Pharmacological characterization of vasorelaxant effects of BMS-180448, a novel cardioselective ATP-sensitive potassium channel opener, in rat aorta | Health & Environmental Research Online (HERO)

HERO ID

3243470

Reference Type

Journal Article

Title

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

Author(s)

Park, YS; Yoo, SE; Shin, HS; Jin, YR; Yun, YP

Year

2003

Is Peer Reviewed?

Yes

Journal

Journal of Pharmacological Sciences
ISSN: 1347-8613
EISSN: 1347-8648

Volume

92

Issue

3

Page Numbers

218-227

Web of Science Id

WOS:000184352300006

Abstract

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 (IC50: 0.97 +/- 0.29 muM), the effect being significantly attenuated by removal of
functional endothelium (IC50: 1.95 +/- 0.23 muM) and pretreatment with N-nitro-L-arginine methyl
ester (L-NAME) or methylene blue. BMS-180448 completely relaxed endothelium-denuded aorta
contracted with phorbol 12,13-dibutyrate, PGF(2alpha), and U46619 with a significantly greater
potency (IC50: 0.069 +/- 0.002, 0.055 +/- 0.002, and 0.068 +/- 0.008 muM, respectively, P<0.05)
than that contracted with phenylephrine (1.95 +/- 0.23 muM) or KCl (0.25 +/- 0.08 muM),
indicating potency change with the type of vasoconstrictor. BMS-180448 (1-3 muM) inhibited Ca2+
(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 Ca2+-free buffer. BMS-
180448 (10 muM) 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
Ca2+ 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.

Keywords

ATP-sensitive K+ channel opener; Ca2+; cAMP; vasorelaxation