Endothelin receptor A blockade ameliorates hypothermic ischemia-reperfusion-related microhemodynamic disturbances during liver transplantation in the rat.
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.
Zhang
Xing-yi
XY
Microcirculation Research Laboratory, University of Otago, Dunedin, New Zealand.
Francis
Richard J B
RJ
Sun Ck
Cheuk-kwan
CK
Wheatley
Antony M
AM
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*
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)