Effects of dronedarone on Acetylcholine-activated current in rabbit SAN cells

1 The effect of the antiarrhythmic drug dronedarone on the Acetylcholine-activated K+ current (I-K(ACh)) was investigated in single cells isolated from sinoatrial node (SAN) tissue of rabbit hearts. 2 Externally perfused dronedarone (0.001-1 mu M) caused a potent, voltage independent block of I-K(ACh). Fitting of the dose response curve of I-K(ACh) block yielded an IC50 value of 63 nM, a value over one order of magnitude lower than those reported for dronedarone block of other cardiac currents. 3 I-K(ACh) block was not due to an inhibitory action of dronedarone on the muscarinic M2 receptor activation, since the drug was effective on I-K(ACh) constitutively activated by intracellular perfusion with GTP-gamma S. 4 External cell perfusion with dronedarone inhibited the activity of I-K(ACh) channels recorded from cell-attached patches by reducing the channel open probability (from 0.56 to 0.11) without modification of the single-channel conductance. 5 These data suggest that dronedarone blocks I-K(ACh) channels either by disrupting the G-protein-mediated activation or by a direct inhibitory interaction with the channel protein.