Exenatide reduces atrial fibrillation susceptibility by inhibiting hKv1.5 and hNav1.5 channels

Qian Zhou; Guoliang Hao; Wensen Xie; Bin Chen; Wuguang Lu; Gongxin Wang; Rongling Zhong; Jiao Chen; Juan Ye; Jianping Shen; Peng Cao

doi:10.1016/j.jbc.2024.107294

Exenatide reduces atrial fibrillation susceptibility by inhibiting hKv1.5 and hNav1.5 channels

J Biol Chem. 2024 Apr 16;300(5):107294. doi: 10.1016/j.jbc.2024.107294. Online ahead of print.

Authors

Qian Zhou¹, Guoliang Hao², Wensen Xie¹, Bin Chen³, Wuguang Lu¹, Gongxin Wang⁴, Rongling Zhong¹, Jiao Chen¹, Juan Ye¹, Jianping Shen¹, Peng Cao⁵

Affiliations

¹ Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
² Institute of Electrophysiology, Henan Academy of Innovations in Medical Science, Zhengzhou, China; Henan SCOPE Research Institute of Electrophysiology Co Ltd, Kaifeng, China; Burdon Sanderson Cardiac Science Centre and BHF Centre of Research Excellence, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
³ Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China; Nanjing Research Institute for Comprehensive Utilization of Wild Plants, Nanjing, China.
⁴ Institute of Electrophysiology, Henan Academy of Innovations in Medical Science, Zhengzhou, China; Henan SCOPE Research Institute of Electrophysiology Co Ltd, Kaifeng, China.
⁵ Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China; State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, China; Animal-Derived Chinese Medicine and Functional Peptides International Collaboration Joint Laboratory, Nanjing University of Chinese Medicine, Nanjing, China; Shandong Academy of Chinese Medicine, Jinan, China. Electronic address: cao_peng@njucm.edu.cn.

PMID: 38636665
DOI: 10.1016/j.jbc.2024.107294

Abstract

Exenatide, a promising cardioprotective agent, protects against cardiac structural remodeling and diastolic dysfunction. Combined blockade of sodium and potassium channels is valuable for managing atrial fibrillation (AF). Here, we explored whether exenatide displayed anti-AF effects by inhibiting human Kv1.5 and Nav1.5 channels. We used the whole-cell patch-clamp technique to investigate the effects of exenatide on hKv1.5 and hNav1.5 channels expressed in human embryonic kidney 293 cells and studied the effects of exenatide on action potential (AP) and other cardiac ionic currents in rat atrial myocytes. Additionally, an electrical mapping system was used to explore the effects of exenatide on electrical properties and AF activity in isolated rat hearts. Finally, a rat AF model, established using acetylcholine and calcium chloride, was employed to evaluate the anti-AF potential of exenatide in rats. Exenatide reversibly suppressed I_Kv1.5 with IC₅₀ of 3.08 μM, preferentially blocked the hKv1.5 channel in its closed state, and positively shifted the voltage-dependent activation curve. Exenatide also reversibly inhibited I_Nav1.5 with IC₅₀ of 3.30 μM, negatively shifted the voltage-dependent inactivation curve, and slowed its recovery from inactivation with significant use-dependency at 5 and 10 Hz. Furthermore, exenatide prolonged AP duration and suppressed the sustained K⁺ current (I_ss) and transient outward K⁺ current (I_to), but without inhibition of L-type Ca²⁺ current (I_Ca,L) in rat atrial myocytes. Exenatide prevented AF incidence and duration in rat hearts and rats. These findings demonstrate that exenatide inhibits I_Kv1.5 and I_Nav1.5in vitro and reduces AF susceptibility in isolated rat hearts and rats.

Keywords: atrial fibrillation; close channel block; exenatide; hKv1.5; hNav1.5; open channel block.