BACKGROUND: In cirrhosis, 11,12-EET induces mesenteric arterial vasodilation, which contributes to the onset of portal hypertension. AIM: To evaluate the haemodynamic effects of in vivo inhibition of EETs production in experimental cirrhosis. METHODS: Sixteen control rats and 16 rats with carbon tetrachloride (CCl4 )-induced cirrhosis were studied. Eight control and 8 cirrhotic rats were treated with the specific epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MS-PPOH; 20mg/kg/day) for three consecutive days. Portal blood flow and renal and splenic resistive indexes were calculated through echographic measurements, while portal and systemic pressure was measured through PE-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 (PE) and acetylcholine (ACh) were evaluated. EETs levels were measured in tissue homogenates of rats liver, kidney and aorta, using an ELISA assay. Urinary Na+ excretion function was also evaluated. RESULTS: In cirrhotic rats, treatment with MS-PPOH significantly reduced portal blood flow and portal pressure compared to vehicle (13.6±5.7 vs 25.3±7.1 ml/min/100 g bw, p<0.05; 9.6±1.1 vs 12.2±2.3 mmHg, p<0.05; respectively) without effects on systemic pressure. An increased response to ACh of mesenteric arteries from cirrhotic rats (pEC50 : -7.083±0.197 vs. -6.517±0.73 in control rats, p<0.05) was reversed after inhibition of EETs production (-6.388±0.263, p<0.05). In liver, kidney and aorta from cirrhotic animals, treatment with MS-PPOH reversed the increase in the levels of EETs. Both in control and cirrhotic rats, MS-PPOH increased urinary Na+ excretion. CONCLUSIONS: In cirrhotic rats, in vivo inhibition of EETs production normalizes the response of mesenteric arteries to vasodilators, with beneficial effects on portal hypertension. This article is protected by copyright. All rights reserved.

Inhibition of Epoxyeicosatrienoic Acid Production in Rats With Cirrhosis Has Beneficial Effects on Portal Hypertension by Reducing Splanchnic Vasodilation

DI PASCOLI, MARCO;ZAMPIERI, FRANCESCA;VERARDO, ALBERTO;PESCE, PAOLA;TURATO, CRISTIAN;ANGELI, PAOLO;SACERDOTI, DAVID;BOLOGNESI, MASSIMO
2016

Abstract

BACKGROUND: In cirrhosis, 11,12-EET induces mesenteric arterial vasodilation, which contributes to the onset of portal hypertension. AIM: To evaluate the haemodynamic effects of in vivo inhibition of EETs production in experimental cirrhosis. METHODS: Sixteen control rats and 16 rats with carbon tetrachloride (CCl4 )-induced cirrhosis were studied. Eight control and 8 cirrhotic rats were treated with the specific epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MS-PPOH; 20mg/kg/day) for three consecutive days. Portal blood flow and renal and splenic resistive indexes were calculated through echographic measurements, while portal and systemic pressure was measured through PE-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 (PE) and acetylcholine (ACh) were evaluated. EETs levels were measured in tissue homogenates of rats liver, kidney and aorta, using an ELISA assay. Urinary Na+ excretion function was also evaluated. RESULTS: In cirrhotic rats, treatment with MS-PPOH significantly reduced portal blood flow and portal pressure compared to vehicle (13.6±5.7 vs 25.3±7.1 ml/min/100 g bw, p<0.05; 9.6±1.1 vs 12.2±2.3 mmHg, p<0.05; respectively) without effects on systemic pressure. An increased response to ACh of mesenteric arteries from cirrhotic rats (pEC50 : -7.083±0.197 vs. -6.517±0.73 in control rats, p<0.05) was reversed after inhibition of EETs production (-6.388±0.263, p<0.05). In liver, kidney and aorta from cirrhotic animals, treatment with MS-PPOH reversed the increase in the levels of EETs. Both in control and cirrhotic rats, MS-PPOH increased urinary Na+ excretion. CONCLUSIONS: In cirrhotic rats, in vivo inhibition of EETs production normalizes the response of mesenteric arteries to vasodilators, with beneficial effects on portal hypertension. This article is protected by copyright. All rights reserved.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11577/3188104
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