Department of Physiology and Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, China.
Department of Clinical Laboratory, Second Hospital of Shanxi Medical University, Taiyuan, China.
Curr Pharm Des. 2020;26(44):5746-5754. doi: 10.2174/1381612826666200701135508.
Zacopride, a potent antagonist of 5-HT3 receptors and an agonist of 5-HT4 receptors, is a gastrointestinal prokinetic agent. In a previous study, we discovered that zacopride selectively stimulated the inward rectifier potassium current (IK1) in the rat and that agonizing IK1 prevented or eliminated aconitine-induced arrhythmias in rats.
Our aims were to confirm that the antiarrhythmic effects of zacopride are mediated by selectively enhancing IK1 in rabbits.
The effects of zacopride on the function of the main ion channels were investigated using a whole-cell patch-clamp technique in rabbits. Effects of zacopride on cardiac arrhythmias were also explored experimentally both in vivo and in vitro.
Zacopride moderately enhanced cardiac IK1 but had no apparent action on voltage-gated sodium current (INa), L- type calcium current (ICa-L), sodium-calcium exchange current (INa/Ca), transient outward potassium current (Ito), or delayed rectifier potassium current (IK) in rabbits. Zacopride also had a marked antiarrhythmic effect in vivo and in vitro. We proved that the resting membrane potential (RMP) was hyperpolarized in the presence of 1 μmol/L zacopride, and the action potential duration (APD) at 90% repolarization (APD90) was shortened by zacopride (0.1-10 μmol/L) in a concentration- dependent manner. Furthermore, zacopride at 1 μmol/L significantly decreased the incidence of drug-induced early afterdepolarization (EAD) in rabbit ventricular myocytes.
Zacopride is a selective agonist of rabbit cardiac IK1 and that IK1 enhancement exerts potential antiarrhythmic effects.
Zacopride 是一种强效的 5-HT3 受体拮抗剂和 5-HT4 受体激动剂，是一种胃肠动力药物。在之前的研究中，我们发现 zacopride 选择性地刺激大鼠内向整流钾电流（IK1），激动 IK1 可预防或消除乌头碱诱导的大鼠心律失常。
我们的目的是确认 zacopride 的抗心律失常作用是通过选择性增强兔 IK1 来介导的。
采用全细胞膜片钳技术在兔体内研究 zacopride 对主要离子通道功能的影响。还通过体内和体外实验探讨了 zacopride 对心脏心律失常的影响。
Zacopride 适度增强了心脏 IK1，但对电压门控钠电流（INa）、L 型钙电流（ICa-L）、钠钙交换电流（INa/Ca）、瞬时外向钾电流（Ito）或延迟整流钾电流（IK）无明显作用。 Zacopride 在体内和体外均具有明显的抗心律失常作用。我们证明了在 1 μmol/L zacopride 存在的情况下，静息膜电位（RMP）超极化，并且 zacopride（0.1-10 μmol/L）以浓度依赖的方式缩短动作电位复极 90%时程（APD90）。此外，1 μmol/L 的 zacopride 可显著降低兔心室肌细胞药物诱导的早期后除极（EAD）的发生率。
Zacopride 是兔心脏 IK1 的选择性激动剂，增强 IK1 发挥潜在的抗心律失常作用。
