Myocardial ischemia and reperfusion have been shown to result in damage to the phospholipid components of cardiac myocyte cell membranes as indicated by the tissue accumulation of unesterified fatty acids (UFA). A portion of this damage and subsequent dysfunction may be a consequence of free radical-induced membrane lipid peroxidative events. alpha-Tocopherol, a lipophilic antioxidant, was used in this study as an agent by which the extent of ischemia and reperfusion injury might be decreased. Increasing rat myocardial tissue levels of alpha-tocopherol by 51% was found to attenuate lipid perturbations as determined by the accumulation of tissue UFA in an isolated heart model of global ischemia and reperfusion. Nontreated hearts made ischemic for 25 min with 30 min of reflow had a significantly increased total UFA level of 5,961 +/- 799 nmol/mg protein (P less than 0.05) compared with control perfused hearts containing 3,116 +/- 463 nmol UFA/mg protein and with alpha-tocopherol-treated ischemic and reperfused hearts containing 3,066 +/- 365 nmol UFA/mg protein. Contractile dysfunction, excessive accumulation of tissue calcium, and release of lactate dehydrogenase after ischemia and reperfusion were also reduced, demonstrating protective effects in alpha-tocopherol-treated hearts. Thus alpha-tocopherol proved effective in the attenuation of ischemia and reperfusion damage. These results suggest that reducing lipid alterations may prove beneficial in protecting against membrane damage subsequent to ischemia and reperfusion.