Electrophysiologic, antiarrhythmic and cardiovascular actions of UM301, a quaternary ammonium compound

The electrophysiologic, antiarrhythmic and cardiovascular actions of UM301 were evaluated in a variety of animal models. UM301 (range, 4.5-10 mg/kg i.v.) converted ouabain-induced ventricular tachycardia to normal sinus rhythm in the anesthetized dog. UM301 (10 mg/kg i.v.) suppressed the ventricular arrhythmias observed in a modified 2 day postinfarction dog preparation; normal sinus rhythm was maintained in excess of 120 min in these conscious animals. The ventricular fibrillation threshold was elevated in four animals after pretreatment with UM301 (5 and 10 mg/kg i.v.) without interfering with electrical cardioversion. In one animal, the spontaneous conversion of ventricular fibrillation to normal sinus rhythm was observed after pretreatment with UM301. In anesthetized dogs, 2 to 8 days after myocardial infarction, UM301 (5 and 10 mg/kg i.v.) prevented the reinduction of re-entrant ventricular tachyarrhythmias using programmed pacing techniques. The antiarrhythmic and antifibrillatory actions of the therapeutic doses of UM301 (i.e., 5 mg/kg i.v.) were associated with significant increases in the refractoriness of atrial, ventricular and atrioventricular conducting tissue. Higher doses of UM301 (10 mg/kg i.v.) progressively increased refractoriness, and the highest dose of UM301 tested (20 mg/kg i.v.) increased refractoriness further and depressed cardiac conduction in these tissues. Acute cardiovascular studies in anesthetized dogs showed that only the highest dose of UM301 tested (20 mg/kg i.v.) produced a significant decrease in the right ventricular force of contraction, cardiac output and arterial pressure. These data demonstrate that UM301, a quaternary ammonium compound, possesses both antiarrhythmic and antifibrillatory properties in various experimental animal models. The antiarrhythmic efficacy of UM301 can be observed in the absence of depressant cardiovascular actions.