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.
BACKGROUND AND PURPOSE:HumanK(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 humanK(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.
Authors: Birgit C Donner; Martina Schullenberg; Nora Geduldig; Anja Hüning; Jan Mersmann; Kai Zacharowski; Alexander Kovacevic; Ulrich Decking; Maria Isabel Aller; Klaus G Schmidt Journal: Basic Res Cardiol Date: 2010-10-27 Impact factor: 17.165
Authors: J Christopher Merritt; Mark Niebauer; Khaldoun Tarakji; Donald Hammer; Roger M Mills Journal: Am J Cardiol Date: 2003-09-15 Impact factor: 2.778
Authors: Philip A Poole-Wilson; Karl Swedberg; John G F Cleland; Andrea Di Lenarda; Peter Hanrath; Michel Komajda; Jacobus Lubsen; Beatrix Lutiger; Marco Metra; Willem J Remme; Christian Torp-Pedersen; Armin Scherhag; Allan Skene Journal: Lancet Date: 2003-07-05 Impact factor: 79.321
Authors: Ann-Kathrin Rahm; Jakob Gierten; Jana Kisselbach; Ingo Staudacher; Kathrin Staudacher; Patrick A Schweizer; Rüdiger Becker; Hugo A Katus; Dierk Thomas Journal: Br J Pharmacol Date: 2012-05 Impact factor: 8.739
Authors: C Seyler; E Duthil-Straub; E Zitron; J Gierten; E P Scholz; R H A Fink; C A Karle; R Becker; H A Katus; D Thomas Journal: Br J Pharmacol Date: 2012-03 Impact factor: 8.739
Authors: Ann-Kathrin Rahm; Felix Wiedmann; Jakob Gierten; Constanze Schmidt; Patrick A Schweizer; Rüdiger Becker; Hugo A Katus; Dierk Thomas Journal: Naunyn Schmiedebergs Arch Pharmacol Date: 2013-12-06 Impact factor: 3.000
Authors: J Jehle; E Ficker; X Wan; I Deschenes; J Kisselbach; F Wiedmann; I Staudacher; C Schmidt; P A Schweizer; R Becker; H A Katus; D Thomas Journal: Br J Pharmacol Date: 2013-03 Impact factor: 8.739
Authors: J Kisselbach; C Seyler; P A Schweizer; R Gerstberger; R Becker; H A Katus; D Thomas Journal: Br J Pharmacol Date: 2014-08-28 Impact factor: 8.739
Authors: Ingo Staudacher; Claudius Illg; Sam Chai; Isabelle Deschenes; Sebastian Seehausen; Dominik Gramlich; Mara Elena Müller; Teresa Wieder; Ann-Kathrin Rahm; Christina Mayer; Patrick A Schweizer; Hugo A Katus; Dierk Thomas Journal: Naunyn Schmiedebergs Arch Pharmacol Date: 2018-07-14 Impact factor: 3.000
Authors: Constanze Schmidt; Felix Wiedmann; Patrick A Schweizer; Rüdiger Becker; Hugo A Katus; Dierk Thomas Journal: Naunyn Schmiedebergs Arch Pharmacol Date: 2012-07-13 Impact factor: 3.000