Background: The Na(+)-Ca(2+) exchanger (NCX) may contribute to Ca(2+) overload and injury in ischemic cardiomyocytes. Recently, NCX overexpression was reported to increase ischemia/reperfusion injury in male and oophorectomized female but not in female mice. We therefore measured the effects of gender and estrogen on [Ca(2+)](i) and [Na(+)](i) during metabolic inhibition (MI) in myocytes from wild-type (WT) and transgenic (TG) mice overexpressing NCX.
Methods and results: Flow cytometry was used with fluo 3 for [Ca(2+)](i) and sodium green for [Na(+)](i) measurements. Male TG mouse myocytes had higher [Ca(2+)](i) after 30 minutes of MI (1086+/-160 nmol/L, n=8) than male WT (688+/-104 nmol/L, n=9, P=0.01). The increase in [Ca(2+)](i) during MI induced by NCX overexpression in female myocytes was not significant, however (TG 552+/-62 nmol/L, n=9; WT 426+/-44 nmol/L, n=7). The magnitude of rise in [Ca(2+)](i) during MI was greater in male than female myocytes. KB-R7943, an NCX inhibitor, abolished the effect of NCX overexpression but did not totally eliminate the effect of gender on [Ca(2+)](i) during MI. NCX current density and basal Na(+) pump function were not influenced by gender. The rise in [Na(+)](i) during MI was greater in male than in female myocytes. Estrogen attenuated the increase in [Ca(2+)](i) and [Na(+)](i) in male myocytes during MI and abolished the gender difference in [Na(+)](i) during MI.
Conclusions: Increased expression of NCX results in a more marked rise in [Ca(2+)](i) during MI in male than in female mouse myocytes. This gender difference appears to be mediated in part by an inhibitory effect of estrogen on the rise in [Na(+)](i), an NCX modifier, during MI.