Activation of IK1 channel by zacopride attenuates left ventricular remodeling in rats with myocardial infarction.

Abstract

Activating IK1 channels is considered to be a promising antiarrhythmic strategy. Zacopride has been identified as a selective IK1 channel agonist and can suppress triggered arrhythmias. Whether this drug also exerts a beneficial effect on cardiac remodeling is unknown, and the present study sought to address this question. Cardiac remodeling was induced through coronary ligation-induced myocardial infarction (MI) in male Sprague-Dawley rats. Zacopride (15 µg/kg) was administered (intraperitoneally) daily for 28 days after MI to determine whether it could attenuate MI-induced cardiac remodeling. A 4-week treatment with zacopride attenuated post-MI cardiac remodeling, as shown by the reduced left ventricular end-diastolic dimension and left ventricular end-systolic dimension and the increased ejection fraction and fractional shortening in zacopride-treated animals compared with animals treated with vehicle (all P < 0.05). Furthermore, zacopride significantly decreased myocardial collagen deposition, cardiomyocyte hypertrophy, the plasma level of brain natriuretic peptide, and cardiomyocyte ultrastructural injury. Zacopride also upregulated the expression of the IK1 channel protein and downregulated the expression of phosphorylated p70S6 kinase (p-p70S6K) and mTOR. These beneficial effects of zacopride were partially abolished by the IK1 channel blocker chloroquine. We conclude that the activation of IK1 channel by zacopride attenuates post-MI cardiac remodeling by suppressing mTOR-p70S6 kinase signaling.

• Authors: Cheng-Fang Liu, Qing-Hua Liu, En-Li Liu, Xu-Wen Zhai, Li Zhang, Tian-E Luo, Wei-Fang Zhang, Qi-Long Feng, Xiang-Li Cui, Zhi-Qing Zhao, Ji-Min Cao, Bo-Wei Wu
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 64 Issue 4 Pg. 345-56 (Oct 2014) ISSN: 1533-4023 [Electronic] United States
• PMID: 25286360 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• Anti-Arrhythmia Agents
• Benzamides
• Bridged Bicyclo Compounds, Heterocyclic
• Potassium Channels, Inwardly Rectifying
• Chloroquine
• zacopride

Topics

• Animals
• Anti-Arrhythmia Agents (administration & dosage, therapeutic use)
• Benzamides (administration & dosage, therapeutic use)
• Bridged Bicyclo Compounds, Heterocyclic (administration & dosage, therapeutic use)
• Chloroquine (blood, pharmacology)
• Echocardiography
• Heart Ventricles (drug effects, metabolism, ultrastructure)
• Male
• Microscopy, Electron, Transmission
• Myocardial Infarction (diagnostic imaging, drug therapy, metabolism, pathology)
• Myocytes, Cardiac (drug effects, metabolism, ultrastructure)
• Potassium Channels, Inwardly Rectifying (agonists, antagonists & inhibitors)
• Rats, Sprague-Dawley
• Ventricular Remodeling (drug effects)