Na ϩ /H ϩ exchanger (NHE) and/or the Na ϩ /HCO 3 Ϫ cotransporter (NBC) were blocked during ischemia in isolated rat hearts. Intracellular Na ϩ concentration ([Na ϩ ]i), intracellular pH (pHi), and energyrelated phosphates were measured by using simultaneous 23 Na and 31 P NMR spectroscopy. Hearts were subjected to 30 min of global ischemia and 30 min of reperfusion. Cariporide (3 M) or HCO 3 Ϫ -free HEPES buffer was used, respectively, to block NHE, NBC, or both. End-ischemic [Na ϩ ]i was 320 Ϯ 18% of baseline in HCO 3 Ϫ -perfused, untreated hearts, 184 Ϯ 6% of baseline when NHE was blocked, 253 Ϯ 19% of baseline when NBC was blocked, and 154 Ϯ 6% of baseline when both NHE and NBC were blocked. End-ischemic pHi was 6.09 Ϯ 0.06 in HCO 3 Ϫ -perfused, untreated hearts, 5.85 Ϯ 0.02 when NHE was blocked, 5.81 Ϯ 0.05 when NBC was blocked, and 5.70 Ϯ 0.01 when both NHE and NBC were blocked. NHE blockade was cardioprotective, but NBC blockade and combined blockade were not, the latter likely due to a reduction in coronary flow, because omission of HCO 3 Ϫ under conditions of NHE blockade severely impaired coronary flow. Combined blockade of NHE and NBC conserved intracellular H ϩ load during reperfusion and led to massive Na ϩ influx when blockades were lifted. Without blockade, both NHE and NBC mediate acid-equivalent efflux in exchange for Na ϩ influx during ischemia, NHE much more than NBC. Blockade of either one does not affect the other.