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Zacopride Exerts an Antiarrhythmic Effect by Specifically Stimulating the Cardiac Inward Rectifier Potassium Current in Rabbits: Exploration of a New Antiarrhythmic Strategy

[ Vol. 26 , Issue. 44 ]

Author(s):

Yuanyuan Lin, Junhu Li, Baozhong Zhu, Qinghua Liu, Xiaojie Bai, Bingmei Chang, Yanlin Guo, Qilong Feng*, Xuewen Li*, Bowei Wu and Jimin Cao   Pages 5746 - 5754 ( 9 )

Abstract:


Background: 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.

Objective: Our aims were to confirm that the antiarrhythmic effects of zacopride are mediated by selectively enhancing IK1 in rabbits.

Methods: 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.

Results: 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.

Conclusion: Zacopride is a selective agonist of rabbit cardiac IK1 and that IK1 enhancement exerts potential antiarrhythmic effects.

Keywords:

Zacopride, inward rectifier potassium current, rabbits, cardiomyocyte, arrhythmias, whole-cell patch-clamp, hyperpolarized.

Affiliation:

Department of Physiology and Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Department of Physiology and Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Department of Clinical Laboratory, Second Hospital of Shanxi Medical University, Taiyuan, Department of Pathophysiology, Shanxi Medical University, Taiyuan, Department of Physiology and Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Department of Biochemistry, Shanxi Medical University, Taiyuan, Department of Pathology, Shanxi Medical University, Taiyuan, Department of Physiology and Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Department of Cardiovascular Medicine, Shanxi Bethune Hospital, Taiyuan, Department of Physiology and Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Department of Physiology and Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan



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