Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 development of unstable angina pectoris and acute myocardial infarction is a process of platelet aggregation and thrombus formation associated with local coronary vasoconstriction. Regional deficiencies in endothelial vasodilator function, due to reduced formation of endothelium-derived relaxing factor (EDRF), may predispose to platelet aggregation and coronary vasoconstriction. Nitroglycerin (NTG), frequently utilized in the management of unstable angina pectoris and acute myocardial infarction, undergoes bioconversion, via a sulfhydryl-dependent process, to nitric oxide, which is identical or closely related to EDRF. Other products of the nitrate bioconversion "cascade" are various S-nitrosothiols, which, like nitric oxide, activate soluble guanylate cyclase, inducing increased formation of cyclic guanosine monophosphate. NTG potentially may act to correct a localized deficiency of EDRF effect, at both the vasculature and platelet levels. In patients with unstable angina, hemodynamic effects and therapeutic efficacy of intravenously infused NTG may be attenuated within hours. Combined therapy with NTG and intravenously infused N-acetylcysteine (NAC) results in potentiation of hemodynamic responses to NTG, markedly augments the effects of NTG on platelet aggregation, and reduces the incidence of acute myocardial infarction in patients with severe unstable angina pectoris. The combination of NTG with intermittent NAC infusion may increase the risk of hypotensive episodes in such patients, whereas continuous coinfusion of the drugs is better tolerated. The combination of NTG with thiol-containing agents, such as NAC, may be of therapeutic value in unstable angina pectoris and in evolving acute myocardial infarction. This is currently under investigation.
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PMID:Thiol-containing agents in the management of unstable angina pectoris and acute myocardial infarction. 192 1

Nitrates are among the most widely prescribed drugs in cardiovascular disease. They are able to prevent and to interrupt episodes of myocardial ischaemia, alleviate anginal symptoms, and exert favourable effects in acute myocardial infarction and in congestive heart failure. Most of these effects can be explained by their ability to relax smooth muscle cells: peripheral vasodilation, in veins and in arteries, reduces cardiac workload, thereby decreasing oxygen consumption; furthermore, nitrates dilate coronary arteries directly, thereby increasing myocardial oxygen supply. However, nitrates also exert effects on blood platelets. These occur by the same mechanisms operating on blood vessels, a stimulation of soluble guanylate cyclase and a consequent increase in cytosolic levels of cyclic GMP. When added to platelet suspensions nitrates inhibit platelet aggregation by almost all known stimuli. Such effects in vitro generally require high concentrations of drugs; evidence has been obtained, however, that nitrates may inhibit platelet function also in vivo. Such evidence derives from ex vivo studies with platelet aggregometry, from experiments showing the synergism of nitrates and prostacyclin and the requirement for nitrate action of sulphydryl group donors such as N-acetyl-cysteine, and from studies on bleeding time. Antiplatelet effects of nitrates may be an explanation for the protection from death and reinfarction, inferred on the basis of meta-analysis of several studies in acute myocardial infarction.
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PMID:[Antiplatelet effects of nitrate derivatives]. 193 57

The vasodilator effects of nitroglycerin (NTG) are mediated via activation of guanylate cyclase; this process is believed to require the availability of free sulfhydryl groups. Previous studies in man have shown that the sulfhydryl donor N-acetylcysteine (NAC) potentiates the systemic and coronary vasodilator effects of NTG. Furthermore, interaction of NTG and NAC may lead to the formation of S-nitroso-NAC, which strongly inhibits platelet aggregation. The effects of intravenous NTG combined with intravenous NAC (5 g 6 hourly) were compared with those of intravenous NTG alone in a double-blind trial in 46 patients with severe unstable angina pectoris unresponsive to conventional treatment, which included calcium antagonists and cutaneous nitrates in all but one patient. Treatment with NTG/NAC (24 patients) and that with NTG alone (22 patients) was associated with a similar frequency of episodes of chest pain and of increments in NTG infusion rate for pain control (10 vs 17; p = NS). The NTG/NAC group had a significantly lower incidence of acute myocardial infarction than the NTG/placebo group (three vs 10 patients; p = .013). Symptomatic hypotension occurred frequently in the NTG/NAC group (seven vs 0 patients; p = .006). Lactate-pyruvate ratios and venous NTG concentrations were not significantly affected by NAC. Subsequently, another 20 consecutive patients were treated with intravenous NTG and continuously infused NAC (10 g/day). Seven remained pain free during the first 24 hr of NTG infusion; 11 required increments in NTG infusion rate for pain control. Acute myocardial infarction occurred in one patient, while none developed symptomatic hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Combined use of nitroglycerin and N-acetylcysteine in the management of unstable angina pectoris. 312 76

Nitroglycerin has maintained its position in the treatment of angina pectoris for more than a century. Efficacy of oral nitrates has been established and compares well with that of other anti-anginal drugs. New delivery systems are being developed for sustained systemic nitrate action. Beneficial action of nitrates in congestive heart failure and their crucial role in unstable angina and acute myocardial infarction has further widened their therapeutic use. A plausible hypothesis of the mechanism of nitrate-induced vasodilation has been presented, involving production of nitrosothiols and activation of guanylate cyclase in the vascular smooth muscle. Recent developments suggest that the rate degradation of nitrates and formation of nitrosothiols in the vascular smooth muscle are linked, offering an explanation to the relatively rapidly developing, but partial vascular tolerance during high-dose nitrate therapy.
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PMID:Efficacy of different forms of nitrates in angina pectoris. 392 83

Besides their well-known relaxing effects on smooth muscle cells--the basis for vasodilation in peripheral arteries and veins and in epicardial coronary arteries--nitrates also exert effects on blood platelets. These occur by the same mechanisms operating in blood vessels, a penetration of the parent molecule or its active metabolites through the plasma membrane, the release of the reactive free radical NO, the stimulation of guanylate cyclase and the consequent increase of cytosolic levels of cyclic guanosinemonophosphate (cGMP). As a consequence, platelets become unspecifically less reactive to a variety of aggregating stimuli. When added to platelet suspensions nitrates indeed inhibit platelet aggregation by virtually all known stimuli. These in vitro anti-platelet effects require high concentrations of the drugs; however, recent evidence has been gathered that such inhibition of platelet function also occurs during the in vivo administration of nitrates. Such evidence derives from direct ex vivo studies with platelet aggregometry, from experiments showing synergism of nitrates with prostacyclin and the amplification of ex vivo effects with sulfhydryl group donors such as N-acetyl-cysteine, and, finally, from studies on the bleeding time. The effects of nitrates on blood platelets may be an explanation for the protection from death and reinfarction inferred on the basis of metaanalysis of several studies in acute myocardial infarction.
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PMID:[Nitrates as thrombocyte function inhibitors]. 794 47

Nitrates are the most widely prescribed drug category in ischemic heart disease, being able to prevent and to interrupt episodes of myocardial ischemia, alleviate anginal symptoms, exert favorable effects in acute myocardial infarction. Their vascular actions, on peripheral arteries and veins, as well as on coronary arteries, can explain most of these effects. However, nitrates also exhibit platelet-inhibiting properties, mediated by the same cellular mechanisms operating on smooth muscle cells, i.e., via stimulation of guanylate cyclase and subsequent increase in cytosolic levels of cyclic GMP. When added to platelet suspensions, nitrates inhibit platelet aggregation induced by most stimuli. These in vitro effects usually require high drug concentrations; there is evidence, however, that nitrates may inhibit platelet function also in vivo. Such evidence derives from a) ex vivo studies with platelet aggregometry; b) the appreciation of a synergism between nitrates and prostacyclin; c) the appreciation of a need, for nitrate actions in vivo, of sulfhydryl group donors, such as N-acetylcysteine, and d) from studies on bleeding time. Antiplatelet effects of nitrates may be an explanation for the protection from cardiac death and reinfarction inferred on the basis of a meta-analysis of many studies of nitrates in acute myocardial infarction.
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PMID:[Nitro derivatives as antiplatelet agents]. 808 22

Brain natriuretic peptide (BNP) is a cardiac hormone with a spectrum of activities quite similar to those of atrial natriuretic peptide (ANP), including diuretic, natriuretic, hypotensive and smooth muscle relaxant activities. These effects are due to the stimulation of guanylate cyclase-linked natriuretic peptide receptors, leading to an increase in cyclic GMP concentration in target cells. BNP has a lower affinity than ANP for C (clearance) receptors, and is less susceptible to degradation by neutral endopeptidase-24.11, resulting in a longer half-life. In the kidney, BNP increases the glomerular filtration rate and inhibits sodium reabsorption in the distal tubule. It also inhibits the release of renin and aldosterone. Unlike ANP, produced by the atria, BNP is mainly synthesized and released into circulation by the left ventricle and is therefore influenced by stimuli involving this cardiac chamber, such as an increase in arterial pressure, left ventricular hypertrophy and dilation. Plasma BNP levels are very low in healthy subjects, and respond modestly, although significantly to physiological stimuli such as changes in posture or sodium intake. In contrast, plasma BNP concentrations increase in disease states such as cirrhosis with ascites, hypertension, chronic renal failure, acute myocardial infarction and congestive heart failure. In the latter condition, plasma BNP concentration is a reliable prognostic index. Evidence obtained by administering BNP to healthy subjects and hypertensive patients suggests that BNP, at physiological and pathophysiological plasma concentrations, markedly influences cardiovascular homeostasis, mainly due to its effects on sodium excretion and the renin-aldosterone axis.
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PMID:[Brain natriuretic peptide]. 871 58

Nitroglycerin and its derivatives are among the most potent drugs to treat angina pectoris. The compounds relax all smooth muscle cells by stimulating the soluble guanylate cyclase. The clinical application takes advantage of the different sensitivities of the vascular smooth muscles (veins > arteries > arterioles) to nitrates. Selective vasodilation of capacity veins and coronary arteries leads to reduced myocardial oxygen consumption and improved myocardial perfusion. Hypotension due to effective dilation of resistance arteries limits the antianginal effects because of reduced coronary perfusion. Treatment of symptoms in stable angina is well established and unquestioned as long as the dose regimen avoids tolerance; however, there is no evidence of reducing mortality with nitrates in these patients. In acute coronary syndromes such as unstable angina pectoris and acute myocardial infarction nitrates, but not nitroprusside, can be applied safely to relief symptoms and to treat vasospasm, if the dose is titrated to avoid hypotension. Recent large multicenter trials (GISSI-3, ISIS-4) have not confirmed the postulate derived from previous studies, that nitrates reduce the mortality from acute myocardial infarction within the first month.
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PMID:[Use of nitrates in coronary heart disease including acute myocardial infarct]. 876 22

Natriuretic peptide system consists of three endogenous ligands, ANP (atrial natriuretic peptide), BNP (brain natriuretic peptide) and CNP (C-type natriuretic peptide), and three receptor subtypes, natriuretic peptide receptor (NPR)-A or guanylate cyclase (GC)-A and NPR-B or GC-B and C receptor (NPR-C). ANP and BNP are mainly secreted from the atrium and ventricle of the heart respectively to act as cardiac hormones whereas CNP is secreted from the endothelium to act as an endothelium-derived relaxing peptide. ANP and BNP regulate body fluid and blood pressure to reduce cardiac pre- and after-load. Recent molecular biology and developmental biotechnology demonstrated the physiological role of ANP and BNP for the determination of basal blood pressure. CNP can modulate the phenotype of vascular smooth muscle cells to regulate vascular remodeling. Therefore, natriuretic peptide system is implicated in the pathophysiology of hypertension, congestive heart failure atherosclerosis and renal diseases. Clinical application of natriuretic peptide system is actively going on progress. Determination of plasma ANP and BNP levels are useful for the evaluation of congestive heart failure, cardiac hypertrophy and acute myocardial infarction. Infusion of ANP improves acute heart failure. Application of NEP (neutral endopeptidase) inhibitor for the treatment of congestive heart failure and hypertension is under clinical trial.
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PMID:[Natriuretic peptide system]. 928 3


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