Why the study?
Does endogenous estrogen increase the sensitivity of cardiac electrophysiology to the hERG blocker E-4031 in an in vivo mouse model?
Does endogenous estrogen increase the sensitivity of cardiac electrophysiology to the hERG blocker E-4031 in an in vivo mouse model?
This in vivo study demonstrates that endogenous estrogens increase the sensitivity of cardiac electrophysiology to hERG blockers, providing a mechanistic basis for female susceptibility to drug-induced long QT syndrome.
Endogenous estrogen may increase hERG-blocker sensitivity in mice; hypothesis-generating for female drug-induced QT risk and requires human validation.
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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Kurokawa et al. (2015) studied this question.
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