Despite extensive research over 25 years, the basic pathophysiology of cerebral vasospasm after subarachnoid hemorrhage (SAH) is unknown, due in part to limitations of current experimental models. Considerable recent clinical and experimental evidence has demonstrated ultrastructural changes in the wall of cerebral arteries exposed to subarachnoid blood, which correspond temporally the the development of angiographic and clinical vasospasm. Structural narrowing of cerebral arteries, as opposed to vasoconstriction, may play an important role in cerebral ischemia associated with vasospasm. Morphologic changes in cerebral arteries after SAH are similar in many respects to those observed in systemic vessels under a number of pathologic conditions. Research in these areas has identified complex interactions between components of blood and the arterial wall, which appear to mediate basic pathologic vascular responses to injury. The primary objective of this research proposal is the development of a small animal (rabbit) model for the selective application of blood components to cerebral arteries. Whole blood will fractionated into its cellular and serum constituents, which will be individually applied to cerebral vessels using a polymeric drug-delivery system. After perfusion-fixation at specific periods of time, vessels will be examined by light and transmission electron microscopy (TEM), and morphologic changes quantitated through morphometric analysis, autoradiography, and assessment of permeability changes. In subsequent years of proposed research, the pathophysiology of morphologic change after SAH will be investigated by selective application of specific arteriopathic substances, determination of critical time exposure to produce morphologic changes, correlation of in vitro changes in vessel physiology to morphologic changes, and testing of potential therapeutic strategies. The proposed model for morphologic changes in cerebral arteries after SAH is unique compared to previous experimental models in several respects: (1) animal costs and handling difficulties are minimized in a small-animal model, (2) the specificity, duration and concentration of substances applies to cerebral arteries can be accurately regulated through a polymeric drug-delivery system, (3) morphometric techniques will provide quantitative analysis of morphologic changes and delineate specific mechanisms mediating these changes, and (4) results of these investigations may be directly applicable to the study of vascular pathophysiology in systemic vessels.
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