Effects Of Estrogen On The IKr Channel And Cardiac Repolarization

Abstract

Females gender itself is a risk factor for drug-induced torsades de pointes (TdP) arrhythmia which is associated with QT prolongation caused by blockade of human ether-a-go-go related gene (hERG) currents. Some clinical evidence suggests that estrogen is a determinant of the gender-differences in drug-induced QT prolongation and baseline QTC intervals. Although the chronic effects of estrogen have been studied, it remains unclear whether the gender differences are due entirely to transcriptional regulations through estrogen receptors. We here found that the most bioactive estrogen, 17beta-estradiol (E2), acutely delayed cardiac repolarization within the physiological serum level (0.1-1 nM). E2 slightly but significantly suppressed hERG currents (Kd = 0.6 nM) by modifying channel gating kinetics. Mutagenesis study showed the interaction of E2 with F656, a common drug-binding site at the inner pore-cavity of hERG. E2 enhanced both hERG suppression and QTC prolongation by its blocker, E4031. The lack of effects of testosterone on hERG currents and E4031-sensitivity implicates the critical role of aromatic centroid present in E2 but not in testosterone, which is supported by data from aromatase-null mice that cannot produce estrogen. The aromatase-null mice showed lower sensitivity to E4031-induced QT prolongation compared with those of wild type mice, and i.v. application of exogenous E2 (0.1 μg/kg) subsequent to E4031 administration rapidly prolonged QT intervals, indicating that aromatized estrogen emphasize the effect of E4031 on cardiac repolarization in vivo. Our data indicate that E2 acutely affects the hERG channel gating and the E4031-induced QTC prolongation, and may provide a novel mechanism for the higher susceptibility to drug-induced arrhythmia in women.