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)

Oxygen free radicals contribute significantly to ischemia-reperfusion myocardial damage in vivo. We studied the effect of reactive products of O2 generated by electrolysis of the saline perfusate on coronary vasomotor tone and endothelium-mediated vasodilator responsiveness in 41 isolated rabbit hearts. Under constant flow conditions, electrolysis induced a progressive increase in perfusion pressure associated with a modest reduction in myocardial contractile function. The responses to the endothelium-independent vasodilators papaverine and adenosine tended to be increased by 1.5- to 2-fold, indicating that the increase in perfusion pressure was due, at least in part, to increased resistance vessel tone. However, resistance vessel dilations to the endothelium-dependent agents acetylcholine and serotonin were markedly reduced. Various degrees of protection against increases in perfusion pressure and inhibition of endothelium-dependent dilation during electrolysis were obtained with catalase, a scavenger of hydrogen peroxide; superoxide dismutase, a scavenger of superoxide; and desferrioxamine, which chelates iron and thereby inhibits hydroxyl radical production. Furthermore the action of nitroprusside, a direct-acting stimulator of soluble guanylate cyclase, was not diminished during the electrolytic treatment. We conclude that inhibition of endothelium-dependent dilation is a prominent action of reactive products of O2 in the coronary resistance bed. In combination with a free radical-induced increase in resistance vessel tone this might limit recovery of myocardial perfusion post ischemia.
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PMID:Free radicals inhibit endothelium-dependent dilation in the coronary resistance bed. 317 68

We studied the effects of endothelium-derived relaxing factor (EDRF), bovine retractor penis muscle inhibitory factor and sodium nitroprusside, three stimulants of guanylate cyclase, on the in vitro aggregation of washed human platelets. Platelet aggregation induced either by collagen or by the thromboxane A2 analogue U46619 was inhibited by all three agents. The anti-aggregatory effect of each agent was inhibited by haemoglobin. The anti-aggregatory effect of EDRF was potentiated by superoxide dismutase. These findings are discussed in relation to a potential role for EDRF in haemostasis.
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PMID:Endothelium-derived relaxing factor inhibits in vitro platelet aggregation. 349 10

Administration of bacterial lipopolysaccharide (LPS) to rats stimulates synthesis of nitric oxide (NO), a free radical molecule that activates soluble guanylate cyclase, thereby increasing intracellular guanosine 3',5'-cyclic monophosphate (cGMP) concentration and inducing systemic vasodilatation. To investigate the effect of endotoxemia on the pulmonary NO/cGMP signal transduction system, we measured the release of cGMP by isolated-perfused lungs of rats that received an intraperitoneal injection of LPS (1 mg/kg) or saline 2 days earlier. Over 90 min, 1.4 +/- 0.78 and 0.079 +/- 0.016 nmol cGMP accumulated in pulmonary perfusates of saline- and LPS-treated rats, respectively (P < 0.05). Despite addition to the perfusate of Zaprinast, superoxide dismutase, or A23187, markedly less cGMP was released from the lungs of rats exposed to LPS than from the lungs of control rats. In contrast, after ventilation with 100 parts per million NO gas, cGMP accumulating in the perfusate of the lungs of both groups of rats was markedly increased, and the quantity of cGMP released from the lungs of LPS-treated rats was similar to that released by control rat lungs (2.8 +/- 0.57 vs. 3.3 +/- 0.88 nmol, P = NS). With the use of immunoblot techniques, equal concentrations of constitutive endothelial NO synthase were detected in the lungs of rats treated with saline or LPS. These results demonstrate that the NO/cGMP signal transduction system is abnormal in the lungs of rats exposed to LPS, at least in part, at the level of endothelial NO synthase activation.
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PMID:In vivo lipopolysaccharide pretreatment inhibits cGMP release from the isolated-perfused rat lung. 749 80

We have examined the interactions of 5-aminosalicylic acid with nitric oxide (NO). Phenylephrine-precontracted rat aortic strips with intact endothelium were further contracted by 5-aminosalicylic acid (50-200 microM) in a concentration-dependent manner. Removal of endothelium, inhibition of guanylate cyclase by methylene blue, inhibition of NO biosynthesis by NG-nitro-L-arginine as well as in inactivation of NO by oxyhemoglobin abolished the effect of 5-aminosalicylic acid. The antiaggregatory effects of 3-morpholinosydnonimine and rat peritoneal neutrophils, which are due to release of NO, were diminished in a concentration-dependent manner by 5-aminosalicylic acid (50-250 microM). In both experimental models the effects of 5-aminosalicylic acid were significantly reduced by superoxide dismutase in a concentration which alone exhibited no effect. Since NO might act as a cytotoxic and vasodilating mediator, our results suggest that inactivation of NO by 5-aminosalicylic acid could contribute to the therapeutic activity of the drug in inflammatory bowel disease.
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PMID:Interaction of 5-aminosalicylic acid with nitric oxide on rat aortic strips and human platelets. 749 69

In this study, we analysed the implication of superoxide (O2-.) and nitric oxide (NO.) free radicals and their resulting product peroxynitrite (ONOO-) in the neuronal death induced by the activation of the glutamatergic receptor of the N-methyl-D-aspartate (NMDA) subtype using cultured cerebellar granule cells. The NOl donor SIN-1 (3-morpholinosydnonimine N-ethylcarbamide), at concentrations which produced a much higher guanylate cyclase activation (i.e. NO. concentration) than NMDA, was not neurotoxic and did not increase the NMDA-induced neuronal death. The absence of involvement of NO. in NMDA-induced neuronal death was confirmed by the ineffectiveness of L-NG-nitroarginine (L-Narg) as a neuroprotective compound. Electron paramagnetic resonance (EPR) experiments, using 5,5-dimethyl pyrroline 1-oxide (DMPO) as a spin trap, indicated that NMDA receptor stimulation led to the generation of O2-. from at least 15-30 min. The generation of O2-. by xanthine (XA)-xanthine oxidase (XO) induced a neuronal death similar to that of NMDA. XA-XO-induced neuronal death was suppressed by addition of either superoxide dismutase (SOD) plus catalase (CAT), or DMPO in the incubation medium. In contrast, NMDA-induced neuronal death was widely blocked by DMPO and other spin trap compounds, but not by SOD +/- CAT. XA-XO-induced neuronal death was not potentiated by SIN-1 indicating that ONOO- is not more toxic than O2-. in our neuronal model.
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PMID:Nitric oxide, superoxide and peroxynitrite: putative mediators of NMDA-induced cell death in cerebellar granule cells. 750 50

We investigated the vasoactive actions of the wound-healing agent tetrachlorodecaoxygen (TCDO). TCDO (20 microM) had no direct effect on tone in isolated calf pulmonary arteries precontracted with potassium with or without 1 microM reduced hemoglobin under O2 or N2 atmosphere. However, TCDO, in a reduced hemoglobin-dependent manner, attenuated contraction produced by serotonin, associated with spectral changes consistent with destruction of serotonin. The loss of tone induced by serotonin catalyzed by TCDO plus reduced hemoglobin was not altered in the presence of superoxide dismutase (SOD) plus catalase. TCDO plus reduced hemoglobin also produced rapid relaxation of isolated rabbit aorta precontracted with norepinephrine (NE), whereas with phenylephrine (PE)-induced bone, the observed relaxation was slow to develop. Neither did TCDO, with or without reduced hemoglobin, alter soluble guanylate cyclase activity in pulmonary artery. Thus, a highly reactive species produced by interaction of TCDO with reduced hemoglobin appears to attenuate the contractile actions of serotonin, NE, and PE, selectively potentially by destroying these vasoactive agents. The vasodilator actions of TCDO (plus reduced hemoglobin) may contribute to wound healing by increasing nutrient blood flow and O2 delivery needed for repair processes and bactericidal activity.
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PMID:Tetrachlorodecaoxygen, a wound healing agent, produces vascular relaxation through hemoglobulin-dependent inactivation of serotonin and norepinephrine. 751 20

Responses to bradykinin (BK) were investigated in the pulmonary vascular bed of the cat under conditions of controlled pulmonary blood flow and constant left atrial pressure when lobar arterial pressure was elevated to a high steady level. Under elevated-tone conditions, BK caused dose-related decreases in lobar arterial pressure. After administration of Hoe-140, a BK B2-receptor antagonist, vasodilator responses to BK were reduced in a selective manner. Vasodilator responses to BK were unchanged by atropine, glibenclamide, meclofenamate, or bronchial occlusion, suggesting that responses are not dependent on the activation of muscarinic receptors or K+ATP channels, the release of vasodilator prostaglandins, or changes in bronchomotor tone. The nitric oxide (NO) synthase inhibitors N omega-nitro-L-arginine benzyl ester and N omega-nitro-L-arginine reduced vasodilator responses to BK in a selective manner, indicating that responses to BK are mediated in part by the release of NO. Methylene blue, an inhibitor of the activation of soluble guanylate cyclase, increased lobar arterial pressure and decreased responses to BK. The increases in lobar arterial pressure in response to methylene blue were partially reversed by the administration of superoxide dismutase, indicating that generation of O2- may inactivate basally released NO. The duration of the response to BK was enhanced by the guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterase inhibitor Zaprinast, suggesting that responses to BK involve increases in cGMP levels. Responses to BK were enhanced by captopril, indicating that BK is rapidly inactivated by kininase II in the lung.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Analysis of responses to bradykinin in the pulmonary vascular bed of the cat. 751 46

Bradykinin (BK) and its analogues induce a typical biphasic response (relaxation followed by contraction) in the isolated rat duodenum. We studied the role of B1 and B2 BK receptors and nitric oxide (NO) in relaxation and contraction of the isolated rat duodenum. Both effects are concentration-dependent: BK has shown an EC50 (contraction) of 3.8 +/- 1.9 x 10(-7) M and an IC50 (relaxation) of 3.0 +/- 0.7 x 10(-9). Similar results were obtained with the selective B2 receptor agonists [Hyp3,Tyr(Me)8]-BK and [Phe8 psi (CH2-NH)Arg9]-BK, showing an EC50 of 9.6 +/- 1.9 x 10(-7) M and 5.6 +/- 2.9 x 10(-7) M and an IC50 of 3.5 +/- 0.6 x 10(-10) M and 6.8 +/- 1.7 x 10(-10) M, respectively. Furthermore, the effects induced by these three agonists were not altered when tissues were treated with 42.1 microM Mergetpa, a carboxypeptidase N inhibitor. While the relaxant and contractile effects elicited by BK were significantly inhibited in the presence of Hoe 140 (0.7 microM), a selective B2 receptor antagonist, those induced by the selective B1 receptor agonist desArg9-BK were not. Furthermore, [Leu8]-desArg9-BK (2.6 microM), which is both a pure and selective B1 receptor antagonist, acted as an agonist on the rat duodenum, inducing a biphasic relaxant and contractile effect. These relaxant and contractile effects were not altered by drugs that inhibit or stimulate NO production, such as L-NAME (200 microM), a combination of L-NAME (200 microM) and indomethacin (2.5 microM), L-arginine (1 mM), or superoxide dismutase (20 U/ml). However, the contractile effect was significantly reduced when tissues were preincubated with methylene blue (100 microM), which inhibits activation of guanylate cyclase. We conclude that 1) BK and its analogues selectively activate a B2 receptor, producing a biphasic effect (relaxation and contraction); 2) DesArg9-BK may either acts via a different receptor which might be another B1 receptor subtype or a typical B1 receptor where [Leu8]-desArg9-BK acts as a partial agonist; and 3) neither NO nor the prostaglandin pathway mediates BK-induced relaxation in the isolated rat duodenum.
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PMID:Role of B1 and B2 receptors and of nitric oxide in bradykinin-induced relaxation and contraction of isolated rat duodenum. 752 22

YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole] inhibited the aggregation of and ATP release from washed rabbit platelets induced by arachidonic acid (AA), collagen, U46619, platelet-activating factor (PAF), and thrombin in a concentration-dependent manner. YC-1 also disaggregated the clumped platelets caused by these inducers. The thromboxane B2 formation caused by collagen, PAF, and thrombin was inhibited by concentrations of YC-1 that did not affect formation of thromboxane B2 and prostaglandin D2 caused by AA. YC-1 suppressed the increase of intracellular Ca2+ concentration and generation of inositol 1,4,5-trisphosphate caused by these five aggregation inducers. Both the cAMP and cGMP contents of platelets were increased by YC-1 in a concentration- and time-dependent manner. Like sodium nitroprusside, YC-1 potentiated formation of cAMP caused by prostaglandin E1 but not that by 3-isobutyl-1-methylxanthine. Adenylate cyclase and cAMP phosphodiesterase activities were not altered by YC-1. Activity of cGMP phosphodiesterase was unaffected by YC-1. Activities of guanylate cyclase in platelet homogenate and cytosolic fraction were activated by YC-1, whereas particulate guanylate cyclase activity was unaffected. The antiplatelet effect of sodium nitroprusside but not that of YC-1 was blocked by hemoglobin and potentiated by superoxide dismutase. After intraperitoneal administration for 30 minutes, YC-1 prolonged the tail bleeding time of conscious mice. These data indicate that YC-1 is a direct soluble guanylate cyclase activator in rabbit platelets. It may also possess antithrombotic potential in vivo.
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PMID:YC-1, a novel activator of platelet guanylate cyclase. 752 71

Endothelium-derived relaxing factor/nitric oxide (EDRF/NO) is produced by the vascular wall and is a key modulator of vascular tone and blood pressure. Since reduced EDRF/NO release from the endothelium is a major key event in the development of atherosclerosis, we investigated the effect of cholesterol on endothelial cell particulate (membrane-bound) NO synthase activity. Low concentrations (up to 0.2 mM) of liposomal cholesterol progressively activated plasma membrane-bound NO synthase. Increasing cholesterol concentration above that which maximally stimulated enzyme activity produced a progressive inhibition with respect to the control value. In time course experiments using endothelial cell plasma membranes enriched with cholesterol, changes in NO production were followed by analogous changes in soluble guanylate cyclase activity (sGC). N-Monomethyl-L-arginine (L-NMMA) (1 mM) inhibited particulate NO synthase activity at all cholesterol concentrations used with subsequent decreases in cGMP production. Egg lecithin liposomes (free of cholesterol) had no effect on NO synthase activity. A three-fold increase in superoxide (O2-) and a 2.5-fold increase in NO formation followed by an eight-fold increase in peroxynitrite (ONOO-) production by cholesterol-treated microsomes isolated from endothelial cells was observed, one which rose further up to eight-fold in the presence of superoxide dismutase (SOD) (10 U/mL). Cholesterol had no effect on Lubrol-PX solubilized membrane-bound NO synthase or on cytosolic (soluble) NO synthase activities of endothelial cells. Cholesterol modulated lipid fluidity of plasma membranes labelled with 1,6-diphenyl-1,3,5-hexatriene (DPH) as indicated by the steady state fluorescence anisotropy [(ro/r)-1]-1. Arrhenius plots of [(ro/r)-1]-1 indicated that the lipid phase separation of the membranes at 26.2 +/- 1.5 degrees was elevated to 34.4 +/- 1.9 degrees in cholesterol-enriched membranes, consistent with a general decrease in membrane fluidity. Cholesterol-enriched plasma membranes treated with egg lecithin liposomes showed a lipid phase separation at 27.5 +/- 1.6 degrees, indicating the reversible effect of cholesterol on membrane lipid fluidity. Arrhenius plots of NO synthase activity exhibited break point at 26.9 +/- 1.8 degrees which rose to 35.6 +/- 2.1 degrees in 0.5 mM cholesterol-treated plasma membranes and decreased to 21.5 +/- 1.4 degrees in plasma membranes treated with 0.2 mM cholesterol. The allosteric properties of plasma membrane-bound NO synthase inhibited by Mn2+ (as reflected by changes in the Hill coefficient) were changed by cholesterol, consistent with modulations of the fluidity of the lipid microenvironment of the enzyme.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Modulation of particulate nitric oxide synthase activity and peroxynitrite synthesis in cholesterol enriched endothelial cell membranes. 754 Mar 91


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