Diltiazem and the reduction of reperfusion-induced arrhythmias in the rat: protection is secondary to modification of ischemic injury and heart rate.

We have used the isolated rat heart with transient coronary artery occlusion to investigate whether diltiazem has an anti-arrhythmic action against reperfusion-induced ventricular arrhythmias. In the first series of studies (early administration group) the drug was administered 5 min prior to the induction of regional ischemia, this resulted in a dose-dependent reduction in reperfusion-induced ventricular fibrillation. With 5 X 10(-8), 10(-7), 5 X 10(-7), 10(-6) and 5 X 10(-6) mols of diltiazem/l, total ventricular fibrillation (reversible plus irreversible) was reduced from its control incidence of 100% (12/12) to 91%, 58% (P = less than 0.05), 17% (P = less than 0.001), 0% (P = less than 0.001) and 0% (P = less than 0.001) respectively. Heart rate was also reduced in a dose-dependent manner, falling from its control value of 268 +/- 6 beats/min to less than 50% with the highest concentration of diltiazem. Coronary flow was increased in a dose-dependent manner in the diltiazem treated groups. In additional studies with an anti-arrhythmic dose of diltiazem (5 X 10(-7) mols/l), hearts were paced to their drug free control value; under these conditions the anti-arrhythmic effect of diltiazem was lost. In further studies, diltiazem (10(-7) and 5 X 10(-7) mols/l) was administered just prior to reperfusion (late administration group), no anti-arrhythmic effects were observed. In additional studies we determined whether, with early administration, diltiazem (5 X 10(-7) mols/l) exerted its anti-arrhythmic effect by altering the relationship between the vulnerability to reperfusion-induced arrhythmias and the duration of preceding ischemia. In diltiazem-free control hearts a bell-shaped profile was observed with a maximum vulnerability after 10 min of ischemia (100% incidence of reperfusion-induced ventricular fibrillation). In diltiazem-treated hearts, a bell-shaped curve was also observed, however, its optimum was shifted to the right and downwards (20 min of ischemia gave maximum vulnerability [41%] to reperfusion-induced arrhythmias). We conclude that the ability of diltiazem to protect the isolated rat heart against reperfusion-induced arrhythmias is secondary to its anti-ischemic effect and in particular to its negative chronotropic properties.