MS-551 - PHARMACOLOGICAL PROFILE OF A NOVEL CLASS-III ANTIARRHYTHMIC AGENT

The class III antiarrhythmic agent properties of the novel compound MS -551 oxyethyl)-3-(4-nitrophenyl)propylamino]ethylamino} 2,4 (1H,3H)-py rimidinedione hydrochloride) have been characterized in vitro and in v ivo. Using isolated canine Purkinje fibers, the effect of MS-551 on th e action potentials was studied. MS-551 (0.7-10 mu g/ml) caused a unif orm and concentration-dependent increase in action potential duration without changing parameters of action potential depolarization. In ane sthetized open-chested dogs, MS-551 (0.1-10 mg/kg i,v.) produced a dos e-dependent increase in both atrial and ventricular effective refracto ry periods (ERP) with QT(c) prolongation. At 0.3 mg/kg i.v., atrial an d ventricular ERP were significantly increased 28 +/- 4 msec and 12 +/ - 2 msec, respectively, and the minimum effective plasma concentration of MS-551 for atrial ERP prolongation was approximately 0.1 mu g/ml. However, MS-551 did not slow intracardiac conduction time (A-H, H-V) e ven at the highest dose studied (30 mg/kg i.v.). These data suggest th at MS-551 has a ''pure'' class III electrophysiological property in do gs. Furthermore, we compared the effects of MS-551 on the hemodynamics in anesthetized dogs with those of d-sotalol. MS-551 (0.1-3 mg/kg) pr oduced dose-dependent decrease in heart rate with QT(c) prolongation a nd slight increase in LVdP/dtmax. In contrast, d-sotalol (0.1-10 mg/kg i.v.) decreased heart rate, mean arterial pressure, LVdP/dtmax and ao rtic flow in a dose-dependent manner. Moreover, we reassessed in anest hetized dogs the cardiovascular toxicity of continuously infused MS-55 1 (2 mg/kg/min for 50 min). At the end of the infusion (total dose: MS -551 100 mg/kg), LVdP/dtmax was decreased 23%, but QT(c) prolongation never exceeded 30%. Thus, arrhythmias, such as torsade de pointes, wer e not seen. In conclusion, MS-551 appears to be a pure and potent clas s III antiarrhythmic agent with a favourable hemodynamic profile. (C) 1993 Wiley-Liss, Inc.