In vivo electrophysiological effects of a selective slow delayed-rectifier potassium channel blocker in anesthetized dogs: potential insights into class III actions.
OBJECTIVE
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.
Research Center, Department of Medicine, Montreal Heart Institute and University of Montreal, 5000 Belanger Street East, Montreal, Quebec, Canada H1T 1C8.
Hideko
H
Nakashima
Uwe
U
Gerlach
Dietmar
D
Schmidt
Stanley
S
Nattel
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology / Q000627:therapeutic use*; D004285:Dogs; D004562:Electrocardiography; D004594:Electrophysiology; D005260:Female; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D009248:Nadolol / Q000494:pharmacology; D010627:Phenethylamines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*
D000319:Adrenergic beta-Antagonists; D002839:Chromans; C420023:HMR 1556; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D013449:Sulfonamides; D009248:Nadolol; C063533:dofetilide