The objectives of these studies are to clarify the mechanism of the cerebral microcirculatory alterations following experimental fluid-percussion brain injury in anesthetized cats and in rabbits. This type of brain injury induces pial arteriolar dilation associated with a reduced responsiveness to the vasoconstrictor effects of arterial hypocapnia and with disturbed autorregulatory dilation in response to arterial hypotension. The vessels which showed these abnormalities have lesions in their vascular smooth muscle and endothelium, and display reduced oxygen consumption. The proposed studies will test the hypothesis that these abnormalities are mediated by free oxygen radicals generated in association with accelerated arachidonate metabolism via cyclooxygenase. The proposed experiments are designed to identify the factors which influence superoxide anion radical generation after brain injury, to determine whether superoxide anion radical generated by brain injury traverses the cell membrane via the anion channel, to identify the enzymatic sources of superoxide, including cyclooxygenase, lipoxygenase, cytochrome P450 reductase and xanthine oxidase, to examine whether substance P, enkephalins or bradykinin initiate the sequence which leads to superoxide production, to examine the effects of oxygen radicals on the blood-brain barrier and to determine whether endothelium-dependent vasodilator reponses are disturbed after brain injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS019316-05
Application #
3399339
Study Section
Neurology B Subcommittee 1 (NEUB)
Project Start
1983-04-01
Project End
1993-03-31
Budget Start
1987-04-01
Budget End
1988-03-31
Support Year
5
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
Levasseur, Joseph E; Alessandri, Beat; Reinert, Michael et al. (2006) Lactate, not glucose, up-regulates mitochondrial oxygen consumption both in sham and lateral fluid percussed rat brains. Neurosurgery 59:1122-30; discussion 1130-1
Kontos, H A (2001) Oxygen radicals in cerebral ischemia: the 2001 Willis lecture. Stroke 32:2712-6
Rosenblum, W I; Wei, E P; Kontos, H A (2001) Dimethylsulfoxide and ethanol, commonly used diluents, prevent dilation of pial arterioles by openers of K(ATP) ion channels. Eur J Pharmacol 430:101-6
Rosenblum, W I; Kontos, H A; Wei, E P (2001) Evidence for a K(ATP) ion channel link in the inhibition of hypercapnic dilation of pial arterioles by 7-nitroindazole and tetrodotoxin. Eur J Pharmacol 417:203-15
Levasseur, J E; Alessandri, B; Reinert, M et al. (2000) Fluid percussion injury transiently increases then decreases brain oxygen consumption in the rat. J Neurotrauma 17:101-12
Wei, E P; Kontos, H A (1999) Blockade of ATP-sensitive potassium channels in cerebral arterioles inhibits vasoconstriction from hypocapnic alkalosis in cats. Stroke 30:851-3;discussion 854
Wei, E P; Kontos, H A; Beckman, J S (1998) Antioxidants inhibit ATP-sensitive potassium channels in cerebral arterioles. Stroke 29:817-22;discussion 823
Kontos, H A; Wei, E P (1998) Cerebral arteriolar dilations by KATP channel activators need L-lysine or L-arginine. Am J Physiol 274:H974-81
Wei, E P; Kontos, H A; Beckman, J S (1996) Mechanisms of cerebral vasodilation by superoxide, hydrogen peroxide, and peroxynitrite. Am J Physiol 271:H1262-6
Kontos, H A; Wei, E P (1996) Arginine analogues inhibit responses mediated by ATP-sensitive K+ channels. Am J Physiol 271:H1498-506

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