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Carvedilol targets human K 2P 3.1 (TASK1) K + leak channels
Author(s) -
Staudacher K,
Staudacher I,
Ficker E,
Seyler C,
Gierten J,
Kisselbach J,
Rahm AK,
Trappe K,
Schweizer PA,
Becker R,
Katus HA,
Thomas D
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2011.01319.x
Subject(s) - carvedilol , repolarization , electrophysiology , membrane potential , cardiac action potential , pharmacology , medicine , voltage clamp , purkinje fibers , effective refractory period , patch clamp , antiarrhythmic agent , anti arrhythmia agents , potassium channel , atrial action potential , chemistry , atenolol , mexiletine , atrial fibrillation , heart failure , heart disease , biochemistry , blood pressure
BACKGROUND AND PURPOSE Human K 2P 3.1 (TASK1) channels represent potential targets for pharmacological management of atrial fibrillation. K 2P channels control excitability by stabilizing membrane potential and by expediting repolarization. In the heart, inhibition of K 2P currents by class III antiarrhythmic drugs results in action potential prolongation and suppression of electrical automaticity. Carvedilol exerts antiarrhythmic activity and suppresses atrial fibrillation following cardiac surgery or cardioversion. The objective of this study was to investigate acute effects of carvedilol on human K 2P 3.1 (hK 2P 3.1) channels. EXPERIMENTAL APPROACH Two‐electrode voltage clamp and whole‐cell patch clamp electrophysiology was used to record hK 2P 3.1 currents from Xenopus oocytes, Chinese hamster ovary (CHO) cells and human pulmonary artery smooth muscle cells (hPASMC). KEY RESULTS Carvedilol concentration‐dependently inhibited hK 2P 3.1 currents in Xenopus oocytes (IC 50 = 3.8 µM) and in mammalian CHO cells (IC 50 = 0.83 µM). In addition, carvedilol sensitivity of native I K2P3.1 was demonstrated in hPASMC. Channels were blocked in open and closed states in frequency‐dependent fashion, resulting in resting membrane potential depolarization by 7.7 mV. Carvedilol shifted the current–voltage (I–V) relationship by −6.9 mV towards hyperpolarized potentials. Open rectification, characteristic of K 2P currents, was not affected. CONCLUSIONS AND IMPLICATIONS The antiarrhythmic drug carvedilol targets hK 2P 3.1 background channels. We propose that cardiac hK 2P 3.1 current blockade may suppress electrical automaticity, prolong atrial refractoriness and contribute to the class III antiarrhythmic action in patients treated with the drug.