The long-term goals of the application are to determine the role played by insulin and the sympathetic nervous system (SNS) in the pathogenesis of obesity-relate hypertension.
The specific aims are: 1) to determine the level of sympathetic activity in obese hypertensive subjects as compared with obese normotensive subjects and normal weight controls in the ad lib state; 2) to determine the relationships between hyperinsulinemia (insulin resistance), SNS activity, and blood pressure (BP) in human obesity-related hypertension; 3) to develop a rat model of obesity-related hypertension based on the chronic administration of a high fat diet; and 4) to determine the between insulin and the SNS, and the SNS and BP in the rat model of obesity-related hypertension. In human subjects, SNS activity is assessed by measurements of plasma norepinephrine (NE) concentration, urinary NE excretion, and the rate of appearance of NE in the circulation as calculated from tracer kinetic experiments. In rats SNS activity is assessed in heart, kidney, white adipose tissue brown adipose tissue, and liver by the measurement of NE turnover rate in these organs In humans and rats the relationship between insulin and the SNS, and the SNS and BP will determined by comparing the impact of interventions that alter insulin resistance and/or the level of circulating insulin on SNS activity and BP. The intervention utilized include, in humans: a protein sparing modified fast; infusion of somatostatin treatment with a long acting somatostatin analogue (octreotide, Sandostatin); an euglycemic hyperinsulinemic glucose clamps. In fat fed rats the interventions include fish oil supplements; oat bran supplements; experimental diabetes induced by streptozotocin; treatment with octreotide. In rats the effect of 2-deoxyglucose on sympathetic activity and BP in fat fed animals will be assessed as well obesity-related hypertension is a major cause of cardiovascular morbidity and mortality in the obese. Although hyperinsulinemia has been linked with hypertension cardiovascular risk in this group, the mechanisms by which insulin acts to affect BP an the cardiovascular system have not been established. The studies proposed in this application will assess the role of insulin-mediated sympathetic stimulation in the pathogenesis of obesity-related hypertension. Clarification of the mechanisms involved has important therapeutic implications and the potential to impact favorably the cardiovascular morbidity prevalent in the obese.
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