Aromatase knockout mice reveal an impact of estrogen on drug-induced alternation of murine electrocardiography parameters

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Author(s)

    • Li Min
    • Department of Bio-Informational Pharmacology, Medical Research Institute, Tokyo Medical Dental University
    • Ebana Yusuke
    • Department of Bio-Informational Pharmacology, Medical Research Institute, Tokyo Medical Dental University
    • Harada Nobuhiro
    • Department of Biochemistry, School of Medicine, Fujita Health University
    • Nakaya Haruaki
    • Department of Pharmacology, Chiba University Graduate School of Medicine
    • Furukawa Tetsushi
    • Department of Bio-Informational Pharmacology, Medical Research Institute, Tokyo Medical Dental University

Abstract

Our <i>in vitro</i> characterization showed that physiological concentrations of estrogen partially suppressed the I<sub>Kr</sub> 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 <i>in vivo</i> proof-of-concept data to support the effects of estrogen on cardiac electrophysiology, we here employed an aromatase knockout mouse as an <i>in vivo</i> 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 <i>in vivo</i> proof of principle and demonstrates that endogenous estrogens increase the sensitivity of E-4031 to cardiac electrophysiology.

Journal

  • The Journal of Toxicological Sciences

    The Journal of Toxicological Sciences 40(3), 339-348, 2015

    The Japanese Society of Toxicology

Codes

  • NII Article ID (NAID)
    130005068413
  • NII NACSIS-CAT ID (NCID)
    AN00002808
  • Text Lang
    ENG
  • ISSN
    0388-1350
  • NDL Article ID
    026522732
  • NDL Call No.
    Z19-1022
  • Data Source
    NDL  J-STAGE 
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