Pharmacologic modulation of experimental postischemic hepatic function.
The present study evaluated and compared the effects of SRI 63-441, a potent platelet activating factor antagonist, superoxide dismutase (SOD), an oxygen free radical scavenger, and ibuprofen, a cyclooxygenase inhibitor on hepatic function after 90 minutes of warm ischemia. After warm ischemia, livers were harvested and underwent 90 minutes of warm, oxygenated, sanguinous perfusion on an isolated liver perfusion apparatus. Pretreatment of donor animals with 20 mg/kg intravenous (I.V.) SRI 63-441 5 minutes before induction of total hepatic ischemia resulted in significantly increased bile production, a significant decrease in transaminase release, and a higher tissue adenosine triphosphate (ATP) content when compared with ischemic nontreated controls. SOD resulted in improved bile production and decreased transaminase liberation only when present in the perfusate at the time of in vitro reperfusion. Ibuprofen did not improve postischemic hepatic function in this model. Electron microscopy revealed patchy hepatocellular vacuolization with an intact sinusoidal endothelium in all ischemic livers. However, the degree of damage was less severe in the livers from those rats pretreated with 20 mg/kg SRI 63-441. This study demonstrates that SRI 63-441 pretreatment significantly reduces hepatic warm ischemic injury, and in the present model, appears superior to two other agents that have been advanced in the treatment of ischemic injury. The use of such agents singly or in combinations have important implications as regards gaining a better understanding of the basic mechanisms in organ ischemia, and moreover, for therapeutic applications in organ ischemia and preservation.
Ontell
S J
SJ
Department of Surgery, University of Pittsburgh School of Medicine, Pennsylvania.
Makowka
L
L
Trager
J
J
Mazzaferro
V
V
Ove
P
P
Starzl
T E
TE
D000818:Animals; D001646:Bile / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006358:Hot Temperature; D007052:Ibuprofen / Q000627:therapeutic use*; D007511:Ischemia / Q000209:etiology*; D008099:Liver / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism / Q000502:physiology / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D010477:Perfusion; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D011806:Quinolinium Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains; D015427:Reperfusion Injury / Q000517:prevention & control*; D013482:Superoxide Dismutase / Q000008:administration & dosage / Q000627:therapeutic use*; D000637:Transaminases / Q000378:metabolism
D010972:Platelet Activating Factor; D011806:Quinolinium Compounds; C050531:SRI 63-441; D013482:Superoxide Dismutase; D000637:Transaminases; D007052:Ibuprofen