Aerobic exercise capacity declines progressively with advancing age eventually leading to increased disability, loss of independence, and reduced quality of life in older adults. The overall goal of this research program is to investigate the mechanism(s) involved in the impaired control of muscle blood flow and vascular tone during dynamic exercise in aging humans. This proposal seeks to mechanistically-link oxidative stress-induced peripheral endothelial dysfunction with impaired vascular control during dynamic exercise in aging humans. The general concept is that age-associated increases in oxidative stress reduce endothelium-derived nitric oxide (NO) bioavailability and cause the production of cyclooxygenase-derived vasoconstrictor prostaglandins (PGs), thus impairing local vasodilator responses during exercise in older adults. To test our hypotheses we will address the following specific aims: (1) we will determine whether the impaired control of muscle blood flow and vascular tone observed during dynamic exercise in older adults is due to age-related impairments in endothelium-dependent vasodilation, and specifically, we will determine the independent and interactive contribution of NO and PGs to this impairment; (2) we will determine whether acute reductions in oxidative stress in older adults improves endothelial vasodilator function and therefore, improves muscle blood flow and local vasodilator responses during exercise. The methods employed to address these aims are state-of-the-art and involve local (intraarterial) administration of various study drugs during exercise to investigate the roles of NO, PGs, and oxidative stress in the control of muscle blood flow in young and older healthy humans. The findings from the proposed studies should provide unique insight into the regulation of muscle blood flow and vascular control during exercise in aging humans, and also could have significant implications for the understanding and treatment of exercise intolerance in diseased populations that also demonstrate endothelial dysfunction e.g., heart failure patients).

Public Health Relevance

Aging is associated with a reduced quality of life which is due, in part, to reductions in exercise capacity. The studies in this application are designed to understand the potential contribution of impaired blood vessel function to exercise intolerance in older adults, and will provide ideas on how to prevent or improve this function, thereby enhancing the quality of life of older adults. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Small Research Grants (R03)
Project #
5R03AG027150-02
Application #
7276022
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Kohanski, Ronald A
Project Start
2006-08-15
Project End
2009-05-31
Budget Start
2007-06-15
Budget End
2009-05-31
Support Year
2
Fiscal Year
2007
Total Cost
$62,775
Indirect Cost
Name
Colorado State University-Fort Collins
Department
Miscellaneous
Type
Other Domestic Higher Education
DUNS #
785979618
City
Fort Collins
State
CO
Country
United States
Zip Code
80523
Crecelius, Anne R; Kirby, Brett S; Dinenno, Frank A (2015) Intravascular ATP and the regulation of blood flow and oxygen delivery in humans. Exerc Sport Sci Rev 43:5-13
Kirby, Brett S; Crecelius, Anne R; Voyles, Wyatt F et al. (2011) Modulation of postjunctional ?-adrenergic vasoconstriction during exercise and exogenous ATP infusions in ageing humans. J Physiol 589:2641-53
Crecelius, Anne R; Kirby, Brett S; Voyles, Wyatt F et al. (2010) Nitric oxide, but not vasodilating prostaglandins, contributes to the improvement of exercise hyperemia via ascorbic acid in healthy older adults. Am J Physiol Heart Circ Physiol 299:H1633-41
Kirby, Brett S; Crecelius, Anne R; Voyles, Wyatt F et al. (2010) Vasodilatory responsiveness to adenosine triphosphate in ageing humans. J Physiol 588:4017-27
Kirby, Brett S; Voyles, Wyatt F; Simpson, Carrie B et al. (2009) Endothelium-dependent vasodilatation and exercise hyperaemia in ageing humans: impact of acute ascorbic acid administration. J Physiol 587:1989-2003
Kirby, Brett S; Voyles, Wyatt F; Carlson, Rick E et al. (2008) Graded sympatholytic effect of exogenous ATP on postjunctional alpha-adrenergic vasoconstriction in the human forearm: implications for vascular control in contracting muscle. J Physiol 586:4305-16
Carlson, Rick E; Kirby, Brett S; Voyles, Wyatt F et al. (2008) Evidence for impaired skeletal muscle contraction-induced rapid vasodilation in aging humans. Am J Physiol Heart Circ Physiol 294:H1963-70
Kirby, Brett S; Carlson, Rick E; Markwald, Rachel R et al. (2007) Mechanical influences on skeletal muscle vascular tone in humans: insight into contraction-induced rapid vasodilatation. J Physiol 583:861-74
Smith, Erica G; Voyles, Wyatt F; Kirby, Brett S et al. (2007) Ageing and leg postjunctional alpha-adrenergic vasoconstrictor responsiveness in healthy men. J Physiol 582:63-71