title: Interaction between NO and COX pathways modulating hepatic endothelial cells from control and cirrhotic rats.
abstract: Reduced intrahepatic nitric oxide (NO) bioavailability and increased cyclooxygenase-1 (COX-1)-derived vasoconstrictor prostanoids modulate the hepatic vascular tone in cirrhosis. We aimed at investigating the reciprocal interactions between NO and COX in the hepatic endothelium of control and cirrhotic rats. NO bioavailability (DAF-FM-DA staining), superoxide (O(2)(-)) content (DHE staining), prostanoid production (PGI(2) and TXA(2) by enzyme immunoassays) as well as COX expression (Western Blot), were determined in hepatic endothelial cells (HEC) from control and cirrhotic rats submitted to different experimental conditions: COX activation, COX inhibition, NO activation and NO inhibition. In control and cirrhotic HEC, COX activation with arachidonic acid reduced NO bioavailability and increased O(2)(-) levels. These effects were abolished by pre-treating HEC with the COX inhibitor indomethacin. In control, but not in cirrhotic HEC, scavenging of O(2)(-) by superoxide dismutase (SOD) incubation partially restored the decrease in NO bioavailability promoted by COX activation. NO supplementation produced a significant and parallel reduction in PGI(2) and TXA(2) production in control HEC, whereas it only reduced TXA(2) production in cirrhotic HEC. By contrast, in control and cirrhotic HEC, NO inhibition did not modify COX expression or activity. Our results demonstrate that NO and COX systems are closely interrelated in HEC. This is especially relevant in cirrhotic HEC where COX inhibition increases NO bioavailability and NO supplementation induces a reduction in TXA(2). These strategies may have beneficial effects ameliorating the vasoconstrictor/vasodilator imbalance of the intrahepatic circulation of cirrhotic livers.
authors.affiliation: Hepatic Hemodynamic Laboratory, Liver Unit, IMDIM, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Ciberehd, University of Barcelona, Barcelona, Spain.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Rosado
authors.forename: Aina
authors.initials: A
authors.lastname: Rodríguez-Vilarrupla
authors.forename: Jorge
authors.initials: J
authors.lastname: Gracia-Sancho
authors.forename: Montserrat
authors.initials: M
authors.lastname: Monclús
authors.forename: Jaume
authors.initials: J
authors.lastname: Bosch
authors.forename: Joan-Carles
authors.initials: JC
authors.lastname: García-Pagán
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001682:Biological Availability; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D007213:Indomethacin / Q000494:pharmacology; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D008103:Liver Cirrhosis / Q000628:therapy*; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000235:genetics / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D014662:Vasoconstrictor Agents; D016718:Arachidonic Acid; D009569:Nitric Oxide; D051545:Cyclooxygenase 1; C496513:Ptgs1 protein, rat; D013482:Superoxide Dismutase; D013930:Thromboxane-A Synthase; D007213:Indomethacin