ENDOTHELIN A-RECEPTOR BLOCKADE WORSENS ENDOTOXIN-INDUCED HEPATIC MICROCIRCULATORY CHANGES AND NECROSIS

Background & Aims: Endothelin 1 is considered to be an important regul ator of sinusoidal blood flow and increases during endotoxemia. The pu rpose of this study was to investigate the role of endothelin 1 in hep atic microcirculation, oxygen transport, and liver injury during endot oxemia. Methods: Male Sprague-Dawley rats were continuously infused wi th 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 signific ant effect on hepatic microcirculation and liver injury. LPS increased the plasma levels of aspartate aminotransferase (AST) and total bilir ubin and decreased the hepatic adenosine triphosphate (ATP) level and bile flow rate. LPS + BQ-485 infusion further increased the plasma lev els of AST and total bilirubin and decreased the bile flow rate and th e hepatic ATP level. Dual-spot microspectroscopy revealed mild decreas es in sinusoidal erythrocyte velocity and oxygen transport in the LPS group and profound decreases in these parameters in the LPS + BQ-485 g roup. Histological examinations revealed massive necrotic changes in t he pericentral regions of the LPS + BQ-485 group. Conclusions: These r esults suggest that blockade of endothelin A receptors disturbs hepati c microcirculation and oxygen transport and aggravates the necrotic in jury induced by endotoxin.