The specific aim of this proposal is to investigate potential mechanisms by which a diet high in saturated fat and refined carbohydrates (sucrose) induces insulin resistance and hypertension compared to a diet high in unrefined carbohydrate and low in fat. Hypertension afflicts one quarter of the adult population in the United States and is a hallmark risk factor for myocardial infarction, stroke and congestive heart failure. Although its cause is largely unknown, it is associated with insulin resistance/ hyperinsulinemia, oxidative stress and endothelial dysfunction. The primary hypothesis to be tested in this grant is that a high-fat, refined carbohydrate diet (HFS) increases the production of reactive oxygen/nitrogen species (e.g. ONOO-), contributing to insulin resistance, as well as sequestrating and inactivating NO leading to hypertension. To test this hypothesis, male and female rats will be raised on either the HFS or a low-fat, complex carbohydrate diet (LFCC) and blood pressure will be measured via the tail-cuff and telemetry methods. Isolated arterial segments will be used to test endothelial function. Plasma/urinary measurements will assess NO metabotites, MDA and cGMP levels. Biochemical studies will be. conducted on several tissues, including aorta, heart and kidney to measure eNOS, iNOS, nNOS and SOD proteins, NOS and SOD activities, nitrotyrosine formation and tissue cGMP levels. Studies will also be conducted to investigate the value of dietary modification (switching to an LFCC diet or antioxidant supplementation) and exercise training for controlling hypertension, as well as the role of caloric restriction on the development of hypertension. The results of these studies may provide a mechanism to explain how HFS type diets cause insulin resistance and hypertension, and how a LFCC diet, antioxidant therapy or exercise training aid in the control of insulin resistance and hypertension.
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