title: 11,12-EET increases porto-sinusoidal resistance and may play a role in endothelial dysfunction of portal hypertension.
abstract: CYP450-dependent epoxyeicosatrienoic acids (EETs) are potent arterial vasodilators, while 20-hydroxyeicosatatraenoic acid (20-HETE) is a vasoconstrictor. We evaluated their role in the control of portal circulation in normal and cirrhotic (CCl(4) induced) isolated perfused rat liver. Phenylephrine (PE) and endothelin-1 (ET-1) increased portal perfusion pressure, as did arachidonic acid (AA), 20-HETE, and 11,12-EET. Inhibition of 20-HETE with 12,12-dibromododecenoic acid (DBDD) did not affect basal pressure nor the responses to PE, ET-1, or AA. However, inhibition of epoxygenase with miconazole caused a significant reduction in the response to ET-1 and to AA, without affecting neither basal pressure nor the response to PE. Hepatic vein EETs concentration increased in response to ET-1, and was increased in cirrhotic, compared to control, livers. 20HETE levels were non-measurable. Miconazole decreased portal perfusion pressure in cirrhotic livers. In conclusion, 20HETE and EETs increase portal resistance; EETs, but not 20-HETE, mediate in part the pressure response to ET-1 in the portal circulation and may be involved in pathophysiology of portal hypertension.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Padova, Via Giustiniani 2, 35100 Padova, Italy. david.sacerdoti@unipd.it
authors.forename: David
authors.initials: D
authors.lastname: Sacerdoti
authors.forename: Houli
authors.initials: H
authors.lastname: Jiang
authors.forename: Silvia
authors.initials: S
authors.lastname: Gaiani
authors.forename: John C
authors.initials: JC
authors.lastname: McGiff
authors.forename: Angelo
authors.initials: A
authors.lastname: Gatta
authors.forename: Massimo
authors.initials: M
authors.lastname: Bolognesi
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002251:Carbon Tetrachloride / Q000009:adverse effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology; D006503:Hepatic Veins / Q000187:drug effects / Q000378:metabolism; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism / Q000494:pharmacology; D006975:Hypertension, Portal / Q000139:chemically induced / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D007260:Infusion Pumps; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008825:Miconazole / Q000494:pharmacology; D009924:Organ Culture Techniques; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D017082:Portal Pressure / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014655:Vascular Resistance / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D019332:Endothelin-1; D006893:Hydroxyeicosatetraenoic Acids; D010656:Phenylephrine; D016718:Arachidonic Acid; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D008825:Miconazole; D003577:Cytochrome P-450 Enzyme System; D002251:Carbon Tetrachloride; D010088:Oxidoreductases; D015126:8,11,14-Eicosatrienoic Acid