Male/female differences in intracellular Na+ regulation during ischemia/reperfusion in mouse heart.
We previously showed that beta-adrenergic stimulation revealed male/female differences in susceptibility to ischemia/reperfusion (I/R) injury. To explore whether altered [Na(+)](i) regulation is involved in the mechanism of this sex difference, we measured [Na(+)](i) by (23)Na NMR spectroscopy in isolated perfused mouse hearts. [Na(+)](i) increased to 195 +/- 3% (mean +/- S.E.) of the pre-ischemic level at 20 min of ischemia in male hearts, whereas [Na(+)](i) accumulation was slightly less in female hearts (176 +/- 2%, P < 0.05). There was no significant difference in the recovery of contractile function after reperfusion (male: 30.6 +/- 3.8%; female: 35.0 +/- 1.9%; P > 0.05). If hearts were treated with isoproterenol (ISO, 10 nmol/l), males exhibited significantly poorer recovery of post-ischemic contractile function than females (male: 13.0 +/- 1.9%; female: 28.1 +/- 1.2%; P < 0.05), and a significantly higher [Na(+)](i) accumulation during ischemia (male: 218 +/- 8%; female: 171 +/- 2%; P < 0.05). This ISO-induced male/female difference in [Na(+)](i) accumulation or contractile function was blocked by the nitric oxide synthase inhibitor, N(omega)-nitro-l-arginine methyl ester (1 micromol/l). Furthermore, in ISO-treated hearts, the Na(+)/K(+)-ATPase inhibitor, ouabain (200 micromol/l) did not abolish the male/female difference in [Na(+)](i) accumulation during I/R or functional protection. Thus the data show that the sex difference in the [Na(+)](i) regulation is mediated through a NO-dependent mechanism, and the difference in susceptibility to I/R injury appears to result from a difference in Na(+) influx.
Imahashi
Kenichi
K
Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, 111 Alexander Drive, RTP, NC 27709, USA.
London
Robert E
RE
Steenbergen
Charles
C
Murphy
Elizabeth
E
D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage; D005260:Female; D007545:Isoproterenol / Q000008:administration & dosage; D008297:Male; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D012727:Sex Characteristics; D012964:Sodium / Q000378:metabolism*
D002316:Cardiotonic Agents; D009569:Nitric Oxide; D012964:Sodium; D007545:Isoproterenol