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Inhibition of the human ether-a-go-go-related gene (HERG) potassium channel by cisapride: affinity for open and
B D Walker1, C B Singleton, J A Bursill
1Department of Medicine, University of New South Wales, Victor Chang Cardiac Research Institute, St Vincent's Hospital, Sydney, Australia. B.Walker@Garvan.unsw.edu.au
Insights
Cisapride blocks the HERG channel, a key factor in cardiac events like QT prolongation. This study reveals cisapride binds to open/inactivated HERG channels, influencing its proarrhythmic effects.
Area of Science:
- Pharmacology
- Molecular Biology
- Cardiology
Background:
- Cisapride, a prokinetic agent, is linked to serious cardiac events.
- The underlying mechanism involves high-affinity blockade of the IKr channel, encoded by HERG.
- Understanding cisapride's interaction with HERG is crucial for managing cardiac risks.
Purpose of the Study:
- To investigate the cellular mechanism of cisapride-induced HERG channel blockade.
- To characterize the kinetics and state-dependence of cisapride's interaction with HERG channels.
- To explore the influence of external potassium concentration on cisapride's HERG channel inhibition.
Main Methods:
- Utilized a chronic transfection model with CHO-K1 cells expressing HERG channels.
- Measured HERG tail currents using electrophysiological techniques (voltage-clamp).
- Assessed time-, voltage-, and frequency-dependence of channel inhibition, including envelope of tails tests.
Main Results:
- Cisapride potently inhibited HERG tail currents at both room and physiological temperatures (IC50 values in nanomolar range).
- Channel blockade demonstrated time-, voltage-, and frequency-dependence, suggesting binding to open and/or inactivated states.
- Cisapride accelerated HERG channel inactivation and shifted the voltage dependence of steady-state inactivation; blockade was sensitive to external potassium concentration.
Conclusions:
- HERG channel inhibition by cisapride is consistent with binding to open and inactivated states.
- The sensitivity of cisapride's HERG blockade to external potassium concentration has clinical implications.
- These findings provide insights into the mechanism of cisapride-induced proarrhythmia and potential therapeutic strategies.
Abstract:
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.