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)

The identification of natriuretic peptides as key regulators of natriuresis and vasodilatation, and the appreciation that their secretion is under the control of cardiac hemodynamic and neurohumoral factors, has caused wide interest. The natriuretic peptides are structurally similar, but genetically distinct peptides that have diverse actions on cardiovascular, renal, and endocrine homeostasis. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are of myocardial cell origin, while cardiac natriuretic peptide (CNP) is of endothelial origin. ANP and BNP bind to the natriuretic peptide receptor (NPR-A) which, via 3' 5'-cyclic guanosine monophosphate (cGMP), mediates natriuresis, vasodialation, renin inhibition, and antimitogenic properties. CNP lacks natriuretic action but possesses vasodilating and growth inhibiting effects via the guanyl cyclase linked natriuretic peptide-B (NPR-B) receptor. All three peptides are cleared by natriuretic peptide-C receptor (NPR-C) and degraded by neutral endopeptidase, both of which are widely expressed in kidney, lung, and vascular wall. Recently, a fourth member of the natriuretic peptide, dendroaspsis natriuretic peptide (DNP) has been reported to be present in human plasma and atrial myocardium.
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PMID:Brain natriuretic peptide: role in cardiovascular and volume homeostasis. 1222 50

Mice with a genetic deletion of the atrial natriuretic peptide (ANP) receptor, guanylyl cyclase A (GC-A -/-), have chronic arterial hypertension and cardiac hypertrophy from the first day of life. To characterize the role of the angiotensin II and endothelin systems in the development of this cardiovascular phenotype, the effects of chronic treatment with either the angiotensin type I (AT1) receptor antagonist losartan or the endothelin A receptor antagonist BSF208075 were tested. Losartan almost completely reversed systemic arterial hypertension and left ventricular hypertrophy of GC-A -/- mice. This was accompanied by a marked regression of the left ventricular mRNA expression of cardiac hypertrophy markers such as ANP and brain natriuretic peptide and a significant reduction of left ventricular and pulmonary interstitial collagen accumulation. BSF208075 had no effect on any of these cardiovascular parameters. Intriguingly, GC-A -/- mice also showed a very marked right ventricular hypertrophy, which was not reversed by losartan or BSF208075 treatment. Analyses of components of the renin-angiotensin system (RAS) revealed an inhibition of renal and systemic RAS contrasting with increased local left ventricular angiotensin II levels in GC-A -/- mice. Collectively, the results suggest that RAS plays a more important role than the endothelin system in the pathogenesis of arterial hypertension as well as left ventricular hypertrophy and fibrosis in GC-A gene-disrupted mice.
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PMID:Left but not right cardiac hypertrophy in atrial natriuretic peptide receptor-deficient mice is prevented by angiotensin type 1 receptor antagonist losartan. 1240 81

We have previously shown that flutamide (specific antagonist of the androgen receptor) has antihypertensive effects. In the present study we examined the mechanisms of flutamide action in the vasculature. The vascular effects of flutamide were assayed in aortae isolated from male or female Sprague-Dawley rats and from rats or mice lacking a functional androgen receptor ( tfm, testicular feminization mutation). The effect of flutamide on coronary flow was tested in isolated hearts. In addition, male hypertensive rats with tfm mutation were treated with flutamide, and blood pressure was monitored. Flutamide induced a relaxation of rat aortae from all the strains used (maximum relaxation at 10 microM: 51.3+/-5.2% of phenylephrine contraction) and increased the coronary flow. The aortic relaxation to flutamide was abolished by endothelium removal, or by inhibition of nitric oxide synthase, guanylyl cyclase, and tyrosine kinase but not by calmodulin inhibition. Flutamide treatment attenuated the development of hypertension in mouse renin transgenic rats with the tfm mutation. Flutamide produces direct vasodilation by inducing release of NO from the endothelium and causes subsequent activation of soluble guanylyl cyclase in an active androgen receptor independent manner. This response may contribute to the observed antihypertensive actions of flutamide.
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PMID:Androgen receptor independent cardiovascular action of the antiandrogen flutamide. 1280 2

Chronic, low-level lead exposure causes hypertension in both animals and humans. The pathogenesis of lead-induced hypertension is multifactorial, including such diverse mechanisms as: inactivation of endogenous nitric oxide and downregulation of soluble guanylate cyclase by reactive oxygen species (ROS), leading to a functional deficiency in nitric oxide; heightened sympathetic activity and plasma norepinephrine together with depressed vascular and elevated renal beta-adrenergic receptor density; elevated plasma angiotensin-converting enzyme (ACE) activity, plasma renin activity (PRA), angiotensin II (Ang-II), and aldosterone levels; increased kininase I and kininase II activities; lead-induced inhibition of vascular smooth muscle Na(+)-K+ ATPase, leading to a rise in cellular Na+ and, hence, Ca2+; and a possible rise in endothelin and thromboxane generation. In this article, we present an overview of the epidemiology and proposed underlying mechanisms of lead-induced hypertension.
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PMID:Lead-induced hypertension: role of oxidative stress. 1525 67

Adrenomedullin (ADM), a ubiquitous vasoactive peptide, has been the target of a multitude of studies concerning its effect on the vascular tone. The present work aims at clarifying a series of its interactions with the renin-angiotensin system. The study uses the rat aorta ring as a model of conductance vessels, with or without vascular endothelium, and the second order branch of rat mesenteric arteries as a model of resistance arteries. Interactions between various concentrations of ADM and angiotensin II (Ang II) were studied, in the presence of L-NAME (a nitric oxide [NO] synthase inhibitor) and methylene blue (MB; a soluble guanylate cyclase inhibitor). Results point out differences in the mechanism of the inhibitory action of ADM upon Ang II effects in the two vessel types studied. Inhibition of Ang II contraction by ADM involves guanylate cyclase in both cases. However, NO is involved in ADM-induced inhibition of angiotensinergic vasoconstriction only in the conductance arteries, not in the resistance ones.
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PMID:Comparative study of the inhibitory effects of adrenomedullin on angiotensin II contraction in rat conductance and resistance arteries. 1529 19

1. If one was to design a hormone to protect the heart, it would have a number of features shown by the cardiac natriuretic peptides atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP). These hormones are made in cardiomyocytes and are released into the circulation in response to atrial and ventricular stretch, respectively. Atrial natriuretic peptide and BNP can reduce the preload and after-load in normal and failing hearts. They reduce blood volume over the short term by sequestering plasma and over the longer term by promoting renal salt and water excretion and by antagonizing the renin-angiotensin-aldosterone system at many levels. Each of these actions affords indirect benefit to a volume- or pressure-threatened heart. 2. Recent studies have identified additional modes of action of the natriuretic peptides that may also confer cardioprotective benefits, especially in heart disease. The emerging findings are: (i) that ANP and BNP antagonize the cardiac hypertrophic action of angiotensin II and continue working under conditions where endothelial nitric oxide (NO) function is compromised, such as in the presence of high glucose in diabetes; (ii) they potentiate the bradycardia caused by inhibitory ('autoprotective') cardio-cardiac reflexes; and, furthermore, (iii) BNP can suppress cardiac sympathetic nerve activity in humans, including those with heart failure. Thus, it appears that natriuretic peptides can shift sympathovagal balance in a beneficial direction (away from the sympathetic). The vagal reflex and antihypertrophic actions of the peptides are mediated by particulate guanylyl cyclase (pGC) natriuretic peptide receptors. 3. The multiple synergistic actions of the natriuretic peptides make them and their pGC receptors attractive targets for therapy in heart disease. Encouragingly, exogenous natriuretic peptides remain effective even when endogenous peptide levels are raised, as is the case in heart failure. They also remain effective in disease states where other protective mechanisms, such as the NO system, have become ineffective, offering yet further encouragement for the therapeutic use of the natriuretic peptides.
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PMID:Cardioprotective functions of atrial natriuretic peptide and B-type natriuretic peptide: a brief review. 1556 95

Although plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are elevated early after myocardial infarction (MI), the significance is not fully understood. We therefore investigated the function of natriuretic peptides after induction of MI in knockout (KO) mice lacking the natriuretic peptide receptor guanylyl cyclase-A, the receptor for ANP and BNP. KO and wild-type (WT) mice were subjected to left coronary artery ligation and then followed up for 4 weeks. Irrespective of genotype, almost all deaths occurred within 1 week after induction of MI. KO mice showed significantly higher mortality because of a higher incidence of acute heart failure, which was associated with diminished water and sodium excretion and with higher cardiac levels of mRNAs encoding ANP, BNP, transforming growth factor-beta1, and type I collagen. By 4 weeks after infarction, left ventricular remodeling, including myocardial hypertrophy and fibrosis, and impairment of left ventricular systolic function were significantly more severe in KO than WT mice. Notably, the enhanced myocardial fibrosis seen in KO mice was virtually absent in infarcted double-KO mice, lacking guanylyl cyclase-A and angiotensin II type 1a receptors, although there was no improvement in survival and no attenuation of cardiac hypertrophy. Thus, guanylyl cyclase-A activation by endogenous cardiac natriuretic peptides protects against acute heart failure and attenuates chronic cardiac remodeling after MI. These beneficial effects are mediated partly through inhibition of the renin-angiotensin system (RAS), although RAS-independent protective actions of guanylyl cyclase-A are also suggested.
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PMID:Role of natriuretic peptide receptor guanylyl cyclase-A in myocardial infarction evaluated using genetically engineered mice. 1599 9

Increased endogenous nitric oxide production has been proposed as an important mediator of the peripheral arterial vasodilation and the hyperdynamic circulation in cirrhosis, whereas a decreased intrahepatic production of nitric oxide has been implicated in the pathogenesis of portal hypertension. The present study investigated the possible beneficial effects of methylene blue, which is a potent inhibitor of guanylate cyclase and nitric oxide synthase, on hyperdynamic circulation and renal function in cirrhotic patients with ascites together with the effects on portal hemodynamics. Twenty patients were evaluated at baseline and during 2 consecutive 4-hr periods after the administration of methylene blue at a dose of 3 mg/kg (10 patients) or placebo (10 patients). Mean arterial pressure, heart rate, cardiac output, systemic vascular resistance, plasma active renin, plasma aldosterone, plasma antidiuretic hormone, serum urea, serum creatinine, serum sodium, urinary flow rate, glomerular filtration rate, effective renal plasma flow, portal flow volume, and portal vein velocity were not modified by methylene blue or placebo. Urinary sodium excretion, fractional sodium excretion and serum nitric oxide levels were significantly decreased 4 hr after methylene blue administration (P < 0.05), to return toward basal levels over a further 4-hr period. It is concluded that methylene blue, at the dose used in the present study, has no effect on systemic and portal hemodynamics in cirrhotic patients with ascites. The reduction in renal sodium excretion, in the absence of changes in renal function and hemodynamics, suggests, at least partly, a direct antinatriuretic effect of methylene blue.
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PMID:Effects of nitric oxide inhibition by methylene blue in cirrhotic patients with ascites. 1730 70

Atrial cardiocytes in the heart of mammals produce in a regulated manner the polypeptide hormones atrial natriuretic factor (ANF, ANP) and brain natriuretic peptide (BNP). The biological actions of ANF and BNP are similar; they include the modulation of systems that tend to increase extracellular fluid volume and blood pressure, such as the renin-angiotensin system and the sympathetic nervous system. Additionally, both hormones have potent growth-regulating properties. ANF and BNP signal by activating membrane-bound guanylyl cyclase receptors, leading to an increase in intracellular cGMP and thus affecting the activity of cGMP-regulated enzymes and ion channels. Under chronic hemodynamic overload, cardiac ANF and BNP synthesis and secretion are increased. This increase is viewed as a cardioprotective mechanism, given the beneficial effects of ANF and BNP on cardiac preload, afterload and cardiovascular growth. As discussed in this review, some basic facts regarding the synthesis and secretion of ANF and BNP and their peripheral effects remain to be clarified. Nevertheless, at the clinical level, the elevation of circulating ANF and BNP in heart failure or following acute coronary syndromes has been shown to have diagnostic and prognostic implications. Moreover, these peptides themselves hold promise as therapeutic agents in the treatment of heart failure. Additional pharmaceutical applications might be gleaned from current preclinical and clinical studies showing beneficial effects of ANF or BNP in the treatment of hypertension, bronchospasm and in tissue remodeling following acute myocardial infarction.
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PMID:The endocrine function of the heart. 1626 46

Nitric oxide (NO) is a biological messenger molecule produced by one of the essential amino acids L-arginine by the catalytic action of the enzyme NO synthase (NOS). The dual role of NO as a protective or toxic molecule is due to several factors, such as; the isoform of NOS involved, concentration of NO and the type of cells in which it is synthesised, the availability of the substrate L-arginine, generation of guanosine 3,5'-cyclic monophosphate (cGMP) from soluble guanylate cyclase and the overall extra and intracellular environment in which NO is produced. NOS activation as a result of trauma (calcium influx) or infection leads to NO production, which activates its downstream receptor sGC to synthesise cGMP and/or leads to protein nitrosylation. This may lead to one or more systemic effects including altered neurotransmission which can be protective or toxic, vaso/bronchodilatation in the cardiovascular and respiratory systems and enhanced immune activity against invading pathogens. In addition to these major functions, NO plays important role in thermoregulation, renal function, gastrointestinal motility, endocrine function, and various functions of the urogenital system ranging from renin secretion to micturation; spermatogenesis to penile erection; and ovulation to implantation and parturition. A schematic summary of the functions of NO and the various isoforms of NOS expressed in body systems is shown in figure 1. In this review, the historical background, biochemistry and biosynthesis of NO and its enzymes together with the mechanism of NO actions in physiology and pathophysiology are discussed.
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PMID:Nitric oxide, a biological double-faced janus--is this good or bad? 1643 90


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