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Degree

Doctor of Philosophy, Ohio State University, Pharmacy, 2003.

Abstract

The primary focus of this thesis deals with understanding pathophysiological aspects of retrovirus (HIV/AIDS) and cocaine related cardiovascular complications. Central goals were to define important interactions between the cardiovascular and immune systems and involvement of oxidant related pathways in relevant animal models and in human tissues. Additional components of this dissertation were to define optimal conditions for cardiovascular performance assessments (contractility and electrophysiology) in mouse models and to develop novel mechanistic insights so that therapy could be further optimized. Using a relevant mouse model of retroviral pathogenesis (LPBM5, “murine AIDS” model) we observed time dependent cardiomyopathy and first-time evidence of reactive nitrogen species in cardiac tissue in this setting; we also corroborated these phenomena in a well-defined set of human tissues from HIV/AIDS autopsy cases. In subsequent investigations we found that a modest exposure of bacterial lipopolysaccharide amplified abnormalities in cardiac structure and function observed in the murine AIDS model, and that this synergistic effect was associated with increased cardiac prevalence of activated monocytes and cardiac myocyte expression of toll-like receptor 4 (TLR4, an important component of cardiac innate immunity). These observations suggest that coincident infection in humans may promote HIV-related cardiac complications. In separate studies we investigated mechanistic aspects of cocaine related cardiovascular toxicity in mice. A single dose of cocaine (30mg/kg) caused acute and protracted electrical abnormalities and protracted endothelial dysfunction in mice, analogous to clinical phenomenon observed in humans. Isolated cell experiments demonstrated that cocaine induced toxicity is related to increased cellular production of oxidants (in the absence of hypoxia). In a pilot clinical study we also investigated the effects of a standardized grape product with respect to vascular performance in normal subjects. We found that this product produced beneficial effects on endothelial function (using a noninvasive ultrasound method of evaluation) and that these were not ethanol-dependent and could protect against detrimental influences of a standard high fat meal. Collectively these studies demonstrate an important role for oxidant related and immune system mediated processes in diverse settings of cardiac and vascular dysfunction.

Subject Headings

Health Sciences, Pharmacology

Keywords

HIV; retrovirus; LP-BM5; murine AIDS; reactive nitrogen species; cocaine; cardiovascular; endothelium; oxidants; brachial artery ultrasound; grapes

Advisor

John Anthony Bauer

Document number: osu1056031201
Permalink: http://rave.ohiolink.edu/etdc/view?acc_num=osu1056031201

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