Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atrial stretch causes the release of atriopeptin (AP, ANF) from preformed vesicular storage sites. The circulating hormone acts on unique receptor sites (containing guanylate cyclase) to release guanosine 3',5'-cyclic monophosphate (cGMP) that mediates the natriuresis and vasodilation and probably the suppression of renin, aldosterone, and vasopressin. The biological effects of atriopeptin are transient because of the rapid inactivation of the circulating hormone (by neutral endopeptidase or clearance receptors) or the second messenger (by cGMP-phosphodiesterase). Heart failure due to chronic cardiac volume overload [aortovenocaval (A-V) fistula] exhibits markedly elevated circulating AP blood levels and urinary cGMP levels, accompanied by induction of ventricular AP gene and protein expression and release. Pharmacological manipulation of endogenous AP, either by inhibiting cGMP phosphodiesterase (i.e., mediator prolongation) or neutral endopeptidase (i.e., prolongation of hormone half-life) in A-V fistula animals results in profound natriuresis and diuresis without hypotension. These pharmacological maneuvers bypass the suppressed renal response to exogenous AP seen in heart failure and provide a rational therapeutic strategy based on our understanding of the underlying physiological and pathological mechanisms.
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PMID:Effect of pharmacological manipulation of endogenous atriopeptin activity on renal function. 131 20

The original observation by de Bold et al. (1981) of a rapid, massive, and short-lasting diuretic and natriuretic effect following injection of rat atrial extracts into intact rats, led to the identification, isolation and purification of the atrial natriuretic factor (ANF). ANF is stored in atrial myocytes and released into the blood stream by atrial distension. Available data suggest that the mechanism of ANF-induced natriuresis involves either renal hemodynamic effects, such as the increase in glomerular filtration rate and reduction of medullary tonicity, or direct effect on sodium transport in the medullary collecting ducts. ANF induces relaxation of vascular smooth muscle, decreases blood pressure and cardiac output. All these effects displayed by ANF are associated to the an inhibition of aldosterone, renin and vasopressin release. Most of these actions are mediated by specific high affinity receptors, which are coupled to a particulate guanylate cyclase. Although ANF levels are increased in some disorders, such as severe heart failure, hypertension, chronic renal failure, the role of the peptide is uncertain. To better define the potential physiopathological role and the possible therapeutic implications of this new hormonal system in conditions of disturbed body fluid and sodium homeostasis, further experimental and clinical data must be awaited.
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PMID:[The physiopathological aspects of the atrial natriuretic factor]. 131 27

The vascular endothelium plays an essential role in regulating the contractility of the adjacent smooth muscle cell through its secretory and metabolic properties. One of these well known properties is the conversion of angiotensin I into angiotensin II. But the endothelium also secretes at least three compounds able to diffuse to the smooth muscle cell and exerting a paracrine action: these are the prostacyclin (PGI2), the endothelium derived relaxing factor (EDRF) and the endothelin 1. The secretion of these different vasoactive compounds by endothelial cells is triggered by mechanical events, such as the shear stress, or by the effect of several humoral factors locally released, for example from platelets. The compound NO (nitric oxide) is produced by the endothelial enzyme NO synthase from its precursor L-arginine, and is responsible for the vasodilatory and antiplatelets properties of EDRF. NO, by activating the soluble guanylate cyclase in the smooth muscle cell, is responsible for the endothelium dependent vasodilatation. We observed in an isolated perfused rat kidney that the compound L-NAME (NG-monomethyl-L-arginine methyl ester), a competitive inhibitor of NO synthase blocking the production of NO, induces renal vasoconstriction and inhibits renin release. This suggests that not only the renal vasoconstriction but also the renal vasodilatation are active processes, permanently regulated by vasoactive compounds such as EDRF. It seems also that EDRF plays an important role in maintaining the secretion of renin. It can be hypothetized that an abnormality in the release or fate of EDRF might perhaps contribute to high blood pressure, by both a direct effect on the vascular tone and an indirect effect on the release of renin, which in turn regulates also the renal and systemic hemodynamics.
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PMID:[Control of vascular tone by the endothelium: the coupling active vasodilation in the kidney to renin secretion]. 163 4

Five weeks of high (8%) sodium intake, resulting in a decline of plasma atrial natriuretic factor (ANF) in normotensive Wistar-Kyoto (WKY) and Wistar rats, did not affect plasma ANF in spontaneously hypertensive rats (SHR) which became severely hypertensive. Regardless of salt consumption, SHR presented more pronounced glomerular particulate guanylate cyclase activation after large ANF doses in vitro than normotensive rats. In response to salt loading, plasma renin activity (PRA) and plasma aldosterone unexpectedly increased in SHR, in contrast to their decrease in the normotensive strains. Thus, SHR fail to react to prolonged high-salt intake as do normotensive rats, i.e. by a fall in plasma ANF, PRA and plasma aldosterone, and have higher stimulated glomerular particulate guanylate cyclase activity. Thus, ANF and its target response in SHR, as well as the PRA-plasma aldosterone reaction to prolonged salt loading, are distinct from those in normotensive strains. Since the relatively increased ANF and its target action in SHR appear to be a reactive antihypertensive defense rather than a primary event, systems other than ANF probably play an important role in the high salt-induced accelerated hypertension of SHR.
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PMID:Distinct plasma atrial natriuretic factor, renin and aldosterone responses to prolonged high-salt intake in hypertensive and normotensive rats. 167 17

Atrial natriuretic factor (ANF) cleaved between Cys105 and Phe106 is the primary metabolite of ANF and circulates in human plasma. Because the role of this metabolite in vivo and its possible interaction with intact ANF are unclear, we studied the biologic effects of a 2-h infusion of rat cleaved ANF101-105/106-126 (15 pmol/kg/min) or vehicle alone in six normal sheep. Infusions of cleaved ANF increased venous plasma levels of cleaved ANF from less than 5 to 260 pmol/L and induced a progressive and significant increase in plasma cyclic GMP (p = 0.025) without significantly affecting plasma ANF levels. These changes were associated with a small (nonsignificant) decrease in arterial pressure and a significant increase in heart rate (HR) and sympathetic nervous activity and were followed by activation of the renin-angiotensin-aldosterone (RAA) axis after infusions were terminated. Unlike ANF itself, cleaved ANF was not natriuretic and did not reduce plasma volume or right atrial pressure. Calculated metabolic clearance rate (MCR) (1.47 +/- 0.4 L/min) and disappearance rate of cleaved ANF from plasma (4.8 +/- 0.37 min) were similar to values reported previously for intact ANF in sheep. These studies show that cleaved ANF stimulates guanylate cyclase and alters hemodynamics and the RAA system in vivo.
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PMID:Biological actions of cleaved atrial natriuretic factor (ANF101-105/106-126) in conscious sheep. 171 1

The proatriopeptins consisting of 126 amino acids is formed and stored by the myocytes of the atria. In its disintegration among others develops the alpha-atriopeptins consisting of 28 amino acids, which in normal blood pressure and blood volume, respectively, is secreted only in small quantities. The content of alpha-atriopeptins in the plasma varies approximately between 4 and 12 pmol/l in the course of 24 hours, the half-life period amounts to 1 to 2 min. In an increase of the blood pressure in the atria and in tachycardia the output of alpha-atriopeptins increases. It is bound to receptors of the cells of the glomerular zone, the vessels, the hypothalamus and the kidneys and activates a guanylate cyclase. The main effects of the alpha-atriopeptins are an inhibition of the secretion of aldosterone, vasopressin and renin, a dilation of the arteries, an increase of the glomerular filtration as well as an increase of the sodium and water excretion. In certain diseases of the kidneys and the heart the content of alpha-atriopeptins in the plasma increases.
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PMID:[Various recent findings concerning the formation, mechanism of action and significance of atrial natriuretic peptides (atriopeptins)]. 214 19

We have reported that a second rat atrial natriuretic peptide, iso-rANP (1-45), as well as the putative ANP homologue, iso-rANP (17-45), elicited circulatory and renal responses in the rat similar to those found after administration of ANP. Iso-rANP also interacted with ANP to potentiate the observed biological activity in the rat. In the present studies in awake dogs, intravenous infusion of low doses (6.3-50 pmol.kg-1.min-1) of iso-rANP(1-45) and iso-rANP(17-45) increased plasma immunoreactive ANP and suppressed plasma renin activity (PRA) and aldosterone. Iso-rANP, like ring-deleted analogues of ANP, may have displaced ANP from ANP clearance receptors to increase plasma ANP concentration, since factors influencing myocardial ANP release were not changed. The effect of iso-rANP (1-45) and (17-45) in lowering PRA and plasma aldosterone may therefore have been indirect, via ANP stimulation of active guanylate cyclase-linked ANP receptors. However, an additional direct effect of iso-rANP on an active receptor cannot be excluded.
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PMID:Infusion of iso-rANP(1-45) or (17-45) increases plasma immunoreactive ANP and lowers plasma renin activity and aldosterone. 214 6

The renal and vascular responses to atrial natriuretic factor (ANF) and glomerular and vascular ANF receptors were studied in adrenalectomized (ADR) rats with or without deoxycorticosterone (DOC) or dexamethasone (Dexa) replacement therapy. As expected, adrenalectomy elicited hypotension, hemoconcentration, and increased plasma renin activity, but no changes in plasma levels of either ANF-(1-98) or ANF-(99-126) were detected. Dexa treatment decreased both ANF-(1-98) and ANF-(99-126), whereas DOC treatment increased only ANF-(1-98). The acute renal response to ANF and furosemide was reduced in ADR rats and partially restored either by steroid replacement or by raising blood pressure. The blunted natriuretic response to ANF in ADR rats was associated with an increased density of glomerular receptors. Norepinephrine-precontracted vascular strips from ADR rats were more sensitive to ANF (ED50: 1.7 x 10(-8) M) than those from sham-operated animals (ED50: 1.5 x 10(-7) M). However, vascular ANF receptor density in mesenteric vessels from ADR animals was decreased. Dexa treatment restored vascular response to that observed in sham-operated animals without a concomitant change in vascular receptor density. Because the presence of guanylate cyclase-coupled and noncoupled ANF receptor subtypes have been described in different tissues, we conclude that the apparent lack of correlation between the biological response to ANF and total binding of ANF to glomeruli or mesenteric artery membranes in ADR rats may be in part caused by a differential regulation of both receptor subtype populations.
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PMID:Glomerular and vascular atrial natriuretic factor receptors in adrenalectomized rats. 254 13

We have synthesized an S-nitrosylated derivative of captopril, S-nitrosocaptopril, that manifests nitrosovasodilatory activity, inhibits angiotensin converting enzyme activity and inhibits platelet aggregation. The direct vasodilatory effects of S-nitrosocaptopril reflect the effects of the thionitrite bond, the presence of which does not in any way influence S-nitrosocaptopril's ability to inhibit angiotensin converting enzyme. Thionitrite stimulation of both vascular and platelet soluble guanylate cyclase activity leads to increases in intracellular cyclic GMP that are accompanied by vasodilatation and platelet inhibition, respectively. S-nitrosocaptopril is a novel hybrid molecule that has potential use in the treatment of hypertension regardless of renin status, angina pectoris and congestive heart failure.
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PMID:S-nitrosocaptopril. I. Molecular characterization and effects on the vasculature and on platelets. 265 76

The response of isolated blood vessels to a variety of vasoactive agonists is modulated by the presence of endothelial cells. Indeed, these cells can release both dilator and constrictor substances. The major endothelium-derived relaxing factor may be nitric oxide, which activates soluble guanylate cyclase in the smooth muscle, although the endothelial cells also secrete an unidentified hyperpolarizing factor. Among the natural stimuli for the release of endothelium-derived relaxing factors are circulating hormones, platelet products, thrombin, shear stress, and certain autacoids. Endothelium-derived relaxing factors may contribute to the regulation of the release of atrial natriuretic factor and renin. The endothelial cells can also release constricting factors; among the likely candidates are superoxide anions or the peptide endothelin. In hypertensive blood vessels, the ability to release endothelium-derived relaxing factors but not endothelium-derived contracting factors is blunted.
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PMID:Endothelium and control of vascular function. State of the Art lecture. 266 25


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