Limited effects of post-ischemic NHE blockade on [Na+]i and pHi in rat hearts explain its lack of cardioprotection

Objective: Na+/H+ exchanger (NHE) blockade fails as reperfusion therapy in patients with acute myocardial infarction. In experimental studies, the reports on the efficacy of NHE blockade only during reperfusion are inconsistent. Differences in the severity of ischemia and in drug delivery may explain these inconsistencies. Little is known about the primary goal of post-ischemic NHE blockade, i.e. reduction of Na-i(+) overload. Methods: Isolated rat hearts were subjected either to 60 min of low flow (0.2 ml/min) ischemia or 25 min of zero flow ischemia. Hearts were reperfused with or without the selective NHE blocker cariporide added to the perfusate. [N+](i) and pH(i) were measured with simultaneous Na-23 and P-31 NMR spectroscopy. Results: After 60 min of low flow ischemia [Na](i) had risen to 424 +/- 14% of baseline and pHi was 6.36 +/- 0.03. After low flow ischemia [Na+](i) and pH(i) recovered similarly in treated and untreated hearts. Recovery of the rate pressure product (RPP) was poorly in both groups. After 25 min of zero flow ischemia [Na+](i) had risen to 279 +/- 7% of baseline and pH(i) was 6.12 +/- 0.02. NHE blockade after zero flow ischemia caused [Na+](i) to decrease during the first 30 s of reperfusion, followed by a partial and transient rise during the second 30 s. Untreated hearts showed a very small rise in [Na+](i) during the first minute. pH(i) recovered 30 s slower in cariporide treated hearts than in untreated hearts (p < 0.05). No effect of cariporide on RPP could be detected since RPP recovered fully in untreated hearts. The end diastolic pressure, however, was increased during reperfusion to a similar extent in both groups. Conclusion: The lack of cardioprotection under these specific conditions of zero flow and low flow ischemia can be explained by the fact that NHE blockade only resulted in a small and transient effect on [Na+](i) and pH(i). (C) 2003 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.