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)

The relaxant effect on smooth muscle of nitro compounds is suggested to be linked with the increase in the tissue level of cyclic GMP by activating guanylate cyclase. In this study, we investigated the effects of nipradilol, a new beta-blocker, which has NO2 residue in the molecular structure, and isosorbide dinitrate (ISDN) on guinea pig tracheal smooth muscle in comparison with the effect of propranolol. Nipradilol and ISDN showed dose-dependent relaxant effects on leukotriene (LT) D4-induced contraction of tracheal smooth muscle, though propranolol had no effect. 8-Bromo-cyclic GMP also showed a relaxant effect dose dependently. Nipradilol and ISDN elevated cyclic GMP levels in tracheal tissue dose dependently; however, propranolol caused no change in cyclic GMP levels. From these results, it is suggested that nipradilol relaxes LTD4-induced contraction of tracheal smooth muscle by increasing the tissue level of cyclic GMP.
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PMID:Effect of nipradilol, a new beta-blocker, on leukotriene D4-induced contraction in guinea pig tracheal smooth muscle. 290 36

1. Contribution of cyclic GMP generation to the relaxation by nipradilol of vascular smooth muscle was studied in the isolated rabbit aorta contracted by phenylephrine (10(-7) M) or prostaglandin F2 alpha (PGF2 alpha, 3 x 10(-6) M). 2. Nipradilol-induced relaxation in both contractions and increase in cyclic GMP content were inhibited by methylene blue (10(-5) M). 3. The relations between the increase in cyclic GMP and the relaxation produced by nipradilol and nitroglycerin were fitted to sigmoid curves. The increase in cyclic GMP at 50% relaxation by nipradilol was smaller than that by nitroglycerin (1.2-fold increase as against 3-fold increase). 4. These results suggest a smaller contribution of cyclic GMP generation through activation of soluble guanylate cyclase to nipradilol-induced relaxation in the rabbit aorta.
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PMID:Contribution of cyclic GMP generation to the relaxation by nipradilol in the rabbit aorta. 771 70

Nipradilol is a beta-adrenoreceptor blocking agent, whose structure contains an NO2 group. Thus, it is possible that it modulates the function of glomerular mesangial cells through the activation of soluble guanylate cyclase. To prove this hypothesis, we examined the effect of nipradilol on soluble guanylate cyclase, intracellular cyclic guanosine monophosphate (cGMP) accumulation, and the mitogenesis of cultured rat glomerular mesangial cells. Nipradilol increased intracellular cGMP accumulation in a dose-dependent manner through the activation of soluble guanylate cyclase. Furthermore, nipradilol inhibited the incorporation of [3H]thymidine into the mesangial cells stimulated by 2.5% fetal bovine serum in a dose-dependent manner. These results indicate that nipradilol may modulate mesangial cell function through an increase in intracellular cGMP resulting from the activation of soluble guanylate cyclase.
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PMID:Nipradilol inhibits rat mesangial cell mitogenesis through the activation of soluble guanylate cyclase. 809 73

The effects of nipradilol, an ocular hypotensive drug, on isolated canine retinal central arteries and on retinal arterioles in vivo were investigated. Nipradilol (10(-9) to 10(-5) mol/l) produced a dose-related relaxation of the arterial strips contracted with prostaglandin F2 alpha which was not influenced by timolol or indometacin. The median effective concentration of this drug was five times that of glycerol trinitrate (GTN). The nipradilol-induced relaxation in the endothelium-intact strips was not influenced by NG-nitro-L-arginine, a nitric oxide synthase inhibitor, but was abolished by oxyhemoglobin and methylene blue. Treatment with high concentrations of sodium nitroprusside abolished the response to nipradilol, as observed with that to GTN. Retinal arterial strips responded to isoproterenol with a slight relaxation which was depressed by nipradilol. In anesthetized dogs, intra-arterial injections of nipradilol dilated the retinal arterioles in the ocular fundus; the dilator potency was approximately one fifth that of GTN. It is concluded that nipradilol dilates canine retinal arteries in vitro and arterioles in vivo, possibly due to activation of soluble guanylate cyclase and increased production of cyclic guanosine monophosphate that are associated with nitric oxide liberated from the molecule itself in the tissue but not derived from the endothelium and perivascular nerve. Beta adrenoceptor blocking action was determined in the retinal artery.
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PMID:Canine retinal arterial and arteriolar dilatation induced by nipradilol, a possible glaucoma therapeutic. 899 Apr 89

Nipradilol (CAS 81486-22-8), a vasodilatory beta-blocker, has been shown to dilate smaller vessels than nitroglycerin does, and the vasodilative effects of nipradilol have been reported to be less mediated by cyclic GMP (guanosine monophosphate) than those of nitroglycerin. To test the hypothesis that cyclic GMP-independent potassium channels have a larger role in nipradilol-induced aortic relaxation than cyclic GMP-dependent mechanisms, the effects of a potassium channel blocker, tetraethylammonium (TEA, CAS 56-34-8), and of a guanylate cyclase inhibitor, methylene blue (MB, CAS 61-73-4), on nipradilol-induced aortic relaxation were investigated and compared with those on nitroglycerin-induced aortic relaxation in isolated rat aortic rings. Relaxation response was expressed as percent relaxation, which is a percentage of the tension developed by 10(-7) mol/l norepinephrine. Nitroglycerin and nipradilol similarly relaxed the aortic ring in a concentration-dependent manner (10(-9)-10(-4) mol/l). In contrast, desnitronipradilol, a nipradilol analogue which has no nitroxy group, induced almost no aortic relaxation. TEA at 10(-3) mol/l, which is selective for calcium-activated potassium channels, inhibited the aortic relaxation induced by nipradilol (10(-5) mol/l) to a significantly greater extent than that induced by nitroglycerin (10(-5) mol/l) (% relaxation: 30.0 +/- 6.8 vs. 51.1 +/- 6.1%, p < 0.05). MB (10(-5) mol/l) suppressed the relaxation by nitroglycerin slightly but not significantly more than that by nipradilol. (% relaxation: 54.7 +/- 9.9 vs. 64.6 +/- 5.7%). The combination of TEA and MB almost completely eliminated the relaxation induced by nipradilol as well as by nitroglycerin. Thus, cyclic GMP-independent calcium activated potassium channels may be more involved in the aortic relaxation by nipradilol than that by nitroglycerin in rats.
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PMID:Relative importance of calcium-activated potassium channels in nipradilol-induced aortic relaxation in rats. 1141 38

Effects of nipradilol, a beta-adrenoceptor blocker with a nitroxy moiety, on phosphoenolpyruvate carboxykinase (PEPCK) gene transcription were examined using a rat hepatoma cell line, H4IIE cells. Dexamethasone was employed as an enhancer of PEPCK gene transcription. Nipradilol, but not timolol (a beta-blocker without a nitroxy moiety), attenuated PEPCK gene transcription both in the control and the dexamethasone-treated cells. The effects of nipradilol were eradicated by methylene blue (an inhibitor of cellular guanylate cyclase). Nipradilol is a unique beta-blocker that suppresses PEPCK gene transcription in hepatocytes likely through liberation of nitric oxide and resultant activation of guanylate cyclase.
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PMID:Effects of nipradilol, a nitric oxide-releasing beta-adrenoceptor blocking agent, on phosphoenolpyruvate carboxykinase gene transcription in a rat hepatoma cell line. 1167 3

We examined the effect of nipradilol on contraction of the posterior ciliary artery induced by high potassium or norepinephrine and on cyclic GMP (cGMP) levels in the posterior ciliary artery of dogs. Nipradilol caused dose-dependent relaxation of KCl-and norepinephrine-induced contractions of posterior ciliary artery. The relaxant effect of nipradilol on norepinephrine-contracted ciliary artery was significantly greater than that on KCl-contracted ciliary artery. In KCl-contracted ciliary artery, N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME, 10(-4) M) did not alter the relaxant effect of nipradilol, whereas 1H-1,2,4-oxadiazolo-4,3-a-quinoxalin-1-one (ODQ, 10(-6) M) significantly inhibited this effect. Ethacrynic acid at 10(-5) M, sulfasalazine at 10(-4) M and S-decylglutathione at 10(-4) M (glutathione S-transferase inhibitors) did not inhibit the relaxant effect of nipradilol. In addition, nipradilol produced dose-dependent increases in cGMP levels in the canine posterior ciliary artery. These findings indicate that nipradilol-induced vasorelaxation in the canine posterior ciliary artery occurs via stimulation of the guanylyl cyclase-cGMP pathway.
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PMID:Nipradilol induces vasodilation of canine isolated posterior ciliary artery via stimulation of the guanylyl cyclase-cGMP pathway. 1209 33

Nipradilol is a new antiglaucoma ophthalmic agent used in Japan. Topical application of nipradilol is reported to increase ocular blood flow. To investigate the action of this drug, we studied the effect of nipradilol on the isolated rabbit ciliary artery. Under the dissecting microscope, ciliary arteries were prepared from rabbit eyes and mounted on a myograph system. The effects of nipradilol on the isolated rabbit ciliary artery were investigated using isometric tension recording methods. Nipradilol provoked a dose-dependent (10 microM-1m M) relaxation in ciliary arteries that were pre-contracted with high-K solutions (K(+): 100.7 m M). It also inhibited the amplitude of smooth muscle contraction evoked by field stimulation. Nipradilol was more effective in relaxing phenylephrine-induced contraction (EC(50): 21.6+/-16.3 microM) compared to high-K solution-induced contractions (EC(50): 230+/-130 microM). Application of N(w)-nitro- L -arginine methylester (300 microM), a nitric oxide (NO) synthase inhibitor, or denudations of endothelium by rubbing the inner surface with a scalp hair did not affect this relaxation. However, NO scavenger carboxy-PTIO (1m M) or methylene blue (10 microM), a guanylate cyclase inhibitor, inhibited the nipradilol-induced relaxation. These results indicate that nipradilol relaxes the rabbit ciliary artery by two different mechanisms. First, the relaxation is due to the NO produced by denitrification of nipradilol itself. Second, nipradilol may act as an alpha-adrenergic antagonist. These actions of nipradilol may explain the mechanisms of increased ocular blood flow in vivo.
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PMID:Vasodilatory effects of nipradilol, an alpha- and beta-adrenergic blocker with nitric oxide releasing action, in rabbit ciliary artery. 1247 Sep 68