5-lipoxygenase inhibition reduces intrahepatic vascular resistance of cirrhotic rat livers: a possible role of cysteinyl-leukotrienes.
OBJECTIVE
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.
Graupera
Mariona
M
Hepatic Hemodynamic Laboratory, Liver Unit, Institut Malaties Digestives Hospital Clinic, University of Barcelona, Barcelona, Spain.
García-Pagán
Juan-Carlos
JC
Titos
Esther
E
Claria
Joan
J
Massaguer
Anna
A
Bosch
Jaime
J
Rodés
Juan
J
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D016227:Benzoquinones / Q000494:pharmacology; D002251:Carbon Tetrachloride; D003545:Cysteine / Q000378:metabolism*; D020024:Leukotriene Antagonists / Q000494:pharmacology; D015289:Leukotrienes / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008102:Liver Circulation / Q000187:drug effects / Q000502:physiology*; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000201:enzymology*; D008297:Male; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013189:SRS-A / Q000031:analogs & derivatives* / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology*
C071435:BAY u9773; D016227:Benzoquinones; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D011422:Propionates; D011804:Quinolines; D013189:SRS-A; C112381:cysteinyl-leukotriene; C059141:verlukast; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone; D002251:Carbon Tetrachloride; D001094:Arachidonate 5-Lipoxygenase; D003545:Cysteine