Abstract
MS-551 is a newly synthesized, nonspecific K+ channel blocker. To elucidate its electrophysiological and potential proarrhythmic effects relative to those of dl-sotalolin 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 QTc 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.
Footnotes
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Send reprint requests to: Luyi Sen, M.D, Division of Cardiology, Department of Medicine, UCLA Medical Center, UCLA School of Medicine, 47–123 CHS, 10833 Le Conte Ave., Los Angeles, CA 90095-1679.
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↵1 This work was supported by the Institute of Biological Sciences, Mitsui Pharmaceuticals, Inc, Tokyo, Japan.
- Abbreviations:
- APD90
- action potential duration at 90% repolarization time
- LVP
- left ventricular pressure
- RVP
- right ventricular pressure
- TdP
- torsade de pointes
- IVR
- idioventricular rate
- VT
- ventricular tachycardia
- NSVT
- nonsustained ventricular tachycardia
- SVT
- sustained ventricular tachycardia
- VF
- ventricular fibrillation
- RVERP
- right ventricular effective refractory period
- MAP
- monophasic action potential
- Received August 21, 1997.
- Accepted January 5, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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