Cyclooxygenase-1 inhibition corrects endothelial dysfunction in cirrhotic rat livers.
OBJECTIVE
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.
Graupera
Mariona
M
Hepatic Hemodynamic Laboratory, Liver Unit, Institut Malalties Digestives, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain.
García-Pagán
Joan-Carles
JC
Parés
Mireia
M
Abraldes
Juan G
JG
Roselló
Joan
J
Bosch
Jaume
J
Rodés
Juan
J
D000818:Animals; D051545:Cyclooxygenase 1; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008099:Liver / Q000098:blood supply*; D008103:Liver Cirrhosis / Q000503:physiopathology*; D008297:Male; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D051381:Rats; D017208:Rats, Wistar
D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D051545:Cyclooxygenase 1; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat