Enhanced endothelial nitric oxide production impairs cerebrovascular tone after brain trauma (1070.1)

Abstract

Enhancend endothelial nitric oxide production impairs cerebrovascular tone after brain traumaNuria Villalba, Thomas Longden, Mark T. Nelson, George C. Wellman and Kalev FreemanDepartment 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.