Inhibition of rat liver fibrogenesis through noradrenergic antagonism

Hepatology. 2002 Feb;35(2):325-31. doi: 10.1053/jhep.2002.31166.


The effect of adrenergic innervation and/or circulating catecholamines on the function of liver fibrogenic cells is poorly understood. Our aim was to investigate the effects of noradrenergic antagonism on carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Two weeks of CCl4 induced an approximately 5-fold increase in the area of fibrosis as compared with controls. The addition of 6-hydroxydopamine (OHDA), a toxin that destroys noradrenergic fibers, decreased fibrosis by 60%. After 6 weeks of CCl4, the area of fibrosis increased about 30-fold in CCl4-treated animals and was decreased by 36% with OHDA. At 2 weeks, OHDA abrogated the CCl4-induced increase in mRNA level of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), an inhibitor of extracellular matrix degradation, and it greatly reduced it at 6 weeks. Finally, when rats treated with CCl4 for 2 weeks also received prazosin, an antagonist of alpha1-adrenergic receptors, fibrosis was decreased by 83%. In conclusion, destruction of noradrenergic fibers or antagonism of noradrenergic signaling through alpha1 receptors inhibited the development of liver fibrosis. Because adrenoreceptor antagonists have a very sound safety profile, they appear as attractive drugs to reduce liver fibrogenesis.

MeSH terms

  • Adrenergic Agents / pharmacology*
  • Adrenergic alpha-Antagonists / pharmacology*
  • Animals
  • Carbon Tetrachloride / pharmacology
  • Liver / drug effects
  • Liver / innervation
  • Liver / pathology
  • Liver Cirrhosis / chemically induced
  • Liver Cirrhosis / pathology
  • Liver Cirrhosis / prevention & control*
  • Male
  • Nerve Fibers / drug effects
  • Norepinephrine / antagonists & inhibitors*
  • Oxidopamine / pharmacology*
  • Prazosin / pharmacology*
  • RNA, Messenger / antagonists & inhibitors
  • Rats
  • Rats, Wistar
  • Tissue Inhibitor of Metalloproteinase-1 / genetics


  • Adrenergic Agents
  • Adrenergic alpha-Antagonists
  • RNA, Messenger
  • Tissue Inhibitor of Metalloproteinase-1
  • Oxidopamine
  • Carbon Tetrachloride
  • Norepinephrine
  • Prazosin