application) Studies are proposed in relation to effects of chronic hypertension and diabetes mellitus on cerebral blood vessels. During chronic hypertension, cerebral vessels undergo hypertrophy and impairment of endothelium-dependent responses, both of which may be related to increases in arterial pulse pressure. Diabetes also impairs endothelium-dependent responses of cerebral vessels, but its effects on cerebral vascular growth have not been examined. The proposed studies will examine two specific aims related to these observations.
The first aim i s to clarify the role of endothelium-derived factors in cerebral vascular hypertrophy during increases in pulse pressure. The investigators propose to use an in vivo method to measure pressure (servo null) and diameter in cerebral arterioles, morphometric methods to determine cerebral arteriolar mass and composition, and arteriovenous (AV) fistulae in Sprague-Dawley rats to increase cerebral arteriolar pulse pressure without increasing mean pressure. Rats with AV fistulae will be treated with L-arginine to test the hypothesis that reduced availability of nitric oxide (NO) may contribute to hypertrophy of cerebral arterioles during increases in arteriolar pulse pressure. To examine the hypothesis that endothelin may mediate cerebral arteriolar hypertrophy during increases in pulse pressure, AV fistulae rats will be treated with a blocker of endothelin (ETA and ETB) receptors. The possibility that increased availability of angiotensin II may contribute to cerebral vascular hypertrophy during increases in pulse pressure will be examined by treating AV fistulae rats with a blocker of angiotensin AT-1 receptors.
The second aim i s to examine effects of diabetes on cerebral vascular structure and function. The investigators will use stretozotocin-treated rats to examine the hypotheses that 1) diabetes may result in atrophy of cerebral arterioles with an increase in arteriolar distensibility, and 2), diabetes may be associated with impaired responses of cerebral arterioles to trophic stimuli (such as increased pulse pressure and angiotensin II), or enhanced responses to trophic inhibitors (such as nitric oxide). Streptozotocin-treated mice and spontaneously diabetic (db/db) mice will be used to examine the possibility that juvenile and adult onset diabetes may have different effects on both structure and endothelium-dependent responses of cerebral arterioles.
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