Cardiac K2P13.1 (THIK-1) two-pore-domain K+ channels: Pharmacological regulation and remodeling in atrial fibrillation.

Cardiac two-pore-domain potassium (K 2P) channels have been proposed as novel antiarrhythmic targets. K 2P 13.1 (THIK-1) channels are expressed in the human heart, and atrial K 2P 13.1 levels are reduced in patients with atrial fibrillation (AF) or heart failure. The first objective of this study was to investigate acute effects of antiarrhythmic drugs on human K 2P 13.1 currents. Second, we assessed atrial K 2P 13.1 remodeling in AF pigs to validate the porcine model for future translational evaluation of K 2P 13.1-based antiarrhythmic concepts. K 2P 13.1 protein expression was studied in domestic pigs during AF induced by atrial burst pacing. AF was associated with 66% reduction of K 2P 13.1 levels in the right atrium at 21-day follow-up. Voltage clamp electrophysiology was employed to elucidate human K 2P 13.1 channel pharmacology in Xenopus oocytes. Propafenone (−26%; 100 μM), mexiletine (−75%; 1.5 mM), propranolol (−38%; 200 μM), and lidocaine (−59%; 100 μM) significantly inhibited K 2P 13.1 currents. By contrast, K 2P 13.1 channels were not markedly affected by quinidine, carvedilol, metoprolol, amiodarone and verapamil. Concentration-dependent K 2P 13.1 blockade by mexiletine occurred rapidly with membrane depolarization and was frequency-independent. Mexiletine reduced K 2P 13.1 open rectification properties and shifted current-voltage relationships towards more negative potentials. In conclusion, atrial expression and AF-associated downregulation of K 2P 13.1 channels in a porcine model resemble human findings and support a general role for K 2P 13.1 in AF pathophysiology. K 2P 13.1 current sensitivity to antiarrhythmic drugs provides a starting point for further development of an emerging antiarrhythmic paradigm. [ABSTRACT FROM AUTHOR]