T. Koga et al., THE PROTECTIVE EFFECTS OF CP-060S ON ISCHEMIA-INDUCED AND REPERFUSION-INDUCED ARRHYTHMIAS IN ANESTHETIZED RATS, British Journal of Pharmacology, 123(7), 1998, pp. 1409-1417
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.