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)

Prolonged exposure to nitrovasodilators produces tolerance and dependence. Nitrovasodilators exert their action on vascular smooth muscle cells by activation of guanylyl cyclase. Nitrates share this mechanism with endothelial NO, which exerts a continuous inhibitory influence on vascular tone. Whether the basal inhibitory endothelial influence might be affected in rat aorta exposed in vitro to a tolerance-inducing concentration of nitroglycerin was investigated in this study. It was found that the basal inhibitory influence, assessed as its inhibitory influence on norepinephrine-induced contraction, and as the contractile effect of N-nitro-L-arginine methyl ester or methylene blue, was the same in nitroglycerin-tolerant and control aortic rings. Our results give an indication that changes in basal inhibitory endothelial influence are not involved in the phenomena of nitrate tolerance and nitrate dependence.
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PMID:The basal endothelial inhibitory influence on vascular tone is not affected in nitroglycerin-tolerant rat aorta. 784 93

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

The in vitro vasorelaxant and in vivo cardiovascular effects of synthetic S-nitrosothiols (RSNOs) were compared to standard nitrovasodilators. S-Nitroso-glutathione (GSNO), S-nitroso-N-acetylcysteine (NACysNO), S-nitroso-galactopyranose (GPSNO), S-nitroso-thioglycerol (TGSNO) and S-nitroso-homocysteine (HCysNO) relaxed phenylephrine (PE) contracted rabbit aorta at 50% effective concentrations (EC50s) of 3-46 nM. While nitroglycerin (GTN) exhibited in vitro tolerance after preincubation, the RSNOs were considerably less cross tolerant to GTN. In conscious dogs, GSNO, NACysNO and GPSNO (1-20 mcg/kg/min i.v.) paralleled nitroprusside (SNP) in reducing mean arterial and central venous pressure (MAP; CVP) with mild tachycardia. GSNO, NACysNO and SNP were more hypotensive and more resistant to isosorbide dinitrate (ISDN) cross tolerance than GTN. NACysNO showed mild self tolerance with low infusion (2.5 mcg/kg/min x 4h x 3 days) and blunted GTN's hypotension. These studies demonstrate that GSNO and NACysNO are SNP-like vasodilators in conscious dogs, which exhibit less cross tolerance to ISDN than GTN. Further, RSNOs relax vascular smooth muscle seemingly independent of nitric oxide (NO) liberation, and nitrate tolerance may involve reduced RSNO formation or NO release rather than desensitized guanylate cyclase (GC).
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PMID:In vitro vasorelaxant and in vivo cardiovascular effects of S-nitrosothiols: comparison to and cross tolerance with standard nitrovasodilators. 793 11

Recently, a new class of drugs has been developed with unique properties with regard to cardiovascular pharmacology: K(+)-channel openers. The increased K+ efflux from smooth muscle cells induced by these drugs is accompanied by a reduced intracellular availability of free Ca++, which in turn induces vascular relaxation. This property is currently being exploited to achieve peripheral and coronary artery dilatation in patients with ischemic heart disease. Cromakalim, pinacidil, and nicorandil, are the most extensively investigated agents in this class. Nicorandil, in addition to its K(+)-channel opener property, also shows a nitrate-like activity on guanylate cyclase of vascular smooth muscle cells. Clinical trials demonstrate that chronic administration of nicorandil can significantly increase exercise tolerance in patients with coronary artery disease. In experimental studies, this drug has also shown protective effects against myocardial injury induced by ischemia and reperfusion, by mechanisms partly independent of its vasodilating properties. These results suggest that K(+)-channel openers may have a relevant place in the pharmacological treatment of patients with ischemic heart disease.
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PMID:[Anti-angina activity of potassium-channel activators]. 802 48

Studies have indicated the involvement of a glutamatergic mechanism in lithium (Li+) action. Glutamatergic agonists, such as kainic acid, are known to promote the synthesis of nitric oxide (NO) and to increase cGMP, while Li+ has displayed a similar, yet unexplained, ability to increase cGMP. NO synthesis is regarded as the principal prodromal event leading to the activation of the guanyl cyclase-cGMP transduction mechanism. In the present study, the involvement of the NO:cGMP pathway in the action of Li+ was examined, while the possibility of a glutamatergic mechanism in this response was also investigated. Parameters examined included cortical accumulation of cGMP and the stable oxidative metabolites of NO, viz. NO2- and NO3-, collectively expressed as NO2-. A significant positive correlation was observed in the in vivo cGMP and NO2- data throughout all the groups. Chronic treatment of rats with LiCl (0.3% m/m) engendered a significant increase in cGMP levels which was inhibited by the NO-synthase (NOS) inhibitor, N-nitro-L-arginine methyl ester (L-NAME). Acute administration of kainic acid resulted in an increased accumulation of NO2-, also prevented by concomitant L-NAME administration. In addition, a synergistic stimulatory response on cortical NO2- was observed in the combination of LiCl and kainic acid. Collectively, these data implicate an involvement of a glutamatergic-mediated NO:cGMP transduction mechanism in the action of Li+.
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PMID:Evidence that lithium induces a glutamatergic: nitric oxide-mediated response in rat brain. 806 3

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

To evaluate the mechanisms involved in nitrate tolerance, we randomized 23 patients with congestive heart failure resulting from coronary artery disease to an isosorbide dinitrate or a molsidomine infusion. The drugs were titrated to decrease pulmonary capillary wedge pressure by > or = 30% or > or = 10 mm Hg. Then isosorbide dinitrate, molsidomine, or placebo was infused in a double-blind randomized manner for 24 hours. In all patients, treatment with enalapril was begun > or = 48 hours before the beginning of the protocol and was continued throughout the study to avoid renin-angiotensin activation. The pulmonary capillary wedge pressure remained significantly decreased at 24 hours during molsidomine infusion only. No significant increase in catecholamines occurred. Because molsidomine differs from organic nitrates by its property of directly stimulating guanylate cyclase without depending on thiol group availability, these results suggest that impaired biotransformation of nitrates is involved in tolerance induced by high doses of isosorbide dinitrate in congestive heart failure.
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PMID:Comparison of the hemodynamic responses to molsidomine and isosorbide dinitrate in congestive heart failure. 807 20

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

The effect of in-vitro isosorbide dinitrate (ISDN)-induced tolerance on the vasodilatory actions of streptozotocin, a nitric oxide containing compound, and papaverine was studied in rat aortic strips precontracted by phenylephrine. Aortas made tolerant to ISDN remained fully responsive to streptozotocin but exhibited a greater response to low concentrations of papaverine compared with control strips. Methylene blue produced parallel displacement to the right of the relaxant concentration-effect curves of both ISDN and streptozotocin, whereas responses to only low concentrations of papaverine were significantly antagonized. These results indicate that the relaxant activity of streptozotocin is due to the stimulation of guanylate cyclase and impaired activity of this enzyme is not likely to be the operating mechanism for nitrate tolerance. It is also suggested that the vasodilating action of papaverine is partly dependent on the tissue cGMP level.
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PMID:Absence of desensitization to the relaxant activity of streptozotocin in isosorbide dinitrate-tolerant rat aorta. 809 34

The effects of molsidomine and its metabolite linsidomine were studied on the guinea-pig isolated trachea and on the human isolated bronchus. These effects were compared with those of nitrate derivatives (sodium nitroprusside, isosorbide dinitrate), theophylline, zardaverine and isoprenaline. Linsidomine exerted a relaxant effect similar to that of sodium nitroprusside on the two types of preparations precontracted with acetylcholine, histamine or potassium chloride. Molsidomine was about one-hundredth as potent as linsidomine, and less efficacious. The effects of the two substances were not modified by removal of the human bronchial epithelium. The concentration-response curves of linsidomine and sodium nitroprusside were significantly shifted to the right by methylene blue (3 x 10(-5) M) but the effects of isoprenaline were unmodified. The effects of linsidomine and sodium nitroprusside were potentiated specifically by zaprinast (10(-6)-10(-5) M), an inhibitor of type Ia or V phosphodiesterases, whereas the effects of isoprenaline were potentiated by zardaverine (10(-9)-10(-8) M), an inhibitor of class III and IV phosphodiesterases. The effects of all three substances (linsidomine, isoprenaline and sodium nitroprusside) were potentiated equally by theophylline (10(-5)-10(-4) M), a nonspecific inhibitor of phosphodiesterases. It is concluded that linsidomine is a potent relaxant of the smooth muscle of the guinea-pig isolated trachea and human isolated bronchus. In terms of potency and efficacy, its effect is much superior to that of the parent compound molsidomine. It is suggested that linsidomine acts, like nitrate derivatives, through the guanylate cyclase-cGMP system.
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PMID:Effect of molsidomine and linsidomine on the human isolated bronchus and the guinea-pig isolated trachea. 809 68


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