Metoprolol Reduces Reperfusion-Induced Fibrillation in he Isolated Rat Heart

Summary We studied the effect of metoprolol on the incidence of reperfusion-induced ventricular fibrillation in the isolated rat heart with transient coronary artery occlusion and reperfusion. When administered prior to ischemia, metoprolol produced a dose-dependent reduction in reperfusion-induced ventricular fibrillation. Thus, with 1, 10, 30, 50, 100, and 200 μmol/L metoprolol, total ventricular fibrillation (reversible plus irreversible) was reduced from its control incidence of 100% to 91%, 83%, 58% (p < 0.05), 25% (p < 0.001), 25% (p < 0.001), and 0% (p < 0.001), respectively. Heart rate was also reduced in a dose-dependent manner from its control value of 268 ± 6 beats/min to <75% at the highest concentration of metoprolol. Coronary flow was unaffected by metoprolol. Doses of metoprolol (1 and 10 μmol/L) that had no significant effect on heart rate had no antiarrhythmic effect. In additional experiments with a higher dose of metoprolol (50 μmol/L), hearts were paced to the rate of the drug-free control group and the antiarrhythmic effect of metoprolol was lost. When drug-free control hearts had their heart rate reduced to that of the metoprolol-treated hearts, a similar antiarrhythmic effect was observed. When metoprolol was administered just prior to reperfusion, no antiarrhythmic effects were observed. In further studies, we investigated the effect of the early administration of metoprolol (50 μmol/L) on the relationship between the vulnerability to reperfusion-induced arrhythmias and the duration of preceding ischemia. Metoprolol-free control hearts exhibited a bell-shaped time–response profile with a maximum vulnerability after 10 min of ischemia (100% incidence of reperfusion-induced ventricular fibrillation). Metoprolol-treated hearts also had a bell-shaped curve, but its optimum was shifted to the right and downwards [20 min of ischemia gave maximum vulnerability (41%) to reperfusion-induced arrhythmias]. In conclusion, in vitro, metoprolol can reduce reperfusion-induced arrhythmias in a dose-dependent manner, but this antiarrhythmic effect is secondary to the drug's action during the preceding period of ischemia and is critically dependent on the negative chronotropic properties of the drug.