Cyclooxygenase-1 inhibition corrects endothelial dysfunction in cirrhotic rat livers

J Hepatol. 2003 Oct;39(4):515-21. doi: 10.1016/s0168-8278(03)00347-7.


Background/aims: Cirrhotic livers exhibit endothelial dysfunction that contributes to the increased hepatic vascular resistance. The present study evaluates the role of cyclooxygenase (COX)-derived prostanoids, implicated in the pathogenesis of endothelial dysfunction in other settings, in the pathogenesis of endothelial dysfunction in cirrhotic livers.

Methods: Endothelial dysfunction was evaluated by performing concentration-effect curves to acetylcholine after precontracting the liver with methoxamine in groups of control and CCl(4)-cirrhotic rat livers preincubated either with vehicle, indomethacin, the COX-1 selective inhibitor, SC-560, the COX-2 selective inhibitor, SC-236, the thromboxane A(2) receptor antagonist, SQ 29,548 or the nitric oxide (NO) synthase inhibitor N(G)-nitro-L-arginine. Thromboxane A(2) (TXA(2)) production was determined in samples of the perfusate.

Results: Cirrhotic livers exhibited endothelial dysfunction, as shown by the significantly lower relaxation to acetylcholine than control livers, that was totally corrected by indomethacin. COX-1 inhibition and TXA(2) blockade, but not COX-2 inhibition, also corrected endothelial dysfunction. Acetylcholine significantly increased TXA(2) production in cirrhotic but not in control livers. Indomethacin and COX-1 inhibition, but not COX-2 or NO inhibition, prevented the increased production of TXA(2).

Conclusions: An increased production of TXA(2) is involved in the pathogenesis of endothelial dysfunction in cirrhotic rat livers. This is mainly mediated by COX-1, but not by COX-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclooxygenase 1
  • Cyclooxygenase Inhibitors / pharmacology*
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / enzymology
  • Endothelium, Vascular / physiopathology*
  • Isoenzymes / antagonists & inhibitors*
  • Liver / blood supply*
  • Liver Cirrhosis / physiopathology*
  • Male
  • Membrane Proteins
  • Prostaglandin-Endoperoxide Synthases
  • Rats
  • Rats, Wistar


  • Cyclooxygenase Inhibitors
  • Isoenzymes
  • Membrane Proteins
  • Cyclooxygenase 1
  • Prostaglandin-Endoperoxide Synthases
  • Ptgs1 protein, rat