Imbalance within central autonomic networks may contribute to the development or maintenance of hypertension. Hypertension, in turn, exerts deleterious effects on the structure and function of the central nervous system, the cerebral circulation being a major target of these actions. The long-term goals of this project are: (a) to identify the mechanisms by which hypertension alters the regulation of the cerebral circulation during neural activity, and (b) to define how these alterations affect the structure and function of the brain. Project 1 will begin by testing the hypothesis that AngII impairs the mechanisms responsible for the increase in CBF induced by neural activation. In particular, the proposed studies will determine whether Ang II exerts this effect by acting on cerebral blood vessels and by interfering with the vascular mechanisms through which neural activity increases blood flow. The following specific hypotheses will be tested: (1) Ang II alters the """"""""coupling"""""""" between cerebral blood flow and neural activity, (2) this effect is mediated by Ang II-induced production of reactive oxygen species in cerebral blood vessels and nitric oxide inactivation, and (3) NAD(P)H oxidase is a major source of the vascular reactive oxygen species contributing to the dysfunction. Studies will be conducted in mice in which arterial pressure is elevated by administration of Ang II. The increase in cerebral blood flow produced in the somatosensory cortex by whisker stimulation will serve as a model of neural activation. Cerebrovascular responses to endothelium-dependent and independent vasodilators, and cerebrovascular production of reactive oxygen species will be studied. The role of radicals will be examined using mice overexpressing superoxide dismutase-1. Mice lacking specific NAD(P)H oxidase subunits will be used to determine whether this enzyme is the source of oxidative stress. Transgenic mice overexpressing components of the renin-angiotensin system will also be used in some experiments. The results of these studies will enhance our understanding of the effects of hypertension on the brain and may provide insights into new treatment strategies aimed at counteracting these detrimental actions.
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