Natriuretic Hormone Research Articles

Biology of natriuretic peptides and their receptors

Increasing evidence suggests that natriuretic peptides (NPs) play diverse roles in mammals, including renal hemodynamics, neuroendocrine, and cardiovascular functions. Collectively, NPs are classified as hypotensive hormones; the main actions of NPs are implicated in eliciting natriuretic, diuretic, steroidogenic, antiproliferative, and vasorelaxant effects, important factors in the control of body fluid volume and blood pressure homeostasis. One of the principal loci involved in the regulatory actions of NPs is their cognate plasma membrane receptor molecules, which are activated by binding with specific NPs. Interaction of NPs with their receptors plays a central role in physiology and pathophysiology of hypertension and cardiovascular disorders. Gaining insight into the intricacies of NPs-specific receptor signaling pathways is of pivotal importance for understanding both hormone-receptor biology and the disease states arising from abnormal hormone receptor interplay. During the last decade there has been a surge in interest in NP receptors; consequently, a wealth of information has emerged concerning molecular structure and function, signaling mechanisms, and use of transgenics and gene-targeted mouse models. The objective of this present review is to summarize and document the previous findings and recent discoveries in the field of the natriuretic peptide hormone family and receptor systems with emphasis on the structure–function relationship, signaling mechanisms, and the physiological and pathophysiological significance in health and disease.

Right heart overload contributes to cardiac natriuretic hormone elevation in patients with heart failure

Background Atrial and brain natriuretic peptides (ANP and BNP) plasma concentration increases and holds a prognostic significance in patients with left ventricular dysfunction. We assessed the hypothesis that right ventricular (RV) overload might significantly contribute to plasma elevation of cardiac natriuretic hormones in patients with heart failure. Methods Forty-one patients with cardiomyopathy and depressed left ventricular (LV) function (ejection fraction, EF, <40%), underwent cardiac magnetic resonance imaging (MRI) and resting plasma determination of ANP and BNP. Nineteen healthy subjects were also studied as control group. Ventricular volumes and function were assessed by MRI. Results In the group of patients, LVEF was 22.6±1.2% (controls: 61.2±1.3%, P<0.001, mean±S.E.M.), while RVEF was 48.2±2.5% (controls: 66.7±1.6%, P<0.001); LV and RV end diastolic/systolic volumes, corrected by body surface area, were 143±7/114±7 ml/m 2 (controls 70±3/27±2 ml/m 2, both P<0.001) and 66±3/37±4 ml/m 2 (controls: 63±4/21±2 ml/m 2, P<0.01 only for end-systolic volume). BNP plasma value was on average 324±39 pg/ml (range: 23–1280, controls 10±2 pg/ml), ANP value was 144±17 pg/ml (range: 26–534, controls 15±1 pg/ml). BNP positively correlated with either end-diastolic or end-systolic RV volume in patients, less with LV systolic, and not with LV diastolic volume. Moreover, a significant negative correlation was observed between BNP and either LVEF or RVEF. Conversely, ANP showed a significant correlation only with end-systolic RV volume and with both RVEF and LVEF. When multivariate stepwise linear regression analysis was applied LVEF resulted the only independent predictor for ANP plasma values ( R=0.591, P<0.001), while LVEF and RV end-diastolic volume for BNP ( R=0.881, P<0.001, and R=0.881, P=0.035, respectively). Conclusions Right heart overload contributes independently to plasma elevation of natriuretic peptides. RV involvement, which is known to independently worsen prognosis in patients with cardiomyopathy, might contribute to their established prognostic power, inducing compensatory secretion of plasma cardiac natriuretic hormones.

Cardenolide and bufadienolide ligands of the sodium pump. how they work together in NaCl sensitive hypertension

For the past 50 years biomedical scientists have been in quest of an unidentified factor (hormone) that elevates blood pressure and regulates renal sodium transport, i.e., natriuretic hormone. Recent discoveries have led to the identification of such factors which are present in humans, rodents and amphibians, and which, in a complex manner, interact with each other and with the other regulatory systems. In experimental NaCl sensitive hypertension brain endogenous ouabain, via activation of renin-angiotensin system and of sympathetic nervous system, stimulates adrenocortical production of marinobufagenin, a natriuretic and a vasoconstrictor. The combined effects of these endogenous factors may account for the classical properties attributed by Dahl, deWardener and others to the hypothetical "natriuretic hormone".

Endogenous digitalis-like factors. an historical overview

The sodium pump is a ubiquitous cell surface enzyme, a Na/K-ATPase, that maintains ion gradients between cells and the extracellular fluid. The extracellular domain of this enzyme contains a highly conserved receptor for a plant-derived family of compounds, the digitalis glycosides, used in the treatment of congestive heart failure, and certain cardiac arrhythmias. The concept that an endogenous modulator of this enzyme, analogous to the cardiac glycosides, emerged from work on two separate areas: the regulation of extracellular fluid (ECF) volume by a natriuretic hormone (NH), and the regulation of peripheral vascular resistance by a circulating inhibitor of vascular Na/K-ATPase. These two areas merged with the hypothesis that natriuretic hormone and the vascular Na/K-ATPase inhibitor were the same factor, and furthermore, that this factor played a causative role in the pathophysiology of certain types of hypertension. In this communication, the development of this field from its beginnings is traced; evidence for the existence of and efforts to identify the structure of this factor are briefly reviewed, and suggestions for future development of the field are put forward.

Cross talk between the intrarenal dopaminergic and cyclooxygenase-2 systems

In mammalian kidney, dopamine produced in the proximal tubule (PT) acts as an autocrine/paracrine natriuretic hormone that inhibits salt and fluid reabsorption in the PT. In high-salt-treated animals, PT dopamine activity increases and inhibits reabsorption, leading to increased salt and fluid delivery to the macula densa (MD) and subsequent natriuresis and diuresis. Regulated cyclooxygenase-2 (COX-2) in the MD represents another intrinsic system mediating renal salt and water homeostasis. Renal cortical COX-2 is inversely related to salt intake, and decreased extracellular NaCl stimulates COX-2 expression in cultured MD/cortical thick ascending limb cells. The current study investigated interactions between renal dopamine and cortical COX-2 systems. In rats fed a control diet, the dopamine precursor l-dihydroxyphenylalanine (l-DOPA) or the DA1 receptor agonist SKF-81297 suppressed cortical COX-2 expression. High salt suppressed cortical COX-2 expression, which was attenuated by inhibition of dopamine production with benserazide or the DA1 receptor antagonist, SCH-23390. In contrast, l-DOPA or the dopamine-metabolizing enzyme inhibitor entacapone suppressed low-salt-induced cortical COX-2 expression. Inhibition of PT reabsorption with the carbonic anhydrase inhibitor acetazolamide suppressed cortical COX-2 expression. In contrast, treatment with distally acting diuretics led to elevation of cortical COX-2. These results indicate that dopamine modulates renal cortical COX-2 expression by modifying PT reabsorption.

Endocrine Paradox in Heart Failure: Resistance to Biological Effects of Cardiac Natriuretic Hormones

We read the interesting minireview by Goetze (1) concerning the biochemistry of pro-B-type natriuretic peptide (proBNP)-derived peptides: the main message is the potential clinical relevance of the proBNP-derived peptides, which should be considered for current clinical interpretation of plasma BNP concentrations and be the focus of ongoing research. Accordingly, the lack of accurate studies on in vivo production/secretion mechanisms and metabolism of BNP- and proBNP-related peptides explains the incomplete knowledge of the pathophysiologic significance of this hormone system. Thus, we agree with Goetze that deeper insight into the biochemistry of these peptides could pave the way for more sensitive and disease-specific assays in the clinical setting. We have some observations concerning the presence of an “endocrine paradox in heart failure” (1). The lack of encoding and processing of the precursor peptides to the mature hormones, atrial natriuretic peptide (ANP) and BNP, which have a potent diuretic and natriuretic effect, could explain the disturbed electrolyte and fluid homeostasis occurring in chronic heart failure (2)(3). However, the hypothesis of heart failure as a syndrome of cardiac natriuretic hormone (CNH) deficiency was challenged when this system was investigated in experimental animals and in humans. In fact, patients with congestive heart failure [New York Heart Association (NYHA) classes III–IV] have greatly increased plasma concentrations of CNHs compared with healthy individuals (up to 500-fold or more for plasma BNP concentration) (1)(2)(3). Goetze (1) tries to explain this paradox of heart failure (i.e., highly increased CNH concentrations in patients with sodium retention) by suggesting that a part of circulating CNH-related peptides (especially proBNP-related peptides) is not biologically active. We agree that increased concentrations of immunoreactive, but biologically inactive, proBNP-related peptides (as well as proANP-related peptides) are present in patients with heart failure. As also correctly pointed out in the … [↵][1]aAddress correspondence to this author at: Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark. Fax 45-35454640; e-mail jpg{at}dadlnet.dk. [1]: #xref-corresp-2-1

BNP—Considering a Heartfelt Message

The natriuretic hormones have been discovered as mediators of the cardiac response to volume overload and mechanical dysfunction. Although there are some physiological differences between atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), it is BNP that has been found to be most useful as a clinical test. BNP is secreted along with an N terminal proBNP cleavage product (NT-proBNP). The similarities between these two tests are far greater than the differences. They are both probably useful in the diagnosis of high-risk patients (e.g. dyspnoeic) and may be useful in monitoring cardiac failure treatment. Although BNP levels in the normal range predict the risk of cardiac events and mortality, there is little evidence to promote their use as a screening test. In such an important condition as cardiac failure we should consider any messages that are likely to be of value, particularly those that are heartfelt.

Right ventricular overload and cardiovascular neuroendocrine derangement in systemic sclerosis

Systemic sclerosis (SSc) may be associated with right ventricular overload, secondary to pulmonary hypertension. In heart failure patients, neuroendocrine derangements can influence clinical evolution and prognosis. The aim of this study was to investigate neurohormonal control affected in SSc patients with and without right ventricular impairment. A prospective series of 28 patients with SSc was studied. In addition to conventional evaluations, extensive neuroendocrine studies were done, including assays of both the vasoconstrictor system (plasma renin activity [PRA], aldosterone and catecholamines) and vasodilatory molecules (brain natriuretic peptide [BNP] and atrial natriuretic peptide [ANP]). A significant relation was observed between echo-Doppler estimated pulmonary systolic pressure (PAP) and neurohormonal activation, in particular between PAP and BNP (R=0.58, p=0.004), ANP (R=0.65, p<0.001) and PRA (R=0.45, p=0.032). Patients with right ventricular overload (i.e., PAP>40 mmHg confirmed at cardiac catheterization) had higher levels of ANP and BNP (147±26 vs 34±6 pg/mL and 344±86 vs 30±7 pg/mL, respectively, p<0.001), PRA (6.4±1.9 vs 1.8±0.4 ng/mL/h, p<0.001) and aldosterone (257±86 vs 114±22 pg/mL, p=0.02). These patients had increased plasma noradrenaline, but not adrenaline (701±87 vs 452±66 pg/mL, p<0.001). SSc patients with right heart failure have a neurohormonal derangement, showing overactivity of the vasoconstrictive system, counteracted by oversecretion of cardiac natriuretic hormones.

Participation of G proteins in natriuretic peptide hormone secretion from heart atria.

The involvement of G proteins in the mechanism underlying the increased atrial natriuretic factor (ANF) secretion observed after atrial muscle stretch (stretch-secretion coupling) was assessed using a combined pharmacological, immunocytochemical, and tissue fractionation approach. It was found that G(i/o) inhibition by pertussis toxin (PTX) abolished stretch-secretion coupling without affecting baseline secretion through a mechanism that is independent of G(q) signaling agonists. Mastoparan-7, a G(i/o) agonist, significantly increased ANF secretion even in the absence of muscle stretch through a PTX-sensitive mechanism. By confocal and electron immunocytochemistry, ANF and G(o) partially colocalized, whereas ultracentrifugation analysis suggested the presence of two populations of granules, one of which was partially associated with G(o), as demonstrated by Western blotting. PTX did not affect basal or endothelin-1-stimulated ANF secretion, in line with the view that endothelin-1 signals mainly through G(q). It is concluded there are at least two types of regulated secretory processes in atrial cardiocytes: one is acutely responsive to muscle stretch and is PTX sensitive, and the other is G(q)mediated and PTX insensitive and may be responsible for changes in secretion after chronic changes in the neuroendocrine environment.

Intravenous administration of 2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxy chroman (gamma-CEHC) to rats and determination of its plasma concentration and urinary sodium excretion.

A natriuretic hormone, 2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxy chroman (gamma-CEHC) was administered intravenously to male Sprague-Dawley rats and the plasma concentration of gamma-CEHC along with urinary sodium (Na+) excretion was investigated. The plasma gamma-CEHC concentrations were fluorimetrically determined by a column-switching HPLC method consisting of both phenyl and octadecyl silica columns, following a pre-column fluorescence derivatization with a fluorescence reagent, 4-N,N-dimethylaminosulfonyl-7-piperazino-2,1,3-benzoxadiazole (DBD-PZ). In rats fed with a high-NaCl (8.0%) diet, plasma gamma-CEHC concentrations rapidly decreased by 20% in 15-45 min after the administration of gamma-CEHC, while Na+ excretion gradually increased with time. Considering these results, the Na+ excretion effect appeared not to be associated with plasma gamma-CEHC concentration. In addition, attempts were made to examine a main urinary metabolite of gamma-CEHC, a large amount of 6-O-sulfated gamma-CEHC found to be present in the urine using an HPLC-tandem mass spectrometry. Thus, it is plausible that gamma-CEHC was easily metabolized to 6-O-sulfated metabolite and excreted into urine in rats.

Essential biochemistry and physiology of (NT-pro)BNP.

Brain natriuretic peptide (BNP) is a 32 amino acid cardiac natriuretic peptide hormone originally isolated from porcine brain tissue. The human BNP gene is located on chromosome 1 and encodes the prohormone proBNP. The biologically active BNP and the remaining part of the prohormone, NT-proBNP (76 amino acids) can be measured by immunoassay in human blood. Cardiac myocytes constitute the major source of BNP related peptides. The main stimulus for peptide synthesis and secretion is myocyte stretch. Recently, cardiac fibroblasts have also been shown to produce BNP. Other neurohormones may stimulate cardiac BNP production in different cardiac cell types. In contrast to atrial natriuretic peptides (ANP/NT-proANP), which originate mainly from atrial tissue, BNP related peptides are produced mainly from ventricular myocytes. Ventricular (NT-pro)BNP production is strongly upregulated in cardiac failure and locally in the area surrounding a myocardial infarction. In peripheral organs BNP binds to the natriuretic peptide receptor type A causing increased intracellular cGMP production. The biological effects include diuresis, vasodilatation, inhibition of renin and aldosterone production and of cardiac and vascular myocyte growth. In mice BNP gene knockout leads to cardiac fibrosis, gene over-expression to hypotension and bone malformations. BNP is cleared from plasma through binding to the natriuretic peptide clearance receptor type C, but it seems relatively resistant to proteolysis by neutral endopeptidase NEP 24.11. Clearance mechanisms for NT-proBNP await further study. While the plasma concentration of NT-proBNP and BNP is approximately equal in normal controls, NT-proBNP plasma concentration is 2-10 times higher than BNP in patients with heart failure. This relative change in peptide levels may be explained by shifts in cardiac secretion and/or clearance mechanisms.

Hormones of the Cardiovascular System

For the past few decades, several hormones secreted by myocardium and blood vessel walls and regulate various physiological functions have been identified. They include natriuretic hormones, endothelins, proteins related to the parathyroid hormone, adrenomedullin and others. Therefore, the heart and blood vessels, apart from their main function, blood circulation, also perform important endocrine function, i.e., they are an organ controlling various physiological processes including hemodynamics, skeletal growth, reproductive function, immunity, etc.

Chitosan nanoparticle-mediated de novo synthesis of a novel natriuretic hormone peptide reverses established asthma in mice

Rationale A family of natriuretic hormone peptides (NHP) with broad physiologic effects on the lung and cardiovascular system has been described. A novel peptide of pro-atrial natriuretic factor, NHP 73-102, causes long-lasting bronchoprotective effect in a prophylactic model of asthma and shows anti-inflammatory activity (Kumar et al, JACI, 2002; Hellerman et al, JACI, 2003). The potential of this peptide in ameliorating established asthma and its immunomodulatory effects was examined in this study using a murine model of allergen [ovalbumin (Ova)]-respiratory syncytial virus (RSV) infection-induced asthma. Methods Mice were sensitized and challenged with Ova and then infected with RSV prior to their intranasal treatment with chitosan nanoparticles either expressing the plasmid encoded peptide (CHIpP) or incorporating NHP 73-102 (CHIP). Lung inflammation was examined by analyses of bronchoalveolar lavage and lung histology. Airway hyperreactivity (enhanced pause, Penh) was measured by whole body plethysmography. Cytokines were measured by intracellular cytokine staining (ICS). Results Therapy with CHIpP reversed Ova-induced airway reactivity (% Penh, P<0.01), pulmonary infiltration as evidenced by a decrease in the % of eosinophils (P<0.05), neutrophils and lymphocytes in the BAL of CHIpP-treated mice compared to controls, and pulmonary pathology as revealed by lung histology. ICS analysis of anti-CD3-stimulated splenocytes of these mice showed a significant decrease in the production of both IFN-g and IL-4 (P<0.01) by CD4+T cells. In contrast, CD4+ Tcells producing IL-10 significantly increased (P<0.05) in treated mice. Conclusions Thus, de novo expression of NHP 73-102 reverses established asthma suggesting that this peptide may be useful as a novel therapy for asthma.

Mechanism of bronchoprotective effects of a novel natriuretic horomone peptide

Rationale The natriuretic hormone peptide, NHP 99–126, a C-terminal peptide of pro-atrial natriuretic factor (proANF), induces bronchodilatory effects in asthmatics. Another plasmid-encoded pro-ANF peptide, pHP 73–102, induces a long-lasting bronchoprotective effect in a mouse model of allergic asthma (Kumar et al, JACI, 2002). Because lung epithelial cells are major targets of pNHP 73–102, the mechanism underlying the effect of NHP 73–102 was examined using human epithelial cells. Methods Human type II alveolar epithelial cells (A549) and normal human bronchial epithelial (NHBE) cells were transfected with pNHP 73–102 to test the effect of this peptide on activation of these cells. Following transfection, cells were analyzed for changes in Ca ++ and nitric oxide (NO) levels. Also, activation of NFκB and ERK 1/2 signaling pathways were examined by luciferase reporter assay and phosphorylation studies respectively Results Analysis of intracellular Ca ++ levels in pNHP 73–102-transfected A549 or NHBE cells showed that the peptide increases Ca ++ release. This Ca ++ release was accompanied by an increase in the production of nitric oxide. Also, expression of pNHP 73–102, but not pVAX control, in phorbol myristate acetate-activated A549 cells, resulted in a significant decrease in expression of a cotransfected NFκB-luciferase reporter. Similarly, transfection of NHBE cells with pNHP 73–102 decreased TNF-α-induced NFκB activation. Furthermore, NHP 73–102, but not ANP, decreased phosphorylation of Erk-1/2 in A549 cells. Conclusions Expression of pNHP 73–102 in epithelial cells causes increased production of NO and a concomitant decrease in activation of NFkB and ERK-1/2. This may account for the bronchodilatory and anti-inflammatory activities of this peptide.

.GAMMA.-Tocopherol Enhances Sodium Excretion as a Natriuretic Hormone Precursor

Endogenous natriuretic factors are believed to be responsible for extracellular fluid homeostasis in mammals. A new endogenous natriuretic factor, Loma Linda University-alpha (LLU-alpha) has recently been proven to be a 2,7,8-trimethyl-2-(2'-carboxyethyl)-6-hydroxychroman (gamma-CEHC), which is a metabolite of gamma-tocopherol (gamma-Toc). The purpose of this study was to investigate whether gamma-Toc could accelerate sodium excretion into rat urine as a natriuretic hormone precursor. Male SD strain rats were divided into two groups; one was a control diet group, while the other was a high NaCl group (50 g/kg diet). Next, the two groups were each subdivided into two groups consisting of a placebo group and a gamma-Toc group. After the oral administration of one experimental dose of 20 mg gamma-Toc or placebo, rat urine was collected at 6 h intervals for 24 h, and then the urine volume, sodium and potassium and gamma-CEHC content were determined. gamma-Toc increased in the urine volume of the high-NaCl intake group. The sodium excretion in the high-NaCl group given gamma-Toc was 8.29+/-2.20 g, while in the control group given gamma-Toc it was 6.24+/-1.49 g from 12-18 h. In contrast, the potassium excretion in the rat urine did not change in any of the groups. Our findings suggested that gamma-Toc accelerates the degree of sodium excretion in rats with a high sodium intake.

Diagnostic accuracy and prognostic relevance of the measurement of cardiac natriuretic peptides: a review.

The pathophysiologic and clinical relevance of cardiac natriuretic hormone (CNH) assays has been investigated in numerous experimental and clinical studies. Authors have sought to evaluate the diagnostic accuracy and prognostic relevance of the measurement of CNHs according to evidence-based laboratory medicine principles. In June 2003, we ran a computerized literature search on National Library of Medicine using keywords "ANP" and "BNP" and found more than 12 300 and 1200 articles, respectively. A more refined search with keywords "ANP or BNP assay" extracted approximately 7000 and 800 articles, respectively. Only studies specifically designed to evaluate the diagnostic accuracy and prognostic relevance of CNH measurements were selected from this huge mass of articles to be discussed in this review. Several studies suggested that CNH assays may be clinically useful for the screening and classification of patients with heart failure, as a prognostic marker in cardiovascular disease, in the follow-up of patients with heart failure, and because they may reduce the need for further cardiac investigation. However, it is difficult to compare even the best-designed studies because not only did the authors evaluate different populations, they also used different gold standards. CNH assays and conventional diagnostic work-ups provide complementary information for evaluation of the presence and severity of cardiac dysfunction and clinical disease. Several aspects of CNH assays are still to be elucidated, and further work is needed to carefully assess their diagnostic accuracy and prognostic value in cardiac disease.

Mechanism of bronchoprotective effects of a novel natriuretic hormone peptide

Background The natriuretic hormone peptide (NHP) 99-126, a C-terminal peptide of pro-atrial natriuretic factor (proANF), induces bronchodilatory effects in people with asthma. Recently, another plasmid-encoded C-terminal peptide, pNHP 73-102, was shown to induce a long-lasting bronchoprotective effect in a mouse model of allergic asthma. Objective This study was carried out to determine the role of lung epithelial cells in the bronchoprotective and anti-inflammatory activity of these peptides. Methods Human type II alveolar epithelial cells (A549) and normal human bronchial epithelial (NHBE) cells were transfected with pNHP 73-102 to test the effect of this peptide on activation of these cells. After transfection, cells were analyzed for changes in Ca ++ and nitric oxide (NO) levels. Also, activation of NFκB and the extracellularly regulated kinase (ERK) 1, 2 signaling pathway was examined by luciferase reporter assay and phosphorylation studies respectively. Results Analysis of intracellular Ca ++ levels in pNHP 73-102 –transfected A549 or NHBE showed that the peptide increases release. This Ca ++ release was accompanied by an increase in the production of NO. Also, overexpression of pNHP 73-102, but not pVAX control, in phorbol myristate acetate–activated A549 cells resulted in a significant decrease in expression of a cotransfected nuclear factorκB (NFκB)–luciferase reporter. Similarly, pNHP 73-102 decreased TNF-α–induced NFκB activation in NHBE cells. Furthermore, NHP 73-102 but not atrial natriuretic peptide decreased phosphorylation of Erk-1, 2 in A549 cells. Conclusions Overexpression of pNHP 73-102 in epithelial cells causes increased production of intracellular Ca ++ and NO, with a concomitant decrease in activation of NFκB and ERK1, 2. These results suggest a bronchodilatory and anti-inflammatory activity of this peptide.

Dopamine acutely decreases apical membrane Na/H exchanger NHE3 protein in mouse renal proximal tubule

Dopamine is a principal natriuretic hormone in mammalian Na+ homeostasis. Dopamine acutely alters glomerular filtration rate (GFR) and decreases Na+ absorption in both the proximal and distal nephron. Proximal tubule natriuresis is effected through inhibition of the apical membrane Na/H exchanger NHE3. We examined whether dopamine directly and acutely decreases apical membrane NHE3 protein using renal tissue in two in vitro systems: renal cortical slices and in vitro perfused single tubules. After incubation with dopamine, NHE3 activity was measured by 22Na flux and NHE3 antigen was measured by immunoblot in apical membrane and total cellular membranes. Direct application of dopamine to either cortical slices or microperfused tubules acutely decreases NHE3 activity and antigen at the apical membrane of the proximal tubule. No change in total cellular NHE3 was detected. One mechanism by which dopamine causes natriuresis is via direct and acute reduction of NHE3 protein at the apical membrane via changes in NHE3 protein trafficking.

Changes in plasma concentrations of immunoreactive ouabain in the tilapia in response to changing salinity: is ouabain a hormone in fish?

Ouabain, a cardiac glycoside and inhibitor of Na +, K +-ATPase, is now believed to be a steroid hormone in mammals, involved in blood pressure and volume regulation and possibly acting as a natriuretic hormone. We have identified ouabain-like immunoreactivity in the plasma and tissues of a euryhaline teleost, the tilapia ( Oreochromis mossambicus), by means of solid-phase extraction followed by a specific radioimmunoassay. Plasma concentrations of immunoreactive ouabain were 5–20 pg/ml. Ouabain immunoreactivity was detected in all the tissues examined, with highest concentrations in the head kidney followed by intestine and body kidney. When the fish in fresh water were transferred to seawater, plasma osmolality increased significantly after 2, 4, 8, and 24 h. Significant increases were observed in plasma ouabain immunoreactivity after 4 and 24 h, and a significant correlation was seen between ouabain immunoreactivity and plasma osmolality. There was also a significant correlation between the plasma osmolality and cortisol concentrations. Upon transfer from seawater to fresh water, significant increases were seen in plasma cortisol after 4 and 8 h and in immunoreactive ouabain after 4 h. When the correlation was analyzed using all the data obtained during the two transfer experiments, plasma ouabain immunoreactivity and cortisol were significantly correlated with plasma osmolality, whereas there was a significant negative correlation between plasma prolactin and osmolality. A significant positive correlation was also seen between plasma cortisol and ouabain immunoreactivity. These results suggest that immunoreactive ouabain may be involved, together with cortisol, in the maintenance of hydromineral balance in the tilapia.

The clinical diagnosis of heart failure is predicted by neurohormonal and immune derangement

To characterize the complex picture of neurohormonal abnormalities in heart failure (HF), a comprehensive characterization was prospectively performed in 105 patients with cardiomyopathy at different clinical stages and compared to 47 sex/age-matched control healthy subjects. To assess the relationship between the diagnosis of HF and clinical and neurohumoral variables, multiple logistic regression with forward stepwise selection (Wald) was used. The diseased condition was predicted by creatinine level, gamma-glutamyl transpeptidase (GGT) activity, TNF-alpha, and plasma levels of several neurohormonal indices: (a) plasma renin activity; angiotensin II; aldosterone; (b) cortisol as a stress marker; (c) norepinephrine levels; (d) triiodothyronine; (e) ANP and BNP. Thus, renal and hepatic dysfunction, overexpression of cardiac natriuretic hormones, of adrenergic and renin–angiotensin–aldosterone system significantly augment the probability of HF, which was decreased by increasing values of thyroid hormone. In conclusion, a complex neurohormonal derangement associated with an overall predominance of vasoconstrictor systems is characteristic of HF syndrome.