Antiarrhythmic Effects of MS-551, a New Class III Antiarrhythmic Agent, on Canine Models of Ventricular Arrhythmia.

Abstract

ABSTRACT-The antiarrhythmic effects of MS-551, which prolongs cardiac action potential duration without affecting the maximum upstroke velocity of the action potential, were assessed in three different canine ventricular arrhythmia models: 1) ventricular tachycardia (VT) induced by electrical stimuli 3-5 days after myocardial infarction, 2) spontaneous ventricular tachyarrhythmias 24 48 hr after two-stage coronary ligation and 3) ventricular tachyarrhythmias induced by digitalis. Intravenous administration of MS-551 (0.1-1 mg/kg) decreased the susceptibility in 10 dogs out of 13 to VT or ventricular fibrillation evoked by programmed electrical stimulation (PES) delivered to the ventricular septum 3 5 days after myocardial infarction. Oral administration of MS-551 (3 mg/kg) also decreased the susceptibility to VT evoked by PES in 7 out of 10 conscious postinfarction dogs. Concurrently, intravenous (0.1-1 mg/kg) or oral (3 mg/kg) administration of MS-551 produced increases in the ven tricular effective refractory periods (ERP) by 7 ± 1%-17 ± 3% or 13 ± 2%, respec tively. Similarly, d-sotalol (0.3-3 mg/kg, i.v. and 10 mg/kg, p.o.) decreased the sus ceptibility to VT with increased ERP. However, MS-551 (1 and 10 mg/kg, i.v.) failed to inhibit both canine two-stage coronary ligation arrhythmia and digitalis arrhythmia. These results suggest that MS-551 is a pure class III antiarrhythmic drug which may be effective in the treatment of life-threatening reentrant tachyarrhythmias, but not in automaticity arrhythmias.

Frequency-Dependent Electrophysiological Effects of Flecainide, Nifekalant and <i>d,l</i>-Sotalol on the Human Atrium

“…Although class III antiarrhythmic drugs can terminate tachyarrhythmia, the effect is relatively weak because of the reverse use-dependency; 18 however, Kamiya et al reported that nifekalant decreased the inducibility of reentrant ventricular tachycardia by extra-stimuli in 3-5 days after myocardial infarction in dogs because of prolongation of ERP. 19 Furthermore, they and Kunimoto et al reported that the extent of ERP prolongation by nifekalant is greater in atrial muscle compared with ventricular muscle, 18,20 which might be effective for terminating and preventing atrial flutter and fibrillation. However, Hirata et al reported that nifekalant increased the vulnerability to atrial fibrillation when the effects of nifekalant on termination and prevention of atrial fibrillation and flutter were studied in a canine model.…”

Effects of MS‐551, a new class III antiarrhythmic drug, on action potential and membrane currents in rabbit ventricular myocytes

“…MS-551 is a new class III drug having a pirimidinedione structure (Figure 1), which is reported to prolong ventricular ERP and exert antifibrillatory action in dogs with myocardial infarction (Kamiya et al, 1992). However, the underlying ionic mechanism(s) responsible for class III effect of MS-551 have not been evaluated.…”

Arrhythmia Models for Drug Research: Classification of Antiarrhythmic Drugs

“…Consistent effectiveness was observed for K + -channel blockers, azimilide (75), dofetilide (48), KCB-328 (49), nifekalant (80), and sematilide (47), with simultaneous QT prolongation in ECG (6). Usually the control arrhythmias were set up as severe ones by applying 3 premature extrastimuli.…”