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 rate of loss of the sulfhydryl group, determined with the Ellman reagent, was used to derive second order rate constants for the reaction of a series of organic nitrates with a series of sulfhydryl compounds. For the organic nitrates, increases in the rate of reaction with cysteine, in general, ran parallel both with increases in pharmacological potency (flow in the Langendorff heart) and with increases in total clearance. Cysteine was the most active sulfhydryl compound examined, which is compatible with a possible role as an important nitrate receptor. Under some conditions the rate of loss of the sulfhydryl group was much greater than the rate of formation of nitrite ion. This indicates the presence of a reaction intermediate, probably a thionitrate. It is suggested that, in vivo, a thionitrate could function as an important intermediate in the activation of guanylate cyclase.
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PMID:The reaction between organic nitrates and sulfhydryl compounds. A possible model system for the activation of organic nitrates. 407 11

Glyceryl trinitrate specifically required cysteine, whereas NaNO2 at concentrations less than 10 mM required one of several thiols or ascorbate, to activate soluble guanylate cyclase from bovine coronary artery. However, guanylate cyclase activation by nitroprusside or nitric oxide did not require the addition of thiols or ascorbate. Whereas various thiols enhanced activation by nitroprusside, none of the thiols tested enhanced activation by nitric oxide. S-Nitrosocysteine, which is formed when cysteine reacts with either NO-2 or nitric oxide, was a potent activator of guanylate cyclase. Similarly, micromolar concentrations of the S-nitroso derivatives of penicillamine, GSH and dithiothreitol, prepared by reacting the thiol with nitric oxide, activated guanylate cyclase. Guanylate cyclase activation by S-nitrosothiols resembled that by nitric oxide and nitroprusside in that activation was inhibited by methemoglobin, ferricyanide and methylene blue. Similarly, guanylate cyclase activation by glyceryl trinitrae plus cysteine, and by NaNO2 plus either a thiol or ascorbate, was inhibited by methemoglobin, ferricyanide and methylene blue. These data suggest that the activation of guanylate cyclase by each of the compounds tested may occur through a common mechanism, perhaps involving nitric oxide. Moreover, these findings suggest that S-nitrosothiols could act as intermediates in the activation of guanylate cyclase by glyceryl trinitrate, NaNO2 and possibly nitroprusside.
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PMID:Requirement of thiols for activation of coronary arterial guanylate cyclase by glyceryl trinitrate and sodium nitrite: possible involvement of S-nitrosothiols. 610 89

Relaxation by nitroglycerin, sodium nitrite, and amyl nitrite of bovine coronary arterial smooth muscle was inhibited by the oxidant methylene blue. Methylene blue also inhibited activation of bovine coronary arterial soluble guanylate cyclase by nitroglycerin, which required addition of cysteine. At concentrations less than 10 mM, sodium nitrite required the addition of one of several thiols or ascorbate to activate guanylate cyclase from bovine coronary artery. Guanylate cyclase activation by large amounts (50 microL) of saturated amyl nitrite gas did not require, but was enhanced by, the addition of thiols or ascorbate. However, similar to sodium nitrite, guanylate cyclase activation by smaller amounts (5 microL) of saturated amyl nitrite gas did require the addition of one of various thiols or ascorbate. Methylene blue markedly inhibited guanylate cyclase activation by sodium nitrite in the presence of cysteine or ascorbate and similarly inhibited enzyme activation by amyl nitrite either in the absence or presence of cysteine or ascorbate. These data support the hypothesis that nitrates and nitrites relax vascular smooth muscle by stimulating cyclic GMP formation. The results further suggest that, similar to relaxation and guanylate cyclase activation by nitroso-containing compounds, relaxation and enzyme activation by nitrates and and nitrites may involve the formation of nitric oxide or complexes of nitric oxide as active intermediates.
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PMID:Methylene blue inhibits coronary arterial relaxation and guanylate cyclase activation by nitroglycerin, sodium nitrite, and amyl nitrite. 611 57

Guanylate cyclase activity was purified to apparent homogeneity from rat liver (7700-fold) and bovine lung (8600-fold) soluble fractions by ammonium sulfate precipitation, DEAE-cellulose chromatography, agarose gel filtration and isoelectric focussing. The purified enzymes did not contain heme and did not respond to NO, nitroprusside or NO-cysteine in the absence of exogenous hematin. By contrast, preformed NO-hemoglobin increased enzyme activity 10-12-fold or 60-80-fold when 4 mM MnCl2 or 4 mM MgCl2, respectively, were employed as the metal ion co-factor. Addition of hematin to the enzyme preparations restored responsiveness to NO, nitroprusside or NO-cysteine to levels seen with NO-hemoglobin. Partial purification of guanylate cyclase from the soluble fraction of bovine lung (2400-fold) by ammonium sulfate precipitation, DEAE-cellulose chromatography, agarose gel filtration and high pressure liquid chromatography (HPLC) resulted in a preparation which contained endogenous heme as indicated by absorbance at 436 nm and responded to NO, nitroprusside and NO-cysteine in the absence of added hematin. By contrast, guanylate cyclase purified from the hepatic supernatant by the identical procedure, did not contain detectable absorption due to heme and did not respond or responded poorly to NO, nitroprusside or NO-cysteine in the absence of exogenous hematin. Analogous to hepatic guanylate cyclase purified by isoelectric focussing, the HPLC purified hepatic enzyme was activated 14-fold by NO-hemoglobin in assays which contained 4 mM MnCl2 and 60-fold in assays with 4 mM MgCl2. Further, addition of hematin to the HPLC purified enzyme restored responsiveness to NO, nitroprusside and NO-cysteine to levels seen with NO-hemoglobin. These effects of hematin were specific for hematin and were not mimicked by albumin, sucrose or dithiothreitol. Moreover, the failure to observe stimulation of purified hepatic guanylate cyclase was not explained by a shift in the concentration response relationship between NO and guanylate cyclase activity. Several observations indicated that neither NO-thiol complexes nor [Fe(CN)5NO]-3 were the proximate moieties responsible for activation of guanylate cyclase by nitroprusside and related agents, as has been previously suggested. These results strongly support the proposal that activation of guanylate cyclase by NO and related agents specifically requires formation of an NO-heme complex.
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PMID:Requirement for heme in the activation of purified guanylate cyclase by nitric oxide. 613 53

We examined the effects of disulfide and thiol compounds on Escherichia coli heat-stable enterotoxin (ST) and cyclic GMP-induced secretion. Both cystamine and cystine (disulfide compounds) reduced the secretory responses to submaximal doses of ST in suckling mice (at 0.5 mumol per mouse) and reduced ST activation of guanylate cyclase (by 33 to 73% at 1 mM). In higher doses, cystamine completely eradicated a maximally effective ST dose as well. In addition, the sulfhydryl (thiol) compounds cysteamine, cysteine, and acetylcysteine strikingly reduced the secretory response and the guanylate cyclase response to ST. Neither the disulfide nor the thiol compounds tested reduced cyclic GMP-induced secretion. These studies suggest that disulfide and thiol compounds both block ST-induced secretion before its activation of guanylate cyclase. Taken with the work of others, these findings suggest that disulfide compounds may alter the oxidation reduction state of a cell or act directly on the guanylate cyclase enzyme, whereas thiol compounds may inactivate ST itself by breaking its disulfide bridges, or it may alter guanylate cyclase activation by ST. Both families of compounds deserve further consideration among potential antisecretory agents for application in the control of ST-induced diarrhea.
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PMID:Reduction of the secretory response to Escherichia coli heat-stable enterotoxin by thiol and disulfide compounds. 613 77

Recent studies have suggested that cyclic GMP accumulation in platelets mediates the antiaggregatory effects of certain nitrogen oxide-containing agents such as sodium nitroprusside, nitric oxide, nitrosoguanidines, and related agents. The vasodilator effect of these agents may involve the formation of S-nitrosothiol intermediates which relax vascular smooth muscle, elevate tissue levels of cyclic GMP, and activate guanylate cyclase. The purpose of this study was to investigate the effects of various synthetic S-nitrosothiols on human platelet aggregation. The S-nitroso derivatives of N-acetylpenicillamine, cysteine, and beta-D-thioglucose inhibited human platelet aggregation in a concentration-dependent fashion when ADP, collagen, U46619, or sodium arachidonate was employed as the aggregating agent. The antiaggregatory effects of the S-nitrosothiols were associated with a rapid and marked increase in intracellular platelet cyclic GMP levels, whereas cyclic AMP levels remained unchanged. Additionally, S-nitrosothiols disaggregated platelets which had been aggregated while concomitantly elevating platelet cyclic GMP levels. Moreover, guanylate cyclase, partially purified from the soluble fraction of human platelets, was markedly activated by S-nitrosothiols in a heme-dependent manner. Methemoglobin, a hemoprotein with a high affinity for nitric oxide, partially reversed the antiaggregatory effects, attenuated the accumulation of cyclic GMP, and inhibited the activation of guanylate cyclase by S-nitrosothiols. These data are consistent with the hypothesis that S-nitrosothiols could serve as active intermediates in the inhibitory action of sodium nitroprusside, nitric oxide, and related nitrogen oxides on platelet aggregation.
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PMID:Inhibition of human platelet aggregation by S-nitrosothiols. Heme-dependent activation of soluble guanylate cyclase and stimulation of cyclic GMP accumulation. 613 48

The effects of thiols on guanylate cyclase activation by nitroglycerin were studied in bovine heart and the effects of cysteinee and nitroglycerin on the tissue levels of cyclic GMP and lactate were studied in beating rat atria. Cysteine (2.5 X 10(-3) M) together with nitroglycerin (1 X 10(-3) M), increased 15-fold the activity of guanylate cyclase. In hypoxia, nitroglycerin (1 X 10(-3) M) together with cystein (5 X 10(-3) M) increased cyclic GMP and decreased the tissue lactate level. It is concluded that cysteine potentiates the effect of nitroglycerin on cyclic GMP formation even in integrated cell systems with an intact physiological function.
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PMID:Effects of cysteine and nitroglycerin on bovine heart guanylate cyclase and on tissue cyclic GMP and lactate of rat atria. 613 95

The biochemical basis of the mechanism of vasodilatation by nitroglycerin (NTG) has not been previously investigated in man. However, evidence from in vitro studies suggests that NTG induces activation of guanylate cyclase via a series of enzymatic reactions that are modulated by the availability of sulfhydryl groups. Cysteine appears to be particularly effective in potentiating guanylate cyclase activation by NTG. To determine whether hemodynamic responsiveness to NTG in man might be modulated by sulfhydryl availability, concentration-response curves for effects of intravenously infused NTG on mean arterial pressure (MAP) and mean pulmonary capillary wedge pressure (PCW) were obtained in 10 patients undergoing cardiac catheterization for investigation of chest pain. NTG infusion was repeated 10 min after the intravenous infusion of 100 mg/kg of the cysteine source N-acetylcysteine (NAC). NAC induced no significant hemodynamic effect, but after NAC infusion there was a significant reduction both in the NTG infusion rate associated with a 10% fall from control values in MAP (25.8 +/- 8.3 to 9.3 +/- 2.7 micrograms/min; p less than .01) and in the infusion rate inducing a 30% reduction in PCW (13.6 +/- 4.6 to 4.2 +/- 1.6 micrograms/min; p less than .02). In a control group of five patients who received no NAC, there was no significant change in responsiveness to NTG between infusions. It is concluded that NAC potentiates the vasodilator effects of NTG in man. This suggests that sulfhydryl availability and/or redox state may be determinants of in vivo responsiveness to NTG.
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PMID:Potentiation of the cardiovascular effects of nitroglycerin by N-acetylcysteine. 613 83

Various NO-forming compounds have in common that along with their mechanically relaxing effect, they increase the concentration of cyclic 3'5'-guanosine monophosphate (cGMP) in vascular smooth muscle. This has been shown for nitroglycerin, NaNO2, nitroprusside-Na, 2'3'-dinitroadenosine-5'-ethylcarboxamide (B-744-99), and more recently for SIN-1, the vasoactive metabolite of molsidomine, and for nicorandil (SG-75). In isolated circular strips of bovine coronary arteries, suspended in a partially depolarizing Tyrode's solution containing 27 mM K+, these drugs produced dose-dependent relaxations which were slightly preceded by concomitant increases in cGMP levels, measured at various moments of drug action by freeze-clamping the strips, and by subsequent determinations of cyclic nucleotide levels by RIA. Levels of cyclic 3',5'-AMP were not significantly changed, except by B-744-99. Inhibition of cGMP hydrolysis by the addition of M & B 22,948 (2-o-propoxyphenyl-8-azapurin-6-one) augmented the nitrate-induced rises in cGMP as well as their relaxing effects on coronary arterial strips. In the presence of the vital stain methylene blue - which was shown in vitro to prevent nitrate-induced activation of guanylate cyclase, the enzyme which forms cGMP from GTP - the relaxant actions as well as the increases in cGMP produced by several of these nitro-compounds in coronary strips were almost abolished. The actions of organic nitrates appear to depend on their previous reduction to NO by a rate-limiting step involving cysteine, whereas those of nitroprusside and SIN-1 are probably independent of cysteine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanism of nitrate-induced vasodilation and tolerance. 614 77

Bovine mesenteric arteries (BMA) were made tolerant to nitroglycerin (GTN) by incubation with high concentrations of GTN at elevated pH. This treatment has previously been shown to reduce the relaxant and cGMP-elevating action of a challenging dose of GTN. The stimulatory action of nitroprusside (NP) or GTN/cysteine on guanylate cyclase (GC) was reduced by 50-60% in GTN-tolerant vessels as compared to control vessels. The stimulatory action of GTN and NP on GC has been suggested to occur through formation of S-nitrosothiols, probably with a previous denitration step required for GTN. However, tolerance induction to GTN was not found to change the rate of nitrite formation from GTN, and exogenous addition of thiols in the GC assay, in order to increase S-nitrosothiol formation, did not restore the GC activity in tolerant vessels back to control level. This is suggested to indicate a direct effect of GTN tolerance on GC. Since the cGMP-phosphodiesterase activity was not affected in GTN-tolerant vessels, the reduced GC activity may be of a crucial importance for the reduced cGMP response in GTN-tolerant BMA as found earlier (Axelsson et al. 1982).
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PMID:Nitroglycerin tolerance in vitro: effect on cGMP turnover in vascular smooth muscle. 615 May 99


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