title: Pharmacological characterization of vasorelaxant effects of BMS-180448, a novel cardioselective ATP-sensitive potassium channel opener, in rat aorta.
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 (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.
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju. Korea.
authors.forename: Yang-Su
authors.initials: YS
authors.lastname: Park
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Yoo
authors.forename: Hwa-Sup
authors.initials: HS
authors.lastname: Shin
authors.forename: Yong-Ri
authors.initials: YR
authors.lastname: Jin
authors.forename: Yeo-Pyo
authors.initials: YP
authors.lastname: Yun
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000502:physiology; D001578:Benzopyrans / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000494:pharmacology*; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D008297:Male; D015221:Potassium Channels / Q000819:agonists / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001578:Benzopyrans; D006146:Guanidines; D015221:Potassium Channels; D014665:Vasodilator Agents; D000255:Adenosine Triphosphate; C084684:BMS 180448