Skeletal muscle vascular beds exhibit a graded vasodilation and elevated blood flow in response to hypoxia as well as during dynamic exercise. Interestingly, the combination of exercise and hypoxia produces a """"""""compensatory"""""""" vasodilator response and an even greater hyperemic response compared to exercise under control conditions in humans. The mechanisms responsible for the compensatory vasodilation and maintained O2 delivery to contracting muscles during exercise with hypoxia remain unclear. It is generally accepted that adenosine plays a major role in hypoxia-induced skeletal muscle vasodilation but does not appear to be obligatory during exercise hyperemia. In this context, this application addresses the overall hypothesis that adenosine participates in the compensatory vasodilator responses seen during exercise by addressing the following specific aims. First, whether adenosine and nitric oxide are obligatory for the compensatory vasodilation during hypoxic exercise. Second, determine the possible contribution of ATP released from erythrocytes during hypoxic exercise has on the adenosine(ADO) mediated compensatory vasodilaton. Third, it is not known if aging blunts the compensatory vasodilator response during hypoxic exercise or if the mechanisms that promote vasodilation during hypoxic exercise are the same or different than those in younger individuals. In addition, these aims will serve as an ideal postdoctoral training vehicle for the proponent and represent a significant extension and expansion of his current skill set using approaches that are well established in the sponsor's laboratory. The strength of the proposed experimental design is that we will study the basic mechanisms of circulatory control during hypoxic exercise in humans. The results of these experiments will provide important new information about the metabolic regulation of skeletal muscle blood flow in humans. The ability to perform physical activity and exercise are or should be essential components of everyday life. For exercise to be performed there must be adequate blood flow to the exercising muscles. This proposal seeks to study the factors that cause blood flow to rise in exercising muscles and how these factors might be influenced by low levels of oxygen. We also seek to study these events in aging humans because older humans sometimes have diseases or conditions that result in low levels of oxygen in the blood. J

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32AR055819-03
Application #
7880117
Study Section
Special Emphasis Panel (ZRG1-F10-H (21))
Program Officer
Boyce, Amanda T
Project Start
2008-07-23
Project End
2011-07-22
Budget Start
2010-07-23
Budget End
2011-07-22
Support Year
3
Fiscal Year
2010
Total Cost
$52,154
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Joyner, Michael J; Casey, Darren P (2015) Regulation of increased blood flow (hyperemia) to muscles during exercise: a hierarchy of competing physiological needs. Physiol Rev 95:549-601
Casey, Darren P; Shepherd, John R A; Joyner, Michael J (2014) Sex and vasodilator responses to hypoxia at rest and during exercise. J Appl Physiol (1985) 116:927-36
Casey, Darren P; Curry, Timothy B; Charkoudian, Nisha et al. (2013) The effects of acute beta-adrenergic blockade on aortic wave reflection in postmenopausal women. Am J Hypertens 26:503-10
Casey, Darren P; Mohamed, Essa A; Joyner, Michael J (2013) Role of nitric oxide and adenosine in the onset of vasodilation during dynamic forearm exercise. Eur J Appl Physiol 113:295-303
Lopez, Marcos G; Silva, Bruno M; Joyner, Michael J et al. (2013) Roles of nitric oxide and prostaglandins in the hyperemic response to a maximal metabolic stimulus: redundancy prevails. Eur J Appl Physiol 113:1449-56
Hart, Emma C; Charkoudian, Nisha; Joyner, Michael J et al. (2013) Relationship between sympathetic nerve activity and aortic wave reflection characteristics in postmenopausal women. Menopause 20:967-72
Lopez, Marcos G; Silva, Bruno M; Joyner, Michael J et al. (2012) Ischemic exercise hyperemia in the human forearm: reproducibility and roles of adenosine and nitric oxide. Eur J Appl Physiol 112:2065-72
Casey, Darren P; Curry, Timothy B; Joyner, Michael J et al. (2012) Acute ?-adrenergic blockade increases aortic wave reflection in young men and women: differing mechanisms between sexes. Hypertension 59:145-50
Casey, Darren P; Joyner, Michael J (2011) Contribution of adenosine to compensatory dilation in hypoperfused contracting human muscles is independent of nitric oxide. J Appl Physiol 110:1181-9
Casey, Darren P; Walker, Branton G; Curry, Timothy B et al. (2011) Ageing reduces the compensatory vasodilatation during hypoxic exercise: the role of nitric oxide. J Physiol 589:1477-88

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