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. MATERIALS AND 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.