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Mesenteric Artery Responsiveness to Acetylcholine and Phenylephrine in Cirrhotic Rats Challenged With Endotoxin: The Role of Tlr4 Publisher Pubmed



Ostadhadi S1, 2 ; Rezayat SM1, 3 ; Ejtemaeimehr S1, 2 ; Tavangar SM4 ; Nikoui V1, 2 ; Jazaeri F1, 2 ; Eftekhari G5 ; Abdollahi A6 ; Dehpour AR1, 2
Authors
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Authors Affiliations
  1. 1. Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  2. 2. Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
  3. 3. Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran
  4. 4. Department of Pathology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  5. 5. Department of Physiology, Tarbiat Modares University, Tehran, Iran
  6. 6. Department of Pathology, Imam Hospital complex, Tehran University of Medical Sciences, Tehran, Iran

Source: Canadian Journal of Physiology and Pharmacology Published:2015


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. © 2015, National Research Council of Canada. All rights reserved.