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)

Nicorandil relaxes coronary vascular smooth muscle by stimulating guanylyl cyclase and increasing cyclic GMP (cGMP) levels (as shown first in our laboratory) as well as by a second mechanism resulting in activation of K+ channels and hyperpolarization. Therefore, we studied the relative contributions of either mechanism to the overall response in bovine circular strips of coronary arteries by simultaneously measuring changes in length and in cGMP levels through radioimmunoassay. Blockade by 10 microM methylene blue of the cGMP increases in strips precontracted by 1 microM of the thromboxane A2 analogue U46619 reduced nicorandil-induced relaxation to 30-50%, and there were no significant changes in cGMP levels. Suppression of the hyperpolarizing component of nicorandil by 80.4 mM K+ or 1 microM glibenclamide in precontracted strips reduced nicorandil relaxation to 50% (K+) or shifted the dose response to the right by a factor of two (glibenclamide) without alteration of increases in cGMP. A quantitative separation of both mechanisms of action was obtained by comparing the correlation between increases in cGMP and relaxation under conditions of inhibited versus noninhibited hyperpolarization. The results indicate that cGMP contributes to the total relaxing effect of nicorandil by 30-40% at low concentrations and 80-90% at high concentrations of nicorandil. From the experiments with glibenclamide, it can be concluded that the probable mechanism by which nicorandil hyperpolarizes is opening glibenclamide-sensitive K+ channels in coronary vascular smooth muscle and that this latter effect mimics those of other K+ channel openers such as cromakalim or pinacidil.
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PMID:Molecular mechanism of action of nicorandil. 128 68

1. Nicorandil, pinacidil and lemakalim relaxed precontracted rings of canine cerebral artery. 2. The order of potency was lemakalim greater than nicorandil approximately equal to pinacidil, but all these agents were less effective than nimodipine. 3. The effects of nicorandil were inhibited by methylene blue but not by glibenclamide, while the effects of pinacidil and lemakalim were inhibited by glibenclamide but not by methylene blue. 4. Thus nicorandil probably causes relaxation mostly by effects on guanylate cyclase while lemakalim and pinacidil produce the same effect by action at ATP-dependent potassium channels.
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PMID:Vasodilatation of canine cerebral arteries by nicorandil, pinacidil and lemakalim. 135 69

The purpose of this study was to investigate the interactions of compounds structurally related to imidazoline at K+ channels located in the rat portal vein. Nicorandil, a K+ channel activator, dose dependently inhibited spontaneous contractions of the isolated rat portal vein. Glibenclamide (0.1-1 microM), an ATP-sensitive K+ channel blocker, competitively antagonized the response to nicorandil, whereas methylene blue (10 microM), a guanylate cyclase inhibitor, did not. Phentolamine, antazoline, tolazoline, and midaglizole also shifted the dose-response curve for nicorandil to the right in the dose range of 1-100 microM. The rank order of potency was glibenclamide much greater than phentolamine = antazoline = midaglizole greater than tolazoline. In contrast, clonidine, idazoxan, imidazole, 1-benzylimidazole, and yohimbine were ineffective. In addition, cromakalim (1-100 nM), a selective K+ channel activator, also inhibited spontaneous contractions of the rat portal vein, and this effect was antagonized by phentolamine in a similar way to that found with nicorandil. These results suggest that some 2-substituted imidazolines, including phentolamine, possibly act as K+ channel blockers, like glibenclamide, in vascular smooth muscle.
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PMID:Effects of imidazoline-related compounds on the mechanical response to nicorandil in the rat portal vein. 139 88

The spasmolytic mechanisms of nicorandil, a novel antianginal drug, were investigated using 3,4-diaminopyridine (3,4-DAP)-induced phasic contractions of isolated canine coronary arteries in comparison with those of cromakalim and pinacidil. Nicorandil (10(-4) M), cromakalim (10(-6) M) and pinacidil (10(-5) M) suppressed the phasic contractions. Pretreatment with glibenclamide (10(-6) M), a specific blocking agent of ATP-sensitive K+ channel, eliminated the suppression of phasic contractions by these drugs; glibenclamide completely eliminated the suppression by cromakalim, while the eliminations against nicorandil and pinacidil were incomplete. The recoveries of peak tensions were only 56.8% and 76.1% for nicorandil and pinacidil, respectively. Nicorandil and pinacidil may suppress the phasic contractions via K+ channel opening and additional mechanisms. Methylene blue (10(-7)-10(-5) M) alone, a guanylate cyclase inhibitor, had no effect on the suppression of phasic contractions by nicorandil. In the presence of glibenclamide (10(-6) M), however, the pretreatment with methylene blue significantly augmented the recovery of peak tension for nicorandil. These results indicate that K+ channel openers may suppress the phasic contractions induced by 3,4-DAP via ATP-sensitive K+ channels, and that additionally, nicorandil may suppress the phasic contractility through guanylate cyclase stimulation, as a nitrate.
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PMID:[The vasospasmolytic effects of nicorandil, cromakalim and pinacidil on 3,4-diaminopyridine-induced phasic contractions in canine coronary arteries as an experimental vasospasm model]. 144 82

Opening of K+ channels in cell membranes with resulting increase in K+ conductance, shifts the membrane potential in a hyperpolarizing direction towards the K+ equilibrium potential. Hyperpolarization reduces the opening probability of ion channels involved in membrane depolarization and excitation is reduced. K+ channel openers are believed to hyperpolarize smooth muscle cells by a direct action on the cell membrane. The best known members of the group are cromakalim, nicorandil and pinacidil, but several new compounds are being evaluated. In addition, it has recently been shown that also clinically well-known drugs like, e.g. diazoxide and minoxidil exhibit K+ channel opening properties. Nicorandil and new compounds containing nitro groups have a dual mechanism of action, also activating guanylate cyclase, an effect that contributes to their cardiovascular effect profile. K+ channel openers have a wide range of effects. Some of their properties and actions are summarized, and their present applications and/or potential for future application, in e.g. hypertension, angina pectoris, asthma, bladder instability, and several other disorders are discussed. It is concluded that K+ channel openning represents an interesting pharmacological principle with many potential clinical applications. However, most available drugs do not seem to have a sufficient tissue selectivity to be useful therapeutic alternatives. Before the potential of the new members of the group on clinical trials can be properly evaluated, clinical experiences are needed.
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PMID:Clinical pharmacology of potassium channel openers. 153 27

Nicorandil increases cyclic 3'5'-guanosine monophosphate (cGMP) in vascular smooth muscle. However, high concentrations are required to activate guanylate cyclase (GC). We examined the relationship between activation of GC, increases in cGMP and relaxation in canine mesenteric artery and vein, renal and coronary artery and thoracic aorta. Nicorandil (10-100 microM) relaxed in each of the blood vessels. Relaxation was associated with elevations of cGMP but independent of release of endothelium-derived relaxing factor, and inhibited by methylene blue and hemoglobin. The organic nitrate esters nitroglycerin, pentaerythritol tetranitrate, isosorbide dinitrate, 2-isosorbide mononitrate, and 5-isosorbide mononitrate each behaved in a similar manner. In each blood vessel pentaerythritol tetranitrate was the most potent and 5-isosorbide mononitrate the least potent relaxant and stimulant of cGMP. Each of the organic nitrate esters (1 microM to 1 mM) except nicorandil stimulated soluble GC activity in the presence of 10 mM cysteine. Nicorandil (EC50 38 mM) increased GC activity. Moreover, nicorandil (0.1 microM to 30 microM) did not inhibit cGMP phosphodiesterase. The EC50 for vascular relaxation was directly correlated with the EC50 for elevation of cGMP for each of the agonists in each blood vessel type. The EC50 for activation of GC was directly related to the reciprocal of the rate constant for nitric oxide formation for each of the organic nitrate esters. However, a direct correlation existed between the EC50 for activation of GC and the EC50 for 1) elevation of cGMP and 2) relaxation, for each of the organic nitrate esters except nicorandil. Thus, the high concentrations of nicorandil required to activate GC cannot account for the low concentrations required to elevate cGMP or relax smooth muscle. We postulate that nicorandil may interact with a membrane receptor or release a second messenger, distinct from nitric oxide or endothelium-derived relaxing factor, which then activates GC. This may represent a physiologic mechanism for regulation of GC activity in smooth muscle.
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PMID:Comparison of nicorandil-induced relaxation, elevations of cyclic guanosine monophosphate and stimulation of guanylate cyclase with organic nitrate esters. 167 47

In endothelium-denuded rat aortic rings, the sustained contractile effects produced by endothelin-1 (ET-1; 3.2 nM) were concentration-dependently overcome by nicorandil, aprikalim (RP 52891), a specific K+ channel opener, and nitroglycerin, a stimulant of guanylate cyclase (EC50: 2.55 +/- 0.06, 0.37 +/- 0.05 and 0.3 +/- 0.008 microM respectively, n = 13-16/group). The decontractant activity of aprikalim was not affected by the guanylate cyclase inhibitor methylene blue (10 microM), whereas it was markedly antagonized by glibenclamide (1 microM) (pKB: 7.19 +/- 0.15), an antagonist of ATP-gated K+ channels in pancreatic beta cells. This sulfonylurea failed to modify nitroglycerin-induced effects, but slightly reduced (10-15%) those produced by high concentrations of nicorandil. By contrast, methylene blue significantly displaced (4-fold) the control concentration-vasorelaxant response curves obtained with nitroglycerin and nicorandil. Zaprinast (20 microM), an inhibitor of soluble low Km cyclic GMP phosphodiesterase, enhanced the effects of nitroglycerin and nicorandil but did not alter those of aprikalim. Nicorandil relaxed ET-1-contracted rings from micropig left circumflex coronary artery with an EC50 of 24 +/- 2.8 microM (n = 7); this effect was antagonized by methylene blue (10 microM) and glibenclamide (3 microM) (2- and 4-fold dextral shift of the control concentration-response curve, respectively). In rat Langendorff-perfused heart with base-line coronary flow reduced by the addition of ET-1 to the perfusion medium, nicorandil and aprikalim increased coronary flow, while nitroglycerin did not. The vasodilator effects of the two compounds were also inhibited by glibenclamide (pKB congruent to 7).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nicorandil: differential contribution of K+ channel opening and guanylate cyclase stimulation to its vasorelaxant effects on various endothelin-1-contracted arterial preparations. Comparison to aprikalim (RP 52891) and nitroglycerin. 168 78

Nicorandil and cromakalim relaxed rat aortic rings denuded of endothelium and precontracted with a low concentration of KCl (25 mM). Glibenclamide (1 microM) strongly antagonized only the effects of cromakalim while those of nicorandil were inhibited by methylene blue, an inhibitor of the soluble form of guanylate cyclase. High concentrations of nicorandil also produced vasorelaxation in aortic preparations contracted with 55 mM KCl, whereas cromakalim did not. In pentobarbital-anesthetized rats a 20-min i.v. infusion of cromakalim (5 micrograms/kg/min) or nicorandil (100 micrograms/kg/min) similarly decreased the mean carotid artery blood pressure. These effects, as well as the antihypertensive activity of nicorandil (5.0 mg/kg p.o.) and cromakalim (0.25 mg/kg p.o.) in spontaneously hypertensive rats were markedly inhibited by glibenclamide (20 mg/kg i.v.). Finally, glibenclamide (4 mg/kg i.v.) displaced to the right the control dose-coronary vasodilatory response curve to nicorandil injected into the left circumflex coronary artery of pentobarbital-anesthetized dogs. In conclusion, these results indicate that in a rat conductive vessel (aorta) nicorandil acts exclusively like nitrates, that is, it stimulates guanylate cyclase, and in resistance vessels (in the intact rat or dog coronary vascular bed) it opens K+ channels, as does cromakalim. Thus, nicorandil can be expected to have a broader spectrum of antianginal activity than drugs with a single mechanism of action. Additionally, as mentioned in the discussion section, substantial evidence exists that K+ channel opening can also afford marked cardioprotection against ischemia.
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PMID:K+ channel opening mediates the vasorelaxant effects of nicorandil in the intact vascular system. 183 48

Nicorandil (SG-75) is a new organic nitrate with pronounced vasodilator properties. We studied whether nicorandil, in analogy to other nitrovasodilatators, exerted its relaxing effects on vascular smooth muscle by stimulating guanylate cyclase, and whether this effect was susceptible to tolerance development. Dose-response curves for the relaxing and cyclic guanosine monophosphate (cGMP) increasing effects of nicorandil were obtained in isolated strips of bovine coronary arteries and compared with those of other nitrovasodilatators. It was found that nicorandil dose-dependently relaxed the strips precontracted with 26.7 mM K+ and that this effect was closely associated with increases in cGMP levels (measured by RIA under various conditions). The correlation between relaxation and rises in cGMP was steeper than with other nitrovasodilatators, suggesting that nicorandil, in addition to its cGMP-mediated effect, also relaxed vascular smooth muscle by a cGMP independent mechanism. In contrast to nitroglycerin (NG), nicorandil caused little development of tolerance or cross-tolerance toward ISDN or IS-5-MN when tested after preincubation of the strips toward the respective substance. Pretreatment with N-acetylcysteine during the preincubation period prevented tolerance towards nicorandil. The results indicate that the relaxant effects of nicorandil consist of a larger cGMP-mediated component and a smaller one which is independent of this nucleotide.
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PMID:Cyclic GMP in nicorandil-induced vasodilatation and tolerance development. 244 21

Nicorandil, a compound having structural similarities to some of the organic nitrates, was studied for its mechanism of vasodilation. Nicorandil is thought to be a K+ channel opening agent. However, little is known about its receptor activation profile, its endothelial dependence, and its effects in atherosclerotic vessels. Nicorandil, at 0.2 to 5 x 10(-6) M, relaxed norepinephrine precontracted rabbit aortic rings in a concentration-dependent manner. Moreover, nicorandil relaxed aortic rings to the same extent in the presence and absence of an intact endothelium. However, nicorandil's effect was diminished in aortic rings from atherosclerotic rabbits. The vasorelaxation action of nicorandil was unaffected by the cyclooxygenase inhibitor ibuprofen or the lipoxygenase inhibitor propyl gallate, suggesting that nicorandil does not act via the release of a vasodilator eicosanoid. Although the nicorandil effect was not influenced by atropine, a muscarinic receptor antagonist, it was significantly attenuated by methylene blue, a guanyl cyclase inhibitor. Thus, nicorandil has some properties in common with organic nitrates and with K+ channel activators but appears to be a unique type of vasodilator.
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PMID:Studies on the mechanism of the vasodilator action of nicorandil. 245 46


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