Blood pressure, reactivity, metabolism and serotonin

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The principal objective of this Project is to establish whether several biological risk factors for cardiovascular disease are associated, individually and in aggregate, with diminished central serotonergic (5- HT) responsivity. Biological risk factors of interest include blood pressure, cardiovascular reactivity and other indices of autonomic dysregulation, and metabolic abnormalities underlying the "insulin resistance syndrome." A second aim is to determine whether individuals differing in central serotonergic responsivity also differs in preclinical indicators of vascular disease. A final objective is to explore the underlying neurobiologic mechanism, for blunted central serotonergic responsivity in rats genetically predisposed to hypertension and insulin resistance. We propose to recruit a community sample of 600 men and women, 30-50 years of age and without a history of cardiovascular disease. Subjects will be administered a neuropsychopharmacologic challenge to evaluate central serotonergic responsivity (plasma prolactin and ACTH responses to the selective 5-HT reuptake, inhibitor, citalopram. A basic evaluation of biological risk factors will be performed on all subjects. A subsample of 300 individuals, derived from the lower and upper tertiles of the distribution of central 5-HT responsivity (as indexed by subject's citalopram-induced prolactin responses), will undergo more detailed examinations. These include ambulatory blood pressure monitoring; psychophysiologic laboratory assessments of cardiovascular reactions to mental stress, heart rate variability, and baroreceptor sensitivity; measurement of visceral adipose tissue with computer tomography; determination of insulin resistance with the frequency sample intravenous glucose tolerance test; and measurement of endothelium-mediated dilation of the brachial artery, carotid artery intima-medial thickness and atherosclerotic plaque. Animal experiments will begin to elucidate the neural mechanism for blunted 5- HT responsivity in spontaneously hypertensive rats. THIS Project will provide the first systematic test of the hypotheses that several sources of risk for atherosclerotic disease aggregate, in part, under the influence of a common neurobiologic mechanism involving altered central serotonergic function. Support for this hypothesis will further our understanding of the origins of risk factors for cardiovascular disease and provide clues to possible commonalities of etiology. (It should be noted that Project 1 data collection is based upon the same participant cohort).