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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
- Source :
- Current Pharmaceutical Design. 26:5746-5754
- Publication Year :
- 2020
- Publisher :
- Bentham Science Publishers Ltd., 2020.
-
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.
- Subjects :
- Agonist
Patch-Clamp Techniques
medicine.drug_class
Action Potentials
Pharmacology
Afterdepolarization
Zacopride
chemistry.chemical_compound
In vivo
Drug Discovery
medicine
Animals
Repolarization
Myocytes, Cardiac
Membrane potential
Inward-rectifier potassium ion channel
Antagonist
Bridged Bicyclo Compounds, Heterocyclic
Rats
Pharmaceutical Preparations
chemistry
Benzamides
Potassium
Rabbits
Anti-Arrhythmia Agents
Subjects
Details
- ISSN :
- 13816128
- Volume :
- 26
- Database :
- OpenAIRE
- Journal :
- Current Pharmaceutical Design
- Accession number :
- edsair.doi.dedup.....0921bfa43fb5d5798a885825a4713465