Aromatase knockout mice reveal an impact of estrogen on drug-induced alternation of murine electrocardiography parameters
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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.
- The Journal of Toxicological Sciences
The Journal of Toxicological Sciences 40(3), 339-348, 2015
The Japanese Society of Toxicology