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)

Around half of all humans with essential hypertension are resistant to salt (blood pressure does not change by more than 5 mm Hg when salt intake is high), and although various inbred strains of rats display salt-insensitive elevated blood pressure, a gene defect to account for the phenotype has not been described. Atrial natriuretic peptide (ANP) is released from the heart in response to atrial stretch and is thought to mediate its natriuretic and vaso-relaxant effects through the guanylyl cyclase-A receptor (GC-A). Here we report that disruption of the GC-A gene results in chronic elevations of blood pressure in mice on a normal salt diet. Unexpectedly, the blood pressure remains elevated and unchanged in response to either minimal or high salt diets. Aldosterone and ANP concentrations are not affected by the genotype. Therefore, mutations in the GC-A gene could explain some salt-resistant forms of essential hypertension and, coupled with previous work, further suggest that the GC-A signaling pathway dominates at the level of peripheral resistance, where it can operate independently of ANP.
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PMID:Salt-resistant hypertension in mice lacking the guanylyl cyclase-A receptor for atrial natriuretic peptide. 747 88

1. Impaired endothelium-dependent relaxation has been previously demonstrated in blood vessels of hypertensive rats and in humans with essential hypertension. Arteries from spontaneously hypertensive rats have been shown to produce, in response to high concentrations of acetylcholine, a vasoconstrictor substance called endothelium-derived contracting factor, the production of which can be inhibited by indomethacin or other cyclo-oxygenase inhibitors, suggesting that it is a prostanoid. The mechanisms involved in endothelium-dependent relaxation of human arteries are unclear, and the potential generation of endothelium-derived contracting factor by endothelium in human hypertension has not been established. 2. We investigated the effects of acetylcholine on precontracted small arteries dissected from gluteal subcutaneous fat biopsies from normotensive subjects and subjects with borderline and mild essential hypertension. Vessels from normotensive subjects and those from borderline hypertensive patients, precontracted by noradrenaline, were relaxed completely by acetylcholine, whereas those from patients with mild essential hypertension relaxed slightly but significantly less, indicating that generation of endothelium-derived relaxing factor (endothelium-derived nitric oxide) was only minimally reduced or that production of minor amounts of endothelium-derived contracting factor occurred in small arteries from these hypertensive subjects. This impairment of endothelium-dependent relaxation was not corrected by indomethacin, which indicated that the contribution of endothelium-derived contracting factor, if any, was minimal in this subset of essential hypertensive patients. In contrast, mesenteric small arteries of adult spontaneously hypertensive rats presented strong contractions in response to the higher concentrations of acetylcholine, which were abolished by exposure to indomethacin. 3. The relaxation induced by acetylcholine in arteries from both hypertensive and normotensive humans was partially blunted (by 30%) by pretreatment with 0.1 mmol/l NG-nitro-L-arginine methyl ester or NG-nitro-monomethyl-L-arginine (inhibitors of nitric oxide synthase) and by 10 mumol/l Methylene Blue (a blocker of soluble guanylate cyclase), indicating the role of endothelium-derived nitric oxide and the generation of its intracellular second messenger cyclic guanosine monophosphate in acetylcholine-induced relaxation. The remaining relaxation elicited by acetylcholine could be blocked with 30 mmol/l KCl or with 10 mumol/l ouabain (inhibitor of Na+, K(+)-ATPase), and, when combined with NG-nitro-L-arginine methyl ester, these interventions abolished acetylcholine-induced relaxation. Tolbutamide at 2 mmol/l or 10 mumol/l glyburide (blockers of ATP-sensitive potassium channels) partially inhibited NG-nitro-L-arginine methyl ester-resistant endothelium-dependent relaxation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Endothelium-dependent relaxation of small arteries from essential hypertensive patients: mechanisms and comparison with normotensive subjects and with responses of vessels from spontaneously hypertensive rats. 754 95

The vascular endothelium is the site of formation of several powerful mediators. One of these is NO, a chemically unstable radical formed by enzymatic conversion of L-arginine in the presence of molecular oxygen. NO elicits relaxation of VSMC by activating cytosolic guanylate cyclase. NO also counteracts platelet adhesion and aggregation. The biological actions of NO make it a key substance in the endogenous defense against vascular occlusion and thrombosis. The basal formation of NO maintains a moderate but significant vasodilation in the systemic resistance vessels and counteracts platelet activity. When blood flow in conduit arteries is increased there is an augmented endothelial formation of NO, eliciting flow-dependent vasodilation. Beside this, several vasodilators (acetylcholine, bradykinin, histamine, substance P) operate by stimulating endothelial NO formation. On the other hand, drugs like nitroglycerin and papaverine operate independently of the vascular endothelium. Vasodilator mechanisms, physiological as well as pharmacological, may therefore be characterized as endothelium-dependent (i.e. NO-mediated), or endothelium-independent (i.e. not mediated by NO). Physiologically, mixed mechanisms occur. Failure of the vascular endothelium to elicit NO-mediated vasodilatation may be due to decreased formation, increased degradation, decreased sensitivity to the NO formed, or a mixture of these factors. Irrespective of the mechanism behind, this is referred to as endothelial dysfunction. Endothelial dysfunction occurs in several cardiovascular settings, like atherosclerosis, hypercholesterolaemia, diabetes, and essential hypertension. Endothelial dysfunction leads to an impaired tissue perfusion, increased local vascular resistance, decreased defense against thrombus formation, and possibly also decreased defense against hypertrophy of the VSMC in the vessel wall media. In patients with CHD, endothelial dysfunction leads to an impaired coronary flow response to physical and mental stress, and to promotion of platelet adherence and aggregability. Endothelial dysfunction is thereby a probable aggravating factor in the atherosclerotic process, adding a functional component on top of the structural lesions characterizing this disease. A particular form of endothelial dysfunction, limited to the arterial resistance vessels, may explain the symptoms and clinical characteristics of microvascular angina. In patients with essential hypertension, endothelial dysfunction prevails, adding a functional component to the structural factors also in this disease. Hitherto, the only therapeutic tools available to restore endothelial dysfunction appear to be restriction of the dietary intake of lipids, possibly reinforced with intake of antioxidants like fish oil and vitamin E. However, large clinical trials to confirm the efficacy of such therapy in reversing endothelial dysfunction have not been conducted. In the future, more directly acting therapeutic regimens, aimed at supporting or substituting the endogenous formation of NO, are likely to appear as well.
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PMID:Endothelial nitric oxide and cardiovascular disease. 815 Dec 63

The discovery of at least 29 genes encoding putative guanylyl cyclases in Caenorhabditis elegans has raised the question as to whether there are numerous receptors yet to be discovered in the mammal. The nematode, however, not only seems ideal to study guanylyl cyclase receptor localization and function, given the large variety of isoforms, but also leads to possible identification of ligands for orphan guanylyl cyclases by the use of genetic and behavioral assays. A recent powerful approach to describe the function of different guanylyl cyclase isoforms in mammals has been the disruption of the corresponding genes in the mouse. A salt resistant elevation of blood pressure, which corresponds to the phenotype of 50% of all human patients with essential hypertension, is observed in mice lacking the GC-A-receptor. Mice missing the GC-C receptor have been shown to be resistant to STa, an E. coli heat-stable enterotoxin, which is largely responsible for travellers diarrhea in adults and mortality due to diarrhea in infants.
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PMID:New insights on the functions of the guanylyl cyclase receptors. 924 17

Human and rat plasma and rat hypothalamus contain a cytochemically detectable substance, the concentration of which rises with an increase in salt intake. The plasma concentration of this material is also raised in essential hypertension and in the spontaneously hypertensive rat (SHR), the Milan hypertensive rat, and the reduced renal mass (RRM) hypertensive rat. In the normal rat, the greatest concentration is found in the hypothalamus of the SHR and the RRM hypertensive rat. The physicochemical characteristics of this cytochemically detectable hypothalamic hypertensive factor (HHF), including chromatographic behavior and molecular weight range, suggest that it may share features common to a substituted guanidine that is present in established nitric oxide synthase (NOS) inhibitors. It was therefore decided to determine the effect on NOS activity of the HHF obtained from mature SHR. The ability of HHF to inhibit NOS activity was studied on (1) NOS extracted from bovine aorta, rat brain, and human platelets by measuring the conversion of radiolabeled L-arginine to L-citrulline and (2) rat liver NOS measured indirectly with a cytochemical technique based on the stimulation of soluble guanylate cyclase activity in hepatocytes by NO. HHF showed a biphasic inhibitory action on platelet NOS activity that was greater with HHF obtained from SHR than from Wistar-Kyoto rats. HHF also had a biphasic inhibitory effect on hepatocyte NOS activity that was more potent when obtained from SHR. It is proposed that the increase in HHF, a novel form of NOS inhibitor that is elevated in SHR, may be involved in the rise in arterial pressure.
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PMID:Hypothalamic hypertensive factor: an inhibitor of nitric oxide synthase activity. 940 72

It has been reported that neurovascular compression of the rostral ventrolateral medulla might be causally related to essential hypertension. Recently, we found that pulsatile compression of the rostral ventrolateral medulla increases sympathetic nerve activity and elevates arterial pressure via activation of glutamate receptors in rats. We also found that increases in sympathetic and cardiovascular activities by microinjection of L-glutamate into the rostral ventrolateral medulla are mediated by c-fos expression-related substance(s) following activation of the nitric oxide-cyclic GMP pathway. Herein, we investigated whether responses to pulsatile compression are mediated by local activation of the nitric oxide-cyclic GMP pathway and/or c-fos expression-related substance(s) in rats. Increases in arterial pressure (15+/-1 mmHg), heart rate (9+/-1 b.p.m.), and sympathetic nerve activity (% change: 8.5+/-1.1%) induced by pulsatile compression were partially but significantly inhibited after local microinjection of a nitric oxide synthase inhibitor, L-N(G)-nitroarginine methyl ester (8+/-2 mmHg, 1+/-1 b.p.m., 4.0+/-1.3%; P<0.05 vs compression without pretreatment) or 7-nitroindazole (7+/-2 mmHg, 2+/-1 b.p.m., 4.0+/-1. 5%; P<0.05), or a soluble guanylate cyclase inhibitor, methylene blue (9+/-1 mmHg, 4+/-1 b.p.m., 4.1+/-1.4%; P<0.05). In addition, increases in arterial pressure, heart rate, and sympathetic nerve activity by pulsatile compression were significantly reduced 6 h after microinjection of antisense oligodeoxynucleotide to c-fos mRNA (2+/-2 mmHg, 2+/-1 b.p.m., 1.0+/-1.0%; P<0.05 vs sense oligodeoxynucleotide). These results suggest that increases in sympathetic and cardiovascular activities induced by pulsatile compression of the rostral ventrolateral medulla are mediated, at least in part, by local activation of the nitric oxide-cyclic GMP pathway and c-fos expression-related substance(s) in rats.
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PMID:Pressor response to pulsatile compression of the rostral ventrolateral medulla mediated by nitric oxide and c-fos expression. 1069 82

Endothelial nitric oxide synthase (eNOS) produces nitric oxide (NO) which, after diffusing into vascular smooth muscle cells, activates guanylate cyclase leading to vasodilatation. A polymorphism (894G to T) in exon 7 of the eNOS gene causes the conversion of Glu to Asp in position 298. The recently described crystal structure of the heme domain of eNOS protein shows that Glu298 is fully solvent accessible and distant from regions integral to enzyme function. Searching for phenotypic expression of eNOS gene variants, we genotyped a group of patients with essential hypertension (H, n = 119) for the Glu298Asp polymorphism and compared them with age- and sex-matched healthy normals (N, n = 85). To specify phenotypic expression further, the hypertensive patients were subdivided into one group that responded well to regular antihypertensive therapy (CH, n = 45) and one group that was resistant to the therapy (RH, n = 74). Patients with BP higher than 140/90 mmHg when on adequate lifestyle modification and triple-combination therapy (including diuretics) were considered resistant. In RH and H groups, a significantly higher frequency of T alleles (P = 0.022 and P = 0.046, respectively) was found compared to normotonics (N). In well-controlled hypertonics, the same tendency was found, but did not reach statistical significance. The Glu298Asp polymorphism may contribute to the complex pathogenesis of essential hypertension and may be a factor in the resistance of these patients to conventional antihypertensive therapy. The presence of this allele may thus be predictive of the patients' therapeutic response.
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PMID:Association of the Glu298Asp polymorphism in the endothelial nitric oxide synthase gene with essential hypertension resistant to conventional therapy. 1139 96

Three types of natriuretic peptides (NP) have been isolated: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). The NP family elicits a number of vascular, renal and endocrine effects that help to maintain blood pressure and extracellular fluid volume. These effects are mediated by the specific binding of NP to cell surface receptors that have been characterized, purified and cloned from cells of the vasculature, kidney, adrenal gland and brain. There are 3 subtypes of NP receptors: type A natriuretic peptide receptor (NPRA), type B natriuretic peptide receptor (NPRB), and type C natriuretic peptide receptor (NPRC). All 3 subtypes affect cellular second messenger activity. NPRA and NPRB are guanylyl cyclase receptors, and their activation increases cGMP levels. Activation of NPRC results in inhibition of adenylyl cyclase activity. Human NPRA has a high structural homology with human NPRB, and contains a highly-conserved guanylyl cyclase domain. ANP and BNP bind primarily to NPRA, which is found in the vasculature, causing vasodilation and inhibition of vascular smooth muscle cell proliferation. The present paper contains a review of NPs and their receptors and the genetic contribution of the NP system to cardiovascular diseases such as essential hypertension and myocardial infarction.
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PMID:The genetic contribution of the natriuretic peptide system to cardiovascular diseases. 1575 53

Four major natriuretic peptides have been isolated: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), and Dendroaspis-type natriuretic peptide (DNP). Natriuretic peptides play an important role in the regulation of cardiovascular homeostasis maintaining blood pressure and extracellular fluid volume. The classical endocrine effects of natriuretic peptides to modulate fluid and electrolyte balance and vascular smooth muscle tone are complemented by autocrine and paracrine actions that include regulation of coronary blood flow and, therefore, myocardial perfusion; modulation of proliferative responses during myocardial and vascular remodeling; and cytoprotective anti-ischemic effects. The actions of natriuretic peptides are mediated by the specific binding of these peptides to three cell surface receptors: type A natriuretic peptide receptor (NPR-A), type B natriuretic peptide receptor (NPR-B), and type C natriuretic peptide receptor (NPR-C). NPR-A and NPR-B are guanylyl cyclase receptors that increase intracellular cGMP concentration and activate cGMP-dependent protein kinases. NPR-C has been presented as a clearance receptor and its activation also results in inhibition of adenylyl cyclase activity. The wide range of effects of natriuretic peptides might be the base for the development of new therapeutic strategies of great benefit in patients with cardiovascular problems including coronary artery disease or heart failure. This review summarizes current literature concerning natriuretic peptides, their receptors and their effects on fluid/electrolyte balance, and vascular and cardiac physiology and pathology, including primary hypertension and myocardial infarction. In addition, we will attempt to provide an update on important issues regarding natriuretic peptides in congestive heart failure.
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PMID:Natriuretic peptides in vascular physiology and pathology. 1870 4

Atrial and brain natriuretic peptides (ANP and BNP, respectively) are cardiac hormones, secretions of which are markedly upregulated during cardiac failure, making their plasma levels clinically useful diagnostic markers. ANP and BNP exert potent diuretic, natriuretic and vasorelaxant effects, which are mediated via their common receptor, guanylyl cyclase (GC)-A (also called natriuretic peptide receptor (NPR)-A). Mice deficient for GC-A are mildly hypertensive and show marked cardiac hypertrophy and fibrosis that is disproportionately severe, given their modestly higher blood pressure. Indeed, the cardiac hypertrophy seen in these mice is enhanced in a blood pressure-independent manner and is suppressed by cardiomyocyte-specific overexpression of GC-A. These results suggest that the actions of a local cardiac ANP/BNP-GC-A system are essential for maintenance of normal cardiac architecture. In addition, GC-A was shown to exert its cardioprotective effects by inhibiting angiotensin II-induced hypertrophic signaling, and recent evidence suggests that regulator of G protein signaling (RGS) subtype 4 is involved in the GC-A-mediated inhibition of Galphaq-coupled hypertrophic signal transduction. Furthermore, several different groups have reported that functional mutations in the promoter region of the human GC-A gene are associated with essential hypertension and ventricular hypertrophy. These findings suggest that endogenous GC-A protects the heart from pathological hypertrophic stimuli, and that humans who express only low levels of GC-A are genetically predisposed to cardiac remodeling and hypertension.
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PMID:Natriuretic Peptide Signaling via Guanylyl Cyclase (GC)-A: An Endogenous Protective Mechanism of the Heart. 2006 48


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