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  • Title: Activity of the Na(+)/H(+) exchanger is critical to reperfusion damage and preconditioning in the isolated rat heart.
    Author: Xiao XH, Allen DG.
    Journal: Cardiovasc Res; 2000 Nov; 48(2):244-53. PubMed ID: 11054471.
    Abstract:
    OBJECTIVE: Removal of protons from the heart during ischemia and/or reperfusion by the cardiac Na(+)/H(+) exchanger (NHE1) leads to Na(+) entry; this causes Ca(2+) influx and is thought to contribute to ischemic and/or reperfusion damage. The extent to which Na(+) enters during ischemia as opposed to reperfusion is disputed and has important implications for the therapeutic use of NHE1 inhibitors as protection against ischemic damage. Preconditioning has recently been proposed to inhibit NHE1 during reperfusion. The objective of the present study was to determine the activity of NHE1 during ischemia, reperfusion and following preconditioning. METHODS: The experiments were on isolated perfused rat hearts in which left ventricular developed pressure (LVDP) and intracellular sodium and pH were measured. RESULTS: LVDP following 30 min of ischemia recovered to 14+/-3% of pre-ischemic level. Application of the NHE1 inhibitor HOE 642 during ischemia and reperfusion improved recovery of LVDP to 77+/-9%. When HOE was applied at the moment of reperfusion the recovery of LVDP was reduced to 54+/-6%. To overcome possible delays in the delivery of HOE, the drug was applied at 28 min of ischemia; under these conditions recovery of LVDP (71+/-7%) was not significantly different to HOE throughout ischemia and reperfusion. HOE had no effect on the recovery of preconditioned hearts. NHE1 activity was assessed by the [Na(+)](i) and pH(i) changes in response to brief exposure to Na(+) lactate (NaL). In control hearts, activity of NHE1 caused a pH(i) recovery of 0. 034+/-0.007 pH units and was associated with a [Na(+)](i) rise of 7. 5+/-0.5 mmol/l. After 5-min reperfusion following ischemia, NaL application caused a pH(i) recovery (0.046+/-0.007) and a larger [Na(+)](i) rise (15.8+/-0.6 mmol/l). After 5-min reperfusion of preconditioned hearts, NaL application caused a smaller recovery pH recovery (0.013+/-0.002) and a smaller [Na(+)](i) rise (4.2+/-0.5 mmol/l). CONCLUSIONS: These findings suggest that NHE1 is activated in early reperfusion after ischemia but inhibited during early reperfusion in preconditioned hearts. Overall our results point to a critical period of activity of NHE1 in early reperfusion which is inhibited by preconditioning.
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