Effect of β-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 β-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 μM at -10 mV When HERG was co-expressed with the accessory subunit KCNE2, an IC50 value of 52 μM was determined. The block by propranolol was voltage-dependent, but it did not change the HERG channel deactivation kinetics. The propranolol analogue ICI18551 ((±)-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 β1-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 β-adrenoceptor blockers occurred only at high micromolar concentrations, which are significantly above the recently established safe margin of 100 (Redfern et al., 2003).