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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS
-estradiol on myocardial pH, Na+, and Ca2+ and ischemia-reperfusion injury
Department of Physiology and Membrane Biology, University of California, Davis, California
Submitted 24 August 2004 ; accepted in final form 20 September 2004
Evidence suggests that 1) ischemia-reperfusion injury is due largely to cytosolic Ca2+ accumulation resulting from functional coupling of Na+/Ca2+ exchange (NCE) with stimulated Na+/H+ exchange (NHE1) and 2) 17
-estradiol (E2) stimulates release of NO, which inhibits NHE1. Thus we tested the hypothesis that acute E2 limits myocardial Na+ and therefore Ca2+ accumulation, thereby limiting ischemia-reperfusion injury. NMR was used to measure cytosolic pH (pHi), Na+ (Na
), and calcium concentration ([Ca2+]i) in Krebs-Henseleit (KH)-perfused hearts from ovariectomized rats (OVX). Left ventricular developed pressure (LVDP) and lactate dehydrogenase (LDH) release were also measured. Control ischemia-reperfusion was 20 min of baseline perfusion, 40 min of global ischemia, and 40 min of reperfusion. The E2 protocol was identical, except that 1 nM E2 was included in the perfusate before ischemia and during reperfusion. E2 significantly limited the changes in pHi, Na
and [Ca2+]i during ischemia (P < 0.05). In control OVX vs. OVX+E2, pHi fell from 6.93 ± 0.03 to 5.98 ± 0.04 vs. 6.96 ± 0.04 to 6.68 ± 0.07; Na
rose from 25 ± 6 to 109 ± 14 meq/kg dry wt vs. 25 ± 1 to 76 ± 3; [Ca2+]i changed from 365 ± 69 to 1,248 ± 180 nM vs. 293 ± 66 to 202 ± 64 nM. E2 also improved recovery of LVDP and diminished release of LDH during reperfusion. Effects of E2 were diminished by 1 µM N
-nitro-L-arginine methyl ester. Thus the data are consistent with the hypothesis. However, E2 limitation of increases in [Ca2+]i is greater than can be accounted for by the thermodynamic effect of reduced Na
accumulation on NCE.
myocardial ischemia; Na+/H+ exchange; Na+/Ca2+ exchange; nuclear magnetic resonance; ischemic biology; ion channels/membrane transport; transplantation
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