Studies are proposed to examine effects of aging on cerebral blood vessels. The goals are to examine mechanisms and consequences of impairment of endothelium-dependent relaxation during aging, and to examine structural changes in cerebral blood vessels during aging. Studies are also planned to determine whether functional changes of cerebral vessels during aging are reversible. Several hypotheses will be tested. First, studies are proposed to examine mechanisms of impairment of endothelium-dependent relaxation in cerebral arterioles in vivo. An in vivo bioassay will be used to test the hypothesis that release of endothelium-derived relaxing factor (EDRF) is impaired by aging. Two approaches are proposed to attempt to restore endothelium-dependent responses to normal in old rats. First, 1-arginine will be applied topically to cerebral arterioles. If synthesis of nitric oxide, which is a major EDRF in the basilar artery, is related to a deficiency of substrate, topical administration of 1-arginine may improve endothelium- dependent responses in aged rats. Second, antioxidants will be administered. Responses to EDRF are inhibited by oxygen radicals, which may be generated during aging. Studies are planned to determine whether acute administration of superoxide dismutase (SOD) and catalase, or chronic administration of PEG SOD, will improve endothelium-dependent relaxation in odd rats. Second, studies are proposed to test the hypothesis that flow-mediated dilatation of cerebral blood vessels is impaired by aging, and that is defect may predispose impaired perfusion of the cerebrum. If responses are impaired, studies are planned to determine whether they can be improved by acute or chronic administration of antioxidants. Third, smooth muscle in cerebral arterioles undergoes atrophy during aging. Studies are planned to determine whether reduction in pulse pressure may contribute to arteriolar atrophy during aging, and whether reduction of arteriolar mass is sufficient to impair vasoconstrictor and vasodilator responses. The students have considerable potential significance. If the abnormality in endothelium-dependent mechanisms can be identified, and reversed with 1-arginine or scavengers of oxygen radicals, it may be possible to correct an important vascular abnormality of aging.
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