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

作者：Kurokawa Junko^*; Sasano Tetsuo; Kodama Masami; Li Min; Ebana Yusuke; Harada Nobuhiro; Honda Shin ichiro; Nakaya Haruaki; Furukawa Tetsushi

来源：Journal of Toxicological Sciences, 2015, 40(3): 339-348.

DOI：10.2131/jts.40.339

• Estrogen
• hERG channel
• Cardiac electrophysiology
• Cardiac toxicology
• ECG

Our in vitro characterization showed that physiological concentrations of estrogen partially suppressed the I-Kr 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.

• 出版日期2015-6