Prevention of ventricular fibrillation by metoprolol in a pig model of acute myocardial ischaemia: absence of a major arrhythmogenic role for cyclic AMP

Absence of a Major Arrhythmogenic Role for Cyclic AMP. Journal of Molecular and Cellular Cardiology (1986) 18, 375-387. We examined the mechanism whereby beta-adrenoceptor antagonism exerts an antiarrhythmic effect in early myocardial ischaemia. Ligation of the anterior descending coronary artery in the anaesthetized open-chest pig resulted in severe transmural anteroseptal ischaemia. Blood flow in the mid-ischaemic zone 20 min after ligation was decreased to 5.7 +/- 0.7% of the preligation control value. Epicardial ST-segment deflections of 6.7 +/- 0.4 mV were recorded over this zone. A distinct phase of ventricular arrhythmias was evident about 10 to 30 min after ligation. A high incidence of ventricular fibrillation (14/16 pigs) was associated with a circumstantial increase in levels of cyclic AMP in ischaemic tissue. Twenty minute values were: 1.10 +/- 0.06, P less than 0.05 v. the non-ischaemic tissue level of 0.86 +/- 0.05 nmol/g. Propranolol 3 mg/kg IV, metoprolol 20 mg/kg IV or sotalol 10 mg/kg IV were given between 30 min prior to and 10 min after ligation. Adequate beta-adrenoceptor antagonism by each agent could be proven. Metoprolol decreased the incidence of ventricular fibrillation (2/13, P less than 0.0005 v. control group), while propranolol or sotalol did not. All three beta-antagonists decreased tissue levels of cyclic AMP prior to ligation. However, the temporary increase in ischaemic tissue after ligation could not be prevented. Furthermore, cyclic AMP in ischaemic tissue 20 min after ligation was higher in the metoprolol group than in the propranolol or sotalol group (0.94 +/- 0.04 v. 0.81 +/- 0.02 P less than 0.05, and 0.79 +/- 0.03 nmol/g P less than 0.01, respectively). Blood flow in the mid-ischaemic zone of the metoprolol group was increased to 8.6 +/- 0.6% of preligation control value (P less than 0.0001 v. control group). In contrast, blood flow in the mid-ischaemic zone of the propranolol or sotalol group was decreased. Metoprolol also reduced epicardial ST-segment deflections over the mid-ischaemic zone to 3.5 +/- 0.2 mV (P less than 0.0001 v. control group). ST-segment deflections in the propranolol group were increased. The mechanism whereby metoprolol prevented ventricular fibrillation may be explained by a decrease in the severity of ischaemia but not in terms of changes of tissue levels of cyclic AMP.