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Modulators of Baroreflex Function in Conditions Associated with Hypertension

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abstract
Hypertension is associated with various physiological and pathophysiological conditions including obesity, type II diabetes and aging. Despite decades of research, the mechanisms involved in the development of hypertension are still poorly understood. Emerging evidence suggests that hypertension is mediated by an imbalance in autonomic nervous system activity. Importantly, baroreflex sensitivity for control of heart rate, an important maker of parasympathetic function, is reduced in conditions associated with hypertension and is believed to precede and contribute to the pathogenesis of hypertension. Therefore, it is critical to identify key factors that regulate brainstem areas controlling autonomic outflow in conditions associated with baroreflex dysfunction. To this end, our goal was to identify factors that modulate baroreflex sensitivity under normal conditions and during alterations of the brain renin-angiotensin system (RAS). Specifically, we determined the contribution of angiotensin peptides and leptin to baroreflex sensitivity in order to understand mechanisms contributing to baroreflex dysfunction in aged and obese individuals. The contribution of brain angiotensin peptides to baroreflex function during aging was assessed in older ASrAOGEN rats with low brain angiotensinogen. These studies show that maintenance of angiotensin-(1-7) and loss of angiotensin II tone within the solitary tract nucleus (NTS) may be an important mechanism contributing to preservation of baroreflex function during aging. Furthermore, we demonstrate the novel finding that exogenous leptin impairs baroreflex sensitivity for control of heart rate and alters autonomic balance at the level of the NTS in younger Sprague-Dawley rats. Leptin-mediated impairments in baroreflex sensitivity are enhanced in younger ASrAOGEN rats suggesting interactions between leptin and the brain RAS for baroreflex modulation. Preliminary data shows a loss of sensitivity to leptin for baroreflex modulation in older Sprague-Dawley rats with elevated circulating leptin levels suggesting resistance to the cardiovascular actions of leptin during aging. Sensitivity to leptin is maintained in older ASrAOGEN rats, associated with low circulating leptin levels, suggesting that long-term reductions in the brain RAS preserves leptin sensitivity during aging. In older Sprague-Dawley rats, baroreflex sensitivity is improved by NTS administration of a leptin antagonist implicating a role for endogenous leptin in age-related baroreflex dysfunction. These findings suggest that reduction of endogenous leptin within the NTS may be a novel mechanism to improve baroreflex function and restore autonomic balance in conditions associated with elevated leptin levels. Collectively, the present findings provide insight into novel mechanisms for preservation of baroreflex function in conditions associated with hypertension, including aging and obesity.
subject
Physiology
Pharmacology
contributor
Arnold, Amy (author)
Milligan, Carol (committee chair)
Diz, Debra I. (committee member)
Howlett, Allyn (committee member)
Eldridge, J. Charles (committee member)
Gallagher, Patricia E. (committee member)
date
2009-12-16T15:50:04Z (accessioned)
2010-06-18T18:56:51Z (accessioned)
2009-12-16T15:50:04Z (available)
2010-06-18T18:56:51Z (available)
2009-12-16T15:50:04Z (issued)
degree
Physiology (discipline)
identifier
http://hdl.handle.net/10339/14653 (uri)
language
en_US (iso)
publisher
Wake Forest University
rights
Release the entire work for access only to the Wake Forest University system for one year from the date below. After one year, release the entire work for access worldwide. (accessRights)
title
Modulators of Baroreflex Function in Conditions Associated with Hypertension
type
Dissertation

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