An oral endothelin-A receptor antagonist blocks collagen synthesis and deposition in advanced rat liver fibrosis.
OBJECTIVE
Endothelin 1 induces contraction, proliferation, and collagen synthesis of hepatic stellate cells in vitro, which may be mediated via the endothelin A receptor. It is unknown if specific blockade of the endothelin A receptor inhibits hepatic fibrosis in vivo.


METHODS
Groups of 10-20 rats with bile duct occlusion were treated with the nonpeptide endothelin-A receptor antagonist LU 135252 at 80 mg. kg(-1). day(-1) from week 1-6 or from week 4-6, or with LU at 10 mg. kg(-1). day(-1) from week 1-6. Animals with bile duct occlusion alone and sham-operated rats without or with LU at 80 mg. kg(-1). day(-1) over 6 weeks served as controls. After 6 weeks, parameters of fibrogenesis were determined.


RESULTS
LU treatment led to improved histology, paralleled by a dose-dependence up to 60% reduction of liver collagen, even when administered at an advanced fibrosis stage. This was accompanied by a decreased messenger RNA of hepatic procollagen alpha1(I) and tissue inhibitor of metalloproteinase 1, 2 major effectors of fibrosis, and of serum procollagen type III, a surrogate marker of liver fibrogenesis.


CONCLUSIONS
Selective endothelin-A receptor blockade can dramatically reduce collagen accumulation in rat secondary biliary fibrosis, a model refractory to most potential antifibrotic agents. Endothelin-A receptor antagonists are promising antifibrotic agents in chronic liver disease.
Cho
J J
JJ
Department of Gastroenterology, University Hospital Benjamin Franklin, Free University of Berlin, Berlin, Germany.
Hocher
B
B
Herbst
H
H
Jia
J D
JD
Ruehl
M
M
Hahn
E G
EG
Riecken
E O
EO
Schuppan
D
D
D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001201:Ascites / Q000188:drug therapy / Q000378:metabolism; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D002779:Cholestasis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000032:analysis / Q000096:biosynthesis*; D018076:DNA, Complementary; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000032:analysis; D005260:Female; D006909:Hydroxyproline / Q000032:analysis; D006975:Hypertension, Portal / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007565:Jaundice / Q000188:drug therapy / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D009929:Organ Size; D010666:Phenylpropionates / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000032:analysis / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics
D018076:DNA, Complementary; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010666:Phenylpropionates; D011743:Pyrimidines; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D019715:Tissue Inhibitor of Metalloproteinase-1; C107831:darusentan; D003094:Collagen; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D001663:Bilirubin; D006909:Hydroxyproline