Aldosterone and cortisol acutely stimulate Na+/H+ exchanger activity in the syncytiotrophoblast of the human placenta: effect of fetal sex.

Na(+)/H(+) exchanger (NHE) activity regulates intracellular pH (pH(i)) in the placental syncytiotrophoblast. In other tissues aldosterone and cortisol have been shown to up-regulate NHE activity via an acute, non-genomic effect. Here we tested the hypothesis that these corticosteroids stimulate NHE in the syncytiotrophoblast. Villous fragments from term placentas were loaded with 1 muM BCECF (pH sensitive fluorescent dye) and the syncytiotrophoblast acidified with a pre-pulse of 20 mM NH(4)Cl. The Na(+)-dependent recovery of pH(i) from this acid load was taken as a measure of NHE activity (pH units/sec, mean +/- SEM, n = number of placentas). In placental villi from female babies aldosterone significantly increased the rate of recovery of pH(i) from an acid load (0.0087 +/- 0.0005 versus 0.0056 +/- 0.0009 pH units/s, n = 8 p < 0.05 Paired Student's t-test) which was inhibited by the mineralocorticoid receptor antagonist, spironolactone (1 microM) but not the glucocorticoid antagonist mifepristone (1 microM). There was no effect on the rate of recovery from an acid load in villi from placenta from male babies. Alone, neither cortisol (1 microM, n = 5) nor carbenoxolone (100 microM, n = 9), an inhibitor of 11-beta-hydroxysteroid dehydrogenase-2 (11-beta-HSD-2), altered the rate of recovery from an acid load. However, simultaneous application of cortisol with carbenoxolone significantly increased the rate of recovery from an acid load but again only in placentas from female babies (0.0080 +/- 0.0017 versus control 0.0037 +/- 0.0005, p < 0.05 pH units/s, n = 9 Paired Student's t-test). Stimulation by cortisol in female tissue was inhibited by mifepristone but not spironolactone. In conclusion, syncytiotrophoblast NHE activity is increased acutely by aldosterone and, when 11-beta-HSD-2 is blocked, by cortisol. These non-genomic effects are only evident in placentas from female babies and are mediated by classical mineralocorticoid and/or glucocorticoid receptors.