Traumatic brain injury (TBI) increases cerebral vascular resistance, damages cerebral vascular endothelial cells and the blood brain barrier and reduces cerebral vasodilatory responses to hypotension, hypoxia and hemodilution. Our overall hypothesis is that traumatic brain injury increases superoxide anion radicals which react with increased NO to form OONO-, impairing the function of cerebral vascular smooth muscle and perivascular nerves.
Aim 1 is to determine the association between NO, O2-, and CBF decreases after traumatic brain injury. NO, superoxide, and CBF will be measured in rats after moderate traumatic brain injury. Studies will be done to see if arginine supplementation restores CBF despite increases in O2- production. Immunohistochemical staining for nitrotyrosine will be used to determine if TBI and L-arginine treatment increases OONO- production.
Aim 2 is to determine if traumatic brain injury reduces the activity of eNOS and/or increases the potentially damaging iNOS and nNOS isoforms, using arginine to citrulline conversion assays with specific inhibitors and mRNA expression studies.
Aim 3 is to determine if traumatic brain injury affects the cerebral vascular responses to endothelium-dependent vasodilator ACh, activators of ATP-sensitive potassium channels like aprikalim, or reduced perfusion pressure, using arteries harvested following traumatic brain injury.
Aim 4 is to determine the effects of TBI and OONO- exposure on perivascular vasodilatory neurotransmitters CGRP, ACh, and anadamide.
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