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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG010269-02
Application #
3122234
Study Section
Clinical Trials (CLIN)
Project Start
1992-06-01
Project End
1997-05-31
Budget Start
1993-06-01
Budget End
1994-05-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Iowa
Department
Type
Schools of Medicine
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Faraci, F M; Heistad, D D (1998) Regulation of the cerebral circulation: role of endothelium and potassium channels. Physiol Rev 78:53-97
Chu, Y; Faraci, F M; Ooboshi, H et al. (1997) Increase in TUNEL positive cells in aorta from diabetic rats. Endothelium 5:241-50
Kitazono, T; Faraci, F M; Heistad, D D (1996) L-arginine restores dilator responses of the basilar artery to acetylcholine during chronic hypertension. Hypertension 27:893-6
Ryan, S M; Waack, B J; Weno, B L et al. (1995) Increases in pulse pressure impair acetylcholine-induced vascular relaxation. Am J Physiol 268:H359-63
Sobey, C G; Brooks 2nd, R M; Heistad, D D (1995) Evidence that expression of inducible nitric oxide synthase in response to endotoxin is augmented in atherosclerotic rabbits. Circ Res 77:536-43
Heistad, D D; Armstrong, M L; Baumbach, G L et al. (1995) Sick vessel syndrome. Recovery of atherosclerotic and hypertensive vessels. Hypertension 26:509-13
Taguchi, H; Faraci, F M; Kitazono, T et al. (1995) Relaxation of the carotid artery to hypoxia is impaired in Watanabe heritable hyperlipidemic rabbits. Arterioscler Thromb Vasc Biol 15:1641-5
Taguchi, H; Faraci, F M; Kitazono, T et al. (1995) Relaxation of the aorta during hypoxia is impaired in chronically hypertensive rats. Hypertension 25:735-8
Taguchi, H; Heistad, D D; Kitazono, T et al. (1995) Dilatation of cerebral arterioles in response to activation of adenylate cyclase is dependent on activation of Ca(2+)-dependent K+ channels. Circ Res 76:1057-62
Kitazono, T; Heistad, D D; Faraci, F M (1995) Dilatation of the basilar artery in response to selective activation of endothelin B receptors in vivo. J Pharmacol Exp Ther 273:1-6

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