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)

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

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

1. The smooth muscle system of the guinea-pig taenia caeci has been used in vitro to characterize the photodynamic action of aluminium phthalocyanine tetrasulphonate (A1PcS4) in the presence or absence of the thiol reductants L-cysteine (Cys), N-acetyl-L-cysteine (NAC), DL-dithiothreitol (DTT) or reduced glutathione (GSH). 2. In all photodynamic experiments the muscle was exposed to A1PcS4 (10(-5) M) for 30 min, followed by a 30 min washout period before photon irradiation at 32,000 lux (lambda > 570 nm) for 30 min. Photodynamic contractions were measured relative to the contractile response to carbachol (5 x 10(-5) M) and relaxation responses were determined in muscle precontracted with either carbachol 5 x 10(-5) M or KCl 23.5 mM. 3. Photon-activation of A1PcS4-sensitized smooth muscle evoked a triphasic response: an initial transient contraction and subsequent relaxation followed by a secondary sustained contraction. Cys 10 mM, NAC 10 mM and DTT 5 mM had no effect on the initial photodynamic contraction but significantly decreased the magnitude of the sustained contraction from mean values of 98% to 18%, 95% to 72% and 93% to 6% of the standard carbachol contraction (5 x 10(-5) M), respectively; GSH 10 mM was without significant effect on either the initial or sustained contraction. 4. In the absence of extracellular calcium the A1PcS4-sensitized smooth muscle did not respond to photon activation but re-introduction of calcium after cessation of illumination produced a sustained contraction which was markedly inhibited by Cys 10 mM. 5. In precontracted AlPcS4-treated muscle preparations photon activation produced a triphasic relaxation response, i.e. a rapid relaxation followed by a transient contraction and a secondary more sustained relaxation. The sustained phase of photodynamic relaxation was potentiated significantly by Cys 10 mM,NAC 10 mM, DTT 5 mM and GSH 10 mM, the relaxation being approximately doubled in magnitude from mean values of 34% to 68%, 30% to 73%, 34% to 68%, and 48% to 77%, respectively, relative to the standard carbachol (5 x l0-5 M) response.6. The cyclic GMP analogue, 8-(4-chlorophenylthio)-guanosine-3':5'-cyclic monophosphate (8-PCPTcGMP)(2 x 10-4 M) alone caused a triphasic relaxation response similar to that produced by photon activation of an AIPcS4-sensitized precontracted preparation in the presence of thiol reductants. The pattern of 8-PCPT-cGMP-induced relaxation was similar in muscle precontracted with carbachol 5 x 10-5M or KCI 23.5 mM.7. It is concluded that the rapid generation of reactive intermediates by photon-activation of boundAlPcS4 leads to membrane permeabilization, calcium entry and muscle contraction. These effects may be opposed by a direct stimulatory action of singlet oxygen on guanylate cyclase which is enhanced by the action of thiol reagents and mimicked by the cyclic GMP analogue, 8-PCPT-cGMP.
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PMID:Photodynamic action of aluminium phthalocyanine tetrasulphonate (A1PcS4) on smooth muscle: effects of thiols and a cyclic GMP analogue. 790 42

Peroxynitrite (ONOO-) is an inflammatory cell-derived oxidant, formed by the reaction of superoxide anion (O2-) with nitric oxide (NO), which was recently reported to relax vascular tissues. In the present study, the potential role of NO in the mechanism of relaxation in isolated bovine endothelium-denuded pulmonary arterial smooth muscle rings to ONOO- was evaluated. Potassium-preconstricted pulmonary arterial rings rapidly relaxed for a prolonged period of time on exposure to ONOO- (0.01-0.1 mM). The relaxation after 1 min of exposure to ONOO- (0.1 mM) was reduced 49 and 87%, respectively, by inhibitors of the stimulation of soluble guanylate cyclase, methylene blue, and LY-83583. In contrast, a scavenger of hydroxyl radicals, dimethyl sulfoxide, did not alter this response. Decomposed 0.1 mM ONOO- (which is primarily nitrite) and 0.1 mM nitrite caused a relaxation of pulmonary artery, which slowly developed over 15 min. Small quantities of NO were detected by chemiluminescence quantification methods when ONOO- was added to buffer. Exposure of pulmonary arterial tissue or buffer containing glutathione (GSH) to ONOO- caused a time-dependent increase in the observed generation of NO, whereas decomposed ONOO- produced 10% of the NO generated by ONOO- on incubation with pulmonary arterial tissue. Treatment with diethyl maleate, an agent that depletes tissue GSH, reduced both the relaxation and the formation of NO detected from pulmonary artery on exposure to ONOO-. GSH solutions treated with ONOO- appear to have generated a nitrosothiol-like vascular relaxant compound. Thus ONOO- appears to relax vascular tissue, in part, by nitrosylating tissue GSH (or other thiols), which subsequently releases NO over prolonged time periods.
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PMID:Involvement of nitric oxide and nitrosothiols in relaxation of pulmonary arteries to peroxynitrite. 820 9

Human endothelial cells cultured from umbilical vein (HUVEC) were tested for their ability to synthesize nitric oxide (NO), which has been identified as an endothelium-derived relaxing factor. The synthesis of this free radical (detected as citrulline, which is produced stoichiometrically with NO from arginine) in HUVEC is Ca2+ dependent, is increased sevenfold by the calcium ionophore ionomycin, and accounts for most basal and ionomycin-induced guanosine 3',5'-cyclic monophosphate (cGMP) production. Loading of cells with reduced glutathione (GSH), but not with N-(2-mercaptopropionyl)- glycine (MPG), led to increased citrulline production, both basally and after ionomycin stimulation. When the cells were depleted of GSH by incubation with 1-chloro-2,4-dinitrobenzene (CDNB), citrulline synthesis and cGMP production were inhibited in a concentration-dependent way. CDNB was not cytotoxic and did not inhibit cGMP increase elicited by sodium nitroprusside; cell loading with GSH (but not with MPG) relieved the block of citrulline synthesis. These results suggest that GSH is necessary in HUVEC for NO synthesis rather than for the NO effect on guanylate cyclase.
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PMID:Nitric oxide synthesis is impaired in glutathione-depleted human umbilical vein endothelial cells. 821 28

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

Previous studies have shown that exposure of Swiss 3T3 cells to mainstream cigarette smoke (CS) trapped in phosphate-buffered saline (smoke-bubbled PBS) resulted in the expression of stress response genes, i.e. haem oxygenase and c-fos, partial inhibition of protein phosphatases 1 and 2A, as well as partial depletion of the cellular glutathione (GSH) pool. Using c-fos gene expression in Swiss 3T3 cells as an indicator for a cellular response against oxidative stress, the following observations are consistent with peroxynitrite as an active principal formed by CS in aqueous solutions: (i) sustained c-fos expression was obtained for smoke-bubbled PBS, peroxynitrite itself and a compound known to stoichiometrically release superoxide and nitric oxide (NO) (3-morpholino-sydnonimine, SIN-1); (ii) c-fos expression in cells exposed to aqueous smoke fractions was inhibited by either the superoxide-scavenging enzyme superoxide dismutase (SOD), in combination with catalase, or the NO-scavenger oxyhaemoglobin (HbO2); and (iii) activation of guanylate cyclase in rat lung cells was observed only when bubbling was performed with filtered smoke and with whole smoke in the presence of SOD/catalase. These results are consistent with a rapid NO-consuming reaction coupled with superoxide-generating properties of the particulate phase of CS. Moreover, (iv) the half-life of the c-fos-inducing activity in smoke-bubbled PBS was found to be <1 h which can be explained by a sustained peroxynitrite formation. Finally, depletion of intracellular thiol levels by smoke-bubbled PBS appears to favour the activation of a redox-sensitive component of the c-fos-inducing pathway.
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PMID:Evidence for peroxynitrite as an oxidative stress-inducing compound of aqueous cigarette smoke fractions. 905 21

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

Cigarette smoke contains different populations of free radicals which may be responsible for endothelial cell (EC) injury of smokers. The purpose of this study was to examine the effects of gas-phase cigarette smoke on EC endothelium-derived relaxing factor (EDRF)/NO-guanylate cyclase (GC)-cGMP pathway and on EC detachment-type injury after incubation with smoke. Furthermore, we examined whether different kind of antioxidants can prevent smoke-caused EC injury. We measured cGMP pathway using direct (sodium nitroprusside, SNP) and indirect (A23187, the calcium ionophore and bradykinin, BK) activators of GC. Directly and indirectly stimulated EC cGMP production dose-dependently decreased and EC detachment increased after incubation with smoke. Externally added thiols (glutathione, GSH; D-Penicillamine, DP; N-acetylcysteine, NAC) protected EC from damage of cGMP production and cell detachment. Other antioxidants (catalase, deferoxamine and superoxide dismutase) were ineffective. These results suggest that the thiol containing GC in EC is destroyed or inactivated or thiol like species responsible for activation of GC is incomplete in EC after incubation with smoke. It is also possible that externally added thiols bind an unknown component of smoke and this way, EC is protected. EC injury may contribute to vascular diseases associated with cigarette smoking.
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PMID:Induction of endothelial cell injury by cigarette smoke. 958 17

Soluble guanylyl cyclase (sGC) is the major physiological target of sydnonimine-based vasodilators such as molsidomine. Decomposition of sydnonimines results in the stoichiometric formation of nitric oxide (NO) and superoxide (O2-), which rapidly react to form peroxynitrite. Inasmuch as sGC is activated by NO but not by peroxynitrite, we investigated the mechanisms underlying sGC activation by 3-morpholinosydnonimine (SIN-1). Stimulation of purified bovine lung sGC by SIN-1 was found to be strongly dependent on glutathione (GSH). By contrast, GSH did not affect sGC activation by NO released from 2,2-diethyl-1-nitroso-oxyhydrazine, indicating that NO/O2- released from SIN-1 converted GSH to an activator of sGC. High performance liquid chromatography identified this product as the thionitrite S-nitrosoglutathione. Further, the reaction product decomposed to release NO upon addition of Cu(NO3)2 in the presence of GSH. Activation of sGC was antagonized by the Cu(I)-specific chelator neocuproine, whereas the Cu(II)-selective drug cuprizone was less potent. Carbon dioxide (delivered as NaHCO3) antagonized S-nitrosation by peroxynitrite but not by SIN-1. Thus, NO/O2- released from SIN-1 mediates a CO2-insensitive conversion of GSH to S-nitrosoglutathione, a thionitrite that activates sGC via trace metal-catalyzed release of NO. These results may provide novel insights into the molecular mechanism underlying the nitrovasodilator action of SIN-1.
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PMID:Activation of soluble guanylyl cyclase by the nitrovasodilator 3-morpholinosydnonimine involves formation of S-nitrosoglutathione. 965 7


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