Increased myoendothelial gap junctions mediate the enhanced response to epoxyeicosatrienoic acid and acetylcholine in mesenteric arterial vessels of cirrhotic rats
Massimo Bolognesi
Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy
Search for more papers by this authorFrancesca Zampieri
Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy
Search for more papers by this authorMarco Di Pascoli
Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy
Search for more papers by this authorAlberto Verardo
Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy
Search for more papers by this authorCristian Turato
Istituto Oncologico Veneto IOV-IRCCS, Padua, Italy
Search for more papers by this authorFiorella Calabrese
Department of Diagnostic Sciences and Special Therapies, University of Padua, Padua, Italy
Search for more papers by this authorFrancesca Lunardi
Department of Diagnostic Sciences and Special Therapies, University of Padua, Padua, Italy
Search for more papers by this authorPatrizia Pontisso
Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy
Search for more papers by this authorPaolo Angeli
Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy
Search for more papers by this authorCarlo Merkel
Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy
Search for more papers by this authorAngelo Gatta
Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy
Search for more papers by this authorDavid Sacerdoti
Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy
Search for more papers by this authorMassimo Bolognesi
Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy
Search for more papers by this authorFrancesca Zampieri
Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy
Search for more papers by this authorMarco Di Pascoli
Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy
Search for more papers by this authorAlberto Verardo
Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy
Search for more papers by this authorCristian Turato
Istituto Oncologico Veneto IOV-IRCCS, Padua, Italy
Search for more papers by this authorFiorella Calabrese
Department of Diagnostic Sciences and Special Therapies, University of Padua, Padua, Italy
Search for more papers by this authorFrancesca Lunardi
Department of Diagnostic Sciences and Special Therapies, University of Padua, Padua, Italy
Search for more papers by this authorPatrizia Pontisso
Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy
Search for more papers by this authorPaolo Angeli
Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy
Search for more papers by this authorCarlo Merkel
Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy
Search for more papers by this authorAngelo Gatta
Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy
Search for more papers by this authorDavid Sacerdoti
Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy
Search for more papers by this authorAbstract
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 (CCl4)-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, NG-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). EC50 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 (EC50: −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 BKCa 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/PGI2-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.
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