The proposed studies are planned in rats to examine the consequences of vascular thrombosis on remote microvascular function and to determine pathomechanisms. Recently, we have documented in two models of vascular thrombosis, acute alterations in the blood-brain barrier (BBB) which are associated with widespread hemodynamic consequences. The acute and more chronic ultrastructural consequences of embolic stroke on the microvasculature and brain parenchyma will be first investigated following common carotid artery thrombosis (CCA). Histopathological outcome will be studied with scanning and transmission electron microscopic procedures combined with vascular permeability studies using horseradish peroxidase. Autoradiographic strategies using labeled platelets and neutrophils will be conducted to complement morphological findings. We hypothesize that platelet emboli and other blood-borne substances are released into the blood stream following CCA thrombosis leading to microvascular occlusion, increased vascular permeability, and in some cases tissue destruction. Pre- liminary data also demonstrate that this thrombogenically activated blood can induce widespread depressions in local cerebral blood flow (1CBF) in both donor and recipient rats. We hypothesize that serotonin, released from aggregating platelets, crosses a damaged BBB barrier, leading to vasoconstriction and decreased 1CBF. Next, in a reproducible model of neocortical microvascular thrombosis, we will determine the significance of BBB alterations on the hemodynamic and histopathological consequences of this insult. We will determine whether histamine is responsible for the hyperemic phase of the evolving infarct and changes in vascular permeability. The pathomechanisms of remote depression of 1CBF following thrombotic stroke will be investigated using regional microdialysis to measure levels of vasoactive substances in the extracellular fluid of remote brain regions. Selective antagonists directed at histamine, serotonin and norepinephrine will be used to alter the hemodynamic conse- quences and histopathological outcome of these thrombotic insults. The complete characterization of the microvascular responses to vascular thrombosis and the importance of these vascular events on histopathological outcome should contribute to our understanding of the pathophysiology of cerebrovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS027127-03
Application #
3413319
Study Section
Neurology A Study Section (NEUA)
Project Start
1990-08-01
Project End
1995-07-31
Budget Start
1992-08-01
Budget End
1993-07-31
Support Year
3
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Type
Schools of Medicine
DUNS #
City
Miami
State
FL
Country
United States
Zip Code
33146
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Bramlett, Helen M; Dietrich, W Dalton (2004) Pathophysiology of cerebral ischemia and brain trauma: similarities and differences. J Cereb Blood Flow Metab 24:133-50
Danton, Gary H; Dietrich, W Dalton (2004) The search for neuroprotective strategies in stroke. AJNR Am J Neuroradiol 25:181-94
Urrea, Carlos; Danton, Gary H; Bramlett, Helen M et al. (2004) The beneficial effect of mild hypothermia in a rat model of repeated thromboembolic insults. Acta Neuropathol (Berl) 107:413-20
Danton, Gary H; Dietrich, W Dalton (2003) Inflammatory mechanisms after ischemia and stroke. J Neuropathol Exp Neurol 62:127-36
Danton, Gary H; Prado, Ricardo; Truettner, Jessie et al. (2002) Endothelial nitric oxide synthase pathophysiology after nonocclusive common carotid artery thrombosis in rats. J Cereb Blood Flow Metab 22:612-9
Watson, Brant D; Prado, Ricardo; Veloso, Alexander et al. (2002) Cerebral blood flow restoration and reperfusion injury after ultraviolet laser-facilitated middle cerebral artery recanalization in rat thrombotic stroke. Stroke 33:428-34
Danton, Gary H; Prado, Ricardo; Watson, Brant D et al. (2002) Temporal profile of enhanced vulnerability of the postthrombotic brain to secondary embolic events. Stroke 33:1113-9
Katz, L M; Lotocki, G; Wang, Y et al. (2001) Regulation of caspases and XIAP in the brain after asphyxial cardiac arrest in rats. Neuroreport 12:3751-4
Dietrich, W D; Truettner, J; Prado, R et al. (2000) Thromboembolic events lead to cortical spreading depression and expression of c-fos, brain-derived neurotrophic factor, glial fibrillary acidic protein, and heat shock protein 70 mRNA in rats. J Cereb Blood Flow Metab 20:103-11

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