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Blockage of the HERG human cardiac K+ channel by the gastrointestinal prokinetic agent cisapride.
Am J Physiol. 1997 11; 273(5):H2534-8.AJ

Abstract

Cisapride, a gastrointestinal prokinetic agent, is known to cause long Q-T syndrome and ventricular arrhythmias. The cellular mechanism is not known. The human ether-á-go-go-related gene (HERG), which encodes the rapidly activating delayed rectifier K+ current and is important in cardiac repolarization, may serve as a target for the action of cisapride. We tested the hypothesis that cisapride blocks HERG. The whole cell patch-clamp recording technique was used to study HERG channels stably expressed heterologously in HEK293 cells. Under voltage-clamp conditions, cisapride block of HERG is dose dependent with a half-maximal inhibitory concentration of 6.5 nM at 22 degrees C (n = 25 cells). Currents rapidly recovered with drug washout. The onset of block by cisapride required channel activation indicative of open or inactivated state blockage. Block of HERG with cisapride after channel activation was voltage dependent. At -20 mV, 10 nM cisapride reduced HERG tail-current amplitude by 5%, whereas, at + 20 mV, the tail-current amplitude was reduced by 45% (n = 4 cells). At -20 and + 20 mV, 100 nM cisapride reduced tail-current amplitude by 66 and 90%, respectively. We conclude that cisapride is a potent blocker of HERG channels expressed in HEK293 cells. This effect may account for the clinical occurrence of Q-T prolongation and ventricular arrhythmias observed with cisapride.

Authors+Show Affiliations

Department of Medicine, University of Wisconsin, Madison 53792, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

9374794

Citation

Mohammad, S, et al. "Blockage of the HERG Human Cardiac K+ Channel By the Gastrointestinal Prokinetic Agent Cisapride." The American Journal of Physiology, vol. 273, no. 5, 1997, pp. H2534-8.
Mohammad S, Zhou Z, Gong Q, et al. Blockage of the HERG human cardiac K+ channel by the gastrointestinal prokinetic agent cisapride. Am J Physiol. 1997;273(5):H2534-8.
Mohammad, S., Zhou, Z., Gong, Q., & January, C. T. (1997). Blockage of the HERG human cardiac K+ channel by the gastrointestinal prokinetic agent cisapride. The American Journal of Physiology, 273(5), H2534-8. https://doi.org/10.1152/ajpheart.1997.273.5.H2534
Mohammad S, et al. Blockage of the HERG Human Cardiac K+ Channel By the Gastrointestinal Prokinetic Agent Cisapride. Am J Physiol. 1997;273(5):H2534-8. PubMed PMID: 9374794.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Blockage of the HERG human cardiac K+ channel by the gastrointestinal prokinetic agent cisapride. AU - Mohammad,S, AU - Zhou,Z, AU - Gong,Q, AU - January,C T, PY - 1997/12/31/pubmed PY - 1997/12/31/medline PY - 1997/12/31/entrez SP - H2534 EP - 8 JF - The American journal of physiology JO - Am. J. Physiol. VL - 273 IS - 5 N2 - Cisapride, a gastrointestinal prokinetic agent, is known to cause long Q-T syndrome and ventricular arrhythmias. The cellular mechanism is not known. The human ether-á-go-go-related gene (HERG), which encodes the rapidly activating delayed rectifier K+ current and is important in cardiac repolarization, may serve as a target for the action of cisapride. We tested the hypothesis that cisapride blocks HERG. The whole cell patch-clamp recording technique was used to study HERG channels stably expressed heterologously in HEK293 cells. Under voltage-clamp conditions, cisapride block of HERG is dose dependent with a half-maximal inhibitory concentration of 6.5 nM at 22 degrees C (n = 25 cells). Currents rapidly recovered with drug washout. The onset of block by cisapride required channel activation indicative of open or inactivated state blockage. Block of HERG with cisapride after channel activation was voltage dependent. At -20 mV, 10 nM cisapride reduced HERG tail-current amplitude by 5%, whereas, at + 20 mV, the tail-current amplitude was reduced by 45% (n = 4 cells). At -20 and + 20 mV, 100 nM cisapride reduced tail-current amplitude by 66 and 90%, respectively. We conclude that cisapride is a potent blocker of HERG channels expressed in HEK293 cells. This effect may account for the clinical occurrence of Q-T prolongation and ventricular arrhythmias observed with cisapride. SN - 0002-9513 UR - https://www.unboundmedicine.com/medline/citation/9374794/Blockage_of_the_HERG_human_cardiac_K+_channel_by_the_gastrointestinal_prokinetic_agent_cisapride_ L2 - http://www.physiology.org/doi/full/10.1152/ajpheart.1997.273.5.H2534?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -