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)

The concept of endothelium-dependent vasodilation was developed after the discovery in 1980 of the endothelium-derived relaxing factor (EDRF) by Furchtgott and Zawadzki. In 1987 Furchgott and Ignarro identified the EDRF with nitric oxide. In the same year Moncada and coworkers demonstrated that the liberation of nitric oxide by endothelial cells was responsible by the biologic activity of EDRF. Nitric oxide is the endogenous mediator responsible by the endothelium-dependent vasodilation and can be considered the endogenous nitrovasodilator. But nitric oxide has a more complex spectrum of action, because it participates in the regulation of platelet activity and preservation of the normal structure of the vessel wall. Nitric oxide is also the terminal product of the biotransformation of therapeutic nitrates responsible by guanylate cyclase activation. Nitrates can be classified as endothelium non dependent vasodilators because some of them release spontaneously nitric oxide from their metabolites, and others are biotransformed to nitric oxide in vascular smooth muscle cells.
Rev Port Cardiol 1995 Jan
PMID:[Nitric oxide-dependent endogenous and exogenous vasodilators. The mechanism of action of nitrates]. 769 56

Many similarities exist between the exogenous nitrates and endothelium-derived relaxing factor, which is nitric oxide or a thiol derivative. Both act by way of guanylate cyclase, which increases intracellular concentrations of cyclic guanosine monophosphate, resulting in smooth muscle cell relaxation and antiplatelet effects. Thiols may be important in the biotransformation of exogenous nitrates and other intracellular processes involving nitric oxide. As such, important interactions might be expected between nitrates and endothelium-dependent processes that involve nitric oxide. This review explores the mechanisms of action, biologic effects and potential interactions between nitrates and endothelium-derived relaxing factor.
J Am Coll Cardiol 1994 Aug
PMID:Nitric oxide and nitrovasodilators: similarities, differences and potential interactions. 803 95

Nitroglycerin provides an external source of nitric oxide which stimulates guanylate cyclase and produces vasodilatation and inhibition of platelet function. The antithrombotic effects of intravenous nitroglycerin were recently documented in various experimental models and in patients with unstable angina. This protocol was designed to evaluate whether these effects could also be detected with transdermal nitroglycerin in patients with stable angina. In a randomized, double-blind, controlled parallel trial, 22 patients received transdermal nitroglycerin, 0.6 mg/hour (11 patients), or placebo (11 patients). Platelet aggregation to adenosine diphosphate (ADP) and to thrombin was measured in whole blood. Thrombus formation was assessed on porcine aortic media exposed to the patient's venous blood for 3 minutes at shear rates of 2,546 and 754 s-1. Platelet aggregation to ADP decreased from 7.7 +/- 0.8 to 5.3 +/- 0.8 ohms (p < 0.05) with nitroglycerin, and to thrombin from 15.6 +/- 1.2 to 12 +/- 1.2 ohms (p < 0.05). Thrombus size at the high-shear rate decreased from 2.8 +/- 0.7 to 1.0 +/- 0.3 microns 2 (p < 0.05), and at the low-shear rate from 2.5 +/- 0.5 to 1.0 +/- 0.2 microns 2 (p < 0.05). Placebo had no significant effect on platelet aggregation and platelet thrombus deposition. These parameters were all reduced by > or = 20% in 8 patients taking nitroglycerin but only in 3 patients taking placebo (p < 0.05). Transdermal nitroglycerin significantly inhibits platelet aggregation and mural thrombus formation in patients with angina pectoris.
Am J Cardiol 1994 Jun 01
PMID:Antithrombotic properties of transdermal nitroglycerin in stable angina pectoris. 819 30

This review discusses the mechanisms of action of the organic nitrates, nitrate tolerance, and the effects of nitrates in patients with stable angina pectoris. The nitrates are prodrugs that enter the vascular smooth muscle, where they are denitrated to form the active agent nitric oxide (NO). NO activates guanylate cyclase, which results in cyclic guanosine monophosphate (cGMP) production and vasodilation as a result of reuptake of calcium by the sarcoplasmic reticulum. NO is identical to endothelium-derived relaxing factor (EDRF), which induces vasodilation, inhibits platelet aggregation, reduces endothelium adhesion, and has anticoagulant and fibrinolytic effects. Thus, the nitrates may be more than vasodilators and, in addition to reducing ischemia, may affect the process of atherosclerosis. The vascular effects of nitrates are attenuated during sustained therapy. Although the basis for the phenomenon of nitrate tolerance is not completely understood, sulfhydryl depletion as well as neurohormonal activation and increased plasma volume may be involved. The administration of N-acetylcysteine, angiotensin-converting enzyme (ACE) inhibitors, or diuretics do not consistently prevent nitrate tolerance. At present, intermittent nitrate therapy is the only way to avoid nitrate tolerance. The intermittent administration of nitrates, however, cannot provide continuous therapeutic benefits, and thus monotherapy with nitrates is not suitable for many patients with stable angina pectoris.
Am J Cardiol 1993 Sep 09
PMID:Nitrates and angina pectoris. 837 99

Nitric oxide is a biological mediator. In nervous system it acts like neurotransmitter and also modulate acute inflammation. In the peripheral nervous system it blocks the nociceptive stimulus through an increase in postsynaptic neurone GMPc level. Nitro-vasodilator drugs like nitroglycerin are metabolised in the cell given rise to short lived intermediates, which liberating nitric oxide that activate the guanylate cyclase enzyme, increasing the GMPc in smooth muscle cell. This study show that nitroglycerin produces an analgesic action. The pain sensitivity to pinprick test in forearm with nitroglycerin has shown a decrease in a significative manner against placebo. We speculate that nitroglycerin could have a similar action as endogenous nitric oxide in nervous system.
Rev Esp Cardiol 1993 Jan
PMID:[The peripheral analgesic action of the exogenous nitric oxide donor: nitroglycerin. A placebo-controlled study of the transdermal action of nitroglycerin on pain sensitivity in the forearm]. 843 Feb 33

3-Nitropropionic acid (NPA), a compound obtained from Astragalus species, elicited a dose-dependent relaxation of precontracted rabbit aortic rings. The remotion of endothelium or the presence of atropine, propranolol or brompheniramine did not modify the vasodilator effect of NPA but methylene blue clearly inhibited it. On the other hand the acute i.v. administration of NPA in normotensive rats or the chronic oral administration of NPA in renal hypertensive dogs, provoked both a decrease in blood pressure and bradycardia. Finally, NPA elicited negative inotropic and chronotropic effects in guinea pig isolated auricles, which were not blocked by atropine and it inhibited the increase in contractile force and heart rate elicited by isoproterenol. The present results indicate that NPA has vasodilator and antihypertensive properties. The arterial relaxation elicited by NPA was inhibited with methylene blue suggesting that it is a consequence of guanylate cyclase stimulation. The hypotensive effect was independent of the animal species or route of administration used. The bradycardia seen in rats and dogs and the negative chronotropic and inotropic effects observed in isolated auricles suggest that the hypotensive effect of NPA is a mixture of vasodilator and cardiodepressor actions. NPA cardiac effects may be related with inhibition of beta-adrenergic mediated responses.
Arch Inst Cardiol Mex
PMID:[An analysis of the antihypertensive properties of 3-nitropropionic acid, a compound from plants in the genus Astragalus]. 846 61

Recent reports suggest that endothelial-dependent relaxant factor, recognized as nitric oxide (NO), reduces myocardial contractility. Here, we showed that both exposures to acetylcholine and bradykinin for 30 min increased cyclic guanylate monophosphate (cyclic GMP) in isolated rat cardiomyocytes. These increases in cyclic GMP were blunted by NW-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase. Hypoxia augmented the cyclic GMP accumulation due to exposures to acetylcholine and bradykinin, which were blunted by L-NAME. The increases in cyclic GMP due to acetylcholine and bradykinin during normoxic and hypoxic conditions were not blunted by aminoguanidine, an inhibitor of inducible NO synthase. These findings revealed that NO is produced in cardiomyocytes due to stimulation of NO synthase and modulates their own guanylate cyclase, which was augmented by hypoxia. NO production, through NO synthase in cardiomyocytes, may constitute autocrine regulations of myocardial contractility and paracrine regulations of coronary vasodilation and platelet aggregation.
J Mol Cell Cardiol 1995 Oct
PMID:Evidence for nitric oxide generation in the cardiomyocytes: its augmentation by hypoxia. 857 31

In the presence of 3-isobutyl-methylxanthine (IBMX), induction of cyclic 3',5'-guanosine monophosphate (GMP) production in human washed platelets (HWP) by nitric oxide donors (NOD) is followed by its accumulation in the surrounding medium in a time- and concentration-dependent manner. Thirty minutes incubation of HWP with 3-morpholino-sydonimine (SIN-1, 10 microM) at 37 degrees C resulted in a 4.6-fold increase of cyclic GMP in platelets, whereas in the extracellular medium the increase was 17.6-fold. Similar results were obtained when other NOD such as S-nitroso-N-acetylpenicyllamine (SNAP) and 3-(2-methoxy-5-chlorophenyl)oxatriazol-5-imine (GEA 3184) and the selective phosphodiesterase inhibitor, zaprinast (M&B 22948, 10 microM), were used. Probenecid (1-300 microM), an inhibitor of organic anion transport, or ouabain (1-300 microM), an inhibitor of Na+/K+ adenine triphosphate (ATP)-ase had no effect on cyclic GMP production or extrusion after stimulation with SIN-1. Significantly prostaglandin A1 (PGA1) and prostaglandin D2 (PGD2) inhibited the efflux of cyclic GMP from platelets induced by SNAP (10 microM) in a concentration-dependent fashion, with an IC50 of 63 +/- 16 and 143 +/- 17 microM, respectively. These studies suggest that the extrusion of cyclic GMP from human platelets after activation of soluble guanylate cyclase by NOD may contribute to the control of cyclic GMP levels in platelets with potential physiological and therapeutic consequences.
Int J Cardiol 1995 Oct
PMID:Nitric oxide donors induce extrusion of cyclic GMP from isolated human blood platelets by a mechanism which may be modulated by prostaglandins. 858 70

The endothelium functions as a semipermeable membrane separating the blood from the body and allowing the transport of macromolecules from the blood to the interstitial space. The endothelium secretes a number of diffusible substances. These include endothelium-derived relaxing factor (EDRF), endothelium-derived hyperpolarizing factor (EDHF), and prostacyclin, in addition to vasoconstrictors including endothelin, angiotensin, and endothelium-derived contracting factor. EDRF is now known to be nitric oxide, or a closely related molecule, which affects signaling by stimulation of soluble guanylate cyclase, causing increased intracellular levels of cyclic guanosine monophosphate (cGMP), in turn leading to relaxation of vascular smooth muscle as well as a variety of additional effects that include altered function of platelets and cardiac myocytes. Nitric oxide can be made available to cellular elements in two ways: by endogenous synthesis via one or more of the three nitric oxide synthases now known to exist in mammalian species; or by exogenous administration of pharmacologic sources of nitric oxide, usually as organic nitrate vasodilators that can be metabolically converted to biologically activated nitric oxide. This process appears to require free sulfydryl groups. The metabolic machinery necessary to convert organic nitrates to a biologically active form exists mainly in the vasculature and not in the myocardium. Numerous studies have demonstrated that the presence of coronary artery disease is associated with interruption of the endogenous production of nitric oxide. Under these circumstances, exogenous nitrates still produce coronary vasodilation as well as relaxation of vascular smooth muscle in the periphery. Other articles in this supplement will focus on the vascular effects of nitric oxide and nitrovasodilators; this article will conclude with a brief discussion of the role of the nitric oxide pathway in the control of cardiac autonomic responsiveness and the potential role of cytokines and the nitric oxide pathway to impair the ability of the myocardium to respond to catecholamines or other stimuli with a normal increase in contractile function.
Am J Cardiol 1996 May 30
PMID:Nitric oxide and nitrovasodilators: similarities, differences, and interactions. 863 22

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.
Am J Cardiol 1996 May 30
PMID:Beneficial actions of nitrates in cardiovascular disease. 863 24


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