Abstract
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.
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