Effect of endotoxin-enhanced hepatic reperfusion injury on endothelium-dependent relaxation in rat aorta.

We have investigated endothelial function in a two-hit model of multiple organ failure. Male Fischer rats were subjected to 20 min of partial hepatic ischemia followed by reperfusion and administration of .5 mg/kg Salmonella enteritidis endotoxin at 30 min of reperfusion. After either 4 or 24 h of reperfusion, rings of aorta were prepared and suspended in bioassay baths, contracted with phenylephrine, and examined for endothelium-dependent relaxation in response to acetylcholine and endothelium-independent relaxation using nitroglycerin. Endothelium-dependent relaxation to acetylcholine was impaired in rings from animals exposed to endotoxin-enhanced reperfusion injury at both 4 h and 24 h. At 24 h of reperfusion the EC50 for acetylcholine relaxation was significantly increased from 45 ± 8 nM to 258 ±105 nM. Endothelium-independent relaxation to nitroglycerin was not affected. The 21-aminosteroid Tirilazad mesylate (U-74006F) prevented endothelial dysfunction; at 24 h of reperfusion the EC50 for acetylcholine relaxation in U-74006F-treated animals was 55 ± 8 nM. Thus, endothelial function is impaired in this model of multiple organ failure and this impairment is prevented by Tirilazad mesylate.