R56865, a Potent New Antiarrhythmic Agent, Effective During Ischemia and Reperfusion in the Rat Heart

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Abstract
The antiarrhythmic effects of R56865 were characterized both in vivo and in vitro. Four groups (n = 12 per group) of anesthetized rats, subjected to 5− or 30-min coronary artery ligation and reperfusion, were studied: saline, dimethyl sulfoxide (DMSO) carrier, and R56865 (0.5 or 2 mg/kg) were administered as an intravenous (i.v.) bolus before ligation. After 5 min of ischemia, the incidences of reperfusion-induced ventricular tachycardia (VT) and fibrillation (VF), which were high in the saline (100 and 75%, respectively) and DMSO (100 and 82%, respectively) control groups, were abolished with both doses of R56865. With 30 min of ischemia, R56865 (2 mg/kg) significantly reduced the incidences of ischemia-induced VT and VF (from 100 and >50% to 25 and 8%, respectively). For in vitro studies, five groups (n = 12 per group) of isolated rat hearts subjected to 10− or 30-min coronary ligation and reperfusion were studied: unmodified buffer and buffer containing DMSO or R56865 (10−-7, 10−-8, 10−-9M). After 10 min of ischemia, R56865 (10−-7M) decreased reperfusion-induced VT and VF (from 100 and 75% in buffer controls to 42 and 8%, respectively) when administered throughout the experiment. With 30 min of ischemia, R56865 (10−-7M) reduced the incidences of ischemia-induced VT and VF (from 75 and 67% in the buffer controls to 25 and 25%, respectively). Although reperfusion after 30 min of ischemia did not induce VF in any of the groups studied, VT and other arrhythmias did occur and their incidences were reduced significantly by R56865. To investigate whether calcium overload might mediate the effects of R56865, hearts were perfused aerobically with a high-calcium/low-sodium medium. VT and VF occurred in 80% of control hearts; R56865 (10−-7M) did not prevent these arrhythmias. In conclusion, R56865 exerts a potent effect against ischemia- and reperfusion-induced arrhythmias through a mechanism which appears to operate during ischemia.