Comparison of the efficacy of mechanistically different antioxidants in the rat hemorrhagic shock model

Four pharmacological mechanisms for antagonizing free radical generation or reactions were compared in terms of their efficacy in attenuating hemorrhagic shock in rats. These included opposing superoxide generation by xanthine oxidase (e.g., oxypurinol), inhibiting arachidonic acid oxidation by cyclooxygenase (e.g., ibuprofen), chelating iron (e.g., desferal), and inhibiting lipid peroxidation (e.g., tirilazad mesylate [U-74006F] and U- 78517G). Animals were hemorrhaged to a mean arterial pressure (MAP) of 43-45 mmHg where they were held for 2 hr. Five minutes prior to the end of the hemorrhage period, either vehicle, U-74006F (10 mg/kg), U-78517G (10 mg/kg), oxypurinol (10 or 25 mg/kg), desferal (10 or 25 mg/kg), or ibuprofen (10 mg/kg) was administered i.v., followed by the reinfusion of shed blood. In vehicle-treated animals, MAP declined progressively over the 2 hr post- reinfusion. Ibuprofen, desferal, and oxypurinol treatments each failed to attenuate this decline. In contrast, both U-74006F and U-78517G resulted in a significantly improved maintenance of MAP. Evidence of shock-induced lipid peroxidation was observed in terms of a 73.8% depletion in liver vitamin E content at 2 hr post-reinfusion in vehicle-treated rats. This decrease was prevented by both U-74006F and U-78517G. Inhibition of free radical-induced lipid peroxidation appears more effective for attenuating free radical pathophysiology in hemorrhagic shock that attempting to inhibit specific pathways of oxygen radical generation.