The long-term goal of HL-46493 is to understand how substances released by contracting skeletal muscles and sympathetic nerves interact and regulate blood flow to the active muscles. This renewal focuses on local and systemic responses to """"""""mismatches"""""""" between muscle blood flow, O2 delivery and metabolism to explore in humans a) whether the pressor response to rhythmic exercise during muscle hypoperfusion improves blood flow to active muscles;b) the potential vasodilator """"""""error signals"""""""" associated with hypoperfusion in active muscles;c) the interactions between these responses;and d) the extent to which challenges to skeletal muscle O2 delivery with hypoxia vs. hypoperfusion evoke similar compensatory adjustments. In this context, the following specific aims will be addressed: 1) We will use a small intra- arterial catheter/balloon system to create graded skeletal muscle hypoperfusion during rhythmic handgripping to evaluate whether the pressor response to exercise with muscle hypoperfusion improves blood flow to the active muscles. We hypothesize that the rise in vasoconstricting muscle sympathetic nerve activity (MSNA) evoked by the combination of rhythmic exercise and hypoperfusion prevents the pressor response from improving blood flow to the contracting muscles. 2) Using the catheter/balloon system, we will measure the local vasodilator responses to muscle hypoperfusion during exercise and use pharmacological tools to explore their nature. We hypothesize that local vasodilator responses to rhythmic exercise with hypoperfusion serve to maintain muscle blood flow during mild and moderate but not heavy rhythmic handgripping when MSNA is likely to rise. We also hypothesize that adenosine (perhaps along with NO) will be the main factor responsible for the compensatory dilation. 3) We will test whether the compensatory vasodilator signals that maintain O2 delivery to active muscles during exercise with mild hypoxia are the same or different than those that cause compensatory vasodilation during normoxic exercise with hypoperfusion. We hypothesize that adenosine (perhaps along with NO) will be the main factor responsible for the compensatory dilation under both circumstances. Summary and Significance: Muscle blood flow is a key determinant of exercise capacity, and it is unknown how systemic sympathoexcitation and local vasodilator responses to exercise with either hypoperfusion or hypoxia interact to regulate blood flow to contracting human skeletal muscles. We propose novel and innovative strategies to address a number of currently unresolved issues and controversies related to these topics in humans.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL046493-18
Application #
7809461
Study Section
Special Emphasis Panel (ZRG1-CVS-B (02))
Program Officer
Reid, Diane M
Project Start
1992-01-17
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
18
Fiscal Year
2010
Total Cost
$370,000
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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Keller-Ross, Manda L; Johnson, Bruce D; Carter, Rickey E et al. (2016) Improved Ventilatory Efficiency with Locomotor Muscle Afferent Inhibition is Strongly Associated with Leg Composition in Heart Failure. Int J Cardiol 202:159-66
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Van Iterson, Erik H; Snyder, Eric M; Joyner, Michael J et al. (2015) Intrathecal fentanyl blockade of afferent neural feedback from skeletal muscle during exercise in heart failure patients: Influence on circulatory power and pulmonary vascular capacitance. Int J Cardiol 201:384-93
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; Ranadive, Sushant M; Joyner, Michael J (2015) Aging is associated with altered vasodilator kinetics in dynamically contracting muscle: role of nitric oxide. J Appl Physiol (1985) 119:232-41
Joyner, Michael J; Casey, Darren P (2014) Muscle blood flow, hypoxia, and hypoperfusion. J Appl Physiol (1985) 116:852-7
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
Taylor, Jennifer L; Hines, Casey N; Nicholson, Wayne T et al. (2014) The effect of ageing and indomethacin on forearm reactive hyperaemia in healthy adults. Exp Physiol 99:859-67

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