Seyler Claudia, Li Jin, Schweizer Patrick A, Katus Hugo A, Thomas Dierk
Department of Cardiology, Medical University Hospital, Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
Department of Cardiology, Medical University Hospital, Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
Eur J Pharmacol. 2014 Feb 5;724:51-7. doi: 10.1016/j.ejphar.2013.12.030. Epub 2013 Dec 27.
The mixed ion channel blocker, vernakalant (RSD1235), is effective in rapid conversion of atrial fibrillation (AF) to sinus rhythm (SR). Suppression of cardiac two-pore-domain potassium (K2P) channels causes action potential prolongation and has recently been proposed as a novel antiarrhythmic strategy. The objective of this study was to investigate acute effects of vernakalant on human K2P2.1 (TREK-1) and K2P3.1 (TASK-1) channels to provide a more complete picture of its antiarrhythmic mechanism of action. The class IC antiarrhythmic drug flecainide was studied as a comparator agent. Two-electrode voltage clamp and whole-cell patch clamp electrophysiology was used to record K2P currents from Xenopus oocytes and Chinese hamster ovary (CHO) cells. Vernakalant inhibited cardiac K2P2.1 channels expressed in Xenopus oocytes and in CHO cells. The IC50 value obtained from mammalian cells (13.3 µM) was close to the range of vernakalant levels reported in patients (2-8 µM), indicating potential clinical significance of K2P2.1 blockade. Open rectification characteristics and current-voltage relationships of K2P2.1 currents were not affected by vernakalant. Vernakalant did not significantly reduce K2P3.1 currents. Finally, the class I antiarrhythmic drug flecainide had no effect on K2P2.1 or K2P3.1 channels. In conclusion, the recently developed antiarrhythmic drug vernakalant targets human K2P2.1 K(+) background channels. This previously unrecognized inhibitory property adds to the multichannel blocking profile of vernakalant and extends the mechanistic basis for its anti-fibrillatory effect.
混合离子通道阻滞剂维纳卡兰（RSD1235）可有效将心房颤动（AF）快速转复为窦性心律（SR）。抑制心脏双孔结构域钾（K2P）通道可导致动作电位延长，最近已被提出作为一种新型抗心律失常策略。本研究的目的是研究维纳卡兰对人K2P2.1（TREK-1）和K2P3.1（TASK-1）通道的急性作用，以更全面地了解其抗心律失常作用机制。将Ic类抗心律失常药物氟卡尼作为对照药物进行研究。采用双电极电压钳和全细胞膜片钳电生理学方法记录非洲爪蟾卵母细胞和中国仓鼠卵巢（CHO）细胞中的K2P电流。维纳卡兰抑制在非洲爪蟾卵母细胞和CHO细胞中表达的心脏K2P2.1通道。从哺乳动物细胞获得的IC50值（13.3µM）接近患者报告的维纳卡兰水平范围（2-8µM），表明阻断K2P2.1具有潜在的临床意义。维纳卡兰不影响K2P2.1电流的开放整流特性和电流-电压关系。维纳卡兰没有显著降低K2P3.1电流。最后，I类抗心律失常药物氟卡尼对K2P2.1或K2P3.1通道没有影响。总之，最近开发的抗心律失常药物维纳卡兰作用于人类K2P2.1钾背景通道。这种先前未被认识的抑制特性增加了维纳卡兰的多通道阻断特性，并扩展了其抗纤颤作用的机制基础。
