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(Circulation. 2001;104:2101.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Gender Influences [Ca²⁺]_i During Metabolic Inhibition in Myocytes Overexpressing the Na⁺-Ca²⁺ Exchanger

Kazuro Sugishita, MD; Zhi Su, PhD; Fenghua Li, MD; Kenneth D. Philipson, PhD; William H. Barry, MD

From the Division of Cardiology, University of Utah Health Sciences Center, Salt Lake City, Utah (K.S., Z.S., F.L., W.H.B.), and the Department of Physiology and Medicine, UCLA School of Medicine, Los Angeles, Calif (K.D.P.).

Correspondence to William H. Barry, MD, Division of Cardiology, University of Utah Health Sciences Center, 50 N Medical Dr, Salt Lake City, UT 84132. E-mail whbarry{at}med.utah.edu

Background— The Na⁺-Ca²⁺ exchanger (NCX) may contribute to Ca²⁺ 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 [Ca²⁺]_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 [Ca²⁺]_i and sodium 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 nmol/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 NCX inhibitor, abolished the effect of NCX overexpression but did not totally eliminate the effect of gender on [Ca²⁺]_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 [Ca²⁺]_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 [Ca²⁺]_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.

Key Words: myocytes • ischemia • calcium • sex • sodium

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