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Increased myoendothelial gap junctions mediate the enhanced response to epoxyeicosatrienoic acid and acetylcholine in mesenteric arterial vessels of cirrhotic rats.
MedLine Citation:
PMID:  21645220     Owner:  NLM     Status:  In-Data-Review    
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.
Massimo Bolognesi; Francesca Zampieri; Marco Di Pascoli; Alberto Verardo; Cristian Turato; Fiorella Calabrese; Francesca Lunardi; Patrizia Pontisso; Paolo Angeli; Carlo Merkel; Angelo Gatta; David Sacerdoti
Publication Detail:
Type:  Journal Article     Date:  2011-03-21
Journal Detail:
Title:  Liver international : official journal of the International Association for the Study of the Liver     Volume:  31     ISSN:  1478-3231     ISO Abbreviation:  Liver Int.     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-06-07     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101160857     Medline TA:  Liver Int     Country:  England    
Other Details:
Languages:  eng     Pagination:  883-92     Citation Subset:  IM    
Copyright Information:
© 2011 John Wiley & Sons A/S.
Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy Istituto Oncologico Veneto IOV-IRCCS, Padua, Italy Department of Diagnostic Sciences and Special Therapies, University of Padua, Padua, Italy.
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