Exenatide reduces atrial fibrillation susceptibility by inhibiting hKv1.5 and hNav1.5 channels
Qian Zhou, Guoliang Hao, Wen-Sen Xie, Bin Chen, Wuguang Lu, Gongxin Wang, Rongling Zhong, Jiao Chen, Juan Ye, Jianping Shen, Peng Cao
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 IC 50 of 3.08 μM, preferentially blocked hKv1.5 channel in its closed state, and positively shifted the voltage-dependent activation curve. Exenatide also reversibly inhibited I Nav1.5 with IC 50 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 Ca 2+ 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 Nav1.5 in vitro and reduces AF susceptibility in isolated rat hearts and rats.