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)

Partially purified soluble rat liver guanylate cyclase [GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2] was activated by superoxide dismutase (superoxide: superoxide oxidoreductase, EC 1.15.1.1). This activation was prevented with KCN or glutathione, inhibitors of superoxide dismutase. Guanylate cyclase preparations formed superoxide ion. Activation by superoxide dismutase was further enhanced by the addition of nitrate reductase. Although guanylate cyclase activity was much greater with Mn2+ than with Mg2+ as sole cation cofactor, activation with superoxide dismutase was not observed when Mn2+ was included in incubations. Catalase also decreased the activation induced with superoxide dismutase. Thus, activation required the formation of both superoxide ion and H2O2 in incubations. Activation of guanylate cyclase could not be achieved by the addition of H2O2 alone. Scavengers of hydroxyl radicals prevented the activation. It is proposed that superoxide ion and hydrogen peroxide can lead to the formation of hydroxyl radicals that activate guanylate cyclase. This mechanism of activation can explain numerous observations of altered guanylate cyclase activity and cyclic GMP accumulation in tissues with oxidizing and reducing agents. This mechanism will also permit physiological regulation of guanylate cyclase and cyclic GMP formation when there is altered redox or free radical formation in tissues in response to hormones, other agents, and processes.
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PMID:Activation of guanylate cyclase by superoxide dismutase and hydroxyl radical: a physiological regulator of guanosine 3',5'-monophosphate formation. 2 77

Paraquat, a herbicide which is known to increase intracellular levels of superoxide anion (O2-), stimulated guanylate cyclase [GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2.] activity. This stimulation by paraquat was seen at concentrations as low as 0.005 mM. The activation of guanylate cyclase by paraquat was not blocked by KCN, an inhibitor of superoxide dismutase [EC 1.15.1.1.], suggesting that the activation process probably does not involve superoxide dismutase which converts superoxide anion to hydrogen peroxide and ultimately to hydroxyl radical. Catalase [EC 1.11.1.6.] did not block the paraquat activation of guanylate cyclase indicating that hydrogen peroxide was probably not involved in the activation process. Butylated hydroxytoluene, a hydroxyl radical scavenger, also had no effect on the paraquat activation of guanylate cyclase activity. Superoxide dismutase inhibited the paraquat activation of guanylate cyclase. Thus, it would appear that superoxide ion itself can activate guanylate cyclase circumventing any requirement for hydroxyl radical formation.
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PMID:Activation of liver guanylate cyclase by paraquat: possible role of superoxide anion. 3 15

The possible mechanism of immunosuppressive effect of emodin (1,3,8-trihydroxy-6-methylanthraquinone) was investigated in this study. Human mononuclear cells (10(6) cells/ml) were stimulated with 0.25% phytohemagglutinin for 24, 48 and 72 h, and the proliferative response was determined by the uptake of tritiated thymidine. In the presence of emodin (10(-6) to 3 x 10(-5) M), the proliferative response was reduced in a dose-dependent manner. Emodin (3 x 10(-7) to 3 x 10(-5) M) also dose dependently reduced the proliferative response to mixed lymphocyte reaction. After 72 h exposure to emodin (10 microM), interleukin-1 (IL-1), interleukin-2 (IL-2) production and IL-2 receptor expression were all reduced. The structure-activity relationship of emodin and 10 other anthraquione derivatives indicates that the free hydroxyl group at the beta-position of the anthraquinone nucleus plays an important role in the immunosuppressive effect. The suppressive activity of emodin was significantly inhibited by catalase (a scavenger of hydrogen peroxide), but little affected by superoxide dismutase (a scavenger of superoxide radical) and mannitol (a scavenger of hydroxyl radical). Methylene blue and hemoglobin, guanylate cyclase inhibitors, did not significantly affect the suppressive activity of emodin. Nordihydroguaiaretic acid (a lipoxygenase inhibitor) significantly potentiated the suppressive activity whereas quinacrine (a phospholipase A2 inhibitor) and indomethacin (a cyclooxygenase inhibitor) did not significantly affect it. The results suggest that the immunosuppressive effect of emodin may be partly mediated through hydrogen peroxide generated from semiquinone and regulated by arachidonic acid metabolites or byproducts.
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PMID:Immunosuppressive effect of emodin, a free radical generator. 153 96

The possible mechanism underlying the vasorelaxant effect of emodin isolated from a Chinese herb, was investigated in this study. Emodin dose dependently relaxed isolated vascular rings of human internal mammary artery and saphenous vein, rabbit thoracic aorta, abdominal aorta and mesenteric artery, and rat thoracic aorta. There were no differences in the sensitivity (IC50) and maximal relaxation between intact and endothelium-denuded preparations of rat aorta. In the presence of emodin (10 microM), the contractile responses of rat aorta to phenylephrine, serotonin and potassium chloride were depressed. The relaxation response to acetylcholine was attenuated by emodin, whereas that to isoproterenol was unaffected. The relaxation response to emodin was inhibited by free radical scavengers, superoxide dismutase, catalase and mannitol, and guanylate cyclase inhibitors, methylene blue and hemoglobin. Catalase was the most effective scavenger. Quinacrine (phospholipase A2 inhibitor), indomethacin (cyclooxygenase inhibitor) and nordihydroguaiaretic acid (NDGA, lipoxygenase inhibitor) potentiated the relaxation induced by emodin. NDGA was the most effective potentiator. Exposure of aortic rings to emodin (10 microM) increased the basal level of guanosine 3',5'-cyclic monophosphate (cGMP). It is suggested that the vasorelaxant effect of emodin may be mainly due to cGMP accumulation as a result of guanylate cyclase activation by free radicals and/or hydrogen peroxide generated from semiquinone.
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PMID:Vasorelaxant effect of emodin, an anthraquinone from a Chinese herb. 166 13

1. Semicarbazide-sensitive amine oxidase (SSAO) is an enzyme activity which can be found in the plasma membrane of rat vascular smooth muscle cells. We have investigated the possibility that the products of deamination by this enzyme, namely ammonia, hydrogen peroxide and the aldehyde, may be important in the modulation of the responses of vascular smooth muscle to extracellular stimuli. 2. The isolated perfused mesenteric arterial bed of the rat was used and dose-pressure response curves (DRC) to bolus injections of adrenaline (Ad) or ATP were plotted by non-linear curve fitting. The relaxant effects of carbachol (CCh), which releases endothelium dependent relaxing factor (ERDF), were studied by co-administering CCh with Ad. The effects of including the preferred SSAO substrate, benzylamine (BZ; 25 microM), in the perfusion fluid throughout the experiment and of inhibition of SSAO by treatment of rats with (E)-2-(3',4'-dimethoxyphenyl)-3-fluoroallylamine (MDL 72145; 1 mg kg-1) 1 h before dissection, have been studied. 3. Neither BZ nor SSAO inhibition affected the DRC to ATP. BZ shifted Ad responses to the left, inhibition of SSAO increased this shift indicating that the amine, but not its metabolites, were responsible for the potentiation of the responses to Ad. DRC to CCh showed a shift to the left and a significant decrease in the Hill slope with BZ, indicative of a potentiation of low doses of CCh more than high doses. Inhibition of SSAO prevented this change and so the metabolites of BZ deamination appeared to be involved in the potentiation. 4. Ammonia generated by SSAO may contribute to the production of EDRF or hydrogen peroxide may sensitize guanylate cyclase to stimulation by EDRF and so explain these findings.
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PMID:Effect of benzylamine and its metabolites on the responses of the isolated perfused mesenteric arterial bed of the rat. 174 92

Current dogma associates reperfusion injury with the introduction of reactive oxygen species (ROS) into the ischemic tissue. The sources of ROS under discussion are xanthine oxidase in the endothelium of small vessels and/or invaded polymorphonuclear leukocytes (PMN). The beneficial effects of both superoxide dismutase and catalase suggest an involvement of superoxide anions and hydrogen peroxide in this pathophysiological process, without describing the targets of their action. In our work we demonstrate that these two ROS effectively interact with two enzymes. Superoxide anions inhibit soluble guanylate cyclase. Its product, cGMP, is considered to antagonize platelet activation and to cause smooth muscle relaxation. Thus O2- can intensify platelet aggregability and small vessel occlusion. Similar effects are elicited by H2O2, which shifts the dose response curve of several agonists towards smaller concentrations by activating cyclooxygenase. This enzyme provides the substrate for thromboxane synthase which generates TxA2, the most potent physiologically occurring platelet aggregating and smooth muscle contacting agonist. These results lead us to the suggestion that the influence of the oxidative burst of PMN in the phenomenon of reperfusion injury should be reconsidered.
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PMID:Physiological targets of superoxide anion and hydrogen peroxide in reperfusion injury. 257 64

The effects of isoproterenol, acetylcholine (Ach), and adenosine, on cyclic AMP (cAMP) and cyclic GMP (cGMP) contents were examined in chick hearts at various stages of embryonic development. The basal cAMP content was highest (87.7 +/- 1.3 pmol/mg protein) in young (3-day) embryonic chick hearts and decreased during development (9.6 +/- 0.6 pmol/mg protein in 9-19-day-old hearts). On the other hand, the cGMP content was lowest (45.5 +/- 2.3 fmol/mg protein) in young (3-day) embryonic chick hearts and increased during development (338 +/- 15.0 fmol/mg protein in 14-19-day-old hearts). Iso increased the cAMP concentration in embryonic hearts at all ages. Ach and Ado had no effect on the cAMP content at all ages. However, the Isoproterenol-induced stimulation of cAMP was inhibited by Ach and Adenosine at all ages. In young embryonic hearts, Ach and Ado increased cGMP concentration only slightly, whereas these agents caused a substantial increase in cGMP concentration in the older hearts. Thus, there was a clear age difference in the effects of Ach and Adenosine on the cGMP and cAMP concentrations. Nitroprusside and hydrogen peroxide increased cGMP concentration in older hearts (greater than 5-day-old) but not in the 3-day-old embryonic hearts. Thus, guanylate cyclase activity may be low in young (3-day-old) hearts. It summary, the cGMP level is very low in young embryonic chick hearts, and increases markedly during development. The changes in cGMP are reciprocal to those of cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Changes in cyclic nucleotide levels during embryonic development of chick hearts. 283 64

We have examined the properties of soluble guanylate cyclase activity in the human neutrophil. The enzyme showed complex regulation by metal ions. A 10-fold higher activity was observed in the presence of Mn2+ than Mg2+, while Ca2+ caused an increase in activity only in the presence of Mg2+ ion. Sodium nitroprusside (SNP), azide and hydrogen peroxide were activators of the enzyme. Dithiothreitol blocked the activation by SNP, suggesting the involvement of thiol groups in the activation process. Carbachol acting through the muscarinic cholinergic receptor caused a dose-dependent activation, which was blocked by atropine. Higher concns of carbachol were required to activate guanylate cyclase than were required for the modulation of enzyme release elicited by N-formyl-L-methionyl-L-leucyl-L-phenylalanine. Nordihydroguaracetic acid inhibited carbachol stimulation of guanylate cyclase. By contrast, trifluoperazine (TFP), a calmodulin antagonist, caused a biphasic modulation of basal activity in the presence or absence of carbachol. Our results indicate that: allosteric interactions of metal ions are important to the regulation of the enzyme, the free radical nitroxide as well as hydrogen peroxide enhances enzyme activity, agonist occupancy of the muscarinic cholinergic receptor activates neutrophil guanylate cyclase probably through a mechanism involving calcium influx and the activation of the lipoxygenase pathway, and a TFP-sensitive site (possibly calmodulin) is involved in the selective regulation of basal enzyme activity.
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PMID:Regulation of human neutrophil guanylate cyclase by metal ions, free radicals and the muscarinic cholinergic receptor. 286 50

Guanylate cyclase activity in the soluble extract of bovine pulmonary arteries is activated by hydrogen peroxide generated by glucose oxidase only in the presence of catalase. This mechanism of guanylate cyclase activation is not blocked by scavengers for superoxide anion or hydroxyl radical, but is selectively inhibited by methylene blue, inactivation of catalase and ethanol. The time dependency of increases in guanylate cyclase activity in the presence of peroxides that are substrates for catalase are associated with the spectral detection of compound I, a species of catalase formed during the metabolism of peroxide. Thus, activation of soluble guanylate cyclase appears to be elicited by compound I of catalase or by a mediator generated by this species.
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PMID:Hydrogen peroxide elicits activation of bovine pulmonary arterial soluble guanylate cyclase by a mechanism associated with its metabolism by catalase. 288 44

Hydrogen peroxide produces concentration-dependent relaxation of precontracted isolated bovine intrapulmonary arterial rings by a mechanism which is independent of the endothelium or prostaglandin mediators. Relaxant responses to hydrogen peroxide concentrations of up to 100 microM were markedly attenuated by the inhibitor of soluble guanylate cyclase activation, methylene blue (10 microM). Micromolar concentrations of hydrogen peroxide elicit time- and concentration-dependent increase in arterial levels of guanosine 3',5'-cyclic monophosphate that are associated with decreases in force. Soluble guanylate cyclase activity is markedly activated by enzymatically generated hydrogen peroxide in a manner that is most closely associated with the concentration of catalase present in the assay, by a mechanism that is inhibited by superoxide anion and the inactivation of catalase. Our data are most consistent with the involvement of compound I, a species of catalase formed during the metabolism of peroxide, in the mechanism of guanylate cyclase activation. The nature of this mechanism of arterial relaxation suggests that it could contribute to the regulation of pulmonary vascular tone by oxygen tension.
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PMID:Hydrogen peroxide elicits pulmonary arterial relaxation and guanylate cyclase activation. 288 94


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