Department of Cardiology, Medical University Hospital Heidelberg, Heidelberg, Germany (C.S., F.W., A.-R.G., A.R., H.A.K., D.T.); Heidelberg Center for Heart Rhythm Disorders, University Hospital Heidelberg, Heidelberg, Germany (C.S., F.W., A.-R.G., A.R., H.A.K., D.T.); and German Centre for Cardiovascular Research, Heidelberg/Mannheim Partner Site, University of Heidelberg, Heidelberg, Germany (C.S., F.W., H.A.K., D.T.).
Department of Cardiology, Medical University Hospital Heidelberg, Heidelberg, Germany (C.S., F.W., A.-R.G., A.R., H.A.K., D.T.); Heidelberg Center for Heart Rhythm Disorders, University Hospital Heidelberg, Heidelberg, Germany (C.S., F.W., A.-R.G., A.R., H.A.K., D.T.); and German Centre for Cardiovascular Research, Heidelberg/Mannheim Partner Site, University of Heidelberg, Heidelberg, Germany (C.S., F.W., H.A.K., D.T.)
J Pharmacol Exp Ther. 2018 Jun;365(3):614-623. doi: 10.1124/jpet.118.247692. Epub 2018 Apr 11.
Cardiac glycosides have been used in the treatment of arrhythmias for more than 200 years. Two-pore-domain (K) potassium channels regulate cardiac action potential repolarization. Recently, K3.1 [tandem of P domains in a weak inward rectifying K channel (TWIK)-related acid-sensitive K channel (TASK)-1] has been implicated in atrial fibrillation pathophysiology and was suggested as an atrial-selective antiarrhythmic drug target. We hypothesized that blockade of cardiac K channels contributes to the mechanism of action of digitoxin and digoxin. All functional human K channels were screened for interactions with cardiac glycosides. Human K channel subunits were expressed in oocytes, and voltage clamp electrophysiology was used to record K currents. Digitoxin significantly inhibited K3.1 and K16.1 channels. By contrast, digoxin displayed isolated inhibitory effects on K3.1. K3.1 outward currents were reduced by 80% (digitoxin, 1 Hz) and 78% (digoxin, 1 Hz). Digitoxin inhibited K3.1 currents with an IC value of 7.4 M. Outward rectification properties of the channel were not affected. Mutagenesis studies revealed that amino acid residues located at the cytoplasmic site of the K3.1 channel pore form parts of a molecular binding site for cardiac glycosides. In conclusion, cardiac glycosides target human K channels. The antiarrhythmic significance of repolarizing atrial K3.1 current block by digoxin and digitoxin requires validation in translational and clinical studies.
强心苷类药物在心律失常治疗中已经使用了 200 多年。双孔域 (K) 钾通道调节心脏动作电位复极化。最近，K3.1（串联 P 域在弱内向整流钾通道（TWIK）相关酸敏感钾通道（TASK）-1）被认为与心房颤动病理生理学有关，并被提议作为一种心房选择性抗心律失常药物靶点。我们假设阻断心脏 K 通道有助于地高辛和洋地黄毒苷的作用机制。筛选了所有功能性人 K 通道以检测与强心苷的相互作用。在卵母细胞中表达人 K 通道亚基，并使用电压钳电生理学记录 K 电流。地高辛显著抑制 K3.1 和 K16.1 通道。相比之下，洋地黄毒苷对 K3.1 表现出孤立的抑制作用。K3.1 外向电流分别减少 80%（地高辛，1 Hz）和 78%（洋地黄毒苷，1 Hz）。地高辛抑制 K3.1 电流的 IC 值为 7.4 M。通道的外向整流特性不受影响。突变研究表明，位于 K3.1 通道孔细胞质部位的氨基酸残基构成了强心苷分子结合位点的一部分。总之，强心苷类药物的靶点是人类 K 通道。地高辛和洋地黄毒苷阻断复极化心房 K3.1 电流的抗心律失常意义需要在转化和临床研究中进行验证。
