The aim was to study the effect of oral administration of three different doses of S-5682 and α-tocopherol on an oxidant-induced injury by tert-butylhydroperoxide (TBOOH) resulting in increased plasma leakage from postcapillary venules in the hamster cheek pouch microcirculation. Hamsters were on a standard laboratory animal diet with normal vitamin E and C content. Five groups of hamsters (n = 6) were treated orally with placebo (10% lactose solution), S-5682 (5, 20 or 80 mg/kg/day) suspended in 10% lactose solution, or α-tocopherol (1 mg/kg/day) for 10 days prior to oxidant challenge with TBOOH. Topical application of 10-4M TBOOH for 5 min to hamsters given FITC-dextran 30 min prior to TBOOH resulted in reversible increases in the number (mean ± SE) of leaks in postcapillary venules: placebo, 117 ± 7 leaks/ cm2; S-5682, 5 mg/kg/day, 68 ± 3 leaks/cm2 (p < 0.01); S-5682,20 mg/kg/day, 41 ± 3 leaks/cm2 (p < 0.01); S-5682, 80 mg/kg/day, 25 ± 2 leaks/cm2 (p < 0.001), and α-tocopherol, 1 mg/kg/day, 18 ± 1 leaks/cm2 (p < 0.001). The efficacy of inhibition of oxidant-induced leakage by S-5682 was similar to that seen with the same dose (20 mg/kg/day) of histamine, bradykinin, leukotriene B4 or ischemia/reperfusion-induced leakage, suggesting a common pathway for the induction of plasma leakage by these mediators. The maximal dose of S-5682 (80 mg/kg/day) was as effective as α-tocopherol (1 mg/kg/day) in inhibiting plasm