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

• Published in: Journal of hepatology 2005-03, Vol.42 (3), p.350-357
• Main Authors: Palmes, Daniel, Skawran, Sebastian, Stratmann, Udo, Armann, Barbara, Minin, Evgeny, Herbst, Hermann, Spiegel, Hans-Ullrich
• Format: Article
• Language: English
• Subjects: Acute liver failure; Animals; Biological and medical sciences; Disease Models, Animal; Endothelin; Endothelin A Receptor Antagonists; Endothelin A receptor blockade; Gastroenterology. Liver. Pancreas. Abdomen; Inflammation; Kupffer Cells - drug effects; Kupffer Cells - pathology; Kupffer Cells - ultrastructure; Liver Failure, Acute - drug therapy; Liver Failure, Acute - physiopathology; Liver Function Tests; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Microcirculation; Microcirculation - drug effects; Microcirculation - pathology; Other diseases. Semiology; Phenylpropionates - therapeutic use; Pyrimidines - therapeutic use; Rats; Survival Analysis
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2004.11.019

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 μg/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.