N-n-butyl haloperidol iodide inhibits H2O2-induced Na+/Ca2+-exchanger activation via the Na+/H+ exchanger in rat ventricular myocytes

作者：Huang Yong Pan; Gao Fen Fei; Wang Bin; Zheng Fu Chun; Zhang Yan Mei; Chen Yi Cun; Huang Zhan Qin; Zheng Yan Shan; Zhong Shu Ping; Shi Gang Gang^*

来源：Drug Design, Development and Therapy, 2014, 8: 1257-1267.

DOI：10.2147/DDDT.S63163

• N-n-butyl haloperidol
• hydrogen peroxide
• Na+/Ca2+ exchanger
• Na+/H+ exchanger

N-n-butyl haloperidol iodide (F-2), a novel compound, has shown palliative effects in myocardial ischemia/reperfusion (I/R) injury. In this study, we investigated the effects of F-2 on the extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK)/Na+/H+ exchanger (NHE)/Na+/Ca2+ exchanger (NCX) signal-transduction pathway involved in H2O2-induced Ca2+ overload, in order to probe the underlying molecular mechanism by which F-2 antagonizes myocardial I/R injury. Acute exposure of rat cardiac myocytes to 100 M H2O2 increased both NHE and NCX activities, as well as levels of phosphorylated MEK and ERK. The H2O2-induced increase in NCX current (I-NCX) was nearly completely inhibited by the MEK inhibitor U0126 (1,4-diamino-2,3-dicyano-1,4-bis[o-aminophenylmercapto] butadiene), but only partly by the NHE inhibitor 5-(N,N-dimethyl)-amiloride (DMA), indicating the I-NCX increase was primarily mediated by the MEK/mitogen-activated protein kinase (MAPK) pathway, and partially through activation of NHE. F-2 attenuated the H2O2-induced I-NCX increase in a concentration-dependent manner. To determine whether pathway inhibition was H2O2-specific, we examined the ability of F-2 to inhibit MEK/ERK activation by epidermal growth factor (EGF), and NHE activation by angiotensin II. F-2 not only inhibited H2O2-induced and EGF-induced MEK/ERK activation, but also completely blocked both H2O2-induced and angiotensin II-induced increases in NHE activity, suggesting that F-2 directly inhibits MEK/ERK and NHE activation. These results show that F-2 exerts multiple inhibitions on the signal-transduction pathway involved in H2O2-induced I-NCX increase, providing an additional mechanism for F-2 alleviating intracellular Ca2+ overload to protect against myocardial I/R injury.

• 出版日期2014
• 单位汕头大学