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

Abstract

Intracellular Ca²⁺ overload, prolongation of the action potential duration (APD), and downregulation of inward rectifier potassium (I_K1) channel are hallmarks of electrical remodeling in cardiac hypertrophy and heart failure (HF). We hypothesized that enhancement of I_K1 currents is a compensation for I_K1 deficit and a novel modulation for cardiac Ca²⁺ homeostasis and pathological remodeling. In adult Sprague-Dawley (SD) rats <i>in vivo</i>, 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 <i>in vitro</i>. The effects of zacopride, a selective I_K1/Kir2.1 channel agonist, on cardiac remodeling/hypertrophy were observed in the settings of 15 μg/kg <i>in vivo</i> and 1 μmol/L <i>in vitro</i>. After exposing to Iso for 3 days and 10 days, rat hearts showed distinct concentric hypertrophy and fibrosis and enhanced pumping function (<i>P</i> < 0.01 or <i>P</i> < 0.05), then progressed to dilatation and dysfunction post 30 days. Compared with the age-matched control, cardiomyocytes exhibited higher cytosolic Ca²⁺ (<i>P</i> < 0.01 or <i>P</i> < 0.05) and lower SR Ca²⁺ content (<i>P</i> < 0.01 or <i>P</i> < 0.05) all through 3, 10, and 30 days of Iso infusion. The expressions of Kir2.1 and SERCA2 were downregulated, while <i>p</i>-CaMKII, <i>p</i>-RyR2, and cleaved caspase-3 were upregulated. Iso-induced electrophysiological abnormalities were also manifested with resting potential (RP) depolarization (<i>P</i> < 0.01), APD prolongation (<i>P</i> < 0.01) in adult cardiomyocytes, and calcium overload in cultured NRVMs (<i>P</i> < 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 (<i>P</i> < 0.05), and abbreviated APD (<i>P</i> < 0.01), thus lowered cytosolic [Ca^{2 +}]_i (<i>P</i> < 0.01 or <i>P</i> < 0.05). I_K1channel blocker BaCl₂ or chloroquine largely reversed the cardioprotection of zacopride. We conclude that cardiac electrical remodeling is concurrent with structural remodeling. By enhancing cardiac I_K1, 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.