THE PROTECTIVE EFFECTS OF CP-060S ON ISCHEMIA-INDUCED AND REPERFUSION-INDUCED ARRHYTHMIAS IN ANESTHETIZED RATS

1 CP-060S is a novel sodium and calcium overload inhibitor, and is als o characterized as a calcium channel blocker. As these activities have each been shown independently to ameliorate ischaemia damage in the m yocardium, the combination may synergistically exert cardioprotection. In this study, therefore, the protective effect of CP-060S against is chaemia- and reperfusion-induced arrhythmia was evaluated in anestheti zed rats. 2 Rats were anaesthetized with pentobarbitone, and the left anterior descending coronary artery was occluded for either 5 min with subsequent reperfusion (a reperfusion-induced arrhythmia model) or 30 min without (an ischaemia-induced arrhythmia model). All drugs were i ntravenously administered 1 min before the onset of occlusion. 3 In th e reperfusion-induced arrhythmia model, the animals in the vehicle-tre ated group exhibited ventricular tachycardia (VT) in 100%, ventricular fibrillation (VF) in 89%, and death caused by sustained VF in 56%. CP -060S (30-300 mu g kg(-1)) dose-dependently suppressed the incidences of arrhythmias. Significant decreases occurred at 100 mu g kg(-1) in V F (incidence: 42%) and mortality (8%), and at 300 mu g kg(-1) in VT (5 0%), VF (33%) and mortality (8%). This protective effect of CP-060S wa s 10 times more potent than that of a pure calcium channel blocker, di ltiazem (30-1000 mu g kg(-1)) we tested, in terms of effective dose ra nges. As both drugs decreased myocardial oxygen consumption estimated by rate-pressure product to a similar extent, the calcium channel bloc king activity of CP-060S would not seem to be sufficient to explain it s potency. 4 In the same model, co-administration of ineffective doses of diltiazem (300 mu g kg(-1)) and a sodium and calcium overload inhi bitor, R56865 (100 mu g kg(-1)), produced significant suppression of V T (incidence: 62%), VF (46%) and mortality (8%). By contrast, co-admin istration of R56865 at the same dose with CP-060S (300 mu g kg(-1)) di d not add to the effect of a single treatment of CP-060S. 5 In the isc haemia-induced arrhythmia model, CP-060S (300 mu g kg(-1)) significant ly decreased the incidence of VF from 75% to 29%, whereas diltiazem (1 mg kg(-1)) was ineffective. 6 These results suggest that CP-060S inhi bits both ischaemia-and reperfusion-induced arrhythmia. The combinatio n of the calcium channel blocking effect and the calcium overload inhi bition was hypothesized to contribute to these potently protective eff ects.