Electrophysiologic, Antiarrhythmic, and Cardioprotective Effects of N-[3,5 Dichlorophenyl] 4-[4-Hydroxy-2-Methoxy-Phenyl] Piperazine Carboxamidine Dihydrochloride (RS-87337)

: N-[3,5-Dichlorophenyl] 4-[4-hydroxy-2-methoxy-phenyl] piperazine carboxamidine dihydrochloride (RS-87337) is a chemically novel antiarrhythmic agent with an electrophysiologic profile characteristic of both class III and class Ia compounds as defined by Vaughan-Williams and Campbell. In isolated superfused guinea pig papillary muscles, RS-87337 (0.1-10 microM) prolonged the duration of the action potential (class III effect) and at higher concentrations (10-30 microM) reduced the maximum rate of membrane depolarisation (class I effect). The rate of onset and of recovery from the latter activity was similar to that of disopyramide, between that of lignocaine and flecainide, which allowed its placement in subclass Ia. When perfused into isolated working rat hearts, RS-87337 (10-1,000 nM) reduced the incidence of ventricular fibrillation that followed coronary artery reperfusion and in anaesthetised rats [RS-87337, 1-5 mg/kg intravenously (i.v.)] enabled more animals to survive the tachycardia, fibrillation, and mortality produced by a similar procedure. In conscious dogs, i.v. (3-10 mg/kg) and oral (15-60 mg/kg) doses of RS-87337 reduced the number of the ectopic electrocardiogram (ECG) complexes observed 24 h after a two-stage coronary ligation. In anaesthetised dogs with paced hearts, i.v. doses of RS-87337 (0.02-5.0 mg/kg) reduced the elevated ECG S-T segment evoked by brief coronary artery occlusion without altering baseline haemodynamic values. We assume that the class III and Ia effects of RS-87337 made an important contribution to the compound's antiarrhythmic and cardioprotective effects.