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

• Main Authors: Huang YP (Author), Gao FF (Author), Wang B (Author), Zheng FC (Author), Zhang YM (Author), Chen YC (Author), Huang ZQ (Author), Zheng YS (Author), Zhong SP (Author), Shi GG (Author)
• Format: Book
• Published: Dove Medical Press, 2014-09-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 1177-8881
• Keywords: Therapeutics. Pharmacology; RM1-950
• Source: Drug Design, Development and Therapy, Vol 2014, Iss default, Pp 1257-1267 (2014)

Yong-Pan Huang,1,* Fen-Fei Gao,1,* Bin Wang,1 Fu-Chun Zheng,2 Yan-Mei Zhang,1 Yi-Cun Chen,1 Zhan-Qin Huang,1 Yan-Shan Zheng,1 Shu-Ping Zhong,3 Gang-Gang Shi1,4 1Department of Pharmacology, 2Department of Pharmacy, First Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong, People's Republic of China; 3Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, CA, USA; 4Department of Cardiovascular Diseases, First Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong, People's Republic of China *These authors contributed equally to this work Abstract: N-n-butyl haloperidol iodide (F2), a novel compound, has shown palliative effects in myocardial ischemia/reperfusion (I/R) injury. In this study, we investigated the effects of F2 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 F2 antagonizes myocardial I/R injury. Acute exposure of rat cardiac myocytes to 100 µM H2O2 increased both NHE and NCX activities, as well as levels of phosphorylated MEK and ERK. The H2O2-induced increase in NCX current (INCX) 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 INCX increase was primarily mediated by the MEK/mitogen-activated protein kinase (MAPK) pathway, and partially through activation of NHE. F2 attenuated the H2O2-induced INCX increase in a concentration-dependent manner. To determine whether pathway inhibition was H2O2-specific, we examined the ability of F2 to inhibit MEK/ERK activation by epidermal growth factor (EGF), and NHE activation by angiotensin II. F2 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 F2 directly inhibits MEK/ERK and NHE activation. These results show that F2 exerts multiple inhibitions on the signal-transduction pathway involved in H2O2-induced INCX increase, providing an additional mechanism for F2 alleviating intracellular Ca2+ overload to protect against myocardial I/R injury. Keywords: N-n-butyl haloperidol, hydrogen peroxide, Na+/Ca2+ exchanger, Na+/H+ exchanger