Objectives: Cardiac ischemia–reperfusion activates Na +/H + exchange; excess Na + and the resulting Ca 2+ overload, through reverse Na +/Ca 2+ exchange, cause cellular injury and cardiac dysfunction. We postulated that inhibiting the Na +/H + isoform-1 exchanger would add to the protection of hearts after long-term cold storage in acidic cardioplegic solution. Methods: Guinea pig hearts were isolated and perfused at 37°C with Krebs-Ringer’s solution (KRS) and then switched to an acidic St. Thomas solution (STS) at 25°C. Perfusion was stopped at 10°C, and hearts were stored for 6 hours in STS at 3.4°C. On reperfusion to 25°C, hearts were perfused with KRS for 60 minutes. Hearts were divided into 4 groups: sham control (SHAM); eniporide (EPR, EMD96785) IV, 1 mg/kg given IV over 15 minutes before heart isolation; EPR intracoronary, 1 μmol/liter in STS given intracoronary after heart isolation; and EPR IV and intracoronary. Results: Values at 60 minutes reperfusion (the percentage of control [100%] before cold storage) are given, respectively, for EPR IV, EPR intracoronary, and EPR IV and intracoronary vs drug-free SHAM (SEM, * p < 0.05 vs SHAM): 72% ± 3%*, 65% ± 3%*, and 81% ± 2%* vs 55% ± 3% for left ventricular pressure; 94% ± 3%*, 96% ± 5%*, and 102% ± 2%* vs 81% ± 3% for coronary flow; 60% ± 2%, 58% ± 3%, and 74%* ± 3% vs 58% ± 4% for cardiac efficiency; 106% ± 2%*, 108% ± 3%*, and 107% ± 2%* vs 116% ± 4% for percentage of O 2 extraction. Infarct size as percentage of ventricular weight was 20% ± 3%*, 31% ± 3%, and 6% ± 2%* vs 35% ± 3% (SHAM) after 60 minutes of reperfusion. Conclusions: Na +/H + isoform-1 exchanger inhibition, particularly if given IV before storage and intracoronary during cooling and rewarming, adds to the protection of cardioplegic solutions.