title: A mechanism for the proarrhythmic effects of cisapride (Propulsid): high affinity blockade of the human cardiac potassium channel HERG.
abstract: Cisapride (Propulsid) is a gastrointestinal prokinetic agent commonly used to treat nocturnal heartburn as well as a variety of other gastrointestinal disorders. The use of cisapride has been associated with acquired long QT syndrome and ventricular arrhythmias such as torsades de pointes which produces sudden cardiac death. These cardiotoxic effects can be due to blockade of one or more types of K+ channel currents in the human heart. For this reason we compared the effects of cisapride on two cloned human cardiac K+ channels, Kv1.5 and the human ether-a-go-go-related gene (HERG) stably transfected into mammalian cells. Using patch clamp electrophysiology, we found that cisapride was a potent inhibitor of HERG displaying an IC50 value of 44.5 nmol/l when tail currents at -40 mV were measured following a 2 s test depolarization to +20 mV. When HERG currents were measured at the end of prolonged (20 s) depolarizing steps to +20 mV, the apparent affinity of cisapride was increased and measured 6.70 nmol/l. The main effect of cisapride was to enhance the rate of HERG current decay thereby reducing current at the end of the voltage clamp pulse. Furthermore, the potency of cisapride for the HERG channel was similar to that observed for the class III antiarrhythmic agent dofetilide (IC50 = 15.3 nmol/l) and the nonsedating antihistamine terfenadine (IC50 = 56.0 nmol/l). In contrast to its effects on HERG, cisapride inhibited Kv1.5 channel currents weakly displaying an IC50 value of 21.2 micromol/l. It is concluded that cisapride displays specific, high affinity block of the human cardiac K+ channel HERG. It is likely that this interaction underlies the proarrhythmic effects of the drug observed under certain clinical settings.
authors.affiliation: Hoechst Marion Roussel, Inc., Cincinnati, OH 45215, USA. davidrampe@hmri.com
authors.forename: D
authors.initials: D
authors.lastname: Rampe
authors.forename: M L
authors.initials: ML
authors.lastname: Roy
authors.forename: A
authors.initials: A
authors.lastname: Dennis
authors.forename: A M
authors.initials: AM
authors.lastname: Brown
mesh_terms: D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D027682:Cation Transport Proteins; D002460:Cell Line; D020117:Cisapride; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels; D006321:Heart / Q000187:drug effects; D006801:Humans; D051666:Kv1.5 Potassium Channel; D009206:Myocardium / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000494:pharmacology; D010880:Piperidines / Q000009:adverse effects / Q000494:pharmacology*; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides / Q000494:pharmacology; D016593:Terfenadine / Q000494:pharmacology; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014162:Transfection; D014407:Tumor Cells, Cultured
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; C496981:KCNA5 protein, human; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D051666:Kv1.5 Potassium Channel; D010627:Phenethylamines; D010880:Piperidines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D016593:Terfenadine; C063533:dofetilide; D020117:Cisapride