Opening of the inward rectifier potassium channel alleviates maladaptive tissue repair following myocardial infarction

Abstract

Activation of the inward rectifier potassium current (IK1) channel has been reported to be associated with suppression of ventricular arrhythmias. In this study, we tested the hypothesis that opening of the IK1 channel with zacopride (ZAC) was involved in the modulation of tissue repair after myocardial infarction. Sprague-Dawley rats were subject to coronary artery ligation and ZAC was administered intraperitoneally (15 µg/kg/day) for 28 days. Compared with the ischemia group, treatment with ZAC significantly reduced the ratio of heart/body weight and the cross-sectional area of cardiomyocytes, suggesting less cardiac hypertrophy. ZAC reduced the accumulation of collagen types I and III, accompanied with decrease of collagen area, which were associated with a reduction of collagen deposition in the fibrotic myocardium. Echocardiography showed improved cardiac function, evidenced by the reduced left ventricular end-diastolic dimension and left ventricular end-systolic dimension, and the increased ejection fraction and fractional shortening in ZAC-treated animals (all P < 0.05 vs. ischemia group). In coincidence with these changes, ZAC upregulated the protein level of the IK1 channel and down-regulated the phosphorylation of mammalian target of rapamycin (mTOR) and 70-kDa ribosomal protein S6 (p70S6) kinase. Administration of chloroquine alone, an IK1 channel antagonist, had no effect on all the parameters measured, but significantly blocked the beneficial effects of ZAC on cardiac repair. In conclusion, opening of the IK1 channel with ZAC inhibits maladaptive tissue repair and improves cardiac function, potentially mediated by the inhibition of ischemia-activated mTOR-p70S6 signaling pathway via the IK1 channel. So the development of pharmacological agents specifically targeting the activation of the IK1 channel may protect the heart against myocardial ischemia-induced cardiac dysfunction.

IK1 Channel Agonist Zacopride Alleviates Cardiac Hypertrophy and Failure via Alterations in Calcium Dyshomeostasis and Electrical Remodeling in Rats

“…Age-matched control rats were administered with the same volume of saline. The dose of zacopride and chloroquine were applied according to our previous study (Liu et al, 2016) and preliminary experiment.…”

“…In rat ventricular myocytes, zacopride significantly enhanced I K1 while with no effect on other ion channels, transporters, or pumps (Liu et al, 2012, Zhai et al, 2017). Liu et al (2016) showed that zacopride inhibited maladaptive cardiac repair following myocardial infarction (MI), and this effect was mediated by the activation of I K1 channel. The present study was designed to demonstrate the potential effect of zacopride on isoproterenol (Iso)-induced ventricular remodeling and to clarify the interplay between electrical remodeling and structural remodeling around Ca 2+ dyshomeostasis.…”

Tetramisole is a new IK1 channel agonist and exerts IK1‐dependent cardioprotective effects in rats

“…Control rats were administered with the same volume of saline. The dose of Tet and CQ were applied according to our previous study 13 and preliminary experiment. Ventricular remodeling was evaluated by echocardiography and histology.…”

“… 3 , 12 Zacopride also attenuated maladaptive cardiac repair following MI, Iso‐, or L‐thyroxine‐ toxicosis. 13 , 14 , 15 So far, zacopride is the only documented selective I K1 channel agonist. Developing more pharmacological tools is an issue to support the theoretical link between I K1 agonism and cardioprotection.…”

Towards the Development of AgoKirs: New Pharmacological Activators to Study Kir2.x Channel and Target Cardiac Disease

“…Rats treated with ZAC showed elevated levels of K ir 2.1 protein in left ventricular tissue [53]. Furthermore, ZAC treatment prevented ischemia-mediated downregulation of left ventricular K ir 2.1 protein [54] (note [55]). Additionally, ZAC enhanced both the inward and outward I K1 current in rat ventricular myocytes [56,57] but not in atrial cardiac myocytes [40].…”