Acute effects of oestrogen on the guinea pig and human IKr channels and drug-induced prolongation of cardiac repolarization
Acute effects of oestrogen on the guinea pig and human IKr channels and drug-induced prolongation of cardiac repolarization
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DOI：
10.1113/jphysiol.2007.150367
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发表时间：
2008-06-15
影响因子：
5.5
通讯作者：
Furukawa, Tetsushi
中科院分区：
文献类型：
--
作者：
Kurokawa, Junko;Tamagawa, Masaji;Furukawa, Tetsushi
女性是与QT间期延长相关的药物性心律失常的风险因素，主要由人ether-a-go-go相关基因（hERG）通道阻断引起。一些临床证据表明，雌激素是药物诱导的QT间期延长和基线QT（C）间期性别差异的决定因素。虽然雌激素的慢性效应已经被研究，但性别差异是否完全是由于雌激素受体的转录调控而引起的仍不清楚。因此，我们研究了最具生物活性的雌激素，17 β-雌二醇（E2）在其生理浓度对心脏复极和药物敏感性的hERG（I-Kr）通道在Langendorff灌注豚鼠心脏，膜片钳豚鼠心肌细胞和培养细胞过表达hERG的急性影响。我们发现，生理浓度的E2部分抑制J（Kr）的受体不依赖的方式。E2诱导的电压依赖性改变导致hERG电流部分抑制。致突变研究表明，一个共同的药物结合残基的内孔腔是关键的E2对hERG通道的影响。此外，E2通过其阻断剂E4031增强hERG抑制和QT（C）延长。睾酮在其生理浓度下对hERG电流和hERG通道的E4031敏感性的影响的缺乏暗示了E2中存在的芳香质心而不是睾酮中存在的关键作用。我们的数据表明，E2急性影响hERG通道门控和E4031诱导的QT（C）延长，并可能提供一个新的机制，为女性药物诱导的心律失常的易感性更高。
Female gender is a risk factor for drug-induced arrhythmias associated with QT prolongation, which results mostly from blockade of the human ether-a-go-go-related gene (hERG) channel. Some clinical evidence suggests that oestrogen is a determinant of the gender-differences in drug-induced QT prolongation and baseline QT(C) intervals. Although the chronic effects of oestrogen have been studied, it remains unclear whether the gender differences are due entirely to transcriptional regulations through oestrogen receptors. We therefore investigated acute effects of the most bioactive oestrogen, 17 beta-oestradiol (E2) at its physiological concentrations on cardiac repolarization and drug-sensitivity of the hERG (I-Kr) channel in Langendorff-perfused guinea pig hearts, patch-clamped guinea pig cardiomyocytes and culture cells over-expressing hERG. We found that physiological concentrations of E2 partially suppressed J(Kr) in a receptor-independent manner. E2-induced modification of voltage-dependence causes partial suppression of hERG currents. Mutagenesis studies showed that a common drug-binding residue at the inner pore cavity was critical for the effects of E2 on the hERG channel. Furthermore, E2 enhanced both hERG suppression and QT(C) prolongation by its blocker, E4031. The lack of effects of testosterone at its physiological concentrations on both of hERG currents and E4031-sensitivity of the hERG channel implicates the critical role of aromatic centroid present in E2 but not in testosterone. Our data indicate that E2 acutely affects the hERG channel gating and the E4031-induced QT(C) prolongation, and may provide a novel mechanism for the higher susceptibility to drug-induced arrhythmia in women.