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.
McKenna
R
R
Upjohn Company, Kalamazoo, Michigan 49001, USA.
Laskey
R E
RE
Wang
Y
Y
Jaeschke
H
H
Mathews
W R
WR
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000503:physiopathology*; D001427:Bacterial Toxins / Q000633:toxicity*; D003250:Constriction; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000503:physiopathology*; D004731:Endotoxins / Q000633:toxicity*; D007511:Ischemia / Q000503:physiopathology*; D015227:Lipid Peroxidation; D008099:Liver / Q000098:blood supply*; D008297:Male; D009102:Multiple Organ Failure / Q000503:physiopathology*; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology; D005996:Nitroglycerin / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011281:Pregnatrienes / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D015427:Reperfusion Injury / Q000503:physiopathology*; D014664:Vasodilation / Q000502:physiology*
D000975:Antioxidants; D001427:Bacterial Toxins; D004731:Endotoxins; D011281:Pregnatrienes; C027952:salmonella toxin; D010656:Phenylephrine; D005996:Nitroglycerin; D000109:Acetylcholine; C053355:tirilazad