Effect of 17 Beta-estradiol on Delayed Outward Potassium Current

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Clinical reports suggest that women may be more prone to develop drug-related QT prolongation and torsades de pointes (TdP) . Lengthening of the QT interval reflects prolonged cardiac repolarization, in which the delayed outward K+ current (Ik) plays a major role. The aim of this study was to investigate the effect of 17 β-estradiol (Es) on Ik using a whole-cell voltage clamp. In isolated guinea pig ventricular myocytes, 10μ mol/L Es decreased Ik.tail elicited by a 5000-msec depolarization, where a slowly activating component of Ik (Iks) dominates (current density using + 50 mV depolariza-tion: control 7.1±2.8vs. Es 5.1±2.0 pA/pF, P<0.05, n=10) . In contrast, 1μ mol/L Es significantly increased Ik.tail elicited by a 250-msec depolariza-tion from -10 to +10 mV (at 0 mV: control 0.68±0.24 vs. Es 0.92±0.24 pA/pF, P<0.05, n=8) . This increase was eliminated by E-4031, suggesting that this increase specifically represents the rapidly activating component of Ik (Ikr) . Es has an acute dose-dependent effect on Ik, and has an opposite effect on Iks and Ikr. These effects may contribute to drug-related QT prolongation and the susceptibility to TdP in women.
昭和大学・昭和医学会の論文