Abstract
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.