Yan Yannan, Abildgaard Lea, Skarsfeldt Mark Alexander, Bomholtz Sofia Hammami, Sørensen Ulrik, Holst Anders Gaarsdal, Grunnet Morten, Diness Jonas Goldin, Bentzen Bo Hjorth
Department of Biomedical Sciences, University of Copenhagen, Denmark.
Acesion Pharma, Denmark.
Int J Cardiol Heart Vasc. 2025 May 7;59:101699. doi: 10.1016/j.ijcha.2025.101699. eCollection 2025 Aug.
The small conductance calcium activated potassium channel (; K2.1-3) is recognized as a possible new anti-arrhythmic drug target for treatment of atrial fibrillation (AF). The aim of this study is to investigate potential ventricular effects of K2 channel inhibition under normal, bradycardic and hypokalemic conditions and compare these to classical class I and III anti-arrhythmic drugs.
Rabbit hearts were isolated, AV-ablated, mounted in an ex vivo Langendorff preparation and perfused with normokalemic (4 mM K) Krebs-Henseleit solution, followed by perfusion with drug (AP14145 3 µM; AP30663 1.5 µM; dofetilide 10 nM; flecainide 1.5 µM) or vehicle control. The perfusion was then changed to hypokalemic solution (2.5 mM K) in presence of drug. Changes in ventricular action potential duration were assessed by monophasic action potential recordings. Neither of the K2 channel inhibitors (AP14145 or AP30663) or flecainide (Na1.5 inhibitor) prolonged ventricular action potential duration (APD90) or increased pro-arrhythmic markers, whereas dofetilide (K11.1 blocker) prolonged APD and increased the susceptibility to ventricular arrhythmia.
These findings suggests that K2 channels have minimal importance for ventricular repolarization in healthy rabbit hearts under both normo- and hypokalemic conditions.
小电导钙激活钾通道（；K2.1 - 3）被认为是治疗心房颤动（AF）的一种可能的新型抗心律失常药物靶点。本研究的目的是研究在正常、心动过缓和低钾血症条件下抑制K2通道对心室的潜在影响，并将这些影响与经典的I类和III类抗心律失常药物进行比较。
分离兔心脏，进行房室结消融，安装在离体Langendorff装置中，用正常血钾（4 mM K）的Krebs - Henseleit溶液灌注，随后用药物（AP14145 3 μM；AP30663 1.5 μM；多非利特10 nM；氟卡尼1.5 μM）或溶剂对照进行灌注。然后在存在药物的情况下将灌注液换成低钾溶液（2.5 mM K）。通过单相动作电位记录评估心室动作电位时程的变化。K2通道抑制剂（AP14145或AP30663）和氟卡尼（Na1.5抑制剂）均未延长心室动作电位时程（APD90）或增加促心律失常标志物，而多非利特（K11.1阻滞剂）延长了APD并增加了室性心律失常的易感性。
这些发现表明，在正常血钾和低钾血症条件下，K2通道对健康兔心脏的心室复极影响极小。
