application): Angiotensin II (Ang II), a peptide integral to the central control of blood pressure, regulates sympathetic neurotransmission. The pathophysiological relevance of Ang II/sympathetic interactions has been examined in hypertension and congestive heart failure; however, the relevance of this interaction at noncardiovascular organs innervated by the sympathetic nervous system has not been examined. Preliminary studies demonstrate that chronic infusion of Ang II to rats resulted in a dose-dependent elimination of weight gain and reduction in body weight through pressor-independent mechanisms. The working hypothesis of the proposed studies is that Ang II regulates body weight by activating the sympathetic nervous system, lipids, reducing food intake and altering secretion of adipose-derived leptin. All of the proposed studies will be performed in a rat model of chronic Ang II infusion. The first hypothesis is that Ang II regulates energy expenditure by activating the sympathetic nervous system. Several different approaches will be used to determine the role of the sympathetic nervous system in the effect of Ang II. First the time course for alterations in norepinephrine (NE) turnover and kinetic parameters of the ligand biding site of the NE transporter will be determined in white and brown adipose tissue. Examination of the time course form alterations in release of NE from slices of white and brown adipose tissue and the in vitro effect of Ang II to increase evoked NE release will be examined. The effect of beta blockade on Ang II-regulation of body weight will be examined. To determine if Ang II increases energy expenditure by altering secretion of leptin protein, the time course for alterations in plasma leptin will be determined. Administration of Ang II to ob/ob mice lacking functional leptin will be examined to determine the role of leptin in Ang II-regulation of body weight. The effect of Ang II to mobilize lipids from brown and white adipose tissue will be determined. The role of AT1 receptor in Ang II-disposition of adipose tissue in response to Ang II infusion will be examined. In Hypothesis 2, the role of alterations in food intake in the weight-reducing effects of Ang II will be determined. The physiologic/ pathophysiologic significance of Ang II-regulation of body weight is related to disease states whereby plasma Ang II concentrations are elevated (congestive heart failure) or decreased (obesity), contributing to the dysregulation of body weight.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Experimental Cardiovascular Sciences Study Section (ECS)
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Velletri, Paul A
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University of Kentucky
Schools of Pharmacy
United States
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Cassis, Lisa A; Urbas, Aaron; Lodder, Robert A (2005) Hyperspectral integrated computational imaging. Anal Bioanal Chem 382:868-72
Cassis, Lisa; Helton, Marc; English, Vicki et al. (2002) Angiotensin II regulates oxygen consumption. Am J Physiol Regul Integr Comp Physiol 282:R445-53
English, V; Cassis, L (1999) Facilitation of sympathetic neurotransmission contributes to angiotensin regulation of body weight. J Neural Transm 106:631-44