Effect of extraluminal ATP application on vascular tone and blood flow in skeletal muscle: implications for exercise hyperemia

Nyberg, Michael; Al‐Khazraji, Baraa K.; Mortensen, Stefan P.; Jackson, Dwayne N.; Ellis, Christopher G.; Hellsten, Ylva

doi:10.1152/ajpregu.00189.2013

Cited by 21 publications

(31 citation statements)

References 67 publications

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“…In this light, the administration of a low dose of ATP to the muscle interstitium does not alter tissue blood flow in human limbs and even causes vasoconstriction of the rat gluteus maximus muscle microcirculation (Nyberg et al . 2013). This contrasts to the increases in limb deep tissue flow seen in the present study when the same dose of ATP was administered intraluminally (Fig.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms for the control of local tissue blood flow during thermal interventions: influence of temperature‐dependent ATP release from human blood and endothelial cells

Kalsi

Chiesa

Trangmar

et al. 2017

Experimental Physiology

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New Findings What is the central question of this study? Skin and muscle blood flow increases with heating and decreases with cooling, but the temperature‐sensitive mechanisms underlying these responses are not fully elucidated. What is the main finding and its importance? We found that local tissue hyperaemia was related to elevations in ATP release from erythrocytes. Increasing intravascular ATP augmented skin and tissue perfusion to levels equal or above thermal hyperaemia. ATP release from isolated erythrocytes was altered by heating and cooling. Our findings suggest that erythrocytes are involved in thermal regulation of blood flow via modulation of ATP release. Local tissue perfusion changes with alterations in temperature during heating and cooling, but the thermosensitivity of the vascular ATP signalling mechanisms for control of blood flow during thermal interventions remains unknown. Here, we tested the hypotheses that the release of the vasodilator mediator ATP from human erythrocytes, but not from endothelial cells or other blood constituents, is sensitive to both increases and reductions in temperature and that increasing intravascular ATP availability with ATP infusion would potentiate thermal hyperaemia in limb tissues. We first measured blood temperature, brachial artery blood flow and plasma [ATP] during passive arm heating and cooling in healthy men and found that they increased by 3.0 ± 1.2°C, 105 ± 25 ml min−1 °C−1 and twofold, respectively, (all P < 0.05) with heating, but decreased or remained unchanged with cooling. In additional men, infusion of ATP into the brachial artery increased skin and deep tissue perfusion to levels equal or above thermal hyperaemia. In isolated erythrocyte samples exposed to different temperatures, ATP release increased 1.9‐fold from 33 to 39°C (P < 0.05) and declined by ∼50% at 20°C (P < 0.05), but no changes were observed in cultured human endothelial cells, plasma or serum samples. In conclusion, increases in plasma [ATP] and skin and deep tissue perfusion with limb heating are associated with elevations in ATP release from erythrocytes, but not from endothelial cells or other blood constituents. Erythrocyte ATP release is also sensitive to temperature reductions, suggesting that erythrocytes may function as thermal sensors and ATP signalling generators for control of tissue perfusion during thermal interventions.

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Section: Discussionmentioning

confidence: 99%

Mechanisms for the control of local tissue blood flow during thermal interventions: influence of temperature‐dependent ATP release from human blood and endothelial cells

Kalsi

Chiesa

Trangmar

et al. 2017

Experimental Physiology

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“…Interstitial ATP can induce vasoconstriction via P2X receptors on the smooth muscle cells or, alternatively, induce vasodilatation by acting on P2Y receptors on the endothelial cells (48). Animal experiments have suggested that the vasodilatory effect of interstitial ATP is stronger than its constrictive effect (93,313).…”

Section: Control Of Exercise Hyperemiamentioning

confidence: 99%

Cardiovascular Adaptations to Exercise Training

Hellsten

Nyberg

2015

Comprehensive Physiology

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Aerobic exercise training leads to cardiovascular changes that markedly increase aerobic power and lead to improved endurance performance. The functionally most important adaptation is the improvement in maximal cardiac output which is the result of an enlargement in cardiac dimension, improved contractility, and an increase in blood volume, allowing for greater filling of the ventricles and a consequent larger stroke volume. In parallel with the greater maximal cardiac output, the perfusion capacity of the muscle is increased, permitting for greater oxygen delivery. To accommodate the higher aerobic demands and perfusion levels, arteries, arterioles, and capillaries adapt in structure and number. The diameters of the larger conduit and resistance arteries are increased minimizing resistance to flow as the cardiac output is distributed in the body and the wall thickness of the conduit and resistance arteries is reduced, a factor contributing to increased arterial compliance. Endurance training may also induce alterations in the vasodilator capacity, although such adaptations are more pronounced in individuals with reduced vascular function. The microvascular net increases in size within the muscle allowing for an improved capacity for oxygen extraction by the muscle through a greater area for diffusion, a shorter diffusion distance, and a longer mean transit time for the erythrocyte to pass through the smallest blood vessels. The present article addresses the effect of endurance training on systemic and peripheral cardiovascular adaptations with a focus on humans, but also covers animal data.

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“…ATP has been proposed to play a role in skeletal muscle vasodilation (11-13) which is supported by its potent vasodilator capacity (20,22,34) and the observation that the concentration of this substance increases in the venous effluent of contracting skeletal muscle of young subjects (17,21). In contrast, ATP has been reported not to increase in venous plasma draining the exercising forearm of older subjects (17).…”

Section: We Recently Demonstrated That Inhibition Of Cgmp-binding Phomentioning

confidence: 99%

“…Since the first report on the hemodynamic response to exercise in older individuals in 1974 (42), evidence has accumulated for an insufficient blood flow to contracting skeletal muscle in aging (3,5,17,18,23,26,28,30,31). This altered regulation with aging could be related to a diminished ability for functional sympatholysis (10,20,36) and/or reduced efficacy of local vasodilator pathways (20,38,40).ATP has been proposed to play a role in skeletal muscle vasodilation (11-13) which is supported by its potent vasodilator capacity (20,22,34) and the observation that the concentration of this substance increases in the venous effluent of contracting skeletal muscle of young subjects (17,21). In contrast, ATP has been reported not to increase in venous plasma draining the exercising forearm of older subjects (17).…”

mentioning

confidence: 99%

Effect of PDE5 inhibition on the modulation of sympathetic α-adrenergic vasoconstriction in contracting skeletal muscle of young and older recreationally active humans

Nyberg

Piil

Egelund

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Nyberg M, Piil P, Egelund J, Sprague RS, Mortensen SP, Hellsten Y. Effect of PDE5 inhibition on the modulation of sympathetic ␣-adrenergic vasoconstriction in contracting skeletal muscle of young and older recreationally active humans. Am J Physiol Heart Circ Physiol 309: H1867-H1875, 2015. First published October 2, 2015; doi:10.1152/ajpheart.00653.2015.-Aging is associated with an altered regulation of blood flow to contracting skeletal muscle; however, the precise mechanisms remain unclear. We recently demonstrated that inhibition of cGMP-binding phosphodiesterase 5 (PDE5) increased blood flow to contracting skeletal muscle of older but not young human subjects. Here we examined whether this effect of PDE5 inhibition was related to an improved ability to blunt ␣-adrenergic vasoconstriction (functional sympatholysis) and/or improved efficacy of local vasodilator pathways. A group of young (23 Ϯ 1 yr) and a group of older (72 Ϯ 1 yr) male subjects performed kneeextensor exercise in a control setting and following intake of the highly selective PDE5 inhibitor sildenafil. During both conditions, exercise was performed without and with arterial tyramine infusion to evoke endogenous norepinephrine release and consequently stimulation of ␣1-and ␣2-adrenergic receptors. The level of the sympatholytic compound ATP was measured in venous plasma by use of the microdialysis technique. Sildenafil increased (P Ͻ 0.05) vascular conductance during exercise in the older group, but tyramine infusion reduced (P Ͻ 0.05) this effect by 38 Ϯ 9%. Similarly, tyramine reduced (P Ͻ 0.05) the vasodilation induced by arterial infusion of a nitric oxide (NO) donor by 54 Ϯ 9% in the older group, and this effect was not altered by sildenafil. Venous plasma [ATP] did not change with PDE5 inhibition in the older subjects during exercise. Collectively, PDE5 inhibition in older humans was not associated with an improved ability for functional sympatholysis. An improved efficacy of the NO system may be one mechanism underlying the effect of PDE5 inhibition on exercise hyperemia in aging.sildenafil; exercise; ATP; nitric oxide; cGMP NEW & NOTEWORTHY We recently demonstrated that inhibition of cGMP-binding phosphodiesterase 5 (PDE5) increased blood flow to contracting skeletal muscle of older but not young human subjects. Here we demonstrate that this effect of PDE5 inhibition on exercise hyperemia was related to an improved efficacy of local nonsympatholytic vasodilator pathways.CONTRACTILE ACTIVITY markedly increases the O 2 demand in skeletal muscle, thus requiring an increase in blood flow and O 2 delivery to the tissue. This increase in blood flow to the exercising muscle is the result of a local attenuation of the vasoconstrictor effect of sympathetic nervous activity, termed functional sympatholysis, and vasodilation induced by local vasoactive mechanisms (6,15). Since the first report on the hemodynamic response to exercise in older individuals in 1974 (42), evidence has accumulated for an insufficient blood flow to contracting skeletal m...

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Effect of extraluminal ATP application on vascular tone and blood flow in skeletal muscle: implications for exercise hyperemia

Cited by 21 publications

References 67 publications

Mechanisms for the control of local tissue blood flow during thermal interventions: influence of temperature‐dependent ATP release from human blood and endothelial cells

Mechanisms for the control of local tissue blood flow during thermal interventions: influence of temperature‐dependent ATP release from human blood and endothelial cells

Cardiovascular Adaptations to Exercise Training

Effect of PDE5 inhibition on the modulation of sympathetic α-adrenergic vasoconstriction in contracting skeletal muscle of young and older recreationally active humans

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