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)

Continuous application of organic nitrates in patients causes a well-documented attenuation of their antianginal efficacy. N-acetylcysteine (NAC) is assumed to reverse this nitrate tolerance by replenishing depleted intracellular sulphydryl groups, but data on NAC application in patients are controversial. Therefore, we studied the effect of NAC on epicardial artery vasomotion under nitrate tolerance, and we examined under these conditions the epicardial artery dilations induced by glyceryl trinitrate (GTN) and those mediated by the endothelium, since the activation of soluble guanylate cyclase is a common mechanism of these two reactions. Tolerance was induced in chronically instrumented dogs by long-term GTN infusion (1.5 micrograms kg-1 min-1 i.v. for 5 to 6 days) and shifted the GTN dose response curve of epicardial arteries to 17- to 20-fold higher doses. However, there was no alteration of epicardial artery dilations induced by SIN-1, another activator of guanylate cyclase, or of endothelium-mediated dilations. Furthermore, NAC (100 mg kg-1 i.v.) did not alter the dose-response relation of GTN under tolerance. In vitro, however, NAC potentiated the activation of purified soluble guanylate cyclase by GTN, while NAC without GTN was ineffective. In non-tolerant dogs, NAC slightly (1.5- to 2-fold) augmentated dilations induced by 0.5-1.5 micrograms kg-1 min-1 GTN, and a similar small augmentation of GTN dilations by NAC is observed in patients, regardless whether they are tolerant to nitrates or not. We conclude: (1) a step prior to the guanylate cyclase activation is responsible for GTN-specific tolerance of epicardial arteries in vivo. (2) NAC does not reverse GTN-specific tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nitrate action on epicardial coronary arteries and tolerance: new aspects based on longterm glyceryl trinitrate infusions in dogs. 251 66

Sodium nitroprusside is a vasodilator and an inhibitor of platelet activation. It is thought that these effects are mediated by the spontaneous release of nitric oxide and stimulation of cytosolic guanylate cyclase. We have found that sodium nitroprusside (5-200 microM) greatly increased a cytosolic ADP-ribosyltransferase that ADP-ribosylates a soluble 39-kDa protein. This activity causes the mono-ADP-ribosylation of the 39-kDa protein, since digestion with snake venom phosphodiesterase releases 5'-AMP. This enzyme is present in platelets, brain, heart, intestine, liver, and lung. The effect of sodium nitroprusside is not related to stimulation of soluble guanylate cyclase and the production of cyclic GMP because cyclic GMP, dibutyryl cyclic GMP, and 8-bromo-cyclic GMP are ineffective. 3-Morpholinosydnonimine (commonly known as SIN-1) (20-1000 micrograms/ml), another compound that acts through the spontaneous formation of nitric oxide as does sodium nitroprusside, also stimulates ADP-ribosylation of the 39-kDa protein. Hemoglobin, which binds nitric oxide, inhibits sodium nitroprusside's activation of the cytosolic ADP-ribosyltransferase. These studies demonstrate a novel action of nitric oxide related to the activation of an endogenous ADP-ribosyltransferase. The physiological role of this ADP-ribosylation needs further exploration.
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PMID:Activation of a cytosolic ADP-ribosyltransferase by nitric oxide-generating agents. 254 78

Various stimulants of the release of EDRF (endothelium-derived relaxing factor) increased intracellular cGMP levels in bovine aortic endothelial cells. ATP was the most effective compound tested, increasing cGMP 7-fold, followed by the calcium ionophore, A23187 (4.8-fold), and bradykinin (4.0-fold). The EC50 values were similar to those obtained when EDRF release was measured with the bioassay technique, which suggests a stimulation of endothelial guanylate cyclase by EDRF. The direct acting stimulants of soluble guanylate cyclase, sodium nitroprusside and SIN-1 (3-morpholino-sydnonimine), also increased the cGMP content of endothelial cells by 9.4 and 7.2 times, respectively. The effects of both groups of stimulants on cGMP levels were antagonized by the lipoxygenase inhibitor, nordihydroguaiaretic acid, and by the radical scavenger, phenylbutylnitrone, whereas gossypol or canavanine only antagonized the EDRF-induced effect on endothelial cGMP levels. Bradykinin, ATP and A23187 also increased the uptake of 45CaCl2 into endothelial cells but since the complete removal of extracellular Ca2+ or blockade of Ca2+ transport by LaCl3 did not affect the ability of these compounds to elevate cGMP levels, the formation of EDRF appears not to be triggered by an influx of extracellular calcium. This study provides evidence that EDRF stimulators enhance cGMP levels in endothelial cells, probably due to a direct activation of guanylate cyclase by EDRF.
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PMID:Effect of calcium on endothelium-derived relaxing factor formation and cGMP levels in endothelial cells. 255 53

The effect of nitroglycerin (NTG)-induced tolerance on the spasmolytic effects of a series of vasodilators was determined to establish potential sites of tolerance. Concentration-effect curves to vasodilators were completed concurrently in U46619-contracted bovine isolated coronary artery rings pre-exposed to 100 microM NTG for 10 min (NTG-tolerant rings) and in control rings not pre-exposed to NTG. Compared to control rings, NTG-tolerant rings were markedly less responsive (P less than .01, n = 8-10) to the spasmolytic actions of NTG, isosorbide dinitrate, sodium nitroprusside (SNP) and 3-morpholinosydonimine (SIN-1), whereas the spasmolytic actions of S-nitroso-N-acetylpenicillamine and nitric oxide were only marginally attenuated in NTG-tolerant rings. On the other hand, no significant difference in the relaxant responses of NTG-tolerant and control coronary artery rings were observed to either the endothelium-dependent vasodilator, A23187 or the guanylate cyclase-independent vasodilator, theophylline. In additional cross-tolerance studies, relaxations to the organic nitrate vasodilator, NTG were significantly more attenuated (P less than .05, n = 5) by tolerance induced by NTG, than by either SNP or SIN-1, whereas the actions of the non-nitrate vasodilators, SNP and SIN-1 were attenuated more by SNP-and SIN-1-induced tolerance than by NTG-induced tolerance (P less than .05, n = 5). We conclude that, in this isolated coronary artery preparation, NTG-induced tolerance affects at least two major sites in the cascade of events between the initial site of NTG action and guanylate cyclase activation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nitroglycerin-induced tolerance affects multiple sites in the organic nitrate bioconversion cascade. 256 71

Since the diminished vasodilatation characterizing tolerance to organic nitrates is associated with lower rises in 3', 5'-cyclic guanosine monophosphate (cGMP) levels, the possibility that nitrovasodilators desensitized guanylate cyclase (GC) when pre-incubated with coronary supernatants was studied. In the absence of cysteine, pre-incubation with nitroglycerin (NG) decreased GC-activity during subsequent incubation to 24 +/- 7% of control values, whereas six other nitrovasodilators had much smaller effects. When cysteine was present during pre-incubation, NG-stimulation of GC remained significantly higher (59 +/- 3%; P less than 0.05), whereas the effects of other nitrovasodilators were not significantly changed. We also found that GC-activity, when reduced by pre-incubation with NG could only be restored by readdition of native coronary supernatant, suggesting that the enzyme became inactivated. NG pre-incubation of GC (in contrast to coronary strips) almost completely abolished the direct and thiol-independent stimulatory effect of 3-morpholinosydnonimine (SIN-1) down to 4.5 +/- 0.2%, whereas pre-incubation with other nitrovasodilators reduced the stimulatory response to SIN-1 to only 59 to 98%. Increasing concentrations of NG during pre-incubation dose-dependently (IC50 = 0.13 mM) reduced the activating effect of SIN-1 during incubation. There was also a time dependence in NG-induced inactivation of GC which followed first order kinetics with a calculated half life of 2.5 min in the absence of a thiol. The latter was increased to 4.0 or 19.2 min, respectively, when glutathione or cysteine-methylester were present during pre-incubation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tolerance to nitroglycerin is caused by reduced guanylate cyclase activation. 256 81

Tolerance to the cyclic GMP-mediated vasodilator action of nitroglycerin develops with prolonged exposure and may be mediated either by formation of less nitric oxide from nitroglycerin or by desensitization of soluble guanylate cyclase to activation with nitric oxide. In the latter case, smooth muscle cells tolerant to nitroglycerin should show cross-tolerance to nitric oxide released from sydnonimines and endothelial cells (endothelium-derived relaxing factor). Therefore cultured smooth muscle cells from rabbit aorta were pretreated for 1 h with vehicle or high concentrations (0.55 mM) of nitroglycerin or the sydnonimine SIN-1. The formation of cyclic GMP induced by subsequent small doses of nitroglycerin, sydnonimine SIN-1 and endothelium-derived relaxing factor (released from cultured endothelial cells) was compared with the changes in activation of soluble guanylate cyclase, cyclic GMP formation and vasodilation in response to the same stimuli in similarly pretreated segments from rabbit thoracic aortae. Both cultured and native smooth muscle cells remained responsive to stimulation with sydnonimine SIN-1 and endothelium-derived relaxing factor after pretreatment with nitroglycerin, vehicle, or sydnonimine SIN-1, even though they were tolerant to nitroglycerin after pretreatment with nitroglycerin. In contrast, activation of soluble guanylate cyclase by nitroglycerin and sydnonimine SIN-1 was attenuated in homogenates of nitrate-tolerant aortae. The findings suggest that nitroglycerin tolerance in intact cells does not involve desensitization of soluble guanylate cyclase, because in intact cells nitrate tolerance can be overcome by direct activators of soluble guanylate cyclase.
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PMID:Endothelium- and sydnonimine-induced responses of native and cultured aortic smooth muscle cells are not impaired by nitroglycerin tolerance. 257 Mar 62

The action of ANF is, at least in part, mediated by the activation of particulate guanylate cyclase. Increases in plasma ANF levels induce a marked increase in the plasma levels and urinary excretion of cyclic GMP. In contrast to agents that stimulate particulate guanylate cyclase, activators of soluble guanylate cyclase, such as the bioactive molsidomine metabolite, SIN 1, induce only a modest, not significant, increase in plasma cyclic GMP levels. Thus, increases in plasma cyclic GMP levels appear to be specific for the activation of particulate guanylate cyclase. Cyclic GMP is stable in whole blood in the presence of EDTA and can easily be measured in plasma and urine. It may therefore be a valuable alternative for ANF measurement in the clinical routine. In contrast to urinary ANF excretion, the urinary excretion of cyclic GMP sensitively reflects increases in plasma ANF levels. Measurement of cyclic GMP excretion may therefore be an alternative for plasma ANF and plasma cyclic GMP measurement especially in situations where blood drawing is difficult, e.g. in newborns. Measurement of basal cyclic GMP followed by determination of increases in cyclic GMP levels after injection of a small ANF bolus dose tests the cellular sensitivity to ANF. This may give further insight in the mechanism of the regulation of ANF effects. Therefore, cyclic GMP in many cases appears to be a sensitive marker for the action of ANF in man.
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PMID:Is cyclic GMP a clinically useful marker for ANF action? 284 15

SIN-1, a metabolite of the vasodilating drug molsidomine, was found to stimulate dose dependently (0.01-1 mM) soluble guanylate cyclase from bovine coronary arteries up to 100-fold the control value. The stimulatory effect of SIN-1 increased with rising concentrations of MnC1(2) or MgC1(2) and was diminished in the presence of methylene blue or ferricyanide. The time course of SIN-1-induced guanylate cyclase stimulation was characterized by a lag phase which was not observed after preincubation of the enzyme with SIN-1. In contrast to nitroglycerin and sodium nitroprusside, SIN-1 did not require the presence of cysteine or other thiols to stimulate guanylate cyclase. The results presented in this study provide further evidence that SIN-1 exerts its dilating effect on coronary vessels via direct stimulation of guanylate cyclase.
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PMID:Stimulation of soluble coronary arterial guanylate cyclase by SIN-1. 286 62

We examined the effect of nitroglycerin (GTN) tolerance on an important determinant of nitrate-antianginal action, large coronary artery dilation, in 11 chronically instrumented conscious dogs. In addition, endothelium-mediated coronary artery dilation was studied because this shares a common dilator pathway with the nitrates, i.e., activation of soluble guanylate cyclase. With long-term GTN (1.5 micrograms/kg/min iv for 5 days) the diameters of the left circumflex and anterior descending coronary arteries showed an initial increase of 8.2 +/- 0.3% and 10.8 +/- 0.9%, respectively, returning to control levels by the second to third day of treatment. On days 4 and 5, the dose-response relations for GTN-induced epicardial artery dilation were shifted (p less than .01) to 17- to 20-fold higher doses. However, there was no attenuation of epicardial artery dilation induced by SIN-1 (n = 7), another activator of guanylate cyclase, or of endothelium-mediated dilation assessed both as flow-dependent dilation (n = 7) and as direct intra-arterial acetylcholine-induced dilation (n = 4). In addition, there was no clear tolerance to the peripheral vascular actions of GTN responsible for reflex tachycardia and increased coronary flow. We conclude that a moderate degree of nitrate tolerance to epicardial artery dilation does not affect the responsiveness to other exogenous or endogenous activators of guanylate cyclase. However, this tolerance to epicardial artery dilation, together with the maintenance of peripheral vascular actions that can induce reflex tachycardia, result in a potentially unfavorable balance of GTN effects.
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PMID:Long-term nitroglycerin treatment: effect on direct and endothelium-mediated large coronary artery dilation in conscious dogs. 288 35

Nitrovasodilators relax vascular smooth muscle by stimulating soluble guanylate cyclase (GC). The resulting rise in cGMP probably initiates Ca extrusion from the smooth muscle cell which causes relaxation. Since repeated administration of organic nitrates, particularly nitroglycerin, leads to tolerance, i.e. a decrease in the vasodilator effect, it was studied whether (a) tolerance was a peripheral phenomenon occurring in the vascular smooth muscle, and (b) was due to an impairment of GC activation. In isolated circular strips of bovine coronary arteries, 90 min pretreatment with nitroglycerin greatly lowered the relaxing as well as the cGMP increasing response to nitroglycerin, indicating tolerance induction. Tolerance, although to a lesser extent, was also obtained with other organic nitrates under similar conditions, including IS 5-MN. Little (nitroprusside Na) to negligible tolerance was obtained with sodium nitrate and SIN-1, the active metabolite of molsidomine. The latter group of drugs stimulated soluble GC in vitro in the absence of cysteine whereas organic nitrates required the presence of this thiol. Preincubation with nitroglycerin almost completely inactivated GC whereas other organic nitrates had little effect. The results indicate that tolerance is caused by an impairment of GC function in the smooth muscle cell, particularly when elicited by nitroglycerin, and that differences in the degree of tolerance development by various nitrovasodilators are possibly due to different mechanisms of activation and inactivation of GC as well as differences in cysteine requirement.
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PMID:Mechanism of vasodilation by nitrates: role of cyclic GMP. 288 20


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