Inhibitory effects of dronedarone on muscarinic K+ current in guinea pig atrial cells

Dronedarone (SR33589), an amiodarone-like noniodinated antiarrhythmic agent, is undergoing clinical trials in atrial fibrillation. Because vagal activation plays a role in the pathophysiology of supraventricular arrhythmias, we have assessed the ability of dronedarone (0.01, 0.1, and 1 microM), compared with amiodarone (0.1, 1, and 10 microM) to inhibit the muscarinic acetylcholine receptor-operated K+ current (I(K(ACh))) in single cells isolated from guinea pig atria (patch-clamp technique). I(K(ACh)) was activated by extracellular application of carbachol (10 microM) or by intracellular loading with GTP-gamma-S (100 microM). Dronedarone and amiodarone reduced the carbachol-induced I(K(ACh)) with an IC50 (concentration required for 50% inhibition) slightly above 10 nM and 1 microM, respectively. Dronedarone also inhibited the GTP-gamma-S induced K+ current by 28% and 58% at 0.01 and 0.1 microM, respectively. These data suggest that dronedarone inhibits I(K(ACh)) by depressing the function of K(ACh) channel itself or associated GTP-binding proteins. Compared with amiodarone, dronedarone is approximately 100 times more potent on I(K(ACh)) and seems more selective in inhibiting I(K(ACh)) with respect to its antagonism of other inward and outward currents reported in the literature. This relative high potency of dronedarone to reduce I(K(ACh)) may be involved, at least in part, in the antiarrhythmic action of dronedarone against atrial fibrillation.