Protective effect of the 21-aminosteroid lipid peroxidation inhibitor tirilazad mesylate (U74006F) on hepatic endothelium in experimental hemorrhagic shock.

Abstract

The effects of the 21-aminosteroid lipid peroxidation inhibitor tirilazad mesylate (U74006F) on ultrastructural damage to the hepatic endothelium in a rat model of hemorrhagic shock were examined. Male Sprague-Dawley rats were anesthetized with urethane and subjected to a 2 hr period of hemorrhagic hypotension (mean arterial pressure clamped at 43-45 mm Hg), followed by reinfusion and follow-up for 2 hr. At the end of the experiment, light microscopic analysis of the livers of animals that received an i.v. injection of vehicle (citrate buffer) just prior to reinfusion showed substantial sinusoidal neutrophil influx. Electron microscopic morphometry revealed significant sinusoidal endothelial degeneration. In contrast, rats that received a 10 mg/kg i.v. bolus of U74006F just prior to posthemorrhage reinfusion displayed a significant preservation of endothelial structural integrity. However, this occurred despite the fact that there was the same degree of hepatic neutrophil influx as in the vehicle-treated rats. These results show that U74006F is capable of protecting endothelial structure, even in the face of significant neutrophil invasion, probably via protection from endothelial cell membrane free radical-induced lipid peroxidation.