title: Modulation of Hyperosmotic and Immune-Induced Disruption of the Blood-Brain Barrier by the Nitric Oxide System.
abstract: OBJECTIVE
  The role of nitric oxide (NO) in modulating the blood-brain barrier (BBB) is not entirely clear. We examined the effect of different NO synthase (NOS) inhibitors and NO donors on the permeability of the BBB in animals with normally functioning brain blood vessels, following disruption by hyperosmotic mannitol and during immune inflammation.
  
  
  METHODS
  We administered L-NAME, aminoguanidine, S-methyl-thiocitrulline (SMT) and 7-indazole (NOS inhibitors) and NOR-4 (an NO donor) into the cerebral ventricle of rats. Disruption of the BBB was induced by intracarotid injection of mannitol (25%). Experimental autoimmune encephalomyelitis (EAE) was induced by brain homogenate. The extent of disruption was evaluated by Evans blue (2%) dye extravasation.
  
  
  RESULTS
  L-NAME (a nonspecific NOS inhibitor) and SMT (a neuronal and endothelial NOS inhibitor) increased mannitol-induced disruption of BBB. This effect was inhibited by NO donors. In animals with a normally functioning BBB, none of these inhibitors or NO donors caused a change in the permeability. 7-indazole (a specific neuronal NOS inhibitor) and aminoguanidine (an inducible NOS inhibitor) had no facilitatory effect on BBB permeability, either alone or in combination with hyperosmotic mannitol. Administration of L-NAME and SMT to rats with EAE significantly aggravated the clinical outcome. In contrast, the administration of NOR-4 diminished clinical signs of EAE.
  
  
  CONCLUSIONS
  The NOS system does not play a role in BBB permeability in naïve animals. Only endothelial NOS takes part in the facilitation of BBB compromised by mannitol and EAE. Extrinsic NO decreases this facilitatory effect.
authors.affiliation: Department of Neurology, the Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Malik
authors.initials: M
authors.lastname: Hasarmeh
authors.forename: Anna
authors.initials: A
authors.lastname: Itzik
authors.forename: Joseph
authors.initials: J
authors.lastname: Weidenfeld
authors.forename: Haim
authors.initials: H
authors.lastname: Ovadia
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000503:physiopathology*; D004195:Disease Models, Animal; D004234:Diuretics, Osmotic / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008353:Mannitol / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D009997:Osmotic Pressure / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D013997:Time Factors
chemical_list: D004234:Diuretics, Osmotic; D004791:Enzyme Inhibitors; C102260:NOR 4; D020030:Nitric Oxide Donors; D011725:Pyridines; D009569:Nitric Oxide; D008353:Mannitol; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester