Enhanced vasoconstrictor prostanoid production by sinusoidal endothelial cells increases portal perfusion pressure in cirrhotic rat livers.
OBJECTIVE
Cyclooxygenase-1 (COX-1) is overexpressed in sinusoidal endothelial cells (SEC) of cirrhotic rat livers, and through an enhanced production of vasoconstrictor prostanoids contributes to increase intrahepatic resistance. Our study was aimed at investigating the role of enhanced AA bioavailability modulating the hepatic vascular tone of cirrhotic livers and identifying which prostanoid is involved.


METHODS
SEC isolated from control and cirrhotic rat livers were incubated with AA, methoxamine or vehicle. TXA(2) was quantified. In addition, portal perfusion pressure (PP) response curves to AA were performed in rat livers pre-incubated with vehicle, SC-560 (COX-1 inhibitor), Furegrelate (inhibitor of TXA(2) synthesis) and SQ-29548 (PGH(2)/TXA(2) receptor blocker). cPLA2 activity was determined in control and cirrhotic livers.


RESULTS
AA and methoxamine incubation promoted a significant increase in TXA(2) release by Cirrhotic-SEC, but not in Control-SEC. AA produced a dose-dependent increase in the PP, associated with increased TXA(2) release. These responses were significantly greater in cirrhotic livers. COX-1 inhibition and PGH(2)/TXA(2) receptor blockade, but not TXA(2) synthase inhibition, markedly attenuated the PP response to AA of cirrhotic livers. Additionally, cirrhotic livers exhibited significantly increased cPLA2 activity.


CONCLUSIONS
An enhanced production of vasoconstrictor prostanoids, probably PGH(2), by SEC contributes to increase vascular tone of cirrhotic livers.
Gracia-Sancho
Jorge
J
Hepatic Hemodynamic Laboratory, Liver Unit, IMDIM, Hospital Clínic, Ciberehd and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Villarroel 170, 08036 Barcelona, Spain.
Laviña
Bàrbara
B
Rodríguez-Vilarrupla
Aina
A
García-Calderó
Héctor
H
Bosch
Jaime
J
García-Pagán
Joan Carles
JC
D000818:Animals; D016718:Arachidonic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D051545:Cyclooxygenase 1 / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008099:Liver / Q000098:blood supply*; D008103:Liver Cirrhosis / Q000503:physiopathology*; D008297:Male; D010477:Perfusion; D010741:Phospholipases A / Q000378:metabolism; D011168:Portal System / Q000187:drug effects / Q000503:physiopathology*; D011312:Pressure; D011453:Prostaglandins / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors; D013929:Thromboxane B2 / Q000096:biosynthesis; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D014661:Vasoconstriction; D014662:Vasoconstrictor Agents / Q000378:metabolism*
D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D011453:Prostaglandins; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D014662:Vasoconstrictor Agents; D016718:Arachidonic Acid; D013929:Thromboxane B2; D051545:Cyclooxygenase 1; D010741:Phospholipases A; D013930:Thromboxane-A Synthase