Effects of diltiazem on reperfusion-induced arrhythmias in vitro and in vivo

Abstract

The effects of the calcium antagonist, diltiazem, on myocardial injury during ischemia and reperfusion were studied both in vitro, in the isolated rat heart, and in vivo, in a closed-chest pig model. In the isolated rat heart, administration of diltiazem before or at the onset of ischemia resulted in a dose-dependent reduction of the incidence and duration of ventricular fibrillation. This reduction was associated with a dose-dependent reduction in overflow of ATP catabolites (adenosine, inosine, hypoxanthine and xanthine). Both changes were significant at concentrations of 3 X 10(-7) M diltiazem and higher. When 3 X 10(-7) M diltiazem was administered upon reperfusion no effect on the incidence of ventricular fibrillation and on ischemia induced total purine overflow was observed. However, the duration of ventricular fibrillation and purine overflow at 5 min after reperfusion were significantly reduced. In the pig experiments all untreated animals (n = 8) showed accelerated idioventricular rhythm (AIVR) upon reperfusion which lasted for 22 +/- 5 min after which sinus rhythm returned. Only two out of five treated animals (450 micrograms/kg/2 h) had an AIVR. Upon reperfusion both groups showed a substantial rise in noradrenaline concentration in the coronary sinus blood, but after 5 min this was significantly less in the treated group. Creatine kinase-kinetics were not altered by diltiazem, but the maximum creatine kinase level was significantly reduced. Within 4 days after the acute experiment 50% of the untreated animals died suddenly, whereas no sudden deaths occurred in the diltiazem group (P less than 0.05). Seven days after the acute experiment, sustained ventricular tachycardia could be induced with programmed electrical stimulation in three out of four surviving untreated pigs. In none of the diltiazem treated pigs was ventricular tachycardia inducible. The results of this study show that the calcium antagonist diltiazem can beneficially influence the events during ischemia and during reperfusion, both in vitro and in vivo; this benefit is associated with a reduction of ATP catabolism, creatine kinase release and noradrenaline overflow. Furthermore, diltiazem reduces electrical instability in the chronic phase of myocardial infarction.