Previous experiments indicate that following experimental concussive brain injury oxygen free radicals produced during cyclooxygenase metabolism of arachidonic acid cause endothelial lesions, irreversible dilation and reduced responsiveness to hypocapnia in cerebral arterioles. The exact chemical factor(s) which stimulate arachidonic acid metabolism following injury are uncertain. We wish to test the hypothesis that endogenous brain bradykinin plays an important role in the generation of these cyclooxygenase dependent abnormalities and in the generation of the transient hypertension and brain edema which follows concussive brain injury. This hypothesis is supported by our knowledge that the brain contains all the components of the kallikrein-kinin system, the known actions of bradykinin and our extensive preliminary investigations showing that endogenous brain bradykinin can produce intense cerebral arteriolar dilation by cyclooxygenase dependent mechanisms. In order to test our hypothesis we will: 1) measure brain bradykinin and kininogen levels after fluid-percussion brain injury, 2) determine whether the kallikrein inhibitor, aprotinin, or a newly developed bradykinin antagonist prevents the arteriolar abnormalities following injury, 3) elucidate whether endogenous brain bradykinin increases local prostaglandin levels, 4) determine whether kallikrein-kinin antagonists prevent formation of prostaglandins following injury, 5) examine the role of bradykinin in the vasogenic brain edema which follows injury, 6) test whether concussive brain injury induces in vivo formation of bradykinin receptors or alters reactivity to other agonists, and 7) determine if bradykinin is important in the CNS generation of the Cushing response which follows concussive injury. To achieve these aims we will utilize in vivo microscopy, RIA, chronic cannulation techniques, 125I-serum albumin and kallikrein-kinin antagonists. Extremely little is known concerning the role of bradykinin in normal or injured neural tissue. These studies will increase our understanding of the CNS kallikrein-kinin system and give us important information concerning the possible role of the pro-inflammatory peptide, bradykinin, in the sequelae of neural trauma. The proposed studies are, therefore, consistent wit our long term goal of elucidating chemical mediators of brain injury.
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