Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several classes of vasodilators have been demonstrated to elicit their affects by activating guanylate cyclase and elevating intracellular concentrations of cyclic GMP. The nitrovasodilators, such as nitroglycerin, generate nitric oxide, which directly activates the soluble isoenzyme of guanylate cyclase resulting in increased intracellular concentrations of cyclic GMP. A second class of agents, the endothelium-dependent vasodilators, such as acetylcholine, requires an intact endothelium to elicit vascular smooth muscle relaxation, in contrast to the nitrovasodilators. These agents stimulate the release of an endothelium-derived relaxing factor (EDRF), which also activates the soluble form of guanylate cyclase, triggering the production of cyclic GMP. The third class of agents includes atrial natriuretic peptides (ANPs). These low-molecular-weight, heat-stable peptides bind to specific receptors on vascular smooth muscle. These receptors appear unique in that they have a dual function possessing both ANP binding and particulate guanylate cyclase activities. Binding to and activation of particulate guanylate cyclase, in the absence of endothelium, results in the elevation of intracellular concentrations of cyclic GMP and relaxation.
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PMID:Biochemical mechanisms underlying vascular smooth muscle relaxation: the guanylate cyclase-cyclic GMP system. 246 67

We compared in vitro the effects of molsidomine, its active metabolite SIN-1, sodium nitroprusside, and the organic nitrates nitroglycerin, isosorbide-5-mononitrate, and isosorbide-2,5-dinitrate on platelet aggregation induced by platelet activating factor and on the activity of soluble guanylate cyclase. In addition, the effects of molsidomine and of isosorbide-5-mononitrate on ex vivo platelet function were studied. In vitro, SIN-1 and sodium nitroprusside were about 100-fold more potent activators of platelet guanylate cyclase and inhibitors of platelet activating factor-induced aggregation than the other agents. In contrast, in ex vivo experiments, not only molsidomine but also isosorbide-5-mononitrate inhibited platelet activating factor-induced aggregation. These data indicate that molsidomine, SIN-1, and organic nitrates can in vivo, like endothelium-derived relaxing factor, inhibit platelet aggregation and exert antithrombotic properties, although nitrates apparently cannot be converted in platelets to active metabolites. Since the antiaggregatory properties are observed when platelet activating factor is used as an aggregant, and since platelet activating factor-induced aggregation is only weakly influenced by inhibitors of cyclo-oxygenase, this effect might be useful clinically.
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PMID:Inhibition of platelet activating factor-induced platelet aggregation by molsidomine, SIN-1, and nitrates in vitro and ex vivo. 248 88

The molecular mechanism of tolerance development to nitrovasodilators, most prominent with nitroglycerin, associated with desensitization of guanylate cyclase is still unclear. Nitric oxide (NO) appears to be the common denominator of this group of drugs that leads to guanylate cyclase activation, followed by increases in levels of cyclic GMP and relaxation. It was therefore decided to study whether NO itself, which causes some tolerance, interferes with the actions of (a) SIN-1 and sodium nitroprusside, both of which are thought to act directly by NO formation, which explains why they cause little tolerance; and (b) with the actions of nitroglycerin, which stimulates cyclic GMP formation only in the presence of cysteine and causes pronounced (large) tolerance. Experiments were performed in circular strips of isolated de-endothelialized bovine coronary artery by measuring isotonic changes in length and cyclic GMP determined by radioimmunoassay. When the strips were treated with submaximal effective concentrations of NO, some tolerance was observed, as shown by moderate attenuation of the rises in cyclic GMP, and a rightward shift of the dose-response curve of the relaxing effects by a dose factor of 10 (DF = 10). Exposure to nitroglycerin, SIN-1, or sodium nitroprusside rendered the strips cross-tolerant to NO to a comparable extent as NO itself, suggesting that under these conditions the NO component of all of these drugs that caused similar tolerance is displayed. When the strips were treated with NO and subsequently challenged with nitroglycerin, SIN-1, or sodium nitroprusside, the NO cross-tolerance was uniformly lower than the tolerance to the challenging agent.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tolerance and cross-tolerance between SIN-1 and nitric oxide in bovine coronary arteries. 248 98

Endothelial cells produce at least three substances that can attenuate the platelet aggregation response: tissue-type plasminogen activator; the platelet inhibitory prostaglandins I2 and E1; and endothelium-derived relaxing factor, one form of which exhibits properties of nitric oxide. Since platelet aggregates formed in vivo are involved in the initiation of many clinically important occlusive vascular syndromes, we tested the hypothesis that these endothelial products act synergistically to disperse platelet aggregates. Our data reveal that tissue-type plasminogen activator, prostaglandin E1, and nitroglycerin (an organic nitrate activator of guanylate cyclase analogous to endothelium-derived relaxing factor) act synergistically to disaggregate platelets and do so in part by modulation of platelet cyclic nucleotides. These data suggest a potential mechanism by which the endothelium protects against the formation of platelet aggregates in vivo and offer a potential strategy for improving the efficacy of thrombolytic therapy.
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PMID:Synergistic disaggregation of platelets by tissue-type plasminogen activator, prostaglandin E1, and nitroglycerin. 250 9

Vascular smooth muscle relaxation elicited by various endogenous substances results from their interaction with vascular endothelial cells to triger the formation of endothelium-derived relaxing factor (EDRF). EDRF from pulmonary and peripheral arteries and veins and from cultured and freshly harvested aortic endothelial cells has been identified pharmacologically and chemically as nitric oxide (NO) or a labile nitroso compound. Endothelium-derived NO (EDNO) and authentic NO activate the cytoplasmic form of guanylate cyclase by heme-dependent mechanism and thereby stimulate intracellular cyclic GMP accumulation in cells including vascular smooth muscle and platelets. Cyclic GMP functions as a second messenger to cause vascular muscle relaxation and inhibition of platelet aggregation and adhesion to vascular endothelial surfaces. EDNO is synthesized from L-arginine and perhaps arginine-containing peptides by an unidentified calcium-requiring process coupled to the occupation of extracellular endothelial receptors. The biological actions of EDNO are terminated by spontaneous oxidation to NO2- and NO3-. The biological half-life of the very lipophilic EDNO is only 3-5 sec and this allows EDNO to function locally as an autacoid. Nitroglycerin and other organic nitrate esters elicit endothelium-independent relaxation after entering vascular smooth muscle cells and undergoing denitration and formation of NO. The pharmacological actions of nitroglycerin are therefore essentially the same as those of EDNO, and the endogenous NO receptor is the heme group bound to soluble guanylate cyclase. EDNO may serve a biological role to modulate local blood flow and platelet function.
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PMID:Endothelium-derived nitric oxide: pharmacology and relationship to the actions of organic nitrate esters. 251 Jan 39

NAC has been thought to reverse nitrate tolerance by replenishing depleted intracellular sulfhydryl groups, however data on interactions between N-acetylcysteine and nitrates in patients with stable angina are controversial and disappointing. Therefore, we studied the effect of NAC 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 nitroglycerine (GTN)-treatment (1.5 micrograms/kg/min for 5 to 6 days). In dogs with GTN-specific tolerance (shift of venous or epicardial artery dilation with 15- to 17-fold higher dosages), NAC (100 mg/kg i.v.) had no dilator effect and did not alter the dose response relations of nitroglycerin. However, in nontolerant dogs (n = 7) NAC augmented (1.5- to 2-fold) the reduction of peripheral vascular resistance induced by 0.5-1.5 microgram/kg/min GTN. In vitro, the augmentation of purified guanylate cyclase activity by GTN (100 microM) was potentiated by NAC (0.01-1.0 mM) in saline or in canine plasma, whereas NAC alone was ineffective. Therefore, NAC does not restore GTN-responsiveness in epicardial arteries or veins in vivo and a small, tolerance-independent augmentation of GTN-induced dilation may result from NAC-induced extracellular formation of a stimulant of guanylate cyclase from GTN.
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PMID:Failure of the sulfhydryl donor N-acetylcysteine (NAC) to reverse nitrate tolerance in large epicardial arteries and the venous capacitance system of the dog. 251 88

The maximal extent of the dilation of epicardial coronary arteries attainable with nitro-compounds was investigated in 12 patients with coronary artery disease. Before and 5, 10, 15, 19, 60 and 64 min after onset of a 4-min-intravenous infusion of 0.025 mg SIN-1/kg bodyweight coronary angiograms were performed in identical projection; simultaneously, the mean pulmonary wedge pressure (PWP) was measured. At 15 and 60 min, 0.8 mg nitroglycerin (NTG) were additionally administered as sublingual spray. Mean diameters of angiographically normal coronary segments were analyzed with the computer-assisted contour detection system CAAS; they increased by an average maximum of 29 +/- 5% prior to NTG (p less than 0.001). PWP decreased from 9.2 +/- 3.1 mmHg to an average minimum of 4.3 +/- 1.6 mmHg (p less than 0.01) prior to NTG. Neither of these SIN-1-effects was significantly augmented by additional NTG: at 19 min coronary dilation amounted to 28 +/- 7% (p less than 0.001), PWP to 3.9 +/- 1.0 mmHg (p less than 0.01). At 60 min coronary dilation still amounted to 24 +/- 8% (p less than 0.001), PWP to 6.2 +/- 2.5 mmHg (p less than 0.05). By the second administration of NTG the maximal effects attained before could be reproduced: coronary dilation 28 +/- 8% (p less than 0.001), PWP 4.6 +/- 2.2 mmHg (p less than 0.01). Thus, the dilation reserve of epicardial coronary arteries for nitrocompounds is approximately 30% on average. These results suggest the possibility of a reproducible maximal activation of the enzyme guanylate cyclase which seems to be the mediator of the nitro-compound-induced vasodilation.
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PMID:Coronary vasodilation with nitrocompounds--is there a maximum? 251 91

Nitroprusside (NP) and nitroglycerin (NG) are potent vasodilators that are used clinically on the basis of their abilities to cause relaxation of smooth muscle. In vitro, both agents cause activation of guanylate cyclase, resulting in increased intracellular cGMP. They also have effects on arachidonate metabolism. Despite apparent similarities in their mechanisms of action, the two drugs have different therapeutic applications based in part on differences in their effectiveness on the arterial and venous systems in vivo. To understand better their target tissue preference, slices of aorta and vena cava were incubated with the agents; cGMP and the vasodilatory prostanoid, prostacyclin, were quantified. NP was more effective in increasing the cGMP content of aorta than of vena cava; it was more active than NG in both tissues. Prostaglandin formation by vascular tissue was influenced by the preliminary equilibration period. Under optimal conditions, it appeared that NG enhanced prostacyclin formation in aorta more than did NP. This in vitro model for NP and NG action may be useful in studying the mechanisms of action of these and other vasoactive agents.
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PMID:Effects of nitroprusside and nitroglycerin on cGMP content and PGI2 formation in aorta and vena cava. 253 35

The long-term patency of the internal mammary artery (IMA) graft is of considerable interest owing to its extensive use in myocardial revascularization. The aim of the present study was to elucidate the role of endothelium in modulating the responses of the porcine IMA to several vasoactive drugs. Isolated ring segments of porcine IMA contracted in a reproducible and dose dependent manner to phenylephrine, potassium chloride and the thromboxane mimic U46619, but the responses to serotonin, histamine and ATP were significantly less prominent. Both acetylcholine and bradykinin elicited endothelium-dependent relaxation which was not inhibited by indomethacin, but by methylene blue, an inhibitor of soluble guanylate cyclase. These two endothelium-dependent drugs and two endothelium-independent relaxing drugs, nitroprusside and nitroglycerin relaxed the IMA in a dose dependent manner which was associated with an elevation of cyclic GMP. The endothelium dependent vasodilator peptides such as bradykinin contain L-arginine in their sequence. Benzoyl derivatives of L-arginine but not L-arginine relaxed the IMA in a dose dependent manner. These data confirm and extend exploratory studies performed with a simpler vascular model which indicate that the precursor of endothelium derived relaxing factor (EDRF) is an arginine moiety.
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PMID:Role of the endothelium and arginine peptides on the vaso-motor response of porcine internal mammary artery. 254 72

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


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