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
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