Estrogen Contributes to Gender Differences in Mouse Ventricular Repolarization

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,slow)(1) reduction, without changes in I(K,slow)(2). 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.