changes.
Abstract: The effects of the cardioselective beta-blocker, metoprolol, were evaluated under double-blind conditions in eighteen patients with angina pectoris. During an introductory run-in period of eight weeks, a placebo was given single-blindly. Thereafter two double-blind crossover periods each of four weeks followed, either 20 mg metroprolol or placebo being given t.i.d. Metoprolol gave a significant reduction in the number of anginal attacks and in nitroglycerin consumption. The patients’ subjective assessments of their daily angina pectoris symptoms also showed a significant improvement compared with the placebo. At the end of each period, a standardized exercise test was performed. In comparison with placebo, metoprolol gave a significant increase of total work performed until the appearance of 1 mm ST-segment depression and until the end of exercise. The heart rate was significantly reduced at rest and during exercise. The blood pressure was significantly reduced only during exercise. None of the patients reported any severe unwanted effects. The complaints reported were mild to moderate, and the frequency during metoprolol treatment was even lower than during placebo treatment. No signs or symptoms of cardiac failure were seen in any of these patients on any occasion. It is concluded that 20 mg metoprolol t.i.d. is of benefit in the treatment of angina pectoris but further benefit might be obtained with higher doses.
Abstract: The possible central integrative mechanisms, responsible for the earlier reported, differentiated reflex engagement of the renal and muscle vessels and the heart from cardiac ventricular receptors and arterial baroreceptors, respectively, were analyzed in atropinized cats. The reflux renal vessel, muscle vessel and heart rate responses, expressed as per cent of maximum, to graded activations of arterial baroreceptors (sinus pressure variations) and stimulations of ventricular receptor afferents in the cardiac nerve were systematically compared. Cardiac nerve stimulation with low frequencies was found to elicit more pronounced reflex renal vessel responses than muscle vessel and heart rate responses. In contrast, elevations of sinus pressure induced equally pronounced renal and muscle vessel responses. High frequency cardiac nerve stimulation elicited maximal reflex renal vessel responses, but only submaximal effects on muscle vessels and heart rate, while intense baroreceptor stimulation induced maximal reflex effector responses throughout. The submaximal heart rate response to cardiac nerve stimulation is probably due to a simultaneous activation of excitatory afferents. On the other hand, the less pronounced muscle than renal vessel responses when the cardiac nerve was stimulated probably reflect a relatively sparse innervation of muscle vasomotor neurons by ventricular receptor afferents, which seem instead to be preferentially oriented towards renal vasomotor and, possibly, cardiac motor neurons.
Abstract: Gas chromatography-mass spectrometry was used to identify metabolites of spironolactone in human blood and urine. In three healthy men about 20% of the radioactivity was excreted in the urine within 24 hr after an oral dose of [20-3H]spironolactone (200 mg + 200 muCi). About half of this radioactivity was extracted with chloroform at pH 3 and from this extract four stable metabolites were isolated by use of column and thin-layer chromatography. Two of these were the previously identified metabolites, canrenone (VII; 2.9% of dose) and the 6beta-hydroxy-sulfoxide (X; 1.8% of the dose). The remaining were the new metabolites, 15alpha-hydroxycanrenone (XI; 0.8% of dose) and the 6beta-hydroxy-thiomethyl derivatives (VI; 0.5% of dose). The principal water-soluble urinary metabolite was canrenoate ester glucuronide (XII; 4.5% of dose). In the 24- to 32-hr pooled serum, canrenone (VII) was the principal metabolite in the organic-extractable fraction; VI was present in appreciable amounts but X and XI were present at extremely low levels.
Abstract: The present study was performed to assess the reliability of lower body negative pressure (LBNP) as a test of orthostatic tolerance. The need for this assessment arose from the prior observation in this laboratory that some subjects show wide day-to-day variation in heart rate responses to LBNP. The extent of these variations was so great as to a raise a serious question as to the value of LBNP as a measure of study-induced alterations (e.g. those produced by bedrest or weightlessness) in orthostatic tolerance. Five healthy volunteers were subjected to a series of tests, consisting of 70 degrees tilt, LBNP, and passive standing. on three occasions preceding and three occasions following a 2 week period of bedrest. Study results show that it is possible to subdivide the volunteers into subgroups which show either great or little day-to-day variability in any of the three tests. All three tests reaveled bedrest-induced alterations in orthostatic tolerande quite adequately. Of the three tests studied, LBNP most frequently resulted in the largest test-induced heart rate alterations, followed by quiet standing and, finally 70 degrees tilt
Abstract: Analyses of the control of glucose metabolism by insulin have been hampered by changes in bloog glucose concentration induced by insulin administration with resultant activation of hypoglycemic counterregulatory mechanisms. To eliminate such mechanisms, we have employed the glucose clamp technique which allows maintenance of fasting blood glucose concentration during and after the administration of insulin. Analyses of six studies performed in young healthy men in the postabsorptive state utilizing the concurrent administration of [14C]glucose and 1 mU/kg per min (40 mU/m2 per min) porcine insulin led to the development of kinetic models for insulin and for glucose. These models account quantitatively for the control of insulin on glucose utilization and on endogenous glucose production during nonsteady states. The glucose model, a parallel three-compartment model, has a central compartment (mass = 68 +/- 7 mg/kg; space of distribution = blood water volume) in rapid equilibrium with a smaller compartment (50 +/- 17 mg/kg) and in slow equilibrium with a larger compartment (96 +/-21 mg/kg). The total plasma equivalent space for the glucose system averaged 15.8 liters or 20.3% body weight. Two modes of glucose loss are introduced in the model. One is a zero-order loss (insulin and glucose independent) from blood to the central nervous system; its magnitude was estimated from published data. The other is an insulin-dependent loss, occurring from the rapidly equilibrating compartment and, in the basal period, is smaller than the insulin-independent loss. Endogenous glucose production averaged 1.74 mg/kg per min in the basal state and enters the central compartment directly. During the glucose clamp experiments plasma insulin levels reached a plateau of 95 +/-8 microU/ml. Over the entire range of insulin levels studied, glucose losses were best correlated with levels of insulin in a slowly equilibrating insulin compartment of a three-compartment insulin model. A proportional control by this compartment on glucose utilization was adequate to satisfy the observed data. Insulin also rapidly decreased the endogenous glucose production to 33% of its basal level (0.58 mg/kg per min), this suppression being maintained for at least 40 min after exogenous insulin infusion was terminated and after plasma insulin concentrations had returned to basal levels. The change in glucose utilization per unit change in insulin in the slowly equilibrating insulin compartment is proposed as a new measure for insulin sensitivity. This defines insulin effects more precisely than previously used measures, such as plasma glucose/plasma insulin concentration ratios. Glucose clamp studies and the modeling of the coupled kinetics of glucose and insulin offers a new and potentially valuable tool to the study of altered states of carbohydrate metabolism.
Abstract: 1. The effect of modifying potassium intake on arterial plasma renin activity, angiotensin II and aldosterone concentrations, renal blood flow and their responses to exogenous angiotensin II has been assessed in twenty-six normal subjects. 2. Reduced potassium intake was associated with a significant increase in circulating renin activity and angiotensin II concentration and a significant reduction in renal blood flow. Conversely, a high potassium intake was associated with a significant increase in plasma aldosterone concentration and renal blood flow without alteration in plasma renin activity or angiotensin II concentration. 3. Reduced potassium intake decreased both the renal vascular and the adrenal response to infused angiotensin II. Conversely, an increased potassium intake enhanced the responsiveness of both systems. 4. The results suggest an important influence of potassium-induced renin-angiotensin system responses on both the renal vasculature and adrenal glomerulosa cell in normal man.
Abstract: The characteristics of steady-state responses of single afferent fibers of carotid chemoreceptors to independent changes in arterial Po2, and Pco2 were investigated in cats. The arterial blood pressure was maintained within the normal limits (115-130 torr). Single chemoreceptor afferent fibers responded to changes both in arterial Po2 and Pco2. The relationship between the activity of chemoreceptors and changes in arterial Pco2 was linear at a constant arterial Po2. The two stimuli showed multiplicative interaction. The activity approached zero (threshold) as arterial Pco2 was decreased at a constant arterial Po2; a decrease in arterial Po2 decreased the arterial Pco2 threshold. These response characteristics of a single fiber suggest that the sensory receptor may be activated through a single mechanism by the two stimuli. The data fit into an idea that the mechanism may involve a conformational change in the membrane-bound polymeric chromophore group which reacts with O2 reversibly and shows a Bohr-shift.
Abstract: The present study was performed to assess the sensitivity of the renin-angiotensin-aldosterone axis to small changes in plasma potassium concentration within the physiologic range. Small increments in potassium levels were accomplished by graded constant infusions of potassium chloride over 2 h (0.17 meq/min; 0.33 meq/min; 0.5 meq/min) in 8 normal subjects on a 10 meq sodium-100 mgq potassium intake. Plasma levels of aldosterone, renin activity, angiotensin II, cortisol, potassium and sodium were measured at frequent intervals. There were no significant changes observed in plasma sodium, renin activity or angiotensin II levels while cortisol levels declined in the expected diurnal pattern. During the 0.17 meq/min (10 meq/h) infusion potassium levels did not increase significantly until 120 min while plasma aldosterone levels rose significantly at 30-60 min. The mean increment above control during the lowest infusion rate was 0.2 meq/liter (5%) for plasma potassium and 13 ng/100 ml (46%) for plasma aldostreone. Although there was a stepwise increase in the increments above control of both potassium and aldosterone levels as the rate of the infusion was increased, the most sensitive area of the dose response curve appears to be 0.1-0.5 meq/liter. in six normal subjects the potassium-lowering effect of glucose ingestion (0.25 g/kg/15 min over a 2-h period) was assessed. The mean maximal potassium decrement below control 0.3 meq/liter (8%) at 90 min was coincident with the mean plasma aldosterone decrement below control of 11 ng/100 ml (46%). Plasma aldosterone then rose to peak levels at 180 min (mean increment 22 ng/100 ml above nadir) while potassium levels remained below control. The rise in plasma aldosterone was associated with a parallel but more rapid rise in plasma renin activity, peaking at a level 108% above control. Ninety minutes after the termination of the glucose ingestion, plasma aldosterone returned to control levels but now in the setting of reduced levels of plasma potassium and elevated levels of plasma renin activity. The data support an important role for physiologic changes in extracellular potassium concentration in the control of aldosterone secretion and indicate that interpretation of studies assessing acute changes in plasma aldosterone must carefully consider minor simultaneous changes in plasma potassium levels. The data also document that acute changes in extracellular potassium concentration play a role in the regulation of renin secretion.
Abstract: The ventilatory responses to isocapnic hypoxia and hypercapnia were studied in seven chronically tracheostomized dogs awake and during anesthesia with pentobarbital (30 mg/kg, iv), ketamine, or thiopental (10 and 15 mg/kg, respectively, followed by infusion). Isocapnic hypoxic ventilatory drive (HVD) was expressed as the parameter A such that the higher the A, the greater the hypoxic drive. HVD(A) was significantly reduced from 259 +/- 28 (mean +/- SEM) in awake dogs, to 96 +/- 14 after pentobarbital, 161 +/- 27 after thiopental, and 213 +/- 23 after ketamine. Hypercapnic ventilatory drive (HCVD) as measured by S (slope of the VE-PACO2 response curve) was significantly reduced from 1.3 +/- .32 in awake dogs to 0.4 +/- .13 after pentobarbital, 0.5 +/- .12 after thiopental, and 0.6 +/- .11 after ketamine. In addition, hypercapnia-induced augmentation of hypoxic drive was markedly diminished by the two barbiturates but was unaffected by ketamine. Therefore, ketamine at this dose level afforded greater protection during exposure to hypoxia than did barbiturates. (Key words: Ventilation, hypoxic response; Hypoxia, ventilation; Oxygen, ventilatory response; Carbon dioxide, ventilatory response; Anesthetics, intravenous, ketamine; Anesthetics, intravenous, thiopental; Hypnotics, barbiturates, pentobarbital.)
Abstract: Occlusion of the circulation to the quadriceps muscle for 20 min resulted in decreases in the muscle ATP and phosphorylcreatine (PC) contents of 1 and 32 per cent, respectively, and increases in ADP and AMP of 7 and 37 per cent. Decrease in PC was statistically significant after 4 min of occlusion, suggesting that the local intramuscular oxygen store was sufficiently depleted at this time as to be limiting to normal mitochondrial function. Pyruvate and lactate concentrations in muscle and the lactate to pyruvate ratio were significantly increased after 15 min of occlusion but not before. The calculated local oxygen store in the muscle was 2.0 mmol O2 - (kg dry muscle)-1. Local oxygen store depletion after 4 and 10 min of occlusion was estimated to be 40-50 and 90-100 per cent complete. Increasing time of pre-exercise occlusion resulted in decreased isometric endurance capacity. The observed decreases in endurance, however, were far greater than could be accounted for by any parallel decrease in the local muscle energy stores.
Abstract: Potassium transport was studied across proximal and distal tubular epithelium in rats on a normal, low- and high-potassium intake during progressive loading with isotonic saline (150 mM) or a moderately hypersomotic urea (200 mM) sodium chloride (100 mM) solution. Free-flow micropuncture and recollection techniques were used during the development of diruesis and tubular fluid (TF) analyzed for inulin-14C, potassium (K) and sodium (Na). Tubular puncture sites were localized by neoprene filling and microdissection. During the large increase in tubular flow rates (10 times): 1) fractional potassium reabsorption fell along the proximal tubule, 2) TFk along the distal tubule remained constant and independent of flow rate in control and high-k rats; thus, net potassium secretion increased in proportion to and was limited by flow rate. 3) In low-K rats TF k fell; with increasing flow rates distal K secretion was not effectively stimulated. 4) Distal tubular sodium reabsorption increased in all animals with flow rate, but tubular Na-K exchange ratios varied greatly. It is suggested that whenever sodium delivery stimulates distal tubular potassium secretion it does so by 1) increasing volume distal tubular potasssium secretion and by 2) augmenting the transepithelial electrical potential difference (lumen negative).
Abstract: The renal vascular response to graded doses of acetylcholine, dopamine and phentolamine, assessed by xenon washout and selective arteriography was used to define the relative contribution of fixed and reversible vascular abnormalities to increased renal vascular resistance in patients with essential or secondary hypertension. The increase in blood flow induced by acetylcholine and dopamine was blunted strikingly in patients with advanced nephrosclerosis, chronic pyelonephritis and polycystic kidney disease and was normal in the kidney contralateral to a significant renal artery stenosis. Conversely, the response to both was potentiated in 9 of 13 (69%) patients with mild essential hypertension. Equivalent potentiation of the response to acetylcholine was induced in normal subjects by increasing renal vascular tone pharmacologically with angiotensin. Phentolamine infused into the renal artery also increased renal blood flow significantly in 6 of 9 (67%) patients with mild essential hypertension, but in none of 15 normal subjects, over a dose reange that paralleled that for alpha-adrenergic blockade. Changes in the selective renal arteriogram were in excellent accord: potentiated response to acetylcholine, phentolamine or dopamine was associated with reversal of the small vessel abnormalities visualized in the arteriogram. The reduced blood flow response in advanced nephrosclerosis or parenchymal disease was associated with a reduced angiographic change during dilator infusion. The results suggest a quantitatively important, functional renal vascular abnormality–perhaps mediated by the sympathetic nervous system–in many patients with mild essential hypertension. Conversely the renal vascular abnormality associated with advanced nephrosclerosis or renal parenchymal disease is largely fixed and is probably due to organic changes.
Abstract: In 14 women with hydatidiform mole, 9 were hyperthyroid. Serum thyroxine (T4) levels varied between 18 and 34 mug/100 ml, and serum triiodothyronine (T3) levels between 300 and 800 ng/100 ml in the hyperthyroid patients. Bioassayable thyroid-stimulating hormone (molar TSH) was found in high concentrations in the serum of 13 patients in whom preoperative serum was available. There was a close correlation between the serum levels of human chorionic gonadotrophin, molar TSH, and T3. Intravenous sodium iodide caused a fall in serum T3 and, to a lesser extent, in T4 in hyperthyroid patients but not in a euthyroid patient. Removal of molar tissue caused a dramatic fall in the serum levels of T3, T4, molar TSH, and human chorionic gonadotrophin. The close correlation between the serum concentrations of molar TSH and human chorionic gonadotrophin lend support to the suggestion that the human chorionic gonadotrophin molecule itself, when present in large amounts, stimulates thyroid function significantly.
Abstract: The influence of renal interstitial pressure on the resistance pattern within the superficial cortical vasculature has been investigated from determinations of 1) the glomerular blood flow eith a modified microsphere technique and 2) the intravascular hydrostatic pressures. Interstitial pressure was monitored via a 50 mum PVC-catheter placed into the subcapsular interstitial space. Two conditions were analyzed viz. a) elevation of uretheral pressure to 20 mm Hg and b) venous stasis to 10-15 mm Hg. Both conditions produced an increase in the interstitial pressure from 1-2 mm Hg to about 5 mm Hg as well as an increased hilar lymph flow and protein flow of about the same size. The vascular reactions were different, however. Uretheral stasis (but not the stasis of a single nephron) produced a decreased resistance in the afferent arteriolae with a concomitant increae in the pressures in the glomerular capillaries, and the peritobular capillary network. In contrast, venous stasis produced only small changes in the parameters studied but for the obvious rise in the peritubular capillary pressure. The results suggest that factors other than the interstitial pressure are governing the afferent vascular tone; the tubular wall tension might be one of these factors.
Abstract: Sodium transport was studied across proximal and distal tubules of rats undergoing progressive intravenous loading with either isomotic saline or urea (200 mosmol)-saline (100 mosmol) solutions. Free-flow as well as recollection micropuncture techniques were used, and tubular fluid (TF) samples were analyzed for inulin-14C and sodium (Na). With administration of progressively larger intravenous saline loads, the delivery of fluid and sodium into the distal tubule rose. Concomitantly, the normally observed decline of tubular sodium concentrations along the distal tubule became attenuated until it was abolished at the highest infusion rates of saline solutions. Absolute reabsorption rates of Na across the distal tubule increased in proportion to tubular flow rate, and no tubular maximum (Tm) was observed. It is suggested that the delivery of increased amounts of sodium to the normally unsaturated later parts of the distal tubule and the elevated tubular sodium concentration after saline loading account for the observed stimulation of distal tubular net sodium transport. The extent of transport stimulation is also subject to control by the amount of urea accumulation along the distal tubule. As the latter declines, sodium reabsorption is proportionately enhanced.
Abstract: The effect of carbon monoxide (CO) on the regional cerebral blood flow was studied by exposing lightly anesthetized rats for 30 min to 0.5, 1.0, 1.5, and 2.0% CO gas mixtures. Cortical cerebral blood flow (CBF) increases of near 200%, 300%, and 400% control were observed at 0.5, 1.0, and 1.5% CO, respectively; whereas at 2.0% CO a reversal of the CBF increase was observed with values declining to near 300% control. The CBF response of subcortical, cerebellar, and brain stem areas was quantitatively similar to that of cortex, indicating that the CBF changes in CO intoxication are general. The decrease in CBF at 2.0% CO was related to significant decreases in arterial CO2 tension. Comparison of the CBF data to previous metabolic results in CO poisoning suggests that the CBF increases are a principal factor in the maintenance of an intact energy state in CO poisoning.
Abstract: This paper reviews the physiology of antidiuretic hormone, including the factors involving the formation, storage and release of the hormone, the metabolism of vasopressin and its physiologic and pharmacologic effects on water and electrolyte transport. The consequences of both deficiency and excess of the hormone are also discussed.
Abstract: The effect of glucagon (50 ng/kg/min) on arterial glycerol concentration and net splanchnic production of total ketones and glucose was studied after an overnight fast in four normal and five insulin-dependent diabetic men. Brachial artery and hepatic vein catheters were inserted and splanchnic blood flow determined using indocyanine green. The glucagon infusion resulted in a mean circulating plasma level of 4,420 pg/ml. In the normal subjects, the glucagon infusion resulted in stimulation of insulin secretion indicated by rising levels of immunoreactive insulin and C-peptide immunoreactivity. Arterial glycerol concentration (an index of lipolysis) declined markedly and net splanchnic total ketone production was virtually abolished. In contrast, the diabetic subjects secreted no insulin (no rise in C-peptide immunoreactivity) in response to glucagon. Arterial glycerol and net splanchnic total ketone production in these subjects rose significantly (P=\textless0.05) when compared with the results in four diabetics who received a saline infusion after undergoing the same catheterization procedure.Net splanchnic glucose production rose markedly during glucagon stimulation in the normals and diabetics despite the marked rise in insulin in the normals. Thus, the same level of circulating insulin which markedly suppressed lipolysis and ketogenesis in the normals failed to inhibit the glucagon-mediated increase in net splanchnic glucose production. It is concluded (a) that glucagon at high concentration is capable of stimulating lipolysis and ketogenesis in insulin-deficient diabetic man; (b) that insulin, mole for mole, has more antilipolytic activity in man than glucagon has lipolytic activity; and (c) that glucagon, on a molar basis, has greater stimulatory activity than insulin has inhibitory activity on hepatic glucose release.
Abstract: 1. The rate of gastric emptying was measured directly in 14 convalescent hospital patients and paracetamol absorption was studied following an oral dose of 1.5 g.2. Rapid gastric emptying was associated with the early appearance of high peak plasma paracetamol concentrations whereas peak concentrations were low and occurred late when gastric emptying was slow.3. There was a significant correlation between the rate of gastric emptying and the 0-4 and 0-24 h urinary excretion of paracetamol and its metabolites.4. In five patients with abnormally slow gastric emptying the mean maximum plasma concentration and 0-4 and 0-24 h urinary excretion of paracetamol were significantly lower than in seven patients with normal gastric emptying rates while the time taken to reach maximum plasma concentrations was longer.5. Individual differences in the rate of gastric emptying may contribute to variable absorption of many drugs.
Abstract: A sensitive and precise radioimmunoassay for the direct measurement of triiodothyronine (T(3)) in human serum has been designed using sodium salicylate to block T(3)-TBG binding. This assay is sufficiently sensitive to quantitate T(3) accurately in 50-100 mul of normal serum and to measure quantities as small as 12.5 pg in 0.2 ml of hypothyroid serum. The T(3) values observed in euthyroid subjects and in patients with various thyroid diseases are as follows: euthyroid (38) 1.10+/-0.25 (SD) ng/ml, hypothyroid (25) 0.39+/-0.21 (SD) ng/ml, and hyperthyroid (24) 5.46+/-4.42 (SD) ng/ml. The levels of T(3) parallel the thyroxine (T(4)) concentration in the sera of these subjects. In eight pregnant women at the time of delivery, T(3) concentrations were in the upper normal range (mean 1.33 ng/ml). The levels of T(3) in cord serum obtained at the time of delivery of these patients (mean 0.53 ng/ml) are distinctly lower and close to the hypothyroid mean. Administration of 10 U of bovine thyroid-stimulating hormone (TSH) to euthyroid subjects causes a two-fold increase in serum T(3) levels within 8 hr. At this time, the increase in serum T(4) concentration is only 41%. In two subjects in whom thyroid secretion was acutely inhibited, one after pituitary surgery and another after thyroidectomy, the serum T(3) fell into the hypothyroid range within 1-2 days. Thus, serum T(3) concentrations appear to be a sensitive index of acute changes in thyroid hormone secretion and should prove to be a useful adjunct to both the clinical and physiological evaluation of thyroid function.
Abstract: We tested the ability of human neutrophils to kill five Candida species and the yeast Torulopsis glabrata. C. parapsilosis and C. pseudotropicalis were found to be killed readily by normal and myeloperoxidase-deficient neutrophils and were selected to probe the myeloperoxidase-independent fungicidal mechanisms of the neutrophil. These organisms were killed with relatively normal (C. parapsilosis) or moderately reduced (C. pseudotropicalis) effectiveness by neutrophils from two boys with X-linked chronic granulomatous disease. Azide (2 mm) and sulfadiazine (4 mm) exerted a relatively small inhibitory effect on the ability of normal neutrophils to kill C. parapsilosis. These compounds did not, however, inhibit the killing of C. parapsilosis by myeloperoxidase-deficient neutrophils, although they blocked their iodination of ingested Candida cells. Anaerobic incubation conditions inhibited the ability of normal neutrophils to kill C. parapsilosis slightly but did not impair this function in myeloperoxidase-deficient cells. All of the Candida species tested had catalase activity, yet their sensitivity to H(2)O(2) in cell-free systems varied considerably. Our C. parapsilosis strain was extraordinarily resistant to H(2)O(2) (LD(75): 0.14 m), as compared with C. pseudotropicalis or with our reference strain of C. albicans (LD(75): 2.3 x 10(-3)m and 3.4 x 10(-3)m, respectively). These data establish the existence in human neutrophils of a second mechanism that exerts microbicidal activity against certain Candida species; the mechanism is unrelated to myeloperoxidase, iodination, or to the direct effects of H(2)O(2) generated by the endogenous metabolic processes of the neutrophil. As yet unidentified, this mechanism appears to remain operative in the neutrophils of subjects with hereditary myeloperoxidase deficiency or chronic granulomatous disease.
Abstract: Studies with the isolated perfused working rat heart were carried out to investigate factors that may enable the heart to recover after periods of anoxia. It was found that the presence of glucose in the perfusion fluid during anoxia was essential for complete post-anoxic recovery and the presence of a high concentration of K(+) increased not only the rate of recovery but also the final extent of recovery. In an attempt to clarify the roles played by glucose and K(+) in aiding the survival and recovery of the anoxic myocardium the concentrations of parameters associated with energy liberation and anaerobic glycolysis (ATP, ADP, AMP, P(i), creatine phosphate, glycogen and lactate) were measured in the presence and absence of glucose during the anoxic phase. Determinations of these parameters were carried out during the working aerobic control period, the anoxic period (K(+) arrest) and the recovery period. The results demonstrated that glucose acted as an energy source during anoxia and thus maintained myocardial concentrations of high-energy phosphates, particularly ATP. These studies have also shown a direct relationship between the ability of the heart to recover and the concentration of myocardial ATP at the time of reoxygenation.
Abstract: The effect of ethanol on the interrelationship of lactate and glucose metabolism was investigated in eight human volunteers. Lactate and glucose kinetics and intervconversion rates were determined by the sequential administration of L-(+) lactate-U-(14)C and glucose-1-(14)C over an 8 hr period. After a 12 hr fast, the glucose turnover and recycling rates were 94.0 +/-3.8 (SEM) and 13.7 +/-1.1 mg/kg per hr, respectively. Approximately 50% of the glucose turnover or 40.7 +/-2.1 mg/kg per hr was converted to lactate, accounting for 50% of the lactate turnover rate. Lactate turnover and lactate conversion to glucose were 81.8 +/-6.2 and 16.7 +/-1.1 mg/kg per hr, respectively. Approximately 20% of the glucose turnover was derived from lactate under these conditions. During the administration of ethanol, the blood lactate concentration doubled and the lactate turnover rate declined slightly. Lactate conversion to glucose was markedly inhibited, decreasing from 16 to 5 mg/kg per hr, and the per cent of the glucose turnover derived from lactate decreased from 18 to 6. Despite the marked inhibition of lactate conversion to glucose, neither the blood glucose concentration nor the glucose turnover rate changed. Both glucose recycling and glucose conversion to lactate were decreased, indicating that ethanol inhibited peripheral glucose utilization. There was no difference in the degree of inhibition of lactate incorporation into glucose produced by ethanol when nonfasted subjects were compared with two subjects who had fasted for 48-72 hr despite the presence of hypoglycemia in the latter. These results indicate that starvation is not a prerequisite for ethanol inhibition of gluconeogenesis from lactate in humans but is necessary for the development of hypoglycemia. Inhibition of lactate incorporation into glucose in nonfasted subjects is probably masked by a concomitant increase in glycogenolysis which prevents hypoglycemia. Ethanol decreases glucose conversion to lactate as well as lactate conversion to glucose, thus inhibiting the Cori cycle.
Abstract: Infusion of ketone bodies to ammonium chloride-loaded acidotic dogs was found to induce significant reduction in urinary excretion of ammonia. This effect could not be attributed to urinary pH variations. Total ammonia production by the left kidney was measured in 25 animals infused during 90 min with the sodium salt of D,L-beta-hydroxybutyric acid adjusted to pH 6.0 or 4.2. Ketonemia averaged 4.5 mM/liter. In all experiments the ammonia content of both urine and renal venous blood fell markedly so that ammoniogenesis was depressed by 60% or more within 60 min after the onset of infusion. Administration of equimolar quantities of sodium acetoacetate adjusted to pH 6.0 resulted in a 50% decrease in renal ammonia production. Infusion of ketone bodies adjusted to pH 6.0 is usually accompanied by a small increase in extracellular bicarbonate (3.7 mM/liter). However infusion of D,L-sodium lactate or sodium bicarbonate in amounts sufficient to induce a similar rise in plasma bicarbonate resulted in only a slight decrement in ammonia production (15%). The continuous infusion of 5% mannitol alone during 90-150 min failed to influence renal ammoniogenesis. Infusion of pure sodium-free beta-hydroxybutyric acid prepared by ion exchange (pH 2.2) resulted in a 50% decrease in renal ammoniogenesis in spite of the fact that both urinary pH and plasma bicarbonate fell significantly. During all experiments where ketones were infused, the renal extraction of glutamine became negligible as the renal glutamine arteriovenous difference was abolished. Renal hemodynamics did not vary significantly. Infusion of beta-hydroxybutyrate into the left renal artery resulted in a rapid decrease in ammoniogenesis by the perfused kidney. The present study indicates that ketone bodies exert their inhibitory influence within the renal tubular cell. Since their effect is independent of urinary or systemic acid-base changes, it is suggested that they depress renal ammoniogenesis by preventing the transformation of glutamine and glutamate into alpha-ketoglutarate in the mitochondria of the renal tubular cell.
Abstract: The reabsorption of water and solute by the papillary collecting duct was studied during water diuresis and vasopressin-induced antidiuresis in young rats with hereditary hypothalamic diabetes insipidus. The tip of the left renal papilla was exposed and fluid was obtained by micropuncture from loops of Henle and from collecting ducts at the papillary tip, and at an average of 1 mm proximal to the tip. In water diuresis the ratio of tubule fluid to plasma (TF/P) osmolality (osm) of loop fluid was 1.73 +/-0.058 (SE); of fluid from the proximal collecting duct, 0.63 +/-0.027; and from the tip, 0.55 +/-0.024; indicating a substantial osmotic pressure difference across the collecting duct epithelium. The fraction of filtered water reabsorbed (x 100) by the terminal collecting duct was 1.58% +/-0.32. In antidiuresis the TF/P osm of loop fluid was 2.65 +/-0.109; of fluid from the proximal collecting duct, 2.20 +/-0.093; and from the tip, 2.71 +/-0.111; indicating a marked decrease in the driving force for water reabsorption. The fraction of filtered water reabsorbed (x 100) by the terminal collecting duct was reduced to 0.58% +/-0.08, while the delivery of solute to the same segment was unchanged from that in water diuresis. The glomerular filtration rate (GFR) of the right kidney declined from 327 +/-24.4 mul/min in water diuresis to 274 +/-24.4 mul/min in antidiuresis (P \textless 0.005); similar results were obtained in a study comparing right and left GFRs in five additional rats. Thus, fractional reabsorption (and very likely the absolute volume) of water reabsorbed by the terminal collecting duct was less in antidiuresis than in water diuresis (mean difference, 1.01% +/-0.29, P \textless 0.005).
Abstract: 1. The effects of angiotensin on the contractility of the transmurally stimulated rabbit portal vein and coeliac artery have been studied in conjunction with its effects on the release and uptake of (+/-)-(3)H-noradrenaline.2. Angiotensin contracted both vein and artery; these responses were enhanced by veratrine and reduced by tetradotoxin. At low (non-contractile) concentrations of angiotensin, contractions elicited by electrical stimulation (0.5-4 Hz) had a quicker onset and reached a higher maximal tension than control responses. Higher concentrations of angiotensin increased the degree of potentiation. Contractions to noradrenaline were not enhanced by angiotensin.3. Pretreatment of the coeliac artery, portal vein and perfused rat heart with angiotensin did not reduce the subsequent uptake of labelled noradrenaline in the presence of angiotensin. Simultaneous treatment with angiotensin and (3)H-noradrenaline caused a small, apparent inhibition of uptake into the portal vein.4. When the portal vein was incubated with (3)H-noradrenaline there was a marked accumulation of label within the tissue; over 90% of the radioactivity retained in the tissue was identified as intact noradrenaline. When the vein, or artery, was superfused with amine-free Krebs there was a steady basal release of label; the greater proportion of this label was identified as deaminated metabolites. Electrcal stimulation evoked a frequency dependent release of (3)H above basal levels. The greater proportion of this increased efflux was due to the release of intact (3)H-noradrenaline, with smaller increases in the amount of O-methylated and deaminated metabolites.5. Angiotensin increased the efflux of labelled noradrenaline + normetanephrine, or of total (3)H, during transmural stimulation (0.5-4 Hz) in both the vein and artery, but did not increase the efflux of deaminated products during electrical stimulation. The output of labelled noradrenaline + normetanephrine was usually doubled in the presence of angiotensin (200-500 ng/ml) during electrical stimulation of the portal vein.6. Cocaine (4 mug/ml) potentiated responses to noradrenaline and transmural stimulation, and doubled the output of (3)H or labelled noradrenaline + nor-metanephrine during electrical stimulation. Cocaine did not alter the potentiating effects of angiotensin.7. Angiotensin elicited transitory increases in the basal efflux of (3)H from both the portal vein and coeliac artery. However, this did not account for the marked increase in efflux seen during electrical stimulation. Vasopressin did not potentiate responses to transmural stimulation or significantly influence the efflux of (3)H from the vein or artery.8. Noradrenaline and 5-hydroxytryptamine, but not acetylcholine, markedly increased the efflux of (3)H from the portal vein. This increase in efflux of label is believed to result from an exchange of exogenous noradrenaline and 5-hydroxytryptamine with labelled tissue stores of noradrenaline.9. It is suggested that angiotensin is able to facilitate the release of the sympathetic transmitter and that this is the basis for its action in potentiating the responses to sympathetic stimulation. It is also suggested that the nor-adrenaline releasing action of angiotensin (by excitation of sympathetic nerve endings) has led to confusion in previous investigations of the effects of angiotensin on noradrenaline uptake.
Abstract: 1. The isolated renal papillae of a rat were centrifuged in a two tube assembly which allowed fluid from the tissue to separate into the lower tube.2. The papillae were centrifuged for 15 min at 300 g and 1500 g consecutively.3. After intraperitoneal injection of Na (131)I-diatrizoate, the activities of urine, and fluid samples obtained from the papilla, were compared. It was found at 1500 g that the median value for papillary fluid activity was 1.52% of the activity of urine. This is evidence that the papillary fluid was virtually free from any contamination from the terminal collecting ducts.4. It is considered that the fluid sample obtained from the papillae by centrifugation at 1500 g is a representative and reproducible sample of interstitial fluid.5. The method was used to demonstrate changes in solute concentrations in the renal papillary fluid, following dehydration of rats.
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. When the vasosensory areas were perfused at non-pulsatile pressures within the normal physiological range of mean pressures, the reflex reduction in systemic vascular resistance produced by a given rise in mean carotid sinus pressure was significantly greater than that resulting from the same rise of aortic arch pressure.3. On the other hand, when the vasosensory areas were perfused at normal pulsatile pressures and within the normal physiological range of mean pressures, there was no difference in the size of the reflex vascular responses elicited by the same rise in mean pressure in the carotid sinuses and in the aortic arch.4. Whereas the vasomotor responses elicited reflexly by changes in mean carotid sinus pressure are modified by alterations in pulse pressure, those evoked by the aortic arch baroreceptors through changes of mean pressure are only weakly affected by modifications in pulse pressure. Evidence for this was obtained from single stepwise changes of mean pressure in each vasosensory area during pulsatile and non-pulsatile perfusion, and from curves relating the mean pressure in the carotid sinuses or aortic arch and systemic arterial perfusion pressure.5. The vasomotor response elicited by combined stimulation of the carotid sinus and aortic arch baroreceptors was greater than either response resulting from their separate stimulation.6. When the mean perfusion pressures in the two vasosensory areas are changed together, the curve relating mean pressure to systemic arterial pressure during pulsatile perfusion of the areas is considerably flatter than that for non-pulsatile perfusion.7. Increasing the pulse pressure in the carotid sinuses or aortic arch caused a decrease in systemic vascular resistance, the response elicited from the carotid sinuses being the larger.8. Altering the phase angle between the pulse pressure waves in the carotid sinuses and aortic arch had no effect on systemic vascular resistance.9. In both vasosensory areas, increasing the pulse frequency caused a reduction in systemic vascular resistance.
Abstract: 1. Vasopressin and oxytocin have been measured in the neurohypophysis of rats which had either been given a 2% (w/v) NaCl solution to drink or been deprived of drinking water for up to 5 days.2. There was a progressive decrease in the vasopressin content of the glands in both groups; the rates of depletion were not significantly different.3. Oxytocin also decreased progressively in both groups but the glands from the ;saline-treated’ rats contained less hormone than those from the ;water-deprived’ animals.4. The differences in gland content of oxytocin could not be correlated with differences between the plasma osmolalities or sodium concentrations of the two groups.
Abstract: This study utilized rates with hereditary hypothalamic diabetes insipidus (D.I.) in order to explore possible mechanisms which prevent full urinary concentration after acute administration of vasopressin in hypothalamic D.I. and which correct this concentrating defect with prolonged therapy.IT WAS FOUND: (a) that the concentrating defect persisted even when the urinary osmolal excretion of D. I. rats was reduced to that of normal animals; (b) that the defect was not corrected more rapidly if larger doses of vasopressin were given; (c) that it persisted even when the D.I. rats were deprived of drinking water after vasopressin was given; (d) that there was osmotic equilibration between urine and renal papilla at a time when the concentrating defect was still evident; and (e) that the correction of the defect was associated with progressive and significant rise of the papillary osmolality. These studies appear to rule out osmotic diuresis, accumulation of exogenous vasopressin, persistent primary polydipsia, or delay in the induction of membrane permeability as causes for the concentrating defect. Rather, subnormal osmolality of the renal papilla, which can be corrected only gradually, accounts for the initial concentrating defect and the long time required for its correction. Reduction of water content and increase of urea content are primarily responsible for restoration of papillary osmolality to normal.
Abstract: The effect of infusions of hyperoncotic solutions on fractional sodium reabsorption by the proximal tubule of the dog was studied by the recollection micropuncture method. Tubule fluid to plasma inulin concentration ratios were measured for identified proximal tubule segments before and after infusion of 25% albumin or dextran solutions. Results were compared with changes in fractional reabsorption during saline diuresis. Plasma volume increased 66% +/- SE 5.8 after infusion of albumin solution and 94% +/- SE 8.2 after infusion of dextran solution. Fractional sodium reabosorption by the proximal tubule was depressed after infusion of both of these hyperoncotic solutions. Nevertheless, changes in sodium excretion after infusion of albumin and dextran were small. In contrast, after infusions of isotonic sodium chloride solution, which increased plasma volume 61% +/- SE 5.8, a decrease in fractional reabsorption of 50.7% +/- SE 7.2 was associated with large changes in sodium excretion.
Abstract: Rats were made acutely hyper- or hyponatremic by infusion of hypertonic saline or water, respectively. Other rats were maintained in these states from 1 to 7 days to observe the effects of time. Brain tissue water, Na, Cl, and K were compared with serum Na and Cl concentration (Na(E) and Cl(E)). The following observations are noted: Brain Cl content varies directly with Cl(E) and brain Na content in the Cl space (Na(e)) varies directly with Na(E), indicating little or no restraint on the inward or outward movement of Na or Cl from the Cl space of brain. The intracellular volume of brain fluid (V(i)) derived as the difference between total water and Cl space, decreases with hypernatremia and increases with hyponatremia. The changes in V(i) in the acute studies are not accompanied by any change in brain K content, or calculated intracellular Na content, and are approximately 0.6 the changes predicted from osmotic behavior of cells, which apply four assumptions: (a) Na(E) is proportional to osmolality; (b) brain osmolality remains equal to plasma osmolality; (c) V(i) is osmotically active; and (d) there is no net gain or loss of solute from V(i). The validity of these assumptions is considered. When changes in osmolality are sustained, V(i) is much closer to control values than when in the acute phase. K content increases in hypernatremia and decreases in hyponatremia. The changes in K content can account for some of the adjustment in V(i) observed over the extended period of hyper- or hyponatremia. The regression of (Na + K)/v upon Na(E) describes a slope less than 1.0 and an intercept of (Na + K)/v equal to 40% of the control (Na + K)/v. These characteristics are interpreted to mean that significant quantities of Na and K in brain are osmotically inactive. The brain protects itself from acute volume changes in response to change in Na(E) by the freedom for Na and Cl to move from the Cl space, by V(i) not changing acutely to the degree predicted from osmotic properties of cells in general, and by significant quantities of Na + K in V(i) being osmotically inactive. With sustained changes in osmolality, V(i) approaches normal values and brain K changes to account for part of this later adjustment.
Abstract: The forces governing the movement of water across the pulmonary capillaries were studied in 39 intact, spontaneously breathing dogs. A situation favoring the net movement of water out of the pulmonary capillaries was created by means of partial pulmonary venous obstruction (left atrial balloon catheter) followed by rapid saline hemodilution. A predetermined difference between pulmonary capillary and plasma colloid osmotic pressures was maintained for periods of 1 to 2 hours. Left atrial (P(LA)) and plasma colloid osmotic pressures (pi(pl)) were measured directly. The water content of the lungs was measured serially by an indicator-dilution technique, and at autopsy by drying the lungs. The rate of accumulation of lung water was measured in four groups of animals: in three of the groups, the capillary hydrostatic and colloid osmotic pressures were varied; in the fourth group, the right lymphatic duct was obstructed in addition. The average rate of water accumulation in the lungs varied in a nonlinear way with the level of the capillary hydrostatic-plasma colloid osmotic pressure difference and was unaffected by the level of the capillary hydrostatic pressure. At low levels of P(LA) - pi(pl), water accumulated in the lung at an average rate of 0.09 g per g dry lung per hour per mm Hg pressure difference. At higher levels of P(LA) - pi(pl) the average rate of accumulation was 0.22 g per g per hour per mm Hg DeltaP; in most of the experiments in this group water accumulated in the lungs slowly during the first 30 minutes of the test period and more rapidly as the period was extended. Obstruction of right lymphatic duct outflow did not alter the rate of water accumulation. Based on the control data of the present experiments, the pericapillary pressure in normal lungs is estimated to be of the order of - 9 mm Hg in the normal dog lung. The filtration coefficient for the pulmonary capillaries is estimated to be of the order of one-tenth to one-twentieth of that for canine muscle capillaries. The data of the present study indicate that edema formation in lung tissue cannot be defined solely in terms of intravascular forces, but may be governed to a significant degree by changes in pericapillary forces in the pulmonary interstitium.
Abstract: The respiratory control system is treated as linear with a transmission delay between ventilation and sensing points (chemoreceptors). To the accepted variables involving body gas stores, ventilatory effects, transmission effects, and steady state pH, P(CO2), P(O2) chemoreceptor response, certain detailed analysis of the central receptors have been added. By construction of a model for medullary CO(2) receptor utilizing expected values of CNS (central nervous system) circulation, CO(2) production, and tissue-buffering effects, results of experimental observation of the effects of alteration of CSF were simulated. The inclusion of CSF effects also allowed simulation of the response to alteration in inspired CO(2), hyperventilation, and the periodic breathing with prolongation of circulation time.
Abstract: The electrophoretic patterns of the sera and urine of two cases of lipoid nephrosis have been obtained and have been compared with a typical pattern of normal serum. The patterns of the pathological sera deviated widely from the normal, indicating relatively low albumin and high globulin content. The comparison of the patterns of nephrotic sera cleared by centrifugation and by ether extraction shows that a large portion of the beta globulin consisted of a labile lipo-protein. The pattern of the nephrotic urine proteins resembled that of normal serum, with, however, significant differences.
