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)

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

Distinct increase and then decrease in content of cyclic nucleotides was observed in dog myocardium ventricles and auricles within early periods of heart infarction (10 min-4 hrs). Within a day after ligation of artery the ratio cAMP/cGMP was considerably decreased as a result of activation of guanylate cyclase and cAMP-phosphodiesterase as well as due to a decrease in activity of adenylate cyclase. Acute ischemia of small area of the heart left ventricle caused impairment of cyclic nucleotide metabolism in all the heart muscle.
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PMID:[The cyclic nucleotide system in various sections of the dog myocardium in experimental infarction]. 256 32

Cyclic AMP and cyclic GMP content and activities of cyclic nucleotide metabolic enzymes were determined in intima and media of atherosclerotic and unaffected human aorta obtained shortly after death due to myocardial infarction. Cyclic AMP content in fatty streaks and atherosclerotic plaques was lower by three- and five-fold, respectively, as compared with uninvolved intima. Cyclic GMP level in atherosclerotic lesions was estimated to be three-fold higher than in grossly normal area. Basal activity of adenylate cyclase in fatty streaks and plaques was two- to six-fold lower than in unaffected intima. Besides, the ability of adenylate cyclase to be stimulated by the stable analogue of prostacyclin, carbacyclin, was suppressed in plaques. Guanylate cyclase activity in fatty streaks was 1.5- to three-fold higher than in normal tissue. The thiol-reducing agent, dithiothreitol, decreased the enzyme activity to normal level, suggesting the oxidative nature of guanylate cyclase activation in the lesion zone. There were no significant changes in cyclic AMP phosphodiestease activity in the regions of the atherosclerotic lesion. Cyclic GMP phosphodiesterase activity in atherosclerotic plaques was two-fold lower than in the intima of unaffected areas. We did not find differences in the content of cyclic nucleotides or related enzyme activities in the media of uninvolved areas of human aorta nor in the media underlying atherosclerotic lesions. Our findings suggest that development of human atherosclerotic lesions is accompanied by dramatic changes in the cyclic nucleotide metabolism featuring gradual hormonal receptor uncoupling from adenylate cyclase, activation of guanylate cyclase in fatty streaks and inhibition of cyclic GMP phosphodiesterase in plaques.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Disorders in the system of cyclic nucleotides in atherosclerosis: cyclic AMP and cyclic GMP content and activity of related enzymes in human aorta. 288 18

Dietary intake of unsaturated fatty acid of eicosapentaenoic acid (EPA) is thought to reduce the size and incidence of myocardial infarction. These beneficial effects are postulated to be due to chronic antithrombotic properties of EPA itself. We studied the possible direct effects of EPA on vascular smooth muscle as well as the ability of EPA to modify the vasoactivity of constrictor mediators in rabbit and cat aortic rings and isolated cat coronary arteries. EPA concentration-dependently (30 to 300 microM) relaxed rabbit and cat aortic rings having an intact endothelium, while EPA did not show any significant vasodilator effects on rings without an endothelium. This EPA-induced vasorelaxation was not altered by the cyclooxygenase inhibitor ibuprofen, but was totally abolished by the guanylate cyclase inhibitor methylene blue, indicating an endothelium-dependent smooth muscle relaxation mechanism. In isolated perfused cat coronary arteries, EPA (3 to 300 microM) exerted a dilator effect which was endothelium-independent and not affected by ibuprofen. The response was attenuated by propyl gallate, a lipoxygenase inhibitor. EPA also inhibited leukotriene (LT) C4, (50 nM) and LTD4 (50 nM)-induced vasoconstriction of isolated cat coronary arteries ranging from a blockade of 10% to 15% (P less than 0.05) at 3 microM of EPA to a blockade of 89% to 93% (P less than 0.01) at 300 microM. In contrast, the thromboxane analog, CTA2, induced coronary constriction was not significantly altered by EPA. Thus, EPA produces endothelium-dependent relaxation in rabbit and cat aorta and endothelium-independent vasodilation in cat coronary arteries (i.e., intact vessels or helical strips). Moreover, EPA exerts acute anti-leukotriene actions in coronary arteries. In the case of long-term dietary intake of EPA, these actions may contribute to the protective action of EPA in myocardial ischemia.
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PMID:Vasoactive effects of eicosapentaenoic acid on isolated vascular smooth muscle. 303 70

Endothelial cells release a potent vasodilator which activates guanylate cyclase and thereby induces relaxation of vascular smooth muscle cells. The so-called endothelium-derived relaxing factor (EDRF) is released by acetylcholine, local and circulating hormones, and substances released from aggregating platelets or formed during activation of the coagulation cascade. Nitric oxide (NO) probably accounts for the factor's activity. Thus, endothelial cells produce endogenous nitrates causing vasodilatation and inhibition of platelet adhesion and aggregation. Under physiological conditions, EDRF may play a role in the prevention of vasospasm and thrombosis. On the other hand, the impairment of endothelial regulatory mechanisms in atherosclerosis and hypertension may be involved in the pathogenesis of vascular occlusion and thereby of myocardial infarction, stroke and peripheral vascular disease.
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PMID:[Endothelium-derived relaxing factor(s): endogenous nitrates in the circulation?]. 306 71

Glyceryl trinitrate, isosorbide dinitrate, and isosorbide-5-mononitrate are organic nitrate esters commonly used in the treatment of angina pectoris, myocardial infarction, and congestive heart failure. Organic nitrate esters have a direct relaxant effect on vascular smooth muscles, and the dilation of coronary vessels improves oxygen supply to the myocardium. The dilation of peripheral veins, and in higher doses peripheral arteries, reduces preload and afterload, and thereby lowers myocardial oxygen consumption. Inhibition of platelet aggregation is another effect that is probably of therapeutic value. Effects on the central nervous system and the myocardium have been shown but not scrutinized for therapeutic importance. Both the relaxing effect on vascular smooth muscle and the effect on platelets are considered to be due to a stimulation of soluble guanylate cyclase by nitric oxide derived from the organic nitrate ester molecule through metabolization catalyzed by enzymes such as glutathione S-transferase, cytochrome P-450, and possibly esterases. The cyclic GMP produced by the guanylate cyclase acts via cGMP-dependent protein kinase. Ultimately, through various processes, the protein kinase lowers intracellular calcium; an increased uptake to and a decreased release from intracellular stores seem to be particularly important.
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PMID:Mechanisms of action of nitrates. 787 67

Nitroglycerin and other organic nitrates are beneficial in ischaemic heart disease and myocardial infarction and as adjunctive therapy in congestive heart failure. The nitrates are inactive prodrugs, and their vascular effects depend on metabolic conversion to vasoactive intermediates like nitric oxide and/or nitrosothiols with subsequent stimulation of guanylate cyclase causing increased formation of cyclic GMP. The compounds relax vascular smooth muscle producing venous dilatation at low concentrations and at higher concentrations dilation of coronary arteries and collaterals and systemic arterial vessels. Nitrate tolerance is, however, a problem with continuous nitrate therapy. Tolerance is most likely to occur with frequent dosing or with the use of long-acting nitrates or transdermal applications resulting in constant plasma concentrations. Therapeutic strategies should be designed to provide a daily low-nitrate period or nitrate-free period to obviate the development of tolerance and thus maintain the antianginal effects.
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PMID:[Nitroglycerin preparations. Effect and tolerance]. 806 82

Atrial natriuretic factor (ANF) promotes natriuresis and diuresis, increases vascular permeability and may induce peripheral vasodilatation. Endothelium-derived relaxing factor (EDRF), which is nitric oxide (NO), promotes local vasodilatation. ANF and EDRF-NO both cause vascular relaxation by generating cGMP via the activation of the particulate and soluble guanylate cyclases, respectively. This study examines the in vivo effect of exogenous ANF administration in normal Wistar rats, and of increased endogenous ANF in an experimental model of heart failure, on plasma and tissue cGMP concentrations. Low-dose ANF increased plasma and pulmonary cGMP concentrations, whereas 10-fold higher doses were necessary to increase aorta cGMP concentrations. Rats with a myocardial infarction had increased plasma ANF and cGMP and pulmonary cGMP concentrations, but aorta cGMP concentration remained similar to that of sham-operated rats. NG nitro L-arginine methyl ester (L-NAME) was administered chronically to sham-operated and myocardial infarction rats to block NO-synthase: soluble guanylate cyclase activity. L-NAME did not lower the increase in plasma ANF concentration or in urinary, plasma or pulmonary cGMP concentration. In contrast, L-NAME reduced the aorta cGMP concentration 6-fold, despite an increased level of circulating ANF. In summary, the pathophysiological range of plasma ANF concentrations greatly increases plasma and pulmonary cGMP concentrations (by activating particulate guanylate cyclase), but has little influence on the aorta cGMP concentration (which remains mainly dependent on NO-synthase: soluble guanylate cyclase activity).
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PMID:Atrial natriuretic factor influences in vivo plasma, lung and aortic wall cGMP concentrations differently. 839 39

Nitroglycerin and the long-acting nitrates have been used in cardiovascular medicine for >100 years. Nitrates are widely utilized for the various anginal syndromes and are also used in congestive heart failure and patients with left ventricular dysfunction. The potential mechanisms for relief of myocardial ischemia with nitrates are multiple. The nitrovasodilators are a related group of drugs that result in the formation of nitric oxide (NO) within vascular smooth muscle cells. NO stimulates the enzyme guanylate cyclase, which results in increases in cyclic guanosine monophosphate and vasodilation. In the presence of atherosclerosis, endothelial dysfunction is ubiquitous and associated with decreased NO availability, probably due to increased destruction of NO by free radical anions. Nitrovasodilators, including the nitrates, supply exogenous NO to the vascular wall and improve the vasodilator state. When nitrates are administered, endothelial-dependent stimuli cause relaxation rather than constriction in the setting of endothelial dysfunction. Nitrates also have antiplatelet effects, and recent evidence confirms that these drugs decrease platelet aggregation and thrombosis formation. This may play an important role in the therapy of acute unstable myocardial ischemia, including unstable angina and myocardial infarction. Nitrate hemodynamic effects have been long known. They are primarily modulated through a decrease in myocardial work that results from smaller cardiac chambers operating with lower systolic and diastolic pressures. These changes are caused by a redistribution of the circulating blood volume away from the heart to the venous capacitance system, with a fall in venous return to the heart. The afterload or arterial effects of nitrates are also useful in decreasing myocardial oxygen consumption. Considerable evidence confirms a variety of mechanisms whereby nitrates increase coronary blood flow, including epicardial coronary artery dilation, stenosis enlargement, enhanced collateral size and flow, improvement of endothelial dysfunction, and prevention or reversal of coronary artery vasoconstriction. These effects help increase nutrient coronary blood flow to zones of myocardial ischemia. Recent data with the nitroglycerin patch confirm that myocardial ischemia is decreased after nitrate administration. Nitroprusside, another nitrovasodilator, is a commonly used intravenous agent for lowering arterial pressure and left ventricular filling pressure. This drug is highly effective for the treatment of acute or severe hypertension and congestive heart failure. However, there are data suggesting that nitroprusside may be deleterious in the presence of acute myocardial ischemia, perhaps by shunting blood away from zones of jeopardized myocardial blood flow. Therefore, nitroprusside cannot be recommended to treat myocardial ischemia; intravenous nitroglycerin should be used in this context.
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PMID:Beneficial actions of nitrates in cardiovascular disease. 863 24

1. Cardiac fibroblasts play an important role in the pathophysiology of cardiac remodelling induced by hypertension and myocardial infarction by undergoing proliferation and depositing extracellular matrix proteins such as collagen. We have examined the effects of atrial natriuretic peptide (ANP) on proliferation and collagen synthesis by adult rat and human cardiac fibroblasts in culture. 2. In cells from both species radioligand studies using 125I-ANP suggested that the majority of binding sites (> 85%) were non-guanylyl cyclase-linked (NPR-C subtype). Nonetheless ANP (10(-9) to 10(-6) M), in the presence of zaprinast, an inhibitor of phosphodiesterase 5 (PDE5), increased fibroblast cyclic GMP levels 3-5 fold in a concentration-dependent manner (P < 0.05). 3. ANP (10(-11) to 10(-6) M), a NPR-C ligand, C-ANF4-23 (10(-11) to 10(-6) M) and zaprinast alone had no significant effect on either basal or serum-stimulated DNA synthesis or fibroblast number. In combination with zaprinast (10(-5) M), however, ANP (10(-9) to 10(-6) M) but not C-ANF4-23 (10(-7) M) inhibited markedly both basal and stimulated fibroblast mitogenesis, an effect reproduced by 8-bromo-cyclic GMP (10(-5) to 10(-3) M). 4. Collagen synthesis, determined by measuring hydroxyproline levels, was stimulated with transforming growth factor-beta1 (40 pM), angiotensin II (10(-7) M) or 2% foetal bovine serum. The increase in collagen production, normalised by cell number, was reduced dramatically (to at or near basal production) by ANP (10(-9) to 10(-7) M) but not C-ANF4-23 (10(-7) M) in the presence of zaprinast. Again 8-bromo-cyclic GMP (10(-5) to 10(-3) M) reproduced the effect. 5. ANP is capable of inhibiting collagen synthesis in adult rat and human cardiac fibroblasts via cyclic GMP, a property unmasked and enhanced by inhibition of PDE5.
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PMID:Effect of atrial natriuretic peptide and cyclic GMP phosphodiesterase inhibition on collagen synthesis by adult cardiac fibroblasts. 972 58


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