Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The neuropeptide eclosion hormone acts directly on the nervous system of the tobacco hornworm, Manduca sexta, to trigger ecdysis behavior at the end of each molt. Previous studies have shown that the action of eclosion hormone is mediated via the intracellular messenger cyclic GMP. In the present study we have investigated the mechanisms involved in the eclosion hormone-stimulated increases in cyclic GMP. No stimulation of guanylate cyclase was seen in homogenized nervous tissue, suggesting that eclosion hormone does not directly stimulate a membrane-bound form of guanylate cyclase. Nitric oxide synthase inhibitors, N-methylarginine and nitroarginine, had no effect on eclosion hormone-stimulated cyclic GMP levels. By contrast, 4-bromophenacyl bromide, an inhibitor of arachidonic acid release, and nordihydroguaiaretic acid, an inhibitor of arachidonic acid metabolism, almost completely abolished the eclosion hormone-stimulated cyclic GMP increase. We hypothesize that eclosion hormone receptors are coupled to a lipase, activation of which causes the release of arachidonic acid. Either the arachidonic acid directly stimulates the soluble guanylate cyclase or further metabolism of arachidonic acid yields compounds that activate guanylate cyclase.
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PMID:Eclosion hormone stimulates cyclic GMP levels in Manduca sexta nervous tissue via arachidonic acid metabolism with little or no contribution from the production of nitric oxide. 135 96

Inhibitory factor (IF), an extract of the bovine retractor penis muscle, when treated with acid, becomes a vasodilator with properties similar to endothelium-derived relaxing factor (EDRF). EDRF has been proposed to be nitric oxide (NO), long known to be a potent vasodilator. Recently, biologically active IF was proposed to be NO, as well, generated by acid activation of inorganic nitrite. We compared acid-activated IF with acid-activated nitrite and found that NO formation was not sufficient to explain the properties of acid-activated IF. Endothelium-denuded rings of rabbit aorta were used to test the smooth muscle-relaxing properties of IF and nitrite. Although both IF (0.5 ml) and nitrite (1 microM) relaxed phenylephrine-contracted rabbit aorta to a similar extent after acid activation (approximately 30%), several significant differences were observed. IF was most active when acid activated by a 5-min, pH 2 step followed by neutralization; nitrite was relatively inactive when acid activated in this manner, and was most active when assayed immediately after acidification to pH 2. Purging with argon for 5 min reduced the smooth muscle-relaxing activity of 1.0 microM nitrite from 27 +/- 2 to 10 +/- 2% relaxation, whereas the activity of IF was not changed by argon purging (control, 31 +/- 2% relaxation; argon purged, 34 +/- 2% relaxation). When IF samples were assayed for nitrite content, the amount of nitrite found (0.5-5 nmol/0.5 ml sample) was not sufficient to explained the observed smooth muscle relaxing activity. Furthermore, acid-activated IF significantly stimulated cyclic GMP production by platelet-soluble guanylate cyclase from 3.2 +/- 0.2 to 12.4 +/- 0.4 pmol/min/mg protein.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evidence that S-nitrosothiols are responsible for the smooth muscle relaxing activity of the bovine retractor penis inhibitory factor. 135 57

(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

Furoxans (1,2,5-oxadiazole-2-oxides) are widely used in organic chemistry as intermediate compounds for the synthesis of various heterocycles. Despite the fact that some furoxans have been found to possess remarkable biological activities, up to now no systematic study on their mode of action has been reported. The aim of the present study was to investigate the molecular mode of the vasodilator action of furoxans. Furoxans, but not the corresponding furazans, concentration-dependently increased coronary flow in an isolated working rat heart preparation. This effect was blunted upon coinfusion with methylene blue. All tested furoxans were demonstrated to increase potently the activity of soluble guanylate cyclase. Enzyme stimulation was found to be mediated by the generation of nitric oxide (NO) following chemical reaction of the furoxans with sulfhydryl groups of low molecular weight thiols and proteins. Furoxans are thus prodrugs which increase the level of cyclic GMP via formation of NO and may therefore be classified as nitrovasodilators. Along with the generation of NO, nitrite and nitrate ions and S-nitrosothiols were formed. The rates of formation of these metabolites, however, did not appear to be related to enzyme stimulation. A tentative reaction scheme that fits the obtained experimental data is proposed. Recently reported cytotoxic, mutagenic, immunosuppressive and anticancer effects of furoxans are discussed in the light of their ability to release NO upon reaction with thiols.
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PMID:Thiol-mediated generation of nitric oxide accounts for the vasodilator action of furoxans. 135 72

1. The mechanism of the vasorelaxant effect of platelet activating factor (PAF) on rat thoracic aorta and the effect of aging on the PAF-induced relaxation were investigated. 2. PAF at concentrations causing relaxation induced marked increases in guanosine 3':5'-cyclic monophosphate (cyclic GMP) production, but did not induce an increase in adenosine 3':5'-cyclic monophosphate (cyclic AMP). 3. Removal of the endothelium by mechanical rubbing, and treatment with the PAF antagonists CV-3988, CV-6209 and FR-900452, the nitric oxide biosynthesis inhibitor, NG-nitro L-arginine, the radical scavenger, haemoglobin, and the soluble guanylate cyclase inhibitor, methylene blue, inhibited PAF-induced relaxation and abolished or attenuated PAF-stimulated cyclic GMP production. 4. The relaxation was greatest in arteries from rats aged 4 weeks. With an increase in age, the response of the arteries to PAF was attenuated. 5. Endothelium-dependent cyclic GMP production also decreased with increase in age of the rats. 6. These results suggest that PAF stimulates production of nitric oxide from L-arginine by acting on the PAF receptors in the endothelium, which in turn stimulates soluble guanylate cyclase in the smooth muscle cells, and so increases production of cyclic GMP, thus relaxing the arteries. Age-associated decrease in PAF-induced relaxation may result from a reduction of cyclic GMP formation.
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PMID:Involvement of nitric oxide pathway in the PAF-induced relaxation of rat thoracic aorta. 135 82

Various parameters of the rat pineal gland display a 24-h rhythm. However, nothing is known about possible 24-h variations in cyclic GMP (cGMP) metabolism. In the present study, 24-h variations in pineal gland cGMP accumulation were investigated by determining the increase in cGMP level with and without inhibitors of phosphodiesterase at different time points over a light/dark cycle (12/12 h). Furthermore, the activity of guanylate cyclase (GC) was determined under substrate-saturated conditions regarding the cytosolic and particulate forms of the enzyme. It has been found that cGMP accumulation and GC activity display biphasic 24-h variations with two peaks--one approximately 7 h after lights "on" and the other approximately 7 h after lights "off." The activity of cytosolic GC remains unchanged in the presence of the nitric oxide (NO) synthesis inhibitor N-monomethyl-L-arginine, indicating that 24-h variations in the activity do not reflect changes in the synthesis of the GC stimulator NO.
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PMID:Biphasic 24-hour variations in cyclic GMP accumulation in the rat pineal gland are due to corresponding changes in the activity of cytosolic and particulate guanylate cyclase. 135 14

The effects of exogenous guanosine 5'-triphosphate (GTP), guanosine 5'-(gamma-thio)triphosphate (GTP gamma S), cysteine and Trolox C, a water soluble vitamin E analogue, were studied on basal and nitrovasodilator-induced cyclic GMP formation in isolated human lymphocytes. Incubation of lymphocytes in the presence of GTP (0.1 mM) and GTP gamma S (0.1 mM) increased cyclic GMP more than twofold. SIN-1 and sodium nitroprusside dose-dependently increased cyclic GMP, but nitroglycerin and sodium nitrite were ineffective. GTP and GTP gamma S potentiated SIN-1 and sodium nitroprusside-induced cyclic GMP formation. In the presence of GTP and GTP gamma S, nitroglycerin, but not sodium nitrite, was able to increase lymphocyte cyclic GMP. Cysteine (1 mM) enhanced cyclic GMP formation induced by sodium nitroprusside and nitroglycerin. Trolox C (0.1 mM) potentiated SIN-1-induced cyclic GMP formation. These results indicate that exogenous GTP and GTP gamma S enhance guanylate cyclase stimulation by spontaneous nitric oxide releasers and nitroglycerin in lymphocytes. Cysteine, a redox-compound and Trolox C, an antioxidant, have different effects on guanylate cyclase activation by nitric oxide releasers, SIN-1 and sodium nitroprusside.
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PMID:Exogenous modification of nitrovasodilator-induced cyclic GMP formation in human lymphocytes. 135 26

The effects of nitric oxide-releasing compounds on Dictyostelium discoideum cell development and guanylyl cyclase activity were studied. The addition of SNP (sodium nitroprusside) or SIN-1 (3-morpholino-syndnonimine) to starved cells inhibited their differentiation and aggregation in a concentration-dependent manner. In contrast to mammalian systems, SNP did not significantly affect guanylyl cyclase activity in cell lysates of D. discoideum, nor did it stimulate cGMP production in intact cells. The results suggest that the inhibitory effects of NO on D. discoideum cell aggregation are through a mechanism independent of an effect on guanylyl cyclase activity.
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PMID:Nitric oxide-releasing compounds inhibit Dictyostelium discoideum aggregation without altering cGMP production. 136 Apr 11

1. The signal transduction pathway for vasorelaxation induced by human alpha-calcitonin gene-related peptide (human alpha-CGRP) was studied in rat thoracic aortic rings preconstricted with noradrenaline (10(-7) M). 2. Vasorelaxation by human alpha-CGRP was inhibited by haemoglobin (10(-6) M) and methylene blue (10(-5) M) but was unaffected by ibuprofen (10(-5) M). 3. Acetylcholine caused a 16 fold increase in levels of guanosine 3':5'-cyclic monophosphate (cyclic GMP) with levels of adenosine 3':5'-cyclic monophosphate (cyclic AMP) being unaltered. Human alpha-CGRP caused a 12 fold increase in levels of cyclic GMP but, in contrast to acetylcholine, evoked a 2.5 fold rise in levels of cyclic AMP. The rises in cyclic nucleotides evoked by human alpha-CGRP and acetylcholine were dependent on the presence of an intact endothelium. 4. NG-nitro-L-arginine (L-NOARG: 10(-5) M), which inhibits nitric oxide synthetase, inhibited the relaxant response to human alpha-CGRP and cyclic GMP accumulation without affecting the cyclic AMP accumulation. 5. The data presented in this paper suggests that human alpha-CGRP relaxes the rat thoracic aorta by releasing nitric oxide and stimulating guanylate cyclase. The stimulation of adenylate cyclase by human alpha-CGRP probably precedes the activation of nitric oxide synthase but could be unrelated to the relaxant response.
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PMID:Human alpha-calcitonin gene-related peptide stimulates adenylate cyclase and guanylate cyclase and relaxes rat thoracic aorta by releasing nitric oxide. 136 70

Olfactory cilia preparation from rats contain considerable activity of soluble guanylate cyclase as indicated by the formation of cyclic GMP (cGMP) upon application of nitroprusside, a nitric oxide generating agent. Stimulation of olfactory cilia with high doses of odorants elicited a delayed and sustained elevation of the cGMP-concentration. The odorant-induced cGMP-response was abolished by L-NG-nitro-arginine, a selective inhibitor of nitric oxide synthesis, as well as by haemoglobin which efficiently binds and inactivates nitric oxide. These observations suggest that the NO/cGMP cascade may plan an important role in signal processing of the olfactory system.
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PMID:Nitric oxide mediated formation of cyclic GMP in the olfactory system. 136 59


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