Interaction of calcium antagonists with beta-adrenoceptor blocking agents

Responsiveness to verapamil, the best studied calcium antagonist, was examined in cardiac preparations of rabbits pretreated with beta-adrenoceptor blockers (propranolol 2 mg/kg or oxprenolol 4 mg/kg s.c.) twice daily for either one or six weeks. Using this dose-regimen, the degree of cardiac beta-adrenoceptor blockade in conscious rabbits was substantial and similar for propranolol and oxprenolol. When administered for one week, neither propranolol nor oxprenolol affected to any marked extent the electrical and mechanical response to verapamil, diltiazem or fendiline in tissues isolated from various parts of the heart. In contrast, pretreatment with propranolol for six weeks resulted in a significant aggravation of the negative inotropic effect of verapamil in both atrial and ventricular muscle, and the verapamil-induced delay in atrio-ventricular and intra-ventricular conduction also became more pronounced. The same long-term administration of oxprenolol, one of the beta-blockers with "intrinsic" sympathomimetic activity, did not alter the atrial or ventricular contractile response to verapamil and did not significantly increase the lengthening of atrio-ventricular conduction time occurring in the presence of verapamil. It is concluded that from the point of view of adverse direct cardiac interactions with verapamil prolonged administration of oxprenolol appears to be less dangerous than chronic treatment with propranolol. It is also assumed that in those cases in which acute administration of verapamil may be necessary, concomitant chronic blockade of cardiac beta-adrenoceptors is less dangerous if drugs known to possess not only beta-adrenoceptor blocking properties, but also some "intrinsic" sympathomimetic activity are applied.