Referenced in: none

Automatically associated channels: Kv11.1

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

Authors: Junko Kurokawa, Tetsuo Sasano, Masami Kodama, Min Li, Yusuke Ebana, Nobuhiro Harada, Shin-Ichiro Honda, Haruaki Nakaya, Tetsushi Furukawa

Journal, date & volume: J Toxicol Sci, 2015 Jun , 40, 339-48

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25972195

Abstract
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.