Liu Cheng-Fang, Liu Qing-Hua, Liu En-Li, Zhai Xu-Wen, Zhang Li, Luo Tian-E, Zhang Wei-Fang, Feng Qi-Long, Cui Xiang-Li, Zhao Zhi-Qing, Cao Ji-Min, Wu Bo-Wei
*Department of Physiology, Shanxi Medical University, Taiyuan, China; †Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA; and ‡Department of Physiology, School of Basic Medicine Peking Union Medical College, Beijing, China.
J Cardiovasc Pharmacol. 2014 Oct;64(4):345-56. doi: 10.1097/FJC.0000000000000127.
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.
激活IK1通道被认为是一种很有前景的抗心律失常策略。扎考必利已被确定为一种选择性IK1通道激动剂，可抑制触发型心律失常。这种药物是否也对心脏重塑产生有益作用尚不清楚，本研究旨在解决这一问题。通过冠状动脉结扎诱导雄性Sprague-Dawley大鼠心肌梗死（MI）来诱导心脏重塑。在心肌梗死后每天腹腔注射扎考必利（15μg/kg），持续28天，以确定其是否能减轻心肌梗死诱导的心脏重塑。与给予赋形剂的动物相比，扎考必利治疗4周可减轻心肌梗死后的心脏重塑，表现为扎考必利治疗组动物的左心室舒张末期内径和左心室收缩末期内径减小，射血分数和缩短分数增加（所有P<0.05）。此外，扎考必利显著降低心肌胶原沉积、心肌细胞肥大、脑钠肽血浆水平和心肌细胞超微结构损伤。扎考必利还上调IK1通道蛋白的表达，下调磷酸化p70S6激酶（p-p70S6K）和mTOR的表达。扎考必利的这些有益作用被IK1通道阻滞剂氯喹部分消除。我们得出结论，扎考必利激活IK1通道可通过抑制mTOR-p70S6激酶信号传导减轻心肌梗死后的心脏重塑。
