Background: While anti-shock therapy provided early after hemorrhage may be beneficial, the problem of delivery of potential therapeutics to ischemic tissue has not been well-appreciated. Polydatin (PD) and 5-aminoimidazole-4-carboxamide 1-β-D-ribonucleoside (AICAR) alleviate mitochondrial dysfunction and acute renal injury (AKI) following resuscitation, but it is unclear whether PD or AICAR are still effective before resuscitation when drug delivery can be still impeded. Because a low volume of polyethylene glycol (PEG) improves tissue perfusion in rats following hemorrhagic shock, we hypothesized that either PD or AICAR, when administered in combination with PEG, will be more effective on restoring hemodynamic function and mitochondrial function than when either drug is administered without PEG. Methods: Rats were randomized into 6 treatment groups (n=8/group): saline, PEG, PD, PD+PEG, AICAR, and AICAR+PEG. Extremity trauma was induced in anesthetized rats followed by pressure-controlled hemorrhage (mean arterial pressure (MAP) = 55 mmHg) for 45 minutes, at which point treatment was administered without fluid resuscitation. MAP, renal blood flow (RBF) and oxygen delivery (DO2), glomerular filtration rate (GFR), and sodium and potassium reabsorption were measured. Two hours after treatment, rats were euthanized to measure renal mitochondrial function. Results: Hemorrhage caused hyperlactatemia and decreased RBF, DO2, GFR, and urine flow; PEG, PD+PEG, and AICAR+PEG similarly improved these parameters, but neither PD nor AICAR alone showed any hemodynamic effects. However, preserved renal mitochondrial respiratory activities were only observed in PD+PEG and AICAR+PEG but not in PD, AICAR, or PEG alone groups. In addition, PD+PEG but not PD alone inhibited the tubular mitochondrial activity during shock as indicated by decreased renal sodium and potassium reabsorption. Conclusion: During hemorrhagic shock, PD or AICAR demonstrated preservation of mitochondrial function only when co-administered with PEG to alleviate tissue ischemia. This finding suggests a potential pharmacologic strategy to improve tissue delivery of therapeutics when resuscitation is limited.