title: Mesenteric artery responsiveness to acetylcholine and phenylephrine in cirrhotic rats challenged with endotoxin: the role of TLR4.
abstract: Cirrhosis is associated with vascular dysfunction and endotoxemia. These experiments were designed to investigate the hypothesis that the administration of a low-dose of lipopolysaccharide (LPS) worsens vascular dysfunction in rats subjected to bile-duct ligation (BDL), and to determine whether LPS initiates changes in vascular Toll-like receptor 4 (TLR4) expression. Four weeks after BDL, the animals were given an intraperitoneal injection of either saline or LPS (1.0 mg/kg body mass). Three hours later, the superior mesenteric artery was isolated, perfused, and then subjected to the vasoconstriction and vasodilatation effects of phenylephrine and acetylcholine, respectively. Our results show that phenylephrine-induced vasoconstriction decreased in the cirrhotic vascular bed (BDL rats) compared with the vascular bed of the sham-operated animals, and that the LPS injections in the cirrhotic (BDL) rats worsened this response. LPS injection administered to the sham-operated animals had no such effect. On the other hand, both the BDL procedure and the LPS injection increased acetylcholine-induced vasorelaxation, but LPS administration to the BDL rats had no effect on this response. The mRNA levels of TLR4 did not change, but immunohistochemical studies showed that TLR4 localization switched from the endothelium to vascular smooth muscle cells following chronic BDL. In conclusion, acute endotoxemia in cirrhotic rats is associated with hyporesponsiveness to phenylephrine and tolerance to the effects of acetylcholine. Altered localization of TLR4 may be responsible for these effects.
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran., Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Sattar
authors.initials: S
authors.lastname: Ostadhadi
authors.forename: Seyed-Mahdi
authors.initials: SM
authors.lastname: Rezayat
authors.forename: Shahram
authors.initials: S
authors.lastname: Ejtemaei-Mehr
authors.forename: Seyed-Mohammad
authors.initials: SM
authors.lastname: Tavangar
authors.forename: Vahid
authors.initials: V
authors.lastname: Nikoui
authors.forename: Farahnaz
authors.initials: F
authors.lastname: Jazaeri
authors.forename: Golnar
authors.initials: G
authors.lastname: Eftekhari
authors.forename: Alireza
authors.initials: A
authors.lastname: Abdollahi
authors.forename: Ahmad-Reza
authors.initials: AR
authors.lastname: Dehpour
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D001652:Bile Ducts / Q000187:drug effects / Q000378:metabolism; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism; D019446:Endotoxemia / Q000378:metabolism; D004731:Endotoxins / Q000494:pharmacology*; D008026:Ligation / Q000379:methods; D008070:Lipopolysaccharides / Q000494:pharmacology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D004731:Endotoxins; D008070:Lipopolysaccharides; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D010656:Phenylephrine; D000109:Acetylcholine
keywords: Toll-like receptor 4; artère mésentérique; cirrhose; cirrhosis; endotoxin; endotoxine; mesenteric artery; rats