Numerous epidemiological studies have shown a close association between obesity and hypertension. The research proposed in this application is designed to test the following hypotheses: a) differences exist in the functional properties of arteries and in the regulation of smooth muscle function that predispose the obese subject to hypertension; b) adrenal corticosteroids contribute to the alterations in arterial wall properties found in obesity; c) the altered arterial wall properties that occur in obesity produce exaggerated responses to stimuli that normally increase arterial blood pressure; and d) caloric restriction and/or exercise ameliorate the alterations in arterial wall properties normally associated with obesity. The following experiments are proposed to test the above hypotheses using lean and obese male Zucker rats: a) Longitudinal studies (4-36 weeks) of changes in arterial pressure will be conducted. At ages of 6, 12, 24 and 36 weeks, cardiac output and in vivo pressor responses to iv norepinephrine and angiotensin II will be determined, and segments of carotid and tail arteries, thoracic aorta, and mesenteric artery branches will be used in vitro for correlative studies of wall mechanics, drug reactivity, Na-pump activity, and 86Rb+ and 45Ca2+ fluxes. b) The effects of adrenalectomy (ADX) with hydrocortisone replacement therapy at normal and low levels in obese rats, and of chronic hydrocortisone or insulin administration in lean (homozygous and heterozygous) rats will be studied to evaluate the role of these hormones in the development of obesity-related arterial wall changes. c) Hemodynamic and arterial wall changes with chronic deoxycorticosterone treatment with a high and low salt diet will be determined in obese and lean rats as well as in ADX obese rats with two levels of hydrocortisone replacement to determine their response to this normally hypertensive perturbation. d) The ability of caloric restriction and/or exercise to ameliorate (start at 12 wks old) or prevent (start at 4 wks old) obesity-related arterial wall changes will be determined. It is anticipated that these studies will provide information to establish a causal relationship between obesity and hypertension, to identify mechanisms that are involved, and indicate the value of exercise and/or caloric restriction as therapeutic measures.
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