Aromatase knockout mice reveal an impact of estrogen on drug-induced alternation of murine electrocardiography parameters
Aromatase knockout mice reveal an impact of estrogen on drug-induced alternation of murine electrocardiography parameters
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DOI：
10.2131/jts.40.339
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发表时间：
2015-06-01
影响因子：
2
通讯作者：
Furukawa, Tetsushi
中科院分区：
文献类型：
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作者：
Kurokawa, Junko;Sasano, Tetsuo;Furukawa, Tetsushi
我们的体外表征表明，生理浓度的雌激素部分抑制豚鼠心室肌细胞中的I-Kr通道电流和CHO-K1细胞中的人ether-a-go-go-related基因（hERG）通道电流，而不管雌激素受体信号传导，并显示部分抑制的hERG电流增强了对hERG阻断剂E-4031的敏感性。为了获得体内概念验证数据以支持雌激素对心脏电生理的影响，我们在这里采用芳香酶敲除小鼠作为体内雌激素无效模型，并通过记录体表心电图（ECG）比较E-4031对野生型小鼠（C57/BL 6 J）心脏电生理参数的急性影响。循环雌激素的消除减弱了E-4031对去神经条件下小鼠心率和QT间期的影响。我们的结果提供了体内原理证明，并表明内源性雌激素增加E-4031对心脏电生理的敏感性。
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.