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)

(6R)-5,6,7,8-Tetrahydro-L-biopterin (R-THBP) is a cofactor not only for aromatic amino acid hydroxylases in mammalian tissues but also for nitric oxide synthase (NOS) induced by endotoxins or cytokines in some kinds of cells. Recently it has been reported that nitric oxide (NO) has biological activity in endothelium and in brain as well. NO activates soluble guanylate cyclase (sGC). Superoxide reacts with NO easily and shortens the half-life of NO actions. We found, in a study using rat cerebellar cytosol fraction, that R-THBP itself did not directly activate sGC, but activated sGC at concentrations ranging from 0.1 to 10 microM only under NO generating conditions of activated NOS and in the presence of sodium nitroprusside. In addition, R-THBP (1 microM) did not alter the NOS activity, which was determined by L-citrulline formation. These results suggest that R-THBP may regulate sGC activity associated with NO formation in the central nervous system.
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PMID:(6R)-5,6,7,8-tetrahydro-L-biopterin modulates nitric oxide-associated soluble guanylate cyclase activity in the rat cerebellum. 135 30

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

Human platelet soluble guanylate cyclase activity was studied with respect to the function of its heme-containing regulatory subunit. As an enzyme source, the 10,000 x g supernatant was used and, since its specific activity proved to be too low for inhibition studies, also a partially purified preparation was employed. The partially purified enzyme was stimulated about 2.5-fold by carbon monoxide and this effect was abolished by illumination with visible light. Sodium nitroprusside also increased the basal activity about fourfold, which, however, is much less than the greater than 100-fold stimulation seen with the supernatant. Superoxide anions generated by the xanthine/xanthine-oxidase system were strongly inhibitory in the enriched preparation as well as in the CO-stimulated platelet supernatant (median effector concentration = 0.1 mU/ml). Unlike CO and NO, the effect of superoxide cannot be mediated through the heme-containing regulatory subunit, since heme-free enzyme, which could not be activated by NO or CO, was inhibited to the same extent as the heme-containing enzyme. Superoxide dismutase did not influence the basal activity, but resulted in a synergistic stimulation in the presence of CO. When Mn2+ replaced Mg2+ as a cofactor, the basal activity was higher but superoxide could not inhibit the enzyme, possibly due to the superoxide-dismutase-like activity of Mn2+. Superoxide turned out to be a potent and reversible inhibitor of soluble guanylate cyclase which, together with endothelium-derived relaxing factor, recently identified as NO, could form a physiologically relevant regulatory effector system.
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PMID:Activation of soluble guanylate cyclase by carbon monoxide and inhibition by superoxide anion. 197 16

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

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 mast cell is the cellular basis for immediate hypersensitivity reactions. The specificity of the immediate hypersensitivity reaction is attributable to IgE molecules fixed to specific membrane receptors which, when stimulated by specific antigen, initiates the process of degranulation of the mast cell. The granules provide three separate sources of biologic activity: performed or primary mediators, newly generated or secondary mediators, and activities associated with the granular matrix. A number of biologic consequences are generated in response to these mediators and these include: increased vascular permeability, vasodilation, smooth muscle spasm, polymorphonuclear leukocyte chemotaxis, stimulation of adenylate and guanylate cyclase, superoxide radical generation, prostaglandin formation, mucous and gastric acid secretion, hypotension, tissue destruction, and mononuclear leukocyte infiltration. This pharmacopia of activities accounts for the clinical aspects of allergic diseases, suggests that the mast cell granule may be involved in the host's defense against parasitic infections, and is compatible with a suggested role of the mast cell as a widely distributed, monocellular endocrine system.
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PMID:The mast cell. 617 51

Reactive oxygen metabolites have been reported to affect platelet aggregation. However, this phenomenon is still poorly understood. In the present study we investigated the effects of superoxide radical and hydrogen peroxide (H2O2) on platelet function in vitro and correlated those effects to possible changes of platelet concentrations of cyclic nucleotides and thromboxane, since these systems play a key role in the response of platelets to activating stimuli. Human platelets were exposed to xanthine-xanthine oxidase (X-XO), a system that generates both superoxide radicals and H2O2. Sixty seconds of incubation with X-XO impaired aggregation in response to ADP (by 48%), collagen (by 71%), or the thromboxane mimetic U-46619 (by 50%). This effect was reversible and occurred in the absence of cell damage. Impairment of aggregation in platelets exposed to X-XO was due to H2O2 formation, since it was prevented by catalase but not by superoxide dismutase. Similarly, incubation with the pure H2O2 generator glucose-glucose oxidase also markedly inhibited ADP-induced platelet aggregation in a dose-dependent fashion. Impaired aggregation by H2O2 was accompanied by a > 10-fold increase in platelet concentrations of guanosine 3',5'-cyclic monophosphate (cGMP), whereas adenosine 3',5'-cyclic monophosphate levels remained unchanged. The inhibitory role of increased cGMP formation was confirmed by the finding that H2O2-induced impairment of platelet aggregation was largely abolished when guanylate cyclase activation was prevented by incubating platelets with the guanylate cyclase inhibitor, LY-83583. Different effects were observed when arachidonic acid was used to stimulate platelets. Exposure to a source of H2O2 did not affect aggregation to arachidonate. Furthermore, in the absence of exogenous H2O2, incubation with catalase, which had no effects on platelet response to ADP, collagen, or U-46619, virtually abolished platelet aggregation and markedly reduced thromboxane B2 production (to 44% of control) when arachidonic acid was used as a stimulus. In conclusion, our data demonstrate that H2O2 may exert complex effects on platelet function in vitro. Low levels of endogenous H2O2 seem to be required to promote thromboxane synthesis and aggregation in response to arachidonic acid. In contrast, exposure to larger (but not toxic) concentrations of exogenous H2O2 may inhibit aggregation to several agonists via stimulation of guanylate cyclase and increased cGMP formation.
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PMID:Modulation of platelet function by reactive oxygen metabolites. 804 96

Myocardial stunning is a phenomenon in which ventricular function is depressed by prior ischemia and remains suboptimal when blood flow is resumed. It is also characterized by coronary vascular endothelial dysfunction that is related to the duration of ischemia and can result in protein leakage, myocardial hemorrhage, or increased coronary vascular resistance. It is thought that local vascular tone is regulated by endothelium derived relaxing factor (EDRF), a compound commonly believed to be identical to nitric oxide (NO). EDRF increases the effects of other vasodilators through the formation of cyclic guanosine monophosphate (cGMP) by guanylate cyclase. Patients with various cardiovascular disorders have been found to have dysfunction in the EDRF system, and EDRF paradoxically produces vasoconstriction in atherosclerotic arteries. Similarly, EDRF stimulation of vasodilation due to acetylcholine, calcium ionophores, or platelets appears to be reduced in coronary arteries that have been damaged by ischemia and reperfusion. By increasing EDRF production or inhibiting its breakdown, EDRF precursors such as L-arginine, the superoxide radical scavenger superoxide dismutase, nitroglycerin, and nitroprusside all cause vasodilation by increasing NO levels in the setting of myocardial ischemia. These therapies may also improve local "microvascular" function, thereby improving ventricular function.
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PMID:Do deficiencies of endothelial derived relaxing factor contribute to myocardial stunning? 846 25

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

Reactive oxygen species such as superoxides, hydrogen peroxide (H2O2) and hydroxyl radicals have been suggested to be involved in the catalytic action of nitric oxide synthase (NOS) to produce NO from L-arginine. An examination was conducted on the effects of oxygen radical scavengers and oxygen radical-generating systems on the activity of neuronal NOS and guanylate cyclase (GC) in rat brains and NOS from the activated murine macrophage cell line J774. Catalase and superoxide dismutase (SOD) showed no significant effects on NOS or GC activity. Nitroblue tetrazolium (NBT, known as a superoxide radical scavenger) and peroxidase (POD) inhibited NOS, but their inhibitory actions were removed by increasing the concentration of arginine or NADPH respectively, in the reaction mixture. NOS and NO-dependent GC were inactivated by ascorbate/FeSO4 (a metal-catalyzed oxidation system), 2'2'-azobis-amidinopropane (a peroxy radical producer), and xanthine/xanthine oxidase (a superoxide generating system). The effects of oxygen radicals or antioxidants on the two isoforms of NOS were almost similar. However, H2O2 activated GC in a dose-dependent manner from 100 microM to 1 mM without significant effects on NOS. H2O2-induced GC activation was blocked by catalase. These results suggested that oxygen radicals inhibited NOS and GC, but H2O2 could activate GC directly.
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PMID:The effects of oxygen radicals on the activity of nitric oxide synthase and guanylate cyclase. 989 52


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