Insights in cullin 3/WNK4 and its relationship to blood pressure regulation and electrolyte homeostasis

One of the most important systems for protein degradation is the ubiquitin–proteasome system (UPS). The highly specific process called ubiquitination is provided by the E3 ubiquitin ligases, which mediates degradation via the proteasome system. The ubiquitin ligases based on cullins are the type of ubiquitin ligases known so far. The complex based on cullin 3 (Cul3) requires that its target protein has a bric-a-brac/tram-track/broad-complex (BTB) domain to recognize it. Cul3 has been widely associated with Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein 1 (Keap1) and the cytoprotective nuclear factor erythroid 2 related factor 2 (Nrf2) pathway and the proper control of cell cycle progression. Recently, Cul3 has been linked to the development of type II pseudohypoaldosteronism (PHAII or Gordon's syndrome) due to the fact that Cul3 has the ability to bind to Kelch-like 3 protein (KLHL3) and therefore mediating the degradation of some members of the WNK kinases. In this work we focused on highlighting how Cul3 system is involved in the regulation of electrolyte homeostasis and blood pressure.     

Atrial natriuretic peptide, B-type natriuretic peptide, and serum collagen markers after acute myocardial infarction.

Experimental data suggest that atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) act locally as antifibrotic factors in heart. We investigated the interrelationships of natriuretic peptides and collagen markers in 93 patients receiving thrombolytic treatment for their first acute myocardial infarction (AMI). Collagen formation following AMI, evaluated as serum levels of amino terminal propeptide of type III procollagen, correlated with NH(2)-terminal proANP (r = 0.45, P < 0.001), BNP (r = 0.55, P < 0.001) and NH(2)-terminal proBNP (r = 0.50, P < 0.01) on day 4 after thrombolysis. Levels of intact amino terminal propeptide of type I procollagen decreased by 34% (P < 0.001), and levels of carboxy terminal cross-linked telopeptide of type I collagen (ICTP) increased by 65% (P < 0.001). ICTP levels correlated with NH(2)-terminal proBNP (r = 0.25, P < 0.05) and BNP (r = 0.28, P < 0.05) on day 4. Our results suggest that ANP and BNP may act as regulators of collagen scar formation and left ventricular remodeling after AMI in humans. Furthermore, degradation of type I collagen is increased after AMI and may be regulated by BNP.     

A possible role of atrial natriuretic peptide in ethanol-induced acute diuresis.

The acute effects of ethanol on plasma atrial natriuretic peptide levels were investigated in 4 clinically healthy males, aged 24-26 years, consumed either 750 ml of water as a control study, or the same beverage with 1 ml/kg alcohol added, which increased the plasma alcohol concentration to 99.12 +/- 15.10 mg/dl at 60 min. Plasma atrial natriuretic peptide levels were significantly higher in the alcohol study compared to the control study at each time point (10, 20, 30, 60, 120 min after drinking onset), and with a peak at 10 min. Atrial natriuretic peptide levels showed a positive significant correlation with plasma antidiuretic hormone in the control group, while no relationship was found between the two peptides in the alcohol study. Moreover, a significant correlation exists between plasma atrial natriuretic peptide levels and systolic arterial blood pressure, and heart rate, and between the variations in atrial natriuretic peptide values and the variations in plasma sodium, serum ethanol, and plasma osmolality in the alcohol study. Acute ethanol intake causes an increase in urinary volume, and a decrease in urinary potassium excretion and urinary osmolality, and no change in urinary sodium excretion. These data suggest that acute ethanol administration causes a rapid increase in plasma levels of atrial natriuretic peptide, which could be an important factor of ethanol-induced diuresis. The main mechanisms for increased atrial natriuretic peptide release from atria after acute ethanol ingestion seem to be atrial stretch, due to the increase in arterial blood pressure, in heart rate, in sympathetic tone, and in plasma osmolality, and to a direct secretory effect by antidiuretic hormone.     

Atrial natriuretic factor-like peptide and its prohormone within single cell organisms.

The present investigation was designed to determine if the atrial natriuretic peptide hormonal system is present within single cell organisms. Paramecium multimicronucleatum were examined with 3 sensitive and specific radioimmunoassays which recognize the N-terminus [amino acids 1-98; proANF(1-98)], the midportion of the N-terminus [amino acids 31-67; proANF(31-67)] and C-terminus (amino acids 99-126; ANF) of the 126 amino acid atrial natriuretic factor (ANF) prohormone. ProANF(1-98), proANF(31-67), and ANF-like peptides were all present within these unicellular organisms at concentrations of 460 +/- 19 pg/ml, 420 +/- 15 pg/ml, and 14.5 +/- 2 pg/ml, respectively. These concentrations are similar to their respective concentrations in the plasma of the rat (Rattus norvegicus). These results suggest that even single cell organisms contain the atrial natriuretic peptide-like hormonal system.     

Atrial and brain natriuretic peptide in adrenal steroidogenesis.

We elucidated the role of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in human and bovine adrenocortical steroidogenesis. The urinary volume, sodium excretion and cyclic GMP (cGMP) excretion and plasma cGMP were markedly increased by the synthetic alpha-human ANP (alpha-hANP) infusion in healthy volunteers. Plasma arginine vasopressin (AVP) and aldosterone levels were significantly suppressed. Both ANP and BNP inhibited aldosterone, 19-OH-androstenedione, cortisol and DHEA secretion dose-dependently and increased the accumulation of intracellular cGMP in cultured human and bovine adrenal cells. alpha-hANP significantly suppressed P450scc-mRNA in cultured bovine adrenal cells stimulated by ACTH. Autoradiography and affinity labeling of [125I]hANP, and Scatchard plot demonstrated a specific ANP receptor in bovine and human adrenal glands. Purified ANP receptor from bovine adrenal glands identified two distinct types of ANP receptors, one is biologically active, the other is silent. A specific BNP receptor was also identified on the human and bovine adrenocortical cell membranes. The binding sites were displaced by unlabelled ANP as well as BNP. BNP showed an effect possibly via a receptor which may be shared with ANP. The mean basal plasma alpha-hANP level was 25 +/- 5 pg/ml in young men. We confirmed the presence of ANP and BNP in bovine and porcine adrenal medulla. Plasma or medullary ANP or BNP may directly modulate the adrenocortical steroidogenesis. We demonstrated that the lack of inhibitory effect of alpha-hANP on cultured aldosterone-producing adenoma (APA) cells was due to the decrease of ANP-specific receptor, which caused the loss of suppression of aldosterone and an increase in intracellular cGMP.     

Radioimmunoassay of atrial natriuretic peptide in human plasma: application to studies of volume and blood pressure homeostasis

Sensitive radioimmunoassay for determination of immunoreactive atrial natriuretic peptide (ANP) in human plasma was developed and employed for the study of plasma ANP concentrations in healthy controls under basal conditions (2.4 +/- 0.1 pmol/l) and during volume expansion by saline infusion (9.6 +/- 2.0 pmol/l and 14.2 +/- 1.8 pmol/l, respectively). Plasma renin activity and plasma aldosterone concentration exhibited opposite changes during saline infusion. In pathological states associated with extracellular fluid volume (ECFV) expansion, ANP concentration were significantly higher than in the controls (liver cirrhosis 8.6 +/- 0.9; congestive heart failure 33.1 +/- 4.8; chronic renal failure before haemodialysis 72.2 +/- 6.4 pmol/l). Further volume expansion in liver cirrhosis by saline infusion led to the further increase in ANP (13.3 +/- 1.3 and 16.1 +/- 1.5 pmol/l, respectively) and ECFV reduction by ultrafiltration during haemodialysis in chronic renal failure diminished but did not normalize plasma ANP (22.5 +/- 2.9 pmol/l). In patients with arterial hypertension the concentration of ANP exceeded the normal range by 62.5% and reached 8.0 +/- 0.5 pmol/l on the average. Our results support the suggestion that ANP is an important regulatory humoral mechanism participating in the regulation of sodium, volume and blood pressure homeostasis.     

Renal regulation of potassium homeostasis in calves in the first week of life including the role of atrial natriuretic peptide

The experiment was carried out on 10 clinically healthy Polish-Friesian var. Black-and-White cow calves, during the first seven days of postnatal life. The results indicate that renal removal of potassium depends primarily on the quantity reabsorbed in the tubules, whereas clearance of the electrolyte, due to stable levels in the blood plasma, depends on the amount excreted in the urine. With stable tubular reabsorption of potassium, a relatively unchanging amount of excreted potassium was observed in the urine. However, reduced tubular reabsorption caused a significant increase in excretion and clearance of the electrolyte. Changes in the amount of filtered potassium play a minor role in the regulation of excretion. Small changes in the blood plasma potassium concentration observed primarily resulted from changes in glomerular filtration rate and tubular reabsorption, since the concentration of electrolyte in the blood after birth remained within the physiological range. The results ofthis study suggest that neonate calf kidneys are sufficiently prepared to regulate kalemia. Atrial natriuretic peptide is not directly involved in the regulation of tubular reabsorption of potassium in calves in the first week of life, although it is highly likely that the peptide is involved in the excretion of potassium in the urine in calves during the first seven days of life.     

Integration of detailed modules in a core model of body fluid homeostasis and blood pressure regulation

This paper presents a contribution to the definition of the interfaces required to perform heterogeneous model integration in the context of integrative physiology. A formalization of the model integration problem is proposed and a coupling method is presented. The extension of the classic Guyton model, a multi-organ, integrated systems model of blood pressure regulation, is used as an example of the application of the proposed method. To this end, the Guyton model has been restructured, extensive sensitivity analyses have been performed, and appropriate transformations have been applied to replace a subset of its constituting modules by integrating a pulsatile heart and an updated representation of the renin-angiotensin system. Simulation results of the extended integrated model are presented and the impacts of their integration within the original model are evaluated.     

慢性动脉血压调节与原发性高血压病——Ⅰ.慢性动脉血压调节

机体在不同条件下维持动脉血压恒定的机理是不相同的。目前认为,长时程或慢性血压调节的关键器官是肾脏,这种调节与机体的水盐平衡有密切的关系。动脉血压的升高可以导致肾脏排尿量（或排钠量）的升高,即动脉血压与肾脏的排尿量（或排钠量）呈明显的正相关关系,称之为“压力-利尿作用”。当血容量升高时,通过肾脏的压力-利尿作用,可以排出过多的容量,维持动脉血压的恒定。只有在肾脏功能受到损伤的条件下,高血容量才可能引起高血压。     

Maintained serum sodium in male ultra-marathoners--the role of fluid intake, vasopressin, and aldosterone in fluid and electrolyte regulation

Exercise-associated hyponatremia (EAH) is a well know electrolyte disorder in endurance athletes. Although fluid overload is the most like etiology, recent studies, however, argued whether EAH is a disorder of vasopressin secretion. The aims of the present study were to investigate (i) the prevalence of EAH in male ultra-marathoners and (ii) whether fluid intake, aldosterone or vasopressin, as measured by copeptin, were associated with post-race serum sodium concentration ([Na+]). In 50 male ultra-marathoners in a 100?km ultra-marathon, serum [Na+], aldosterone, copeptin, serum and urine osmolality, and body mass were measured pre- and post-race. Fluid intake, renal function parameters and urine excretion were measured. No athlete developed EAH. Copeptin and aldosterone increased; a significant correlation was found between the change in copeptin and the change in serum [Na+], no correlation was found between aldosterone and serum [Na+]. Serum [Na+] increased by 1.6%; body mass decreased by 1.9?kg. The change in serum [Na+] and body mass correlated significantly and negatively. The fluid intake of ~?0.58?l/h was positively related to the change in body mass and negatively to both post-race serum [Na+] and the change in serum [Na+]. We conclude that serum [Na+] was maintained by both the mechanisms of fluid intake and the hormonal regulation of vasopressin.     

C-type natriuretic peptide in bovine chromaffin cells. The regulation of its biosynthesis and secretion.

We report here the regulation of the biosynthesis and the secretion of C-type natriuretic peptide (CNP) in cultured bovine chromaffin cells. The combined treatment with protein kinase A and -C activators induced a 6-fold increase of intracellular levels of CNP-(1-103). The biosynthesized CNP-(1-103) was co-released with its mature forms, typically CNP-(51-103), upon stimulation by nicotine or depolarizing agents. This confirms the neuropeptidic character of this third member of the natriuretic peptide family, which might act as a neuromodulator or neurotransmitter.     

Role of zinc in regulation of arterial blood pressure and in the etiopathogenesis of arterial hypertension

Increased gastrointestinal absorption and urinary excretion of zinc has been confirmed in experimental and clinical studies on primary arterial hypertension as a result from changes of intracellular and extracellular zinc content. In arterial hypertension, the levels of zinc in serum, lymphocyte, and bone decrease while increasing in heart, erythrocytes, kidney, liver, suprarenal glands and spleen. These changes result in the loss of zinc homeostasis that leads to various degrees of deficiency, not entirely compensated by nutritional factors or increased absorption in the gastrointestinal tract. Loss of zinc homeostasis can be both cause and effect of high blood pressure. In the present review, the role of zinc metabolism changes and its mechanisms in arterial hypertension are discussed.     

Locally different role of atrial natriuretic peptide (ANP) in the pericardial fluid

Pericardial fluid (PF) contains several vasoactive agents in higher concentrations than venous plasma (VP). However, with human atrial natriuretic peptide (ANP) controversial data have been reported in earlier studies performed on a limited number of patients (less than 20). The present study was designed to characterize the ANP levels in human PF and cardiac tissues, and to ascertain whether myocardial ischemic state is a major factor in determining ANP production of the human heart. In a total of 316 consecutive patients undergoing open heart surgery ANP levels in VP, PF, atrial and ventricular tissues were measured by radioimmunoassay and analyzed by high-performance liquid chromatography (HPLC). The data are presented as median and 25th-75th percentiles. Our results showed ANP concentration [ANP] of PF significantly exceeded that of VP and [ANP] in the atrial tissue was significantly higher than in the ventricular tissue (p < 0.001). In patients without myocardial ischemia (valvular heart disease) [ANP] in the PF was 258.3 (189.9-342.5) pg/ml, in the VP 28.4 (11.7-57.6) pg/ml and 151.7 (78.4-447.6) ng/mg in the atrial, 0.4 (0.2-1.6) ng/mg in the ventricular tissue. The corresponding values for patients with coronary artery disease were 208.1 (153.8-318.9) pg/ml in the PF, 19.8 (9.4-27.9) pg/ml in the VP, 129.6 (66.5-455.0) ng/mg in the atrial and 1.0 (0.1-1.8) ng/mg in the ventricular tissue. The ventricular tissue levels correlated to the atrial tissue levels (r = 0.317; p < 0.05). Great difference (p < 0.001) was found in the atrial tissue levels between females [414.6 (119.7-734.4) ng/mg] and males [105.4 (65.3-204.2) ng/mg]. In HPLC analysis the majority of the pericardial fluid and tissue ir-ANP coeluted with human ANP [99-126]. In conclusion, [ANP] in PF of cardiosurgical patients is higher by an order of magnitude than in VP. Intrapericardial ANP may reflect the peptide concentration in the myocardial interstitium and may represent a paracrine regulatory mechanism, which seems independent of ANP-induced putative antiischemic influences.     

Consistent changes in the circadian rhythms of blood pressure and atrial natriuretic peptide in congestive heart failure.

We demonstrated in previous works that the circadian rhythms of blood pressure (BP) and atrial natriuretic peptide (ANP) are antiphasic in normal subjects and in essential hypertension. The aim of the present study was to assess the circadian rhythms of BP and ANP in 20 patients with stable congestive heart failure (CHF), divided into two groups of 10 according to their New York Heart Association functional class. A matched control group of 10 normal volunteers was also studied. Noninvasive BP monitoring at 15-min intervals was performed for 24 h. Peripheral blood samples were also obtained at 4-h intervals starting from 08:00 h. The mean (+/- SEM) circadian mesors of ANP plasma levels were 13.4 +/- 1.7 pmol/L in the control group, 28.6 +/- 2.4 pmol/L in the group of 10 patients in class II, and 81.5 +/- 12 pmol/L in the group of 10 patients in class III-IV. In normal subjects, plasma ANP concentration was highest at 04:00 h (21.5 +/- 2.7 pmol/L) and lowest at 16:00 h (8.8 +/- 2.4 pmol/L; p less than 0.01). Both groups of patients with CHF showed no significant circadian change in the plasma levels of ANP and also a significantly blunted circadian rhythm of BP. Cosinor analysis confirmed the loss of the circadian rhythms of ANP and BP in CHF patients. Our findings support the existence of a causal relationship between the circadian rhythms of ANP and BP.     

Atrial natriuretic peptide in the granular cells of the snail heart

Cardiomyocytes of vertebrates combine contractile and endocrine functions. They synthesize and secrete atrial natriuretic peptide (ANP), which is localized in their specific granules. The presence of ANP has been shown in some tissues of invertebrates, including the heart of molluscs. We have studied localization of ANP in cells of the snail heart. METHOD: The atrial and ventricular tissues of the snail Helix pomatia were studied by electron microscope immunocytochemistry, using anti-ANP antibodies. ANP-immunoreactivity has been detected in granules of granular cells located on the luminal surface of the snail myocardium. These cells are abundant in the atrium being very rare in the ventricle. Granular cells at different stages of maturation were revealed. Immature granular cells have light granules of moderate size with homogeneous tight content, while mature granular cells are huge in size and all their granules are fused together. The material of these granules loosens up and almost completely fills up the cytoplasm. No ANP-immunoreactivity was observed in muscle cells or nerve fibers. A possible origin of granular cells from the cardiac endothelial cells is discussed. The molluscan heart, similar to that of vertebrates, is a bifunctional organ. However, contrary to the heart of vertebrates, in the molluscan heart contractile and endocrine functions are separated between different types of cells.