Novel electrophysiological properties of dronedarone: inhibition of human cardiac two-pore-domain potassium (K2P) channels.
Dronedarone is currently used for the treatment of paroxysmal and persistent atrial fibrillation (AF). Pharmacological inhibition of cardiac two-pore-domain potassium (K(2P)) channels results in action potential prolongation and has recently been proposed as novel antiarrhythmic strategy. We hypothesized that blockade of human K(2P) channels contributes to the electrophysiological efficacy of dronedarone in AF. Two-electrode voltage clamp and whole-cell patch clamp electrophysiology was used to record K(2P) currents from Xenopus oocytes and Chinese hamster ovary cells. All functional human K(2P) channels were screened for dronedarone sensitivity, revealing significant and concentration-dependent inhibition of cardiac K(2P)2.1 (TREK1; IC(50) = 26.7 μM) and K(2P)3.1 channels (TASK1; IC(50) = 18.7 μM) with maximum current reduction of 60.3 and 65.5 % in oocytes. IC(50) values obtained from mammalian cells yielded 6.1 μM (K(2P)2.1) and 5.2 μM (K(2P)3.1). The molecular mechanism of action was studied in detail. Dronedarone block affected open and closed channels. K(2P)3.1 currents were reduced in frequency-dependent fashion in contrast to K(2P)2.1. Mutagenesis studies revealed that amino acid residues implicated in K(2P)3.1 drug interactions were not required for dronedarone blockade. The class III antiarrhythmic drug dronedarone targets multiple human cardiac two-pore-domain potassium channels, including atrial-selective K(2P)3.1 currents. K(2P) current inhibition by dronedarone represents a previously unrecognized mechanism of action that extends the multichannel blocking profile of the drug.
Department of Cardiology, Medical University Hospital, Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
Constanze
C
Schmidt
Felix
F
Wiedmann
Patrick A
PA
Schweizer
Rüdiger
R
Becker
Hugo A
HA
Katus
Dierk
D
Thomas
D000638:Amiodarone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D000077764:Dronedarone; D015640:Ion Channel Gating / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors* / Q000235:genetics; D014162:Transfection; D014982:Xenopus laevis
D026902:Potassium Channel Blockers; D024683:Potassium Channels, Tandem Pore Domain; D000077764:Dronedarone; D000638:Amiodarone