Antiarrhythmic, electrophysiologic and hemodynamic effects of ACC-9358.
The antiarrhythmic, electrophysiologic and hemodynamic effects of a new antiarrhythmic agent, ACC-9358, were evaluated. In anesthetized dogs, ACC-9358 converted ouabain-induced ventricular tachycardia to normal sinus rhythm at a cumulative dose equal to encainide or flecainide and less than disopyramide. In 24-hr coronary artery ligated dogs, ACC-9358 suppressed spontaneous ventricular arrhythmias for up to 6 hr after oral or i.v. administration. The antiarrhythmic effect and plasma concentrations of ACC-9358 correlated well for both oral (r = 0.88) and i.v. (r = 0.87) administration. ACC-9358, flecainide and disopyramide were equieffective in converting crush-stimulation-induced atrial flutter in anesthetized dogs to normal sinus rhythm. In alpha-chloralose-anesthetized, closed-chest dogs, ACC-9358 slowed impulse conduction through the atria, atrioventricular node, His-Purkinje system and ventricles and prolonged atrial functional refractory period. In conscious dogs, ACC-9358 increased heart rate, reduced stroke volume and had no effect on mean arterial pressure, systemic vascular resistance or cardiac output. In alpha-chloralose-anesthetized dogs, ACC-9358-induced sinus tachycardia was unaffected by propranolol but was blocked by hexamethonium or vagotomy. In isolated cat ventricular muscle, the IC50 for the negative inotropic effect of ACC-9358 was significantly greater than flecainide or disopyramide. These results indicate that ACC-9358 is a potent, broad-spectrum, long-acting, orally and intravenously active class Ic antiarrhythmic agent that 1) may be devoid of active metabolites, 2) exerts little or no vascular effects and 3) has less direct cardiodepressant activity than flecainide or disopyramide.
Brown
B S
BS
Department of Pharmaceutical Research, Du Pont Critical Care, Inc., Waukegan, Illinois.
Calzadilla
S V
SV
Diemer
M J
MJ
Hartman
J C
JC
Reynolds
R D
RD
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy; D002415:Cats; D004285:Dogs; D004562:Electrocardiography; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D011759:Pyrrolidines / Q000097:blood / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D011759:Pyrrolidines; C048492:4-hydroxy-N-phenyl-3,5-bis(1-pyrrolidinylmethyl)benzamide