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Effect of β‐Adrenoceptor Blockers on HumanEther‐a‐go‐go‐Related Gene (HERG) Potassium Channels
Author(s) -
Dupuis Delphine S.,
Klaerke Dan A.,
Olesen SørenPeter
Publication year - 2005
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2005.pto960206.x
Subject(s) - herg , atenolol , chemistry , pharmacology , potassium channel , propranolol , voltage clamp , ic50 , potassium channel blocker , patch clamp , medicine , receptor , membrane potential , biochemistry , in vitro , blood pressure
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 IC 50 value of 81 μM at −10 mV. When HERG was co‐expressed with the accessory subunit KCNE2, an IC 50 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 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 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).