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)

The effects of nitrates on a Ca+2 increase and the content of cyclic nucleotides in human platelets were studied. Nitroglycerin (GTN), isosorbide dinitrate (ISDN) and sodium nitroprusside (NP) were found to inhibit dose-dependently the intracellular Ca+2 increase induced by the platelet activating factor (PAF). The inhibiting effect of NP was at lower concentrations than those of GTN and ISDN. GTN calcium blocking action did not change significantly regardless of vasopressin, serotonin or PAF used as inducers of the intracellular Ca+2 increase. GTN suppressed the PAF provoked Mn+2 entering into the cells. NP and GTN induced increase of the cGMP content correlated with their calcium blocking activity. They did not augment the level of cAMP. Methylene blue (MB), a guanylate cyclase and glutathione reductase inhibitor, decreased the calcium blocking effect of GTN and its influence on the cGMP content but failed to suppress the inhibitory effect of NP. Ascorbic acid increased the calcium blocking effect of NP but did not influence the inhibitory effect of GTN. An increase in Ca+2 content induced by PAF in platelets from patients with chronic congestive heart failure was significantly higher in the group with dilatation cardiomyopathy. The effect of 10 mg of ISDN sublingually on forearm venous tone was higher in patients with initially elevated venous tone. There was a direct statistical correlation between the IC50 of GTN calcium blocking effects in platelets and the elevation of a forearm venous tone reaction from a statistic mean reaction to ISDN.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[New approaches to the study of the mechanism of action of nitrates]. 285 8

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

LY83583 (6-anilino-5,8-quinolinedione), considered to be a relatively specific repressor of cyclic GMP formation, is shown in the present study to inhibit (K(i) = 3 microM) glutathione reductase from bovine intestinal mucosa. As glutathione disulphide has been reported to inhibit guanylate cyclase irreversibly [Braughler, Biochem Pharmacol 32: 811-818, 1983], the inhibition of glutathione reductase should affect the activity of guanylate cyclase and may thus have physiological implications in the action of endothelium-derived relaxation factor and the design of muscle relaxants. LY83583 is reduced by NADPH and glutathione reductase in aerobic media and this may offer a route to the metabolic activation of LY83583. These results may have significant implications for the design of heart-regulating drugs (e.g. those used in angina), such as glyceryl trinitrate, which act via guanylate cyclase.
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PMID:A direct link between LY83583, a selective repressor of cyclic GMP formation, and glutathione metabolism. 810 Oct 80

In cultured rat hepatocytes, we have previously demonstrated that inhibition of interleukin-1 (IL-1)-mediated nitric oxide (NO) synthesis is associated with depletion of intracellular reduced glutathione (GSH) in toxin-mediated oxidative injury. To further examine NO's effects on GSH metabolism in rat hepatocytes, IL-1-mediated NO synthesis was examined in the context of 1) cysteine, cystine, and methionine uptake; 2) gene transcription and enzyme activities for gamma-glutamylcysteine synthetase, the rate-limiting enzyme in GSH synthesis, glutathione reductase, and glutathione peroxidase; and 3) GSH and oxidized glutathione (GSSG) levels. Inhibition of NO synthesis decreased the GSH content and GSH/GSSG ratio in a guanylyl cyclase-independent fashion. Enzyme activity and steady-state levels of mRNA for gamma-glutamylcysteine synthetase were also depressed. Nuclear run-on analysis demonstrated ablation of gamma-glutamylcysteine synthetase gene transcription. Hepatocellular uptake of cysteine, cystine, and methionine was not altered. Activity and steady-state mRNA levels for glutathione reductase and glutathione peroxidase were not affected. These results indicate that IL-1-mediated NO synthesis regulates hepatocyte GSH synthesis through a mechanism that is dependent on transcriptional regulation of the rate-limiting enzyme in GSH synthesis. In the setting of oxidative stress and IL-1 exposure, hepatocyte synthesis of NO may be protective through regulation of GSH synthesis.
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PMID:Interleukin-1-induced nitric oxide production modulates glutathione synthesis in cultured rat hepatocytes. 884 15

The actions of thiols on coronary vascular tone in the intact heart are unknown. Glutathione (GSH), glutathione disulfide (GSSG), and L-cysteine (10-1,000 microM each) and GSH ethyl ester (3-300 microM) were infused into isolated rat hearts perfused with Krebs buffer at a constant pressure by the Langendorff method. GSH, GSSG, and GSH ethyl ester, but not L-cysteine, caused a concentration-dependent increase in coronary flow with the following order of potency: GSH ethyl ester > GSH = GSSG. The nitric oxide synthase inhibitor NG-monomethyl-L-arginine (300 microM), prevented the increase in coronary flow with GSH and attenuated that with GSSG (300 microM each). The vasodilation with GSH or GSSG and the associated increase in myocardial guanosine 3',5'-cyclic monophosphate were abolished by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (a specific inhibitor of soluble guanylate cyclase) at 1 and 3 microM, respectively. The vasodilator action of GSH was abolished by superoxide dismutase (50 U/ml). Inhibition of GSH reductase abolished GSSG-induced vasodilation. Neither glibenclamide (1 microM) nor indomethacin (4 microM) affected the vasodilator action of GSH and GSSG. We conclude that GSH and GSSG cause coronary vasodilation that is mediated by a nitric oxide- and guanylate cyclase-dependent mechanism, possibly mediated by the reaction between GSH and peroxynitrite to form S-nitrosoglutathione, a nitric oxide donor.
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PMID:Glutathione causes coronary vasodilation via a nitric oxide- and soluble guanylate cyclase-dependent mechanism. 932 11

This study examines the mechanism of relaxation of isolated endothelium-removed bovine coronary arteries (BCAs) to the thiol oxidant diamide. BCAs precontracted with KCl or the thromboxane A(2) receptor agonist U46619 showed a concentration-dependent reversible relaxation on exposure to 10 micromol/L to 1 mmol/L diamide. This relaxation was enhanced by an inhibitor of glutathione reductase, and it was not altered by severe hypoxia, the presence of inhibitors of soluble guanylate cyclase, K(+) channels, tyrosine kinases, or probes that modulate levels of superoxide. The relaxation was almost eliminated when BCAs were precontracted with a phorbol ester that causes a contraction that is largely independent of extracellular Ca(2+). The initial transient contraction elicited by 5-hydroxytryptamine in Ca(2+)-free solution was not altered by the presence of 1 mmol/L diamide; however, a subsequent tonic contraction on addition of CaCl(2) was inhibited by diamide. Diamide also inhibited contractions caused by the addition of CaCl(2) to Ca(2+)-free Krebs' buffer containing Bay K8644 (an L-type Ca(2+) channel opener) or KCl. Relaxation to diamide was attenuated by L-type Ca(2+) channel blockers (nifedipine and diltiazem). Thus, thiol oxidation elicited by diamide appears to activate a novel redox-regulated vasodilator mechanism that seems to inhibit extracellular Ca(2+) influx.
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PMID:Thiol oxidation activates a novel redox-regulated coronary vasodilator mechanism involving inhibition of Ca2+ influx. 1107 38