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


METHODS
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.


RESULTS
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.


CONCLUSIONS
Microcirculatory disturbances correlate with liver dysfunction in ALF. ETAR blockade represents a new therapeutic approach to ALF by reducing microcirculatory lesions and their sequelae.
Palmes
Daniel
D
Surgical Research, Department of General Surgery, Muenster University Hospital, Waldeyerstr. 1, 48149 Muenster, Germany.
Skawran
Sebastian
S
Stratmann
Udo
U
Armann
Barbara
B
Minin
Evgeny
E
Herbst
Hermann
H
Spiegel
Hans-Ullrich
HU
D000818:Animals; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D007249:Inflammation; D007728:Kupffer Cells / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D017114:Liver Failure, Acute / Q000188:drug therapy* / Q000503:physiopathology*; D008111:Liver Function Tests; D008833:Microcirculation / Q000187:drug effects* / Q000473:pathology; D010666:Phenylpropionates / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D051381:Rats; D016019:Survival Analysis
D065130:Endothelin A Receptor Antagonists; D010666:Phenylpropionates; D011743:Pyrimidines; C107831:darusentan