Pharmacological characterization of vasorelaxant effects of BMS-180448, a novel cardioselective ATP-sensitive potassium channel opener, in rat aorta.

摘要

This study was designed to characterize vasorelaxant effects of BMS-180448 ((3S-trans)-N-(4-chlorophenyl)-N'-cyano-N"-(6-cyano-3,4-dihydro-3-hydroxy- 2,2-dimethyl-2H-1-benzopyran-4-yl)), a prototype cardioselective ATP-sensitive potassium channel opener, in rat aorta. BMS-180448 relaxed phenylephrine-precontracted endothelium-intact aortic rings (IC(50): 0.97 +/- 0.29 micro M), the effect being significantly attenuated by removal of functional endothelium (IC(50): 1.95 +/- 0.23 micro M) and pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME) or methylene blue. BMS-180448 completely relaxed endothelium-denuded aorta contracted with phorbol 12,13-dibutyrate, PGF(2)(alpha), and U46619 with a significantly greater potency (IC(50): 0.069 +/- 0.002, 0.055 +/- 0.002, and 0.068 +/- 0.008 micro M, respectively, P<0.05) than that contracted with phenylephrine (1.95 +/- 0.23 micro M) or KCl (0.25 +/- 0.08 micro M), indicating potency change with the type of vasoconstrictor. BMS-180448 (1 - 3 micro M) inhibited Ca(2+) (0.5 - 2.5 mM)-induced contraction of endothelium-denuded aorta evoked in the presence of high KCl (65.4 mM), but had no effect on contraction induced by phenylephrine in Ca(2+)-free buffer. BMS-180448 (10 micro M) increased cAMP level in aorta by approximately two-fold compared with the control, comparable to forskolin, an adenylate cyclase activator. These findings suggest that cardioselective BMS-180448 still exerts significant vasorelaxant activity in rat aorta contracted with various vasoconstrictors via multiple mechanisms including the blockade of extracellular Ca(2+) influx through voltage-dependent channels and activation of the adenylate cyclase and nitric oxide pathway, with the possibility of hemodynamic implications in certain clinical conditions such as myocardial infarction and hypertension.