Electrophysiological effects of ACC-9358, a novel class I antiarrhythmic agent, on isolated canine Purkinje fibers and ventricular muscle.
Class I antiarrhythmic agents are heterogeneous with respect to their cardiac electrophysiological effects and have been subdivided into three categories: la, lb and lc. The purpose of the present study was to determine the classification and investigate the mechanism of action of ACC-9358 [4-hydroxy-N-phenyl-3,5-bis (1-pyrrolidinyl-methyl)benzamide], a novel class I antiarrhythmic agent currently under clinical investigation. The effects of ACC-9358 on action potentials from isolated canine Purkinje fibers and ventricular muscle were examined using standard microelectrode techniques. In Purkinje fibers, ACC-9358 (1-50 microM) exerted a dose-dependent reduction in maximum upstroke velocity (Vmax) and action potential duration at 50 and 90% repolarization (APD50 and APD90). The reduction of Vmax was voltage-dependent (greater at an extracellular potassium concentration of 6 mM than at 2.7 mM), frequency-dependent (greater at a basic cycle length of 500 than at 2000 msec) and very slow in onset (rate constant of 0.017 action potentials-1) and offset (recovery half-time of 66.9 sec). In Purkinje fibers, ACC-9358 attenuated the action potential shortening effects of lidocaine but not that of nicardipine or nicorandil and shortened APD50 to a greater extent at a basic cycle length of 2000 than at 500 msec. In ventricular muscle, ACC-9358 (1-50 microM) exerted a dose-dependent reduction in Vmax and prolongation of APD50 and APD90.(ABSTRACT TRUNCATED AT 250 WORDS)
Brown
B S
BS
Department of Pharmaceutical Research, Du Pont Critical Care, Waukegan, Illinois.
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006329:Heart Conduction System / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects; D066298:In Vitro Techniques; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D009529:Nicardipine / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011690:Purkinje Fibers / Q000187:drug effects* / Q000502:physiology; D011759:Pyrrolidines / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D011759:Pyrrolidines; C048492:4-hydroxy-N-phenyl-3,5-bis(1-pyrrolidinylmethyl)benzamide; D008012:Lidocaine; D009529:Nicardipine; D011188:Potassium