TY - JOUR

T1 - Effect of beta-adrenoceptor blockers on human ether-a-go-go-related gene (HERG) potassium channels.

AU - Dupuis, Delphine S

AU - Klaerke, Dan A

AU - Olesen, Søren-Peter

N1 - Keywords: Action Potentials; Adrenergic beta-Antagonists; Animals; Cell Line; Dose-Response Relationship, Drug; Electrophysiology; Gene Expression; Humans; Inhibitory Concentration 50; Metoprolol; Oocytes; Patch-Clamp Techniques; Potassium Channels, Voltage-Gated; Propanolamines; Propranolol; Species Specificity; Xenopus

PY - 2005

Y1 - 2005

N2 - 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).

AB - 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).

U2 - 10.1111/j.1742-7843.2005.pto960206.x

DO - 10.1111/j.1742-7843.2005.pto960206.x

M3 - Journal article

C2 - 15679475

VL - 96

SP - 123

EP - 130

JO - Basic and Clinical Pharmacology and Toxicology

JF - Basic and Clinical Pharmacology and Toxicology

SN - 1742-7835

IS - 2

ER -