Grover G J, Sleph P G, Parham C S, Brittain R J, Krapcho J, Moreland S
Department of Pharmacology, Squibb Institute for Medical Research, Princeton, New Jersey 08543-4000.
J Cardiovasc Pharmacol. 1990 Aug;16(2):219-27. doi: 10.1097/00005344-199008000-00007.
We tested the benzazepine, SQ 31,486 for its ability to selectively block the voltage-dependent calcium channel and to protect the ischemic myocardium. SQ 31,486 was found to be a selective calcium antagonist in vascular tissue with an IC50 value of 1.5 microM in KCl-contracted rabbit aorta. SQ 31,486 decreased contractile function and increased coronary flow in nonischemic isolated rat hearts in a concentration-dependent manner. SQ 31,486 also significantly reduced postischemic lactate dehydrogenase (LDH) release and end-diastolic pressure (EDP) compared to vehicle. Reperfusion double product [heart rate (HR) x left ventricular developed pressure (LVDP)] was also significantly improved by SQ 31,486. Diltiazem was a less potent anti-ischemic agent and was significantly more cardiodepressant relative to its anti-ischemic efficacy than was SQ 31,486. Thus, SQ 31,486 should have a larger therapeutic index. In a model of pacing-induced myocardial ischemia in anesthetized, open chest dogs, SQ 31,486 reduced pacing-induced ST-segment elevation approximately 50% at 10, 40, and 70 min after drug administration. This protective effect occurred despite a lack of effect of SQ 31,486 on ischemic regional blood flow and peripheral hemodynamic status.
我们测试了苯并氮䓬类药物SQ 31,486选择性阻断电压依赖性钙通道和保护缺血心肌的能力。结果发现，SQ 31,486是血管组织中的一种选择性钙拮抗剂，在氯化钾收缩的兔主动脉中IC50值为1.5微摩尔。SQ 31,486以浓度依赖性方式降低非缺血离体大鼠心脏的收缩功能并增加冠脉血流量。与赋形剂相比，SQ 31,486还显著降低缺血后乳酸脱氢酶（LDH）释放和舒张末期压力（EDP）。SQ 31,486也显著改善了再灌注双乘积[心率（HR）×左心室舒张末压（LVDP）]。地尔硫䓬是一种效力较弱的抗缺血药物，相对于其抗缺血疗效，其心脏抑制作用比SQ 31,486显著更强。因此，SQ 31,486应该具有更大的治疗指数。在麻醉开胸犬起搏诱导的心肌缺血模型中，给药后10、40和70分钟时，SQ 31,486使起搏诱导的ST段抬高降低约50%。尽管SQ 31,486对缺血区域血流和外周血流动力学状态没有影响，但仍出现了这种保护作用。
