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 with IC 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 with IC 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 () and transient outward K current (), but without inhibition of L-type Ca current ( in rat atrial myocytes. Exenatide prevented AF incidence and duration in rat hearts and rats. These findings demonstrate that exenatide inhibits and and reduces AF susceptibility in isolated rat hearts and rats.

中文翻译：

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艾塞那肽通过抑制 hKv1.5 和 hNav1.5 通道降低心房颤动的易感性


艾塞那肽是一种有前途的心脏保护剂，可防止心脏结构重塑和舒张功能障碍。联合阻断钠和钾通道对于控制心房颤动 (AF) 很有价值。在这里，我们探讨了艾塞那肽是否通过抑制人类 Kv1.5 和 Nav1.5 通道而发挥抗房颤作用。我们使用全细胞膜片钳技术研究了艾塞那肽对人胚胎肾 293 细胞中表达的 hKv1.5 和 hNav1.5 通道的影响，并研究了艾塞那肽对动作电位 (AP) 和其他心脏离子电流的影响。大鼠心房肌细胞。此外，还使用电测绘系统来探索艾塞那肽对离体大鼠心脏电特性和房颤活性的影响。最后，采用乙酰胆碱和氯化钙建立的大鼠房颤模型来评价艾塞那肽对大鼠的抗房颤潜力。艾塞那肽可逆地抑制 IC 为 3.08 μM，优先阻断处于关闭状态的 hKv1.5 通道，并正向移动电压依赖性激活曲线。艾塞那肽还具有可逆性抑制作用，IC 值为 3.30 μM，使电压依赖性灭活曲线发生负向移动，并减慢其灭活恢复速度，在 5 和 10 Hz 下具有显着的使用依赖性。此外，艾塞那肽可延长 AP 持续时间并抑制大鼠心房肌细胞中的持续 K 电流 () 和瞬时外向 K 电流 ()，但不抑制 L 型 Ca 电流 ()。艾塞那肽可预防大鼠心脏和大鼠的 AF 发生率和持续时间。研究结果表明，艾塞那肽可抑制并降低离体大鼠心脏和大鼠的 AF 易感性。