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)

Here, we demonstrate that the metabolism of glyceryl trinitrate (GTN) to nitric oxide (NO) occurs not only in bovine aortic smooth muscle cells (SMCs) but also in endothelial cells (ECs) and that this biotransformation is enhanced by pretreatment with Escherichia coli lipopolysaccharide (LPS). Two bioassay systems were used: inhibition of platelet aggregation and measurement of cGMP after stimulation by NO of guanylate cyclase in SMCs or ECs. In addition, NO produced from GTN by cells was measured as nitrite (NO2-), one of its breakdown products. Indomethacin (10 microM)-treated SMCs or ECs enhanced the platelet inhibitory activity of GTN. This effect was abrogated by coincubation with oxyhemoglobin (oxyHb; 10 microM), indicating release of NO from GTN. LPS (0.5 microgram/ml; 18 h) enhanced at least 2- to 3-fold the capacity of SMCs or ECs to form NO from GTN, and this enhancement was attenuated when cycloheximide (10 micrograms/ml) was incubated together with LPS. Furthermore, when incubated with GTN (200 microM) SMCs or ECs treated with LPS (0.5 microgram/ml; 18 h) released more NO from GTN than nontreated cells as indicated by a much higher (8- to 9-fold) increase in the levels of cGMP. Exposure of SMCs to GTN (600 microM) for 30 min led to an increase in the levels of NO2- dependent on cell numbers, which was enhanced when SMCs were treated with LPS. Incubation of nontreated or LPS-treated cells with NG-monomethyl-L-arginine (300 microM; 60 min) did not influence the metabolism of GTN to NO. SMCs failed to enhance the antiplatelet activity of sodium nitroprusside. Anesthetized rats treated with an intraperitoneal injection of LPS (20 mg/kg) 18 h beforehand showed enhanced hypotensive responses to GTN (0.25-1 mg/kg). These effects were blocked by methylene blue (10 mg/kg) but not by indomethacin (3 mg/kg). LPS did not alter the hypotensive responses induced by phentolamine, verapamil, or SIN-1. Thus, both in vitro and in vivo, LPS induces the enzyme(s) metabolizing GTN to NO.
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PMID:Metabolism of glyceryl trinitrate to nitric oxide by endothelial cells and smooth muscle cells and its induction by Escherichia coli lipopolysaccharide. 131 May 43

EDRF (endothelium-derived relaxing factor) is a cellular and intercellular messenger that activates soluble guanylate cyclase. In blood vessels it is released from the endothelium and causes relaxation of vascular smooth muscle. Halothane previously has been shown to attenuate EDRF-induced vasodilation elicited by the receptor-mediated vasodilators acetylcholine and bradykinin and to alter muscarinic receptor activity. We examined and compared the effects of the inhaled anesthetics halothane, enflurane, and isoflurane on endothelium-dependent vasodilation and tested the hypothesis that these agents inhibit EDRF-mediated vasodilation solely through inhibition of endothelial cell receptor-mediated EDRF release. Isolated rat thoracic aortic rings were mounted for isometric tension recording and preconstricted with phenylephrine. Cumulative dose-response curves were obtained to methacholine, a receptor-mediated endothelium-dependent dilator; to A23187, a nonreceptor-mediated endothelium-dependent dilator; and to sodium nitroprusside, a direct-acting endothelium-independent dilator before, during, and after inhalational anesthetic exposure. Both receptor-mediated and non-receptor-mediated endothelium-dependent relaxation by methacholine and A23187, respectively, were significantly (P less than 0.01 to P less than 0.05) and reversibly attenuated by halothane, enflurane, and isoflurane at 2 MAC and by isoflurane at 1 MAC. Endothelium-independent relaxation by sodium nitroprusside, an agent that acts directly on the vascular smooth muscle cell to activate guanylate cyclase, was unaffected by any of the anesthetics at any concentration tested. Indomethacin had no significant effect on the inhibition of endothelium-dependent vasodilation by these inhalational anesthetics. We conclude that halothane, enflurane, and isoflurane inhibit endothelium-dependent vasodilation; that isoflurane is more potent than halothane and enflurane in this regard.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Halothane, enflurane, and isoflurane attenuate both receptor- and non-receptor-mediated EDRF production in rat thoracic aorta. 159 87

Inhibition of endothelium-dependent relaxation by NG-monomethyl L-arginine (L-NMMA) and its reversal by excess L- but not D-arginine is used to support the hypothesis that the endothelium-derived relaxing factor (EDRF) is generated exclusively from the metabolism of L-arginine. However, in freshly isolated vascular tissues, L-arginine is a poor vasodilator when compared to the N-substituted arginine compound, N alpha-benzoyl L-arginine ethyl ester (BAEE). Here, we show that such N-substituted compounds are potent hypotensive agents in anesthetized rats. In contrast, L-arginine elicits hypotensive effect only at higher concentrations (greater than 100 mg/kg). This effect of L-arginine is not antagonized by L-NMMA. Furthermore, D-arginine, L-homoarginine and L-lysine also have hypotensive effects at these concentrations. Indomethacin treatment partially attenuates the hypotensive effects of the basic amino acids. In contrast, the hypotensive effect of BAEE is antagonized by L-NMMA in a dose-dependent manner and by methylene blue, which is an inhibitor of soluble guanylate cyclase. In addition, substitution at the arginine moiety determines the hypotensive effect. When the amino acid glycine is inserted between the benzoyl group and arginine as in benzoyl-glycine-arginine, significant attenuation of the hypotensive effect is observed. These data demonstrate that compounds such as BAEE generate an EDRF-like agent in vivo and basic amino acids such as L-arginine elicit hypotension at concentrations above 100 mg/kg by mechanisms other than the generation of EDRF.
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PMID:Effect of N-substituted arginine compounds on blood pressure in anesthetized rats. 160 91

The cardiovascular effects of N-methyl-1,2-diphenyl ethanolamine (compound M) and N-isobutyl-1,2-diphenyl ethanolamine (compound E) were examined in anaesthetized rats and their effects were compared with those of verapamil and diltiazem. Administration of compound M (10-80 mumole/kg), compound E (2-16 mumole/kg), diltiazem (1.5-24 mumole/kg) or verapamil (1.25-10 mumole/kg) induced dose-dependent decreases in arterial blood pressure and heart rate. The induced cardiovascular changes were not antagonized by chlorpheniramine, cimetidine or imidazole. Indomethacin antagonized the diltiazem-induced hypotension without any effect on that of compounds M and E. The effects of all compounds tested were antagonized by pretreatment of the rats with CaCl2 (1.2-2.4 mmole/kg). Furthermore, methylene blue significantly antagonized the compound E- and diltiazem-induced hypotension. Treatment of the animals with propranolol enhanced the compound M- and E-induced hypotension. Compounds M and E antagonized the NA-induced increase in arterial blood pressure in a competitive manner. Compounds M and E seem to exert their cardiovascular effects via interference with the influx of extracellular Ca2+. Furthermore, compound E and diltiazem may act partially via activation of guanylyl cyclase.
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PMID:Cardiovascular depressant effects of N-methyl- and N-isobutyl-1,2-diphenyl ethanolamines: elucidation of the mechanisms of action. 188 33

Since thrombin causes an endothelium-dependent relaxation of precontracted pig coronary arteries, the ability of thrombocytin, a serine proteinase from the venom of the common lancehead, Bothrops atrox, to induce endothelium-dependent changes in the vascular tone was investigated. Relaxation of pig coronary rings did not appear in vessels denuded of the endothelium. Thrombocytin (0.1-2.0 micrograms/ml) caused an endothelium-dependent, reversible, transient relaxation of PGF2 alpha-precontracted arteries which could be blocked by heparin and relatively high concentrations of alpha-NAPAP, a synthetic competitive thrombin inhibitor. Indomethacin and hirudin did not influence the relaxant effect. Both the thrombocytin- and bradykinin-induced relaxation were diminished by the guanylate cyclase inhibitor methylene blue and by NG-monomethyl-L-arginine. The thrombocytin-induced relaxation was absent in de-endothelialized vessels. Thrombocytin was able to induce aggregation of human blood platelets in Tyrode's solution at the same concentration range as used for the relaxation. Batroxobin neither relaxed precontracted arteries nor aggregated human blood platelets in vitro. The present studies show that the serine proteinase thrombocytin is not only able to aggregate platelets but may also release endothelium-derived relaxing factor from the vascular endothelium.
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PMID:Endothelium-dependent relaxant effect of thrombocytin, a serine proteinase from Bothrops atrox snake venom, on isolated pig coronary arteries. 192 73

In order to investigate the involvement of endothelium-derived vasoactive substances in deoxycorticosterone acetate (DOCA)-salt hypertension, the responses to noradrenaline, acetylcholine, sodium nitroprusside and papaverine were studied in the absence and presence of indomethacin. Noradrenaline was equally effective in evoking a constrictor response of aorta, with or without endothelium, isolated from DOCA-salt hypertensive rats, while in controls, noradrenaline induced higher submaximal responses in rubbed than in unrubbed preparations. A decreased response to acetylcholine, an endothelium-dependent vasodilator, was observed in aorta with endothelium which had been precontracted with noradrenaline isolated from hypertensive rats. The relaxant response was lost after removal of the endothelium in both control and DOCA-salt hypertensive groups. The response to sodium nitroprusside, an endothelium-independent agent, in aorta isolated from hypertensive rats as well as the response to papaverine, an agent partially dependent on the endothelium, was not altered. Indomethacin treatment altered the response to noradrenaline only in unrubbed aorta of hypertensive rats. In these preparations, a biphasic response to noradrenaline was observed. At lower concentrations noradrenaline induced the characteristic constrictor response, while at higher concentrations a relaxant response was obtained that was abolished by methylene blue, a guanylate cyclase inhibitor. This could indicate that noradrenaline induced the release of endothelium-derived relaxing factor (EDRF) in aorta of hypertensive rats. Furthermore, indomethacin treatment restored the decreased response to acetylcholine in aorta isolated from DOCA-salt hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Indirect evidence for an endothelium-derived contracting factor release in aorta of deoxycorticosterone acetate-salt hypertensive rats. 215 57

In dog mesenteric vein strips, contractions induced by histamine relative to those induced by 5 mM Ba++ were potentiated by removal of endothelium. The induced contractions were potentiated by AA861, a lipoxygenase inhibitor, and methylene blue, a guanylate cyclase inhibitor, to an appreciably greater extent in the strips with endothelium than in those with damaged endothelium. Indomethacin did not potentiate the contraction induced by histamine. Cimetidine potentiated the contraction in control strips and those without endothelium to a similar extent whereas chlorpheniramine suppressed the contraction. Contractile responses to acetylcholine, norepinephrine, serotonin and prostaglandin (PG) F2 alpha were not potentiated by removal of endothelium. It may be concluded that histamine activates histaminergic receptors, possibly H1 but not H2, in endothelial cells and results in a release of vasodilator substance produced by lipoxygenase, which accumulates cellular cyclic GMP and relaxes mesenteric veins. The H1 and H2 receptors in smooth muscle cells appear to be responsible for contractions and relaxations, respectively. Acetylcholine, norepinephrine, serotonin and PGF2 alpha do not seem to release vasodilator substances from endothelium in an amount sufficient to cause significant relaxations of venous smooth muscle.
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PMID:Endothelium-dependent changes in the response to vasoconstrictor substances of isolated dog mesenteric veins. 287 60

The objective of this study was to examine the relationship between responses of bovine intrapulmonary artery and vein to arachidonic acid and cyclic nucleotide levels in order to better understand the mechanism of relaxation elicited by arachidonic acid and acetylcholine. Arachidonic acid relaxed phenylephrine-precontracted arterial rings and elevated both cyclic GMP and cyclic AMP levels in arteries with intact endothelium. In contrast, endothelium-damaged arterial rings contracted to arachidonic acid without demonstrating significant changes in cyclic nucleotide levels. Indomethacin partially inhibited endothelium-dependent relaxation and abolished cyclic AMP accumulation whereas methylene blue, a guanylate cyclase inhibitor, partially inhibited relaxation and abolished cyclic GMP accumulation in response to arachidonic acid. All vessel responses were blocked by a combination of the two inhibitors. Prostaglandin (PG) I2 relaxed arterial rings and elevated cyclic AMP levels whereas PGE2 and PGF2 alpha caused contraction, suggesting that the indomethacin-sensitive component of arachidonic acid-elicited relaxation is due to PGI2 formation and cyclic AMP accumulation. The methylene blue-sensitive component is attributed to an endothelium-dependent but cyclooxygenase-independent generation of a substance causing cyclic GMP accumulation. Intrapulmonary veins contracted to arachidonic acid with no changes in cyclic nucleotide levels and PGI2 was without effect. Homogenates of intrapulmonary artery and vein formed 6-keto-PGF1 alpha, PGF2 alpha and PGE2 from [14C]arachidonic acid, which was inhibited by indomethacin. Thus, bovine intrapulmonary vein may not possess receptors for PGI2. The failure of endothelium-intact vein to relax to acetylcholine may be related to the lack of a relaxant effect by arachidonic acid, perhaps attributed to the absence of generation of an endothelium-derived relaxing factor.
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PMID:Differences in responsiveness of intrapulmonary artery and vein to arachidonic acid: mechanism of arterial relaxation involves cyclic guanosine 3':5'-monophosphate and cyclic adenosine 3':5'-monophosphate. 298 87

The sulfhydryl reagent thimerosal, as well as acetylcholine and Ca2+-ionophore A23187, produced concentration-dependent relaxations of intact rabbit aortic strips. The ability of strips to relax in response to these agents was dependent on the presence of vascular endothelium. Purposely removing the endothelium led to a complete loss of the relaxation responses. Thimerosal was at least as efficacious as A23187 in inducing endothelium-dependent relaxations, but its relaxations developed much slower than those induced by A23187 or acetylcholine. A small concentration of thimerosal that had no appreciable effect by itself, potentiated the relaxing response to acetylcholine in endothelium-intact preparations. Endothelium-dependent relaxations induced by larger concentrations of thimerosal, as well as relaxations produced by acetylcholine, were inhibited by the antioxidant and lipoxygenase inhibitor nordihydroguaiaretic acid, by haemoglobin, and by the inhibitor of soluble guanylate cyclase methylene blue. Indomethacin had no effect on these relaxations. The thiol compounds glutathione, 2-mercaptoethanol and a low concentration of dithiothreitol prevented (and reversed) relaxations induced by thimerosal, but had little or no effect on ACh relaxations. A high concentration of dithiothreitol also markedly inhibited the ACh relaxation. These results are consistent with the hypothesis that thimerosal stimulates endothelial cells to produce a relaxing substance whose properties are similar or the same as those of the endothelium-derived relaxing factor (EDRF) released in response to acetylcholine or A23187. The biochemical mechanism by which thimerosal induces the formation and/or release of this relaxing substance is likely to be different from ACh.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Thimerosal induces endothelium-dependent vascular smooth muscle relaxations by interacting with thiol groups. Relaxations are likely to be mediated by endothelium-derived relaxing factor (EDRF). 310 78

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


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