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)

Superfusion of rat cremaster muscles with the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) elicited significant leukocyte adhesion to postcapillary venules (20- to 30-microns diameter), an effect that was attenuated by pretreatment with L-arginine (an NO precursor) or sodium nitroprusside (SNP) (an exogenous source of NO). In contrast to the effects of pretreatment, addition of SNP or L-arginine to the superfusate 30 min after the initiation of NO synthase inhibition failed to reverse the L-NAME-induced leukocyte adherence. However, this effect was reversed by administration of an anti-CD18 monoclonal antibody or 8-bromoguanosine 3',5'-cyclic monophosphate 30 min after L-NAME superfusion was initiated. These findings indicate that L-NAME promotes leukocyte adhesion to venular endothelium by a CD18-dependent mechanism in skeletal muscle and suggest that the failure of L-arginine or SNP to reverse L-NAME-induced leukocyte adherence is not due to a defect in signaling events that occur subsequent to activation of guanylate cyclase by NO derived from these agents. Because the simultaneous administration of superoxide dismutase (scavenges superoxide radicals) and SNP or L-arginine, but not superoxide dismutase alone, decreased L-NAME-induced leukocyte adherence, our results suggest that leukocyte adhesion caused by NO synthase inhibition may result in the generation of superoxide.
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PMID:Leukocyte adhesion induced by inhibition of nitric oxide production in skeletal muscle. 754 40

In the present study we demonstrated that human erythrocytes possess a NO synthase (NOS) that can be activated by oxidative stress and Ca2+ accumulation to produce nitric oxide (NO), and that this activation could be involved in the pathogenesis of toxic anaemia in breast cancer patients. By causing oxidative stress in human erythrocytes with hydrogen peroxide (H2O2) (100 microM), or by increasing the intracellular calcium concentration using various doses (up to 100 microM) of the calcium ionophore A23187, a gradual increase in both NO and peroxynitrite (ONOO-) release that was inhibited by N-monomethyl-L-arginine (L-NMMA) (1mM) was observed. Time-dependent experiments using hemolysates showed a linear rise of NO production which was elevated by 60% in the presence of superoxide dismutase (SOD) (100 U). NOS isolated from hemolysates was constitutively expressed and was dependent on NADPH, Ca2+/calmodulin, tetrahydrobiopterin and flavins. In reconstitution experiments, when purified NOS, isolated from erythrocytes, was added to purified soluble guanylate cyclase (sGC), isolated from endothelial cells, in the presence of the appropriate cofactors and substrates, a linear increase in cGMP production at various concentrations (up to 50 microM) of H2O2 was observed. Furthermore, it was shown that erythrocytes from breast cancer patients were subjected to higher oxidative stress by ONOO- (100 microM), with a consequential increase of membrane rigidity, than erythrocytes from healthy individuals. Such mechanic changes may result in shortening of the lifespan of erythrocytes, a feature of toxic anemia in cancer patients.
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PMID:Nitric oxide and peroxynitrite production by human erythrocytes: a causative factor of toxic anemia in breast cancer patients. 754 67

The effect of 6-anilino-5,8-quinolinedione (LY83583), an inhibitor of guanylyl cyclase (GC), on the growth of human brain tumor cells (U-373 MG astrocytoma and SK-N-MC neuroblastoma) was evaluated. LY83583 inhibited the growth of these cells in a dose-dependent manner. This growth inhibition was found to be the result of decreased cell viability as assessed by the trypan blue exclusion method. The LY83583-induced decrease in cell viability was not altered by dibutyryl cyclic GMP, but significantly was reversed by superoxide dismutase and catalase, indicating that these effects of LY83583 may not be due to the inhibition of GC, but due to the formation of superoxide anion. The LY83583-induced decrease in cell viability was potentiated by cotreatment with sodium nitroprusside (SNP), a nitric oxide (NO) donor. This SNP-induced potentiation was significantly blocked by various scavengers for hydroxyl radicals or by intracellular Ca2+ release blockers. These results suggest that the potentiation effects of SNP may be mediated through the generation of hydroxyl radicals which can be formed by the interaction of superoxide anion (from LY83583) and NO (from SNP), and that intracellular Ca2+ release from internal stores may play an important role in the cytotoxic mechanism of hydroxyl radicals.
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PMID:Mechanism of potentiation of LY83583-induced growth inhibition by sodium nitroprusside in human brain tumor cells. 762 54

The hypothesis was tested that plasma from ischemic hindlimbs facilitates hypertension. Ischemia-induced hypertension was generated in rats by infrarenal aortic cross clamping for 5 h after which plasma was obtained from femoral vein blood. In vitro contractile activity of naive aortic rings incubated for 2 h in plasma collected from ischemic rats demonstrated reduced relaxation to acetylcholine and nitroglycerin. Methylene blue (10(-5) M) induced greater contraction in rings incubated in control vs. ischemic plasma, suggesting that endogenous guanylate cyclase activity is decreased by ischemic plasma. However, 8-bromo-guanosine 3',5'-cyclic monophosphate (cGMP) relaxed equally strips incubated in ischemic or control plasma. Acetylcholine-induced nitrite release was significantly lower in ischemic vs. control plasma-incubated strips (8.6 +/- 2.7 vs. 28.2 +/- 2.3 ng/10 mg tissue wt, respectively). The impaired relaxation to acetylcholine in ischemic plasma-incubated rings was significantly increased by L-arginine but not by prior treatment of ischemic plasma with heating or superoxide dismutase and catalase. These findings suggest the impaired relaxation is mediated through inhibition of the nitric oxide-cGMP pathway. Prolonged blunting of vasodilation by ischemic plasma may therefore contribute to maintenance of a sustained vasoconstriction and ischemic hypertension.
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PMID:Inhibition of vascular nitric oxide-cGMP pathway by plasma from ischemic hindlimb of rats. 763 55

1. The present study investigates whether or not chronic feeding of rats with a diet enriched in fish oil affects the reactivity of balloon-injured carotid arteries. The left carotid arteries were injured in vivo by the repeated passage of a balloon catheter. Both the right (control artery) and the left carotid arteries were excised 24 h after the injury, and suspended in organ chambers for the measurement of changes in isometric tension in the presence of indomethacin. 2. Phenylephrine evoked similar concentration-contraction curves in the right (control) carotid arteries without endothelium from control and fish oil-fed rats. Balloon injury decreased the contractility of carotid arteries to phenylephrine in both types of rats and the pEC50 for phenylephrine was significantly decreased in balloon-injured arteries from control rats compared to those obtained in arteries from fish oil-fed rats (pEC50 7.59 +/- 0.1 and 7.28 +/- 0.06, respectively) while maximal contractions were similar (1.93 +/- 0.15 g and 1.79 +/- 0.12 g, respectively). 3. The treatment of control right carotid arteries without endothelium with either NG-nitro-L-arginine (an inhibitor of nitric oxide synthase) or superoxide dismutase (which protects nitric oxide from degradation) did not affect significantly the contractions to phenylephrine in either group. In these preparations, methylene blue (an inhibitor of soluble guanylate cyclase) decreased slightly but significantly maximal contractions to phenylephrine in both groups. The treatment of balloon-injured carotid arteries with NG-nitro-L-arginine or methylene blue partly restored contractions to phenylephrine in arteries from both types of rat. Superoxide dismutase further depressed the contractility to the alpha l-adrenoceptor agonist in balloon-injured arteries from control diet-fed rats but had no effect in balloon-injured preparations from fish oil-fed rats.4. 3-Morpholino-sydnonimine (SIN-1, a donor of nitric oxide) evoked similar concentration-dependent relaxations in control and balloon-injured carotid arteries from both types of rat.5. Balloon injury caused an increase in the tissue content of cyclic GMP in carotid arteries from control diet-fed rats. This production of cyclic GMP was abolished by N0-nitro-L-arginine. Superoxide dismutase potentiated significantly the production of cyclic GMP caused by balloon injury in control but not in fish oil-fed rats.6 These observations confirm that in vivo balloon injury causes the production of nitric oxide in the injured blood vessel wall. This production of nitric oxide from L-arginine accounts for the decreased contractility to phenylephrine and the accumulation of cyclic GMP in balloon-injured arteries. They further indicate that chronic feeding of rats with fish oil potentiates the L-arginine-nitric oxide pathway in the injured vessel leading to an enhanced hyporeactivity to phenylephrine.
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PMID:Potentiation of the hyporeactivity induced by in vivo endothelial injury in the rat carotid artery by chronic treatment with fish oil. 767 Jul 27

Methylene blue appears to inhibit nitric oxide-stimulated soluble guanylyl cyclase and has been widely used for inhibition of cGMP-mediated processes. We report here that endothelium-dependent relaxation of isolated blood vessels and NO synthase-dependent cGMP formation in cultured endothelial cells were both markedly more sensitive to inhibition by methylene blue than effects induced by direct activation of soluble guanylyl cyclase. These discrepancies were also observed when superoxide dismutase (SOD) was present to protect NO from inactivation by superoxide anion. Subsequent experiments showed that formation of L-citrulline by purified NO synthase was completely inhibited by 30 microM methylene blue (IC50 = 5.3 and 9.2 microM in the absence and presence of SOD, respectively), whereas guanylyl cyclase stimulated by S-nitrosoglutathione was far less sensitive to the drug (50% inhibition at approximately 60 microM, and maximal inhibition of 72% at 1 mM methylene blue). Experimental evidence indicated that oxidation of NADPH, tetrahydrobiopterin or reduced flavins does not account for the inhibitory effects of methylene blue. Our data suggest that methylene blue acts as a direct inhibitor of NO synthase and is a much less specific and potent inhibitor of guanylyl cyclase than hitherto assumed.
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PMID:Inhibition of nitric oxide synthesis by methylene blue. 767 77

In addition to mediating several physiological functions, nitric oxide (NO) has been implicated in the cytotoxicities observed following activation of macrophages or excess stimulation of neurons by glutamate. We extend our previous observations of glutamate-stimulated, NO-mediated neurotoxicity in primary cultures of rat fetal cortical, striatal, and hippocampal neurons. Neurotoxicity elicited by either NMDA or sodium nitroprusside (SNP) exhibits a similar concentration-effect relationship and time course. The concentration-effect curve of NMDA-induced neurotoxicity is shifted to the right in the presence of nitro-L-arginine and farther to the right in arginine-free media. The rank order of potency of several NO synthase (NOS) inhibitors in preventing neurotoxicity is the same as the rank order of these compounds in inhibiting NOS, and this inhibition is stereospecific. NMDA neurotoxicity is also prevented by flavoprotein inhibitors and calmodulin inhibitors, fitting with the roles of flavoproteins and calmodulin as NOS regulators. 8-Bromo-cGMP and guanylyl cyclase inhibitors do not affect neurotoxicity, while superoxide dismutase attenuates neurotoxicity. NOS neurons appear to be the source of neurotoxic NO in culture, as lesions of these neurons with 20 microM quisqualate diminish subsequent NMDA neurotoxicity. Moreover, NMDA neurotoxicity develops over time in culture coincident with the expression of NOS. Immunohistochemical localization of NOS in cultures and intact brain demonstrates widespread distribution of the cell processes suggesting that NOS neurons contact the majority of cortical neurons and so could mediate widespread neurotoxicity.
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PMID:Mechanisms of nitric oxide-mediated neurotoxicity in primary brain cultures. 768 76

The objective of this study was to determine the role of superoxide ion in the formation of nitric oxide by brain NO synthase. NO synthase activity was detected by activation of guanylate cyclase in broken cell preparations. NO synthase activity was dependent on NADPH and was inhibited by EGTA, hemoglobin, Nw-methyl-L-arginine and nitroblue tetrazolium. While the addition of exogenous superoxide dismutase significantly enhanced NO synthase activity, bovine liver catalase completely abolished NO formation. None of these NO synthase modulators, however, altered NO-dependent stimulation of guanylate cyclase activity. These observations indicate that catalytic conversion of L-arginine to nitric oxide by cytosolic, isoform of brain NO synthase requires superoxide ion, hydrogen peroxide and possibly hydroxyl radical.
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PMID:Nitric oxide synthase: involvement of oxygen radicals in conversion of L-arginine to nitric oxide. 768 3

Previous research by our laboratory demonstrated that in vivo administration of morphine to rats suppresses concanavalin-A (Con-A)-stimulated proliferation of splenic lymphocytes in a dose-dependent, naltrexone-reversible manner. More recently, we showed that morphine-induced suppression of Con A-stimulated proliferation of lymphocytes depends on an increase in macrophage production of nitric oxide (NO) in splenocyte cultures. The present study investigated effector mechanisms through which morphine-induced increases in macrophage-derived NO decrease lymphocyte proliferation in Con A-stimulated splenocyte cultures. The results show that the addition of hemoglobin, a scavenger of extracellular NO, to Con A-stimulated splenocyte cultures dose-dependently attenuates the suppressive effect of morphine on proliferation. The addition of superoxide dismutase, a scavenger of superoxide anions, to splenocyte cultures does not antagonize the suppressive effect of morphine on Con A-stimulated proliferation. The addition of either methylene blue or 6-anilino-5, 8-quinolinedione (LY 83583), two inhibitors of soluble guanylate cyclase, to splenocyte cultures dose-dependently antagonizes the suppressive effect of morphine on Con A-stimulated proliferation. Taken together with our previous results, the present results suggest that in vivo administration of morphine increases the synthesis and extracellular release of NO from macrophages in Con A-stimulated splenocyte cultures. The results further suggest that the formation of the oxidant peroxynitrite through a reaction between NO and superoxide anion does not contribute significantly to the suppression of lymphocyte proliferation; instead, the activation of soluble guanylate cyclase by NO in target cells, most likely the lymphocytes, accounts more completely for the morphine-induced suppression of lymphocyte proliferation.
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PMID:Mechanisms whereby macrophage-derived nitric oxide is involved in morphine-induced suppression of splenic lymphocyte proliferation. 785 59

The present study in isolated rat lungs demonstrates that nitric oxide gas (.NO, 70 nM) added to the perfusate containing a small amount of hemolysate [175 microliters of lysed red blood cells (RBC) per 50 ml of Earle's balanced salt solution (EBSS)] triggered profound and sustained vasoconstriction. Vasoconstriction was not observed when .NO was added to lungs perfused with washed intact rat or human RBC or with oxyhemoglobin (Hgb 20 microM). The presence of hemolysate in the perfusate also caused vasoconstriction in response to n-acetylcysteine (50 microM), glutathione (10(-4) M), or ascorbic acid (10(-4) M) and potentiated greatly the vasoconstrictor response to 5 mM KCl. Not only .NO, but also nitroprusside (SNP) or L-arginine and paradoxically three .NO synthesis inhibitors, including N-monomethyl L-arginine, L-NAME, and nitroblue tetrazolium, which have different mechanisms of action, each caused in the presence of hemolysate large vasoconstrictive responses. Hemolysate itself enhanced O2 consumption by slices of lung; no effects of this dose of .NO on lung slice respiration were seen in the absence of hemolysate. Both Hgb and hemolysate lowered perfusate cGMP levels to the same degree suggesting that the vasoconstrictive response was not due to unique effects of hemolysate on guanylyl cyclase. Addition of superoxide dismutase (SOD) and catalase (CAT) to the hemolysate containing perfusate, or addition of a cyclooxygenase or 5-lipoxygenase inhibitor, virtually abolished the .NO induced vasoconstriction. The latter data are consistent with the concept that exposure of the vasculature to hemolysate may result in the formation of peroxynitrite. However, SOD and CAT did not abolish the pulmonary vasoconstriction induced by L-arginine or by NAC. Our data indicate that hemolysate has profound effects on lung vessel tone regulation and on lung tissue mitochondrial function, yet the precise molecular mechanisms responsible for the action of hemolysate are likely to be very complex.
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PMID:Nitric oxide-related vasoconstriction in lungs perfused with red cell lysate. 789 7


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