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 (ETA and ETB) 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 ETA receptor antagonist (BQ-610; 0.3 mg/kg) or ETB 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); ETB antagonist—2 h; ETA antagonist—2 h; vehicle—6 h; ETA antagonist—6 h; and ETB 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 ETA receptor antagonist-treated liver grafts although there was still evidence of hepatic injury. The ETB receptor antagonist had little effect on the I/R-induced changes to the hepatic microcirculation.Conclusions. Our results indicate that the ETA antagonism ameliorates hypothermic I/R-related microhemodynamic disturbances during OLT in the rat, suggesting that application of an ETA antagonist to liver grafts may have therapeutic potential in human liver transplantation.