title: Tezosentan, a novel endothelin receptor antagonist, markedly reduces rat hepatic ischemia and reperfusion injury in three different models.
abstract: This study investigated the effects of dual endothelin (ET) receptor blockade in rat models of liver ischemia and reperfusion injury (IRI). Three models of IRI were used: (1) in vivo total hepatic warm ischemia with portal shunting for 60 minutes with control (saline) and treatment groups (15 mg/kg tezosentan intravenously prior to reperfusion), (2) ex vivo hepatic perfusion after 24 hours of cold storage in University of Wisconsin solution with control and treatment groups (10 mg/kg tezosentan in the perfusate), and (3) syngeneic liver transplantation (LT) after 24 hours of cold storage in University of Wisconsin solution with control and treatment groups (10 mg/kg tezosentan intravenously prior to reperfusion). Tezosentan treatment significantly improved serum transaminase and histology after IRI in all 3 models. This correlated with reduced vascular resistance, improved bile production, and an improved oxygen extraction ratio. Treatment led to a reduction in neutrophil infiltration and interleukin-1 beta and macrophage inflammatory protein 2 production. A reduction in endothelial cell injury as measured by purine nucleoside phosphorylase was seen. Survival after LT was significantly increased with tezosentan treatment (90% versus 50%). In conclusion, this is the first investigation to examine dual receptor ET blockade in 3 models of hepatic IRI and the first to use the parenterally administered agent tezosentan. The results demonstrate that in both warm and cold IRI tezosentan administration improves sinusoidal hemodynamics and is associated with improved tissue oxygenation and reduced endothelial cell damage. In addition, reduced tissue inflammation, injury, and leukocyte chemotactic signaling were seen. These results provide compelling data for the further investigation of the use of tezosentan in hepatic IRI.
authors.affiliation: Dumont-UCLA Transplant Center, Department of Surgery, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095-7054, USA. dgfarmer@mednet.ucla.edu
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Farmer
authors.forename: Fady
authors.initials: F
authors.lastname: Kaldas
authors.forename: Dean
authors.initials: D
authors.lastname: Anselmo
authors.forename: Masamichi
authors.initials: M
authors.lastname: Katori
authors.forename: Xiu-Da
authors.initials: XD
authors.lastname: Shen
authors.forename: Charles
authors.initials: C
authors.lastname: Lassman
authors.forename: Marian
authors.initials: M
authors.lastname: Kaldas
authors.forename: Martine
authors.initials: M
authors.lastname: Clozel
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Busuttil
authors.forename: Jerzy
authors.initials: J
authors.lastname: Kupiec-Weglinski
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D006439:Hemodynamics / Q000187:drug effects; D007511:Ischemia / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology*; D016031:Liver Transplantation; D008297:Male; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology*; D013777:Tetrazoles / Q000494:pharmacology*; D052096:Warm Ischemia
chemical_list: D065128:Endothelin Receptor Antagonists; D011725:Pyridines; D013777:Tetrazoles; C120582:tezosentan