title: Acepromazine inhibits hERG potassium ion channels expressed in human embryonic kidney 293 cells.
abstract: The effects of acepromazine on human ether-à-go-go-related gene (hERG) potassium channels were investigated using whole-cell voltage-clamp technique in human embryonic kidney (HEK293) cells transfected with hERG. The hERG currents were recorded with or without acepromazine, and the steady-state and peak tail currents were analyzed for the evaluating the drug effects. Acepromazine inhibited the hERG currents in a concentration-dependent manner with an IC50value of 1.5 µM and Hill coefficient of 1.1. Acepromazine blocked hERG currents in a voltage-dependent manner between -40 and +10 mV. Before and after application of acepromazine, the half activation potentials of hERG currents changed to hyperpolarizing direction. Acepromazine blocked both the steady-state hERG currents by depolarizing pulse and the peak tail currents by repolarizing pulse; however, the extent of blocking by acepromazine in the repolarizing pulse was more profound than that in the depolarizing pulse, indicating that acepromazine has a high affinity for the open state of the channels, with a relatively lower affinity for the closed state of hERG channels. A fast application of acepromazine during the tail currents inhibited the open state of hERG channels in a concentration-dependent. The steady-state inactivation of hERG currents shifted to the hyperpolarized direction by acepromazine. These results suggest that acepromazine inhibits the hERG channels probably by an open- and inactivated-channel blocking mechanism. Regarding to the fact that the hERG channels are the potential target of drug-induced long QT syndrome, our results suggest that acepromazine can possibly induce a cardiac arrhythmia through the inhibition of hERG channels.
authors.affiliation: Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
authors.forename: Young Shin
authors.initials: YS
authors.lastname: Joo
authors.affiliation: Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
authors.forename: Hong Joon
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Integrated Research Institute of Pharmaceutical, The Catholic University of Korea, Seoul 14662, Korea.
authors.forename: Jin-Sung
authors.initials: JS
authors.lastname: Choi
authors.affiliation: Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
authors.forename: Ki-Wug
authors.initials: KW
authors.lastname: Sung
keywords: Acepromazine; Long QT syndrome; Patch-clamp technique; Potassium channel; hERG currents