The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Letter
Aromatase knockout mice reveal an impact of estrogen on drug-induced alternation of murine electrocardiography parameters
Junko KurokawaTetsuo SasanoMasami KodamaMin LiYusuke EbanaNobuhiro HaradaShin-ichiro HondaHaruaki NakayaTetsushi Furukawa
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2015 Volume 40 Issue 3 Pages 339-348

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Abstract

Our in vitro characterization showed that physiological concentrations of estrogen partially suppressed the IKr channel current in guinea pig ventricular myocytes and the human ether-a-go-go-related gene (hERG) channel currents in CHO-K1 cells regardless of estrogen receptor signaling and revealed that the partially suppressed hERG currents enhanced the sensitivity to the hERG blocker E-4031. To obtain in vivo proof-of-concept data to support the effects of estrogen on cardiac electrophysiology, we here employed an aromatase knockout mouse as an in vivo estrogen-null model and compared the acute effects of E-4031 on cardiac electrophysiological parameters with those in wild-type mice (C57/BL6J) by recording surface electrocardiogram (ECG). The ablation of circulating estrogens blunted the effects of E-4031 on heart rate and QT interval in mice under a denervation condition. Our result provides in vivo proof of principle and demonstrates that endogenous estrogens increase the sensitivity of E-4031 to cardiac electrophysiology.

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© 2015 The Japanese Society of Toxicology
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