j Mol Cell Cardiol 18, 375-387 (1986) Prevention of Ventricular Fibrillation by Metoprolol in a Pig Model of Acute Myocardial Ischaemia: Absence of a Major Arrhythmogenlc Role for Cyclic AMP C. A. Muller, L. H. Opie, C. W. Hammt, M. Peisach*, D. Gihwala* with the assistance ofJ. M. Steyn~, H. M. Bassetw Ischaemic Heart Disease Research Unit of the Medical Research Council, Departmentof Medicine and w of Pharmacology, University of Cape Town and GrooteSchuurHospital, Cape Town, South Africa; t Department of Cardiology, University of Hamburg, Germany; *National Accelerator Centre, Faure, South Africa; ~Department of Pharmacology, University of the Orange FreeState, Bloemfontein, South Africa (Received28 January 1985, acceptedin revised form 22 November 1985) C. A. MULLER, L. H. OPIE, C. W. HAMM, M. PEISACH, D. GIHWALA, J. M. STEYNAND H. M. BASSET. Prevention of Ventricular Fibrillation by Metoprolol in a Pig Model of Acute Myocardial Ischaemia: Absence of a Major Arrhythmogenic Role for Cyclic AMP. Journalof Molecularand 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 ofventricular arrhythmias was evident about 10 to 30 min after ligation. A high incidence ofventricular fibrillation (14/18 pigs) was associated with a circumstan- tial increase in levels of cyclic AMP in ischaemic tissue. Twenty minute values were: 1.10 +_ 0.06, P < 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 rain after ligation. Adequate beta-adrenoceptor antagonism by each agent could be proven. Metoprolol decreased the incidence ofventricular fibrillation (2/13, P < 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 meto- protol group than in the propranolol or sotalol group (0.94+0.04 v. 0.81 +0.02 P<0.05, and 0.79 + 0.03 nmol/g P < 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 < 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 < 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 ofischaemia but not in terms of changes of tissue levels of cyclic AMP. KEY WORDS : Beta-adrenoceptor antagonism ; Coronary artery ligation ; Cyclic AMP; Ventricular fibrillation ; Propranolol; Metoprotol ; Sotalol. Introduction Links between adrenergic activity and ven- tricular fibrillation [9] have recently been emphasized by the reduction in the incidence of ventricular fibrillation achieved by the beta-adrenoceptor antagonists metoprolol or propranolol given to patients with acute myo- cardial infarction [10, 21]. Cyclic AMP, the intracellular messenger of beta-adrenergic stimulation, rises in ischaemic tissue at the onset ofventricular fibrillation in baboon, cat and pig models of acute regional ischaemia [5, 23-26"]. Increases in myocardial cyclic AMP resulting from beta-adrenergic stimulation or phosphodiesterase inhibition are associated with a decrease in the ventricular fibrillation threshold in the isolated rat heart model [19]. The beta-adrenoceptor antagonist propranol- 0022-2828/86/040375 + 13 $03.00/0 9 1986 Academic Press Inc. (London) Limited