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)

This study was undertaken to examine the alterations in vascular relaxation responsiveness to endothelium-dependent or -independent vasodilators, including atrial natriuretic peptide (ANP) and acetylcholine, in aortas of Watanabe heritable hyperlipidemic (WHHL) rabbits during the progression of the atherosclerotic plaque. WHHL rabbits were divided into two groups according to age: group 1, 6-11 months, and group 2, 12-18 months. The isolated thoracic aortas obtained from both normal (control) and WHHL rabbits were suspended in a bath containing oxygenated Krebs' buffer for recording of isometric force. The endothelium-dependent relaxation evoked by acetylcholine was reduced in group 1 WHHL rabbits and decreased progressively in proportion to the degree of atherosclerosis progression when compared with age-matched control rabbits. ANP-induced relaxation was not significantly decreased in group 1 WHHL rabbits. However, ANP-induced relaxation was markedly impaired in group 2 WHHL rabbits. Thoracic aortas with severe atherosclerosis were less sensitive to ANP, with a significant increase in the median effective dose, although maximum relaxation induced by ANP was not reduced. Accumulation of cyclic GMP induced by ANP and acetylcholine was markedly reduced in atherosclerotic arteries obtained from group 2 WHHL rabbits compared with control rabbits. Vascular relaxation elicited by nitroglycerin or isoproterenol was not significantly impaired in atherosclerotic arteries from either group 1 or group 2 WHHL rabbits. From these results, we suggest that ANP-induced cyclic GMP formation and vascular relaxation via particulate guanylate cyclase in vascular smooth muscle cells are impaired in severely atherosclerotic arteries.
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PMID:Impaired vasodilatory response to atrial natriuretic peptide during atherosclerosis progression. 131 25

Nitroglycerin and the long-acting nitrates are widely used in all of the anginal syndromes and have proven effectiveness in relieving or preventing myocardial ischemia. Recent developments into nitrate mechanisms of action provide new insights as to the many anti-ischemic effects of these agents. Important concepts relating to coronary arterial endothelial function are germane to nitrate therapy. Endothelial-derived relaxing factor (EDRF) is presently believed to be nitric oxide (NO), which exerts vasodilatory and/or antiplatelet actions by increasing intracellular cyclic guanosine monophosphate as a result of activation of the enzyme guanylate cyclase. In the setting of coronary atherosclerosis, or even hyperlipidemia without histologic vascular disease, endothelial dysfunction may be present, promoting a vasoconstrictor/proplatelet aggregatory milieu. Nitroglycerin and the organic nitrates are NO donors; NO is the final product of nitrate metabolism, and in the vascular smooth muscle NO induces relaxation, resulting in vasodilation of arteries and veins. In the presence of inadequate EDRF production and/or release, it appears that nitroglycerin may partially replenish EDRF-like activity. Nitrates have long been known to have major peripheral circulatory actions resulting in a marked decrease in cardiac work. Venodilation and arterial relaxation result in a decrease in intracardiac chamber size and pressures, with a resultant decrease in myocardial oxygen consumption. In addition, a variety of direct coronary circulatory actions of the nitrates have been documented. These include not only epicardial coronary artery dilation, but the prevention of coronary vasoconstriction, enhanced collateral flow, and coronary stenosis enlargement. Recent work suggests that the nitrates may also act by preventing distal coronary artery or collateral vasoconstriction, which can reduce blood flow downstream from a total coronary obstruction. Thus, there are many anti-ischemic mechanisms of action by which nitroglycerin and the organic nitrates may be beneficial in both acute and chronic ischemic heart disease syndromes. The unique salutory effects of the nitrates in subjects with left ventricular dysfunction or congestive heart failure make these drugs particularly attractive for patients with abnormal systolic function and intermittent myocardial ischemia. Finally, the emergent role of intravenous nitroglycerin in acute myocardial infarction offers new prospects that nitrate therapy may prove to be beneficial in acute myocardial infarction as well as postmyocardial infarction for the reduction of left ventricular remodeling.
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PMID:Mechanisms of action of the organic nitrates in the treatment of myocardial ischemia. 152 24

The endothelium-derived relaxing factor (EDRF) is nitric oxide (NO) or a closely related nitrosothiol derivative. It is formed from the amino acid, L-arginine. NO is rapidly inactivated locally and is instantly destroyed by haemoglobin when released into the blood stream. EDRF-NO as well as NO generated from vasodilator nitrates act by activation of soluble guanylate cyclase, elevating cellular cyclic GMP levels, causing vasodilatation and inhibition of platelet aggregation. Endothelium-dependent vasodilatation is attenuated in hypertension, atherosclerosis and diabetes. This is due to either loss of endothelium or deficient formation of EDRF-NO. In these conditions, therapy with exogenous nitrates may substitute for a failing endogenous mechanism.
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PMID:Endogenous and exogenous nitrates. 155 42

The vasodilator action of organic nitrates is thought to be mediated by an increase in the level of cGMP following stimulation of the cytosolic enzyme guanylate cyclase in the vascular smooth muscle cell. However, direct evidence for the formation of the putative active metabolite, nitric oxide (NO) within the different compartments of the vascular wall is still missing. We here demonstrate for the first time that cultured vascular smooth muscle cells as well as endothelial cells from different species actively metabolize organic nitrates to NO. We furthermore present evidence for an outward transport of cGMP from both cell types following stimulation of soluble guanylate cyclase. The rate of NO release closely correlated with the rate of cGMP egression. Biotransformation of organic nitrates to NO appeared to comprise at least two different components, a heat-sensitive enzymatic pathway which is short-lived and prone to rapid desensitization and a second non-enzymatic component which is apparently unsaturable and longer lasting. The marked decrease in the release of NO and cGMP upon the repeated administration of organic nitrates suggests that the phenomenon of "nitrate tolerance" is mainly due to an impaired biotransformation. We propose that the metabolism of nitrates to NO may have important implications for the prevention of atherosclerosis and the therapeutic modulation of blood cell function.
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PMID:Biotransformation of organic nitrates to nitric oxide by vascular smooth muscle and endothelial cells. 165 70

The endothelial cells can release both relaxing and contracting substances. The former include prostacyclin and endothelium-derived relaxing factor (EDRF, which most likely is nitric oxide, or a nitrosoderivative releasing nitric oxide, derived from L-arginine). Candidates as endothelium-derived contracting factors (EDCF) include superoxide anions thromboxane A2 and the peptide endothelin. Endothelium-derived relaxing factor causes relaxation of vascular smooth muscle by activation of the soluble form of guanylate cyclase which leads to an accumulation of cyclic GMP; it also reduces platelet adhesion and aggregation. The latter effect is synergistic with the inhibition evoked by prostacyclin. The release of EDRF and prostacyclin plays a key role in the protective role of the endothelium against vasospasm and the unwanted coagulation of blood. Indeed, thrombin and aggregating platelets are potent stimuli for the release of EDRF. The platelet-products responsible are the adenine nucleotides, ADP and ATP, which activate P2y-purinergic receptors on the endothelial cells and 5-hydroxytryptamine (serotonin) that stimulates 5-HT1-like serotonergic receptors. The response to serotonin, but not that to the adenine nucleotides, is mediated by a pertussis toxin-sensitive mechanism. When endothelial cells regenerate, or are cultured, they selectively lose the pertussis toxin-sensitive mechanism of release, which results in a marked decrease in sensitivity to exogenous and platelet-released serotonin. As a consequence, the endothelial cells exhibit a considerably reduced response to aggregating platelets. This phenomenon, which can be exacerbated by hypercholesterolemia, favors ongoing platelet aggregation and vasospasm, and constitutes a first step toward atherosclerosis.
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PMID:Platelet-derived serotonin, the endothelium, and cardiovascular disease. 171 75

Endothelial cells contain an enzyme(s) which produces nitric oxide from L-arginine in response to a variety of mechanical stimuli as well as to autacoids and local and circulating hormones. Nitric oxide is a potent vasodilator and inhibitor of platelet function; it exerts its effects via activation of soluble guanylate cyclase and subsequent formation of cyclic 3'-5'-guanosine monophosphate. In the kidney, activation of the endothelial L-arginine pathway is associated with increases in renal blood flow, diuresis and natriuresis, while the glomerular filtration rate remains constant. The activity of the endothelial L-arginine pathway is impaired in hypertension and during chronic therapy with cyclosporine A. In addition, diabetes and atherosclerosis impair this pathway. Thus, the endothelial L-arginine pathway plays an important role in the local regulation of blood flow. Alterations in the activity of this pathway may play an important role in the pathophysiology of hypertension and renal disease.
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PMID:The endothelial L-arginine/nitric oxide pathway and the renal circulation. 175 83

EDRF is a potent, endogenous vasodilator that is produced and released from endothelial cells and subsequently causes the relaxation of VSM through the activation of soluble guanylate cyclase and an increase in VSM cyclic GMP. Structurally, EDRF is likely to be NO or a related nitrogen oxide-containing compound. It is synthesized in endothelial and other cell types from L-arginine by a calcium-calmodulin and NADPH-dependent enzyme. Its action is very similar to the nitrovasodilators that act directly on VSM. EDRF is present in all vascular beds, large and small vessels, and in a wide range of species. Its role in human vascular physiology and pathophysiology is just beginning to be understood. EDRF is a potent endogenous vasodilator and inhibitor of platelet aggregation and adhesion. Its activity is impaired in hypertension and atherosclerosis, and its absence due to endothelial damage may play a role in cerebral and coronary vasospasm. It is a mediator of flow-dependent vasodilation, and its inhibition by hypoxia may contribute to the hypoxic pulmonary vasoconstrictor response. Endothelial cell damage and impairment of EDRF production may also contribute to acute and chronic pulmonary hypertension. A further understanding of the chemical nature and synthetic pathways of EDRF should lead to the production of analogs and antagonists, which may play an important role in future treatments for atherosclerosis, myocardial infarction, angina, hypertension, and other vascular diseases. The recent realization that EDRF serves as the second messenger for guanylate cyclase activation and cyclic GMP production in a variety of cell types outside of the cardiovascular system, including renal and respiratory epithelium, cerebellar neurons, macrophages, and adrenocytes, suggests even broader implications. The importance of EDRF to the anesthesiologist may go beyond an understanding of its role in cardiovascular physiological and pathophysiological states. Initial studies have shown that the endothelium may play a role in mediating the vascular actions of anesthetics, and that anesthetics can inhibit the production, release, or action of EDRF. How are these interactions mediated? Are there significant differences between anesthetics with regard to their effects on EDRF? Is there a clinically significant effect of anesthetics on basal activity of EDRF, or only in response to exogenous stimulation? Conversely, it is important to determine if alterations in endothelial cell function by various disease states such as hypertension, atherosclerosis, adult respiratory distress syndrome, cerebral vasospasm, and others cause changes in the vascular actions of anesthetics. The potential interactions of anesthetics with EDRF production and action in cell types other than the endothelium have not yet been explored.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Endothelium-derived relaxing factor: basic review and clinical implications. 186 89

The endothelium-derived relaxing factor (EDRF) is nitric oxide (NO) or a closely related nitrosothiol derivative, and is formed from the amino acid, L-arginine. NO is rapidly inactivated locally, released into the blood stream and instantly destroyed by haemoglobin. EDRF-NO and NO generated from vasodilator nitrates work by activation of soluble guanylate cyclase, elevating cyclic guanosine monophosphate (GMP) levels to cause vasodilatation and inhibition of platelet aggregation. Endothelium-dependent vasodilatation is attenuated in hypertension, atherosclerosis and diabetes through either loss of endothelium or deficient formation of EDRF-NO. In these conditions exogenous nitrates may substitute for a failing endogenous mechanism.
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PMID:Endogenous nitrates--implications for treatment and prevention. 187 72

Key discoveries in the past decade revealed that the endothelium can modulate the tone of underlying vascular smooth muscle by the synthesis/release of potent vasorelaxant (endothelium-derived relaxing factors; EDRF) and vasoconstrictor substances (endothelium-derived contracting factors; EDCF). It has become evident that the synthesis and release of these substances contribute to the multitude of physiological functions the vascular endothelium performs. Accumulating evidence suggests that at least one of the EDRFs is identical with nitric oxide (NO) or a labile nitroso compound, which is produced from L-arginine by an NADPH- and Ca(2+)-dependent enzyme, arginine oxidase. The existence of more than one chemically distinct EDRF has been proposed, including an endothelium-derived hyperpolarizing factor (EDHF). The target of EDRF (NO) is soluble guanylate cyclase (increase in cyclic GMP) while EDHF appears to activate a K(+)-channel in vascular smooth muscle. Recent data suggest that muscarinic receptor subtypes selectively mediate the release of EDRF(NO) (M2) and EDHF (M1). EDRF(NO) affects not only the underlying vascular smooth muscle, but also platelets, inhibiting their aggregation and adhesion to the endothelium. The antiaggregatory effect of EDRF is synergistic with prostacyclin, so their combined release may represent a physiological mechanism aimed at preventing thrombus formation. An additional proposed biological function of EDRF(NO) is cytoprotection by virtue of scavenging superoxide radicals. The endothelium can also mediate vasoconstriction by the release of a variety of endothelium-derived contracting factors (EDCF). Other than the unique peptide endothelin, the nature of EDCFs has not yet been firmly established. Autoregulation of cerebral and renal blood flow and hypoxic pulmonary vasoconstriction may represent the physiological role of endothelium-dependent vasoconstriction. Growing evidence indicates that the endothelium can serve as a unique mechanoreceptor, sensing and transducing physical stimuli (e.g., shear forces, pressure) into changes in vascular tone by the release of EDRFs or EDCFs. In physiological states, a delicate balance exists between endothelium-derived vasodilators and vasoconstrictors. Alterations in this balance can result in local (vasospasm) and generalized (hypertension) increase in vascular tone and also in facilitated thrombus formation. Endothelial dysfunction may also contribute to the pathophysiology of angiopathies associated with hypercholesterolemia and atherosclerosis.
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PMID:Endothelium-derived relaxing and contracting factors. 187 96

This paper review the actual knowledges about the physiological role of nitric oxide, sintetized from amino acid L-arginine. The nitric oxide sintetized in the vascular endothelium has a fundamental role in vascular tone, blood flow and arterial pressure control, acting stimulating guanylate cyclase on vascular smooth muscle. Nitric oxide could be considered the endogenous nitrovasodilator. Its action on the cardiovascular system are imitated by nitroglycerine, sodium nitroprusside and related compounds. Probably the disturbance in the synthesis or release of nitric oxide may be involved in the pathophysiology of hypertension, vasospasm and atherosclerosis. Recently has been shown that nitric oxide synthesis from L-arginine also occurs in other different cells like macrophages, central nervous system, liver, neutrophils, adrenal glands, playing different biological effects. Changes in nitric oxide synthesis or action in those systems, could be related to different pathological disorders as inflammation, atherosclerosis and cancer. The found of a substance as simple as nitric oxide, let suppose that we are in the presence of a biological mediator with a very early evolutionary origin, probably widespread in all the animal kingdom, and which represents the universal transduction system for activation of the soluble guanylate cyclase enzyme.
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PMID:[Nitric oxide: from endogenous vasodilator to biologic mediator]. 209 54


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