ATP‐mediated vasodilatation occurs via activation of inwardly rectifying potassium channels in humans

Crecelius, Anne R.; Kirby, Brett S.; Luckasen, Gary J.; Larson, Dennis G.; Dinenno, Frank A.

doi:10.1113/jphysiol.2012.234245

Cited by 62 publications

(111 citation statements)

References 38 publications

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“…2002; Crecelius et al . 2012). However, the role of intravascular ATP as a thermal mediator of skin and limb deep tissue vasodilatation has not been investigated.…”

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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“…2002; Crecelius et al . 2012). However, the role of intravascular ATP as a thermal mediator of skin and limb deep tissue vasodilatation has not been investigated.…”

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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“…In this study, K ϩ -mediated vasodilation occurred through both inwardly rectifying K ϩ (K IR ) channels and Na ϩ -K ϩ -ATPase, similar to the mechanisms of K ϩ -mediated vasodilation in humans (17,21). Furthermore, these animal data substantiated early observations showing that changes in interstitial K ϩ concentration after brief muscle contraction have the appropriate magnitude and time course to have a significant involvement in the hyperemic response (26,35,39,50,53,54) and that smooth muscle vascular hyperpolarization may be essential to observe rapid vasodilation (33).…”

mentioning

confidence: 96%

“…To inhibit traditional endothelium-derived vasodilators that have not independently been shown to be playing a role in rapid vasodilation, N G -monomethyl-L-arginine (L-NMMA; Bachem, Germany) was administered to inhibit NO synthase-mediated production of NO in combination with ketorolac (Hospira, Lake Forest, IL) to inhibit cyclooxygenase-mediated synthesis of PGs. Loading doses of L-NMMA and ketorolac were 25 mg (5 mg/min for 5 min) and 6 mg (600 g/min for 10 min), respectively (17,19). Depending on the protocol, maintenance doses of either BaCl 2 (0.45 mol·dl forearm volume Ϫ1 ·min Ϫ1 ), ouabain (2.7 nmol/min), L-NMMA (1.25 mg/min), or ketorolac (150 g/min) were infused for 3 min before each set of single contractions to ensure continuous blockade (see Experimental Protocols below).…”

Section: Vasoactive Drug Infusionsmentioning

confidence: 99%

“…To inhibit K ϩ -mediated hyperpolarization and vasodilation, both ouabain octahydrate (no. 03125, Sigma, St. Louis, MO) and BaCl2 [10% (wt/vol) BDH-3238, EMD Chemicals, Gibbstown, NJ] were administered intra-arterially as previously described (17). Ouabain was infused at 2.7 nmol/min for 15 min as a loading dose to inhibit Na ϩ -K ϩ -ATPase, and BaCl2, was infused at 0.45 mol·dl forearm volume Ϫ1 ·min Ϫ1 with a minimum dose of 4 mol/min to a maximum dose of 5 mol/min for 3 min as a loading dose to inhibit K IR channels (9,17,21,27,37).…”

Section: Vasoactive Drug Infusionsmentioning

confidence: 99%

“…03125, Sigma, St. Louis, MO) and BaCl2 [10% (wt/vol) BDH-3238, EMD Chemicals, Gibbstown, NJ] were administered intra-arterially as previously described (17). Ouabain was infused at 2.7 nmol/min for 15 min as a loading dose to inhibit Na ϩ -K ϩ -ATPase, and BaCl2, was infused at 0.45 mol·dl forearm volume Ϫ1 ·min Ϫ1 with a minimum dose of 4 mol/min to a maximum dose of 5 mol/min for 3 min as a loading dose to inhibit K IR channels (9,17,21,27,37). This dose of BaCl2 has been adjusted to forearm volume compared with our previous study (17) to maximize efficacy while still remaining within doses safe for human administration and specific for KIR channels (21,36).…”

Section: Vasoactive Drug Infusionsmentioning

confidence: 99%

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Mechanisms of rapid vasodilation after a brief contraction in human skeletal muscle

Crecelius

Kirby

Luckasen

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Crecelius AR, Kirby BS, Luckasen GJ, Larson DG, Dinenno FA. Mechanisms of rapid vasodilation after a brief contraction in human skeletal muscle. Am J Physiol Heart Circ Physiol 305: H29-H40, 2013. First published May 3, 2013 doi:10.1152/ajpheart.00298.2013.-A monophasic increase in skeletal muscle blood flow is observed after a brief single forearm contraction in humans, yet the underlying vascular signaling pathways remain largely undetermined. Evidence from experimental animals indicates an obligatory role of vasodilation via K ϩ -mediated smooth muscle hyperpolarization, and human data suggest little to no independent role for nitric oxide (NO) or vasodilating prostaglandins (PGs). We tested the hypothesis that K ϩ -mediated vascular hyperpolarization underlies the rapid vasodilation in humans and that combined inhibition of NO and PGs would have a minimal effect on this response. We measured forearm blood flow (Doppler ultrasound) and calculated vascular conductance 10 s before and for 30 s after a single 1-s dynamic forearm contraction at 10%, 20%, and 40% maximum voluntary contraction in 16 young adults. To inhibit K ϩ -mediated vasodilation, BaCl2 and ouabain were infused intraarterially to inhibit inwardly rectifying K ϩ channels and Na ϩ -K ϩ -ATPase, respectively. Combined enzymatic inhibition of NO and PG synthesis occurred via N G -monomethyl-L-arginine (L-NMMA; NO synthase) and ketorolac (cyclooxygenase), respectively. In protocol 1 (n ϭ 8), BaCl 2 ϩ ouabain reduced peak vasodilation (range: 30 -45%, P Ͻ 0.05) and total postcontraction vasodilation (area under the curve, ϳ55-75% from control) at all intensities. Contrary to our hypothesis, L-NMMA ϩ ketorolac had a further impact (peak: ϳ60% and area under the curve: ϳ80% from control). In protocol 2 (n ϭ 8), the order of inhibitors was reversed, and the findings were remarkably similar. We conclude that K ϩ -mediated hyperpolarization and NO and PGs, in combination, significantly contribute to contraction-induced rapid vasodilation and that inhibition of these signaling pathways nearly abolishes this phenomenon in humans.hyperemia; exercise; potassium THE REGULATION of skeletal muscle hyperemia during muscle contractions is complex and involves a variety of signals that control both the arteriovenous perfusion pressure gradient and arteriolar caliber (10, 13). In an attempt to isolate the local mechanisms underlying exercise hyperemia, early experiments used a single brief muscle contraction to allow for contractioninduced hyperemia without the continuous interruption of the blood flow response or further stimulus for hyperemia, as occurs with repeated contractions (16). In this regard, the single contraction model can serve as a tool to examine feedforward mechanisms of hyperemia that are largely independent of changes in tissue oxidative metabolism (48). The typical response is characterized by an intensity-dependent, rapid, monophasic increase in blood flow that occurs immediately (within one cardiac cycle) after contraction, achieves full magni...

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Cardiovascular Adaptations to Exercise Training

Hellsten

Nyberg

2015

Comprehensive Physiology

209

185

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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‐mediated vasodilatation occurs via activation of inwardly rectifying potassium channels in humans

Cited by 62 publications

References 38 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

Mechanisms of rapid vasodilation after a brief contraction in human skeletal muscle

Cardiovascular Adaptations to Exercise Training

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