Inhibition of the human ether‐a‐go‐go‐related gene (HERG) potassium channel by cisapride: affinity for open and inactivated states

British Journal of Pharmacology - Tập 128 Số 2 - Trang 444-450 - 1999
Bruce D. Walker1, Cameron B. Singleton1, Jane A. Bursill1, Kenneth R. Wyse1, Stella M. Valenzuela2, Min Qiu2, Samuel N. Breit2, Terence J. Campbell1
1Department of Medicine, University of New South Wales, Victor Chang Cardiac Research Institute, St Vincent's Hospital, Sydney, Australia
2Centre for Immunology, St Vincent’s Hospital, Sydney, Australia

Tóm tắt

Cisapride is a prokinetic agent which has been associated with QT prolongation, torsades de pointes and cardiac arrest. The cellular mechanism for these observations is high affinity blockade of IKr (encoded by HERG). In a chronic transfection model using CHO‐K1 cells, cisapride inhibited HERG tail currents after a step to +25 mV with similar potency at room and physiological temperatures (IC50 16.4 nM at 20–22°C and 23.6 nM at 37°C). Channel inhibition exhibited time‐, voltage‐ and frequency‐dependence. In an envelope of tails test, channel blockade increased from 27±8% after a 120 ms depolarizing step to 50±4% after a 1.0 s step. These findings suggested affinity for open and/or inactivated channel states. Inactivation was significantly accelerated by cisapride in a concentration‐dependent manner and there was a small (−7 mV) shift in the voltage dependence of steady state inactivation. Channel blockade by cisapride was modulated by [K+]o, with a 26% reduction in the potency of channel blockade when [K+]o was increased from 1 to 10 mM. In conclusion, HERG channel inhibition by cisapride exhibits features consistent with open and inactivated state binding and is sensitive to external potassium concentration. These features may have significant clinical implications with regard to the mechanism and treatment of cisapride‐induced proarrhythmia. British Journal of Pharmacology (1999) 128, 444–450; doi:10.1038/sj.bjp.0702774

Từ khóa


Tài liệu tham khảo

10.1016/S0140-6736(95)90595-2

10.1016/0165-0270(94)90031-0

BRAN S., 1995, Long QT syndrome during high dose cisapride, Arch. Intern. Med., 155, 756, 10.1001/archinte.1995.00430070125014

CARLSSON L., 1997, Electrophysiological characterization of the prokinetic agents cisapride and mosapride in vivo and in vitro: implications for proarrhythmic potential, J. Pharm. Exp. Ther., 282, 220

10.1016/S0079-6107(98)00002-9

10.1161/01.CIR.96.7.2149

10.1016/0092-8674(95)90358-5

10.1161/01.CIR.97.2.204

10.1007/BF00608226

HOOVER C.A., 1996, Cardiac arrest associated with combination cisapride and itraconazole therapy, J. Cardiovasc. Pharmacol. Therapeut., 1, 255, 10.1177/107424849600100309

10.1161/01.CIR.94.10.2572

10.1097/00005344-199705000-00016

10.1038/40882

10.1152/ajpheart.1997.273.5.H2534

MORGAN T.K., 1992, Progress in Medicinal Chemistry, 65

10.1111/j.1476-5381.1996.tb15295.x

10.1016/S0014-5793(97)01249-0

10.1161/01.CIR.94.4.817

10.1016/0092-8674(95)90340-2

SANGUINETTI M.C., 1990, Two components of cardiac delayed rectifier K+ current, J. Gen. Physiol., 96, 195, 10.1085/jgp.96.1.195

10.1038/sj.bjp.0700989

10.1016/0014-5793(96)00355-9

10.1038/379833a0

SNYDERS D.J., 1996, High affinity open channel block by dofetilide of HERG expressed in a human cell line, J. Pharmacol. Exp. Ther., 49, 949

10.1085/jgp.107.5.611

10.1161/01.CIR.96.10.3696

UNITED STATES FOOD AND DRUG ADMINISTRATION. (1998). Talk paper. June 29.

10.1038/sj.bjp.0702502

10.1111/j.1469-7793.1997.045bl.x

10.1016/S0014-5793(97)01245-3

10.1177/107424849700200307

10.2165/00003495-199447010-00008

10.1056/NEJM199607253350416

10.1161/01.CIR.93.3.407

Thông tin
Thông tin xuất bản

British Journal of Pharmacology

Tập 128 Số 2

444-450

Thông tin tác giả