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[摘要]：Rationale: Fast-transient outward K+ (I-to,I-f) and ultrarapid delayed rectifier K+ currents (I-K,I-slow, also known as I-Kur) contribute to mouse cardiac repolarization. Gender studies on these currents have reported conflicting results. Objective: Key missing information in these studies is the estral stage of the animals. We revisited gender-related differences in K+ currents, taking into consideration the females' estral stage. We hypothesized that changes in estrogen levels during the estral cycle could play a role in determining the densities of K+ currents underlying ventricular repolarization. Methods and Results: Peak total K+ current (I-K,I-total) densities (pA/pF, at +40 mV) were much higher in males (48.6+/-3.0) versus females at estrus (27.2+/-2.3) but not at diestrus-2 (39.1+/-3.4). Underlying this change, I-to,I-f and I-K,I-slow were lower in females at estrus versus males and diestrus-2 (I-K,I-slow: male 21.9+/-1.8, estrus 14.6+/-0.6, diestrus-2 20.3+/-1.4; I-to,I-f: male 26.8+/-1.9, estrus 14.9+/-1.6, diestrus-2 22.1+/-2.1). Lower I-K,I-slow in estrus was attributable to only I-K,I-slow1 reduction, without changes in I-K,I-slow2. Estrogen treatment of ovariectomized mice decreased I-K,I-total (46.4+/-3.0 to 28.4+/-1.6), I-to,I-f (26.6+/-1.6 to 12.8+/-1.0) and I-K,I-slow (22.2+/-1.6 to 17.2+/-1.4). Transcript levels of Kv4.3 and Kv1.5 (underlying I-to,I-f and I-K,I-slow, respectively) were lower in estrus versus diestrus-2 and male. In ovariectomized mice, estrogen treatment resulted in downregulation of Kv4.3 and Kv1.5 but not Kv4.2, KChIP2, or Kv2.1 transcripts. K+ current reduction in high estrogenic conditions were associated with prolongation of the action potential duration and corrected QT interval. Conclusion: Downregulation of Kv4.3 and Kv1.5 transcripts by estrogen are one mechanism defining gender-related differences in mouse ventricular repolarization. (Circ Res. 2009; 105: 343-352.) |
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