The protective effects of CP-060S on ischaemia- and reperfusion-induced arrhythmias in anaesthetized rats

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Abstract
1. CP-060S is a novel sodium and calcium overload inhibitor, and is also characterized as a calcium channel blocker. As these activities have each been shown independently to ameliorate ischaemia damage in the myocardium, the combination may synergistically exert cardioprotection. In this study, therefore, the protective effect of CP-060S against ischaemia- and reperfusion-induced arrhythmia was evaluated in anesthetized 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 intravenously administered 1 min before the onset of occlusion. 3. In the reperfusion-induced arrhythmia model, the animals in the vehicle-treated group exhibited ventricular tachycardia (VT) in 100%, ventricular fibrillation (VF) in 89%, and death caused by sustained VF in 56%. CP-060S (30-300 microg kg(-1)) dose-dependently suppressed the incidences of arrhythmias. Significant decreases occurred at 100 microg kg(-1) in VF (incidence: 42%) and mortality (8%), and at 300 microg kg(-1) in VT (50%), VF (33%) and mortality (8%). This protective effect of CP-060S was 10 times more potent than that of a pure calcium channel blocker, diltiazem (30-1000 microg kg(-1)) we tested, in terms of effective dose ranges. As both drugs decreased myocardial oxygen consumption estimated by rate-pressure product to a similar extent, the calcium channel blocking activity of CP-060S would not seem to be sufficient to explain its potency. 4. In the same model, co-administration of ineffective doses of diltiazem (300 microg kg(-1)) and a sodium and calcium overload inhibitor, R56865 (100 microg kg(-1)), produced significant suppression of VT (incidence: 62%), VF (46%) and mortality (8%). By contrast, co-administration of R56865 at the same dose with CP-060S (300 microg kg(-1)) did not add to the effect of a single treatment of CP-060S. 5. In the ischaemia-induced arrhythmia model, CP-060S (300 microg kg(-1)) significantly decreased the incidence of VF from 75% to 29%, whereas diltiazem (1 mg kg(-1)) was ineffective. 6. These results suggest that CP-060S inhibits both ischaemia- and reperfusion-induced arrhythmia. The combination of the calcium channel blocking effect and the calcium overload inhibition was hypothesized to contribute to these potently protective effects.