Inhibition of the human ether-a-go-go-related gene (HERG) potassium channel by cisapride: affinity for open and inactivated states.
1 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). 2 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 degrees C and 23.6 nM at 37 degrees C). 3 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. 4 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. 5 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. 6 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.
Walker
B D
BD
Department of Medicine, University of New South Wales, Victor Chang Cardiac Research Institute, St Vincent's Hospital, Sydney, Australia. B.Walker@Garvan.unsw.edu.au
Singleton
C B
CB
Bursill
J A
JA
Wyse
K R
KR
Valenzuela
S M
SM
Qiu
M R
MR
Breit
S N
SN
Campbell
T J
TJ
D000818:Animals; D016466:CHO Cells; D027682:Cation Transport Proteins; D020117:Cisapride / Q000494:pharmacology*; D006224:Cricetinae; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D007700:Kinetics; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D013696:Temperature; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005765:Gastrointestinal Agents; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D020117:Cisapride