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)

1. The involvement was assessed of an endogenous nitric oxide-like substance in contractions of canine bronchi to acetylcholine. 2. Canine third order bronchial rings, in some of which the epithelium was removed mechanically, were suspended in organ chambers and isometric tension was recorded. In some experiments, the content of guanosine 3',5'-cyclic monophosphate (cyclic GMP) of the bronchi was also measured. 3. Acetylcholine induced concentration-dependent contractions. The contractions were potentiated by nitro-L-arginine (an inhibitor of the synthesis of nitric oxide), oxyhaemoglobin (a scavenger of nitric oxide), and methylene blue (an inhibitor of soluble guanylate cyclase). The magnitude of the potentiation to acetylcholine-induced contractions by these inhibitors were not significantly different between tissues with and without epithelium. 4. Acetylcholine induced a concentration-dependent increase in intracellular content of cyclic GMP, which was similar in bronchi with and without epithelium. These increases were abolished by nitro-L-arginine and methylene blue. 5. During contractions to acetylcholine, exogenous nitric oxide relaxed the canine bronchi. The relaxations were not affected by nitro-L-arginine, but were augmented by superoxide dismutase plus catalase, and were abolished by methylene blue. 6. These observations suggest that, during contraction evoked by acetylcholine, the production of an endogenous nitric oxide-like substance increases and in turn attenuates the response of the airways to the muscarinic agonist. However, the endogenous nitric oxide-like substance does not play a major role in the epithelium-dependent attenuation of the contraction to acetylcholine in canine bronchi.
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PMID:Attenuation of contractions to acetylcholine in canine bronchi by an endogenous nitric oxide-like substance. 839 1

1. In this study we investigated the role of catalase in relaxation induced by hydroxylamine, sodium azide, glyceryl trinitrate and hydrogen peroxide in isolated rings of rat aorta. 2. Hydrogen peroxide (1 microM-1 mM)-induced concentration-dependent relaxation of phenylephrine (PE)-induced tone in endothelium-containing rings. In endothelium-denuded rings, however, higher concentrations (30 microM-1 mM) of hydrogen peroxide were required to produce relaxation. The endothelium-dependent component of hydrogen peroxide-induced relaxation was abolished following pretreatment with N(O)-nitro-L-arginine methyl ester (L-NAME, 30 microM). L-NAME (30 microM) had no effect, however, on hydrogen peroxide-induced relaxation in endothelium-denuded rings. 3. Pretreatment of endothelium-denuded rings with catalase (1000 u ml-1) blocked relaxation induced by hydrogen peroxide (10 microM-1 mM). The ability of catalase to inhibit hydrogen peroxide-induced relaxation was partially blocked following incubation with 3-amino-1,2, 4-triazole (AT, 50 mM) for 30 min and completely blocked at 90 min. 4. Pretreatment of endothelium-denuded rings with methylene blue (MeB, 30 microM) inhibited relaxation induced by hydrogen peroxide (10 microM-1 mM), sodium azide (1-300 nM), hydroxylamine (1-300 nM) and glyceryl trinitrate (1-100 nM) suggesting that each acted by stimulation of soluble guanylate cyclase. 5. Pretreatment of endothelium-denuded rings with AT (1-50 mM, 90 min) to inhibit endogenous catalase blocked relaxation induced by sodium azide (1-300 nM) and hydroxylamine (1-300 nM) but had no effect on relaxation induced by hydrogen peroxide (10 microM-1 mM) or glyceryl trinitrate (1-100 nM). 6. In a cell-free system, incubation of sodium azide (10 microM-3 mM) and hydroxylamine (10 microM-30 mM) but not glyceryl trinitrate (10 microM-1 mM) with catalase (1000 u ml-1) in the presence of hydrogen peroxide (1 mM) led to production of nitrite, a major breakdown product of nitric oxide. AT (1-100 mM) inhibited, in a concentration-dependent manner, the formation of nitrite from azide in the presence of hydrogen peroxide. 7. These data suggest that metabolism by catalase plays an important role in the relaxation induced by hydroxylamine and sodium azide in isolated rings of rat aorta. Relaxation appears to be due to formation of nitric oxide and activation of soluble guanylate cyclase. In contrast, metabolism by catalase does not appear to be involved in the relaxant actions of hydrogen peroxide or glyceryl trinitrate.
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PMID:The inhibitory effect of 3-amino-1,2,4-triazole on relaxation induced by hydroxylamine and sodium azide but not hydrogen peroxide or glyceryl trinitrate in rat aorta. 871 11

Our previous studies in isolated endothelium-removed calf pulmonary arteries suggest that PO2-elicited responses are primarily mediated through modulation of guanosine 3',5'-cyclic monophosphate via changes in the generation of H2O2 originating from superoxide anion (O2-.) produced by NADH oxidase activity. In the present study we examined the importance of this mechanism in PO2-elicited responses of endothelium-removed calf coronary arteries. NADH oxidase activity was found to be the major source of O2-. in the homogenate of endothelium-removed calf coronary arteries detected by lucigenin-elicited chemiluminescence. Precontracted endothelium-removed calf coronary arteries show a relaxation to hypoxia, and reoxygenation causes a transient additional relaxation before the recovery of normoxic levels of force. Under these conditions the detection of O2-. was decreased by hypoxia and a transient overproduction was observed during reoxygenation. The relaxation to reoxygenation, but not to hypoxia, was significantly inhibited by a scavenger of O2-. that prevents the formation of H2O2 (nitro blue tetrazolium), an inhibitor of NAD(P)H oxidases and other O2(-.)-generating flavoproteins (diphenyliodonium), and inhibition of the stimulation of soluble guanylate cyclase (LY-83583). A scavenger of O2-. that promotes H2O2 formation (Tiron) did not inhibit the PO2-elicited responses examined. Hypoxia and diphenyliodonium (but not Tiron) decreased the metabolism of endogenous H2O2 by catalase (as measured by the H2O2-dependent co-oxidation of methanol to formaldehyde by catalase), and reoxygenation caused a stimulation of H2O2 metabolism by catalase. The presence of endothelium resulted in minor modifications of the PO2 responses, which were partially mediated via prostaglandins and nitric oxide on the basis of the effects of indomethacin and nitro-L-arginine, respectively. These results suggest that in calf coronary arteries the stimulation of guanylate cyclase via H2O2 originating from NADH-derived O2-(.) production contributes to the transient relaxation to posthypoxic reoxygenation, but not the response to hypoxia.
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PMID:Oxygen-elicited responses in calf coronary arteries: role of H2O2 production via NADH-derived superoxide. 878 Feb 2

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

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 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

1. To investigate the participation of guanylyl cyclase in the muscarinic regulation of the cardiac L-type calcium current (ICa), we examined the effects of three guanylyl cyclase inhibitors, 1H-[1,2,4]oxidiazo-lo[4,3-a]quinoxaline-1-one (ODQ), 6-anilino-5,8-quinolinedione (LY 83583), and methylene blue (MBlue), on the beta-adrenoceptor; muscarinic receptor and nitric oxide (NO) regulation of ICa and on the muscarinic activated potassium current I(K,ACh), in frog atrial and ventricular myocytes. 2. ODQ (10 microM) and LY 83583 (30 microM) antagonized the inhibitory effect of an NO-donor (S-nitroso-N-acetylpenicillamine, SNAP, 1 microM) on the isoprenaline (Iso)-stimulated ICa which was consistent with their inhibitory action on guanylyl cyclase. However, MBlue (30 microM) had no effect under similar conditions. 3. In the absence of SNAP, LY 83583 (30 microM) potentiated the stimulations of ICa by either Iso (20 nM), forskolin (0.2 microM) or intracellular cyclic AMP (5-10 microM). ODQ (10 microM) had no effect under these conditions, while MBlue (30 microM) inhibited the Iso-stimulated ICa. 4. LY 83583 and MBlue, but not ODQ, reduced the inhibitory effect of up to 10 microM acetylcholine (ACh) on ICa. 5. MBlue, but not LY 83583 and ODQ, antagonized the activation of I(K,ACh) by ACh in the presence of intracellular GTP, and this inhibition was weakened when I(K,ACh) was activated by intracellular GTPgammaS. 6. The potentiating effect of LY 83583 on Iso-stimulated ICa was absent in the presence of either DL-dithiothreitol (DTT, 100 microM) or a combination of superoxide dismutase (150 u ml(-1)) and catalase (100 u ml(-1)). 7. All together, our data demonstrate that, among the three compounds tested, only ODQ acts in a manner which is consistent with its inhibitory action on the NO-sensitive guanylyl cyclase. The two other compounds produced severe side effects which may involve superoxide anion generation in the case of LY 83583 and alteration of beta-adrenoceptor and muscarinic receptor-coupling mechanisms in the case of M Blue.
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PMID:A comparative study of the effects of three guanylyl cyclase inhibitors on the L-type Ca2+ and muscarinic K+ currents in frog cardiac myocytes. 925 16

Nitronyl nitroxides react with nitric oxide radical (.NO) to form imino nitroxides. We used a nitronyl nitroxide, [2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3 oxide] (CPTIO) to evaluate the contribution of .NO to basal tone and acetylcholine-induced endothelium-dependent relaxation in control vs. diabetic rat aortic rings. In rings precontracted with phenylephrine, CPTIO produced an additional increment in tension that was greater in control vs. diabetic rings. Tension after CPTIO was similar to that observed in rings pretreated with the NO synthase inhibitor, L-nitroarginine or in rings without endothelium. This increment was insensitive to indomethacin, cysteine, tetraethylammonium or catalase, but was sensitive to inhibition by the soluble guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxaline-1-one. L-Nitroarginine blocked relaxation to ACH by 100 and 90% in control and diabetic rings, respectively. In contrast, CPTIO produced a concentration-dependent inhibition of ACH-induced relaxation that was greater in control rings. The residual CPTIO-resistant component of relaxation was equivalent to 26 and 43% of initial precontraction in control vs. diabetic rings, respectively, and was not altered by indomethacin, catalase, cysteine or tetraethylammonium but was significantly inhibited by 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxaline-1-one. These data suggest the release of additional unknown factor(s) that cannot be discerned using NO synthase inhibitors only. This CPTIO-resistant dilator is likely not a cyclooxygenase product or a hyperpolarizing factor but a factor that acts, in part, by activation of guanylate cyclase. This substance is possibly .NO that is not available for reaction with CPTIO either by its diffusibility and sequestration or molecular rearrangement to a redox active form (i.e., not free .NO) or is a completely different vasodilator. The use of a more lipid soluble nitronyl nitroxide derivative suggests a portion of the CPTIO-resistant relaxation in diabetic (but not control) rings could be explained by .NO sequestered in the lipid phase.
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PMID:Use of a nitronyl nitroxide to discriminate the contribution of nitric oxide radical in endothelium-dependent relaxation of control and diabetic blood vessels. 933 18


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