The overall objective of this proposal is to determine the extent to which age-related changes in sympathetic nervous system (SNS) function, sensitivity to the metabolic effects of insulin, and salt-sensitivity of blood pressure contribute to hypertension in the elderly. Three hypotheses will be tested. Data from our initial studies suggest that there is an age-related increase in SNS activity and a decrease in responsiveness to alpha-adrenergic stimulation in normotensive elderly which appears to represent appropriate down-regulation to their heightened level of SNS activity. Hypothesis 1: Hypertension in elderly humans is related in part to an age-related increase in SNS activity coupled with diminished ability to normally down-regulate alpha-adrenergic responsiveness.
Four specific aims pertain to this hypothesis: 1) To determine if an age-related increase in systemic SNS activity (the rate of norepinephrine (NE) release into an extravascular compartment derived from NE kinetics) occurs in hypertensive as well as normotensive elderly humans, 2) To develop a flow-compartment model for regional norepinephrine kinetics to determine the level of SNS activity in the forearm, 3) To determine if the responsiveness to alpha-adrenergic stimulation measured in platelet membrane alpha2-adrenergic receptors and by vascular responses to alpha-adrenergic stimulation (alpha-adrenergic agonist mediated changes in forearm blood flow and venoconstriction) is increased in elderly hypertensives relative to normotensives, and 4) To determine if there is altered regulation of alpha-adrenergic responsiveness mediated by changes in SNS activity in elderly hypertensives. Older hypertensives are more likely to have insulin resistance and salt-sensitivity of blood pressure. The potential interactions between insulin and sodium and SNS activity will be tested in Hypothesis 2: Salt-sensitivity of blood pressure will be greatest in the setting of decreased sensitivity to the metabolic effects of insulin and heightened SNS activity, and Hypothesis 3: During dietary salt loading, sodium-sensitive hypertensive elderly will demonstrate increased SNS activation compared with sodium-resistant hypertensive and sodium-resistant normotensive elderly controls. Sensitivity to the metabolic effects of insulin will be determined by analysis of glucose and insulin values obtained during a tolbutamide-assisted intravenous glucose tolerance test. Salt sensitivity of blood pressure will be determined from the difference in blood pressure between a low-salt compared to a high-salt diet. We hypothesize that the compensatory mechanisms which normally allow adaptation to these ow related changes (e.g. down-regulation of alpha-adrenergic responsiveness or response to dietary sodium) are impaired in older hypertensives. The outcome of these studies will be new insights into the interactions between aging, SNS function, insulin resistance and salt-sensitivity of blood pressure in older humans.
