An exploratory analysis of effects of poyendarone, a deuterated analogue of dronedarone, on the canine model of paroxysmal atrial fibrillation

Abstract

Poyendarone, a deuterated analogue of dronedarone, is expected to reduce the onset of cardiovascular adverse events of dronedarone, including congestive heart failure and excessive QT-interval prolongation. Since information is still lacking on the anti-atrial fibrillatory property of poyendarone, we assessed it along with effects on the inter-atrial conduction time (IACT) and atrial effective refractory period (AERP) using the canine paroxysmal atrial fibrillation model. Poyendarone hydrochloride (n = 4) and dronedarone hydrochloride (n = 4) in intravenous doses of 0.3 and 3 mg/kg/30 s were cumulatively administered. Poyendarone hardly altered sinoatrial rate, but dronedarone decreased it in a dose-related manner, whereas both drugs slightly but significantly reduced idioventricular rate. Poyendarone shortened duration of burst pacing-induced atrial fibrillation, whereas such abbreviation was not observed by dronedarone. Poyendarone and dronedarone similarly prolonged IACT in a frequency-dependent manner, indicating that their I_Na inhibitory actions may be similar. The high dose of poyendarone prolonged AERP in a reverse frequency-dependent manner, extent of which at basic pacing cycle lengths of 300 and 400 ms was comparable to that of dronedarone. However, the extent at a basic pacing cycle length of 200 ms was tended to be greater in poyendarone than in dronedarone, suggesting greater I_Ks inhibitory action of poyendarone. The deuteration of dronedarone attenuated the inhibition of sinus automaticity and prolonged the AERP with keeping the blood pressure and ventricular rate stable. Thus, poyendarone may have both more potent anti-atrial fibrillatory action and wider cardiovascular safety margin than dronedarone.