Rationale: Fast-transient outward K⁺ (I_to,f) and ultrarapid delayed rectifier K⁺ currents (I_K,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,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,f and I_K,slow were lower in females at estrus versus males and diestrus-2 (I_K,slow: male 21.9±1.8, estrus 14.6±0.6, diestrus-2 20.3±1.4; I_to,f: male 26.8±1.9, estrus 14.9±1.6, diestrus-2 22.1±2.1). Lower I_K,slow in estrus was attributable to only I_K,slow1 reduction, without changes in I_K,slow2. Estrogen treatment of ovariectomized mice decreased I_K,total (46.4±3.0 to 28.4±1.6), I_to,f (26.6±1.6 to 12.8±1.0) and I_K,slow (22.2±1.6 to 17.2±1.4). Transcript levels of Kv4.3 and Kv1.5 (underlying I_to,f and I_K,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.