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)

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

Organic nitrates develop their vasodilating potency by stimulating the enzyme guanylate cyclase. There are still several theories concerning the molecular mechanism of enzyme activation, the most likely of which sees nitric oxide (NO.) as the true modulator of the soluble guanylate cyclase. We therefore examined the release of nitric oxide from organic nitrates by means of a difference-spectrophotometric method and found that our results correlated well with the extent of enzyme activation. The more NO. was liberated from the compounds in question, the higher was the enzyme activation observed. When the examined nitrates were used in a concentration which caused a half-maximal enzyme stimulation, the result was a NO. liberation of striking uniformity. This correlation also applied to SIN-1 for which it has been assumed up to now that the intact molecule itself is able to stimulate the enzyme and not the nitric oxide released from it. We found the reaction between organic nitrates and cysteine to be highly dependent on temperature, while the extent of the observed enhancement increased with the number of nitrate groups per molecule. We also studied the potential effects of certain compounds on non-enzymatic NO. release and found that, in addition to methylene blue, thionine and brilliantcresyl blue, but not ferricyanide, were also effective inhibitors. So it seems likely that both an enzymatic and a non-enzymatic mode of inhibition of enzyme activity does exist. Since oxyhemoglobin is an effective scavenger of nitric oxide, its addition can inhibit enzyme activation by nitrovasodilators. Our results stress the important role of the non-enzymatic liberation of NO. from organic nitrates and related compounds as possible, perhaps even as the principal mode of activation of soluble guanylate cyclase by nitrovasodilators.
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PMID:Correlation between nitric oxide formation during degradation of organic nitrates and activation of guanylate cyclase. 288 63

The effect of different organic nitrates on the activity of soluble guanylate cyclase prepared from rat liver was investigated. We found a close correlation between the number of nitrate ester groups and the potency of guanylate cyclase activation. For erythrityl tetranitrate (ETN, EC50 = 14.5 microM), glyceryl trinitrate (GTN, EC50 = 60 microM), isoidide dinitrate (IIDN, EC50 = 0.24 mM) and isosorbide-5-nitrate (IS-5-N, EC50 = 1 mM), we were able to set up an equation by which the EC50 could be calculated from the number of nitrate groups per molecule. Compared to these results, the effect of sterical factors and lipophilicity on organic nitrate-induced activation of guanylate cyclase was small. However, there were still significant differences in the EC50 values for the cyclic mononitrates. Isosorbide-2-nitrate (IS-2-N, EC50 = 0.75 mM) was found to be more potent than the stereoisomeric isosorbide-5-nitrate. Similarly, the cyclic dinitrates isomannide dinitrate (IMDN, EC50 = 0.20 mM), isoidide dinitrate and isosorbide dinitrate (ISDN, EC50 = 0.28 mM) exhibited small but significant differences in their guanylate cyclase stimulatory potency. Two lipophilic ester derivatives of isosorbide-5-nitrate showed a 2-fold potency difference for vasodilation but were equipotent for activation of guanylate cyclase (EC50 = 0.85 mM). Also, the increase in lipophilicity due to esterification of the free hydroxylic group had no major influence on guanylate cyclase activation by isosorbide-5-nitrate. These results demonstrate that in a cell-free system, the potency of organic nitrates for guanylate cyclase activation is mainly determined by the number of nitrate groups. Since organic nitrate-induced activation of guanylate cyclase may involve the formation of nitric oxide free radicals, it is conceivable that the differences in potency reflect a varying degree of nitric oxide release from each compound tested.
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PMID:Structure-activity relationship of organic nitrates for activation of guanylate cyclase. 289 14

We continuously studied the quantitative formation of nitric oxide (NO), nitrite and nitrate ions from several organic nitrate esters in the presence of various thiol-containing compounds by spectroscopy and HPLC. The results indicate that there are different pathways of decomposition depending on the chemical nature of the mercaptan tested. The amino acid cysteine is known to function as an essential cofactor for guanylate cyclase activation by organic nitrates in vitro. For comparison we investigated several structural analogues with respect to their nitric oxide or nitrite ion releasing potency. Both were found to represent the main products resulting from nitrate ester breakdown besides the respective alcohols. We found that only those compounds were able to activate the enzyme in the presence of nitroglycerin (GTN) which induce the release of NO as well. On the other hand, nearly all other thiols tested caused an in vitro decomposition of organic nitrates by producing excess nitrite and the corresponding disulfide without the formation of NO. Thus, the decomposition of organic nitrates to nitrite ions does not contribute at all to activation of guanylate cyclase. Our results confirm that the liberation of nitric oxide is the common principle of action for all nitrovasodilators. In addition, our results suggest that the thiol consuming transformation of organic nitrates into nitrite ions (ratio NO/nitrite 1:10) may lead to a depletion of cysteine stores, resulting in a decreased formation of NO and, consequently, in a decrease of guanylate cyclase activation, clinically arising as nitrate tolerance.
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PMID:Explanation of the discrepancy between the degree of organic nitrate decomposition, nitrite formation and guanylate cyclase stimulation. 290 Jul 66

Previously, it was shown that the D enantiomer of isoidide dinitrate was 10-fold more potent than the L enantiomer and 10-fold less potent than glyceryl trinitrate for stimulating cyclic GMP accumulation and relaxation of isolated rat aorta. In the present study, these organic nitrates were tested for their ability to induce tolerance to organic nitrate-induced relaxation, cyclic GMP accumulation, and guanylate cyclase activation in rat aorta in vitro. To compensate for the differences in vasodilator potency, tolerance was induced by incubating isolated rat aorta with concentrations of organic nitrates 1,000-fold greater than the EC50 for relaxation. Under these conditions, the EC50 for relaxation was increased significantly for each organic nitrate and to a similar degree on subsequent reexposure. These data suggest that the potential for inducing in vitro tolerance to relaxation was the same for the three organic nitrates tested. When activation of soluble guanylate cyclase by these compounds was assessed, the enantiomers of isoidide dinitrate were equipotent, but less potent than glyceryl trinitrate, suggesting that the site of enantioselectivity is not guanylate cyclase itself. In blood vessels made tolerant to organic nitrates by pretreatment with glyceryl trinitrate, vasodilator activity, cyclic GMP accumulation, and guanylate cyclase activation were attenuated on reexposure to each organic nitrate. In addition, differences in the potency of the three organic nitrates and the enantioselectivity of isoidide dinitrate for relaxation were abolished in tolerant tissue, whereas the potency difference between glyceryl trinitrate and isoidide dinitrate for activation of guanylate cyclase was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of in vitro organic nitrate tolerance on relaxation, cyclic GMP accumulation, and guanylate cyclase activation by glyceryl trinitrate and the enantiomers of isoidide dinitrate. 290 20

Tolerance of vascular smooth muscle to nitroglycerin could be induced by an impaired biotransformation of nitroglycerin to nitric oxide, the activator of soluble guanylate cyclase, or by desensitization of guanylate cyclase to activation with nitric oxide. The latter would imply that there would also be tolerance to nitric oxide delivered from sodium nitroprusside or endothelial cells. Therefore, endothelium-denuded segments of rabbit aorta were treated with nitroglycerin to induce tolerance, and were then assessed for mechanical response, cyclic GMP content, and activity of soluble guanylate cyclase after addition of nitrovasodilators. Nitrate tolerance decreased the vasodilation and the increase in cyclic GMP elicited by nitroglycerin, but not that elicited by sodium nitroprusside or endothelium-derived relaxing factor, in norepinephrine-contracted segments. However, soluble guanylate cyclase in the supernatants of homogenates of nitrate-tolerant aortas was desensitized to activation with nitroglycerin and sodium nitroprusside. As the guanylate cyclase was still responsive to activation by nitric oxide in the intact, tolerant smooth muscle, an impaired biotransformation of nitroglycerin rather than desensitization of soluble guanylate cyclase may be the mechanism by which nitrate tolerance develops.
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PMID:Desensitization of guanylate cyclase in nitrate tolerance does not impair endothelium-dependent responses. 290 5

Tolerance to nitrate vasodilators appears to be a general phenomenon that encompasses all known drugs belonging to this group, with the possible exception of molsidomine, for which tolerance has not yet been unambiguously proven. The mechanism behind tolerance development is still obscure, although decreased distribution of drug to the target tissue (i.e. the vascular wall) may be important. In addition, the production of cyclic guanosine-3',5'-monophosphate (cGMP) [the alleged mediator of nitrate-induced vascular smooth muscle relaxation] is reduced in tolerant tissue, while its degradation is increased. These changes could be due to a direct effect on the enzymes involved in the formation and degradation of cGMP in the cell, i.e. guanylate cyclase and phosphodiesterase, respectively. Furthermore, there is some evidence that the degradation of organic nitroesters in the vascular wall is reduced in tolerant tissue. This could result in a reduced production of unstable chemical intermediates (e.g. nitrosothiols), which have been suggested to act as mediators of guanylate cyclase.
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PMID:Nitrate tolerance from a biochemical point of view. 304 Mar 74

Tolerance and cross-tolerance to the relaxant effects of S-nitroso-N-acetylpenicillamine (SNAP) and nitroglycerin were examined in rat aortic rings. Nitroglycerin-tolerant rings remained fully responsive to SNAP and sodium nitroprusside. Thus, reduced metabolic activation of nitroglycerin, rather than impaired guanylate cyclase activity, appeared to be the operating mechanism for nitrate tolerance in this preparation. Under similar conditions, SNAP incubation induced less tolerance than nitroglycerin. S-nitrosothiols, therefore, appear to be less tolerance-producing than nitroglycerin.
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PMID:Tolerance to relaxation in rat aorta: comparison of an S-nitrosothiol with nitroglycerin. 312 76

Many physiological important substances elicit a relaxing effect on blood vessels which is mediated by (a) substance(s) [EDRF(s)] released from the endothelial cells. EDRF(s) stimulate(s) guanylate cyclase, increasing cGMP at the smooth muscle level, resulting in relaxation. Since this mechanism of action is very similar to that of nitrovasodilator substances, we investigated whether EDRF(s) would act via the "organic nitrate receptor", which is thought to be the common site of action for organic nitrovasodilator substances. The relaxation effect of EDRF-mediated substances (histamine and acetylcholine) was investigated on contracted rat aorta preparations in which the affinity of the organic nitrate receptor was lowered by a treatment with high doses of nitroglycerin. The dose-relaxation curve of nitroglycerin on aorta preparations of pre-treated animals showed a highly significant shift to the right compared to preparations of control rats, proving the nitrate-receptor tolerance. However, when the same preparations were tested for their reactivity to acetylcholine or histamine, no differences could be demonstrated. These results indicate that, although it is known that organic nitrates and EDRF relax vascular smooth muscle cells by stimulating guanylate cyclase, this stimulation is mediated by a different mechanism.
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PMID:Influence of vascular tolerance to nitroglycerin on endothelium-dependent relaxation. 312 95

Tolerance development to organic nitrates, with respect to blood pressure reduction and precipitation of headache, had been assumed for almost a century but it was not until 1980 that the anti-ischemic effect was proven to be subject to this phenomenon, in a placebo-controlled, double-blind study carried out by our group exemplarily employing long-term treatment with isosorbide dinitrate (ISDN) in sustained-release form. Subsequent studies showed that tolerance development was also incurred during administration of ISDN, nonsustained-release form, 40 mg q.i.d. and on application of transdermal nitroglycerin patch systems. Both changes in the pharmacokinetics and activation of counter-regulatory mechanisms can be excluded as meaningful etiologic factors for the development of nitrate tolerance. It must be assumed that intracellular changes in the target organ which are associated with a diminished responsiveness for guanylate cyclase activation are at the basis of tolerance development. Prerequisite, according to laboratory experiments and clinical observations, are high concentrations of nitrates. After development of tolerance, on allowing a nitrate-free interval to intervene, the attenuated effects rapidly resume. Consequently, we investigated the hypothesis that tolerance could be avoided by an intermittent administration of nitrates which prevented accumulation of high serum concentrations. This was confirmed in two placebo-controlled, double-blind studies. Both during treatment with 20 mg ISDN in the morning and at midday as well as with the once-daily administration of 120 mg ISDN sustained-release form in the morning, there was an unequivocal anti-ischemic effect without tolerance development together with a significant reduction in the rate of anginal attacks and nitrate consumption.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Avoidance of tolerance development to long term therapy with nitrates through correct dosage]. 354 18


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