Prolonged AP duration by estrogen is independent of INaL
The rapid and inward Na+ currents determine the dynamics of the ascending branch of AP (Vikram et al., 2017). On the other hand, I NaL, a small and sustained Na+ influx, lasts for hundreds of milliseconds and maintains the plateau phase of AP with inward calcium current (Portero et al., 2017; Zaza & Rocchetti, 2013). Therefore, we analyzed the AP to explore the relationship between estrogen, sodium currents and AP. Estrogen at medium concentration prolonged the AP duration, which may explain why women have longer AP duration and longer QTc interval than men of the same age (Salem, Alexandre, Bachelot, & Funck-Brentano, 2016). It seems that the prolonged AP duration caused by estrogen was independent of I NaL which is likely that the treatment time of estrogen is too short to increase theI NaL. Short-term estrogen treatment failed to amplify I NaL, but increased a certain amount ofI NaL. With the prolongation of estrogen treatment time, I NaL increased significantly, just as theI NaL in female mice exposed to estrogen for a long time is larger than that in male mice (Lowe et al., 2012). In addition, the prolonged AP duration induced by estrogen may be associated with the increase in calcium currents (Papp et al., 2017; X. Yang et al., 2018).
Notably, the shortened AP duration induced by stress was abolished by estrogen. Although β-adrenergic overstimulation increasedI NaL, however, it did not prolong the AP duration. The shortened AP duration might be caused by the increase and rapid inactivation of the L-type calcium current in the early stage of repolarization following β-adrenergic activation (Sala et al., 2018). Also, ISO treatment increased slow delayed rectifier potassium current which will shorten the AP duration (Banyasz et al., 2014; Gong JQX, 2020). During the occurrence of heart failure, the electrophysiological remodeling of the myocardium is manifested by an increase inI NaL and the prolongation of AP duration, which may be related to time and the degree of stress (B. Hegyi et al., 2019) . So, under acute stress, it is likely that estrogen may inversely regulates L-type calcium current or potassium currents to prolong the AP duration while reducing the increase in I NaL. Therefore, we will further study the regulation of estrogen on calcium and potassium channels under stress.