The purpose of this study was to determine the changes in endothelin (ET) receptor subtype expression and their functional significance after endotoxin pretreatment. Rats were pretreated with lipopolysaccharide (LPS) or sterile saline (control). After 24 h, liver samples were homogenized and competitive receptor binding assays were performed. There was no significant difference in ET receptor binding affinity between the control and LPS groups. However, the receptor subtype density showed a significant increase in ETBreceptors in LPS-treated rats, whereas the amount of ETAreceptors was almost identical between the two groups. In control, almost all ET receptors (95%) were displaced by using combined ETAantagonist (BQ-610) and ETBagonist (IRL-1620) as competitors, whereas only 80% (P< 0.05 versus control) was displaced in LPS group, raising the possibility of novel type of ET receptor expression. An infusion of ETBagonist (Sarafotoxin 6c, S6c) through portal vein in isolated perfused livers produced the same pressure response in both LPS and control groups; however, the portal pressure increase in response to the ET-1, which binds all ET receptors, was significantly potentiated in LPS-treated rats compared to controls. We conclude that altered regulation of ET receptors, in particular, the appearance of ET binding capacity that is not displaced by ETAor ETBcompetitors, may explain the hyper-response of the portal venous system to ET-1 during endotoxemia.