In
cirrhosis,
11,12-epoxyeicosatrienoic acid (EET) induces mesenteric arterial vasodilation, which contributes to the onset of
portal hypertension. We evaluated the hemodynamic effects of in vivo inhibition of EET production in experimental
cirrhosis. Sixteen control rats and 16 rats with
carbon tetrachloride-induced
cirrhosis were studied. Eight controls and eight rats with
cirrhosis were treated with the specific epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (
MS-PPOH; 20 mg/kg/day) for 3 consecutive days. Portal blood flow and renal and splenic resistive indexes were calculated through echographic measurements, while portal and systemic pressures were measured through polyethylene-50
catheters. Small resistance mesenteric arteries were connected to a pressure servo controller in a video-monitored perfusion system, and concentration-response curves to
phenylephrine and
acetylcholine were evaluated. EET levels were measured in tissue homogenates of rat liver, kidney, and aorta, using an
enzyme-linked
immunosorbent assay. Urinary Na(+) excretion function was also evaluated. In rats with
cirrhosis, treatment with
MS-PPOH significantly reduced portal blood flow and portal pressure compared to vehicle (13.6 ± 5.7 versus 25.3 ± 7.1 mL/min/100 g
body weight, P < 0.05; 9.6 ± 1.1 versus 12.2 ± 2.3 mm Hg, P < 0.05; respectively) without effects on systemic pressure. An increased response to
acetylcholine of mesenteric arteries from rats with
cirrhosis (50% effect concentration -7.083 ± 0.197 versus -6.517 ± 0.73 in control rats, P < 0.05) was reversed after inhibition of EET production (-6.388 ± 0.263, P < 0.05). In liver, kidney, and aorta from animals with
cirrhosis, treatment with
MS-PPOH reversed the increase in EET levels. In both controls and rats with
cirrhosis,
MS-PPOH increased urinary Na(+) excretion.
CONCLUSION: In rats with
cirrhosis, in vivo inhibition of EET production normalizes the response of mesenteric arteries to
vasodilators, with beneficial effects on
portal hypertension. (Hepatology 2016;64:923-930).