Pharmacological evaluation of new calcium antagonists: 2-Substituted 3-dimethylamino-5,6-methylenedioxyindenes. Antiarrhythmic effects

Abstract

The 2-n-propyl- and 2-n-butyl-3-dimethylamino-5,6-methylenedioxyindene hydrochlorides (MDIs) were previously shown to be calcium antagonists with an intracellular site of action. The present investigation was designed to explore the antiarrhythmic properties of the MDIs using the pathophysiological model of the ouabain-toxic dog. Cardiac arrhythmias in dogs were induced by intravenous administration of a loading dose of 55–60 μg/kg of ouabain, followed by a continuous infusion of a maintenance dose of 0.072 μg/kg per minute of the cardiac glycoside. Intravenous doses of 5–30 mg/kg of either of the MDIs administered to arrhythmic dogs resulted in a dose-dependent conversion to sinus rhythm which was preceded by a dose-dependent drop in diastolic blood pressure. Systolic pressure was unaltered, and the effects of the MDIs on heart rate were variable but generally unimpressive and not dose related. Pretreatment of dogs with single (30 mg/kg) or multiple (six injections of 10 mg/kg each) doses of the MDIs prior to ouabain administration afforded a significant protection of the animals against ouabain-induced arrhythmias, with the "time-to-onset" of arrhythmias being 4.5 to 8 times longer in the presence of the MDI pretreatments as compared with non-protected dogs. These findings indicate that the MDIs possess significant antiarrhythmic properties against ouabain-induced arrhythmias, and may lower blood pressure by direct arteriolar dilation without significant effects on cardiac chronotropy or inotropy.