Grover G J, Parham C S, Whigan D B, Mitroka J G
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey, USA.
J Pharmacol Exp Ther. 1996 Feb;276(2):380-7.
BMS-180448 has been found to retain the cardioprotective potency of its chemically related analog, cromakalim, although having significantly less peripheral vasodilating activity. The effect of the ATP-sensitive potassium channel opener, BMS-180448, on postischemic recovery of function (segmental shortening) was determined in open chested, anesthetized dogs instrumented with ultrasonic crystals. The plasma concentration of the effective and ineffective doses of BMS-180448 was compared to concentrations used in isolated rat hearts. BMS-180448 was given as a total dose of 4.2, 1.4 or 0.5 mg/kg over 30 min, starting 15 min before ischemia. Ischemia was initiated by a complete occlusion of the left anterior descending coronary artery for 15 min. Reperfusion was maintained for 3 hr and segmental shortening was measured. During ischemia, systolic bulging was observed in the ischemic region in drug- and vehicle-treated groups. Upon reperfusion, some contractile functional recovery was observed in vehicle-treated controls within minutes, but quickly decreased so that slight bulging was observed up to 3 hr into reperfusion. High dose BMS-180448 significantly improved the recovery of contractile function such that, by 3 hr after reperfusion, segmental shortening had recovered to 60% of base line. The 1.4-mg/kg dose also significantly improved reperfusion function, but 0.5 mg/kg of BMS-180448 was without effect. None of the doses of BMS-180448 significantly affected peripheral hemodynamic status or collateral blood flow. The plasma concentration of the 1.4-mg/kg dose was approximately 3 microM during ischemia. In isolated rat hearts, BMS-180448 significantly increased postischemic function at 3 microM and higher concentrations, which agrees with the dog data. BMS-180448 was protective in a dose-dependent manner in a canine model of stunned myocardium, and the concentrations necessary for protection are similar to that for rats.
已发现BMS - 180448虽外周血管舒张活性明显较低，但仍保留了其化学相关类似物克罗卡林的心脏保护效力。在开胸、麻醉并装有超声晶体的犬身上，测定了ATP敏感性钾通道开放剂BMS - 180448对缺血后功能恢复（节段性缩短）的影响。将BMS - 180448有效剂量和无效剂量的血浆浓度与在离体大鼠心脏中使用的浓度进行了比较。BMS - 180448在缺血前15分钟开始，在30分钟内以4.2、1.4或0.5 mg/kg的总剂量给药。通过完全闭塞左前降支冠状动脉15分钟引发缺血。再灌注维持3小时并测量节段性缩短。在缺血期间，在药物治疗组和溶剂对照组的缺血区域均观察到收缩期膨出。再灌注时，溶剂对照组在数分钟内观察到一些收缩功能恢复，但很快下降，以至于在再灌注3小时内观察到轻微膨出。高剂量BMS - 180448显著改善了收缩功能的恢复，以至于再灌注3小时后，节段性缩短恢复到基线的60%。1.4 mg/kg剂量也显著改善了再灌注功能，但0.5 mg/kg的BMS - 180448无效。BMS - 180448的任何剂量均未显著影响外周血流动力学状态或侧支血流。缺血期间1.4 mg/kg剂量的血浆浓度约为3 microM。在离体大鼠心脏中，BMS - 180448在3 microM及更高浓度时显著增加缺血后功能，这与犬的数据一致。在犬顿抑心肌模型中，BMS - 180448呈剂量依赖性保护作用，保护所需浓度与大鼠相似。
