The central hypothesis of this project is that nitric oxide synthase (eNOS, nNOS and iNOS) and cyclooxygenase (COX-2) play a critical role in regulating basal and agonist-induced increases in permeability of the blood-brain barrier (BBB). Functionally, nitric oxide synthase can be divided into constitutive and inducible forms. The constitutive form (bNOS/nNOS and e NOS) is active under basal conditions and is stimulated by receptor mediated increases in intracellular calcium. While nitric oxide plays an important role in reactivity of the cerebral microcirculation, its role in regulating basal and agonist-induced increases in permeability of the BBB remains unclear. The investigator s first aim is to examine the role of constitutive nitric oxide in basal and agonist-induced increases in the transport of molecules across the BBB. The applicant s hypothesis is that constitutive nitric oxide synthase regulates basal permeability of the BBB and accounts for increases in BBB permeability in response to important vasoactive agonists released during cerebrovascular trauma. Inducible nitric oxide synthase is cytosolic in origin, calcium-independent, and releases nitric oxide over long periods of time in response to lipopolysaccharide and cytokines. It appears that cerebrovascular trauma increases the release of nitric oxide from inducible sources. The role of inducible nitric oxide in agonist-induced increases in permeability of the BBB in vivo remains unclear.
The second aim of the study is to examine the role of inducible nitric oxide synthase in basal and stimulated increases in permeability of the BBB in response to lipopolysaccharide and cytokines known to be released during brain trauma. The investigator s hypothesis is that inducible nitric oxide synthase plays an important role in long-term changes in the permeability of the BBB following brain trauma. As with nitric oxide synthase, there are specific isoforms of cyclooxygenase, COX-1 and COX-2. COX-1 is constitutively expressed and appears to play an important role in many cellular functions, but may not be an important mediator of acute or chronic inflammation. COX-2 is the inducible form of cyclooxygenase and appears to play an important role in acute and chronic inflammation. However, the role of COX-2 in permeability of the BBB remains unclear.
The third aim i s to examine the contribution of COX-2 in regulating the permeability of the BBB in response to lipopolysaccharide and cytokines. The hypothesis is that activation of COX-2, presumably by inducible nitric oxide, plays an important role in increases in permeability of the BBB during brain trauma. The overall goal of the described studies is to provide new insights into the role of constitutive and inducible nitric oxide synthase and COX-2 in basal and agonist-induced increases in the permeability of the BBB.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL040781-09
Application #
2901109
Study Section
Special Emphasis Panel (ZRG4-PHRA (01))
Project Start
1989-08-01
Project End
2001-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
9
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198
Arrick, Denise M; Sharpe, Glenda M; Sun, Hong et al. (2008) Losartan improves impaired nitric oxide synthase-dependent dilatation of cerebral arterioles in type 1 diabetic rats. Brain Res 1209:128-35
Trickler, W J; Mayhan, W G; Miller, D W (2005) Brain microvessel endothelial cell responses to tumor necrosis factor-alpha involve a nuclear factor kappa B (NF-kappaB) signal transduction pathway. Brain Res 1048:24-31
Sun, Hong; Fang, Qin; Mayhan, William G (2004) Inward rectifier potassium channels in the basilar artery during chronic alcohol consumption. Alcohol Clin Exp Res 28:1557-61
Mayhan, William G; Mayhan, Jill F; Sun, Hong et al. (2004) In vivo properties of potassium channels in cerebral blood vessels during diabetes mellitus. Microcirculation 11:605-13
Mayhan, William G; Sun, Hong; Mayhan, Jill F et al. (2004) Influence of exercise on dilatation of the basilar artery during diabetes mellitus. J Appl Physiol 96:1730-7
Schwaninger, RoseAnn M; Sun, Hong; Mayhan, William G (2003) Impaired nitric oxide synthase-dependent dilatation of cerebral arterioles in type II diabetic rats. Life Sci 73:3415-25
Trauernicht, Anna K; Sun, Hong; Patel, Kaushik P et al. (2003) Enalapril prevents impaired nitric oxide synthase-dependent dilatation of cerebral arterioles in diabetic rats. Stroke 34:2698-703
Fang, Qin; Sun, Hong; Mayhan, William G (2003) Impairment of nitric oxide synthase-dependent dilatation of cerebral arterioles during infusion of nicotine. Am J Physiol Heart Circ Physiol 284:H528-34
Mayhan, William G (2003) Pial vessel permeability to tracers using cranial windows. Methods Mol Med 89:121-31
Mayhan, William G; Sharpe, Glenda M (2002) Acute and chronic treatment with nicotine impairs reactivity of arterioles in response to activation of potassium channels. J Cardiovasc Pharmacol 39:695-703

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