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)

Hemoglobin at 1 microM reduced and at 10 microM abolished the endothelium-dependent relaxation induced by acetylcholine or by A23187 in rabbit aortic rings. Similarly, methylene blue at 10 microM reduced and at 50 microM abolished relaxation induced by acetylcholine and by A23187. Furthermore, hemoglobin (1-10 microM) and methylene blue (10-50 microM) each induced a dose-dependent inhibition of the endothelium-independent relaxation produced by glyceryl trinitrate, but neither had any effect on the relaxation produced by isoproterenol. The inhibitory effects of hemoglobin and methylene blue may be due to blockade of guanylate cyclase, as the rises in cyclic GMP content which accompany relaxation induced by acetylcholine, A23187 or glyceryl trinitrate were abolished. Isoproterenol-induced relaxation took place with no change in cyclic GMP content. Hemoglobin and methylene blue appear therefore to inhibit selectively vaso-relaxation induced by agents which increase cyclic GMP levels. Hemoglobin and methylene blue augment tone in aortic rings, particularly when endothelial cells are present, suggesting that the endothelium-derived relaxing factor (EDRF) might be released spontaneously in low concentrations. The possibility that hemoglobin inhibits endothelium-dependent and glyceryl trinitrate-induced relaxation by binding EDRF and nitric oxide, respectively, is discussed together with the proposal that methylene blue might produce its effects by oxidizing a component of guanylate cyclase, possibly a ferrous heme group linked to the enzyme molecule. Methylene blue might, in addition, interact directly with EDRF.
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PMID:Selective blockade of endothelium-dependent and glyceryl trinitrate-induced relaxation by hemoglobin and by methylene blue in the rabbit aorta. 298 68

The aim of the present study was to exclude a potential role of hemoglobin in the formation of nitric oxide (NO) from several nitrovasodilators. NO was measured with a chemiluminescence technique after purging with argon from the aqueous solution. Nitric oxide generation occurred in the absence of hemoglobin or non-heme iron. Sodium nitroprusside and SIN-1 released NO spontaneously. Nitroglycerin produced NO only in the presence of those thiols which are effective co-stimulators of guanylate cyclase. All other thiols degraded nitroglycerin only into nitrite ions without formation of NO. Our results support the role of nitric oxide as terminal activator of guanylate cyclase stimulation by nitrovasodilators.
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PMID:Nitric oxide (NO) formation from nitrovasodilators occurs independently of hemoglobin or non-heme iron. 312 57

The effects of lysolecithin (lysophosphatidylcholine) derived from egg yolk as well as of synthetic lysolecithins with different aliphatic chain lengths on tension development of rabbit aortic strips were investigated. Lysolecithins caused slowly progressing, dose-dependent relaxation that was inhibited by hemoglobin, methylene blue, and nordihydroguiaretic acid. Indomethacin caused no inhibition of relaxation. The degree of relaxation was endothelium-dependent and appeared to be related to the activation of guanylate cyclase [GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2]. Superoxide dismutase failed to influence relaxation. Lysolecithins with the longest aliphatic chain were the most potent relaxants of aortic strips. The experiments suggest a role of lysolecithins through their weak detergent action on membrane dynamics of endothelial cells, resulting in the production of cyclic GMP and the relaxation of arterial smooth muscle. Lysolecithins differ in several respects from endothelium-derived relaxing factor. Endothelium-derived relaxing factor is an unstable humoral substance released from endothelium and is identical to nitric oxide, itself a labile substance causing vascular relaxation and cyclic GMP accumulation. Lysolecithins may represent a different type of endothelium-dependent muscle relaxant.
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PMID:Lysolecithins as endothelium-dependent vascular smooth muscle relaxants that differ from endothelium-derived relaxing factor (nitric oxide) 326 49

The present study was designed to investigate whether endothelium-derived relaxing factor (EDRF) produced by cultured human endothelial cells (HEC) inhibits the aggregation of human platelets. Microcarrier beads covered with HEC from umbilical veins (approximately 2 X 10(6)) or empty beads (as controls) were co-incubated in an aggregometer with washed human platelets (approximately 5 X 10(7)). Indomethacin was present throughout and no prostacyclin production (measured as 6-keto-PGF1 alpha by radioimmunoassay) could be detected. The presence of HEC markedly inhibited thrombin-induced platelet aggregation and this inhibition was further enhanced by bradykinin, a stimulator of EDRF production. The anti-platelet aggregatory effect was blocked by treating the HEC with the inhibitor of EDRF production gossypol, by treating the platelets with the inhibitor of soluble guanylate cyclase methylene blue, or by adding the EDRF scavenger oxyhemoglobin to the aggregation mixture. The antiaggregatory material was labile, since the supernatant of indomethacin-treated cultured HEC did not inhibit aggregation. In the absence of indomethacin, the prostacyclin-mediated antiaggregatory effect of HEC was not inhibited by gossypol, methylene blue or hemoglobin. These data strongly suggest that the EDRF formed by HEC is an inhibitor of platelet aggregation and may constitute an important defense mechanism against vasospasm and platelet aggregation.
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PMID:Endothelium-derived relaxing factor from cultured human endothelial cells inhibits aggregation of human platelets. 349 84

When tested at concentrations producing submaximal responses, the N-nitroso carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine (methylnitro-nitrosoguanidine) elicited a 2-fold greater increase in guanosine 3',5'-monophosphate (cyclic GMP) accumulation in slices and a 5-fold greater stimulation of guanylate cyclase activity in whole homogenates of rat liver examined 24 h after 75% hepatectomy compared to the corresponding methylnitro-nitrosoguanidine responses in sham-operated and unoperated controls. Enhanced methylnitro-nitrosoguanidine sensitivity of guanylate cyclase in whole homogenates of regenerating liver was attributable to altered responsiveness of the enzyme activity of the 100 000 X g soluble fraction, which contained 98% of the methylnitro-nitrosoguanidine responsive activity. Basal cyclic GMP accumulation and guanylate cyclase activities of these systems, and their responses to concentrations of methylnitro-nitrosoguanidine eliciting maximal stimulation were unchanged after partial hepatectomy or sham operation, compared to unoperated controls. The findings of (a) increased heme concentrations in the supernatant and the high molecular weight Sephadex G-25 fraction of sham operated, compared to regenerating liver, (b) suppression of methylnitro-nitrosoguanidine responsive activity after addition of exogenous hemoglobin to supernatants from regenerating liver, and (c) enhancement of the responsiveness of soluble guanylate cyclase from sham operated liver to submaximal methylnitro-nitrosoguanidine after reduction of endogenous heme content by in situ perfusion, all suggested that the difference in methylnitro-nitrosoguanidine action observed in control vs. regenerating liver are related to a lower heme-protein content of the latter. These results emphasize the importance of endogenous heme as a factor modulating the response of the hepatic guanylate cyclase system to methylnitro-nitrosoguanidine.
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PMID:Increased responsiveness of the hepatic guanylate cyclase-guanosine 3',5'-monophosphate system to nitrosoguanidine following partial hepatectomy. 610 69

The cyclic GMP content of diethylstilbestrol-induced renal tumors in the male golden hamster was increased nearly 130-fold over that in kidney from control animals. Cyclic GMP in tumors was 91.80 +/- 19.18 pmoles cyclic GMP/mg protein compared to 0.72 +/- 0.07 in control kidneys. Cyclic AMP in tumors was also increased over control, however, to a much lesser degree (2.7-fold). In control kidneys, 84.6% of homogenate guanylate cyclase activity was recovered in the 100,000 X g supernatant fraction. Total homogenate guanylate cyclase activity from diethylstilbestrol-induced renal tumors was increased 5.5-fold over that in control kidneys and only 8.1% was associated with the 100,000 X g supernatant fraction. Neither the soluble or particulate guanylate cyclase from renal tumors could be activated by nitric oxide. The unresponsiveness of tumor guanylate cyclase to nitric oxide was independent of the cation cofactor, and not due to a shift in the dose response curve for nitric oxide. Responsiveness to nitric oxide was not restored by thiols, sugars, other proteins, or hemoglobin. Basal cyclic AMP formation by soluble guanylate cyclase from renal tumors was dramatically increased over that observed in control kidneys, and could not be increased further by nitric oxide. This is the first study of cyclic GMP and guanylate cyclase in a primary estrogen-induced tumor. The possibility that the changes observed in guanylate cyclase from diethylstilbestrol-induced renal tumors are related to in vivo activation of the enzyme by epoxide metabolites of diethylstilbestrol is discussed.
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PMID:Alterations in the subcellular distribution of Guanylate cyclase and its responsiveness to nitric oxide in diethylstilbestrol-induced renal tumors. 612 81

Guanylate cyclase activity was purified to apparent homogeneity from rat liver (7700-fold) and bovine lung (8600-fold) soluble fractions by ammonium sulfate precipitation, DEAE-cellulose chromatography, agarose gel filtration and isoelectric focussing. The purified enzymes did not contain heme and did not respond to NO, nitroprusside or NO-cysteine in the absence of exogenous hematin. By contrast, preformed NO-hemoglobin increased enzyme activity 10-12-fold or 60-80-fold when 4 mM MnCl2 or 4 mM MgCl2, respectively, were employed as the metal ion co-factor. Addition of hematin to the enzyme preparations restored responsiveness to NO, nitroprusside or NO-cysteine to levels seen with NO-hemoglobin. Partial purification of guanylate cyclase from the soluble fraction of bovine lung (2400-fold) by ammonium sulfate precipitation, DEAE-cellulose chromatography, agarose gel filtration and high pressure liquid chromatography (HPLC) resulted in a preparation which contained endogenous heme as indicated by absorbance at 436 nm and responded to NO, nitroprusside and NO-cysteine in the absence of added hematin. By contrast, guanylate cyclase purified from the hepatic supernatant by the identical procedure, did not contain detectable absorption due to heme and did not respond or responded poorly to NO, nitroprusside or NO-cysteine in the absence of exogenous hematin. Analogous to hepatic guanylate cyclase purified by isoelectric focussing, the HPLC purified hepatic enzyme was activated 14-fold by NO-hemoglobin in assays which contained 4 mM MnCl2 and 60-fold in assays with 4 mM MgCl2. Further, addition of hematin to the HPLC purified enzyme restored responsiveness to NO, nitroprusside and NO-cysteine to levels seen with NO-hemoglobin. These effects of hematin were specific for hematin and were not mimicked by albumin, sucrose or dithiothreitol. Moreover, the failure to observe stimulation of purified hepatic guanylate cyclase was not explained by a shift in the concentration response relationship between NO and guanylate cyclase activity. Several observations indicated that neither NO-thiol complexes nor [Fe(CN)5NO]-3 were the proximate moieties responsible for activation of guanylate cyclase by nitroprusside and related agents, as has been previously suggested. These results strongly support the proposal that activation of guanylate cyclase by NO and related agents specifically requires formation of an NO-heme complex.
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PMID:Requirement for heme in the activation of purified guanylate cyclase by nitric oxide. 613 53

A brief review is first presented of findings during the past few years by the authors and by others on the nonprostaglandin endothelium-dependent relaxation of isolated arteries by a large number of vasoactive agents. Among these agents are acetylcholine (ACh); the calcium ionophore A23187; ATP and ADP; substance P; bradykinin (canine, human, and porcine arteries); histamine, acting via an H1-receptor (rat arteries); thrombin (canine arteries); serotonin (canine coronary artery); and norepinephrine, acting via an alpha2-receptor (canine coronary artery). The endothelium-derived relaxing factor (EDRF) released by ACh and other agents has not yet been identified. Our original hypothesis that arachidonic acid is the precursor of EDRF is not supported by the finding that other unsaturated fatty acids in addition to arachidonic acid, and even stearic acid, elicited nonprostaglandin endothelium-dependent relaxations. Methylene blue and hemoglobin (but not methemoglobin) rapidly inhibited relaxation of rabbit aorta by ACh or A23187, suggesting that our proposal that EDRF is a labile free radical may be correct. The endothelium-dependent relaxation by each of these agents was shown to be preceded by an endothelium-dependent increase in cyclic GMP in the smooth muscle--a finding consistent with the hypothesis that EDRF stimulates guanylate cyclase in the muscle, leading to an increase in cyclic GMP that somehow activates relaxation. Some questions relating to the potential physiological important of endothelium-dependent relaxations are discussed.
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PMID:Endothelial cells as mediators of vasodilation of arteries. 620 42

Catalase promotes the H2O2-dependent oxidation of phenylhydrazine to benzene but simultaneously is subject to a pseudo-first order inactivation process. Each inactivation event is subtended by catalytic turnover of three molecules of phenylhydrazine and 52 molecules of H2O2. The dimethyl ester of N-phenylprotoporphyrin IX is extracted with acidic methanol from the inactivated enzyme, but the prosthetic heme with a phenyl sigma-bonded to the iron atom is obtained by gentle extraction with 2-butanone. The absolute chirality of N-ethylprotoporphyrin IX isolated from catalase inactivated with ethylhydrazine confirms that the prosthetic heme has the same chiral orientation in the active site as it does in hemoglobin. The known inactivation of methemoglobin by phenylhydrazine is shown to depend on H2O2 but not oxygen. The results demonstrate that the H2O2-dependent oxidation of phenylhydrazine by catalase and other hemoproteins results in sigma-coordination of a phenyl residue to the prosthetic heme iron. This process may play a role not only in phenylhydrazine-mediated erythrocyte lysis but also in the activation of guanylate cyclase.
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PMID:Inactivation of catalase by phenylhydrazine. Formation of a stable aryl-iron heme complex. 688 92

A role for the NO-cGMP pathway in mediating chemosensory activation of feeding is suggested by intense NADPH diaphorase staining observed in nerve fibers that project from sensory cells in the lips to the CNS and by the presence in the CNS of a NO-activated guanylyl cyclase. In preparations reduced to isolated lips and CNS, intracellular recordings were made from motoneurons driven by the interneurons of the central pattern generator (CPG) for feeding. Fictive feeding in such preparations can be recorded from these motoneurons following the application of sucrose to the lips. Sucrose activation of fictive feeding is inhibited by the NO scavenger hemoglobin, the NO synthase inhibitor N omega-Nitro-L-Arginine Methyl Ester (L-NAME) and by methylene blue, an inhibitor of guanylyl cyclase. Fictive feeding in isolated lip-CNS preparations can be activated without sucrose by superfusion of NO donor molecules such as SNAP and hydroxylamine and by the nonhydrolyzable analog of cGMP, 8-bromo-cGMP. The feeding CPG can also be activated centrally by depolarizing a modulatory interneuron, the slow oscillator (SO). When the CPG is activated in this way, fictive feeding is not susceptible to inhibition by hemoglobin, the most potent of the inhibitors of sucrose-activated fictive feeding. Behavioral experiments on intact snails confirm the findings from in vitro experiments and show that hemoglobin prevents feeding and methylene blue significantly delays the onset of feeding. These results indicate (1) that NO is a putative chemosensory transmitter in the snail L. stagnalis, (2) that the NO-cGMP pathway can mediate chemosensory activation of specific patterns of centrally generated behavior, (3) that NO is not involved in transmission within the central network of neurons responsible for the behavior, and more generally (4) that a freely diffusing and highly reactive gaseous signalling molecule can have restricted and specific behavioral functions.
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PMID:Behavioral role for nitric oxide in chemosensory activation of feeding in a mollusc. 747 16


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