Losartan prevents portal hypertension-induced, redox-mediated endothelial dysfunction in the mesenteric artery in rats.
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.
Dal-Ros
Stéphanie
S
UMR CNRS 7213 Laboratoire de Biophotonique et de Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France.
Oswald-Mammosser
Monique
M
Pestrikova
Tatiana
T
Schott
Christa
C
Boehm
Nelly
N
Bronner
Christian
C
Chataigneau
Thierry
T
Gény
Bernard
B
Schini-Kerth
Valérie B
VB
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
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