Evidence suggests that 1) ischemia-reperfusion injury is due largely to cytosolic Ca 2ϩ accumulation resulting from functional coupling of Na ϩ /Ca 2ϩ exchange (NCE) with stimulated Na ϩ /H ϩ 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 ϩ and therefore Ca 2ϩ accumulation, thereby limiting ischemia-reperfusion injury. NMR was used to measure cytosolic pH (pHi), Na ϩ (Na i ϩ ), and calcium concentration ([Ca 2ϩ ]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 pH i, Na i ϩ , and [Ca 2ϩ ]i during ischemia (P Ͻ 0.05). In control OVX vs. OVXϩE2, pH i fell from 6.93 Ϯ 0.03 to 5.98 Ϯ 0.04 vs. 6.96 Ϯ 0.04 to 6.68 Ϯ 0.07; Na i ϩ rose from 25 Ϯ 6 to 109 Ϯ 14 meq/kg dry wt vs. 25 Ϯ 1 to 76 Ϯ 3; [Ca 2ϩ ]i changed from 365 Ϯ 69 to 1,248 Ϯ 180 nM vs. 293 Ϯ 66 to 202 Ϯ 64 nM. E2 also improved recovery of LVDP and diminished release of LDH during reperfusion. Effects of E2 were diminished by 1 M N -nitro-L-arginine methyl ester. Thus the data are consistent with the hypothesis. However, E2 limitation of increases in [Ca 2ϩ ]i is greater than can be accounted for by the thermodynamic effect of reduced Na i ϩ accumulation on NCE. myocardial ischemia; Na ϩ /H ϩ exchange; Na ϩ /Ca 2ϩ exchange; nuclear magnetic resonance; ischemic biology; ion channels/membrane transport; transplantation IT IS CLEAR THAT OUR UNDERSTANDING of the effects of endogenous and exogenous estrogen on the cardiovascular system, and in particular on its role in modifying susceptibility to ischemic injury, is deficient. It is more important than ever that fundamental research be conducted to understand the basis for the effects of estrogen (50). Because results of various studies are inconsistent and/or difficult to interpret, we have taken a reductionist approach to testing the acute effects of exogenous 17-estradiol (E2) on ischemic myocardium within the context of the well-accepted paradigm that ischemic injury is largely the result of the following chain of events. Anaerobic metabolism decreases cytosolic pH (pH i ), which stimulates pHregulatory Na ϩ /H ϩ exchange (NHE1) to increase Na ϩ uptake and thereby increase intracellular Na ϩ (Na i ϩ ). Increases in (3,7,31,37,46,49). In the heart, there are questions about whether the bulk of Na ϩ and Ca 2ϩ entry occurs during ischemia or reperfusion, but there is a growing consensus that much of the Ca 2ϩ entry is Na ϩ dependent (36). Numerous studies have shown that E2 stimulates NOS activity and/or the release of nitric oxide (NO) in the heart (20,39,40) and that female hormonelinked changes in Na ϩ...
Many studies suggest myocardial ischemia-reperfusion (I/R) injury results largely from cytosolic proton (H i)-stimulated increases in cytosolic Na (Na i), which cause Na/Ca exchange-mediated increases in cytosolic Ca concentration ([Ca] i). Because cold, crystalloid cardioplegia (CCC) limits [H] i, we tested the hypothesis that in newborn hearts, CCC diminishes H i, Nai, and Cai accumulation during I/R to limit injury. NMR measured intracellular pH (pH i), Nai, [Ca]i, and ATP in isolated Langendorff-perfused newborn rabbit hearts. The control ischemia protocol was 30 min for baseline perfusion, 40 min for global ischemia, and 40 min for reperfusion, all at 37°C. CCC protocols were the same, except that ice-cold CCC was infused for 5 min before ischemia and heart temperature was lowered to 12°C during ischemia. Normal potassium CCC solution (NKCCC) was identical to the control perfusate, except for temperature; the high potassium (HKCCC) was identical to NKCCC, except that an additional 11 mmol/l KCl was substituted isosmotically for NaCl. NKCCC and HKCCC were not significantly different for any measurement. The following were different (P Ͻ 0.05). End-ischemia pH i was higher in the CCC than in the control group. Similarly, CCC limited increases in Na i during I/R. End-ischemia Nai values (in meq/kg dry wt) were 115 Ϯ 16 in the control group, 49 Ϯ 13 in the NKCCC group, and 37 Ϯ 12 in the HKCCC group. CCC also improved [Ca] i recovery during reperfusion. After 40 min of reperfusion, [Ca]i values (in nmol/l) were 302 Ϯ 50 in the control group, 145 Ϯ 13 in the NKCCC group, and 182 Ϯ 19 in the HKCCC group. CCC limited ATP depletion during ischemia and improved recovery of ATP and left ventricular developed pressure and decreased creatine kinase release during reperfusion. Surprisingly, CCC did not significantly limit [Ca]i during ischemia. The latter is explained as the result of Ca release from intracellular buffers on cooling. nuclear magnetic resonance; Na/Ca exchanger; Na/H exchanger; ischemia RESULTS OF NUMEROUS STUDIES (2,7,10,13,15,35,37,42,44,46,48) are consistent with the interpretation that myocardial ischemia-reperfusion injury is in part caused by the following chain of events: 1) decreased cytosolic pH (pH i ) stimulates Na-dependent pH regulation, 2) increased Na uptake increases cytosolic Na (Na i ), 3) increased Na i decreases Ca efflux via Na/Ca exchange, and 4) increased cytosolic Ca concentration ([Ca] i ) stimulates a cascade of events that cause injury. Controversy remains concerning whether the bulk of Ca entry occurs during ischemia or reperfusion, but there is near consensus that much of the Ca entry is a consequence of Na loading (13, 41). It has also been repeatedly demonstrated that cold, crystalloid cardioplegia (CCC) decreases the ischemiainduced fall in pH i (6).Because newborn and adult hearts respond differently to hypoxia, ischemia, and cardioplegia (6,9,11, 19,37) and the need for basic science studies aimed at understanding and improving cardioplegia for newborns has not diminis...
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