Lack of Concordance Between the Antiarrhythmic and Antifibrillatory Actions of UM-424, a Quaternary Ammonium Analogue of Propranolol

Abstract

UM-424, 1-dimethyl isopropylamino-3-(2-phenylphenoxy)-propan-2-ol chloride, is a quaternary ammonium derivative of propranolol. Previous studies have demonstrated UM-424 to suppress the development of ventricular arrhythmias in a variety of experimental canine models, while lacking significant beta-adrenergic blocking and cardiodepressant actions. In the present studies, slight and transient reductions in heart rate, coronary flow, and indices of cardiac force and pressure developed only after the intravenous administration of 10.0 mg/kg UM-424. The positive inotropic response to intravenous isoproterenol was not altered significantly by 1.0-10.0 mg/kg UM-424. In conscious dogs 4-7 days after anterior myocardial infarction, UM-424 administered intravenously in a single (5.0 mg/kg) or multiple (5.0 mg/kg q 6 h for 24 h) dose schedule increased the ventricular refractory period from 146 +/- 4 to 180 +/- 3 ms (p less than 0.01), and suppressed the initiation of ventricular tachycardia by programmed ventricular stimulation in six of nine postinfarction dogs tested. However, the incidence of subsequent ventricular fibrillation developing in response to acute ischemia at a site remote from previous myocardial infarction was 100% in both UM-424 (n = 8)- and vehicle (n = 8)-treated postinfarction dogs. These findings suggest UM-424 is ineffective in preventing the development of ischemic ventricular fibrillation in the presence of previous myocardial injury, despite the efficacy of this agent in suppressing other experimentally induced ventricular arrhythmias.