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High potency inhibition of hERG potassium channels by the sodium–calcium exchange inhibitor KB‐R7943
Author(s) -
Cheng Hongwei,
Zhang Yihong,
Du Chunyun,
Dempsey Christopher E,
Hancox Jules C
Publication year - 2012
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2011.01688.x
Subject(s) - herg , chemistry , depolarization , potassium channel , patch clamp , biophysics , ventricular action potential , sodium calcium exchanger , pharmacology , cardiac action potential , ion channel , biochemistry , repolarization , electrophysiology , medicine , intracellular , biology , receptor
BACKGROUND AND PURPOSE KB‐R7943 is an isothiourea derivative that is used widely as a pharmacological inhibitor of sodium–calcium exchange (NCX) in experiments on cardiac and other tissue types. This study investigated KB‐R7943 inhibition of hERG (human ether‐à‐go‐go‐related gene ) K + channels that underpin the cardiac rapid delayed rectifier potassium current, I Kr . EXPERIMENTAL APPROACH Whole‐cell patch‐clamp measurements were made of hERG current (I hERG ) carried by wild‐type or mutant hERG channels and of native rabbit ventricular I Kr . Docking simulations utilized a hERG homology model built on a MthK‐based template. KEY RESULTS KB‐R7943 inhibited both I hERG and native I Kr rapidly on membrane depolarization with IC 50 values of ∼89 and ∼120 nM, respectively, for current tails at −40 mV following depolarizing voltage commands to +20 mV. Marked I hERG inhibition also occurred under ventricular action potential voltage clamp. I hERG inhibition by KB‐R7943 exhibited both time‐ and voltage‐dependence but showed no preference for inactivated over activated channels. Results of alanine mutagenesis and docking simulations indicate that KB‐R7943 can bind to a pocket formed of the side chains of aromatic residues Y652 and F656, with the compound's nitrobenzyl group orientated towards the cytoplasmic side of the channel pore. The structurally related NCX inhibitor SN‐6 also inhibited I hERG , but with a markedly reduced potency. CONCLUSIONS AND IMPLICATIONS KB‐R7943 inhibits I hERG /I Kr with a potency that exceeds that reported previously for acute cardiac NCX inhibition. Our results also support the feasibility of benzyloxyphenyl‐containing NCX inhibitors with reduced potential, in comparison with KB‐R7943, to inhibit hERG.