title: Comparison of the effects of methadone and heroin on human ether-à-go-go-related gene channels.
abstract: Torsades de pointes (TdP) is a life-threatening form of ventricular arrhythmia that occurs under conditions of delayed cardiac repolarization indicated by prolonged QT intervals in ECG recordings. The main mechanism of QT prolongation and TdP is block of the rapid component of the cardiac delayed rectifier K(+) current (I(Kr)), which is encoded by hERG (human ether-à-go-go-related gene). The opioid agonist methadone has previously been demonstrated to inhibit hERG currents, and there are reports of serious cardiac arrhythmias and deaths from TdP and ventricular fibrillation in patients taking methadone. The aim of the present study was to compare the effects of the opioid agonists methadone and heroin (3,6-diacetylmorphine) on hERG currents stably expressed in human embryonic kidney (HEK 293) cells using the whole-cell configuration of the patch-clamp technique. Both methadone and heroin inhibit hERG currents in a concentration-dependent manner. The following values were calculated for IC(50) (concentration causing half-maximal inhibition) and n (the Hill coefficient): 4.8 microM and 0.9 for methadone, 427 microM and 0.7 for heroin. In conclusion, the potency for block of hERG currents is about 100-fold lower for heroin when compared to methadone.
authors.affiliation: Federal Institute for Drugs and Medical Devices, Kurt-Georg-Kiesinger-Allee 3, 53175, Bonn, Germany. Jochen.Zuenkler@bfarm.de
authors.forename: Bernd J
authors.initials: BJ
authors.lastname: Zünkler
authors.forename: Maria
authors.initials: M
authors.lastname: Wos-Maganga
mesh_terms: D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects* / Q000235:genetics; D057809:HEK293 Cells; D003932:Heroin / Q000494:pharmacology*; D006801:Humans; D008691:Methadone / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D016171:Torsades de Pointes / Q000503:physiopathology
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D009294:Narcotics; D026902:Potassium Channel Blockers; D003932:Heroin; D008691:Methadone