Effects of a new class III antiarrhythmic drug nibentan in a canine model of vagally mediated atrial fibrillation.
Nibentan, a new class III antiarrhythmic drug, is highly effective in patients with atrial flutter and fibrillation. However, its mechanism of action remains unclear. The aim of this study was to investigate the effects of nibentan using a canine model of vagally sustained atrial fibrillation (AF). Nibentan was intravenously infused to anesthetized open-chest dogs during vagally induced AF. Cumulative doses of nibentan (0.063, 0.125, and 0.250 mg/kg) successfully terminated AF in 78, 88, and 100% as well as prevented AF reinduction in 11, 63, and 90% of cases, respectively. All doses of nibentan significantly and rate-independently increased atrial effective refractory period (AERP) with and without vagal stimulation. Activation mapping (224 epicardial electrodes) during AF showed that nibentan reduced the number of simultaneously occurring reentrant wavelets. Herewith the atrial excitation slowed down until conduction failure of reentrant wavelets led to arrhythmia termination. These changes in activation patterns can be accounted for by nibentan-induced increase of AERP (55 +/- 9%, 82 +/- 12%, and 90 +/- 6%; p < 0.01) and wavelength for reentry (47 +/- 7%, 68 +/- 12%, and 72 +/- 4%; p < 0.01) at rapid atrial rates in the presence of vagal stimulation. In conclusion, the high efficacy of nibentan against AF was associated with significant rate-independent increase in AERP and in wavelength, and might be in part explained by block of both delayed rectifier (I(K)) and muscarinic I(K,ACh) currents.
Fedorov
V V
VV
Laboratory of Heart Electrophysiology, Institute of Experimental Cardiology, Cardiology Research Center, Moscow, Russia. lvros@mail.sitek.ru
Sharifov
O F
OF
Beloshapko
G G
GG
Yushmanova
A V
AV
Rosenshtraukh
L V
LV
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000188:drug therapy*; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004558:Electric Stimulation / Q000009:adverse effects; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D014630:Vagus Nerve
D000889:Anti-Arrhythmia Agents; D001549:Benzamides; C105049:nibentan