Probiotics (VSL#3) prevent endothelial dysfunction in rats with portal hypertension: role of the angiotensin system.
OBJECTIVE
Portal hypertension characterized by generalized vasodilatation with endothelial dysfunction affecting nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) has been suggested to involve bacterial translocation and/or the angiotensin system. The possibility that ingestion of probiotics prevents endothelial dysfunction in rats following common bile duct ligation (CBDL) was evaluated.


METHODS
Rats received either control drinking water or the probiotic VSL#3 solution (50 billion bacteria.kg body wt⁻¹.day⁻¹) for 7 weeks. After 3 weeks, rats underwent surgery with either resection of the common bile duct or sham surgery. The reactivity of mesenteric artery rings was assessed in organ chambers, expression of proteins by immunofluorescence and Western blot analysis, oxidative stress using dihydroethidium, and plasma pro-inflammatory cytokine levels by flow cytometry.


RESULTS
Both NO- and EDH-mediated relaxations to acetylcholine were reduced in the CBDL group compared to the sham group, and associated with a reduced expression of Cx37, Cx40, Cx43, IKCa and SKCa and an increased expression of endothelial NO synthase (eNOS). In aortic sections, increased expression of NADPH oxidase subunits, angiotensin converting enzyme, AT1 receptors and angiotensin II, and formation of ROS and peroxynitrite were observed. VSL#3 prevented the deleterious effect of CBDL on EDH-mediated relaxations, vascular expression of connexins, IKCa, SKCa and eNOS, oxidative stress, and the angiotensin system. VSL#3 prevented the CBDL-induced increased plasma TNF-α, IL-1α and MCP-1 levels.


CONCLUSIONS
These findings indicate that VSL#3 ingestion prevents endothelial dysfunction in the mesenteric artery of CBDL rats, and this effect is associated with an improved vascular oxidative stress most likely by reducing bacterial translocation and the local angiotensin system.
UMR CNRS 7213, Laboratoire de Biophotonique et de Pharmacologie, Faculty of Pharmacy, University of Strasbourg, Illkirch, France.
Sherzad K
SK
Rashid
Noureddine
N
Idris-Khodja
UMR CNRS 7213, Laboratoire de Biophotonique et de Pharmacologie, Faculty of Pharmacy, University of Strasbourg, Illkirch, France.
Noureddine Idris
NI
Khodja
UMR CNRS 7213, Laboratoire de Biophotonique et de Pharmacologie, Faculty of Pharmacy, University of Strasbourg, Illkirch, France.
Cyril
C
Auger
UMR CNRS 7213, Laboratoire de Biophotonique et de Pharmacologie, Faculty of Pharmacy, University of Strasbourg, Illkirch, France.
Mahmoud
M
Alhosin
Institut d'Histologie et INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg, Faculty of Medicine, University of Strasbourg, Strasbourg, France.
Nelly
N
Boehm
Service de Physiologie et d'Explorations Fonctionnelles, Pôle de Pathologie Thoracique, Hôpitaux Universitaires de Strasbourg, Faculty of Medicine, University of Strasbourg, Strasbourg, France.
Monique
M
Oswald-Mammosser
UMR CNRS 7213, Laboratoire de Biophotonique et de Pharmacologie, Faculty of Pharmacy, University of Strasbourg, Illkirch, France.
Valérie B
VB
Schini-Kerth
D000809:Angiotensins / Q000737:chemistry / Q000502:physiology*; D000818:Animals; D018988:Bacterial Translocation; D001835:Body Weight / Q000187:drug effects; D003135:Common Bile Duct / Q000601:surgery; D016207:Cytokines / Q000378:metabolism; D004727:Endothelium / Q000473:pathology*; D006975:Hypertension, Portal / Q000473:pathology*; D007249:Inflammation; D008099:Liver / Q000187:drug effects; D008103:Liver Cirrhosis / Q000503:physiopathology; D008297:Male; D008638:Mesenteric Arteries / Q000473:pathology; D008928:Mitochondria / Q000473:pathology; D009569:Nitric Oxide / Q000737:chemistry; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress; D019936:Probiotics / Q000737:chemistry* / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D013154:Spleen / Q000187:drug effects
D000809:Angiotensins; D016207:Cytokines; D017382:Reactive Oxygen Species; D009569:Nitric Oxide