Zacopride exerts an antiarrhythmic effect by specifically stimulating the cardiac inward rectifier potassium current in rabbits: exploration of a new antiarrhythmic strategy.

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 (I-KI) in the rat and that agonizing I-K1 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 I-K1 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 I-K1 but had no apparent action on voltage-gated sodium current (I-Na), L- type calcium current (ICa-L), sodium-calcium exchange current (I-Na/Ca), transient outward potassium current (10, or delayed rectifier potassium current (I-K) 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 mu mol/L zacopride, and the action potential duration (APD) at 90% repolarization (APD(90)) was shortened by zacopride (0.1-10 mu mol/L) in a concentration- dependent manner. Furthermore, zacopride at 1 mu mol/L significantly decreased the incidence of drug-induced early afterdepolarization (EAD) in rabbit ventricular myocytes. Conclusion: Zacopride is a selective agonist of rabbit cardiac I-KI and that I-KI enhancement exerts potential antiarrhythmic effects.