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

---

Query: EC:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
...
PMID:Effects of imidazoline-related compounds on the mechanical response to nicorandil in the rat portal vein. 139 88

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.
...
PMID:K+ channel opening mediates the vasorelaxant effects of nicorandil in the intact vascular system. 183 48

Glibenclamide enhanced the activity in the rat of guanylate cyclase in a number of extra-pancreatic tissues. Thus, glibenclamide enhanced guanylate cyclase activity in vitro two- to threefold in liver, kidney, heart, spleen and colon at a concentration of 1 mumol/l. Dose-response curves of glibenclamide on hepatic guanylate cyclase revealed that more than half-maximal stimulation was observed at a concentration as low as 10 nmol/l (p less than 0.001) and no stimulation of guanylate cyclase was seen when the concentration was decreased to 1 nmol/l. Maximal enhancement was seen at 100 nmol/l of glibenclamide. Varying the concentration of the guanylate cyclase co-factor manganese had no effect on the glibenclamide enhancement of guanylate cyclase. In addition to the increased insulin receptors found recently in monocytes and fibroblasts, the present findings may help explain the extra-pancreatic effects of glibenclamide and possibly of other sulphonylurea drugs.
...
PMID:Direct effect of glibenclamide on guanylate cyclase activity in the rat in vitro. 612 72

The ionic mechanisms by which nitric oxide (NO) or a related compound mediates the inhibitory junction potentials (IJPs) of the opossum esophageal circular smooth muscle were studied using microelectrodes and double sucrose gap. The NO donors, 3-morpholino-sydnonimine hydrochloride and sodium nitroprusside, induced 15- to 20-mV hyperpolarizations that reversed near the potassium equilibrium potential as did the IJPs. They inhibited the IJPs and decreased electrotonic potentials (increased conductance) even during restoration of the resting membrane potential by application of depolarizing current. Quinine was more efficacious than apamin in inhibiting the IJPs or NO donor hyperpolarizations, whereas the other K+ channel blockers tested (tetraethylammonium, charybdotoxin, 4-aminopyridine, Cs+, and glibenclamide) were without effect. Glibenclamide abolished the hyperpolarizing effects of the K+ channel opener BRL-34915. Low Cl- Krebs (isethionate substitutions) caused hyperpolarizations, increased electrotonic potentials, and reduced IJPs. The neural blockers, tetrodotoxin, omega-conotoxin GVIA, and N omega-nitro-L-arginine methyl ester, inhibited IJPs but not the responses to NO donors, indicating a postjunctional effect. Methylene blue and cystamine, soluble guanylate cyclase inhibitors, suppressed IJPs and responses to NO donors. We conclude that NO mediates esophageal IJPs, which depend on guanosine 3',5'-cyclic monophosphate elevation and activation of quinine- and apamin-sensitive K+ channels.
...
PMID:K+ channel opening mediates hyperpolarizations by nitric oxide donors and IJPs in opossum esophagus. 776 67

Nitric oxide (NO) released from nonadrenergic-noncholinergic (NANC) nerves seems to be a principal mediator of the relaxation of penile erectile tissue necessary for erection, and drugs acting by release of NO have been shown to produce erection when injected intracorporeally into impotent patients. By producing hyperpolarization, K+ channel openers are effective in relaxing isolated penile erectile tissue from rabbit and man, and can produce tumescence and erection when injected intracorporeally into animals. Nicorandil is classified as a K+ channel opener, but it also acts as a donor of NO. In the present study, the effects of nicorandil on isolated preparations from human corpus cavernosum (CC) and deep cavernous artery (Acc) were compared with those of cromakalim (K+ channel opener) and SIN-1 (NO donor). Nicorandil produced a concentration-dependent relaxation of CC and Acc preparations. The relaxations obtained at the highest nicorandil concentration used (10(-4) M.) were 75 +/- 3% and 66 +/- 4% in CC preparations contracted by noradrenaline and endothelin-1, respectively. The corresponding effects in Acc preparations were 70 +/- 14% and 73 +/- 5%. Glibenclamide (blocking ATP-dependent K+ channels) significantly reduced the nicorandil-induced relaxation in CC, but not in Acc. Methylene blue (believed to block soluble guanylate cyclase) reduced nicorandil's relaxant effect in CC, although statistical significance was not obtained. NG-nitro-L-arginine 10(-4) M. (NO synthase inhibitor) did not significantly influence the effect of nicorandil on precontracted preparations in either tissue. In CC preparations contracted by electrical field stimulation, nicorandil and cromakalim concentration dependently inhibited the responses. This effect was significantly counteracted by glibenclamide. It is concluded that nicorandil is effective in relaxing human CC chiefly by its K+ channel opening action, and to some extent by its ability to release NO. For nicorandil's relaxing effect on Acc, ATP dependent K+ channels seem to be of limited importance. If effective in impotent patients, the drug may represent a new, interesting approach to the treatment of erectile dysfunction.
...
PMID:Effects of nicorandil on human isolated corpus cavernosum and cavernous artery. 812 2

We examined the hypothesis that dilatation of the basilar artery in response to activation of ATP-sensitive potassium channels is impaired in stroke-prone spontaneously hypertensive rats (SHRSP). Changes in basilar artery diameter in response to aprikalim, a direct activator of ATP-sensitive potassium channels, were measured in anesthetized SHRSP and normotensive Wistar-Kyoto (WKY) rats through a cranial window. Topical application of aprikalim increased basilar artery diameter in WKY rats. Glibenclamide, a selective inhibitor of ATP-sensitive potassium channels, abolished aprikalim-induced vasodilatation. Thus, ATP-sensitive potassium channels are functional in the basilar artery of WKY rats in vivo. Aprikalim (10(-6) mol/L) dilated the basilar artery by 31 +/- 5% (mean +/- SEM) in WKY rats but only 5 +/- 1% in SHRSP. The concentration-response curve to aprikalim in SHRSP was significantly shifted to the right, but the response to the highest concentration of aprikalim (10(-5.5) mol/L) was similar in SHRSP and WKY rats. Vasodilatation in response to norepinephrine was also impaired in SHRSP. Dilator responses of the basilar artery to forskolin, a direct activator of adenylate cyclase, and nitroprusside, a direct activator of guanylate cyclase, were normal in SHRSP. The findings suggest that dilatation of the basilar artery in response to direct activation of ATP-sensitive potassium channels is impaired in SHRSP compared with WKY rats in vivo.
...
PMID:ATP-sensitive potassium channels in the basilar artery during chronic hypertension. 822 27

1. The involvement of nitric oxide (NO) and the signal transduction mechanisms mediating neurogenic relaxations were investigated in deep intracavernous penile arteries with an internal lumen diameter of 600-900 microns, isolated from the corpus cavernosum of young horses. 2. The presence of nitric oxide synthase (NOS)-positive nerves was examined in cross and longitudinal sections of isolated penile arteries processed for NADPH-diaphorase (NADPH-d) histochemistry. NADPH-d-positive nerve fibres were observed in the adventitia-media junction of deep penile arteries and in relation to the trabecular smooth muscle. 3. Electrical field stimulation (EFS) evoked frequency-dependent relaxations of both endothelium-intact and denuded arterial preparations treated with guanethidine (10(-5) M) and atropine (10(-7) M), and contracted with 10(-6) M phenylephrine. These EFS-induced relaxations were tetrodotoxin-sensitive indicating their non-adrenergic non-cholinergic (NANC) neurogenic origin. 4. EFS-evoked relaxations were abolished at the lowest frequency (0.5-2 Hz) and attenuated at higher frequencies (4-32 Hz) by the NOS inhibitor, NG-nitro-L-arginine (L-NOARG, 3 x 10(-3) M). This inhibitory effect was antagonized by the NO precursor, L-arginine (3 x 10(-3) M). NG-nitro-D-arginine (10(-4) M) did not affect the relaxations to EFS. 5. Incubation with either the NO scavenger, oxyhaemoglobin (10(-5) M), or methylene blue (10(-5) M), an inhibitor of guanylate cyclase activation by NO, caused significant inhibitions of the EFS-evoked relaxations, and while oxyhaemoglobin abolished the relaxations to exogenously added NO (acidified sodium nitrite, 10(-6) - 10(-3) M), there still persisted a relaxation to NO of 24.4 +/- 5.1% (n = 6) in the presence of methylene blue. 6. Glibenclamide (3 x 10(-6) M), an inhibitor of ATP-activated K(+)-channels, did not alter the relaxations to either EFS-stimulation or NO, while the blocker of Ca(2+)-activated K(+)-channels, charybdotoxin (3 x 10(-8) M), caused a significant inhibition of both the electrically-induced relaxations and the relaxations to exogenously added NO. Furthermore, charybdotoxin blocked relaxations induced by the cell permeable analogue of cyclic GMP, 8-bromo cyclic GMP (8 Br-cyclic GMP). 7. These results suggest that relaxations of horse deep penile arteries induced by NANC nerve stimulation involve mainly NO or a NO-like substance from nitrergic nerves. NO would stimulate the accumulation of cyclic GMP followed by increases in the open probability of Ca(2+)-activated K(+)-channels and hyperpolarization leading to relaxation of horse penile arteries.
...
PMID:Involvement of nitric oxide in the non-adrenergic non-cholinergic neurotransmission of horse deep penile arteries: role of charybdotoxin-sensitive K(+)-channels. 859 Sep 74

1. The aims of this study were to compare in the rat isolated perfused lung preparation, the dilator actions of nicorandil, pinacidil and nitroglycerin on the hypoxic pulmonary pressure response with or without hypercapnic acidosis and to investigate the possible involvement of K channels and EDRF in these effects. 2. Isolated lungs from male Wistar rats (260-320 g) were ventilated with 21%O2 + 5%CO2 + 74%N2 (normoxia) or 5%CO2 + 95%N2 (hypoxia) and perfused with a salt solution supplemented with ficoll and gassed with 40%CO2 + 60%N2 to produce hypercapnic acidosis. Glibenclamide (1 microM), charybdotoxin (0.1 microM), NG-nitro-L-arginine methyl ester (L-NAME, 100 microM) and methylene blue (30 microM) were used to block KATP channels, KCa channels, EDRF synthesis and guanylate cyclase, respectively. 3. Hypoxic pressure response was significantly increased by hypercapnic acidosis (+115%, P < 0.001), L-NAME (+111%, P < 0.001), methylene blue (+100%, P < 0.05) but not by glibenclamide or charybdotoxin. In contrast none of these inhibitors affected the hypoxic hypercapnic acidosis response. 4. Nicorandil, pinacidil and nitroglycerin caused relaxation during the hypoxic pressure response and hypoxic hypercapnic acidosis response. Nicorandil was more potent in the latter. Glibenclamide inhibited the relaxant effects of nicorandil and pinacidil but not those of nitroglycerin during hypoxia alone. In contrast, glibenclamide inhibited the relaxant effects of the three drugs during hypoxia + hypercapnia. Charybdotoxin inhibited the relaxant effect of pinacidil during normocapnia and hypoxia but not those of nicorandil or nitroglycerin. Methylene blue inhibited partially the dilator response to pinacidil but did not modify the effects of nitroglycerin or nicorandil. 5. It is concluded that in the rat isolated lung preparation, EDRF limits hypoxic pulmonary vasoconstriction but not hypoxic vasoconstriction potentiated by hypercapnic acidosis, whereas KATP or KCa channels are not involved in either case. Nicorandil and pinacidil dilate pulmonary vessels mainly through KATP channels but the effects of pinacidil may also involve an additional mechanism of action through KCa channels. Finally it is suggested that nitroglycerin may partly exert its relaxant effects through KATP channels.
...
PMID:Comparison of the effects of nicorandil, pinacidil and nitroglycerin on hypoxic and hypercapnic pulmonary vasoconstriction in the isolated perfused lung of rat. 864 7

1. The mechanisms by which nicorandil causes relaxation of rat isolated small mesenteric arteries mounted on a Mulvany myograph was investigated by use of a combination of putatively mechanism-specific antagonists. 2. In arteries precontracted by the thromboxane-mimetic, U46619, the EC50 for cromakalim and levcromakalim-induced relaxation curves were raised by 36 and 17 fold by glibenclamide (3 microM) while the EC50 for nicorandil-induced relaxation was unaffected by either glibenclamide or methylene blue (10 microM). A combination of these antagonists raised the EC50 for nicorandil by 8 fold. 3. In U46619-contracted arteries, nifedipine (100 nM) did not affect the cromakalim relaxation curve but it raised the EC50 for nicorandil by 5 fold. The combination of methylene blue, glibenclamide and nifedipine further inhibited the maximum relaxation to nicorandil. 4. In separate experiments, membrane potential (Em) and force responses were measured simultaneously. In arteries depolarized and contracted by U46619 both nicorandil and cromakalim repolarized (delta Em, 35 mV) and relaxed (100%) the vessels. Glibenclamide (3 microM) did not alter the relaxation-concentration curve to nicorandil but reduced the maximum repolarization to delta 10.8 mV. In contrast to Em and relaxation-response curves to cromakalim were shifted to the right by glibenclamide by 30-100 fold. 5. In unstimulated arteries, nicorandil (but not cromakalim) -induced hyperpolarization was significantly antagonized by methylene blue (10 microM) (6.6 fold rightward shift) or nifedipine (100 nM) (2.6 fold). In depolarized arteries (U46619), nifedipine but not methylene blue inhibited the nicorandil-induced hyperpolarization. 6. In arteries precontracted to 50% tissue maximum by either KCl or U46619, nifedipine (100 nM) relaxed the artery but failed to repolarize the Em. Presumably voltage-operated calcium channels (VOCC) were blocked preventing contraction but the artery remained depolarized, presumably through non VOCC mechanisms. 7. These data suggest that nicorandil may relax small arteries through 3 parallel pathways, (i) NO-donor mediated stimulation of guanylate cyclase and increase in cyclic GMP, (ii) K+ATP channel opening, and (iii) nifedipine-sensitive VOCC inhibition. Em data suggest that nicorandil-induced repolarization is caused principally through opening K+ATP channels. Blockade of this hyperpolarization by glibenclamide is not sufficient to alter the relaxation, indicating dissociation of nicorandil-induced changes in membrane potential and relaxation. 8. These results highlight the 'chameleon' actions of nicorandil where there is no apparent association of Em repolarization with relaxation, in contrast to the parallel responses for cromakalim.
...
PMID:Analysis of relaxation and repolarization mechanisms of nicorandil in rat mesenteric artery. 898

1. The present study was designed to investigate whether potassium (K+) channels are involved in the relaxations to nitric oxide (NO) of pig intravesical ureteral preparations suspended in organ baths for isometric tension recordings. In ureteral strips treated with guanethidine (10(-5) M) and atropine (10(-7) M) to block adrenergic neurotransmission and muscarinic receptors, respectively, NO was either released from nitrergic nerves by electrical field stimulation (EFS, 0.5-10 Hz., 1 ms duration, 20 s trains), or exogenously-applied as an acidified solution of sodium nitrite (NaNO2, 10(-6)-10(-3) M). 2. Incubation with an inhibitor of guanylate cyclase activation by NO, methylene blue (10(-5) M) did not change the basal tension of intravesical ureteral strips but inhibited the relaxation induced by EFS or exogenous NO on ureteral preparations contracted with the thromboxane analogue U46619 (10(-7) M). 3. Incubation with charybdotoxin (3 x 10(-8) M) and apamin (5 x 10(-7) M), which are inhibitors of large and small conductance calcium (Ca2+)-activated K+ channels, respectively, did not modify basal tension or the relaxations induced by EFS and exogenous NO. Treatment with charybdotoxin or apamin plus methylene blue (10(-5) M) significantly reduced the relaxations to EFS and exogenous NO. However, in both cases the reductions were similar to the inhibition evoked by methylene blue alone. The combined addition of charybdotoxin plus apamin did not change the relaxations to EFS or exogenously added NO of the porcine intravesical ureter. 4. Cromakalim (10(-8) 3 x 10(-6) M), an opener of ATP-sensitive K+ channels, evoked a dose-dependent relaxation with a pD2 of 7.3 +/- 0.2 and maximum relaxant effect of a 71.8 +/- 4.2% of the contraction induced by U46619 in the pig intravesical ureter. The blocker of ATP-sensitive K+ channels, glibenclamide (10(-6) M), inhibited markedly the relaxations to cromakalim. 5. Glibenclamide (10(-6) M) had no effect on the basal tone of ureteral preparations but significantly reduced the relaxations induced by both EFS and exogenous NO. Combined treatment with methylene blue (10(-5) M) and glibenclamide (10(-6) M) did not exert an effect greater than that of methylene blue alone on either EFS- or NO-evoked relaxations of the pig ureter. 6. The present results suggest that NO acts as an inhibitory neurotransmitter in the pig intravesical ureter and relaxes smooth muscle through a guanylate cyclase-dependent mechanism which seems to favour the opening of glibenclamide-sensitive K+ channels.
...
PMID:Involvement of a glibenclamide-sensitive mechanism in the nitrergic neurotransmission of the pig intravesical ureter. 905 Dec 98


1 2 3 Next >>

---