J Pharmacol Exp Ther 2001 May 01;2972:753-61.

High-affinity blockade of human ether-a-go-go-related gene human cardiac potassium channels by the novel antiarrhythmic drug BRL-32872.

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Human ether-a-go-go-related gene (HERG) potassium channels are one primary target for the pharmacological treatment of cardiac arrhythmias by class III antiarrhythmic drugs. These drugs are characterized by high antiarrhythmic efficacy, but they can also initiate life-threatening "torsade de pointes" tachyarrhythmias. Recently, it has been suggested that combining potassium and calcium channel blocking mechanisms reduces the proarrhythmic potential of selective class III antiarrhythmic agents. BRL-32872 is a novel antiarrhythmic drug that inhibits potassium and calcium currents in isolated cardiomyocytes. In our study, we investigated the effects of BRL-32872 on cloned HERG channels heterologously expressed in Xenopus oocytes. Using the two-microelectrode voltage clamp technique, we found that BRL-32872 caused a high-affinity, state-dependent block of open HERG channels (IC(50) = 241 nM) in a frequency-dependent manner with slow unbinding kinetics. Inactivated channels mainly had to open to be blocked by BRL-32872. The HERG S620T mutant channel, which has a strongly reduced degree of inactivation, was 51-fold less sensitive to BRL-32872 block, indicating that BRL-32872 binding was enhanced by the inactivation process. In an additional approach, we studied HERG channels expressed in a human cell line (HEK 293) using the whole-cell patch-clamp technique. BRL-32872 inhibited HERG currents in HEK 293 cells in a dose-dependent manner, with an IC(50) value of 19.8 nM. We conclude that BRL-32872 is a potent blocker of HERG potassium channels, which accounts for the class III antiarrhythmic action of BRL-32872.

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Species referenced: Xenopus laevis
Genes referenced: gnao1 kcnh1 kcnh2