Although the protection against myocardial ischemia-reperfusion injury by allopurinol has previously been attributed to inhibition of xanthine oxidase, the demonstration of protective effects in species devoid of detectable myocardial xanthine oxidase activity argues against this hypothesis. In the present study, the effects of allopurinol pretreatment in a model of heart-lung transplantation were examined in swine, a species devoid of myocardial xanthine oxidase activity. Twenty-eight experiments were performed utilizing the heart-lung transplantation model--seven controls (14 animals, 7 donors and 7 recipients) with no preoperative pharmacological intervention, and twenty-one in the experimental group (42 animals, 21 donors and 21 recipients) with donor and recipient pretreated with allopurinol 50 mg/kg/day for 3 days. The effect of allopurinol was determined on day 2 blood samples assessing red cell antioxidant status by measurement of malondialdehyde (MDA) formation in response to in vitro peroxidative challenge. The experimental group was divided into subgroups--namely, nonresponders (8 pairs of animals) and responders (13 pairs of animals) based on the range (mean +/- 2 SD) of erythrocyte MDA levels in the control group. Heart-lung transplantation was performed in the three groups (control , nonresponders , and responders ) on day 3 following the final dose of allopurinol administration in the experimental group. Based on postsurgical assessments of cardiac and pulmonary function integrity, animals showing the greatest red cell antioxidant response following allopurinol treatment showed significantly better recovery compared with the control group. In contrast, animals that did not respond to allopurinol pretreatment showed results similar to those of the control (i.e., untreated) group. Furthermore, red cell MDA levels in all the allopurinol-treated animals were found to correlate positively (P < 0.001) with the extent of myocardial and lung dysfunction, as indicated by cardiac index and lung water measurements, respectively. The present study suggests that allopurinol protection against ischemia-reperfusion injury may involve generalized alterations in tissue antioxidant status, and that the measurement of erythrocyte susceptibility to oxidative challenge could provide a useful approach to optimizing the effectiveness of therapeutic interventions undertaken prior to surgery in order to minimize the risk of damage resulting from postischemic tissue reperfusion.