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1 National Inst Envir. Health Sciences, Laboratory of Signal Transduction, Research Triangle Park, North Carolina, United States
2 Biochemistry, Univerisity of Alberta, Edmonton, Canada
3 Pathology, Duke Univ Medical Center, Durham, North Carolina, United States
* To whom correspondence should be addressed. E-mail: lfliegel{at}ualberta.ca.
In the myocardium, the Na+/H+ exchanger isoform-1 (NHE1) activity is detrimental during ischemia-reperfusion (I/R) injury, causing increased intracellular Na+ (Na+i) accumulation that results in subsequent Ca2+ overload. We tested the hypothesis that increased expression of NHE1 would accentuate myocardial I/R injury. Transgenic mice were created that increased the Na+/H+ exchanger activity specifically in the myocardium. Intact hearts from transgenic mice at 10-15 weeks of age showed no change in heart performance, resting pHi or phosphocreatine/ATP levels. Transgenic and wild-type hearts were subjected to 20 minutes of ischemia followed by 40 minutes of reperfusion. Surprisingly, the percent recovery of rate-pressure product (%RPP) after I/R improved in NHE1 overexpressing hearts 64 +/- 5% vs 41 +/- 5% % in WT (p<0.05). In addition, NMR spectroscopy revealed that NHE1 overexpressor hearts contained higher ATP during early reperfusion (levels p<0.05) and there was no difference in Na+ accumulation during I/R between transgenic and wild-type hearts. A NHE1 inhibitor, HOE642 (cariporide), equivalently protected both wild-type and NHE1 overexpressing hearts. When hearts were perfused with bicarbonate-free HEPES buffer to eliminate the contribution of HCO3- transporters to intracellular pH (pHi) regulation, there was no difference in contractile recovery after reperfusion between controls and transgenics, but NHE1 overexpressing hearts showed a greater decrease in ATP during ischemia. These results indicate that the basal activity of NHE1 is not rate limiting in causing damage during I/R, therefore increasing the level of NHE1 does not enhance injury and can have some small protective effects.
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