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)

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

We have directly compared the effects of the nitrates isosorbide-5-mononitrate, nitroglycerin and isosorbide dinitrate and of the nitric oxide-containing sodium nitroprusside and 3-morpholino-sydnonimine (SIN 1) as well as of the bioinactive precursor of SIN 1, molsidomine, on platelet activating factor-induced platelet aggregation and activation of soluble guanylate cyclase. The effects of these agents on the aggregation and on soluble guanylate cyclase activity of human platelets were closely correlated. Whereas nitroprusside and SIN 1 were very potent inhibitors of aggregation and activators of soluble guanylate cyclase in micromolar concentrations, the other drugs were effective only at millimolar concentrations. Preincubation of platelets with cysteine did not or only slightly increase the ability of isosorbide-5'-mononitrate and isosorbide dinitrate to inhibit aggregation, but a clear increase was observed after preincubation with nitroglycerin. These data support the concept that cyclic GMP is the mediator of nitric oxide-induced inhibition of platelet aggregation and indicate that nitrates cannot directly inhibit aggregation or be converted to nitric oxide-containing agents by a specific mechanism in platelets. The data also suggest that SIN 1 and nitroprusside, but not or only to a certain degree the nitrates, can be considered as exogenous endothelium-derived relaxing factors.
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PMID:Direct comparison of the effects of nitroprusside, SIN 1, and various nitrates on platelet aggregation and soluble guanylate cyclase activity. 290 6

Molsidomine is enzymatically metabolized in the liver to SIN-1 and readily converted into the active metabolite SIN-1A, which carries a free nitroso group. Evidence obtained in isolated circular strips from bovine coronary arteries indicates that SIN-1 increases cyclic guanosine monophosphate in close association with its relaxant effects in coronary strips under various pharmacologic conditions, suggesting that cyclic guanosine monophosphate mediates relaxation. Various nitrovasodilators act by the same mechanism, which is stimulation of guanylate cyclase. In this study the effect of nitroglycerin depended on the presence of a special thiol, cysteine, whereas SIN-1 was active also in the absence of cysteine. Cysteine deficiency was found to be associated with tolerance. After prolonged exposure to the drug, tolerance toward nitroglycerin developed in coronary strips that was antagonized by cysteine. SIN-1 produced no significant tolerance and was also fully active in nitroglycerin-tolerant strips. We conclude that SIN-1 relaxes vascular smooth muscle by direct stimulation of guanylate cyclase, whereas nitroglycerin probably must be converted into a cyclase stimulator by a cysteine-dependent reaction.
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PMID:Mechanism of vasodilation by molsidomine. 298 23

The mode of action of the in vitro active metabolites SIN-1 and SIN-1A of the vasodilator prodrug molsidomine was studied in bovine coronary artery strips. Both compounds increased cyclic GMP levels in close association with, but prior to their relaxing action. Relaxation and rises in cyclic GMP by SIN-1 were potentiated by M & B 22,948, an inhibitor of cyclic GMP phosphodiesterase and attenuated by methylene blue, a dye that inhibits activation of guanylate cyclase by SIN-1 and various nitrovasodilators. A single significant correlation between rises in cGMP and relaxation was obtained for both SIN compounds and various nitrovasodilators. Relaxation by SIN-1A was independent of the presence of endothelium and was not affected by various inhibitors of arachidonic acid metabolism. In contrast to nitroglycerin, SIN-1 did not induce substantial tolerance nor were its actions reduced in artery strips that were tolerant to nitroglycerin. The results indicate that SIN-1A relaxes coronary smooth muscle by a direct stimulant effect on soluble guanylate cyclase in vascular smooth muscle cells.
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PMID:Cyclic GMP as the mediator of molsidomine-induced vasodilatation. 300 72

The aim of the present study was to exclude a potential role of hemoglobin in the formation of nitric oxide (NO) from several nitrovasodilators. NO was measured with a chemiluminescence technique after purging with argon from the aqueous solution. Nitric oxide generation occurred in the absence of hemoglobin or non-heme iron. Sodium nitroprusside and SIN-1 released NO spontaneously. Nitroglycerin produced NO only in the presence of those thiols which are effective co-stimulators of guanylate cyclase. All other thiols degraded nitroglycerin only into nitrite ions without formation of NO. Our results support the role of nitric oxide as terminal activator of guanylate cyclase stimulation by nitrovasodilators.
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PMID:Nitric oxide (NO) formation from nitrovasodilators occurs independently of hemoglobin or non-heme iron. 312 57

Various NO-forming compounds have in common that along with their mechanically relaxing effect, they increase the concentration of cyclic 3'5'-guanosine monophosphate (cGMP) in vascular smooth muscle. This has been shown for nitroglycerin, NaNO2, nitroprusside-Na, 2'3'-dinitroadenosine-5'-ethylcarboxamide (B-744-99), and more recently for SIN-1, the vasoactive metabolite of molsidomine, and for nicorandil (SG-75). In isolated circular strips of bovine coronary arteries, suspended in a partially depolarizing Tyrode's solution containing 27 mM K+, these drugs produced dose-dependent relaxations which were slightly preceded by concomitant increases in cGMP levels, measured at various moments of drug action by freeze-clamping the strips, and by subsequent determinations of cyclic nucleotide levels by RIA. Levels of cyclic 3',5'-AMP were not significantly changed, except by B-744-99. Inhibition of cGMP hydrolysis by the addition of M & B 22,948 (2-o-propoxyphenyl-8-azapurin-6-one) augmented the nitrate-induced rises in cGMP as well as their relaxing effects on coronary arterial strips. In the presence of the vital stain methylene blue - which was shown in vitro to prevent nitrate-induced activation of guanylate cyclase, the enzyme which forms cGMP from GTP - the relaxant actions as well as the increases in cGMP produced by several of these nitro-compounds in coronary strips were almost abolished. The actions of organic nitrates appear to depend on their previous reduction to NO by a rate-limiting step involving cysteine, whereas those of nitroprusside and SIN-1 are probably independent of cysteine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanism of nitrate-induced vasodilation and tolerance. 614 77

The effects of nitroglycerin and SIN-1 on atrial rate and intracellular levels of cGMP were studied in the isolated spontaneously beating rat atria. Basal atrial rate was 254 +/- 5 beats X min-1 in the group of experiments performed with SIN-1 and 276 +/- 8 beats X min-1 in that performed with nitroglycerin. No chronotropic effect was detected when nitroglycerin or SIN-1 were added in concentrations ranging from 10(-11)M to 10(-4)M. Measurements of cGMP levels showed that the nucleotide content of atrial tissue increased from a control value of 46.98 +/- 12.1 fmol X mg-1 (w.w.) to 86.4 +/- 3.2 fmol X mg-1 with 10(-5)M SIN-1 and to 107.6 +/- 12.2 fmol X mg-1 with 10(-5)M nitroglycerin (P less than 0.05). The data show no alteration in the chronotropic activity despite the increments in cGMP levels, probably due to an uncoupling between the guanylate cyclase sensitive to SIN-1 and nitroglycerin and the cGMP dependent protein kinase.
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PMID:[Effects of nitroglycerin and SIN-1 on spontaneous incidence and cGMP levels in the isolated rat atrium]. 632 44

The effect of a novel antianginal agent, molsidomine (N-ethoxycarbonyl-3-morpholinosydnonimine) (SIN-10) and its metabolites, 3-morpholinosydnonimine (SIN-1) and N-nitroso-N-morpholinoaminoacetonitrile (SIN-1A) on isolated dog blood vessels were investigated. SIN-1 and SIN-1A elicited a concentration-dependent relaxation of prostaglandin F2 alpha, contracted strips, while SIN-10 was without effect even in a concentration of 10(-4) M. The mean effective concentration (EC50) values of SIN-1A were much lower than SIN-1 and other vasodilators including nitroglycerin. The time course of relaxation was more rapid and transient in response to SIN-1A than to SIN-1. Adrenergic and cholinergic blocking agents did not affect the relaxing responses to SIN-1 and SIN-1A. SIN-1A also attenuated the norepinephrine-, KCl-, Ca2+-, or electrical transmural stimulation-induced contractile response, but SIN-1A increased the [3H]norepinephrine release from the adrenergic nerve terminals in response to transmural stimulation. Methemoglobin, which reportedly binds nitric oxide, or methylene blue, an inhibitor of guanylate cyclase, attenuated the relaxing response to SIN-1A. These results indicate that the vasodilating action of molsidomine results from the direct action on the vascular smooth muscle and suggest that the action is caused by its metabolites, probably SIN-1A, which contains a nitric oxide-moiety in the molecule. The possible mechanism of vasorelaxing action of SIN-1A is discussed in comparison with that of nitroglycerin.
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PMID:Vasorelaxing actions of molsidomine and its metabolites, in comparison with nitroglycerin. 641 60

The biochemical signaling pathways involved in nitric oxide (NO)-mediated cholinergic inhibition of L-type Ca2+ current (ICa[L]) were investigated in isolated primary pacemaker cells from the rabbit sinoatrial node (SAN) using the nystatin-perforated whole-cell voltage clamp technique. Carbamylcholine (CCh; 1 microM), a stable analogue of acetylcholine, significantly inhibited ICa(L) after it had been augmented by isoproterenol (ISO; 1 microM). CCh also activated an outward K+ current, IK(ACh). Both of these effects of CCh were blocked completely by atropine. Preincubation of the SAN cells with L-nitro-arginine methyl ester (L-NAME; 0.2-1 mM), which inhibits NO synthase (NOS), abolished the CCh-induced attenuation of ICa(L) but had no effect on IK(ACh). Coincubation of cells with both L-NAME and the endogenous substrate of NOS, L-arginine (1 nM), restored the CCh-induced attenuation of ICa(L), indicating that L-NAME did not directly interfere with the muscarinic action of CCh on ICa(L). In the presence of ISO the CCh-induced inhibition of ICa(L) could be mimicked by the NO donor 3-morpholino-sydnonimine (SIN-1; 0.1 mM). SIN-1 had no effect on its own or after a maximal effect of CCh had developed, indicating that it does not inhibit ICa(L) directly. SIN-1 failed to activate IK(ACh), demonstrating that it did not activate muscarinic receptors. Both CCh and NO are known to activate guanylyl cyclase and elevate intracellular cGMP. External application of methylene blue (10 microM), which interferes with the ability of NO to activate guanylyl cyclase, blocked the CCh-induced attenuation of ICa(L). However, it also blocked the activation of IK(ACh), suggesting an additional effect on muscarinic receptors or G proteins. To address this, a separate series of experiments was performed using conventional whole-cell recordings with methylene blue in the pipette. Under these conditions, the CCh-induced attenuation of ICa(L) was blocked, but the activation of IK(ACh) was still observed. Methylene blue also blocked the SIN-1-induced decrease in ICa(L). 6-anilino-5,8-quinolinedione (LY83583; 30 microM), an agent known to decrease both basal and CCh-stimulated cGMP levels, prevented the inhibitory effects of both CCh and SIN-1 on ICa(L), but had no effect on the activation of IK(ACh) by CCh. In combination, these results show that CCh- and NO-induced inhibition of ICa(L) is mediated by cGMP.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A cellular mechanism for nitric oxide-mediated cholinergic control of mammalian heart rate. 749 38

Experiments were designed to compare the relaxing activities of the new sydnonimine C87-3754 with SIN-1 in arteries and veins of the dog, and to determine whether C87-3754 can prevent endothelium-dependent contractions. Rings of coronary and femoral arteries, and saphenous veins were suspended in organ chambers for the measurement of changes in isometric tension. SIN-1 and C87-3754 evoked concentration-dependent relaxations in all rings of blood vessels contracted with a submaximal concentration of either prostaglandin F2 alpha, endothelin-1, phenylephrine, or norepinephrine. In both arteries and veins, the concentration-relaxation curves to C87-3754 were shifted significantly to the right (by two to three logarithmic units) of that to SIN-1. The presence of endothelium significantly inhibited the relaxations to SIN-1 but did not affect those to C87-3754. The treatment of coronary arteries with methylene blue or oxyhemoglobin significantly impaired the relaxation to SIN-1 and C87-3754. Neither C87-3754 nor its prodrug pirsidomine (CAS 936) affected the membrane potential in coronary arteries. The endothelium-dependent contractions evoked by nitro L-arginine, arachidonic acid, and the calcium ionophore A23187 in basilar arteries of the dog were inhibited by C87-3754. These results indicate that the sydnonimine C87-3754 is a dilator of both arterial and venous smooth muscle, and can prevent endothelium-mediated contractions in cerebral arteries of the dog. The inhibition of vascular tone is likely to involve the activation of soluble guanylate cyclase, causing enhanced production of cyclic guanosine monophosphate in the smooth muscle without a change in membrane potential.
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PMID:The sydnonimine C87-3754 evokes endothelium-independent relaxations and prevents endothelium-dependent contractions in blood vessels of the dog. 750 62


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