Activation of the hepatic endothelin-system in rats with biliary liver fibrosis

Circulating plasma endothelin-1 (ET-1) is elevated in liver cirrhosis, in a disease-stage-dependent manner. However, ET-1 exerts its effects mainly via paracrine and autocrine pathways. Therefore, the aim of the present study was to analyze the hepatic endothelin (ET) system in liver cirrhosis resulting from bile duct obstruction (BDO). Wistar rats were subjected for 6 weeks to either sham operation (control) or BDO. Thereafter, hepatic ET-1 concentrations were elevated 7.2-fold in BDO compared to control (p <0.001), whereas big ET-1 was unchanged. The density of both ET receptor subtypes was upregulated in BDO (ETA: 7.4-fold and ETB: 4.9-fold vs control, p < 0.001, respectively). The affinity of both receptor subtypes was significantly reduced in BDO. In conclusion, our data demonstrated for the first time that the hepatic ET system in liver cirrhosis is characterized by a simultaneous upregulation of both ET-1 tissue concentration as well as the density of hepatic ETA- and ETB-receptors, suggesting a synergistic activation of the hepatic ET system in rats with BDO. The increased ET-1 tissue concentration is not a result of an altered big ET-1 synthesis in biliary liver fibrosis, suggesting an increased activity of endothelin-converting enzyme (ECE) in liver cirrhosis.