title: Traumatic brain injury disrupts cerebrovascular tone through endothelial inducible nitric oxide synthase expression and nitric oxide gain of function.
abstract: BACKGROUND
  Traumatic brain injury (TBI) has been reported to increase the concentration of nitric oxide (NO) in the brain and can lead to loss of cerebrovascular tone; however, the sources, amounts, and consequences of excess NO on the cerebral vasculature are unknown. Our objective was to elucidate the mechanism of decreased cerebral artery tone after TBI.
  
  
  RESULTS
  Cerebral arteries were isolated from rats 24 hours after moderate fluid‐percussion TBI. Pressure‐induced increases in vasoconstriction (myogenic tone) and smooth muscle Ca2+ were severely blunted in cerebral arteries after TBI. However, myogenic tone and smooth muscle Ca2+ were restored by inhibition of NO synthesis or endothelium removal, suggesting that TBI increased endothelial NO levels. Live native cell NO, indexed by 4,5‐diaminofluorescein (DAF‐2 DA) fluorescence, was increased in endothelium and smooth muscle of cerebral arteries after TBI. Clamped concentrations of 20 to 30 nmol/L NO were required to simulate the loss of myogenic tone and increased (DAF‐2T) fluorescence observed following TBI. In comparison, basal NO in control arteries was estimated as 0.4 nmol/L. Consistent with TBI causing enhanced NO‐mediated vasodilation, inhibitors of guanylyl cyclase, protein kinase G, and large‐conductance Ca2+‐activated potassium (BK) channel restored function of arteries from animals with TBI. Expression of the inducible isoform of NO synthase was upregulated in cerebral arteries isolated from animals with TBI, and the inducible isoform of NO synthase inhibitor 1400W restored myogenic responses following TBI.
  
  
  CONCLUSIONS
  The mechanism of profound cerebral artery vasodilation after TBI is a gain of function in vascular NO production by 60‐fold over controls, resulting from upregulation of the inducible isoform of NO synthase in the endothelium.
authors.affiliation: From the Departments of Pharmacology, University of Vermont, Burlington, VT
authors.forename: Nuria
authors.initials: N
authors.lastname: Villalba
authors.forename: Swapnil K
authors.initials: SK
authors.lastname: Sonkusare
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Longden
authors.forename: Tram L
authors.initials: TL
authors.lastname: Tran
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Sackheim
authors.forename: Mark T
authors.initials: MT
authors.lastname: Nelson
authors.forename: George C
authors.initials: GC
authors.lastname: Wellman
authors.forename: Kalev
authors.initials: K
authors.lastname: Freeman
mesh_terms: D000818:Animals; D062186:Arterial Pressure; D001930:Brain Injuries / Q000201:enzymology* / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002536:Cerebral Arteries / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000378:metabolism; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D008297:Male; D040542:Mechanotransduction, Cellular; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D015854:Up-Regulation; D014661:Vasoconstriction; D014664:Vasodilation / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D051036:Large-Conductance Calcium-Activated Potassium Channels; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D006162:Guanylate Cyclase; D002118:Calcium