Based on results obtained during the current project period, I propose to test the hypothesis that hyperinsulinemia contributes importantly to cardiovascular and baroreflex dysfunction during dietary-induced obesity in rats. Obese rats will be produced by programming pups to overeat and then maintaining them on a high-fat diet immediately after weaning. Blood pressure will be monitored routinely by tail-cuff measurement and any changes thereby detected will be verified by direct intra-arterial recording in the same rats. Initial experiments will determine whether the cardiovascular and baroreflex alterations associated with obesity can be reversed or alleviated by dietary restriction or exercise training. Other experiments will attempt to replicate the cardiovascular and baroreflex impairment in obese rats by chronic intravenous infusion of exogenous insulin in normotensive non-obese rats. Similar measurements will be done during intracerebroventricular infusions to determine whether insulin affects cardiovascular and baroreflex function by acting centrally. Assuming that obesity predisposes rats to hypertension, the additive effects of aortic coarctation or DOCA-salt hypertension in obese rats, or of combining dietary-induced obesity with other predisposing factors will also be studied.
My specific aims will be to: (1) establish whether rats with dietary-induced obesity are reasonable models for obesity-hypertension in man by finding out if dietary restriction and/or exercise will restore normal cardiovascular and baroreflex function, (2) record cardiovascular and baroreflex effects of chronic intravenous or intracerebroventricular infusions of insulin in normotensive non-obese rats, and (3) quantify cardiovascular and baroreflex function in before and after induction of aortic-coarctation or DOCA-salt hypertension. By using rats with dietary-induced obesity as models for obesity-hypertension in man, underlying mechanisms can be explored and identified to improve our understanding of how obesity predisposes to hypertension.
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