Amelioration of microcirculatory damage by an endothelin A receptor antagonist in a rat model of reversible acute liver failure

Abstract

Hepatocellular damage in acute liver failure (ALF) is aggravated by proinflammatory and cytotoxic mediators released from sinusoidal-lining cells. We studied a selective endothelin A receptor (ETAR) antagonist for its potential influence on the microcirculation in the setting of ALF. Seventy Wistar rats were divided into five groups: (I) induction of ALF by a 70% liver resection combined with injection of 400 microg/kg endotoxin, (II) ALF treated with the ETAR antagonist LU 135252 (1 mg/kg b.w. i.v.), (III) sham operation, (IV) injection of endotoxin, (V) 70% liver resection. Liver microcirculation was measured by intravital microscopy. Parenchymal injury, growth fractions, endothelin (ET)-1 and ETAR were studied by histology and immunohistology. Survival, liver function, and morphology were followed up to 14 days. 100% mortality, impaired liver function, widespread endothelial lesions, highest ET-1 and ETAR levels, a decreased perfusion rate, reduced sinusoidal diameter, as well as an increase in both leukocyte-endothelium interactions and sinusoidal blood flow were observed after induction of ALF. ETAR antagonist-treated rats showed decreased ET-1 and ETAR levels as well as improved microcirculatory function, morphology, liver function, and 85% survival. Microcirculatory disturbances correlate with liver dysfunction in ALF. ETAR blockade represents a new therapeutic approach to ALF by reducing microcirculatory lesions and their sequelae.