endothelin-1 and 11-12-epoxy-5-8-14-eicosatrienoic-acid

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.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Arachidonic Acid; Carbon Tetrachloride; Cytochrome P-450 Enzyme System; Endothelin-1; Hepatic Veins; Hydroxyeicosatetraenoic Acids; Hypertension, Portal; Infusion Pumps; Liver; Liver Cirrhosis, Experimental; Male; Miconazole; Organ Culture Techniques; Oxidoreductases; Phenylephrine; Portal Pressure; Rats; Rats, Sprague-Dawley; Vascular Resistance; Vasoconstriction; Vasodilation