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.