Grover G J, Sleph P G, Dzwonczyk S, McCullough J R
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey.
J Pharmacol Exp Ther. 1993 Oct;267(1):102-7.
A novel pyranoquinoline analog (BMS-188107) of the ATP-sensitive potassium channel (KATP) opener cromakalim was previously shown to be devoid of KATP opening activity in nonischemic myocardium and vascular smooth muscle, but appeared to be a relatively potent calcium antagonist. This clear differentiation between channels within a structural series is a novel finding. With the idea that KATP openers are often more active in ischemic relative to nonischemic myocardium, we determined the cardioprotective effects of this agent in isolated rat hearts and whether these anti-ischemic effects are abolished by KATP blockade. Isolated rat hearts were subjected to 25 min of global ischemia and 30 min of reperfusion and the severity of ischemic/reperfusion injury was determined. BMS-188107 was given before ischemia at 0.5 to 10 microM. Pretreatment (before ischemia) with BMS-188107 caused significant cardiodepressant activity and increased coronary flow only at a concentration of 10 microM, although modest negative inotropic effects were observed at the 0.5 and 1 microM concentrations. Significant improvements in postischemic contractile function and reductions in lactate dehydrogenase release were observed with 1 to 10 microM BMS-188107, indicating significant reductions in ischemic/reperfusion injury. Neither the pre- nor the postischemic effects of 1 to 10 microM BMS-188107 were significantly altered by the KATP blockers sodium 5-hydroxydecanoate (100 microM) or glyburide (1 microM). Previous studies did not determine the effect of BMS-188107 on sodium channels and thus, the effect of this agent on maximum upstroke velocity of the action potential was determined.(ABSTRACT TRUNCATED AT 250 WORDS)
一种新型的吡喃喹啉类似物（BMS - 188107），它是ATP敏感性钾通道（KATP）开放剂色满卡林的类似物，先前研究表明其在非缺血心肌和血管平滑肌中缺乏KATP开放活性，但似乎是一种相对强效的钙拮抗剂。在一个结构系列的通道之间存在这种明显差异是一个新发现。鉴于KATP开放剂通常在缺血心肌中比在非缺血心肌中更具活性，我们确定了该药物在离体大鼠心脏中的心脏保护作用，以及这些抗缺血作用是否会因KATP阻断而消除。将离体大鼠心脏进行25分钟的全心缺血和30分钟的再灌注，并测定缺血/再灌注损伤的严重程度。在缺血前给予BMS - 188107，浓度为0.5至10微摩尔。BMS - 188107在缺血前预处理时，仅在浓度为10微摩尔时引起显著的心脏抑制活性并增加冠状动脉血流量，尽管在0.5和1微摩尔浓度时观察到适度的负性肌力作用。使用1至10微摩尔的BMS - 188107可观察到缺血后收缩功能的显著改善以及乳酸脱氢酶释放的减少，表明缺血/再灌注损伤显著减轻。1至10微摩尔的BMS - 188107在缺血前和缺血后的作用均未因KATP阻滞剂5 - 羟基癸酸钠（100微摩尔）或格列本脲（1微摩尔）而发生显著改变。先前的研究未确定BMS - 188107对钠通道的影响，因此，测定了该药物对动作电位最大上升速度的影响。（摘要截断于250字）
