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)

Oxygen metabolites have been reported to produce vasoconstriction and/or vasodilation in a variety of in vitro or in vivo vascular preparations. Certain basic mechanisms appear to contribute to these responses. Hydrogen peroxide can produce either vasodilation or constriction via stimulation of prostaglandins. The soluble form of guanylate cyclase in vascular smooth muscle, an enzyme which produces the intracellular mediator of relaxation cyclic GMP, is also a site of action of vasoactive O2 metabolites. Guanylate cyclase is directly activated by nanomolar concentrations of nitric oxide (produced by endothelial cells or nitrovasodilator drugs) or H2O2 (via its metabolism by catalase). These cyclic GMP-mediated mechanisms of relaxation are inhibited by superoxide anion, produced from endogenous sources after inhibition of superoxide dismutase or produced by pharmacological agents that undergo redox cycling. In addition, O2 metabolites may modulate vascular tone via the chemical destruction of physiological contractile agents (e.g. norepinephrine) and relaxant agents (e.g. nitric oxide), and via injury to cells important for the regulation of vascular tone (e.g. endothelium). We have found in a variety of preparations that reexposure to O2 after a brief period of severe hypoxia produces vascular responses that appear to be mediated by intracellular H2O2 generation. Thus, active O2 species may contribute to vascular responses in pathophysiological situations associated with their formation (e.g. inflammation, ischemia/reperfusion, etc.) and to the physiological regulation of vascular tone produced by changes in O2 tension (e.g. reactive hyperemia, hypoxic vasoconstriction, etc).
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PMID:Activated oxygen metabolites as regulators of vascular tone. 179 78

We have examined the mechanism governing guanosine 3',5'-cyclic monophosphate (cGMP)-associated photoinduced relaxation elicited by long-wavelength ultraviolet (UV) light of endothelium-removed, isolated bovine pulmonary arteries. Hypoxia, produced by gassing of the organ bath solution with 95% N2-5% CO2, inhibited photorelaxation. Photorelaxation was also inhibited by cyanide (1 mM NaCN) but was potentiated by lactate (5 mM). Irradiation of bovine pulmonary arterial smooth muscle with UV light (or exposure to exogenous H2O2) stimulated cyanide-inhibitable oxidation of methanol to formaldehyde, suggesting that UV light increased H2O2 metabolism via catalase. The UV light-induced oxidation of methanol by pulmonary arterial smooth muscle was also inhibited by hypoxia. Consumption of O2 was detected when pulmonary arterial tissue was exposed to UV light, but cyanide failed to interfere with this effect, consistent with the photochemical reduction of O2 within vascular smooth muscle in a manner independent of mitochondrial respiration. We propose that photorelaxation is associated with the intracellular photochemical reduction of O2 to form H2O2, which elicits increases of vascular smooth muscle cGMP levels via the catalase-dependent activation of soluble guanylate cyclase. In addition, we hypothesize that the photooxidation of NAD(P)H could contribute to the generation of H2O2, since the enhancement of photorelaxation by lactate may originate from increased levels of NADH.
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PMID:Association of pulmonary artery photorelaxation with H2O2 metabolism by catalase. 192 95

We have recently suggested that relaxation of isolated precontracted intrapulmonary arteries from calves to H2O2 or O2 may involve the activation of guanylate cyclase by peroxide metabolism via catalase. In this study, ethanol, an agent that modulates peroxide metabolism by catalase and selectively inhibits the activation of guanylate cyclase by H2O2 but not by nitric oxide-related activators, was employed to further investigate the role of catalase in pulmonary arterial relaxation and guanylate cyclase activation by O2 and H2O2. In precontracted pulmonary arteries, ethanol reverses H2O2-elicited relaxation and increases in guanosine 3',5'-cyclic monophosphate (cGMP) tissue levels without affecting similar responses to nitroprusside. The pulmonary arteries employed in this study show a hypoxic contraction that is associated with decreases in cGMP levels, and reoxygenation produces a somewhat phasic relaxation and a marked increase in cGMP levels. Ethanol produces an O2 tension-dependent contraction and reverses relaxation to reoxygenation associated with inhibition of O2-elicited increases in cGMP levels. Thus ethanol appears to function as a mimic of hypoxia by inhibiting relaxations elicited by O2. These findings support a hypothesized role for H2O2-dependent activation of guanylate cyclase in O2-dependent regulation of pulmonary arterial smooth muscle tone.
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PMID:Inhibition of cGMP-associated pulmonary arterial relaxation to H2O2 and O2 by ethanol. 197 Sep 24

The mechanism of modulation of cyclic GMP-associated vascular responses by methylene blue, an agent employed to inhibit the activation of soluble guanylate cyclase in tissues, was investigated in the cremaster muscle microcirculation of pentobarbital-anesthetized rats. The effect of topically applied agents on the diameter of third-order arterioles (15-20 microns diameter) was determined by in vivo television microscopy. Topical application (100 microliters) of acetylcholine (0.01 microgram) or nitric oxide (0.06-6 micrograms) caused vasodilator responses that were inhibited (P less than .05, n = 6-8) 64% and 30 to 100%, respectively, by suffusion of the preparation with 5 microM methylene blue. Agents that are thought to produce activation of guanylate cyclase via cellular metabolism to nitric oxide, nitroglycerin (0.5 ng-0.5 microgram) or nitroprusside (0.5 ng-0.5 microgram), also produced vasodilation. However, methylene blue suffusion did not inhibit these responses (n = 6-9). The inhibition of vasodilation to acetylcholine or nitric oxide by methylene blue was completely prevented by suffusion of superoxide dismutase, but not affected by suffusion of catalase. Based on the current conceptualization of the mechanism of action of these vasodilator agents in isolated larger blood vessels, methylene blue appears to inhibit responses in this skeletal muscle microcirculatory preparation through the extracellular generation of superoxide anion and not via a direct interaction with guanylate cyclase.
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PMID:Methylene blue inhibits vasodilation of skeletal muscle arterioles to acetylcholine and nitric oxide via the extracellular generation of superoxide anion. 216 87

We have reported evidence that endothelium-independent relaxations of isolated bovine pulmonary arteries to H2O2 and to reoxygenation with 95% O2-5% CO2 after brief exposure to N2 (5% CO2) appear to be mediated by the activation of guanylate cyclase via H2O2 metabolism through catalase. Treatment of endothelium-removed pulmonary arteries with a potential guanylate cyclase-inhibitor, LY 83583, or with the inhibitor of the Zn+2, Cu+2-superoxide dismutase (SOD) diethyldithiocarbamic acid (DETCA), antagonized guanosine 3',5'-cyclic monophosphate (cGMP)-associated relaxation to H2O2, to reoxygenation and to glyceryl trinitrate, but not the adenosine 3',5'-cyclic monophosphate-associated relaxation to isoproterenol. Superoxide anion (O2-.) levels, detected by lucigenin-elicited chemiluminescence, were enhanced by LY 83583 or DETCA treatment of pulmonary arteries at ambient PO2. Chemiluminescence produced by LY 83583 was markedly potentiated by DETCA treatment, decreased at addition of exogenous SOD, and inhibited markedly by anoxia. LY 83583, but not DETCA, stimulated cyanide-insensitive O2 consumption, consistent with redox cycling of the compound independent of mitochondrial respiration. We propose that O2-. generated on the metabolism of LY 83583, or from cellular electron donors after SOD inhibition by DETCA, inhibits cGMP-mediated relaxations of pulmonary arteries.
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PMID:Superoxide anion inhibits cGMP-associated bovine pulmonary arterial relaxation. 217 63

The same factors that regulate the activation of purified hepatic soluble guanylate cyclase by diverse agents possessing distinct requirements for enzyme activation were found to modulate cyclic GMP formation in intact viable hepatic cells. A comparison was made between activation of heme-deficient or heme-reconstituted guanylate cyclase and stimulation of cyclic GMP formation in mouse hepatic slices that were 95% viable and showed no active efflux of cyclic GMP. Heme-dependent activators of guanylate cyclase elicited a greater -fold increase in hepatic cyclic GMP levels in slices from phenobarbital-pretreated than control mice. Brilliant cresyl blue and KCN inhibited both enzyme activation and hepatic cyclic GMP accumulation caused by agents that generate nitric oxide. Hepatic slices from 3,5-diethoxycarbonyl-1,4-dihydrocollidine-treated mice, which are known to develop sharp increases in hepatic protoporphyrin IX/heme concentration ratios, showed elevated resting cyclic GMP levels whereas phenobarbital pretreatment produced decreased resting cyclic GMP levels compared to controls. Guanylate cyclase activation by azide required added catalase, and both enzyme activation and hepatic cyclic GMP formation were inhibited by aminotriazole. Enzyme activation by glyceryl trinitrate and NaNO2 required added thiols. Hepatic slices from acetaminophen-pretreated mice showed marked depletion of sulfhydryls and decreased cyclic GMP formation in response to these enzyme activators. Both effects were completely restored by treatment of thiol-depleted mice with N-acetylcysteine. These observations lend support to the general view that information gained from studies on the regulatory properties of purified soluble guanylate cyclase bears a close relationship to studies on regulatory mechanisms that modulate cyclic GMP formation in intact cells.
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PMID:Hepatic cyclic GMP formation is regulated by similar factors that modulate activation of purified hepatic soluble guanylate cyclase. 243 23

The effects of O2 tension on force in precontracted isolated pulmonary arterial smooth muscle from calf lungs was characterized to investigate the mechanism of O2 tension sensing. These arteries display a decrease in force with increasing O2 tension that is antagonized via inhibition of soluble guanylate cyclase activation by 10 microM methylene blue or inactivation of catalase by pretreatment with 50 mM 3-amino-1,2,4-triazole for 30 min. O2 tension-dependent relaxation is associated with an increase in intracellular H2O2 metabolism through catalase (detected as the peroxide-dependent inactivation of tissue catalase activity by aminotriazole) and cyclic guanosine 5'-monophosphate (cGMP), known mediators of relaxation in calf pulmonary arteries. Thus a recently reconstructed mechanism of activation of soluble guanylate cyclase involving the metabolism of H2O2 by catalase appears to function as an O2 tension sensor in pulmonary arteries.
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PMID:H2O2 and cGMP may function as an O2 sensor in the pulmonary artery. 253 81

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

Conditions necessary for the activation by ascorbic acid of soluble guanylate cyclase purified from bovine lung have been examined. Ascorbic acid (0.1-10 mM) did not directly activate the enzyme, nonetheless, pronounced activation by ascorbate (3-10 mM) was observed in incubation mixtures containing 1 microM bovine liver catalase. Superoxide dismutase (SOD) and mannitol did not affect the catalase-dependent activation of guanylate cyclase elicited by ascorbate, suggesting that superoxide anion and hydroxyl radical were not mediating the activation of the enzyme. However, SOD enhanced the relatively low level activation of the enzyme elicited by catalase in the absence of added ascorbate. Pronounced inhibition (both with and without added ascorbate) was observed of catalase-dependent activation of guanylate cyclase by either ethanol (100 mM) or a fungal catalase preparation. Neither ethanol nor fungal catalase inhibited activation of guanylate cyclase by S-nitrosyl-N-acetyl-penicillamine (SNAP), a source of the nitric oxide free radical. These observations indicate that autoxidation of ascorbic acid or thiols present with the guanylate cyclase preparation leads to generation of H2O2, and its metabolism by bovine liver catalase mediates the concomitant activation of guanylate cyclase. The mechanism of activation appears to be associated with the presence of Compound I of catalase and to be inhibited by superoxide anion.
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PMID:Ascorbate activates soluble guanylate cyclase via H2O2-metabolism by catalase. 257 61

A series of six beta-adrenergic blocking drugs including propranolol, bufetolol, bunitrolol, pindolol, labetalol and acebutolol were examined for effects on adenylate cyclase, guanylate cyclase and calmodulin-dependent phosphodiesterase from heart. The adrenergic blocking agents had no apparent effects on basal activities of adenylate cyclase, guanylate cyclase and phosphodiesterase. The drugs blocked the enhancement of adenylate cyclase activity by isoproterenol, but not by guanine nucleotide or fluoride. The inhibitory effects of beta-antagonists were overcome by sufficiently large doses of isoproterenol. Sodium azide specifically required catalase whereas NaNO2 required cysteine to activate myocardial guanylate cyclase. Among beta-adrenergic blocking drugs tested, both pindolol and acebutolol inhibited the stimulation of guanylate cyclase by NaNo2 or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). However, other beta-blocking drugs did not significantly affect the activation by NaN3, NaNO2 and MNNG. Several beta-antagonists, such as labetalol, bunitrolol, pindolol and acebutolol were also effective in blocking the activation of phosphodiesterase by calmodulin. The inhibitory effects of beta-adrenergic blocking drugs, i.e. pindolol and acebutolol upon either nitroso compound-stimulated guanylate cyclase or calmodulin-activated phosphodiesterase display little correlation with their potency as beta-adrenergic blocking agents. These data suggest that beta-antagonists may have another site of action which is not directly related to the control of catecholamine metabolism.
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PMID:Different effects of various beta-adrenoceptor antagonists on adenylate cyclase, guanylate cyclase and calmodulin-dependent phosphodiesterase in heart. 286 Sep 6


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