Na+ overload during ischemia and reperfusion in rat hearts:: Comparison of the Na+/H+ exchange blockers EIPA, cariporide and eniporide

Intracellular myocardial Na+ overload during ischemia is an important cause of reperfusion injury via reversed Na+/Ca2+ exchange. Prevention of this Na+ overload can be accomplished by blocking the different Na+ influx routes. In this study the effect of ischemic inhibition of the Na+/H+ exchanger (NHE) on [Na+](i), pH(i) and post-ischemic contractile recovery was tested, using three different NHE-blockers: EIPA, cariporide and eniporide. pH(i) and [Na+](i) were measured using simultaneous P-31 and Na-23 NMR spectroscopy, respectively, in paced (5 Hz) isolated, Langendorff perfused rat hearts while contractility was assessed by an intraventricular balloon. NHE-blockers (3 muM) were administered during 5 min prior to 30 min of global ischemia followed by 30 min drug-free reperfusion. NHE blockade markedly reduced ischemic Na+ overload; after 30 min of ischemia [Na+](i) had increased to 293+/-26, 212+/-6, 157+/-5 and 146+/-6% of baseline values in untreated and EIPA (p<0.01 vs. untreated), cariporide (p<0.01 vs. untreated) and eniporide (p<0.01 vs. untreated) treated hearts, respectively. Ischemic acidosis did not differ significantly between groups. During reperfusion, however, recovery of pH(i) was significantly delayed in treated hearts. The rate pressure product recovered to 12.0 +/- 1.9, 12.1 +/- 2.1, 19.5 +/- 2.8 and 20.4 +/- 2.5x10(3) mmHg/min in untreated and EIPA, cariporide (p<0.01 vs. untreated) and eniporide (p<0.01 vs. untreated) treated hearts, respectively. In conclusion, blocking the NHE reduced ischemic Na+ overload and improved post-ischemic contractile recovery. EIPA, however, was less effective and exhibited more side effects than cariporide and eniporide in the concentrations used.