NaV1.5 or KCa2 channel blockade does not increase arrhythmia risk in hypokalemic rabbit hearts, unlike KV11.1 inhibition with dofetilide

IF 2.5 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS

IJC Heart and Vasculature Pub Date : 2025-05-07 DOI:10.1016/j.ijcha.2025.101699

Yannan Yan , Lea Abildgaard , Mark Alexander Skarsfeldt , Sofia Hammami Bomholtz , Ulrik Sørensen , Anders Gaarsdal Holst , Morten Grunnet , Jonas Goldin Diness , Bo Hjorth Bentzen

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引用次数: 0

Abstract

Aims

The small conductance calcium activated potassium channel (KCNN1-3; K_Ca2.1–3) 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 K_Ca2 channel inhibition under normal, bradycardic and hypokalemic conditions and compare these to classical class I and III anti-arrhythmic drugs.

Methods and results

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 K_Ca2 channel inhibitors (AP14145 or AP30663) or flecainide (Na_V1.5 inhibitor) prolonged ventricular action potential duration (APD90) or increased pro-arrhythmic markers, whereas dofetilide (K_V11.1 blocker) prolonged APD and increased the susceptibility to ventricular arrhythmia.

Conclusions

These findings suggests that K_Ca2 channels have minimal importance for ventricular repolarization in healthy rabbit hearts under both normo- and hypokalemic conditions.

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与多非利特抑制KV11.1不同，NaV1.5或KCa2通道阻断不会增加低钾血症兔心脏心律失常的风险

目的：小电导钙活化钾通道(KCNN1-3；KCa2.1-3)被认为是治疗心房颤动（AF）可能的新的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KCa2通道抑制的潜在心室效应，并将其与经典的I类和III类抗心律失常药物进行比较。方法和结果兔心脏分离，经av消融，置于离体Langendorff制剂中，灌注等钾化（4 mM K+） Krebs-Henseleit溶液，再灌注药物(AP14145 3µM；Ap30663 1.5µm；多非利特10 nM；flecainide 1.5µM)或车辆控制。然后在药物存在的情况下将灌注改为低钾溶液（2.5 mM K+）。通过单相动作电位记录评估心室动作电位持续时间的变化。KCa2通道抑制剂（AP14145或AP30663）或flecainide （NaV1.5抑制剂）均未延长心室动作电位持续时间（APD90）或增加促心律失常标志物，而多非利特（KV11.1阻滞剂）延长APD并增加室性心律失常的易感性。这些发现表明，在正常和低钾条件下，KCa2通道对健康兔心脏心室再极化的重要性很小。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

IJC Heart and Vasculature Medicine-Cardiology and Cardiovascular Medicine

CiteScore

4.90

自引率

10.30%

发文量

216

审稿时长

56 days

期刊介绍： IJC Heart & Vasculature is an online-only, open-access journal dedicated to publishing original articles and reviews (also Editorials and Letters to the Editor) which report on structural and functional cardiovascular pathology, with an emphasis on imaging and disease pathophysiology. Articles must be authentic, educational, clinically relevant, and original in their content and scientific approach. IJC Heart & Vasculature requires the highest standards of scientific integrity in order to promote reliable, reproducible and verifiable research findings. All authors are advised to consult the Principles of Ethical Publishing in the International Journal of Cardiology before submitting a manuscript. Submission of a manuscript to this journal gives the publisher the right to publish that paper if it is accepted. Manuscripts may be edited to improve clarity and expression.