AUTHOR=Liu Qing-Hua , Qiao Xi , Zhang Li-Jun , Wang Jin , Zhang Li , Zhai Xu-Wen , Ren Xiao-Ze , Li Yu , Cao Xiao-Na , Feng Qi-Long , Cao Ji-Min , Wu Bo-Wei 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2019.00929

DOI=10.3389/fphar.2019.00929

ISSN=1663-9812

ABSTRACT=<p>Intracellular Ca<sup>2+</sup> overload, prolongation of the action potential duration (APD), and downregulation of inward rectifier potassium (I<sub>K1</sub>) channel are hallmarks of electrical remodeling in cardiac hypertrophy and heart failure (HF). We hypothesized that enhancement of I<sub>K1</sub> currents is a compensation for I<sub>K1</sub> deficit and a novel modulation for cardiac Ca<sup>2+</sup> homeostasis and pathological remodeling. In adult Sprague-Dawley (SD) rats <italic>in vivo</italic>, 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 to 3 days SD rat pups and treated with 1 μmol/L Iso for 24 h <italic>in vitro</italic>. The effects of zacopride, a selective I<sub>K1</sub>/Kir2.1 channel agonist, on cardiac remodeling/hypertrophy were observed in the settings of 15 μg/kg <italic>in vivo</italic> and 1 μmol/L <italic>in vitro</italic>. After exposing to Iso for 3 days and 10 days, rat hearts showed distinct concentric hypertrophy and fibrosis and enhanced pumping function (<italic>P</italic> &lt; 0.01 or <italic>P</italic> &lt; 0.05), then progressed to dilatation and dysfunction post 30 days. Compared with the age-matched control, cardiomyocytes exhibited higher cytosolic Ca<sup>2+</sup> (<italic>P</italic> &lt; 0.01 or <italic>P</italic> &lt; 0.05) and lower SR Ca<sup>2+</sup> content (<italic>P</italic> &lt; 0.01 or <italic>P</italic> &lt; 0.05) all through 3, 10, and 30 days of Iso infusion. The expressions of Kir2.1 and SERCA2 were downregulated, while <italic>p</italic>-CaMKII, <italic>p</italic>-RyR2, and cleaved caspase-3 were upregulated. Iso-induced electrophysiological abnormalities were also manifested with resting potential (RP) depolarization (<italic>P</italic> &lt; 0.01), APD prolongation (<italic>P</italic> &lt; 0.01) in adult cardiomyocytes, and calcium overload in cultured NRVMs (<italic>P</italic> &lt; 0.01). Zacopride treatment effectively retarded myocardial hypertrophy and fibrosis, preserved the expression of Kir2.1 and some key players in Ca<sup>2+</sup> homeostasis, normalized the RP (<italic>P</italic> &lt; 0.05), and abbreviated APD (<italic>P</italic> &lt; 0.01), thus lowered cytosolic [Ca<sup>2 +</sup>]<sub>i</sub> (<italic>P</italic> &lt; 0.01 or <italic>P</italic> &lt; 0.05). I<sub>K1</sub>channel blocker BaCl<sub>2</sub> or chloroquine largely reversed the cardioprotection of zacopride. We conclude that cardiac electrical remodeling is concurrent with structural remodeling. By enhancing cardiac I<sub>K1</sub>, zacopride prevents Iso-induced electrical remodeling around intracellular Ca<sup>2+</sup> overload, thereby attenuates cardiac structural disorder and dysfunction. Early electrical interventions may provide protection on cardiac remodeling.</p>