Background. This study determines whether controlled reperfusion or diazoxide improves intramyocyte Na+ homeostasis using a porcine model of severe ischemia-reperfusion injury. Methods. Three groups (n = 10 pigs per group) had 75 minutes of left anterior descending artery occlusion during bypass. Group 1 had no treatment (control group), group 2 had controlled reperfusion (500 mL warm cardioplegia) (controlled reperfusion group), and group 3 had diazoxide (50 μmol/L before left anterior descending artery occlusion) (diazoxide group). Biopsies were taken from the left anterior descending artery region before ischemia and at 3, 5, and 10 minutes postreperfusion. Intra-myocyte Na+ and water contents were determined using atomic absorption spectroscopy, and Na+ concentrations were calculated. Results. Intra-myocyte Na+ increased for the diazoxide group pigs at 3-minutes postreperfusion (21.9 ± 2.9 vs 34.0 ± 3.4 μmol/mL; p = 0.02), but decreased to 19.9 ± 3.2 μmol/mL at 10 minutes postreperfusion (p = 1.0 vs baseline). At 10 minutes postreperfusion, intra-myocyte Na+ in the controlled reperfusion group was lower than baseline (22.3 ± 2.7 vs 17.2 ± 3.1 μmol/mL; p < 0.001). Intra-myocyte Na+ at 10 minutes postreperfusion for the diazoxide and controlled reperfusion groups was lower than for the control group (p < 0.05). Conclusions. Diazoxide and controlled reperfusion improved intra-myocyte Na+ homeostasis after severe ischemia-reperfusion injury. © 2003 by The Society of Thoracic Surgeons.