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Liver Int. 2011 Jul;31(6):881-90. doi: 10.1111/j.1478-3231.2011.02509.x. Epub 2011 Mar 21.

Increased myoendothelial gap junctions mediate the enhanced response to epoxyeicosatrienoic acid and acetylcholine in mesenteric arterial vessels of cirrhotic rats.

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  • 1Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy. massimo.bolognesi@unipd.it

Abstract

BACKGROUND:

Cirrhotic portal hypertension is characterized by mesenteric arterial vasodilation and hyporeactivity to vasoconstrictors.

AIM:

We evaluated the role of epoxyeicosatrienoic acid (EET) and of myoendothelial gap junctions (GJ) in the haemodynamic alterations of experimental cirrhosis.

METHODS:

Thirty-five control rats and 35 rats with carbon tetrachloride (CCl(4))-induced cirrhosis were studied. Small resistance mesenteric arteries (diameter <350 μm) were connected to a pressure servo controller in a video-monitored perfusion system. Concentration-response curves to acetylcholine (ACh) were evaluated in mesenteric arteries pre-incubated with indomethacin, N(G)-nitro-L-arginine-methyl-ester and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one before and after the epoxygenase inhibitor miconazole or 18α-glycyrrhetinic acid (18α-GA) (GJ inhibitor). EC(50) was calculated. Concentration-response curves to 11,12-EET were also evaluated. mRNA and protein expression of connexins (Cxs) in the mesenteric arteries was evaluated by real-time PCR and immunohistochemistry.

RESULTS:

The ACh response was increased in cirrhotic rats (EC(50): -6.55±0.10 vs. -6.01±0.10 log[M]; P<0.01) and was blunted by miconazole only in cirrhotic animals. 18α-GA blunted the response to ACh more in cirrhotic than that in control rats (P<0.05). Concentration-response curves to 11,12-EET showed an increased endothelium-dependent vasodilating response in cirrhotic rats (P<0.05); the BK(Ca) inhibitor Iberiotoxin (25 nM) blocked the response in normal rats but not in cirrhotic rats, while 18α-GA blunted the response in cirrhotic rats but not in control rats. An increased mRNA and protein expression of Cx40 and Cx43 in cirrhotic arteries was detected (P<0.05).

CONCLUSIONS:

The increased nitric oxide/PGI(2)-independent vasodilation of mesenteric arterial circulation in cirrhosis is because of, at least in part, hyperreactivity to 11,12-EET through an increased expression of myoendothelial GJs.

[PubMed - indexed for MEDLINE]

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