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)

Earlier studies have shown that inhibition of aggregation of washed platelets (WP) by NO was enhanced almost 100-fold by H2O2. In the present study, the interactions of H2O2 with nitrosothiols, the influence of the presence of plasma and the mechanism of the synergism were investigated. H2O2 strongly enhanced the inhibitory effects of S-nitrosoglutathione (GSNO) on thrombin-induced aggregation of WP. S-Nitrosoalbumin also inhibited platelets, and this was similarly enhanced by H2O2. The synergism with H2O2 was demonstrable for both exogenous GSNO and NO in the presence of plasma when platelets were stimulated with collagen. The inhibition of platelets by GSNO and H2O2 was completely inhibited by guanylate cyclase inhibitors. Synergism was also observed whether the H2O2 was added simultaneously or 1 min before or after the GSNO (or NO). This suggests that the action of H2O2 follows the occupation by NO of haem sites in guanylate cyclase and that a prior reaction between NO and H2O2 was not required. In the absence of exogenous GSNO or NO, H2O2 inhibited activation of platelets in plasma, an effect abolished by guanylate cyclase inhibitors. This suggested that endogenous NO donors in plasma or NO synthesized in platelets may interact with H2O2. Addition of NG-nitro-L-arginine methyl ester (hydrochloride) (L-NAME) decreased the effects of the H2O2 by 25%, indicating that the major endogenous source of NO in platelet-rich plasma was not derived from platelet synthesis of NO but from NO donors in plasma, such as nitrosothiols. Inhibition by H2O2 was also enhanced by beta-mercaptosuccinate, a glutathione peroxidase inhibitor that protects the H2O2. These results suggest a potent synergism of H2O2 with endogenous plasma nitrosothiols that inhibit platelet function through an intracellular mechanism involving guanylate cyclase.
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PMID:The synergism of hydrogen peroxide with plasma S-nitrosothiols in the inhibition of platelet activation. 883 16

We investigated the role of potassium channels in the vasodilator action of hydrogen peroxide, peroxynitrite, and superoxide on cerebral arterioles. We studied the effect of topical application of these agents in anesthetized cats equipped with cranial windows. Hydrogen peroxide and peroxynitrite induced dose-dependent dilation that was inhibited by glyburide, an inhibitor of ATP-sensitive potassium channels. Superoxide, generated by xanthine oxidase acting on xanthine in the presence of catalase, also induced dose-dependent dilation of cerebral arterioles that was unaffected by glyburide but inhibited completely by tetraethylammonium chloride, an inhibitor of calcium-activated potassium channels. The vasodilations from hydrogen peroxide, peroxynitrite, or superoxide were unaffected by inhibition of soluble guanylate cyclase with LY-83583. The findings provide pharmacological evidence that hydrogen peroxide and peroxynitrite reversibly dilate cerebral arterioles by activating ATP-sensitive potassium channels, probably through an oxidant mechanism, whereas superoxide dilates cerebral arterioles by opening calcium-activated potassium channels. Activation of soluble guanylate cyclase is not a mediator of the vasodilator action of these agents in cerebral arterioles.
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PMID:Mechanisms of cerebral vasodilation by superoxide, hydrogen peroxide, and peroxynitrite. 885 67

Our previous studies on the mechanism of relaxation of calf pulmonary arteries to H2O2 detected a role for increased formation of guanosine-3',5'-cyclic monophosphate as a result of a catalase-elicited activation of soluble guanylate cyclase. We have also shown that lactate elicits relaxation through increasing H2O2 produced from NADH oxidase-derived superoxide anion (O2-.). Because nitric oxide (NO) is a potential inhibitor of catalase, we examined the effects of exposure of endothelium-denuded bovine calf pulmonary arteries to an elevated physiological level of NO on relaxation to H2O2 and lactate. Treatment of pulmonary arteries with approximately 50 nM of NO gas for 2 min caused a subsequent inhibition of relaxation to H2O2 (10(-6) to 10(-3)M) and lactate (1-10 mM), without markedly altering relaxation responses to S-nitroso-N-acetylpenicillamine (10(-9) to 10(-6) M) or isoproterenol (10(-9) to 10(-6) M). This NO exposure caused a 63 and 70% inhibition of the metabolism by smooth muscle catalase of both endogenously produced and exogenous (100 microM) H2O2, respectively, as measured by the H2O2-dependent cooxidation of methanol to formaldehyde. A similar treatment of purified catalase with NO caused subsequent inhibition of its ability to metabolize H2O2, associated with changes in the spectra of catalase (increases in the absorbance at 535 and 570 nm) to a species that resembled compound II, an inactive form of catalase. The exposure of pulmonary arteries to NO also resulted in the detection of H2O2 release (by catalase-inhibitable luminol/ peroxidase-chemiluminescence). Thus exposure of pulmonary arteries to increased physiological levels of NO may promote altered vasoactive responses involving H2O2 as a result of the inhibition of catalase.
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PMID:Nitric oxide inhibits pulmonary artery catalase and H2O2-associated relaxation. 894 7

The effects on rat aorta of EUK-8, a salen-manganese complex with high superoxide dismutase and catalase activities, were investigated. EUK-8 protected the acetylcholine-induced relaxation of rat aortic rings from inhibition by superoxide anions and reduced H2O2-induced relaxation. Moreover, EUK-8 dose-dependently relaxed rat aorta precontracted with phenylephrine (10(-6) M) and decreased the vascular tone of noncontracted aortic rings. The relaxant effect of EUK-8 was significantly potentiated by endothelium abrasion and/or preincubation with N-nitro-L-arginine methyl ester (10(-5) M and 5 x 10(-4) M), an inhibitor of nitric oxide synthase. Indomethacin (10(-5) M) had no effect on the action of EUK-8, showing that it was not dependent on prostacyclin synthesis. Methylene blue (10(-5) M), an inhibitor of soluble guanylate cyclase, partly abolished relaxation induced by EUK-8. Incubation of rat aorta with EUK-8 (10(-4) M) induced an increase in vascular cyclic AMP content. The lack of inhibition by dl-propranolol showed that adenylate cyclase activation by EUK-8 was not mediated through beta-adrenergic receptors. The inhibition of the effects of EUK-8 by tetraethylammonium (10(-2) M) and glibenclamide (10(-5) and 2 x 10(-5) M) showed the implication of potassium channels in the intracellular cascade triggered by EUK-8. The vasorelaxant activity of EUK-8 was neither affected by xanthine oxidase inhibition (incubation with oxypurinol 25 microM) nor by superoxide anion scavenging (incubation with oxypurinol 125 microM). Finally, the ligand for EUK-8 (EUK-8 without manganese), which has the same aromatic structure as EUK-8 without its antioxidant activities because of the absence of manganese, conversely potentiated phenylephrine-induced contraction of aortic rings. We conclude that the vasorelaxant effect of EUK-8 observed under our experimental conditions is essentially mediated through an activation of adenylate cyclase and soluble guanylate cyclase of smooth muscle cells and is different from a classical antioxidant effect of protection of nitric oxide.
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PMID:Vasodilatory effects of a salen-manganese complex with potent oxyradical scavenger activities. 907 25

Perfusate levels of nitric oxide (NO)-containing compounds and guanosine 3',5'-cyclic monophosphate (cGMP) are increased in hypoxia-induced hypertensive rat lungs. To test if increased cGMP was due to NO stimulation of soluble guanylate cyclase (sGC), we examined effects of inhibition of NO synthase with N omega-nitro-L-arginine (L-NNA) on perfusate accumulation of cGMP in physiological salt solution (PSS)-perfused hypertensive lungs isolated from rats exposed for 3-4 wk to hypobaric hypoxia. Because 200 microM L-NNA did not reduce cGMP, we next examined inhibitors of other pathways of stimulation of either sGC or particulate GC (pGC). Neither 5 microM Zn-protophorphyrin, an inhibitor of CO production by heme oxygenase, nor 10 mM aminotriazole, an inhibitor of H2O2 metabolism by catalase, reduced perfusate cGMP. However, an antiserum to atrial natriuretic peptide (ANP; 100 microliters antiserum/30 ml PSS), to inhibit ANP activation of pGC, completely prevented accumulation of the nucleotide. ANP antiserum was also more effective than L-NNA in reducing lung tissue cGMP. In contrast, L-NNA but not ANP antiserum increased resting vascular tone. These results suggested that whereas ANP determined perfusate and tissue levels of cGMP, NO regulated vascular tone. To test if perfusate cGMP reflected ANP stimulation of pGC in endothelial rather than smooth muscle cells, we examined effects of 10 microM Zaprinast, an inhibitor of cGMP hydrolysis in smooth muscle but not endothelial cells, and found no increase of cGMP in hypertensive lungs. ANP levels were not elevated in hypertensive lungs, and it is unclear by what mechanism the ANP-stimulated activity of pGC is increased in hypertensive pulmonary vascular endothelial cells.
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PMID:Atrial natriuretic peptide accounts for increased cGMP in hypoxia-induced hypertensive rat lungs. 922 14

Azide, in the absence of other stimuli, enhanced neutrophil migration in a chemotactic way. The effect of azide on migration was significant at concentrations > or = 1 microM and maximal at 10 microM azide. Although azide itself could not induce exocytosis, at concentrations > or = 10 microM azide enhanced exocytosis induced by a combination of the chemotactic peptide f-methionyl-leucyl-phenylalanine (fMLP) and cytochalasin B (CB). Azide can be oxidized by catalase and myeloperoxidase in the presence of H2O2, resulting in the generation of nitric oxide (NO). Formation of NO from azide was detected by ESR spectroscopy with carboxy-PTIO as a NO-selective probe, and by measurement of nitrite formation. Azide-induced migration, and the enhancement by azide of fMLP/CB-induced exocytosis, were blocked by pre-incubating cells with aminotriazole, an inhibitor of catalase and myeloperoxidase, suggesting that the effect of azide was mediated by NO. Azide-induced migration, but not the enhancement by azide of fMLP/CB-induced exocytosis, was inhibited to a large extent by inhibitors of soluble guanylate cyclase and by inhibitors of cGMP-dependent protein kinase. These observations suggest that azide-induced migration is mediated via cGMP and cGMP-dependent protein kinase, while the enhancement of fMLP/CB-induced exocytosis is not. Azide caused a sustained elevation of the intracellular Ca2+-concentration of neutrophils stimulated with fMLP/CB, which was not affected by inhibitors of the cGMP-signalling cascade. Since neutrophil exocytosis has been shown to be closely correlated with increases in intracellular Ca2+, a further increase by azide of the intracellular Ca2+-level of cells stimulated with fMLP/CB provides a likely mechanism for the enhancement of fMLP/CB-induced exocytosis by azide.
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PMID:Sodium azide enhances neutrophil migration and exocytosis: involvement of nitric oxide, cyclic GMP and calcium. 971 94

Nitric oxide has several signalling mechanisms that can potentially control force generation by vascular smooth muscle. Some of these mechanisms include the stimulation of cGMP production by the soluble heme-containing form of guanylate cyclase (sGC), inhibition of mitochondrial respiration, and the modulation of vasoactive mediator release by the endothelium. Reactive O2 species (ROS) can also regulate force generation by vascular smooth muscle through mechanisms including the stimulation of production of vasoactive prostaglandins, the stimulation of sGC by catalase-mediated metabolism of H2O2 and inhibition of sGC activation by superoxide, the activation of protein kinase C, and the modulation of mediator release from the endothelium. Interactions between NO and ROS signalling mechanisms result in additional processes which modulate vascular force generation. For example, NO-elicited stimulation of sGC can be attenuated by superoxide, and this results in the formation of peroxynitrite (ONOO-). However, high levels of NO result in a ONOO- and thiol dependent formation of a species which regenerates NO in a time-dependent manner. It appears that NO inhibits catalase through an O2 and superoxide dependent process which results in inhibition of relaxation mediated by H2O2-elicited stimulation of sGC. Furthermore, evidence exists suggesting additional signalling mechanisms resulting from interactions between regulatory systems involving NO and ROS which appear to be important in control of vascular force generation in pathophysiological states.
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PMID:Oxidant--nitric oxide signalling mechanisms in vascular tissue. 972 33

Murine macrophage nitric oxide synthase (NOS) was expressed in E. coli and purified in the presence (holoNOS) or absence (H4B-free NOS) of (6R)-tetrahydro-L-biopterin (H4B). Isolation of active enzyme required the coexpression of calmodulin. Recombinant holoNOS displayed similar spectral characteristics and activity as the enzyme isolated from murine macrophages. H4B-free NOS exhibited a Soret band at approximately 420 nm and, by analytical gel filtration, consisted of a mixture of monomers and dimers. H4B-free NOS catalyzed the oxidation of NG-hydroxy-L-arginine (NHA) with either hydrogen peroxide (H2O2) or NADPH and O2 as substrates. No product formation from arginine was observed under either condition. The amino acid products of NHA oxidation in both the H2O2 and NADPH/O2 reactions were determined to be citrulline and Ndelta-cyanoornithine (CN-orn). Nitrite and nitrate were also formed. Chemiluminescent analysis did not detect the formation of nitric oxide (*NO) in the NADPH/O2 reaction. The initial inorganic product of the NADPH/O2 reaction is proposed to be the nitroxyl anion (NO-) based on the formation of a ferrous nitrosyl complex using the heme domain of soluble guanylate cyclase as a trap, and the formation of a ferrous nitrosyl complex of H4B-free NOS during turnover of NHA and NADPH. NO- is unstable and, under the conditions of the reaction, is oxidized to nitrite and nitrate. At 25 degreesC, the H2O2-supported reaction had a specific activity of 120 +/- 14 nmol min-1 mg-1 and the NADPH-supported reaction had a specific activity of 31 +/- 6 nmol min-1 mg-1 with a KM,app for NHA of 129 +/- 9 microM. HoloNOS catalyzed the H2O2-supported reaction with a specific activity of 815 +/- 30 nmol min-1 mg-1 and the NADPH-dependent reaction to produce *NO and citrulline at 171 +/- 20 nmol min-1 mg-1 with a KM, app for NHA in the NADPH reaction of 36.9 +/- 0.3 microM.
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PMID:Reactions catalyzed by tetrahydrobiopterin-free nitric oxide synthase. 979 13

Peroxynitrite (ONOO-), a potent oxidant formed by reaction of nitric oxide (NO.) with superoxide anion, can activate guanylyl cyclase and is able to induce vasodilation or inhibit platelet aggregation and leukocyte adhesion, via thiol-dependent formation of NO. Reaction of ONOO- with thiols is thought to proceed through formation of a S-nitrothiol (thionitrate; RSNO2) intermediate and yields low levels of S-nitrosothiols (thionitrites; RSNO), both of which are theoretical sources of NO. Kinetic analysis of NO. production after reaction of ONOO- with GSH established that NO. originates exclusively from the thionitrite GSNO. Further mechanistic investigations indicated that GSNO formation by ONOO- does not occur via one-electron oxidation mechanisms. Nitrosation of GSH could theoretically proceed via intermediate formation of the thionitrate GSNO2, which, after rearrangement to the corresponding sulfenyl nitrite (GSONO), can react with GSH to form GSNO and GSOH. However, no evidence for such a mechanism was found in experiments with NO2. or with the stable nitrothiol tert-butylthionitrate. Using high performance liquid chromatography with chemiluminescence detection, formation of H2O2 was observed after reaction of ONOO- with GSH under both aerobic and anaerobic conditions, at levels similar to the yield of GSNO, indicative of a direct nucleophilic nitrosation mechanism with elimination of HOO-. Our results indicate that ONOO- may contribute to S-nitrosation in vivo and that direct nitrosation of thiols or other nucleophilic substrates by ONOO- may represent an important and often overlooked component of NO. biochemistry.
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PMID:Formation of S-nitrosothiols via direct nucleophilic nitrosation of thiols by peroxynitrite with elimination of hydrogen peroxide. 980 85

The nitrovasodilator 3-morpholinosydnonimine (SIN-1) slowly decomposes to release both nitric oxide (NO) and superoxide (O2-) and thereby produces peroxynitrite (ONOO-), a powerful oxidant which has been proposed to mediate the toxic actions caused by NO. Indeed, ONOO has been shown to cause neuronal death and it has been proposed to occur in different disorders of the CNS such as brain ischaemia, AIDS-associated dementia, amyothrophic lateral sclerosis, etc. We have found that SIN-1 was only slightly toxic to 1-week-old rat cortical neurones in primary culture (LC50=2.5+/-0.5 mM). Superoxide dismutase (SOD; 100 U/ml) significantly increased SIN-1-induced toxicity, an effect that was enhanced in the presence of HbO2, abolished by catalase and accompanied by the formation of hydrogen peroxide (H2O2). We have also found that 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ), a selective inhibitor of soluble guanylate cyclase, enhances cell death induced by SIN-1 (0.2-0.5 mM) + SOD (100 U/ml) in a concentration-dependent way (EC50=0.073+/-0.004 microM). Simultaneously, ODQ inhibits the elevation of cyclic GMP concentrations induced by SIN-1 + SOD in cortical cells (IC50=0.022+/-0.014 microM). Finally, we have also shown that the cyclic GMP mimetic, 8-bromo-cyclic GMP reverses the potentiating effect induced by ODQ on SIN-1 + SOD-induced neuronal death and inhibits the neurotoxicity induced by H2O2 (100 microM). Taken together, these data suggest that H2O2 is the species responsible for the potentiation by SOD of SIN-1-induced cell death and that cyclic GMP elevations confer selective cytoprotection against this H2O2-mediated component of cell death.
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PMID:Neuronal death induced by SIN-1 in the presence of superoxide dismutase: protection by cyclic GMP. 983 36


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