In humans, both essential hypertension and the aging process have been associated with the development of similar cognitive deficits. These deficits, which primarily involve learning and memory, can be detected by the use of sensitive psychometric tests. The pathophysiologic basis of this cognitive decline is unclear, but both conditions have also been associated with decreases in regional cerebral blood flow, particularly to the temporal and frontal lobes. The effect of chronic antihypertensive treatment on cognitive function in aging is as yet unresolved; both improvement and worsening of cognitive function has been reported with various antihypertensive drugs. For example, the evidence regarding the central sympatholytic agents is weighted toward negative cognitive effects, while angiotensin converting enzyme-inhibitors appear to be neutral or perhaps even beneficial. A rat model will be useful in explaining these differences because age-associated learning deficits have been demonstrated in several varieties of rats. The main objective of this proposal will be to examine the effect of chronic administration antihypertensive drugs on cognitive performance and regional cerebral blood flow in aging rats. We plan to study two types of rats: normotensive Wistar (WKY) and spontaneously hypertensive (SHR) rats. Prototype antihypertensive drugs from each of five different pharmacological classes will be administered to both types of rats over an 18 month period. Systemic blood pressure will be lowered to a predetermined therapeutic level in all rats and monitored throughout the study. Sham-treated control animals will be included. Cognitive effects of the drugs will be evaluated every three months with neurobehavioral tests that have proven reliable in detecting learning deficits in aging rats. At the conclusion of the 18 month treatment period, regional cerebral blood flow to 12 major brain areas will be determined by autoradiographic methods. Drug-treated and control animals will be compared with regard to longitudinal changes in cognitive performance. Relative differences among the various drugs will be examined in terms of effects on cognitive function. Differences in cognitive performance will be correlated with changes in regional cerebral blood flow observed over the duration of the study.
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