Hypertonic saline with dextran (HSD) has been recently introduced for prehospital resuscitation of hemorrhagic shock, and is currently undergoing clinical investigation. To determine the effect of clinically relevant amounts of hypertonic saline (7.5% NaCl) and/or 6% dextran 70 on non-ischemic and post-ischemic hearts, we infused rat hearts (Langendorff, 20 minutes global ischemia, 37 degrees, 40 minutes' reperfusion) with: 1) 0.9% NaCl (control); 2) 7.5% NaCl/dextran; 3) 7.5% NaCl; or 4) dextran. We found that 7.5% NaCl alone or with dextran depressed ventricular function (developed pressure, DP; contractility, +dP/dt; and relaxation rate, -dP/dt) in non-ischemic hearts. In contrast, equimolar (2,400 mOsm) sucrose increased myocardial contractility (+dP/dt) of non-ischemic hearts. Coronary flow was unchanged by the addition of 7.5% NaCl, dextran, or sucrose. Treatment of ischemic hearts with 7.5% NaCl/dextran, dextran alone, or sucrose improved recovery of ventricular function compared to 0.9% or 7.5% NaCl. Furthermore, dextran (but not sucrose) with or without 7.5% NaCl reduced myocardial hydrogen peroxide (H2O2) levels during ischemia and reperfusion. We conclude that when given in clinically relevant amounts in the isolated rat heart: 1) 7.5% NaCl directly depresses myocardial function; 2) 7.5% NaCl alone does not improve post-ischemic ventricular function; 3) 7.5% NaCl with dextran or dextran alone improves post-ischemic ventricular function in part by reducing myocardial H2O2; and 4) sucrose equimolar to 7.5% HSD increases ventricular function in non-ischemic and post-ischemic hearts. This investigation suggests that the post-shock benefit of HSD is unrelated to direct myocardial effects of saline but is due in part to toxic oxygen metabolite scavenging by dextran.