Effects of 2-Substituted 3-Dimethylamino-5,6-Methylenedioxyindenes on Calcium-Induced Arrhythmias

Abstract

Summary: Pharmacological, biochemical, and electrophysiological studies have demonstrated that the 2-n-propyl (Pr) and 2-n-butyl (Bu) 3-dimethylamino-5,6-methylenedioxyindenes (MDIs) are intraceilular calcium antagonists. The MDIs exhibit coronary dilating properties in the in vitro rabbit heart and possess antiarrhythmic activity in vivo in the anesthetized ouabain toxic dog. The results of the present investigation demonstrate that the MDIs possess significant antiarrhythmic activity against calcium-induced arrhythmias in anesthetized rats and dogs. Pretreatment of dogs with an acute dose (30 mg/kg, i.v.) of either MDI significantly delayed both the onset of arrhythmias and the subsequent time to death resulting from a continuous intravenous infusion of calcium (500 mg/kg/hr, CaCl₂ 2H₂O). Pretreatment of rats with an acute dose (3.75 mg/kg, i.v.) of either MDI provided virtually complete protection against bradycardia, arrhythmias, and death induced by an acute intravenous dose of calcium (1 ml/kg of a 10% CaCl₂ 2H₂O solution). The antiarrhythmic potency of the MDIs in rats was equivalent to that of verapamil, but the latter drug produced bradycardia, electrocardiographic alterations, and atrioventricular block, whereas the MDIs exhibited no intrinsic deleterious effects on cardiac function. Prenylamine (a membrane calcium antagonist) and diphenylhydantoin demonstrated no antiarrhythmic properties in this rat model at comparable doses to the MDIs.