© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
In vivo electrophysiological effects of a selective slow delayed-rectifier potassium channel blocker in anesthetized dogs: potential insights into class III actions
aResearch Center, Department of Medicine, Montreal Heart Institute and University of Montreal, 5000 Belanger Street East, Montreal, Quebec, Canada H1T 1C8
bAventis Pharmaceuticals, Frankfurt, Germany
* Corresponding author. Tel.: +1-514-376-3330; fax: +1-514-376-1355. nattel{at}icm.umontreal.ca
Objectives: This study evaluated the in vivo electrophysiological effects of a highly selective slow delayed-rectifier K+-current blocker, HMR 1556, to gain insights into the consequences of selectively inhibiting the slow delayed-rectifier current in vivo. Methods: Atrial and ventricular effective refractory periods, sinus node recovery time, Wenckebach cycle-length, atrial fibrillation duration and electrocardiographic intervals were measured before and after intravenous HMR 1556. Results: HMR 1556 increased atrial and ventricular refractory periods (e.g. by 6±4% and 27±6% at cycle lengths of 360 and 400 ms, respectively), QT intervals and sinus-node recovery times. Beta-adrenoceptor blockade with nadolol abolished all effects except those on ventricular refractoriness and changed positive use-dependent effects on refractoriness to reverse use-dependent ones. In the presence of dofetilide to block rapid delayed-rectifier current, HMR 1556 effects were potentiated (e.g. atrial and ventricular refractory periods increased by 26±3% and 34±3% at cycle lengths of 360 and 400 ms, respectively). HMR 1556 reduced vagal atrial fibrillation duration from 1077±81 to 471±38 s, an effect abolished by nadolol and greatly potentiated by dofetilide (duration 77±30 s). HMR 1556 increased Wenckebach cycle length only in the presence of dofetilide. Conclusions: Slowed delayed-rectifier current inhibition affects atrial repolarization, sinus node function and atrial fibrillation in vivo, but only in the presence of intact beta-adrenergic tone, and delays ventricular repolarization even when beta-adrenoceptors are blocked. The slow delayed-rectifier current is particularly important when rapid delayed-rectifier current is suppressed, illustrating the importance of repolarization reserve.
KEYWORDS Antiarrhythmic agents; Arrhythmia (mechanisms); Ion channels; K-channel; Long QT syndrome
Time for primary review 22 days
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