http://www.fasebj.org/content/28/1_Supplement/1070.1.short
+ Author Affiliations
Abstract
Enhancend endothelial nitric oxide production impairs cerebrovascular tone after brain trauma
Nuria Villalba, Thomas Longden, Mark T. Nelson, George C. Wellman and Kalev Freeman
Department of Pharmacology, University of Vermont, Burlington, VT
Cerebral autoregulation is altered after traumatic
brain injury (TBI) reflecting an impairment in myogenic tone and that
may
contributeing to patient morbidity in patients with
TBI. We hypothesized that TBI alters nitric oxide (NO)-dependent
signaling
mechanisms leading to decreased cerebral vascular
tone. We studied isolated cerebral arteries from adult rats after
moderate
fluid percussion TBI or sham surgery. We found that
both endothelial and smooth muscle (SM) NO levels—indexed by
4,5-diaminofluorescein
(DAF-2) fluorescence—were increased in cerebral
arteries from TBI animals. Arteries from TBI animals exhibited decreased
cytosolic
SM Ca2+ and reduced myogenic tone compared to controls. Endothelial removal restored myogenic response constriction in TBI animals.
Further, inhibition of NO synthase with Nω-L-arginine (L-NNA) restored both myogenic tone and SM Ca2+, and reduced DAF-2 fluorescence in arteries from TBI animals. The guanylyl cyclase inhibitor (ODQ) and protein kinase G (PKG)
inhibitor (RP-8-Br-cGMPS) both elicited robust enhanced constrictions in TBI animals. Further, constriction caused by inhibition of SM
large-conductance Ca2+-activated
potassium (BK) channels with paxilline was augmented in TBI arteries.
Addition of 30 nM clamped NO to control arteries
provided vasodilation equivalent to that observed
in TBI and increased the DAF-2 signal to a comparable level observed in
untreated TBI preparations. These data demonstrate
that trauma causes persistent changes in endothelial NO production
underlying
profound cerebral artery dilation, and provides a
quantitative measure of the degree of NO elevation, which is on the
order
of 30 nM.
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