Department of Pharmacology (Key Laboratory of Cardiovascular Medicine Research, Ministry of Education; State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, Harbin, Heilongjiang 150081, PR China.
Department of Cardiology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, PR China.
Eur J Pharmacol. 2014 Jul 15;735:202-10. doi: 10.1016/j.ejphar.2014.04.012. Epub 2014 Apr 21.
Cisapride has been shown to have electrophysiological effects on the heart. The aim of this study was to investigate whether cisapride has effects on cardiac hypertrophy. Rat and cellular models of cardiac hypertrophy were used in this study. Cell surface area (CSA), mRNA and protein expression were used to evaluate cardiac hypertrophy. Cardiac function was measured by echocardiography. Cisapride attenuated ISO-induced increase in CSA in a dose-dependent manner in cultured neonatal rat cardiomyocytes. A significant anti-hypertrophic effect was achieved by cisapride 0.01μM (P<0.05). Cisapride repressed the increased mRNA levels of ANP, BNP, β-MHC in ISO-treated cells (P<0.05). However, mallotoxin or GR113808 did not influence anti-hypertrophic effects of cisapride. In addition, cisapride inhibited the increase of intracellular Ca(2+) ([Ca(2+)]i) and the upregulation of protein levels of calcineurin and NFATc-3 (P<0.05) as well as prevented the downregulation of p-NFATc-3 (P<0.01) induced by ISO. Consistently, cisapride (0.5mg/kg/day) produced inhibitory effects on cardiac hypertrophy, including the suppression of ANP, BNP, β-MHC, calcineurin, and NFATc-3; elevation of p-NFATc-3; reduction of cross-sectional area of cardiomyocytes in rat heart; and restoration of cardiac dysfunction by improving left ventricular diastolic and systolic performance. Importantly, cisapride 0.5 and 5.0mg/kg/day did not cause prolongation of QT and QTc intervals in rats. In conclusion, cisapride possesses a prominent anti-hypertrophic property which is likely to be conferred by its ability to downregulate Ca(2+)/calcineurin/NFAT and the present data provide new insight into this drug action.
西沙必利对心脏具有电生理作用。本研究旨在探讨西沙必利是否对心肌肥厚有影响。本研究采用大鼠和心肌肥厚细胞模型。采用细胞表面积（CSA）、mRNA 和蛋白表达来评估心肌肥厚。通过超声心动图测量心功能。西沙必利在培养的新生大鼠心肌细胞中呈浓度依赖性地减弱 ISO 诱导的 CSA 增加。西沙必利 0.01μM 可显著抑制心肌肥厚（P<0.05）。西沙必利抑制 ISO 处理细胞中 ANP、BNP、β-MHC 的 mRNA 水平增加（P<0.05）。然而，mallotoxin 或 GR113808 并不影响西沙必利的抗肥厚作用。此外，西沙必利抑制 ISO 诱导的细胞内 Ca2+（[Ca2+]i）增加和钙调神经磷酸酶和 NFATc-3 蛋白水平的上调（P<0.05），并防止 ISO 诱导的 p-NFATc-3 下调（P<0.01）。一致地，西沙必利（0.5mg/kg/天）对心肌肥厚具有抑制作用，包括抑制 ANP、BNP、β-MHC、钙调神经磷酸酶和 NFATc-3；升高 p-NFATc-3；减少大鼠心肌细胞横截面积；并通过改善左心室舒张和收缩功能来恢复心功能障碍。重要的是，西沙必利 0.5 和 5.0mg/kg/天不会导致大鼠 QT 和 QTc 间期延长。总之，西沙必利具有显著的抗肥厚特性，这可能与其下调 Ca2+/钙调神经磷酸酶/NFAT 的能力有关，并且本数据为该药物作用提供了新的见解。
