title: Tumor necrosis factor-alpha increases cerebral blood flow and ultrastructural capillary damage through the release of nitric oxide in the rat brain.
abstract: Tumor necrosis factor-alpha (TNFalpha) is a proinflammatory cytokine implicated in cerebrovascular pathology. The aim of the present study was to characterize the simultaneous effects of an intracarotid administration of TNFalpha on cerebral blood flow (CBF) and the ultrastructure of the blood-brain barrier (BBB) and to determine whether nitric oxide (NO) is a mediator of the TNFalpha-induced alterations in CBF and BBB. TNFalpha (2.5 microg/kg) or saline was infused into the right common carotid artery of male Wistar rats (n = 70). NO production was inhibited with L-NAME (20 mg/kg, i.v.). CBF was monitored for 2 h with laser-Doppler flowmetry. Tissue samples were taken from the unilateral frontoparietal cortex and prepared for electron microscopy. The proportion of capillaries with swollen astrocytic endfeet and the lumen diameter of the capillaries were measured. TNFalpha significantly increased CBF, which reached a maximum of 190% of the baseline 1 h after the cessation of TNFalpha infusion. L-NAME completely prevented the increase in CBF. TNFalpha elevated the swelling of the astrocytic endfeet from a baseline value of 22.4 +/- 9.35% to 64.9 +/- 3.16%. The administration of L-NAME before TNFalpha infusion prevented the astrocytic swelling. These results demonstrate that TNFalpha increases CBF and the swelling of astrocytes through the production of NO. Our data additionally demonstrate that the breakdown of the BBB by circulating TNFalpha may involve the astrocytic endfeet.
authors.affiliation: Department of Anatomy, School of Medicine, University of Szeged, Szeged, Hungary. farkase@anat-fm.szote.u-szeged.hu
authors.forename: Eszter
authors.initials: E
authors.lastname: Farkas
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Süle
authors.forename: Valéria
authors.initials: V
authors.lastname: Tóth-Szuki
authors.forename: Adrienne
authors.initials: A
authors.lastname: Mátyás
authors.forename: Péter
authors.initials: P
authors.lastname: Antal
authors.forename: Ibolya G
authors.initials: IG
authors.lastname: Farkas
authors.forename: András
authors.initials: A
authors.lastname: Mihály
authors.forename: Ferenc
authors.initials: F
authors.lastname: Bari
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002196:Capillaries / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007261:Infusions, Intra-Arterial; D017078:Laser-Doppler Flowmetry; D008297:Male; D008854:Microscopy, Electron; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester