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, pHi and post-ischemic contractile recovery was tested, using three different NHE-blockers: EIPA, cariporide and eniporide. pHi and [Na+]i were measured using simultaneous 31P and 23Na NMR spectroscopy, respectively, in paced (5 Hz) isolated, Langendorff perfused rat hearts while contractility was assessed by an intraventricular balloon. NHE-blockers (3 μM) 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 pHi 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 ± 2.5 × 103 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.