Abstract

The overall goal of the application is to define the role of products of a cytochrome P450 w-hydroxylase enzyme located in cerebral arterial muscle in mediating pressure-induced activation and hypoxia-induced inhibition of the cerebral vasculature. They will test the hypothesis that autoregulation of cerebral blood flow and the cerebral vascular response to hypoxia are mediated by a common mechanism involving regulation of smooth muscle potassium channel activity and membrane potential. They plan to test the ability of the cerebral vasculature to form the P450 w-hydroxylase product 20-HETE upon elevation of transmural and arterial pressure, and the ability of reduced PO2 to inhibit such production. They also plan to determine if the action of hypoxia, and the parenchymal/endothelial factors released by hypoxia involves increasing potassium channel activity and hyperpolarizing the vascular muscle membrane. They will also determine if there is linkage between increased P450 w-hydroxylase activity in response to increasing transmural pressure and the cerebral vascular responses to changes in PO2.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS032321-08S1
Application #
6661844
Study Section
Neurology B Subcommittee 2 (NEUB)
Program Officer
Jacobs, Tom P
Project Start
1994-09-01
Project End
2003-03-31
Budget Start
2001-04-01
Budget End
2003-03-31
Support Year
8
Fiscal Year
2002
Total Cost
$42,000
Indirect Cost

  Institution

Name
Medical College of Wisconsin
Department
Physiology
Type
Schools of Medicine
DUNS #
073134603
City
Milwaukee
State
WI
Country
United States
Zip Code
53226

  Publications

Medhora, Meetha; Daniels, John; Mundey, Kavita et al. (2003) Epoxygenase-driven angiogenesis in human lung microvascular endothelial cells. Am J Physiol Heart Circ Physiol 284:H215-24
Bylund, Johan; Harder, Adam G; Maier, Kristopher G et al. (2003) Leukotriene B4 omega-side chain hydroxylation by CYP4F5 and CYP4F6. Arch Biochem Biophys 412:34-41
Medhora, Meetha; Bousamra 2nd, Michael; Zhu, Daling et al. (2002) Upregulation of collagens detected by gene array in a model of flow-induced pulmonary vascular remodeling. Am J Physiol Heart Circ Physiol 282:H414-22
Liu, Yanping; Harder, David R; Lombard, Julian H (2002) Interaction of myogenic mechanisms and hypoxic dilation in rat middle cerebral arteries. Am J Physiol Heart Circ Physiol 283:H2276-81
Bylund, Johan; Zhang, Chenyang; Harder, David R (2002) Identification of a novel cytochrome P450, CYP4X1, with unique localization specific to the brain. Biochem Biophys Res Commun 296:677-84
Nithipatikom, K; Grall, A J; Holmes, B B et al. (2001) Liquid chromatographic-electrospray ionization-mass spectrometric analysis of cytochrome P450 metabolites of arachidonic acid. Anal Biochem 298:327-36
Medhora, M; Narayanan, J; Harder, D (2001) Dual regulation of the cerebral microvasculature by epoxyeicosatrienoic acids. Trends Cardiovasc Med 11:38-42
Medhora, M; Narayanan, J; Harder, D et al. (2001) Identifying endothelium-derived hyperpolarizing factor: recent approaches to assay the role of epoxyeicosatrienoic acids. Jpn J Pharmacol 86:369-75
Gebremedhin, D; Lange, A R; Lowry, T F et al. (2000) Production of 20-HETE and its role in autoregulation of cerebral blood flow. Circ Res 87:60-5
Medhora, M; Harder, D (1998) Functional role of epoxyeicosatrienoic acids and their production in astrocytes: approaches for gene transfer and therapy (review). Int J Mol Med 2:661-9

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