Uchida W, Masuda N, Taguchi T, Shibasaki K, Shirai Y, Asano M, Matsumoto Y, Tsuzuki R, Fujikura T, Takenaka T
Cardiovascular and Atherosclerosis Research Laboratories, Yamanouchi Institute for Drug Discovery Research, Ibaraki, Japan.
J Cardiovasc Pharmacol. 1994 Feb;23(2):180-7.
Pharmacologic profiles of YM934, a newly synthesized 1,4-benzoxazin derivative K channel opener were evaluated in in vitro and in vivo experiments. In isolated rat portal vein, YM934 and a benzopyran derivative K channel opener lemakalim inhibited the frequency of spontaneous rhythmic contractions concentration dependently, with IC50 values of 14 and 38 nM, respectively. These inhibitory effects were competitively antagonized by glibenclamide (an ATP-sensitive K channel blocker; 10(-7)-3 x 10(-6) M). In isolated rabbit aorta, YM934 (10(-8)-10(-6) M) and lemakalim (10(-8)-10(-6) M) relaxed the contractions induced by 20 mM KCl concentration dependently but were ineffective against the contractions induced by 50 mM KCl. YM934 (10(-8)-3 x 10(-6) M) and lemakalim (3 x 10(-8)-10(-5) M), but not the calcium antagonist nifedipine, relaxed the contractions induced by norepinephrine (NE 10(-6) M) or prostaglandin F2 alpha (PGF2 alpha 3 x 10(-6) M) in the aorta. In pentobarbital-anesthetized dogs, YM934 (1-10 micrograms/kg intravenously, i.v.) dose-dependently increased coronary artery blood flow (CBF), and decreased total peripheral resistance (TPR) and mean blood pressure (MBP). YM934 selectively increased CBF, but had little effect on vertebral, carotid, mesenteric, renal and femoral artery BF. These vasodilatory effects of YM934 were antagonized by glibenclamide. YM934 is a potent K channel opener and possesses potent vasodilatory effects, with particularly pronounced effects on the coronary artery. These effects of YM934 may, like lemakalim, be mediated by opening of ATP-sensitive K channels.
在体外和体内实验中评估了新合成的1,4 - 苯并恶嗪衍生物钾通道开放剂YM934的药理学特性。在离体大鼠门静脉中，YM934和苯并吡喃衍生物钾通道开放剂雷马卡林浓度依赖性地抑制自发性节律性收缩频率，IC50值分别为14和38 nM。这些抑制作用被格列本脲（一种ATP敏感性钾通道阻滞剂；10(-7)-3×10(-6)M）竞争性拮抗。在离体兔主动脉中，YM934（10(-8)-10(-6)M）和雷马卡林（10(-8)-10(-6)M）浓度依赖性地舒张由20 mM氯化钾诱导的收缩，但对由50 mM氯化钾诱导的收缩无效。YM934（10(-8)-3×10(-6)M）和雷马卡林（3×10(-8)-10(-5)M），但不是钙拮抗剂硝苯地平，可舒张主动脉中由去甲肾上腺素（NE 10(-6)M）或前列腺素F2α（PGF2α 3×10(-6)M）诱导的收缩。在戊巴比妥麻醉的犬中，YM934（1 - 10微克/千克静脉注射，i.v.）剂量依赖性地增加冠状动脉血流量（CBF），并降低总外周阻力（TPR）和平均血压（MBP）。YM934选择性增加CBF，但对椎动脉、颈动脉、肠系膜动脉、肾动脉和股动脉血流量影响很小。YM934的这些血管舒张作用被格列本脲拮抗。YM934是一种有效的钾通道开放剂，具有强大的血管舒张作用，对冠状动脉的作用尤为明显。YM934的这些作用可能与雷马卡林一样，是通过开放ATP敏感性钾通道介导的。
