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

The possible endothelial factors involved in endothelium-dependent relaxations induced by acetylcholine (ACh) in aorta, mesenteric and femoral arteries of rabbit were analyzed. In thoracic aorta precontracted with noradrenaline, NG-nitro-L-arginine methyl ester (L-NAME) and methylene blue (MB), inhibitors of nitric oxide (NO) synthase and guanylate cyclase, practically abolished ACh relaxation. This relaxation was reduced by the Na+ pump inhibition with ouabain and K(+)-free solution, and by the blockade of Ca(2+)-dependent K+ channels with tetraethylammonium (TEA). Ouabain reduced the relaxation produced by the NO donor, sodium nitroprusside (SNP). In the mesenteric artery, L-NAME and MB produced a small reduction of ACh relaxation. However, ouabain, K(+)-free medium and TEA markedly decreased this relaxation. SNP induced a relaxation which was diminished by ouabain. In segments precontracted with high K+, ACh relaxation was abolished by L-NAME and MB. In femoral arteries, L-NAME and MB reduced ACh relaxation. The stimulated cGMP concentrations caused by ACh or SNP were less in the aorta than in mesenteric and femoral arteries. These results suggest that ACh relaxation is mediated: in aorta by endothelial NO which may hyperpolarize to some extent the smooth muscle cells through the sodium pump activation, in mesenteric artery by endothelium-derived hyperpolarizing factor and NO, the latter being clearly expressed in segments contracted with high K+, and in femoral artery essentially by endothelial NO release.
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PMID:Heterogeneity of endothelium-dependent mechanisms in different rabbit arteries. 757 2

We recently reported that intrathecal (i.t.) administration of prostaglandin (PG) E2 or PGF2 alpha in conscious mice induced allodynia through a pathway that includes the glutamate receptor system. Allodynia induced by PGE2 and PGF2 alpha was blocked by antagonists for NMDA and metabotropic glutamate receptor subtypes, respectively. In the present study, we examined the possibility for the involvement of nitric oxide (NO) in the PG-evoked allodynia. Allodynia was assessed once every 5 min by light stroking of the flank of mice with a paintbrush. Intrathecal administration of L-arginine, a substrate of nitric oxide synthase (NOS), in conscious mice resulted in allodynia. Dose dependency of L-arginine for allodynia showed a bell-shaped pattern (1-10 micrograms/mouse). The maximal allodynic effect was observed with 5.0 micrograms at 10-15 min after i.t. injection, similar in time course and magnitude to that induced by L-glutamate. L-Arginine-induced allodynia was dose-dependently reduced by the NOS inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) and the soluble guanylate cyclase inhibitor methylene blue with IC50 values of 7.68 and 8.70 pg/mouse, respectively. PGE2-induced allodynia was also dose-dependently inhibited by L-NAME and methylene blue with IC50 values of 94.7 and 74.9 pg/mouse. PGF2 alpha-induced allodynia was inhibited by methylene blue with an IC50 value of 40.6 pg/mouse, but not by L-NAME at doses up to 1.0 ng.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nitric oxide mediates allodynia induced by intrathecal administration of prostaglandin E2 or prostaglandin F2 alpha in conscious mice. 765 39

Responses to substance P were investigated in the pulmonary vascular bed of the cat with controlled pulmonary blood flow and constant left atrial pressure. Under baseline conditions, intralobar injections of substance P caused small, inconsistent reductions in lobar arterial pressure (AP) and significant reductions in mean systemic AP without affecting left atrial pressure. Decreases in lobar AP were significant and dose related when lobar vascular resistance was increased with U-46619, a thromboxane A2 mimetic. When compared with other vasodilator agents, the order of potency was substance P approximately bradykinin > pituitary adenylate cyclase activating polypeptide (PACAP) > acetylcholine (in nmol). Pulmonary vasodilator responses to substance P were unchanged by administration of atropine, glibenclamide, or sodium meclofenamate or when airflow to the left lower lung lobe was interrupted by bronchial occlusion. The NO synthesis inhibitor, N omega-nitro-L-argininemethyl ester (L-NAME), and the soluble guanylate cyclase inhibitor, methylene blue (MB), selectively inhibited pulmonary vasodilator responses to substance P and to acetylcholine. MB or L-NAME had no significant effect on pulmonary vasodilator responses to albuterol, lemakalim, or PACAP, whereas MB inhibited and L-NAME enhanced vasodilator responses to NO and sodium nitroprusside. The present investigation demonstrates that, when tone is increased experimentally, substance P has potent pulmonary vasodilator activity, and responses are not dependent on changes in bronchomotor tone, on the activation of muscarinic receptors or ATP-sensitive K+ channels, or on the release of a dilator prostaglandin but do involve, at least in part, endothelium-derived NO release and soluble guanylate cyclase activation.
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PMID:Analysis of responses to substance P in the pulmonary vascular bed of the cat. 768 May 35

1. The effects of acute inhibition of nitric oxide (NO) synthase on cardiovascular responses to vasodilator challenges have already been described. We now report the responses to vasodilators during and after chronic NO synthase inhibition. 2. In conscious Brattleboro rats, the regional haemodynamic effects of 3 min infusions of acetylcholine (4 micrograms min-1), sodium nitroprusside (15 micrograms min-1) or adrenaline (0.2 micrograms min-1) were assessed (from areas under or over curves (AUC, AOC)) under control conditions, 6 and 72 h after the addition of the NO synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA) to the drinking water (1 mg ml-1), and 6, 24 and 48 h after the withdrawal of L-NMMA. In a separate group of Brattleboro rats, responses to acetylcholine, sodium nitroprusside and adrenaline were assessed before and 6 h after the onset of oral ingestion of the more potent nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 0.05 mg ml-1). 3. Acetylcholine caused renal vasodilation (87 +/- 11 units) and mesenteric vasoconstriction (-31 +/- 5 units), sodium nitroprusside caused vasodilatation in renal (96 +/- 12 units), mesenteric (222 +/- 13 units) and hindquarters (49 +/- 15 units) vascular beds, whereas adrenaline caused hindquarters vasodilatation (92 +/- 8 units). Seventy two h after the onset of oral ingestion of L-NMMA, acetylcholine had a decreased renal vasodilator (59 +/- 9 units) effect, sodium nitroprusside had an increased renal vasodilator (142 +/- 23 units) action, while adrenaline had a decreased hindquarters vasodilator (55 +/- 6 units) influence. Twenty four h after withdrawal of L-NMMA, the renal vasodilator effect of acetylcholine was greater than the control response (106 +/- 14 units), but the regional haemodynamic effects of sodium nitroprusside and adrenaline were not different from those under control conditions. Hence, the increased renal vasodilator response to acetylcholine was probably due to changes in muscarinic receptor-mediated mechanisms rather than to any increase in guanylyl cyclase or its sensitivity to NO.
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PMID:Effects of chronic treatment with nitric oxide synthase inhibitors on regional haemodynamic responses to vasodilators in conscious Brattleboro rats. 768 4

The effects of interferon gamma (gamma IFN) on the MHCII antigen expression by human cultured astrocytoma cells were investigated. The co-incubation of gamma IFN with T67 astrocytoma cells produced a dose-dependent increase of MHCII antigen expression as evaluated by flow cytometric (FACS) analysis and confocal laser microscopy analysis. The number of MHCII molecules expressed by gamma IFN-pretreated astrocytoma cells was reduced by co-incubation with N omega-nitro-L-arginine methyl ester (L-NAME), a selective inhibitor of the nitric oxide (NO)-synthesizing enzyme. In addition, methylene blue, which inhibits the biological activity of NO acting at the guanylate cyclase level, strongly antagonized the MHCII antigen expression on astrocytoma cells induced by gamma IFN. Furthermore, gamma IFN increased the activity of the inducible isoform of NO-synthase as well as the concentration of nitrite, one of the breakdown products of NO and the antiplatelet activity of astrocytoma cells. In conclusion, the present data show that gamma IFN increases the synthesis and release of NO by cultured astrocytoma cells and this could co-participate in the MHCII antigen expression by this cell type. Therefore, the generation of NO by cultured astrocytoma cells may represent an important step in the development of the immunocompetent activity of astrocytes.
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PMID:The generation of nitric oxide participates in gamma IFN-induced MHC class II antigen expression by cultured astrocytoma cells. 769 70

1. The effects of hydrogen peroxide (H2O2, 0.1-1 mM) on the tone of the rings of rabbit aorta precontracted with phenylephrine (0.2-0.3 microM) were studied. 2. H2O2 induced a concentration-dependent relaxation of both the intact and endothelium-denuded rings. However, in the presence of intact endothelium, H2O2-induced responses were 2-3 fold larger than in its absence, demonstrating the existence of endothelium-independent and endothelium-dependent components of the vasorelaxant action of H2O2. 3. The endothelium-dependent component of H2O2-induced relaxation was prevented by NG-nitro-L-arginine methyl ester (L-NAME, 30 microM) or NG-monomethyl-L-arginine (300 microM), inhibitors of nitric oxide synthase (NOS), in a manner that was reversible by L-, but not by D-arginine (2mM). The inhibitors of NOS did not affect the responses of denuded rings. 4. Methylene blue (10 microM), an inhibitor of soluble guanylate cyclase, blocked H2O2-induced relaxation of both the intact and denuded rings. 5. H2O2 (1 mM) enhanced the efflux of cyclic GMP from both the endothelium-intact and denuded rings. The effect of H2O2 was 4 fold greater in the presence of intact endothelium and this endothelium-dependent component was abolished after the inhibition of NOS by L-NAME (30 microM). 6. In contrast to the effects of H2O2, the vasorelaxant action of stable organic peroxides, tert-butyl hydroperoxide or cumene hydroperoxide, did not have an endothelium-dependent component. Moreover, they did not potentiate the efflux of cyclic GMP from the rings of rabbit aorta. 7. Exogenous donors of NO, specifically, 3-morpholinosydnonimine (SIN-1), glyceryl trinitrate or sodium nitroprusside were used to decrease the tone of denuded rings to the level induced by endogenous NO released from intact endothelium. This procedure did not influence the vasorelaxant activity of H202, showing that H202 does not potentiate the vasorelaxant action of NO within the smooth muscle.8. Thus, H202-induced relaxation in the rabbit aorta has both endothelium-dependent and independent components. The endothelium-dependent component of the relaxant action of H202 is due to enhanced endothelial synthesis of NO.
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PMID:Involvement of nitric oxide in the endothelium-dependent relaxation induced by hydrogen peroxide in the rabbit aorta. 769 74

The activation of the L-arginine: nitric oxide (NO) pathway in the cat adrenal medulla by different stimuli which induce the release of catecholamines was studied. Stimuli that evoke catecholamine release, such as electrical stimulation of splanchnic nerves (50 V, 5 Hz, 1 ms), methacholine (100 microM), dimethyl-4-phenylpiperazinium iodide (DMPP; 10 microM), high K+ (35 mM) and alamethicin (15 micrograms ml-1) also caused a rise in cyclic GMP in the perfused cat adrenal medulla. NG-nitro-L-arginine methyl ester (L-NAME; 1 mM) abolished the rise in cyclic GMP induced by these stimuli without affecting the catecholamine release. Bovine adrenal medulla cytosol contained an NO synthase which was L-arginine- and Ca(2+)-dependent. In conclusion cat and bovine adrenal medulla stimulated with a variety of secretagogues synthesize NO from L-arginine to activate the soluble guanylate cyclase. The present data do not rule out a role for cyclic GMP in the regulation of catecholamine secretion; however, it seems more plausible that cyclic GMP may play a role in controlling local blood flow and thus the access of the released catecholamines to the systemic circulation during stressful conflicts.
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PMID:Activation of adrenal medullary L-arginine: nitric oxide pathway by stimuli which induce the release of catecholamines. 769 97

1. The effect of nitric oxide on the efficacy of synaptic transmission in the chick ciliary ganglion of post-hatched birds has been determined by use of the size of the postganglionic compound action potential resulting from chemical transmission through the ganglion as a measure of synaptic efficacy. 2. Sodium nitroprusside (100 microM) increased the synaptic efficacy by an average 26%. This is likely to be due to its ability to release nitric oxide, as potassium ferricyanide (100 microM) did not cause a potentiation. Sodium azide (100 microM), shown in sympathetic ganglia to stimulate production of cyclic GMP, did not modulate synaptic efficacy significantly. 3. 8-Br-cyclic-GMP (100 microM) increased synaptic efficacy by an average 61%. The addition of 8-Br-cyclic-AMP (100 microM) had less effect, increasing transmission by on average 46%. 4. The nitric oxide synthase blocker, NG-nitro-L-arginine methyl ester (L-NAME, 100 microM) was added prior to the tetanic stimulation of the preganglionic nerves at 30 Hz for 20 s, a procedure known to produce both post-tetanic potentiation and long-term potentiation of synaptic transmission through the ganglion. L-NAME reduced the long-term potentiation by an average of 47% but did not significantly change the post-tetanic potentiation. 5. Following the brief application of 8-Br-cyclic AMP, 8-Br-cyclic GMP and sodium nitroprusside there was an enhancement of the efficacy of synaptic transmission that persisted after the withdrawal of the drugs. The maximum increase in synaptic efficacy following the brief addition of 8-Br-cyclic GMP was 116%, sodium nitroprusside was 110% and 8-Br-cyclic AMP was 126%.6. These results suggest that nitric oxide modulates synaptic transmission through the ganglion by acting on an endogenous guanylate cyclase that produces cyclic GMP.
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PMID:The effect of nitric oxide on the efficacy of synaptic transmission through the chick ciliary ganglion. 769 54

The aim of this study was to investigate the role of NO-cGMP pathway in NMDA-induced NGF mRNA expression by T67 astrocytoma cells. Levels of nitrite, a breakdown product of NO, in supernatants of NMDA-treated astrocytoma cells were significantly higher compared with control cells, this effect being reversed by the specific NO synthase inhibitor L-NAME. Furthermore, NGF mRNA expression was induced by NMDA treatment, this effect being inhibited by pretreating cells with L-NAME. Moreover, methylene blue, an inhibitor of NO biological activity at guanylate cyclase level, inhibited NMDA-induced NGF mRNA expression and this effect was reversed by dbt2-cGMP. These findings suggest that NO-cGMP pathway mediates the synthesis of NGF mRNA.
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PMID:NMDA-dependent NGF mRNA expression by human astrocytoma cells is mediated by nitric oxide. 769 84


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