ANTIARRHYTHMIC ACTIVITY OF SOME ISOQUINOLINE DERIVATIVES DETERMINED BY A RAPID SCREENING PROCEDURE IN THE MOUSE

¹ Departments of Pharmaceutics and Pharmacology, University of Tennessee Medical Units, Memphis, Tennessee

Chloroform inhalation leading rapidly to respiratory arrest produced ventricular fibrillation. Pretreatment with quinidine prevented the development of the arrhythmia and provided the basis for development of an antiarrhythmic test procedure. The screening procedure was found to provide a rapid means of detecting compounds with antiarrhythmic activity and of estimating their acute toxicities at effective antiarrhythmic dose levels. Results obtained with graded doses of the more active compounds studied were used to calculate antiarrhythmic ED50 values while the LD50 values were obtained in separate groups of animals. Estimates were made of the antiarrhythmic activity and acute toxicity of quinidine, procainamide, some new isoquinoline derivatives, propranolol, atropine, oxyphenonium, papaverine, reserpine, phenylephrine, methoxamine, naphazoline, diphenhydramine, antazoline, phenindamine and some combinations of these agents. Of the compounds tested, the most potent was M-8 (5-(3,4,5-trimethoxybenzoyloxy)-2-ethyldecahydroisoquinoline). It was also found to possess a therapeutic index equivalent to quinidine. The most interesting combination studied was comprised of quinidine and propranolol. The therapeutic index of quinidine was increased 12-fold by the coadministration of a low dose of propranolol (<ED 0.01).