Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
HCR (Heidelberg Center for Heart Rhythm Disorders), University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
Europace. 2020 Sep 1;22(9):1409-1418. doi: 10.1093/europace/euaa129.
Non-vitamin K antagonist oral anticoagulants (NOACs) are widely used in the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF). The efficacy of NOACs has been attributed in part to pleiotropic effects that are mediated through effects on thrombin, factor Xa, and their respective receptors. Direct pharmacological effects of NOACs and cardiac ion channels have not been addressed to date. We hypothesized that the favourable clinical outcome of NOAC use may be associated with previously unrecognized effects on atrial repolarizing potassium channels.
This study was designed to elucidate acute pharmacological effects of NOACs on cloned ion channels Kv11.1, Kv1.5, Kv4.3, Kir2.1, Kir2.2, and K2P2.1 contributing to IKr, IKur, Ito, IK1, and IK2P K+ currents. Human genes, KCNH2, KCNA5, KCND3, KCNJ2, KCNJ12, and KCNK2, were heterologously expressed in Xenopus laevis oocytes, and currents were recorded using voltage-clamp electrophysiology. Apixaban, dabigatran, edoxaban, and rivaroxaban applied at 1 µM did not significantly affect peak current amplitudes of Kv11.1, Kv1.5, Kv4.3, Kir2.1, Kir2.2, or K2P2.1 K+ channels. Furthermore, biophysical characterization did not reveal significant effects of NOACs on current-voltage relationships of study channels.
Apixaban, dabigatran, edoxaban, and rivaroxaban did not exhibit direct functional interactions with human atrial K+ channels underlying IKr, IKur, Ito, IK1, and IK2P currents that could account for beneficial clinical outcome associated with the drugs. Indirect or chronic effects and potential underlying signalling mechanisms remain to be investigated.
非维生素 K 拮抗剂口服抗凝剂（NOACs）广泛用于预防非瓣膜性心房颤动（AF）患者的中风和全身性栓塞。NOAC 的疗效部分归因于通过对凝血酶、因子 Xa 及其各自受体的作用产生的多效性效应。迄今为止，尚未涉及 NOAC 和心脏离子通道的直接药理作用。我们假设，NOAC 使用的良好临床结果可能与以前未被认识到的对心房复极化钾通道的影响有关。
本研究旨在阐明 NOAC 对克隆离子通道 Kv11.1、Kv1.5、Kv4.3、Kir2.1、Kir2.2 和 K2P2.1 的急性药理作用，这些离子通道与 IKr、IKur、Ito、IK1 和 IK2P K+电流有关。KCNH2、KCNA5、KCND3、KCNJ2、KCNJ12 和 KCNK2 等人的基因在非洲爪蟾卵母细胞中异源表达，并使用电压钳电生理学记录电流。在 1µM 时，阿哌沙班、达比加群、依度沙班和利伐沙班均未显著影响 Kv11.1、Kv1.5、Kv4.3、Kir2.1、Kir2.2 或 K2P2.1 K+通道的峰值电流幅度。此外，生物物理特性分析并未显示 NOAC 对研究通道电流-电压关系有显著影响。
阿哌沙班、达比加群、依度沙班和利伐沙班与 Kv11.1、Kv1.5、Kv4.3、Kir2.1、Kir2.2 或 K2P2.1 K+通道没有直接的功能相互作用，这些通道构成了 IKr、IKur、Ito、IK1 和 IK2P 电流，而这些电流与药物的有益临床结果有关。间接或慢性作用和潜在的潜在信号机制仍有待研究。
