Previous experiments indicate that following experimental concussive brain injury oxygen free radicals produced during cyclooxygenase metabolism of arachidonic acid cause endothelial lesions, dilation, reduced responsiveness to hypocapnia and abnormal responsiveness to acetylcholine in cerebral arterioles. We now have evidence that specific agonists, including acetylcholine and bradykinin, may be in part responsible for stimulating arachidonic acid metabolism following injury. We therefore wish to test the following hypotheses. Hypothesis 1: Following concussive brain injury receptor-mediated mechanisms contribute to an increased metabolism of polyunsaturated fatty acids and the production of oxygen radicals which cause cerebrovascular and brain dysfunction. Hypothesis 2: Pharmacologic inhibition of fatty acid metabolism, free radical production or free radical action will reduce the cerebrovascular dysfunction caused by traumatic brain injury (TBI). Our general aims are to understand 1) factors responsible for initiation and regulation of fatty acid metabolism following injury, 2) the pathways and products of this metabolism, 3) the cerebrovascular consequences of increased fatty acid metabolism and radical production and 4) how pharmacologic intervention can prevent, reduce or reverse the injury process. To accomplish our aims we will utilize microscopy and radioimmunoassay to correlate simultaneous in vivo arteriolar diameter responses and in vivo cyclooxygenase and lipoxygenase synthetic responses. We will also employ gas chromatography/mass spectrometry to identify and measure fatty acids and their metabolites. Little is known about regulation of the changes in fatty acid metabolism and the concomitant cerebrovascular consequences of increased oxygen radical production following brain injury. The proposed studies will address these problems and are consistent with our long term goal of elucidating chemical mediators of and therapeutic agents for brain injury.
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