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

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Citation

Walker BD, Singleton CB, Bursill JA, Wyse KR, Valenzuela SM, Qiu MR, Breit SN, Campbell TJ

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

Br J Pharmacol. 1999 Sep;128(2):444-50.

PubMed ID
10510456 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
CisapridePotassium voltage-gated channel subfamily H member 2ProteinHumans
Unknown
Inhibitor
Details