title: Blockage of the HERG human cardiac K+ channel by the gastrointestinal prokinetic agent cisapride.
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.affiliation: Department of Medicine, University of Wisconsin, Madison 53792, USA.
authors.forename: S
authors.initials: S
authors.lastname: Mohammad
authors.forename: Z
authors.initials: Z
authors.lastname: Zhou
authors.forename: Q
authors.initials: Q
authors.lastname: Gong
authors.forename: C T
authors.initials: CT
authors.lastname: January
mesh_terms: D027682:Cation Transport Proteins; D002460:Cell Line; D020117:Cisapride; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D006801:Humans; D008133:Long QT Syndrome; D008564:Membrane Potentials / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology*; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000096:biosynthesis / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014162:Transfection
chemical_list: 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; D010880:Piperidines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011994:Recombinant Proteins; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D020117:Cisapride