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Giraffes - the tallest extant animals on Earth - are renowned for their high central arterial blood pressure, which is necessary to secure brain perfusion. Arterial pressure may exceed 300 mmHg and has historically been attributed to an exceptionally large heart. Recently, this has been refuted by several studies demonstrating that the mass of giraffe heart is similar to that of other mammals when expressed relative to body mass. It thus remains unexplained how the normal-sized giraffe heart generates such massive arterial pressures. We hypothesized that giraffe hearts have a small intraventricular cavity and a relatively thick ventricular wall, allowing for generation of high arterial pressures at normal left ventricular wall tension. In nine anaesthetized giraffes (495±38 kg), we determined in vivo ventricular dimensions using echocardiography along with intraventricular and aortic pressures to calculate left ventricular wall stress. Cardiac output was also determined by inert gas rebreathing to provide an additional and independent estimate of stroke volume. Echocardiography and inert gas-rebreathing yielded similar cardiac outputs of 16.1±2.5 and 16.4±1.4 l min-1, respectively. End-diastolic and end-systolic volumes were 521±61 ml and 228±42 ml, respectively, yielding an ejection fraction of 56±4% and a stroke volume of 0.59 ml kg-1. Left ventricular circumferential wall stress was 7.83±1.76 kPa. We conclude that, relative to body mass, a small left ventricular cavity and a low stroke volume characterizes the giraffe heart. The adaptations result in typical mammalian left ventricular wall tensions, but produce a lowered cardiac output. [ABSTRACT FROM AUTHOR]

Abstract: This study describes the distribution of intravenously injected polyacrylic acid (PAA) coated γ-Fe2O3 NPs (10mgkg−1) at the organ, cellular and subcellular levels in healthy BALB/cJ mice and in parallel addresses the effects of NP injection on kidney function, blood pressure and vascular contractility. Magnetic resonance imaging (MRI) and transmission electron microscopy (TEM) showed accumulation of NPs in the liver within 1h after intravenous infusion, accommodated by intracellular uptake in endothelial and Kupffer cells with subsequent intracellular uptake in renal cells, particularly the cytoplasm of the proximal tubule, in podocytes and mesangial cells. The renofunctional effects of NPs were evaluated by arterial acid–base status and measurements of glomerular filtration rate (GFR) after instrumentation with chronically indwelling catheters. Arterial pH was 7.46±0.02 and 7.41±0.02 in mice 0.5h after injections of saline or NP, and did not change over the next 12h. In addition, the injections of NP did not affect arterial PCO2 or [HCO3 −] either. Twenty-four and 96h after NP injections, the GFR averaged 0.35±0.04 and 0.35±0.01mlmin−1 g−1, respectively, values which were statistically comparable with controls (0.29±0.02 and 0.33±0.1ml–1 min–1 25g–1). Mean arterial blood pressure (MAP) decreased 12–24h after NP injections (111.1±11.5 vs 123.0±6.1min−1) associated with a decreased contractility of small mesenteric arteries revealed by myography to characterize endothelial function. In conclusion, our study demonstrates that accumulation of superparamagnetic iron oxide nanoparticles does not affect kidney function in healthy mice but temporarily decreases blood pressure. [Copyright &y& Elsevier]

A major rate-limiting step in the renin-angiotensin-aldosterone system is the release of active renin from endocrine cells (juxtaglomerular (JG) cells) in the media layer of the afferent glomerular arterioles. The number and distribution of JG cells vary with age and the physiological level of stimulation; fetal life and chronic stimulation by extracellular volume contraction is associated with recruitment of renin-producing cells. Upon stimulation of renin release, labeled renin granules 'disappear;' the number of granules decrease; cell membrane surface area increases in single cells, and release is quantal. Together, this indicates exocytosis as the predominant mode of release. JG cells release few percent of total renin content by physiological stimulation, and recruitment of renin cells is preferred to recruitment of granules during prolonged stimulation. Several endocrine and paracrine agonists, neurotransmitters, and cell swelling converge on the stimulatory cyclic AMP (cAMP) pathway. Renin secretion is attenuated in mice deficient in beta-adrenoceptors, prostaglandin E-EP4 receptors, Gsα protein, and adenylyl cyclases 5 and 6. Phosphodiesterases (PDE) 3 and 4 degrade cAMP in JG cells, and PDE3 is inhibited by cyclic GMP (cGMP) and couples the cGMP pathway to the cAMP pathway. Cyclic AMP enhances K-current in JG cells and is permissive for secretion by stabilizing membrane potential far from threshold that activates L-type voltage-gated calcium channels. Intracellular calcium paradoxically inhibits renin secretion likely through attenuated formation and enhanced degradation of cAMP; by activation of chloride currents and interaction with calcineurin. Connexin 40 is necessary for localization of JG cells in the vascular wall and for pressure- and macula densa-dependent suppression of renin release. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system is essential for body fluid homeostasis and blood pressure regulation. This review focuses on the homeostatic regulation of the secretion of active renin in the kidney, primarily in humans. Under physiological conditions, renin secretion is determined mainly by sodium intake, but the specific pathways involved and the relations between them are not well defined. In animals, renin secretion is a log-linear function of sodium intake. Close associations exist between sodium intake, total body sodium, extracellular fluid volume, and blood volume. Plasma volume increases by about 1.5 mL/mmol increase in daily sodium intake. Several lines of evidence indicate that central blood volume may vary substantially without measurable changes in arterial blood pressure. At least five intertwining feedback loops of renin regulation are identifiable based on controlled variables (blood volume, arterial blood pressure), efferent pathways to the kidney (nervous, humoral), and pathways operating via the macula densa. Taken together, the available evidence favors the notion that under physiological conditions (1) volume-mediated regulation of renin secretion is the primary regulator, (2) macula densa mediated mechanisms play a substantial role as co-mediator although the controlled variables are not well defined so far, and (3) regulation via arterial blood pressure is the exception rather than the rule. Improved quantitative analyses based on in vivo and in silico models are warranted. [ABSTRACT FROM AUTHOR]

Pulmonary surfactant protein D (SP-D) is a host defence lectin of the innate immune system that enhances clearance of pathogens and modulates inflammatory responses. Recently it has been found that systemic SP-D is associated with metabolic disturbances and that SP-D deficient mice are mildly obese. However, the mechanism behind SP-D's role in energy metabolism is not known. Here we report that SP-D deficient mice had significantly higher ad libitum energy intake compared to wild-type mice and unchanged energy expenditure. This resulted in accumulation but also redistribution of fat tissue. Blood pressure was unchanged. The change in energy intake was unrelated to the basal levels of hypothalamic Proopiomelanocortin (POMC) and Agouti-related peptide (AgRP) gene expression. Neither short time systemic, nor intracereberoventricular SP-D treatment altered the hypothalamic signalling or body weight accumulation. In ad libitum fed animals, serum leptin, insulin, and glucose were significantly increased in mice deficient in SP-D, and indicative of insulin resistance. However, restricted diets eliminated all metabolic differences except the distribution of body fat. SP-D deficiency was further associated with elevated levels of systemic bacterial lipopolysaccharide. In conclusion, our findings suggest that lack of SP-D mediates modulation of food intake not directly involving hypothalamic regulatory pathways. The resulting accumulation of adipose tissue was associated with insulin resistance. The data suggest SP-D as a regulator of energy intake and body composition and an inhibitor of metabolic endotoxemia. SP-D may play a causal role at the crossroads of inflammation, obesity, and insulin resistance. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE In rodents, the endothelial KCa channels, KCa3.1 and KCa2.3, have been shown to play a crucial role in initiating endothelium-derived hyperpolarizing factor (EDHF) vasodilator responses. However, it is not known to what extent these channels are involved in blood pressure regulation in large mammals, which would also allow us to address safety issues. We therefore characterized canine endothelial KCa3.1 and KCa2.3 functions and evaluated the effect of the KCa3.1/KCa2.3 activator SKA-31 on blood pressure and heart rate in dogs. EXPERIMENTAL APPROACH Canine endothelial KCa3.1/KCa2.3 functions were studied by patch-clamp electrophysiology and wire myography in mesenteric arteries. Systemic cardiovascular actions of acute SKA-31 administration were monitored in conscious, unstressed beagle dogs. KEY RESULTS Mesenteric endothelial cells expressed functional KCa3.1 and KCa2.3 channels that were strongly activated by SKA-31. SKA-31 hyperpolarized the endothelial membrane and doubled endothelial hyperpolarization-dependent vasodilator responses in mesenteric arteries. SKA-31 (2 mg·kg−1, i.v.) rapidly decreased the MAP by 28 ± 6 mmHg; this response was transient (8 ± 1 s), and the initial drop was followed by a fast and pronounced increase in HR (+109 ± 7 beats min−1) reflecting baroreceptor activation. SKA-31 significantly augmented similar transient depressor responses elicited by ACh (20 ng·kg−1) and doubled the magnitude of the response over time. CONCLUSIONS AND IMPLICATIONS Activation of endothelial KCa3.1 and KCa2.3 lowers arterial blood pressure in dogs by an immediate electrical vasodilator mechanism. The results support the concept that pharmacological activation of these channels may represent a potential unique endothelium-specific antihypertensive therapy. [ABSTRACT FROM AUTHOR]

Patients with cirrhosis exhibit impaired regulation of the arterial blood pressure, reduced baroreflex sensitivity (BRS), and prolonged QT interval. In addition, a considerable number of patients have a pulmonary dysfunction with hypoxemia, impaired lung diffusing capacity (DLCO), and presence of hepatopulmonary syndrome (HPS). BRS is reduced at exposure to chronic hypoxia such as during sojourn in high altitudes. In this study, we assessed the relation of BRS to pulmonary dysfunction and cardiovascular characteristics and the effects of hyperoxia. Forty-three patients with cirrhosis and 12 healthy matched controls underwent hemodynamic and pulmonary investigations. BRS was assessed by cross-spectral analysis of variabilities between blood pressure and heart rate time series. A 100% oxygen test was performed with the assessment of arterial oxygen tensions (Pao2) and alveolar-arterial oxygen gradient. Baseline BRS was significantly reduced in the cirrhotic patients compared with the controls (4.7 ± 0.8 vs. 10.3 ± 2.0 ms/mmHg; P < 0.001). The frequency-corrected QT interval was significantly prolonged in the cirrhotic patients (P < 0.05). There was no significant difference in BRS according to presence of HPS, Pao2, DLco, or Child-Turcotte score, but BRS correlated with metabolic and hemodynamic characteristics. After 100% oxygen inhalation, BRS and the QT interval remained unchanged in the cirrhotic patients. In conclusion, BRS is significantly reduced in patients with cirrhosis compared with controls, but it is unrelated to the degree of pulmonary dysfunction and portal hypertension. Acute hyperoxia does not significantly revert the low BRS or the prolonged QT interval in cirrhosis. [ABSTRACT FROM AUTHOR]

It was hypothesized that renal sympathetic nerve activity (RSNA) and neuronal nitric oxide synthase (nNOS) are involved in the acute inhibition of renin secretion and the natriuresis following slow NaCI loading (NaLoad) and that RSNA participates in the regulation of arterial blood pressure (MABP). This was tested by NaLoad after chronic renal denervation with and without inhibition of nNOS by S-methyl-thiocitrulline (SMTC). In addition, the acute effects of renal denervation on MABP and sodium balance were assessed. Rats were investigated in the conscious, catheterized state, in metabolic cages, and acutely during anesthesia. NaLoad was performed over 2 h by intravenous infusion of hypertonic solution (50 µmol·min-1 kg body mass-1) at constant body volume conditions. SMTC was coinfused in amounts (20 µg·min-1µkg-1) reported to selectively inhibit nNOS. Directly measured MABPs of acutely and chronically denervated rats were less than control (15% and 9%, respectively, P < 0.005). Plasma renin concentration (PRC) was reduced by renal denervation (14.5 ± 0.2 vs. 19.3 ± 1.3 mlU/l, P < 0.005) and by nNOS inhibition (12.4 ± 2.3 vs. 19.6 ± 1.6 mlU/l, P < 0.005). NaLoad reduced PRC (P < 0.05) and elevated MABP modestly (P < 0.05) and increased sodium excretion six-fold, irrespective of renal denervation and SMTC. The metabolic data demonstrated that renal denervation lowered sodium balance during the first days after denervation (P < 0.001). These data show that renal denervation decreases MABP and renin secretion. However, neither renal denervation nor nNOS inhibition affects either the renin down-regulation or the natriuretic response to acute sodium loading. Acute sodium-driven renin regulation seems independent of RSNA and nNOS under the present conditions. [ABSTRACT FROM AUTHOR]

The article presents a medical study that focuses on the hemodynamic and neuroendocrine responses to changes in sodium intake in compensated heart failure. Results of the showed a similar renal, hemodynamic and neuroendocrine responses to modifications in sodium intake in individuals with treated compensated heart failure and in healthy individuals.

Hormones are specific molecules measured in biological fluids by elaborate analytical systems requiring meticulous attention. Variation between laboratories can be expected. However, recently published measurements of AVP, OXT, and BNP in human plasma under basal/control conditions include numbers which, between publications, vary by 100-10 000-fold. Generally, the methods descriptions are scant, at best, and provide no information about quality control measures. Clearly, two results describing the same basal hormone concentration by numbers three orders of magnitude apart are incongruent providing reason for concern. Basal concentrations of bioactive AVP, OXT, and BNP in human plasma are in the order of 1-10 pmol/L. Therefore, assay systems applied to plasma must be able to measure concentrations of less than 1 pmol/L with appropriate specificity and accuracy. Basal concentrations of AVP, OXT, and BNP above 100 pmol/L should be reconsidered, as such results do not reflect bioactive hormone levels in humans, rats, or mice. Any concentration above 1000 pmol/L is of concern because such levels of bioactive hormone may be seen only under extreme conditions, if at all., (© 2024 The Author(s). Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

Replicability of experimental results and optimal use of experimental animals are everybody's concern. Current efforts towards increased replicability include guidelines and checklists as tools for experimenters, referees, editors and publishers. Guidelines are also provided for appropriate use of animals. To ensure the quality of experimental results, the number of animals must be adequate, that is, sufficiently large, for the purpose of the given experiment. To comply with current ethical recommendations, the use of animals should be reduced as much as possible. Therefore, determination of the number of animals for a given scientific objective includes contrasting considerations. Current guidelines for animal experimentation, notably from the National Institute of Health, mandate (with very few exceptions) inclusion of animals of both sexes in experimental designs statistically powered to address the difference between the two groups. Notably, absence of evidence for sex differences between the organ or system functions under study does not qualify as an exception. Mandatory, equal representation of both sexes raises several questions including ethical ones. Other guidelines, by public regulators and major publishers, do not seem to have a similar selective focus on sex differences. In summary, current concerns about replicability of scientific results are justified. Concomitantly, the knowledge of sex differences also between non-reproductive, non-endocrine organ functions is increasing. In principle, sex matters in any experimental context. However, an indiscriminate demand for inclusion of both sexes in all experimental protocols seems a waste of animals, money and time, violating traditional principles of animal experimentation, particularly that of reduction., (© 2020 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

The classical concepts of human sodium balance include 1) a total pool of Na + of ≈4,200 mmol (total body sodium, TBS) distributed primarily in the extracellular fluid (ECV) and bone, 2) intake variations of 0.03 to ≈6 mmol·kg body mass -1 ·day -1 , 3) asymptotic transitions between steady states with a halftime (T½) of 21 h, 4) changes in TBS driven by sodium intake measuring ≈1.3 day [ΔTBS/Δ(Na + intake/day)], 5) adjustment of Na + excretion to match any diet thus providing metabolic steady state, and 6) regulation of TBS via controlled excretion (90-95% renal) mediated by surrogate variables. The present focus areas include 1) uneven, nonosmotic distribution of increments in TBS primarily in "skin," 2) long-term instability of TBS during constant Na + intake, and 3) physiological regulation of renal Na + excretion primarily by neurohumoral mechanisms dependent on ECV rather than arterial pressure. Under physiological conditions 1) the nonosmotic distribution of Na + seems conceptually important, but quantitatively ill defined; 2) long-term variations in TBS represent significant deviations from steady state, but the importance is undetermined; and 3) the neurohumoral mechanisms of sodium homeostasis competing with pressure natriuresis are essential for systematic analysis of short-term and long-term regulation of TBS. Sodium homeostasis and blood pressure regulation are intimately related. Real progress is slow and will accelerate only through recognition of the present level of ignorance. Nonosmotic distribution of sodium, pressure natriuresis, and volume-mediated regulation of renal sodium excretion are essential intertwined concepts in need of clear definitions, conscious models, and future attention.

Natriuretic peptides are structurally related, functionally diverse hormones. Circulating atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are delivered predominantly by the heart. Two C-type natriuretic peptides (CNPs) are paracrine messengers, notably in bone, brain, and vessels. Natriuretic peptides act by binding to the extracellular domains of three receptors, NPR-A, NPR-B, and NPR-C of which the first two are guanylate cyclases. NPR-C is coupled to inhibitory proteins. Atrial wall stress is the major regulator of ANP secretion; however, atrial pressure changes plasma ANP only modestly and transiently, and the relation between plasma ANP and atrial wall tension (or extracellular volume or sodium intake) is weak. Absence and overexpression of ANP-related genes are associated with modest blood pressure changes. ANP augments vascular permeability and reduces vascular contractility, renin and aldosterone secretion, sympathetic nerve activity, and renal tubular sodium transport. Within the physiological range of plasma ANP, the responses to step-up changes are unimpressive; in man, the systemic physiological effects include diminution of renin secretion, aldosterone secretion, and cardiac preload. For BNP, the available evidence does not show that cardiac release to the blood is related to sodium homeostasis or body fluid control. CNPs are not circulating hormones, but primarily paracrine messengers important to ossification, nervous system development, and endothelial function. Normally, natriuretic peptides are not powerful natriuretic/diuretic hormones; common conclusions are not consistently supported by hard data. ANP may provide fine-tuning of reno-cardiovascular relationships, but seems, together with BNP, primarily involved in the regulation of cardiac performance and remodeling. © 2017 American Physiological Society. Compr Physiol 8:1211-1249, 2018., (Copyright © 2018 American Physiological Society. All rights reserved.)

Background: Variation in the carboxylesterase 1 gene (CES1) may contribute to the efficacy of ACEIs. Accordingly, we examined the impact of CES1 variants on plasma angiotensin II (ATII)/angiotensin I (ATI) ratio in patients with congestive heart failure (CHF) that underwent ACEI dose titrations. Five of these variants have previously been associated with drug response or increased CES1 expression, i.e., CES1 copy number variation, the variant of the duplicated CES1 gene with high transcriptional activity, rs71647871, rs2244613, and rs3815583. Additionally, nine variants, representatives of CES1Var, and three other CES1 variants were examined., Methods: Patients with CHF, and clinical indication for ACEIs were categorized according to their CES1 genotype. Differences in mean plasma ATII/ATI ratios between genotype groups after ACEI dose titration, expressed as the least square mean (LSM) with 95% confidence intervals (CIs), were assessed by analysis of variance., Results: A total of 200 patients were recruited and 127 patients (63.5%) completed the study. The mean duration of the CHF drug dose titration was 6.2 (SD 3.6) months. After ACEI dose titration, there was no difference in mean plasma ATII/ATI ratios between subjects with the investigated CES1 variants, and only one previously unexplored variation (rs2302722) qualified for further assessment. In the fully adjusted analysis of effects of rs2302722 on plasma ATII/ATI ratios, the difference in mean ATII/ATI ratio between the GG genotype and the minor allele carriers (GT and TT) was not significant, with a relative difference in LSMs of 0.67 (95% CI 0.43-1.07; P = 0.10). Results of analyses that only included enalapril-treated patients remained non-significant after Bonferroni correction for multiple parallel comparisons (difference in LSM 0.60 [95% CI 0.37-0.98], P = 0.045)., Conclusion: These findings indicate that the included single variants of CES1 do not significantly influence plasma ATII/ATI ratios in CHF patients treated with ACEIs and are unlikely to be primary determinants of ACEI efficacy., Competing Interests: The authors have declared that no competing interests exist.

The "Guytonian paradigm" places the direct effect of arterial pressure, on renal excretion of salt and water, at the center of long-term control of blood pressure, and thus the pathogenesis of hypertension. It originated in the sixties and remains influential within the field of hypertension research. However, the concept of one central long-term feedback loop, through which arterial pressure is maintained by its influence on renal function, has been questioned. Furthermore, some concepts in the paradigm are undermined by experimental observations. For example, volume retention and increased cardiac output induced by high salt intake do not necessarily lead to increased arterial pressure. Indeed, in multiple models of salt-sensitive hypertension the major abnormality appears to be failure of the vasodilator response to increased cardiac output, seen in salt-resistant animals, rather than an increase in cardiac output itself. There is also evidence that renal control of extracellular fluid volume is driven chiefly by volume-dependent neurohumoral control mechanisms rather than through direct or indirect effects of changes in arterial pressure, compatible with the concept that renal sodium excretion is controlled by parallel actions of different feedback systems, including hormones, reflexes, and renal arterial pressure. Moreover, we still do not fully understand the sequence of events underlying the phenomenon of "whole body autoregulation." Thus the events by which volume retention may develop to hypertension characterized by increased peripheral resistance remain enigmatic. Finally, by definition, animal models of hypertension are not "essential hypertension;" progress in our understanding of essential hypertension depends on new results on system functions in patients., (Copyright © 2016 the American Physiological Society.)

1. Herein, we review mechanisms of sodium balance operating at constant mean arterial blood pressure (MABP); that is, under conditions where MABP does not provide the primary signal to the kidney. 2. Relative constancy of body fluids requires accurate regulation of total body sodium (TBS). Normally, plenty of sodium is ingested and balance is achieved by control of renal excretion driven by multiple central nervous, cardiovascular, endocrine and renal tubular mechanisms. Subtle changes in sodium balance are associated with parallel changes in extracellular volume (due to fast and precise osmoregulation), but not necessarily in MABP. Therefore, signals other than MABP seem to be the primary link between TBS and kidney function. 3. Renal functions involved in sodium homeostasis include: (i) the rate of glomerular filtration (GFR) determined by renal haemodynamics, including tubuloglomerular feedback (TGF); (ii) proximal tubular reabsorption involving glomerulotubular balance (GTB) and neurohumoral control; (iii) macula densa mechanisms influencing TGF and renin secretion; and (iv) distal tubular reabsorption dominated by the renin-angiotensin-aldosterone system (RAAS). 4. The present review focuses on the interactive, homeostatic operation of TBS, MABP, GTB, TGF and the RAAS. Regulation of sodium balance involves neurohumoral control of tubular sodium reabsorption, including proximal reabsorption. Central nervous system-mediated regulation of the latter modulates renin secretion. Homeostatically, the RAAS-TGF interaction seems analogous to a spring-shock absorber set-up: non-adaptive RAAS functions determine the new steady state position, whereas TGF controls the rate of change. Recruitment of renin-secreting cells during sustained stimulation may be essential for chronic adaptation, although details of this afferent arteriolar cell plasticity are unclear at present.

Background: Hyponatremia is a frequent condition in elderly patients. In diagnostic workup, a 24-hour urine sample is used to measure urinary osmolality and urinary sodium concentration necessary to confirm the diagnosis of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). This study was undertaken to test the hypothesis that a spot urine sample would be sufficient for urinalysis., Methods: In nine patients with SIADH, morning spot and 24-hour urine samples were examined for osmolality and sodium concentration. Levels of arginine vasopressin, atrial natriuretic and brain natriuretic peptides, renin, and aldosterone were measured in the supine and upright positions of patients and compared with nine healthy age-matched control patients., Results: The patients had low plasma osmolality (median 266 mOsm/kg) and measurable levels of arginine vasopressin (median 1.8 pg/mL). Values of osmolality in the spot urine (median 298 mOsm/kg) and in the 24-hour urine (median 215 mOsm/kg) did not differ significantly; neither did sodium concentration (medians 80 mmol/L in the spot urine versus 45 mmol/L in the 24-hour urine). Patients had significantly elevated plasma levels of brain natriuretic peptide (P = 0.007), elevated mean arterial blood pressure (P = 0.03), and lower plasma levels of creatinine (P = 0.002) compared to the controls., Conclusion: A spot urine sample seems to be sufficient to confirm the diagnosis of SIADH.

Renin secretion is regulated in part by renal nerves operating through beta1-receptors of the renal juxtaglomerular cells. Slow sodium loading may decrease plasma renin concentration (PRC) and cause natriuresis at constant mean arterial blood pressure (MAP) and glomerular filtration rate (GFR). We hypothesized that in this setting, renin secretion and renin-dependent sodium excretion are controlled by via the renal nerves and therefore are eliminated or reduced by blocking the action of norepinephrine on the juxtaglomerular cells with the beta1-receptor antagonist metoprolol. This was tested in conscious dogs by infusion of NaCl (20 micromol.kg(-1).min(-1) for 180 min, NaLoad) during regular or low-sodium diet (0.03 mmol.kg(-1).day(-1), LowNa) with and without metoprolol (2 mg/kg plus 0.9 mg.kg(-1).h(-1)). Vasopressin V2 receptors were blocked by Otsuka compound OPC31260 to facilitate clearance measurements. Body fluid volume was maintained by servocontrolled fluid infusion. Metoprolol per se did not affect MAP, heart rate, or sodium excretion significantly, but reduced PRC and ANG II by 30-40%, increased plasma atrial natriuretic peptide (ANP), and tripled potassium excretion. LowNa per se increased PRC (+53%), ANG II (+93%), and aldosterone (+660%), and shifted the vasopressin function curve to the left. NaLoad elevated plasma [Na+] by 4.5% and vasopressin by threefold, but MAP and plasma ANP remained unchanged. NaLoad decreased PRC by approximately 30%, ANG II by approximately 40%, and aldosterone by approximately 60%, regardless of diet and metoprolol. The natriuretic response to NaLoad was augmented during metoprolol regardless of diet. In conclusion, PRC depended on dietary sodium and beta1-adrenergic control as expected; however, the acute sodium-driven decrease in PRC at constant MAP and GFR was unaffected by beta1-receptor blockade demonstrating that renin may be regulated without changes in MAP, GFR, or beta1-mediated effects of norepinephrine. Low-sodium diet augments vasopressin secretion, whereas ANP secretion is reduced.

Background: Recent data indicate that aldosterone aggravates cyclosporin A (CsA)-induced nephrotoxicity. We examined whether the mineralocorticoid receptor (MR) blocker eplerenone (EPL) antagonized early deterioration of renal function and blood pressure (BP) increase in CsA-treated rats., Methods: Male Sprague-Dawley rats received CsA (15 mg/kg/day i.p.) and/or EPL (100 mg/kg/day p.o.) for 21 days. After 2 weeks, arterial, venous and urinary bladder catheters were implanted and the rats were trained to accept a restraining device allowing arterial blood sampling and direct measurement of BP and renal function. BP was measured on-line in conscious rats., Results: CsA significantly increased systolic BP: 139 +/- 4 versus 134 +/- 2 mmHg, reduced body weight gain: -5 +/- 6 versus 36 +/- 7 g, glomerular filtration rate (GFR): 1.02 +/- 0.16 versus 2.64 +/- 0.27 ml/min, renal blood flow (RBF): 5.3 +/- 2.4 versus 13.5 +/- 2.1 ml/min and lithium clearance (C(Li+)): 0.16 +/- 0.04 versus 0.26 +/- 0.07 ml/min compared to controls. These changes were prevented by simultaneous EPL treatment: systolic BP, 130 +/- 4 mmHg; weight gain, 53 +/- 7 g; GFR, 1.67 +/- 0.26 ml/min; RBF, 12.3 +/- 2.1 ml/min and C(Li+), 0.27 +/- 0.03 ml/min. Analysis of kidney morphology after the CsA treatment showed hyaline vacuolization in tubules and vascular depositions in arterioles; these changes were less pronounced after combination therapy. No significant changes were seen regarding haemoglobin, haematocrit, plasma renin and vasopressin, plasma and urinary sodium, potassium, or osmolality., Conclusions: MR blockade by EPL prevented short-term alterations in GFR, RBF and hypertension associated with CsA nephrotoxicity. We conclude that the aldosterone-MR pathway contributes markedly to the renal toxicity induced by this calcineurin inhibitor.

Responses to acute sodium loading depend on the load and on the level of chronic sodium intake. To test the hypothesis that an acute step increase in total body sodium (TBS) elicits a natriuretic response, which is dependent on the chronic level of TBS, we measured the effects of a bolus of NaCl during different low-sodium diets spanning a 25-fold change in sodium intake on elements of the renin-angiotensin-aldosterone system (RAAS) and on natriuresis. To custom-made, low-sodium chow (0.003%), NaCl was added to provide four levels of intake, 0.03-0.75 mmol.kg(-1).day(-1) for 7 days. Acute NaCl administration increased PV (+6.3-8.9%) and plasma sodium concentration (~2%) and decreased plasma protein concentration (-6.4-8.1%). Plasma ANG II and aldosterone concentrations decreased transiently. Potassium excretion increased substantially. Sodium excretion, arterial blood pressure, glomerular filtration rate, urine flow, plasma potassium, and plasma renin activity did not change. The results indicate that sodium excretion is controlled by neurohumoral mechanisms that are quite resistant to acute changes in plasma volume and colloid osmotic pressure and are not down-regulated within 2 h. With previous data, we demonstrate that RAAS variables are log-linearly related to sodium intake over a >250-fold range in sodium intake, defining dietary sodium function lines that are simple measures of the sodium sensitivity of the RAAS. The dietary function line for plasma ANG II concentration increases from theoretical zero at a daily sodium intake of 17 mmol Na/kg (intercept) with a slope of 16 pM increase per decade of decrease in dietary sodium intake.

Background: Data describing activation of brain natriuretic peptide (BNP) system relative to the renin-angiotensin-aldosterone system (RAAS) are sparse in the early phase of heart failure (HF)., Aims: To compare activation of BNP system relative to RAAS hyperactivity and to assess diagnostic accuracy of cardiac peptides to detect any left ventricular dysfunction (LVD) in patients referred from primary care with suspected HF before institution of medical therapy., Methods: Of 166 referred patients 150 were consecutively included (14 were excluded and two refused consent). Echocardiography and measurements of neurohormonal activity were performed. Systolic dysfunction (LVSD) was defined as an ejection fraction