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Reactive oxygen species are a key mediator of myocardial reperfusion injury. Endogenous cellular defenses against reactive oxygen species often become overwhelmed after ischemia and reperfusion. Therefore, exogenous supplementation of various antioxidant compounds has been hypothesized to protect against reperfusion. Reduced glutathione (GSH) is an important endogenous antioxidant that affords protection against oxidative damage. Oral administration of GSH is limited due to poor gastrointestinal absorption. A liposomal preparation of glutathione (lipGSH) capable of oral administration was investigated for its ability to attenuate tissue injury and increase myocardial glutathione levels in an isolated heart model of reperfusion injury. Male, New Zealand white rabbits were assigned randomly among 4 groups as follows: control and daily oral administration of lipGSH for 3, 7, or 14 days. At completion of the dosing regimen, hearts were harvested and perfused in a retrograde manner with the use of a Langendorff apparatus. The hearts were subjected to 30 minutes of global ischemia followed by 60 minutes of reperfusion. Hearts from lipGSH-treated rabbits exhibited better recovery of left ventricular contractile function during reperfusion and had attenuated oxidative damage. Furthermore, hearts from lipGSH-treated animals had increased myocardial tissue levels of GSH demonstrating effective absorption of lipGSH.