5-lipoxygenase inhibition reduces intrahepatic vascular resistance of cirrhotic rat livers: a possible role of cysteinyl-leukotrienes

Gastroenterology. 2002 Feb;122(2):387-93. doi: 10.1053/gast.2002.31040.


Background & aims: Cysteinyl-leukotrienes (Cys-LTs) increase intrahepatic vascular resistance in normal rat livers. CCl4 cirrhotic rat livers have increased Cys-LT production and 5-lipoxygenase messenger RNA (mRNA) expression. The aim of this study was to investigate the role of 5-lipoxygenase-derived eicosanoids regulating intrahepatic vascular tone in control and CCl4-induced cirrhotic rat livers.

Methods: In different groups of portally perfused control and cirrhotic rat livers, the following were analyzed: a portal perfusion pressure (PP) dose-response curve to LTD4; the effects on PP caused by either vehicle, the selective 5-lipoxygenase inhibitor AA-861, the selective Cys-LT1 receptor antagonist MK-571, or the dual Cys-LT1 and Cys-LT2 receptor antagonist BAY u9773; and immunohistochemistry for 5-lipoxygenase in liver sections of cirrhotic and control livers.

Results: Cirrhotic livers have a hyperesponse to LTD4. In control livers, AA-861 and MK-571 produced a moderate and similar reduction in PP. In cirrhotic livers, 5-lipoxygenase inhibition produced a marked and significantly greater reduction in PP than in controls. However, no effect on PP was observed after MK-571 or BAY u9773. 5-Lipoxygenase-positive cells were markedly increased in cirrhotic livers.

Conclusions: Our results suggest that 5-lipoxygenase-derived eicosanoids may contribute to the increased intrahepatic vascular resistance of cirrhotic rat livers and therefore the pathogenesis of portal hypertension.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arachidonate 5-Lipoxygenase / metabolism
  • Benzoquinones / pharmacology
  • Carbon Tetrachloride
  • Cysteine / metabolism*
  • Leukotriene Antagonists / pharmacology
  • Leukotrienes / metabolism*
  • Lipoxygenase Inhibitors* / pharmacology
  • Liver Circulation / drug effects
  • Liver Circulation / physiology*
  • Liver Cirrhosis / chemically induced
  • Liver Cirrhosis / enzymology*
  • Male
  • Propionates / pharmacology
  • Quinolines / pharmacology
  • Rats
  • Rats, Wistar
  • SRS-A / analogs & derivatives*
  • SRS-A / pharmacology
  • Vascular Resistance / drug effects
  • Vascular Resistance / physiology*


  • BAY u9773
  • Benzoquinones
  • Leukotriene Antagonists
  • Leukotrienes
  • Lipoxygenase Inhibitors
  • Propionates
  • Quinolines
  • SRS-A
  • cysteinyl-leukotriene
  • verlukast
  • 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone
  • Carbon Tetrachloride
  • Arachidonate 5-Lipoxygenase
  • Cysteine