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)

We have directly compared the effects of the nitrates isosorbide-5-mononitrate, nitroglycerin and isosorbide dinitrate and of the nitric oxide-containing sodium nitroprusside and 3-morpholino-sydnonimine (SIN 1) as well as of the bioinactive precursor of SIN 1, molsidomine, on platelet activating factor-induced platelet aggregation and activation of soluble guanylate cyclase. The effects of these agents on the aggregation and on soluble guanylate cyclase activity of human platelets were closely correlated. Whereas nitroprusside and SIN 1 were very potent inhibitors of aggregation and activators of soluble guanylate cyclase in micromolar concentrations, the other drugs were effective only at millimolar concentrations. Preincubation of platelets with cysteine did not or only slightly increase the ability of isosorbide-5'-mononitrate and isosorbide dinitrate to inhibit aggregation, but a clear increase was observed after preincubation with nitroglycerin. These data support the concept that cyclic GMP is the mediator of nitric oxide-induced inhibition of platelet aggregation and indicate that nitrates cannot directly inhibit aggregation or be converted to nitric oxide-containing agents by a specific mechanism in platelets. The data also suggest that SIN 1 and nitroprusside, but not or only to a certain degree the nitrates, can be considered as exogenous endothelium-derived relaxing factors.
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PMID:Direct comparison of the effects of nitroprusside, SIN 1, and various nitrates on platelet aggregation and soluble guanylate cyclase activity. 290 6

Tolerance of vascular smooth muscle to nitroglycerin could be induced by an impaired biotransformation of nitroglycerin to nitric oxide, the activator of soluble guanylate cyclase, or by desensitization of guanylate cyclase to activation with nitric oxide. The latter would imply that there would also be tolerance to nitric oxide delivered from sodium nitroprusside or endothelial cells. Therefore, endothelium-denuded segments of rabbit aorta were treated with nitroglycerin to induce tolerance, and were then assessed for mechanical response, cyclic GMP content, and activity of soluble guanylate cyclase after addition of nitrovasodilators. Nitrate tolerance decreased the vasodilation and the increase in cyclic GMP elicited by nitroglycerin, but not that elicited by sodium nitroprusside or endothelium-derived relaxing factor, in norepinephrine-contracted segments. However, soluble guanylate cyclase in the supernatants of homogenates of nitrate-tolerant aortas was desensitized to activation with nitroglycerin and sodium nitroprusside. As the guanylate cyclase was still responsive to activation by nitric oxide in the intact, tolerant smooth muscle, an impaired biotransformation of nitroglycerin rather than desensitization of soluble guanylate cyclase may be the mechanism by which nitrate tolerance develops.
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PMID:Desensitization of guanylate cyclase in nitrate tolerance does not impair endothelium-dependent responses. 290 5

Molsidomine is enzymatically metabolized in the liver to SIN-1 and readily converted into the active metabolite SIN-1A, which carries a free nitroso group. Evidence obtained in isolated circular strips from bovine coronary arteries indicates that SIN-1 increases cyclic guanosine monophosphate in close association with its relaxant effects in coronary strips under various pharmacologic conditions, suggesting that cyclic guanosine monophosphate mediates relaxation. Various nitrovasodilators act by the same mechanism, which is stimulation of guanylate cyclase. In this study the effect of nitroglycerin depended on the presence of a special thiol, cysteine, whereas SIN-1 was active also in the absence of cysteine. Cysteine deficiency was found to be associated with tolerance. After prolonged exposure to the drug, tolerance toward nitroglycerin developed in coronary strips that was antagonized by cysteine. SIN-1 produced no significant tolerance and was also fully active in nitroglycerin-tolerant strips. We conclude that SIN-1 relaxes vascular smooth muscle by direct stimulation of guanylate cyclase, whereas nitroglycerin probably must be converted into a cyclase stimulator by a cysteine-dependent reaction.
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PMID:Mechanism of vasodilation by molsidomine. 298 23

The present study investigated possible involvement of cysteine (CSH) and reduced glutathione (GSH) as critical cellular sulfhydryls which mediate nitroglycerin (GTN)-induced cyclic GMP accumulation and relaxation in bovine coronary artery (BCA). Tolerance to the relaxant effects of GTN was induced in BCA in vitro by preincubation with 1 mM GTN for 2 h. GTN-tolerant BCA were at least 100-fold less sensitive than non-tolerant BCA to the relaxant effects of GTN. Consistent with a relationship between tolerance to both GTN-induced cyclic GMP accumulation and relaxation, cyclic GMP accumulation induced by 1 microM GTN was markedly reduced in GTN-tolerant BCA when compared with non-tolerant BCA. Incubation with 1 mM CSH for 1 h did not significantly alter GTN-induced cyclic GMP accumulation or relaxation in either GTN-tolerant or non-tolerant BCA. Levels of CSH, GSH and glutathione-disulfide (GSSG) were measured in non-tolerant BCA, GTN-tolerant BCA and GTN-tolerant BCA incubated with 1 mM CSH for 1 h. Levels of CSH and GSH were lower in GTN-tolerant BCA than in non-tolerant BCA, whereas GSSG levels were similar in both. In GTN-tolerant BCA incubated with 1 mM CSH, CSH levels were more than 10-fold above, and GSH levels were similar to corresponding values obtained in non-tolerant BCA. These data indicate that although incubation with CSH did not significantly reverse tolerance to GTN-induced cyclic GMP accumulation and relaxation in BCA, it did effectively raise the level of CSH and GSH in GTN-tolerant BCA, at least to corresponding levels found in non-tolerant BCA. These results indicate that the relaxant effects of GTN in BCA do not correlate with tissue levels of CSH and GSH. The findings do not support the hypothesis that CSH and GSH are the cellular sulfhydryls involved in mediating GTN-induced guanylate cyclase activation, cyclic GMP accumulation and relaxation in intact BCA.
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PMID:Dissociation of cysteine and glutathione levels from nitroglycerin-induced relaxation. 299 Sep 47

The mode of action of the in vitro active metabolites SIN-1 and SIN-1A of the vasodilator prodrug molsidomine was studied in bovine coronary artery strips. Both compounds increased cyclic GMP levels in close association with, but prior to their relaxing action. Relaxation and rises in cyclic GMP by SIN-1 were potentiated by M & B 22,948, an inhibitor of cyclic GMP phosphodiesterase and attenuated by methylene blue, a dye that inhibits activation of guanylate cyclase by SIN-1 and various nitrovasodilators. A single significant correlation between rises in cGMP and relaxation was obtained for both SIN compounds and various nitrovasodilators. Relaxation by SIN-1A was independent of the presence of endothelium and was not affected by various inhibitors of arachidonic acid metabolism. In contrast to nitroglycerin, SIN-1 did not induce substantial tolerance nor were its actions reduced in artery strips that were tolerant to nitroglycerin. The results indicate that SIN-1A relaxes coronary smooth muscle by a direct stimulant effect on soluble guanylate cyclase in vascular smooth muscle cells.
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PMID:Cyclic GMP as the mediator of molsidomine-induced vasodilatation. 300 72

The mechanism whereby nitroglycerin relaxes vascular smooth muscle remains uncertain. A current hypothesis suggests that nitroglycerin reacts with critical cellular sulfhydryl groups to form an intermediate, which activates guanylate cyclase, resulting in cGMP accumulation and relaxation. This study investigated further the potential involvement of sulfhydryls in nitroglycerin-induced vascular smooth muscle relaxation by evaluating effects of a variety of sulfhydryl alkylating and reducing agents on responses to nitroglycerin and other relaxants in bovine coronary arterial strips submaximally contracted using 30 mM K. Whereas 10(-4) M 5,5'-dithiobis-(2-nitrobenzoic acid), 10(-5) MN-ethylmaleimide, and 10(-4) MN-naphthylmaleimide did not affect nitroglycerin-induced relaxation, 10(-4) MN-ethylmaleimide and 10(-4) M ethacrynic acid significantly inhibited relaxation induced by nitroglycerin. Both ethacrynic acid and N-ethylmaleimide at 10(-4) M also inhibited relaxation induced by sodium nitroprusside. N-ethylmaleimide, but not ethacrynic acid, inhibited relaxation induced by isoproterenol and forskolin. Ethacrynic acid significantly reduced both relaxation and cGMP elevation induced by both 10(-7) M nitroglycerin and 10(-7) M sodium nitroprusside. Ethacrynic acid, but not N-ethylmaleimide, significantly reduced relaxation induced by 8-Br-cGMP. Pretreatment with the sulfhydryl-containing agents N-acetylcysteine, 2-mercaptoethanol, or dithiothreitol, at 10(-3) M did not affect nitroglycerin-induced relaxation in nontolerant arteries. Similarly, N-acetylcysteine and dithiothreitol did not alter the depressed responses to nitroglycerin in arteries in which tolerance to nitroglycerin was induced in vitro. A slight but statistically significant reversal of nitroglycerin-tolerance occurred after treatment of tolerant arteries with 2-mercaptoethanol.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of sulfhydryl reagents on nitroglycerin-induced relaxation of bovine coronary artery. 302 84

The effects of nitrates on Ca2+ increase and cyclic nucleotide content in human platelets were studied. Nitroglycerin, isosorbide dinitrate and sodium nitroprusside were found to inhibit the intracellular Ca2+ increase induced by the platelet activating factor, ADP and a stable thromboxane A2 analog--U46619. The inhibiting effect of sodium nitroprusside manifested itself at lower concentrations than those of nitroglycerin and isosorbide dinitrate. Nitroglycerin suppressed the Mn2+ entry into the cells and caused a 2-fold increase of the cGMP content which correlates with the calcium blocking activity. Methylene blue, a guanylate cyclase and glutathione reductase inhibitor, decreased the calcium blocking effect of nitroglycerin and its influence on the cyclic nucleotide content but failed to suppress the inhibitory effect of sodium nitroprusside. The data obtained suggest that the effects of nitrates on platelets are mediated by their influence on guanylate cyclase which leads to a cyclic nucleotide content increase and to a calcium blocking effect.
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PMID:[Calcium-blocking effect of nitro compounds in human platelets: correlation with changes in the cyclic guanosine monophosphate level]. 303 39

Although prostaglandin E1 is used to dilate the constricted ductus arteriosus in infants with cyanotic heart disease, the mechanism is unknown. To test the hypothesis that the cyclic nucleotides adenosine 3',5'-monophosphate (cAMP) and guanosine 3',5'-monophosphate (cGMP) play a role in relaxation, isolated rings of the ductus arteriosus of fetal lambs were studied. Tension of isometric contraction was measured by force displacement transducers. After contraction with oxygen, a control group was compared with rings in which the stimulus for relaxation was either nitrogen gas, prostaglandin E1 (PGE1), nitroglycerin (NTG), or nitroprusside (NPS). During relaxation, tissue was frozen at 30 seconds and at 1, 2, and 5 minutes and analyzed for cAMP and cGMP. PGE1 (10(-6) mol/L) decreased tension by 33% compared with 70% for nitrogen gas, 81% for NTG (10(-5) mol/L), and 92% for NPS (10(-5) mol/L). The maximal relaxation induced by PGE1 was associated with an 11-fold increase in cAMP; PGE1 had no significant effect on cGMP tissue levels. Nitrogen gas, NTG, and NPS produced similar increases in cAMP, and eight-, 25-, and nine-fold increases in cGMP, respectively. These results suggest that the patency of the ductus arteriosus is dependent on activation of both guanylate cyclase and adenylate cyclase and that the nitrovasodilators may be clinically useful in maintaining patency of the ductus arteriosus.
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PMID:Role of cyclic nucleotides in relaxation of fetal lamb ductus arteriosus. 303 77

cGMP appears to be the intracellular messenger involved in smooth muscle relaxant effects of three major groups of vasodilators, the ANFs, the nitrovasodilators (such as nitroglycerin, sodium nitroprusside, sodium nitrite, isosorbide dinitrate), and the endothelium-dependent vasodilators (such as ACh, histamine, bradykinin, adenosine triphosphate, A23187). The endothelium-dependent vasodilators apparently act by stimulating the release of EDRF from endothelial cells, which in turn activates soluble guanylate cyclase in vascular smooth muscle cells. Because of similarities between EDRF and the nitrovasodilators, EDRF has been termed the "endogenous nitrovasodilators." Very recent evidence suggests that EDRF may be identical with nitric oxide, the intermediate substance generated by the nitrovasodilators, thus further illustrating the similarities between nitrovasodilator-induced and endothelium-dependent vasodilation. Following the elevation of cGMP levels in smooth muscle, cGMP-kinase becomes activated and phosphorylates cellular protein or proteins involved in the regulation of cytosolic free Ca2+ concentrations. This mechanism vasoconstrictor. In the absence of vasoconstrictors, cGMP, even at basal levels, seems to be important for maintaining cytosolic Ca2+ at low concentrations and for keeping the vascular smooth muscle in a relatively relaxed state. Future experiments will need to clarify further the role of cGMP and cGMP-kinase in physiologic and pathophysiologic regulation of blood vessels. Of prime interest is the identity of functional substrates for cGMP-kinase in vascular smooth muscle.
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PMID:Molecular mechanisms of endothelium-mediated vasodilation. 305 34

Previous studies have suggested that (1) nitroglycerin causes vasodilatation by interacting with sulfhydryl groups in vascular smooth muscle, thereby activating guanylate cyclase and increasing the intracellular concentration of cyclic GMP, and (2) N-acetylcysteine, a source of sulfhydryl groups, potentiates the peripheral vasodilatory effect of nitroglycerin. This study was performed to explore the influence of N-acetylcysteine on nitroglycerin-induced coronary dilatation. In 18 patients (13 men and five women, 30 to 76 years old), coronary sinus blood flow (by thermodilution) was measured before and during intracoronary administration of nitroglycerin, 25 micrograms, both before and 5 min after a 15 min intravenous infusion of (1) 5% dextrose in water (n = 8, control) or (2) 100 mg/kg N-acetylcysteine (n = 10). Nitroglycerin caused no change in heart rate or systemic arterial pressure. In the control patients, coronary sinus blood flow behaved similarly during the two injections: it was 134 +/- 36 ml/min (mean +/- SD) before and 183 +/- 50 ml/min during injection No. 1 (average increase, 49 +/- 25 ml/min; average percent increase, 38 +/- 21%); and it was 131 +/- 34 ml/min before and 178 +/- 45 ml/min during injection No. 2 (average increase, 47 +/- 23 ml/min; average percent increase, 37 +/- 20%) (NS compared with injection 1). In the patients who received N-acetylcysteine, coronary sinus blood flow was 149 +/- 48 ml/min before and 191 +/- 54 ml/min during injection 1 (average increase, 42 +/- 15 ml/min; average percent increase, 30 +/- 12%) (NS compared with eight control values).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Potentiation of nitroglycerin-induced coronary dilatation by N-acetylcysteine. 307 76


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