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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS023432-01
Application #
3406909
Study Section
Neurology A Study Section (NEUA)
Project Start
1986-09-01
Project End
1989-08-31
Budget Start
1986-09-01
Budget End
1987-08-31
Support Year
1
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Type
Overall Medical
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
Zhang, X M; Ellis, E F (1991) Superoxide dismutase decreases mortality, blood pressure, and cerebral blood flow responses induced by acute hypertension in rats. Stroke 22:489-94
Ellis, E F; Police, R J; Yancey, L et al. (1990) Dilation of cerebral arterioles by cytochrome P-450 metabolites of arachidonic acid. Am J Physiol 259:H1171-7
Zhang, X M; Ellis, E F (1990) Superoxide dismutase reduces permeability and edema induced by hypertension in rats. Am J Physiol 259:H497-503
Dragan, Y P; Ellis, E F (1990) 5-Hydroxytryptamine and the metabolism of arachidonic acid by the lipoxygenase and cyclooxygenase of washed human platelets. Biochem Pharmacol 40:309-14
Dragan, Y P; Ellis, E F (1990) Effect of adenine nucleotides on cyclooxygenase and lipoxygenase enzyme products of arachidonic acid in human platelets. Biochem Pharmacol 39:27-32
Dragan, Y P; Ellis, E F (1990) Optimization of an assay for studying the effects of agents on cyclooxygenase and lipoxygenase metabolism of arachidonic acid in washed human platelets. Prostaglandins Leukot Essent Fatty Acids 39:105-9
Haberl, R L; Heizer, M L; Marmarou, A et al. (1989) Laser-Doppler assessment of brain microcirculation: effect of systemic alterations. Am J Physiol 256:H1247-54
Haberl, R L; Heizer, M L; Ellis, E F (1989) Laser-Doppler assessment of brain microcirculation: effect of local alterations. Am J Physiol 256:H1255-60
Ellis, E F; Police, R J; Rice, L Y et al. (1989) Increased plasma PGE2, 6-keto-PGF1 alpha, and 12-HETE levels following experimental concussive brain injury. J Neurotrauma 6:31-7
Ellis, E F; Chao, J; Heizer, M L (1989) Brain kininogen following experimental brain injury: evidence for a secondary event. J Neurosurg 71:437-42

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