Gender influences [Ca2+](i) during metabolic inhibition in myocytes overexpressing the Na+-Ca2+ exchanger

Background-The Na+-Ca2+ exchanger (NCX) may contribute to Ca2+ overload and injury in ischemic cardiomyocytes. Recently, NCX overexpression was report ed to increase ischemia/reperfusion injury in male and oophorectomized fema le but not in female mice. We therefore measured the effects of gender and estrogen on [Ca2+](i) and [Na+](i) during metabolic inhibition (MI) in myoc ytes from wild-type (WT) and transgenic (TG) mice overexpressing NCX. Methods and Results-Flow cytometry was used with fluo 3 for [Ca2+](i) and s odium green for [Na+]i measurements. Male TG mouse myocytes had higher [Ca2 +](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 [Ca2+](i) during MI induced by NCX overexpression in female myocytes was not significant, however (TG 552 +/- 62 nmoI/L, n=9; WT 426 +/- 44 nmol/L, n=7). The magnitude of rise in [ Ca2+](i) during MI was greater in male than female myocytes. KB-R7943, an N CX inhibitor, abolished the effect of NCX overexpression but did not totall y eliminate the effect of gender on [Ca2+](i) during MI. NCX current densit y and basal Na+ pump function were not influenced by gender. The rise in [N a+](i) during MI was greater in male than in female myocytes. Estrogen atte nuated the increase in [Ca2+](i) and [Na+](i) in male myocytes during MI an d abolished the gender difference in [Na+](i) during MI. Conclusions-Increased expression of NCX results in a more marked rise in [C a2+](i) during MI in male than in female mouse myocytes. This gender differ ence appears to be mediated in part by an inhibitory effect of estrogen on the rise in [Na+](i), an NCX modifier, during MI.