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)

1. The formation of an S-nitrosothiol compound, S-nitroso-N-acetylcysteine (SNAC) has recently been proposed to mediate the augmentation of the anti-aggregatory and haemodynamic effects of glyceryl trinitrate observed in the presence of N-acetylcysteine. This study investigated the effects on an isolated coronary artery preparation of acute and prolonged exposure to S-nitrosothiol compounds and nitric oxide (NO). 2. Single doses of NO and of the S-nitrosothiol compounds, SNAC and S-nitroso-N-acetyl-penicillamine (SNAP), induced rapid, but transient, relaxations in U46619-contracted bovine isolated coronary artery rings. Peak relaxation responses to SNAP and NO were attenuated in the presence of N-acetylcysteine, cysteine, ascorbic acid and methylene blue. The duration of the relaxation responses to SNAC was two to three times longer than those to SNAP and NO. In the presence of N-acetylcysteine (but not cysteine, ascorbic acid or methylene blue) the duration of the relaxation responses to SNAP and NO (but not to SNAC) was markedly increased. H.p.l.c. assay confirmed that, in the presence of N-acetylcysteine, SNAP and, to a lesser degree, NO were converted to the relatively more stable and longer acting vasodilator, SNAC. 3. When compared to control rings, coronary artery rings superfused with glyceryl trinitrate were subsequently markedly less responsive to the vasodilator actions of glyceryl trinitrate, whereas responsiveness to SNAC or NO was only marginally reduced. On the other hand, coronary artery rings superfused with SNAC or NO were subsequently less responsive to glyceryl trinitrate, SNAC and NO. Thus prolonged vascular exposure to SNAC or NO induced a form of tolerance different from that induced with glyceryl trinitrate and which is possibly associated with impaired guanylate cyclase activity. 4. Coronary artery rings superfused with NO were markedly less responsive to glyceryl trinitrate and NO, whereas responses to the endothelium-dependent vasodilator A23187 and to theophylline were not significantly attenuated. 5. It is concluded that formation of the more stable vasodilator SNAC occurs on incubation of N-acetylcysteine with SNAP or NO. While coronary artery responsiveness to SNAC and NO is virtually unchanged in the presence of glyceryl trinitrate-induced tolerance, after prolonged exposure to SNAC or NO tolerance may develop to these vasodilators with cross-tolerance to glyceryl trinitrate but not A23187. Thus, formation or therapeutic utilization of SNAC may acutely circumvent the problem of glyceryl trinitrate-induced tolerance but, during prolonged vascular exposure to SNAC, attenuation of vascular responsiveness may occur to a wide range of vasodilators.
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PMID:S-nitrosothiols as vasodilators: implications regarding tolerance to nitric oxide-containing vasodilators. 251 92

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

N-acetylcysteine is assumed to reverse nitrate tolerance by replenishing depleted intracellular sulfhydryl groups, but data on interactions of N-acetylcysteine and nitrates in patients with stable angina are controversial and disappointing. Therefore, we studied the effect of N-acetylcysteine on nitrate responsiveness of epicardial arteries and of the venous system (assessed as changes in effective vascular compliance) in dogs (n = 12) during long-term nitroglycerin treatment (1.5 micrograms/kg/min i.v. for 5-6 days). In dogs with nitroglycerin-specific tolerance (shift of venous or epicardial artery dilation to 15-17-fold higher dosages), N-acetylcysteine (100 mg/kg i.v.) had no dilator effect and did not alter the dose-response relations of nitroglycerin. Yet, in nontolerant dogs (n = 17), N-acetylcysteine augmented (1.5-2.0-fold) the dilation of epicardial arteries and the reduction of peripheral vascular resistance induced by 0.5-1.5 micrograms/kg/min nitroglycerin. In vitro, the augmentation of purified guanylate cyclase activity by nitroglycerin (10-100 microM) was potentiated by N-acetylcysteine (0.01-1.0 mM) in saline or in canine plasma, but N-acetylcysteine alone was ineffective. We conclude that 1) N-acetylcysteine does not restore nitroglycerin responsiveness in tolerant epicardial arteries or veins in vivo, 2) a small, tolerance-independent augmentation of nitroglycerin-induced dilation may result from N-acetylcysteine-induced extracellular formation of a stimulant of guanylate cyclase from nitroglycerin.
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PMID:Nitrate tolerance in epicardial arteries or in the venous system is not reversed by N-acetylcysteine in vivo, but tolerance-independent interactions exist. 256 37

It is now generally accepted that organic nitrates generate their vasodilator action via production of nitric oxide. However, the cellular location of the metabolic enzyme(s) responsible for such conversion has not been defined. We examined the production of nitric oxide, via chemiluminescence detection, by various cellular fractions of the bovine coronary artery. We were able to show that the highest activity resides in the plasma membrane. Future isolation and characterization of such metabolic systems will greatly assist our understanding of nitrate action and tolerance. Several cellular mechanisms for nitrate tolerance have been proposed. Among the most popular theories is the "intracellular sulfhydryl depletion hypothesis" originally proposed by Needleman et al. The primary supportive data for this mechanism are that exogeneously added thiols (such as N-acetylcysteine) can potentiate the in vivo activity of nitroglycerin and can partially reverse nitrate tolerance. We showed that a cellular-impermeant thiol, viz: glutathione, can also potentiate the hemodynamic effect of nitroglycerin in rats. We subsequently showed that exogenously administered thiols can promote the formation of vasoactive S-nitrosothiols in blood. Thus, the beneficial effects of thiols on nitrate action might be mediated through an extracellular pathway. Another cellular mechanism for nitrate tolerance suggested that tolerance is caused by an alteration of the enzyme, guanylate cyclase. We showed, however, that blood vessels made tolerant to nitroglycerin remain fully responsive (in terms of in vitro relaxation) toward nitric oxide and S-nitrosothiols. These data showed that, as far as relaxation is concerned, nitrate tolerance did not cause a significant alteration of guanylate cyclase activity toward nitric oxide and S-nitrosothiols.
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PMID:Cellular mechanisms of nitrate action. 257 80

Platelet aggregation is currently felt to play an important role in the pathogenesis of ischemic vascular disorders. The smooth muscle relaxant, nitroglycerin, has been shown to inhibit platelet aggregation in vitro, but at concentrations that were felt to be unattainable in vivo. Because the in vivo action of nitroglycerin on smooth muscle cells has been shown to depend on the presence of reduced cytosolic sulfhydryl groups, the inhibitory effect of nitroglycerin on platelet aggregation was examined in the presence of the reduced thiol, N-acetylcysteine. Millimolar concentrations of N-acetylcysteine potentiated markedly the inhibitory effect of nitroglycerin on platelet aggregation induced by ADP, epinephrine, collagen, and arachidonate, decreasing the 50% inhibitory concentration (IC50) approximately 50-fold for each of these agents. Other guanylate cyclase activators inhibited ADP-induced aggregation similarly and this inhibition was likewise potentiated by N-acetylcysteine. Platelet guanosine 3',5'-cyclic monophosphate content increased fivefold in the presence of nitroglycerin and N-acetylcysteine 2 min before maximal inhibition of ADP-induced aggregation was achieved, while simultaneously measured cyclic AMP did not change relative to base-line levels. In the absence of N-acetylcysteine, nitroglycerin induced a marked decrease in platelet-reduced glutathione content as S-nitroso-thiol adducts were produced. The synthetic S-nitroso-thiol, S-nitroso-N-acetylcysteine, markedly inhibited platelet aggregation with an IC50 of 6 nM. These data show that N-acetylcysteine markedly potentiates the inhibition of platelet aggregation by nitroglycerin and likely does so by inducing the formation of an S-nitrosothiol adduct(s), which activate guanylate cyclase.
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PMID:N-Acetylcysteine potentiates inhibition of platelet aggregation by nitroglycerin. 286 86

The mechanism whereby nitroglycerin relaxes vascular smooth muscle remains uncertain. A current hypothesis suggests that nitroglycerin reacts with critical cellular sulfhydryl groups to form an intermediate, which activates guanylate cyclase, resulting in cGMP accumulation and relaxation. This study investigated further the potential involvement of sulfhydryls in nitroglycerin-induced vascular smooth muscle relaxation by evaluating effects of a variety of sulfhydryl alkylating and reducing agents on responses to nitroglycerin and other relaxants in bovine coronary arterial strips submaximally contracted using 30 mM K. Whereas 10(-4) M 5,5'-dithiobis-(2-nitrobenzoic acid), 10(-5) MN-ethylmaleimide, and 10(-4) MN-naphthylmaleimide did not affect nitroglycerin-induced relaxation, 10(-4) MN-ethylmaleimide and 10(-4) M ethacrynic acid significantly inhibited relaxation induced by nitroglycerin. Both ethacrynic acid and N-ethylmaleimide at 10(-4) M also inhibited relaxation induced by sodium nitroprusside. N-ethylmaleimide, but not ethacrynic acid, inhibited relaxation induced by isoproterenol and forskolin. Ethacrynic acid significantly reduced both relaxation and cGMP elevation induced by both 10(-7) M nitroglycerin and 10(-7) M sodium nitroprusside. Ethacrynic acid, but not N-ethylmaleimide, significantly reduced relaxation induced by 8-Br-cGMP. Pretreatment with the sulfhydryl-containing agents N-acetylcysteine, 2-mercaptoethanol, or dithiothreitol, at 10(-3) M did not affect nitroglycerin-induced relaxation in nontolerant arteries. Similarly, N-acetylcysteine and dithiothreitol did not alter the depressed responses to nitroglycerin in arteries in which tolerance to nitroglycerin was induced in vitro. A slight but statistically significant reversal of nitroglycerin-tolerance occurred after treatment of tolerant arteries with 2-mercaptoethanol.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of sulfhydryl reagents on nitroglycerin-induced relaxation of bovine coronary artery. 302 84

Previous studies have suggested that (1) nitroglycerin causes vasodilatation by interacting with sulfhydryl groups in vascular smooth muscle, thereby activating guanylate cyclase and increasing the intracellular concentration of cyclic GMP, and (2) N-acetylcysteine, a source of sulfhydryl groups, potentiates the peripheral vasodilatory effect of nitroglycerin. This study was performed to explore the influence of N-acetylcysteine on nitroglycerin-induced coronary dilatation. In 18 patients (13 men and five women, 30 to 76 years old), coronary sinus blood flow (by thermodilution) was measured before and during intracoronary administration of nitroglycerin, 25 micrograms, both before and 5 min after a 15 min intravenous infusion of (1) 5% dextrose in water (n = 8, control) or (2) 100 mg/kg N-acetylcysteine (n = 10). Nitroglycerin caused no change in heart rate or systemic arterial pressure. In the control patients, coronary sinus blood flow behaved similarly during the two injections: it was 134 +/- 36 ml/min (mean +/- SD) before and 183 +/- 50 ml/min during injection No. 1 (average increase, 49 +/- 25 ml/min; average percent increase, 38 +/- 21%); and it was 131 +/- 34 ml/min before and 178 +/- 45 ml/min during injection No. 2 (average increase, 47 +/- 23 ml/min; average percent increase, 37 +/- 20%) (NS compared with injection 1). In the patients who received N-acetylcysteine, coronary sinus blood flow was 149 +/- 48 ml/min before and 191 +/- 54 ml/min during injection 1 (average increase, 42 +/- 15 ml/min; average percent increase, 30 +/- 12%) (NS compared with eight control values).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Potentiation of nitroglycerin-induced coronary dilatation by N-acetylcysteine. 307 76

The vasodilator effects of nitroglycerin (NTG) are mediated via activation of guanylate cyclase; this process is believed to require the availability of free sulfhydryl groups. Previous studies in man have shown that the sulfhydryl donor N-acetylcysteine (NAC) potentiates the systemic and coronary vasodilator effects of NTG. Furthermore, interaction of NTG and NAC may lead to the formation of S-nitroso-NAC, which strongly inhibits platelet aggregation. The effects of intravenous NTG combined with intravenous NAC (5 g 6 hourly) were compared with those of intravenous NTG alone in a double-blind trial in 46 patients with severe unstable angina pectoris unresponsive to conventional treatment, which included calcium antagonists and cutaneous nitrates in all but one patient. Treatment with NTG/NAC (24 patients) and that with NTG alone (22 patients) was associated with a similar frequency of episodes of chest pain and of increments in NTG infusion rate for pain control (10 vs 17; p = NS). The NTG/NAC group had a significantly lower incidence of acute myocardial infarction than the NTG/placebo group (three vs 10 patients; p = .013). Symptomatic hypotension occurred frequently in the NTG/NAC group (seven vs 0 patients; p = .006). Lactate-pyruvate ratios and venous NTG concentrations were not significantly affected by NAC. Subsequently, another 20 consecutive patients were treated with intravenous NTG and continuously infused NAC (10 g/day). Seven remained pain free during the first 24 hr of NTG infusion; 11 required increments in NTG infusion rate for pain control. Acute myocardial infarction occurred in one patient, while none developed symptomatic hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Combined use of nitroglycerin and N-acetylcysteine in the management of unstable angina pectoris. 312 76

The biochemical basis of the mechanism of vasodilatation by nitroglycerin (NTG) has not been previously investigated in man. However, evidence from in vitro studies suggests that NTG induces activation of guanylate cyclase via a series of enzymatic reactions that are modulated by the availability of sulfhydryl groups. Cysteine appears to be particularly effective in potentiating guanylate cyclase activation by NTG. To determine whether hemodynamic responsiveness to NTG in man might be modulated by sulfhydryl availability, concentration-response curves for effects of intravenously infused NTG on mean arterial pressure (MAP) and mean pulmonary capillary wedge pressure (PCW) were obtained in 10 patients undergoing cardiac catheterization for investigation of chest pain. NTG infusion was repeated 10 min after the intravenous infusion of 100 mg/kg of the cysteine source N-acetylcysteine (NAC). NAC induced no significant hemodynamic effect, but after NAC infusion there was a significant reduction both in the NTG infusion rate associated with a 10% fall from control values in MAP (25.8 +/- 8.3 to 9.3 +/- 2.7 micrograms/min; p less than .01) and in the infusion rate inducing a 30% reduction in PCW (13.6 +/- 4.6 to 4.2 +/- 1.6 micrograms/min; p less than .02). In a control group of five patients who received no NAC, there was no significant change in responsiveness to NTG between infusions. It is concluded that NAC potentiates the vasodilator effects of NTG in man. This suggests that sulfhydryl availability and/or redox state may be determinants of in vivo responsiveness to NTG.
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PMID:Potentiation of the cardiovascular effects of nitroglycerin by N-acetylcysteine. 613 83

Nitrosothiols are powerful vasodilators. They act by releasing nitric oxide, which activates the heme protein guanylate cyclase. We have studied the kinetics of nitrosothiol formation of glutathione, cysteine, N-acetylcysteine, human serum albumin, and bovine serum albumin upon reaction with nitric oxide (NO) in the presence of oxygen. These studies have been made at low pH as well as at physiological pH. At pH 7.0, contrary to published reports, nitric oxide by itself does not react with thiols to yield nitrosothiol. However, formation of nitrosothiols is observed in the presence of oxygen. For all thiols studied, the rates of nitrosothiol formation were first order in O2 concentration and second order in NO concentration and at lower concentrations (< 5 mM thiol) also depended on thiol concentrations. Analysis of the kinetic data indicated that the rate-limiting step was the reaction of NO with oxygen. Analysis of the reaction products suggest that the main nitrosating species is N2O3: RSH+N2O3-->RSNO+NO2- + H+. Rate constants for this reaction for glutathione and several other low molecular weight thiols are in the range of 3-1.5 x 10(5) M-1 s-1, and for human and bovine serum albumins 0.3 x 10(5) M-1 s-1 and 0.06 x 10(5) M-1 s-1, respectively. The data further indicate that the reaction rate of the nitrosating species N2O3 with thiols is competitive with its rate of hydrolysis. At physiological concentrations nitrosoglutathione formation represents a significant metabolic fate of N2O3, and at glutathione concentrations of 5 mM or higher almost all of N2O3 formed is consumed in nitrosation of glutathione. Implications of these results for in vivo nitrosation of thiols are discussed.
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PMID:Kinetics of nitrosation of thiols by nitric oxide in the presence of oxygen. 749 6


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