Department of Physiology, First Hospital, Shanxi Medical University, Taiyuan, China.
J Cardiovasc Pharmacol. 2012 Jan;59(1):37-48. doi: 10.1097/FJC.0b013e3182350bcc.
Modulation of the inward rectifier K current (IK1) has profound effect on cardiac excitability and underlies new antiarrhythmic strategies. However, IK1-specific pharmacological tools, especially the selective IK1 agonists, are still lacking in the market. Zacopride, a gastrointestinal prokinetic drug, was found to be a selective IK1 channel agonist. By using the whole-cell patch clamp technique, it was found that zacopride (0.1-10 μmole/L) dose dependently enhanced the IK1 current in isolated rat cardiomyocytes, had no effects on other ion channels, transporters, or pumps. At the same dosage range, zacopride hyperpolarized the resting potential and shortened the action potential duration. When applied at the optimal dose of 1.0 μmole/L, zacopride could prevent or eliminate aconitine induced after depolarization and triggered activity in isolated cardiomyocytes. In a rat model of aconitine-induced arrhythmias both ex vivo and in vivo, zacopride (1.0 μmole/L or 25 μg/kg, respectively) treatment apparently protected the heart from ventricular tachyarrhythmias, which compares favorably with 7.5 mg/kg of lidocaine, a classical aconitine antidote. In conclusion, zacopride was found to be a selective IK1 agonist, and agonizing IK1 could prevent or eliminate aconitine-induced arrhythmias in the rat.
内向整流钾电流 (IK1) 的调节对心脏兴奋性有深远影响，是新的抗心律失常策略的基础。然而，市场上仍然缺乏专门针对 IK1 的药理学工具，特别是选择性 IK1 激动剂。Zacopride 是一种胃肠动力药物，被发现是一种选择性 IK1 通道激动剂。通过使用全细胞膜片钳技术，发现 zacopride（0.1-10 μmole/L）剂量依赖性地增强了分离的大鼠心肌细胞中的 IK1 电流，对其他离子通道、转运体或泵没有影响。在相同的剂量范围内，zacopride 使静息电位超极化并缩短动作电位持续时间。当以最佳剂量 1.0 μmole/L 应用时，zacopride 可预防或消除在分离的心肌细胞中由乌头碱引起的后除极和触发活动。在乌头碱诱导的心律失常的大鼠模型中，无论是在离体还是在体内，zacopride（分别为 1.0 μmole/L 或 25 μg/kg）治疗明显保护心脏免受室性心动过速和心律失常的影响，与经典的乌头碱解毒剂 7.5 mg/kg 的利多卡因相比具有优势。总之，zacopride 被发现是一种选择性 IK1 激动剂，激动 IK1 可以预防或消除大鼠中的乌头碱诱导的心律失常。
