MS‐551: Pharmacological profile of a novel class III antiarrhythmic agent

Abstract

Abstract The class II antiarrhythmic agent properties of the novel compound MS‐551 (1,3‐dimethyl‐6‐{(2‐[N‐(2‐hydroxyethyl‐3‐(4‐nitrophenyl)propylamino]ethylamino} ) 2,4 (1H3H)‐pyrimidinedione hydrochloride) have been characterized in vitro and in vivo. Using isolated canine Purkinje fibers, the effect of MS551 on the action potentials was studied. MS‐551 (0.1‐10μg/ml) caused a uniform and concentration‐dependent increase in action potential duration without changing parameters of action potential depolarization. IN anesthetized open‐chested dogs. MS‐551 (0.1‐10 mg/kg i,v.) produced a dose‐dependent increase in both atrial and ventricular effective refractory periods 9ERP) with QT c prolongation. At 0.3 mg/kg i.v., atrial and ventricular ERP were significantly increased 28 ± 4 mec and 12 ± 2 msec, respectively, and the minimum e4ffective plasma concentration of MS‐551 for atrial ERP prolongation was approximately 0.1 μg/ml. However, MS‐551 did not slow intracardiac conduction time (A‐H, H‐V) even at the highest dose studied (30 mg/kg i.v.). These data suggest that MS‐551 has a “pure” class III electrophysioloigcal property in dogs. 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) produced dose‐dependent decrease in heart rate with QT c prolongation and slight increase in LVdP/dtmax. In contrast d ‐sotalol (0.1‐10 mg/kg i.v.) depcreased heart rate, mean arterial pressure, LVdP/dtmax and aortic flow in a dose‐dependent manner. Moreover, we reassessed in anesthetized dogs the cardiovascular toxicity of continuously infused MS‐551 (2 mg/kg/min for 50 min). Ath 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 , were not seen. In conclusion, MS‐551 appears to be a pure and potent class III antiarrhythmic agent with a favourable hemodhynamic profile. © 1993 wiley‐Liss, Inc.