This is a 2-year exploratory research grant application (R21) responding to a February 2000 NIA/ NIAMSD/NIDDK-sponsored Program Announcement 'Skeletal Muscle Perfusion, Aging, and Cardiovascular Disease" (PA-00-056). The goal of the PA is to support studies of potential changes in skeletal muscle blood flow due to aging, and the mechanisms responsible for such changes. Accordingly, the Specific Aims of the present proposal will be to determine if: 1) tonic (basal) perfusion of the leg decreases with age in healthy adult humans and, if so, the decreases: (a) are progressive with age from young adulthood; (b) occur in both men and women; (c) are associated with corresponding reductions in vascular conductance; and (d) are associated with corresponding reductions in cardiac output (systemic arterial blood flow); 2) the postulated decreases in whole-leg blood flow and vascular conductance with age are associated with augmented sympathetic alpha-adrenergic vasoconstrictor tone; and 3) the postulated decreases in whole-leg blood flow and vascular conductance with age are associated with reduced vascular endothelial nitric oxide-mediated vasodilator tone. Based on our extensive preliminary results, we hypothesize that basal perfusion of the leg will decrease progressively across age in both men and women due to corresponding reductions in leg vascular conductance. In addition, the decline in femoral blood flow with age may be associated with a reduction in systemic arterial blood flow in women. Finally, we hypothesize that the decreases in leg blood flow and vascular conductance with age in both men and women will be associated with both augmented alpha-adrenergic vasoconstrictor tone and reduced vascular endothelial nitric oxide vasodilator tone. After extensive screening to establish eligibility, femoral blood flow, arterial blood pressure, and femoral vascular conductance will be determined under supine baseline conditions as well as in response to blockade of alpha-adrenergic receptors (intra-femoral phentolamine) and nitric intra-femoral L-NMMA) in vivoin groups of young, middle-aged, and older healthy men and oxide synthase (women. Leg skin blood flow, muscle sympathetic nerve activity, plasma catecholamine concentrations, leg fat-free mass, and other measurements also will be obtained. All experimental protocols will be conducted in the University of Colorado at Boulder General Clinical Research Center. The expected results should provide new insight into the effects of age and gender on basal limb perfusion in adult humans and the underlying mechanisms.

R21AG019365

2001-04-15

2004-03-31