ACTIONS AND INTERACTIONS OF E-4031 AND TEDISAMIL ON REPERFUSION-INDUCED ARRHYTHMIAS AND QT INTERVAL IN RAT INVIVO

The effects of the I(to) blocker, tedisamil (0.1, 1.0, and 3.0 mg/kg, IV), and the I(K) blocker, E-4031 (0.1, 1.0, and 3.0 mg/kg, IV), on the incidence and duration of reperfusion-induced arrhythmias were compared in the anesthetized rat (n = 12 per group). Reperfusion arrhythmias were evaluated after a 5 minute occlusion period of the left main coronary artery. In the absence of any pronounced effect on blood pressure, tedisamil and E-4031 reduced heart rate in a dose-dependent manner. During the preischemic period, QTc interval was increased by tedisamil but was not changed by E-4031. Both compounds increased the QTc interval during the ischemic period and also during the reperfusion. E-4031 was unable to reduce the incidence and duration of reperfusion-induced ventricular arrhythmias after 5 minutes of coronary artery occlusion. Tedisamil dose-dependently reduced the duration of reperfusion arrhythmias and their incidence. In a second set of experiments, the combination of tedisamil (1.0 mg/kg) with E-4031 (1.0 mg/kg) was administered. The electrocardiographic action of this combination was similar to that observed with tedisamil given alone. However, with the combination the incidence of fibrillation was reduced from 83% in the control group to 8% in the treated group (p < 0.001), and the mortality was reduced from 67% to 0% (p < 0.001), that is, to a greater extent than with tedisamil (1.0 mg/kg) alone. The results show that the blockade of I(to) by tedisamil allows a reduction of reperfusion-induced mortality and that a specific I(K) blocker (E-4031) is devoid of antifibrillatory action in the anesthetized rat. However, as E-4031 might potentiate the antifibrillatory effect of tedisamil, an action on other currents might be envisaged both for tedisamil and E-4031.