Gender Influences [Ca]i During Metabolic Inhibition in Myocytes Overexpressing the Na-Ca Exchanger

Background—The Na-Ca exchanger (NCX) may contribute to Ca 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]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]i and sodium green for [Na ]i measurements. Male TG mouse myocytes had higher [Ca]i after 30 minutes of MI (10866160 nmol/L, n58) than male WT (6886104 nmol/L, n59, P50.01). The increase in [Ca]i during MI induced by NCX overexpression in female myocytes was not significant, however (TG 552662 nmol/L, n59; WT 426644 nmol/L, n57). The magnitude of rise in [Ca]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]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]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]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. (Circulation. 2001;104:2101-2106.)