Our long term goals are to expand our knowledge concerning mechanisms regulating brain microcirculation. These mechanisms are vitally important in providing appropriate flow to the brain, whose function is especially sensitive to impaired delivery of oxygen and nutrients. Present studies focus on the role of endothelium in controlling diameter of arterioles, and on the ways in which endothelial damage can derange flow. Two groups of studies are planned. All are relatively unique because they are conducted on microcirculation in vivo. Surface arterioles on the mouse brain are observed by intravital microscopy. The first group of studies investigates the role of endothelium in producing relaxing or constricting factors (EDRFs, EDCFs) when stimulated by selective vasoactive agonists or during autoregulation to an increase in blood pressure. Endothelial injury, produced in situ by helium neon laser/Evans blue causes a focus of lost capacity to produce EDRFs or EDCFs and provides a method for testing which agonists are dependent upon such an endothelial mechanism for their action. Pharmacologic probes, followed by chemical measurements will be used to determine the chemical nature of the endothelium derived mediators (e.g. prostanoids, other eicosanoids). We will also use pharmacologic probes to determine the role of protein kinase C, and of guanylate or adenylate cyclase and of L-arginine in mediating the synthesis, release or effects of the endothelium derived mediators. The second group of studies concerns the production of platelet aggregation by endothelial injury in the arterioles. Pharmacologic probes will be used to study the role of altered synthesis/release of an antiaggregant endothelium derived relaxing factor in promoting local platelet adhesion/aggregation at a site injured by light/dye. The capture of embolizing platelets at such a site will be studied for its relevance to repetitive symptoms of transient ischemic attacks. Pharmacologic probes will be used to assess the role of increased release of such an EDRF in decreasing platelet aggregation when flow and shear are increased. The role of L-arginine in regulating the antiaggregating and antiadhesive properties of this EDRF will be investigated.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL035935-09
Application #
3350405
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1985-09-30
Project End
1995-09-29
Budget Start
1993-09-30
Budget End
1994-09-29
Support Year
9
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
Rosenblum, W I (1997) Tetrahydrobiopterin, a cofactor for nitric oxide synthase, produces endothelium-dependent dilation of mouse pial arterioles. Stroke 28:186-9
Rosenblum, W I (1997) Selective impairment of response to acetylcholine after ischemia/reperfusion in mice. Stroke 28:448-51; discussion 451-2
Rosenblum, W I; Nelson, G H (1996) Singlet oxygen scavengers affect laser-dye impairment of endothelium-dependent responses of brain arterioles. Am J Physiol 270:H1258-63
Rosenblum, W I (1996) Conservation of flow demonstrated using the two-slit velocimeter and cross correlator in epiilluminated surface microvessels of the mouse brain. Microcirculation 3:187-90
Rosenblum, W I; Murata, S (1996) Antisense evidence for two functionally active forms of nitric oxide synthase in brain microvascular endothelium. Biochem Biophys Res Commun 224:535-43
Rosenblum, W I; Nelson, G H; Bei, R A et al. (1996) Vitamin E ameliorates adverse effects of endothelial injury in brain arterioles. Am J Physiol 271:H637-42
Rosenblum, W I; Nelson, G H; Wormley, B et al. (1996) Role of platelet-endothelial cell adhesion molecule (PECAM) in platelet adhesion/aggregation over injured but not denuded endothelium in vivo and ex vivo. Stroke 27:709-11
Rosenblum, W I; Wormley, B (1995) Selective depression of endothelium-dependent dilations during cerebral ischemia. Stroke 26:1877-81;discussion 1882
Rosenblum, W I; Nelson, G H; Murata, S (1995) Protein synthesis and rapid recovery of endothelium-dependent dilation after endothelial injury of pial arterioles. Am J Physiol 268:H512-5
Murata, S; Rosenblum, W I; Shimizu, T et al. (1995) Delayed platelet adhesion/aggregation at sites of endothelial injury in mouse cerebral arterioles after transient elevations of blood pressure and shear. Stroke 26:650-3;discussion 654

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