Endothelin A-receptor blockade worsens endotoxin-induced hepatic microcirculatory changes and necrosis

Background & Aims: Endothelin 1 is considered to be an important regulator of sinusoidal blood flow and increases during endotoxemia. The purpose of this study was to investigate the role of endothelin 1 in hepatic microcirculation, oxygen transport, and liver injury during endotoxemia. Methods: Male Sprague-Dawley rats were continuously infused with 2.5 mL/h of saline, 0.8 mg.kg(-1).h(-1) of lipopolysaccharide (LPS), 3 mg.kg(-1).h(-1) of BQ-485, an endothelin A-receptor antagonist, or LPS plus BQ-485 for 7 hours. Results: BQ-485 infusion had no significant effect on hepatic microcirculation and liver injury. LPS increased the plasma levels of aspartate aminotransferase (AST) and total bilirubin and decreased the hepatic adenosine triphosphate (ATP) level and bile flow rate. LPS + BQ-485 infusion further increased the plasma levels of AST and total bilirubin and decreased the bile flow rate and the hepatic ATP level. Dual-spot microspectroscopy revealed mild decreases in sinusoidal erythrocyte velocity and oxygen transport in the LPS group and profound decreases in these parameters in the LPS + BQ-485 group. Histological examinations revealed massive necrotic changes in the pericentral regions of the LPS + BQ-485 group. Conclusions: These results suggest that blockade of endothelin A receptors disturbs hepatic microcirculation and oxygen transport and aggravates the necrotic injury induced by endotoxin.