The matching of blood flow and oxygen delivery to tissue oxygen demand is one of the most fundamental physiological processes. Recent evidence indicates that the red blood cell can act as a """"""""sensor"""""""" and releases ATP during mismatches in oxygen demand and delivery, and this ATP can evoke vasodilation and improve local blood flow under such conditions via binding to purinergic (P2y) receptors on the endothelium. In addition to the direct vasodilatory effect, we have recently demonstrated that ATP is also capable of inhibiting sympathetic vasoconstriction (""""""""sympatholytic""""""""), which could further aid in blood flow and oxygen distribution. Our preliminary data indicates that the forearm vasodilator responses to ATP are not due to breakdown to adenosine, and importantly, are independent of nitric oxide and vasodilating prostaglandins. Thus, the overall goal of this exploratory research program is to directly test the hypothesis that endothelium-dependent ATP- mediated vasodilation is due to vascular smooth muscle cell hyperpolarization in humans, and to further test whether the proposed pathways are involved in vascular control in contracting muscle. To test our hypotheses we will address the following specific aims: (1) we will determine whether the forearm vasodilator responses to local intra-arterial administration of ATP are reduced by individual and combined inhibition of inward rectifying potassium channels (KIR;via barium chloride) and Na+/K+ ATPase activity (via oubain);and (2) we will determine whether the forearm vasodilator responses to graded rhythmic handgrip exercise and the ability of muscle contractions to blunt sympathetic 1-adrenergic receptor mediated vasoconstriction are impaired after inhibition of KIR channels and Na+/K+ ATPase activity in humans. The methods employed to address these aims are state-of-the-art and involve local (intra-arterial) administration of various study drugs at rest and during exercise, and measurements of forearm arterial and venous plasma ATP concentrations in young healthy humans. The findings from the proposed studies should provide unique insight into the mechanisms by which circulating ATP causes local vasodilation, and whether the hypothesized signaling pathways evoking hyperpolarization are involved in vascular control in contracting skeletal muscle. Given that impaired endothelium-dependent vasodilation is a hallmark of patients at risk or whom already exhibit cardiovascular disease, and that ATP release from red blood cells of certain patients (e.g. diabetics) is impaired, our findings regarding the mechanisms underlying ATP-mediated vasodilation could have significant implications for understanding impaired local vascular control during physiological (e.g., exercise, hypoxia) and pathophysiological (e.g., coronary and cerebrovascular ischemia) conditions in older healthy and diseased humans.

Public Health Relevance

The studies outlined in this application are designed to address fundamental questions regarding how blood flow and oxygen delivery are controlled to peripheral tissues in humans. Understanding these basic regulatory mechanisms will provide important information that may stimulate ideas on how to improve regional blood flow and oxygen delivery in patient populations at risk for both acute and chronic cardiovascular complications.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL102720-02
Application #
8102000
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Reid, Diane M
Project Start
2010-07-01
Project End
2013-04-30
Budget Start
2011-05-01
Budget End
2013-04-30
Support Year
2
Fiscal Year
2011
Total Cost
$178,203
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
Hearon Jr, Christopher M; Kirby, Brett S; Luckasen, Gary J et al. (2016) Endothelium-dependent vasodilatory signalling modulates ?1 -adrenergic vasoconstriction in contracting skeletal muscle of humans. J Physiol 594:7435-7453
Hearon Jr, Christopher M; Dinenno, Frank A (2016) Regulation of skeletal muscle blood flow during exercise in ageing humans. J Physiol 594:2261-73
Dinenno, Frank A (2016) Skeletal muscle vasodilation during systemic hypoxia in humans. J Appl Physiol (1985) 120:216-25
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
Crecelius, Anne R; Kirby, Brett S; Hearon Jr, Christopher M et al. (2015) Contracting human skeletal muscle maintains the ability to blunt ?1 -adrenergic vasoconstriction during KIR channel and Na(+) /K(+) -ATPase inhibition. J Physiol 593:2735-51
Crecelius, Anne R; Luckasen, Gary J; Larson, Dennis G et al. (2014) KIR channel activation contributes to onset and steady-state exercise hyperemia in humans. Am J Physiol Heart Circ Physiol 307:H782-91
Crecelius, Anne R; Richards, Jennifer C; Luckasen, Gary J et al. (2013) Reactive hyperemia occurs via activation of inwardly rectifying potassium channels and Na+/K+-ATPase in humans. Circ Res 113:1023-32
Crecelius, Anne R; Kirby, Brett S; Luckasen, Gary J et al. (2013) Mechanisms of rapid vasodilation after a brief contraction in human skeletal muscle. Am J Physiol Heart Circ Physiol 305:H29-40
Kirby, Brett S; Crecelius, Anne R; Richards, Jennifer C et al. (2013) Sources of intravascular ATP during exercise in humans: critical role for skeletal muscle perfusion. Exp Physiol 98:988-98
Crecelius, Anne R; Kirby, Brett S; Richards, Jennifer C et al. (2013) Mechanical effects of muscle contraction increase intravascular ATP draining quiescent and active skeletal muscle in humans. J Appl Physiol (1985) 114:1085-93

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