It is postulated that the development of obesity exacerbates hypertensive disease in conjunction with changes in the activity of hypothalamic neurons which integrate sympatho-adrenal secretion in response to changes in plasma glucose concentrations. The opioid peptide, beta-endorphin, is a major determinant of the activity of such neurons within the paraventricular nucleus of the hypothalamus (PVH). This hypothesis will be tested in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats following selective lesioning of parvocellular PVH neurons by microinjection of the excitotoxin, N-methyl-D-aspartic acid (NMDA). Dietary obesity (DO) will be produced by feeding with a highly palatable diet. An initial series of experiments will correlate changes in hypothalamic beta-endorphin concentration (radioimmunoassay), plasma insulin levels (radioimmunoassay) and plasma catecholamine concentrations (HPLC-EC) with alterations in the rate of rise of blood pressure in sham or NMDA-lesioned SHR and WKY as DO develops. Specific hemodynamic and renal abnormalities associated with obesity-accelerated hypertension will be identified by measuring alterations in plasma volume (radio-iodinated serum albumin dilution) and baroreflex sensitivity in conscious, unrestrained rats following chronic (2 month) changes in diet. Relationships between plasma insulin levels, blood glucose regulation and reflex circulatory function will be examined during chronic DO following the challenge of insulin- induced hypoglycemia. Changes in distribution of regional blood flow (radio-labelled microspheres) and plasma catecholamine levels will be measured. The participation of renal sympathetic nerves in the observed responses to DO will be assessed in unlesioned SHR and WKY following renal denervation. Finally, comparisions will be made between the chronic circulatory changes caused by DO and the acute hemodynamic and plasma catecholamine responses triggered by discrete injection of beta- endorphin into the PVH of conscious SHR and WKY. The results will demarcate the role of a specific group of hypothalamic neurons in regulation of key metabolic and circulatory control systems using a novel experimental model of obesity-accelerated hypertension. The observed changes in hemodynamics, renal and sympatho-adrenal function may suggest more appropriate and effective therapeutic interventions.
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