title: Endothelin receptor A blockade ameliorates hypothermic ischemia-reperfusion-related microhemodynamic disturbances during liver transplantation in the rat.
abstract: BACKGROUND
  The objective of this study was to investigate the effect of graft treatment with specific endothelin receptor antagonists (ET(A) and ET(B)) on the microhemodynamic disturbances which occur following ischemia/reperfusion injury during orthotopic liver transplantation (OLT) in the rat.
  
  
  METHODS
  OLT was performed in male Sprague-Dawley rats. An ET(A) receptor antagonist (BQ-610; 0.3 mg/kg) or ET(B) receptor antagonist IRL-1038 (20 nmol/kg) was administered intraportally into liver grafts in vitro at the beginning of 2- and 6-h cold storage (4 degrees C) using physiological saline. Sham-operated animals served as controls (Cont). Seven groups were studied: Cont; vehicle-2 h (saline treated); ET(B) antagonist-2 h; ET(A) antagonist-2 h; vehicle-6 h; ET(A) antagonist-6 h; and ET(B) antagonist-6 h. At 1 h after graft implantation, the liver microcirculation was investigated by intravital fluorescence microscopy.
  
  
  RESULTS
  In vehicle-treated livers, the hepatic microcirculation was markedly impaired compared with the Cont as manifested by a reduced lobular perfusion index, increased incidence of sinusoidal nonperfusion, elevated leukocyte adhesion in sinusoids and terminal hepatic venules, and increased hepatic venous resistance (23-fold; 6-h group). In addition, plasma liver enzymes were significantly elevated in the vehicle treated groups. Alterations to all these parameters were markedly reduced in the ET(A) receptor antagonist-treated liver grafts although there was still evidence of hepatic injury. The ET(B) receptor antagonist had little effect on the I/R-induced changes to the hepatic microcirculation.
  
  
  CONCLUSIONS
  Our results indicate that the ET(A) antagonism ameliorates hypothermic I/R-related microhemodynamic disturbances during OLT in the rat, suggesting that application of an ET(A) antagonist to liver grafts may have therapeutic potential in human liver transplantation.
authors.affiliation: Microcirculation Research Laboratory, University of Otago, Dunedin, New Zealand.
authors.forename: Xing-yi
authors.initials: XY
authors.lastname: Zhang
authors.forename: Richard J B
authors.initials: RJ
authors.lastname: Francis
authors.forename: Cheuk-kwan
authors.initials: CK
authors.lastname: Sun Ck
authors.forename: Antony M
authors.initials: AM
authors.lastname: Wheatley
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000276:immunology; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology; D007036:Hypothermia, Induced; D007962:Leukocytes / Q000166:cytology; D008102:Liver Circulation / Q000502:physiology*; D016031:Liver Transplantation / Q000502:physiology*; D008297:Male; D008833:Microcirculation / Q000502:physiology; D008853:Microscopy / Q000379:methods; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D015427:Reperfusion Injury / Q000378:metabolism*
chemical_list: D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D009842:Oligopeptides; D010446:Peptide Fragments; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C087220:BQ 610; C077420:Cys(11)-Cys(15)-endothelin-1 (11-21)