The endothelium regulates the contractile state of cerebral arteries and arterioles through the release of relaxing factors. In recent years, an endothelial-dependent dilator process, other than nitric oxide (NO) or prostacyclin, has been discovered. This new process, termed """"""""endothelium-derived hyperpolarizing factor"""""""" or EDHF, is upregulated to compensate for diminished endothelial-derived NO following traumatic brain injury. Thus, EDHF could be an important mechanism to maintain cerebral perfusion when the NO dilator mechanism is compromised. This proposal addresses the mechanism of the EDHF-mediated dilations in cerebral arteries following traumatic brain injury to the rat.
In Specific Aim 1, studies are proposed to determine if the mechanism of EDHF-mediated dilations following traumatic brain injury involves the metabolism of arachidonic acid through the P450 epoxygenase pathway.
In Specific Aim 2, studies are proposed to determine if the mechanism of EDHF-mediated dilations following traumatic brain injury involves an increased production of hydrogen peroxide (H2O2).
In Specific Aim 3 studies are proposed to measure Ca2+ and membrane potential in endothelium and vascular smooth muscle during EDHF dilations following traumatic brain injury. Diameter changes of pressurized branches of middle cerebral arteries (bMCAs), isolated from injured (controlled cortical impact injury) and non-injured cortex, will be compared following agonist induced EDHF dilations. A combination of pharmacological interventions, optical methods for selectively measuring [Ca2+] and membrane potential of vascular smooth muscle and endothelium, electrophysiological techniques, and analytic methods to measure P450 epoxygenase metabolites and H2O2 are proposed to address the aims.
In Specific Aim 4 EDHF dilations will be studied in vivo during normal conditions and following traumatic brain injury. We propose to study the EDHF response using laser Doppler flowmetry and measurement of pial arteriole diameter. We speculate that EDHF upregulation is an important intrinsic mechanism to maintain cerebral perfusion. Understanding the mechanism of EDHF-mediated dilations following traumatic brain injury will allow better insight into the regulation of cerebral blood flow following brain injury. Further, it will allow us to test the hypothesis that the EDHF upregulation is protective and could lead to new therapeutic strategies for treatment of traumatic brain injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS038660-09
Application #
7798023
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2009-02-01
Budget End
2010-01-31
Support Year
9
Fiscal Year
2009
Total Cost
$191,838
Indirect Cost
Name
Baylor College of Medicine
Department
Type
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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Yamal, Jose-Miguel; Robertson, Claudia S; Rubin, M Laura et al. (2014) Enrollment of racially/ethnically diverse participants in traumatic brain injury trials: effect of availability of exception from informed consent. Clin Trials 11:187-94
Robertson, Claudia S; Yamal, Jose-Miguel; Tilley, Barbara C (2014) Erythropoietin for traumatic brain injury--reply. JAMA 312:1929
Robertson, Claudia S; Hannay, H Julia; Yamal, José-Miguel et al. (2014) Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial. JAMA 312:36-47

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