Journal
JOURNAL OF TOXICOLOGICAL SCIENCES
Volume 40, Issue 3, Pages 339-348Publisher
JAPANESE SOC TOXICOLOGICAL SCIENCES
DOI: 10.2131/jts.40.339
Keywords
Estrogen; hERG channel; Cardiac electrophysiology; Cardiac toxicology; ECG
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Funding
- Ministry of Education, Science, Culture, Sports and Technology of Japan [23136703, 25461045, 23390205, 25670126, 15H04684, 23390053]
- Restart Postdoctoral Fellowship from Japan Society for the Promotion of Science (JSPS)
- Takeda Science Foundation
- program of Activation of Gender Equity/Gender Medicine and Enrichment of Life of Tokyo Medical and Dental University
- Grants-in-Aid for Scientific Research [26293052, 25670126, 15H04684, 25461045, 25461398, 15K15049, 14J40079, 23390205, 23390053] Funding Source: KAKEN
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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.
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