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. 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°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.