Antiarrhythmic, hemodynamic and cardiac electrophysiological evaluation of N-(2,6-dimethylphenyl)-N'-[3-(1-methylethylamino)propyl]urea (Wy-42,362).

ABSTRACT

The antiarrhythmic, hemodynamic and cardiac electrophysiological effects of (Wy-42,362, in the following briefly called Wy) N-(2,6-dimethylphenyl)-N'-[3-(1-methylethylamino)propyl]urea were examined in several experimental preparations. Wy is an effective antiarrhythmic agent when administered i.v. or p.o. in various models of canine cardiac arrhythmia. Wy elevated ventricular fibrillatory threshold voltage and reverted ouabain-induced, 24- and 48-h post coronary artery ligation-induced Ventricular arrhythmias,, and aconitine-induced atrial arrhythmias at i.v. doses of 4-15 mg/kg. Wy lacked anticholinergic or CNS-stimulant activity. In closed-chest anesthetized dogs, Wy at 15 or 25 mg/kg i.v. decreased cardiac output (CO). Unlike disopyramide, i.v. Wy did not produce greater reductions in CO in anesthetized dogs subjected to previous infarction (72-96 h) as compared to normal intact dogs. Wy at 10 or 15 mg/kg i.v. produced slight to moderate decreases in contractile force and showed a tendency to reduce heart rate and blood pressure. Wy produced a generalized depression of cardiac impulse conduction in open-chest, pentobarbital anesthetized dogs but conscious dogs exhibited relatively little ECG evidence of such depression following double the therapeutic i.v. dose. In isolated canine cardiac Purkinje fibers bathed in normal K+-containing physiological solutions. Wy (1-2 X 10(-5) mol/l) produced significant reductions in action potential duration while 2 X 10(-5) mol/l also reduced Vmax and shifted membrane responsiveness curves to the right suggesting depressant action on fast Na+ channel conductance. The data indicate that Wy is an effective antiarrhythmic agent presumably with a class I mechanism of action.