An oral endothelin-A receptor antagonist blocks collagen synthesis and deposition in advanced rat liver fibrosis

Background & Aims: 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 sewed 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 alpha 1(I) and tissue inhibitor of metalloproteinase 1, 2 major effecters 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.