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.
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