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

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Abstract
The effect of the antiarrhythmic drug dronedarone on the Acetylcholine-activated K+ current (IK(ACh)) was investigated in single cells isolated from sinoatrial node (SAN) tissue of rabbit hearts.Externally perfused dronedarone (0.001–1 μM) caused a potent, voltage independent block of IK(ACh). Fitting of the dose response curve of IK(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.IK(ACh) block was not due to an inhibitory action of dronedarone on the muscarinic M2 receptor activation, since the drug was effective on IK(ACh) constitutively activated by intracellular perfusion with GTP-γS.External cell perfusion with dronedarone inhibited the activity of IK(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.These data suggest that dronedarone blocks IK(ACh) channels either by disrupting the G-protein-mediated activation or by a direct inhibitory interaction with the channel protein.