Vol. 285, Issue 2, 687-694, May 1998

Electrophysiological Effects of MS-551, a New Class III Agent: Comparison with dl-Sotalol in Dogs¹

Luyi Sen, Guanggen Cui, Yoshihide Sakaguchi and Bramah N. Singh

Cardiovascular Research Laboratory and the Division of Cardiology, VAMC/LA and UCLA School of Medicine, Los Angeles, California

MS-551 is a newly synthesized, nonspecific K⁺ channel blocker. To elucidate its electrophysiological and potential proarrhythmic effects relative to those of dl-sotalol in vivo, serial changes in ECGs, endocardial and epicardial monophasic action potential durations, and left and right ventricular pressures were measured simultaneously in pentobarbital-anesthetized open-chest dogs. Complete heart block was produced by the injection of 37% formaldehyde into the atrioventricular node. Intravenous administration of MS-551 produced prolongation of action potential duration at 90% repolarization time (APD₉₀) immediately after the beginning of infusion and reached plateau at 10 min. MS-551 (1 mg/kg) caused 73 ± 8% increase in APD₉₀ and 28 ± 5% increase in QT_c at basic cycle length of 700 msec. The maximal prolongation of APD₉₀ induced by 1 mg/kg MS-551 was 39% greater than that by the same dose of sotalol (P < .01). The dose-response curve of prolongation of ventricular effective refractory period produced by MS-551 was shifted significantly to the left compared with that induced by sotalol. The EC₅₀ was 0.5 ± 0.1 mg/kg and 1.2 ± 0.2 mg/kg for MS-551 and sotalol, respectively (P < .05). When 0.5 mg/kg MS-551 doses were used, no ventricular arrhythmia was induced by stimulation at 200-msec basic cycle length. When 1.5 mg/kg sotalol was administered, 5 of 15 developed torsade de pointes, 2 of 15 developed ventricular fibrillation and 5 of 15 developed sustained ventricular tachycardia. The idioventricular rates and left ventricular pressures were reduced significantly by sotalol, not by MS-551. In conclusion, MS-551 is a potent class III antiarrhythmic agent that selectively prolongs repolarization in the ventricular myocardium and appears to be devoid of autonomic effects. Dose for dose, it is more potent in prolonging the APD₉₀ and the right ventricular effective refractory period possibly with a lower tendency for the development of proarrhythmia in a canine heart-block model.