Effect of sibutramine HCl on cardiac hERG K+ channel.
Common clinically used drugs block the delayed rectifier K(+) channels and prolong the cardiac action potential duration associated with long QT syndrome. Here, we investigated the mechanism of hERG K(+) channel current (I(hERG)) blockade expressed in HEK-293 cells by sibutramine HCl, a serotonin-norepinephrine reuptake inhibitor. Sibutramine HCl inhibited I (hERG) in a concentration-dependent manner with the half-maximal inhibitory concentration (IC(50)) value of 2.5 microM at -40 mV. I(hERG) inhibition by sibutramine HCl showed weak voltage dependency, but the time-dependence of I(hERG) inhibition was developed relatively rapidly on membrane depolarization. On hERG channel gating for the S6 and pore regions, the S6 residue hERG mutant Y652A and F656A largely reduced the blocking potency of I(hERG), unlike the pore-region mutants T623A and S624A. These results indicate that sibutramine HCl preferentially inhibits the hERG potassium channel through the residue Y652 and F656, in a supratherapeutic concentration should be avoided by patients with high susceptibility for cardiac arrhythmia.
Kim
Ki-Suk
KS
Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Yuseong, Daejeon 305-343, South Korea.
Kim
Eun-Joo
EJ
Lee
Hyang-Ae
HA
Park
Sang-Joon
SJ
D000818:Animals; D001067:Appetite Depressants / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D003503:Cyclobutanes / Q000378:metabolism* / Q000494:pharmacology; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D016297:Mutagenesis, Site-Directed; D009206:Myocardium / Q000378:metabolism; D018408:Patch-Clamp Techniques
D001067:Appetite Depressants; D003503:Cyclobutanes; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C058254:sibutramine
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