title: N-n-butyl haloperidol iodide inhibits H2O2-induced Na+/Ca2+-exchanger activation via the Na+/H+ exchanger in rat ventricular myocytes.
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(+)/Ca(2+) exchanger (NCX) signal-transduction pathway involved in H2O2-induced Ca(2+) 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 (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. F2 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 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 I NCX increase, providing an additional mechanism for F2 alleviating intracellular Ca(2+) overload to protect against myocardial I/R injury.
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou, Guangdong, People's Republic of China.
authors.forename: Yong-Pan
authors.initials: YP
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou, Guangdong, People's Republic of China.
authors.forename: Fen-Fei
authors.initials: FF
authors.lastname: Gao
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou, Guangdong, People's Republic of China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, First Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong, People's Republic of China.
authors.forename: Fu-Chun
authors.initials: FC
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou, Guangdong, People's Republic of China.
authors.forename: Yan-Mei
authors.initials: YM
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou, Guangdong, People's Republic of China.
authors.forename: Yi-Cun
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou, Guangdong, People's Republic of China.
authors.forename: Zhan-Qin
authors.initials: ZQ
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou, Guangdong, People's Republic of China.
authors.forename: Yan-Shan
authors.initials: YS
authors.lastname: Zheng
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Shu-Ping
authors.initials: SP
authors.lastname: Zhong
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou, Guangdong, People's Republic of China ; Department of Cardiovascular Diseases, First Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong, People's Republic of China.
authors.forename: Gang-Gang
authors.initials: GG
authors.lastname: Shi
mesh_terms: D000818:Animals; D006220:Haloperidol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D019831:Sodium-Calcium Exchanger / Q000819:agonists / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C482574:N-n-butyl haloperidol iodide; D019831:Sodium-Calcium Exchanger; D017923:Sodium-Hydrogen Exchangers; D006861:Hydrogen Peroxide; D006220:Haloperidol
keywords: N-n-butyl haloperidol; Na+/Ca2+ exchanger; Na+/H+ exchanger; hydrogen peroxide