The Na⁺/H⁺ exchanger (NHE) and/or the Na⁺/HCO₃^- co-transporter (NBC) were blocked during ischemia in isolated rat hearts. [Na⁺]_i, pH_i and energy related phosphates were measured using simultaneous ²³Na and ³¹P NMR spectroscopy. Hearts were subjected to 30 minutes of global ischemia and 30 minutes of reperfusion. Cariporide (3 µM) or bicarbonate free HEPES buffer was used to block the NHE, the NBC or both, respectively. End-ischemic [Na⁺]_i was 320 ± 18 % of baseline in bicarbonate perfused, untreated hearts, 184 ± 6 % of baseline when the NHE was blocked, 253 ± 19 % of baseline when the NBC was blocked and 154 ± 6 % of baseline when both the NHE and the NBC were blocked. End-ischemic pH_i was 6.09 ± 0.06 in bicarbonate perfused, untreated hearts, 5.85 ± 0.02 when the NHE was blocked, 5.81 ± 0.05 when the NBC was blocked and 5.70 ± 0.01 when both the NHE and the NBC were blocked. NHE blockade was cardioprotective, NBC blockade and combined blockade were not, the latter likely due to a reduction in coronary flow, since omission of bicarbonate under conditions of NHE blockade severely impaired coronary flow. Combined blockade of the NHE and the NBC conserved H⁺_i load during reperfusion and lead to massive Na⁺ influx when blockades were lifted. Without blockade, both the NHE and the NBC mediate acid equivalent efflux in exchange for Na⁺ influx during ischemia, the NHE much more than the NBC. Blockade of either one does not affect the other one.