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 activ ation plays a role in the pathophysiology of supraventricular arrhythmias, we have assessed the ability of dronedarone (0.01, 0.1, and 1 muM), compare d with amiodarone (0.1, 1, and 10 muM) to inhibit the muscarinic acetylchol ine receptor-operated K+ current (I-K(ACh)) in single cells isolated from g uinea pig atria (patch-clamp technique). I-K(ACh) was activated by extracel lular application of carbachol (10 muM) or by intracellular loading with GT P-gamma -S (100 muM). Dronedarone and amiodarone reduced the carbachol-indu ced I-K(ACh) with an IC50 (concentration required for 50% inhibition) sligh tly above 10 nM and 1 muM, respectively. Dronedarone also inhibited the GTP -gamma -S induced K+ current by 28% and 58% at 0.01 and 0.1 muM, respective ly. These data suggest that dronedarone inhibits I-K(ACh) by depressing the function of K-ACh channel itself or associated GTP-binding proteins. Compa red 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 it s antagonism of other inward and outward currents reported in the literatur e. This relative high potency of dronedarone to reduce I-K(ACh) may be invo lved, at least in part, in the antiarrhythmic action of dronedarone against atrial fibrillation.