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Front. Pharmacol. | doi: 10.3389/fphar.2019.00929

IK1 channel agonist zacopride alleviates cardiac hypertrophy and failure via improving calcium dyshomeostasis and electrical remodeling in rats

 Qing-Hua Liu1, Xi Qiao1, Li-Jun Zhang1, Jin Wang1,  Li Zhang2, Xu-Wen Zhai1, Yu Li3, Xiao-Na Cao3, Qi-Long Feng1, Ji-Min Cao1* and Bo-Wei Wu1*
  • 1Shanxi Medical University, China
  • 2Shanxi Provincial Children's Hospital, China
  • 3Beijing Sport University, China

Intracellular Ca2+ overload, prolongation of the action potential duration (APD) and downregulation of inward rectifier potassium (IK1) channel are hallmarks of electrical remodeling in cardiac hypertrophy and heart failure (HF). We hypothesized that enhancement of IK1 currents is a compensation for IK1 deficit and a novel modulation for cardiac Ca2+ homeostasis and pathological remodeling. In adult Sprague-Dawley (SD) rats in vivo, cardiac hypertrophy was induced by isoproterenol (Iso) injection (i.p., 3 mg/kg/d) for 3, 10 and 30 days. Neonatal rat ventricular myocytes (NRVMs) were isolated from 1-3-days SD rat pups, and treated with 1 μmol/L Iso for 24 h in vitro. The effects of zacopride, a selective IK1 /Kir2.1 channel agonist, on cardiac remodeling/ hypertrophy were observed in the settings of 15 μg/kg in vivo and 1 μmol/L in vitro. After exposing to Iso for 3 days and 10 days, rat hearts showed distinct concentric hypertrophy, fibrosis and enhanced pumping function (P < 0.01 or P < 0.05), then progressed to dilatation and dysfunction post 30 days. Compared with the age- matched control, cardiomyocytes exhibited higher cytosolic Ca2+ (P < 0.01 or P < 0.05) and lower SR Ca2+ content (P < 0.01 or P < 0.05) all through 3, 10 and 30 days of Iso infusion. The expressions of Kir2.1 and SERCA2 were downregulated, while p-CaMKII, p-RyR2 and cleaved caspase-3 were upregulated. Iso induced electrophysiological abnormalities were also manifested with resting potential (RP) depolarization (P < 0.01), APD prolongation (P < 0.01) in adult cardiomyocytes, and calcium overload in cultured NRVMs (P < 0.01). Zacopride treatment effectively retarded myocardial hypertrophy and fibrosis, preserved the expression of Kir2.1 and some key players in Ca2+ homeostasis, normalized the RP (P < 0.05), abbreviated APD (P < 0.01), thus lowered cytosolic [Ca2 +]i (P < 0.01 or P < 0.05). IK1channel blocker BaCl2 or chloroquine largely reversed the cardioprotection of zacopride. We conclude that cardiac electrical remodeling is concurrent with structural remodeling. By enhancing cardiac IK1, zacopride prevents Iso-induced electrical remodeling around intracellular Ca2+ overload, thereby attenuates cardiac structural disorder and dysfunction. Early electrical interventions may provide protection on cardiac remodeling.

Keywords: inward rectifier potassium channel, Isoproterenol, calcium overload, cardiac remodeling, zacopride

Received: 21 Feb 2019; Accepted: 22 Jul 2019.

Copyright: © 2019 Liu, Qiao, Zhang, Wang, Zhang, Zhai, Li, Cao, Feng, Cao and Wu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Prof. Ji-Min Cao, Shanxi Medical University, Taiyuan, China, caojimin@sxmu.edu.cn
Prof. Bo-Wei Wu, Shanxi Medical University, Taiyuan, China, qweasd299@163.com