title: Losartan prevents portal hypertension-induced, redox-mediated endothelial dysfunction in the mesenteric artery in rats.
abstract: OBJECTIVE
  Advanced stages of portal hypertension are characterized by generalized vasodilatation and a hyperdynamic syndrome that leads to complications such as hepatopulmonary syndrome. We assessed the endothelial function--particularly the formation of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF)--in rats following common bile duct ligation (CBDL) to determine the underlying mechanisms of these processes.
  
  
  METHODS
  Reactivity of mesenteric artery rings from male Wistar rats was determined in organ chambers. The expression levels of connexins (Cx) (Cx37, Cx40, Cx43), intermediate and small conductance Ca(2+)-activated K(+) channels (IK(Ca), SK(Ca)), endothelial NO synthase (eNOS), NADPH oxidase subunits, and nitrotyrosines were assessed by immunohistochemistry in mesenteric and pulmonary arteries. The vascular formation of reactive oxygen species (ROS) was evaluated using dihydroethidine. Control rats or those that had undergone CBDL were given either the NADPH oxidase inhibitor apocynin or the angiotensin II receptor type 1 antagonist losartan.
  
  
  RESULTS
  Decreased EDHF-mediated relaxations to acetylcholine and red wine polyphenols were observed in CBDL rats, compared with controls, whereas the level of NO-mediated relaxation was similar. Impaired EDHF-mediated relaxations were associated with reduced vascular expression of Cx37, Cx40, Cx43, IK(Ca) and SK(Ca); increased expression of eNOS and NADPH oxidase subunits; and increased vascular formation of ROS and peroxynitrites. These effects were prevented by exposure to apocynin or losartan.
  
  
  CONCLUSIONS
  CBDL is associated with reduced EDHF-mediated relaxations in the mesenteric artery, whereas NO-mediated relaxations persisted. These findings indicate that impaired EDHF-mediated relaxation involves an excessive vascular oxidative stress, most likely following activation of angiotensin II type 1 receptors.
authors.affiliation: UMR CNRS 7213 Laboratoire de Biophotonique et de Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Dal-Ros
authors.forename: Monique
authors.initials: M
authors.lastname: Oswald-Mammosser
authors.forename: Tatiana
authors.initials: T
authors.lastname: Pestrikova
authors.forename: Christa
authors.initials: C
authors.lastname: Schott
authors.forename: Nelly
authors.initials: N
authors.lastname: Boehm
authors.forename: Christian
authors.initials: C
authors.lastname: Bronner
authors.forename: Thierry
authors.initials: T
authors.lastname: Chataigneau
authors.forename: Bernard
authors.initials: B
authors.lastname: Gény
authors.forename: Valérie B
authors.initials: VB
authors.lastname: Schini-Kerth
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001685:Biological Factors / Q000502:physiology; D017630:Connexins / Q000032:analysis; D004730:Endothelium, Vascular / Q000503:physiopathology*; D006975:Hypertension, Portal / Q000473:pathology / Q000503:physiopathology*; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D008638:Mesenteric Arteries / Q000503:physiopathology*; D019255:NADPH Oxidases / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D015221:Potassium Channels / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000098:Acetophenones; D047228:Angiotensin II Type 1 Receptor Blockers; D001685:Biological Factors; D017630:Connexins; D015221:Potassium Channels; C067410:endothelium-dependent hyperpolarization factor; C056165:acetovanillone; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases; D019808:Losartan