title: Effect of beta-adrenoceptor blockers on human ether-a-go-go-related gene (HERG) potassium channels.
abstract: Patients with congenital long QT syndrome may develop arrhythmias under conditions of increased sympathetic tone. We have addressed whether some of the beta-adrenoceptor blockers commonly used to prevent the development of these arrhythmias could per se block the cardiac HERG (Human Ether-a-go-go-Related Gene) potassium channels, which would be a most unwanted side effect. HERG potassium channels were heterologously expressed in Xenopus oocytes and the currents measured by two-electrode-voltage-clamp technique. Propranolol caused a concentration-dependent inhibition of HERG current with an IC50 value of 81 microM at -10 mV. When HERG was co-expressed with the accessory subunit KCNE2, an IC50 value of 52 microM was determined. The block by propranolol was voltage-dependent, but it did not change the HERG channel deactivation kinetics. The propranolol analogue ICI118551 ((+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride) blocked the HERG channel with similar affinity, whereas the beta1-receptor antagonists metoprolol and atenolol showed weak effects. Further, the four compounds blocked HERG channels expressed in a mammalian HEK293 cell line. These data showed that HERG blockade by beta-adrenoceptor blockers occurred only at high micromolar concentrations, which are significantly above the recently established safe margin of 100 (Redfern et al., 2003).
authors.affiliation: Department of Medical Physiology and Copenhagen Heart Arrhythmia Research Center, University of Copenhagen, Panum Institute, 3 Blegdamsvej, DK 2200 Copenhagen N and NeuroSearch, DK-2750 Ballerup, Denmark. delphine.dupuis@pharma.novartis.com
authors.forename: Delphine S
authors.initials: DS
authors.lastname: Dupuis
authors.forename: Dan A
authors.initials: DA
authors.lastname: Klaerke
authors.forename: Søren-Peter
authors.initials: SP
authors.lastname: Olesen
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000319:Adrenergic beta-Antagonists / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D020128:Inhibitory Concentration 50; D008790:Metoprolol / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects* / Q000235:genetics*; D011412:Propanolamines / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D013045:Species Specificity; D014981:Xenopus
chemical_list: D000319:Adrenergic beta-Antagonists; D024642:Potassium Channels, Voltage-Gated; D011412:Propanolamines; C026777:ICI 118551; D011433:Propranolol; D008790:Metoprolol