Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nebivolol is a recently developed beta-blocker provided with vasodilator properties. Because the mechanism of the putative endothelium-dependent effect of this beta-adrenoceptor blocker has not been completely elucidated, the aim of this study was to investigate the effects of nebivolol on an isolated resistance vascular bed and on cell messengers and constitutive nitric-oxide synthase activity (cNOS) in endothelial cells. Experiments were carried out using the rat mesenteric vascular bed and cultured bovine coronary postcapillary venular endothelial cells from bovine heart (CVEC). In mesenteric vascular bed preconstricted by 30 microM noradrenaline and 0.3 microM U46619, dl-nebivolol induced a concentration-dependent relaxing effect at concentrations between 3 and 30 microM; this effect was changed to a concentration-dependent vasoconstrictor response either in endothelium-denuded preparations or in intact preparations pretreated with 100 microM N(omega)-nitro-L-arginine methyl ester plus 3 microM indomethacin. The vasorelaxant effect of dl-nebivolol in preconstricted preparations was completely blocked by pretreatment either with the phospholipase C inhibitor U73122 (1 microM) or with the endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin (1 microM) for 30 min. The cellular level of the inositol trisphosphate metabolite inositol monophosphate in coronary postcapillary venular endothelial cells was not affected by dl-nebivolol in the concentration range 100 nM to 1 microM, but it was concentration dependently increased after exposure for 15 min to 10 and 30 microM dl-nebivolol. The activity of cNOS was almost doubled after a 5-min exposure to 10 microM dl-nebivolol and was significantly impaired by thapsigargin and N(omega)-nitro-L-arginine methyl ester treatment, although it was unaffected by N(omega)-nitro-D-arginine methyl ester. These findings demonstrate that nebivolol, in micromolar concentrations, induces vasorelaxation through activation of inositol phosphate metabolism and stimulation of cNOS activity in endothelial cells.
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PMID:Inositol phosphate metabolism and nitric-oxide synthase activity in endothelial cells are involved in the vasorelaxant activity of nebivolol. 1064 Mar 8

Nebivolol is a highly selective beta1-adrenoreceptor-blocking agent with a peculiar pharmacodynamic profile. It has peripheral acute vasodilating properties that are mediated by modulation of the endogenous production of nitric oxide. In this study we analyzed the different signaling pathways implicated in the response of human umbilical vein endothelial cells to nebivolol. Its effect on endothelial transduction pathways was determined by assaying phospholipase C and A2 activities and cyclic adenosine monophosphate (AMP) production. Variations in intracellular calcium concentration were also measured. Our results showed that nebivolol activates a calcium-independent transduction pathway that implicates an increase in adenylate cyclase and phospholipase A2 activity. Beta1- or beta2-Adrenoreceptor antagonists do not inhibit the action of nebivolol. However, its action on cyclic AMP production is inhibited by bupranolol, a beta1-3-adrenoreceptor antagonist, and S-(-)-cyanopindolol, a selective beta3-adrenoreceptor antagonist. Nebivolol also dose-dependently increased nitrite production. This effect was inhibited by bupranolol, suggesting that the possible action of nebivolol on beta3-adrenoreceptor is involved in its vasodilating properties. This study suggests that nebivolol could behave as a beta3-adrenoreceptor agonist and induce some calcium-independent pathways implicating phospholipase A2 and adenylate cyclase. This agonistic activity of nebivolol seems to be responsible for its endothelium-dependent vasodilating activity.
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PMID:Nebivolol induces calcium-independent signaling in endothelial cells by a possible beta-adrenergic pathway. 1148 68