The effect of alpha- and beta-adrenoceptor antagonist agents on reperfusion ventricular fibrillation and metabolic status in the isolated perfused rat heart

This study was designed to assess the effect of alpha-and beta-adrenoceptor antagonist agents on reperfusion ventricular fibrillation and myocardial metabolic status preceding the onset of reperfusion ventricular fibrillation in the isolated Langendorff perfused rat heart. Prazosin (alpha 1 antagonist), yohimbine (alpha 2 -antagonist) and phentolamine (alpha 1 - and alpha 2 -antagonist) protected against reperfusion ventricular fibrillation, the median effective dose (ED 50 ) values being 2.0, 0.7 and 2.5 μmol/liter, respectively, when given before coronary artery ligation. The ability of alpha-antagonist agents to prevent reperfusion ventricular fibrillation appeared to be the consequence of alpha-adrenoceptor antagonism or the consequence of “membrane-stabilizing activity,” or both. Reserpinization before reperfusion reduced but did not eliminate reperfusion ventricular fibrillation. Relative to the reported dissociation constants of myocardial alpha-adrenoceptors, yohimbine (alphas-antagonist) appeared more active; such antiarrhythmic potential apparently has not been reported previously. The beta-adrenoceptor antagonist agents dl-propranolol (ED 50 value, 3 μmol/liter) and metoprolol in high concentrations (ED 50 value, 50 μmol/liter) prevented reperfusion ventricular fibrillation, whereas atenolol was virtually without effect. d-Propranolol (ED 50 value, 2.5 μmol/liter), the propranolol isomer with modest beta-antagonist activity but with marked membrane-stabilizing activity, evoked protection equivalent to that of racemic propranolol. Beta-adrenoceptor antagonists did not appear to prevent reperfusion ventricular fibrillation as a consequence of receptor antagonism but rather by membrane-stabilizing activity. Some circumstantial association was evident between improved metabolic status on reperfusion, in preservation of tissue levels of adenosine triphosphate and phosphocreatine, reduction of tissue levels of lactate and cyclic adenosine monophosphate and protection against reperfusion ventricular fibrillation. However, agents affording a similar degree of metabolic preservation were associated with different degrees of protection against reperfusion ventricular fibrillation. Of the four possible protective procedures: alpha-receptor antagonism, beta-adrenoceptor antagonism, membrane-stabilizing activity and metabolic preservation, alpha-receptor antagonism and membrane-stabilizing activity most warrant further evaluation, especially in other species.