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 effects of a monoclonal antibody (B8E5) directed against the second extracellular loop of the muscarinic M(2) receptor were studied on the L-type Ca(2+) currents (I(Ca,L)) of guinea pig ventricular myocytes using the whole cell patch-clamp technique. Similar to carbachol, B8E5 reduced the isoproterenol (ISO)-stimulated I(Ca,L) but did not significantly affect basal I(Ca,L). Atropine blocked the inhibitory effect of B8E5. The electrophysiological parameters of ISO-stimulated I(Ca,L) were not modified in presence of B8E5. Inhibition of I(Ca,L) by B8E5 was still observed when intracellular cAMP was either enhanced by forskolin or maintained constant by using a hydrolysis-resistant cAMP analog (8-bromoadenosine 3',5'-cyclic monophosphate) or by applying the phosphodiesterase inhibitor IBMX. The effect of B8E5 was mimicked by 8-bromoguanosine 3',5'-cyclic monophosphate, a potent stimulator of cGMP-dependent protein kinase, and prevented by a selective inhibitor of nitric oxide-sensitive guanylyl cyclase [1H-(1,2,4)oxadiazolo[4,3-a]quinoxaline-1-one]. These results indicate that the antibody B8E5 inhibits the beta-adrenergic-stimulated I(Ca,L) through activation of the M(2) muscarinic receptor and further suggest that the antibody acts not via the classical pathway of decreasing intracellular cAMP, but rather by increasing cGMP.
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PMID:cGMP-mediated inhibition of cardiac L-type Ca(2+) current by a monoclonal antibody against the M(2) ACh receptor. 1154 62

In the trigone (three portions) and proximal urethra isolated from castrated male pigs, transmural electrical stimulation (0.5-10 Hz) induced no or slight contractions followed by frequency-related relaxations. Atropine suppressed the contraction and potentiated the relaxation. N(G)-nitro-L-arginine methylester (L-NAME), a nitric oxide (NO) synthase inhibitor, depressed or abolished the relaxation induced by low frequency stimulation, but only slightly attenuated the response to high frequency stimulation. L-Arginine reversed the inhibitory effect. L-NAME-sensitive relaxation by 1 Hz stimulation was abolished by 1H-(1,2,4)oxadiazolo-(4,3-a)quinoxalin-1-one (ODQ), a guanylate cyclase inhibitor. Release of NO by nerve stimulation to trigonal strips was determined by increased formation of cyclic GMP in the incubation media containing guanylate cyclase and GTP. L-NAME-resistant relaxation by 10 Hz stimulation was not impaired by ODQ, capsaicin, chymotrypsin, K(+) channel inhibitors and beta-adrenoceptor antagonists. Similar results were obtained in the trigone and urethra from normal male and female pigs. Detrusor muscle responded to nerve stimulation with contraction followed by slight relaxation. Relaxations at 1 and 10 Hz stimulation under treatment with atropine and alpha,beta-methylene ATP were partially attenuated by L-NAME. It is concluded that there is no significant difference in the inhibitory responses, sensitive and resistant to L-NAME, to nerve stimulation in the trigone and proximal urethra from castrated and non-castrated male and female pigs. Relaxations to stimulation at 1 Hz seem to be mediated exclusively by neurogenic NO and cyclic GMP generation, whereas those to 10 Hz stimulation is mainly associated with non-NO relaxing factor(s), peptides, K(+) channel openers and beta-adrenoceptor agonist being unlikely involved.
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PMID:Functional role of inhibitory and excitatory nerves in the porcine lower urinary tract. 1245 May 73

1-Hydroxy-2, 3, 5-trimethoxyxanthone (HM-1) is a xanthone isolated from Halenia elliptica, a Tibetan medicinal herb. HM-1 (0.33-42.1 microM) produced a concentration-dependent relaxation in rat coronary artery rings pre-contracted with 1 microM 5-hydroxytryptamine (5-HT), with an EC(50) of 1.67+/-0.27 microM. Removal of the endothelium significantly affected the vasodilator potency of HM-1, resulting in 46% decrease in E(max) value. The endothelium-dependent effects of HM-1 was confirmed when its vasorelaxant effect was inhibited after addition of nitric oxide synthase (NOS) inhibitor N(omega)-nitro-l-arginine methyl ester (100 microM) or the soluble guanylate cyclase inhibitor 1H-[1, 2, 4] oxadiazolo [4,3-alpha] quinoxalin-1-one (ODQ, 10 microM). Atropine (100 nM), flurbiprofen (10 microM), propranolol (100 microM), pyrilamine (10 microM), cimetidine (10 microM) and SQ22536 (100 microM) had no effect on the vasorelaxant activity of HM-1 indicated the non-involvement of other receptor/enzyme systems. In endothelium-denuded coronary artery rings, the vasorelaxant effect of HM-1 was unaffected by potassium channel blockers such as tetraethylammonium (10 mM), iberiotoxin (100 nM), barium chloride (100 microM) and 4-aminopyridine (1 mM). The involvement of Ca(2+) channel in 5-HT-primed artery ring preparations incubated with Ca(2+)-free buffer was confirmed when HM-1 (9.93 microM) partially abolished the CaCl(2)-induced vasoconstriction (87% inhibition in intact-endothelium artery rings; 50% inhibition in endothelium-denuded rings). In the KCl-primed preparations incubated with Ca(2+)-free buffer, HM-1 (9.93 microM) produced a 27.3% inhibition in endothelium-denuded rings. HM-1 (3.31-33.1 microM) had minimal relaxant effects (14.4%-20.3%) on the contractile response generated by 10 microM phorbol 12,13-diacetate (PDA) in Ca(2+)-free solutions, suggesting minimal effects on intracellular Ca(2+) mechanisms. These findings suggest the vasodilator action of HM-1 involved both an endothelium-dependent mechanism involving NO and an endothelium-independent mechanism by inhibiting Ca(2+) influx through L-type voltage-operated Ca(2+) channels; a minor contribution to the effects of HM-1 may be related to inhibition of the protein kinase C-mediated release of intracellular Ca(2+) stores.
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PMID:Mechanisms of the vasorelaxant effect of 1-hydroxy-2, 3, 5-trimethoxy-xanthone, isolated from a Tibetan herb, Halenia elliptica, on rat coronary artery. 1782 18

In Brazilian folk medicine, extracts from Piper species are used to reduce blood pressure. Previously, we demonstrated the vasodilatory activity of crude extracts from leaves of Piper truncatum explaining their possible use in the treatment of hypertension in traditional medicine. In the present study, we investigated the effects of eudesmin, a lignan isolated from hexane extract of leaves from Piper truncatum, on the contractility of rat aortas and the possible mechanisms involved in its vascular action. Eudesmin induced an intense concentration-dependent relaxation of aortic rings precontracted with phenylephrine. The concentration of eudesmin necessary to reduce phenylephrine-induced aortic contraction by 50% (IC(50)) was 10.69+/-0.67 microg/ml. Eudesmin-induced vasodilation required an intact endothelium since vascular relaxation was inhibited by mechanic removal of endothelium, and by pretreatment with nitric oxide synthase inhibitor and soluble guanylate cyclase inhibitor. Relaxation induced by eudesmin was also impaired in the presence of indomethacin and diphenhydramine, a cyclooxygenase inhibitor and an antagonist of type 1 histamine receptor (H(1)), respectively. IC(50) was increased to 18.1+/-1.8 and 18.1+/-2.6 microg/ml (P<0.05; n=6) after exposure to indomethacin and diphenhydramine, respectively. Atropine (muscarinic receptor antagonist), propranolol (beta-adrenoceptor antagonist) and glibenclamide (ATP-sensitive K(+) channel blocker) did not alter the effect of eudesmin. These results indicate that eudesmin-induced vascular relaxation in rat aorta is mediated by release of nitric oxide and prostanoid through the involvement of histamine receptor present in the endothelial cells.
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PMID:The lignan eudesmin extracted from Piper truncatum induced vascular relaxation via activation of endothelial histamine H1 receptors. 1937 38

Bj-PRO-7a and Bj-PRO-10c belong to a family of proline-rich oligopeptides (PROs) identified in Bothrops jararaca (Bj) crude venom. Previous studies have shown an antihypertensive effect evoked by theses peptides. However, the mechanisms underlying the direct effects on vessels and heart remain to be unraveled. Thus, we investigated the effect of the Bj-PRO-7a and Bj-PRO-10c in the aorta and coronary arteries and in cardiac contractility in normotensive (Wistar) and hypertensive (SHR) rats. Pre-constricted aortic rings were exposed to increasing concentrations of Bj-PROs in presence or absence of muscarinic type 1 receptor antagonist (Pirenzepine), nonselective muscarinic receptor antagonist (Atropine), nitric oxide synthase inhibitor (L-NAME), guanylyl cyclase inhibitor (ODQ), adenylyl cyclase inhibitor (MDL), or argininosuccinate synthetase inhibitor (MDLA). The effects of Bj-PROs in the cardiac contractility and coronary vasomotricity were evaluated using Langendorff perfused heart preparation. The rat hearts were perfused with Bj-PRO-7a or Bj-PRO-10c in absence or presence of L-NAME, ODQ or MDL. Both Bj-PROs induced endothelium-dependent vasorelaxation in aortic rings from Wistars and SHRs. These effects were inhibited by L-NAME, ODQ or MDL. Atropine and Pirenzepine blocked the vasorelaxant effect of Bj-PRO-7a in aorta from both strains. MDLA inhibited the Bj-PRO-10c-induced vasorelaxation in aortic rings from SHR, but not Wistar. The Bj-PRO-7a induced coronary vasodilation only in SHR. L-NAME, ODQ and MDL inhibited this effect. Bj-PRO-10c induced coronary vasodilatation in both strains, which was blocked by L-NAME, ODQ and MDL. Bj-PRO-7a decreased the dP/dt max in Wistar hearts and the dP/dt min in Wistar and SHR hearts. These effects were abolished by L-NAME. Bj-PRO-10c decreased dP/dt max and dP/dt min in hearts from normotensive and hypertensive animals, which were abolished in the presence of L-NAME, MDL and ODQ. In summary, the Bj-PROs induced endothelium-dependent vasorelaxation in rat thoracic aorta, coronary vasodilation and negative inotropic effects through mechanisms mediated by activation of nitric oxide pathway.
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PMID:BJ-PRO-7A and BJ-PRO-10C induce vasodilatation and inotropic effects in normotensive and hypertensive rats: Role of nitric oxide and muscarinic receptors. 3035 32


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