title: Nontoxic effect of tacrolimus on normally perfused isolated liver and protective effect on hypoperfused liver.
abstract: BACKGROUND
  Cyclosporine A has been shown to detrimentally affect post-transplantation vascular tone. Tacrolimus (FK506), an immunosuppressant whose mechanism of action is similar to that of cyclosporine A, is more potent in vitro and has a reportedly high level of safety. The effects of tacrolimus on hepatic vasculature and metabolism in isolated, dually perfused (through both the hepatic artery and porta) rat liver under normal conditions and again in association with a state of hypoperfusion followed by reperfusion, imitating the liver's clinical state during organ transplant, were investigated.
  
  
  METHODS
  Three groups were perfused normally with Krebs-Henseleit solution and three groups were hypoperfused (75% flow reduction) for two hours. Saline, tacrolimus 4 ng/ml, or tacrolimus 40 ng/ml was injected in three normally perfused and three hypoperfused liver groups to determine drug effects under normal conditions and in low-flow-reflow state. Non-radioactive microspheres were later administered to all livers via the artery to assess microcirculatory patency.
  
  
  RESULTS
  Tacrolimus did not affect the normally perfused livers. Liver hypoperfusion without treatment (saline injection) caused wet-dry weight ratio increase, abnormal increases in hepatic artery pressure and resistance values, and non-physiologically low oxygen extraction during reperfusion. Hypoperfusion + tacrolimus 4 or 40 ng/ml yielded values closer to those of the normally perfused livers. Finally, more microspheres were trapped in the hypoperfused+saline-treated liver circulation than in the normally perfused or hypoperfused+tacrolimus 4 or 40 ng/ml livers.
  
  
  CONCLUSIONS
  Tacrolimus appears to be nontoxic in the isolated liver and to mitigate microcirculatory derangement associated with low-flow-reflow states.
authors.affiliation: Organ Transplantation Unit, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Richard
authors.initials: R
authors.lastname: Nakache
authors.forename: Ivgeny
authors.initials: I
authors.lastname: Isretil
authors.forename: Perla
authors.initials: P
authors.lastname: Ekstein
authors.forename: Nehama
authors.initials: N
authors.lastname: Almogy
authors.forename: Dimitri
authors.initials: D
authors.lastname: Fedorov
authors.forename: Beatriz
authors.initials: B
authors.lastname: Lifschitz-Mercer
authors.forename: Avi A
authors.initials: AA
authors.lastname: Weinbroum
mesh_terms: D000818:Animals; D007166:Immunosuppressive Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D008099:Liver / Q000098:blood supply / Q000187:drug effects* / Q000293:injuries / Q000503:physiopathology; D016031:Liver Transplantation; D008297:Male; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D007166:Immunosuppressive Agents; D016559:Tacrolimus