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... 33,48,53], understanding the mechanism that controls muscle blood flow during exercise remains incomplete [see e.g. 48,54,55]. ...
... Undoubtedly, the discoveries of the endothelium-dependent regulation of vascular tone and blood perfusion, starting from PGI 2 and followed by NO [for a review see 75], constituted a milestone in our understanding of blood flow regulation. However, NO and PGI 2 release still cannot explain the magnitude of the exerciseinduced increase in muscle blood flow [49,54] nor coronary blood flow [36], and the role of ATP and other mediators has been proposed. ...
... This is why the knowledge concerning the mechanism controlling the blood flow in humans during exercise is still rather incomplete [see 37,76]. Nevertheless, in the present review we summarize the evidence of the role of NO, PGI 2 and ATP [49,54,64,79] in the regulation of blood flow and exercise capacity in humans. ...
In this review, we present the relation between power generation capabilities and pulmonary oxygen uptake during incremental cycling exercise in humans and the effect of exercise intensity on the oxygen cost of work. We also discuss the importance of oxygen delivery to the working muscles as a factor determining maximal oxygen uptake in humans. Subsequently, we outline the importance of coronary blood flow, myocardial oxygen uptake and myocardial metabolic stability for exercise tolerance. Finally, we describe mechanisms of endothelium-dependent regulation of coronary and skeletal muscle blood flow, dysregulation of which may impair exercise capacity and increase the cardiovascular risk of exercise.
Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. All rights reserved.
... It is widely known that NO is an important coronary and peripheral vasodilator during exercise 33 . However, in view of the available data, NO action alone could not explain the huge exercise-induced increase in skeletal muscles 34 and coronary blood flow 35 . There is growing body of evidence that exercise-induced PGI 2 might play an important role in regulation of coronary and muscle blood flow. ...
We assessed exercise performance, coronary blood flow and cardiac reserve of female ApoE/LDLR−/−
mice with advanced atherosclerosis compared with age-matched, wild-type C57BL6/J mice. Exercise
capacity was assessed as whole body maximal oxygen consumption (V’O2max), maximum running
velocity (vmax) and maximum distance (DISTmax) during treadmill exercise. Cardiac systolic and diastolic
function in basal conditions and in response to dobutamine (mimicking exercise-induced cardiac stress)
were assessed by Magnetic Resonance Imaging (MRI) in vivo. Function of coronary circulation was
assessed in isolated perfused hearts. In female ApoE/LDLR−/− mice V’O2max, vmax and DISTmax were not
impaired as compared with C57BL6/J mice. Cardiac function at rest and systolic and diastolic cardiac
reserve were also preserved in female ApoE/LDLR−/− mice as evidenced by preserved fractional area
change and similar fall in systolic and end diastolic area after dobutamine. Moreover, endotheliumdependent
responses of coronary circulation induced by bradykinin (Bk) and acetylcholine (ACh)
were preserved, while endothelium-independent responses induced by NO-donors were augmented
in female ApoE/LDLR−/− mice. Basal COX-2-dependent production of 6-keto-PGF1α was increased.
Concluding, we suggest that robust compensatory mechanisms in coronary circulation involving PGI2-
and NO-pathways may efficiently counterbalance coronary atherosclerosis-induced impairment in
V’O2max and exercise capacity.
... applies to ATP as well as to adenosine. Thus the main arguments in favor of ATP as a key mediator of skeletal muscle vasodilation during exercise are the magnitude of the flow it can evoke and also its ability to interfere with sympathetic vasoconstriction (403). However, many of the general concerns related to adenosine and exercise hyperemia also apply to ATP and ADP. ...
This review focuses on how blood flow to contracting skeletal muscles is regulated during exercise in humans. The idea is that blood flow to the contracting muscles links oxygen in the atmosphere with the contracting muscles where it is consumed. In this context, we take a top down approach and review the basics of oxygen consumption at rest and during exercise in humans, how these values change with training, and the systemic hemodynamic adaptations that support them. We highlight the very high muscle blood flow responses to exercise discovered in the 1980s. We also discuss the vasodilating factors in the contracting muscles responsible for these very high flows. Finally, the competition between demand for blood flow by contracting muscles and maximum systemic cardiac output is discussed as a potential challenge to blood pressure regulation during heavy large muscle mass or whole body exercise in humans. At this time, no one dominant dilator mechanism accounts for exercise hyperemia. Additionally, complex interactions between the sympathetic nervous system and the microcirculation facilitate high levels of systemic oxygen extraction and permit just enough sympathetic control of blood flow to contracting muscles to regulate blood pressure during large muscle mass exercise in humans.
Copyright © 2015 the American Physiological Society.
... Recently, we have shown that K ϩ -stimulated hyperpolarization of resistance vessels via the activation of inwardly rectifying potassium (K IR ) channels and Na ϩ -K ϩ -ATPase contributes to a large portion (ϳ50%) of the hyperemic response following a single muscle contraction in the human forearm and, combined with NO and PGs, accounts for nearly all (ϳ80%) of the immediate total vasodilator response (7). In addition, activation of K IR channels underlies the majority of ATP-mediated vasodilation (6), a substance proposed to be involved in vascular regulation during exercise in humans (21,32,46). Lastly, inhibition of K IR channels significantly reduces the immediate peak reactive hyperemic response to temporary muscle ischemia and combined inhibition of K IR channels and Na ϩ -K ϩ -ATPase nearly abolishes the total [area under the curve (AUC)] response (12). ...
We tested the hypothesis that activation of inwardly-rectifying potassium (KIR) channels and Na(+)/K(+)-ATPase, two pathways that lead to hyperpolarization of vascular cells, contributes to both the onset and steady-state hyperemic response to exercise. We also determined whether after inhibiting these pathways, nitric oxide (NO) and prostaglandins (PGs) are involved in the hyperemic response. Forearm blood flow (FBF; Doppler ultrasound) was determined during rhythmic handgrip exercise at 10% maximal voluntary contraction for 5 minutes in the following conditions: control (saline; T1); combined inhibition of KIR channels and Na(+)/K(+)-ATPase alone [via barium chloride (BaCl2) and ouabain, respectively; T2]; and with additional combined nitric oxide synthase (L-NMMA) and cyclooxygenase inhibition (ketorolac; T3). In T2, the total hyperemic responses were attenuated ~50% from control (P<0.05) at exercise onset, and there was minimal further effect in T3 (Protocol 1; n=11). In Protocol 2 (n=8), steady-state FBF was significantly reduced during T2 vs T1 (133±15 vs 167±17 ml/min; Δ from control: -20±3%; P<0.05), and further reduced during T3 (120±15 ml/min; -29±3%; P<0.05 vs T2). In Protocol 3 (n=8), BaCl2 alone reduced FBF during onset (~50%) and steady-state exercise (~30%) as observed in Protocols 1 and 2, respectively, and addition of ouabain had no further impact. Our data implicate activation of KIR channels as a novel contributing pathway to exercise hyperemia in humans.
New findings:
• What is the central question of this study? This study investigated the effect of an elevated baseline blood flow, via either high-dose intra-arterial infusion of adenosine or adenosine triphosphate, on the rapid onset vasodilatory response to a single forearm muscle contraction. • What is the main finding and its importance? The peak response to a single contraction is unaffected by augmented baseline blood flow, and thus is likely due to a feedforward vasodilatory mechanism.
Abstract:
The hyperemic responses to single muscle contractions are proportional to exercise intensity, which in turn is proportional to tissue metabolic demand. Hence, we tested the hypotheses that the rapid onset vasodilatory response post single muscle contraction would be unaffected when baseline blood flow was increased via infusion of either high-dose intra-arterial infusion of adenosine (ADO) or adenosine triphosphate (ATP). Twenty-four healthy young participants (28 ± 1 years) performed a single forearm contraction (20% MVC) at minute 75 of a continuous infusion of ADO (n = 6), ATP (n = 8), or saline (control, n = 10). Brachial artery diameter and blood velocity were measured using Doppler ultrasound. Resting forearm vascular conductance (FVC; ml·min-1 ·100 mmHg-1 ·dl FAV-1 ) was significantly higher during ADO (33 ± 7) and ATP (33 ± 6) compared to control (7 ± 1, p < 0.05). Peak FVC post-contraction during ADO and ATP were significantly greater than control (p < 0.05), but not different from one another. Peak ∆FVC from baseline was similar in all three conditions (control: 14 ± 1, ADO: 24 ± 2, ATP: 23 ± 6; p = 0.15). Total FVC (area under the curve) did not significantly differ between ADO and ATP (333 ± 69 and 440 ± 125); however, ATP total FVC was significantly greater compared to control (150 ± 19, p < 0.05). We conclude that the peak response to a single contraction is unaffected by augmented baseline blood flow, and thus is likely due to a feedforward vasodilatory mechanism. This article is protected by copyright. All rights reserved.
Through oxygen-dependent release of the vasodilator ATP, the mobile erythrocyte plays a fundamental role in matching microvascular oxygen supply with local tissue oxygen demand. Signal transduction within the erythrocyte and microves- sels as well as feedback mechanisms controlling ATP release have been described. Our understanding of the impact of this novel control mechanism will rely on the integration of in vivo experiments and computational models. ©, 2009 Int. Union Physiol. Sci./Am. Physiol. Soc.
Key points
ATP is a substance in the blood vessels that can cause vasodilatation and increase blood flow and oxygen delivery in humans.
The exact signalling pathways that ATP stimulates to cause vasodilatation are not well known.
We show that a large portion of ATP‐mediated vasodilatation occurs through the activation of inwardly rectifying potassium channels (K ir ).
Our results lend insight into the vasodilator mechanisms of ATP, a substance that is important for vascular control.
Further, our results may stimulate additional investigations in humans regarding the activation of K ir channels and subsequent vascular hyperpolarization during other physiologically relevant conditions.
Abstract Circulating ATP possesses unique vasomotor properties in humans and has been hypothesized to play a role in vascular control under a variety of physiological conditions. However, the primary downstream signalling mechanisms underlying ATP‐mediated vasodilatation remain unclear. The purpose of the present experiment was to determine whether ATP‐mediated vasodilatation is independent of nitric oxide (NO) and prostaglandin (PG) synthesis and occurs primarily via the activation of Na ⁺ /K ⁺ ‐ATPase and inwardly rectifying potassium (K IR ) channels in humans. In all protocols, young healthy adults were studied and forearm vascular conductance (FVC) was calculated from forearm blood flow (measured via venous occlusion plethysmography) and intra‐arterial blood pressure to quantify local vasodilatation. Vasodilator responses (%ΔFVC) during intra‐arterial ATP infusions were unchanged following combined inhibition of NO and PGs ( n = 8; P > 0.05) whereas the responses to KCl were greater ( P < 0.05). Combined infusion of ouabain (to inhibit Na ⁺ /K ⁺ ‐ATPase) and barium chloride (BaCl 2 ; to inhibit K IR channels) abolished KCl‐mediated vasodilatation ( n = 6; %ΔFVC = 134 ± 13 vs. 4 ± 5%; P < 0.05), demonstrating effective blockade of direct vascular hyperpolarization. The vasodilator responses to three different doses of ATP were inhibited on average 56 ± 5% ( n = 16) following combined ouabain plus BaCl 2 infusion. In follow‐up studies, BaCl 2 alone inhibited the vasodilator responses to ATP on average 51 ± 3% ( n = 6), which was not different than that observed for combined ouabain plus BaCl 2 administration. Our novel results indicate that the primary mechanism of ATP‐mediated vasodilatation is vascular hyperpolarization via activation of K IR channels. These observations translate in vitro findings to humans in vivo and may help explain the unique vasomotor properties of intravascular ATP in the human circulation.
Abstract The regulation of blood flow to skeletal muscle involves a complex interaction between several locally formed vasodilators that are produced both in the skeletal muscle interstitium and intravascularly. The gas nitric oxide (NO) and the purines ATP and adenosine, are potent vasodilators that are formed by multiple cell types and released into the skeletal muscle interstitium and in plasma in response to muscle contraction. Cellular sources of ATP and NO in plasma are erythrocytes and endothelial cells, whereas interstitial sources are skeletal muscle cells and endothelial cells. Adenosine originates primarily from extracellular degradation of ATP. During exercise the concentrations of ATP and adenosine increase markedly in the interstitium with smaller increases occurring in plasma, and thus the interstitial concentration during exercise is severalfold higher than in plasma. The concentration of NO metabolites (NOx) in interstitium and plasma does not change during exercise and is similar in the two compartments. Adenosine and NO have been shown to contribute to exercise hyperaemia whereas the role of ATP remains unclear due to lack of specific purinergic receptor blockers. The relative role of intravascular versus interstitial vasodilators is not known but evidence suggests that both compartments are important. In cardiovascular disease, a reduced capacity to form adenosine in the muscle interstitium may be a contributing factor in increased peripheral vascular resistance.
Potassium (K(+)) released from contracting skeletal muscle is considered a vasodilatory agent. This concept is mainly based on experiments infusing non-physiological doses of K(+). The aim of the present study was to investigate the role of K(+) in blood flow regulation.
We measured leg blood flow (LBF) and arterio-venous (A-V) O(2) difference in 13 subjects while infusing K(+) into the femoral artery at a rate of 0.2, 0.4, 0.6 and 0.8 mmol min(-1).
The lowest dose increased the calculated femoral artery plasma K(+) concentration by approx.1 mmol L(-1). Graded K(+) infusions increased LBF from 0.39 +/- 0.06 to 0.56 +/- 0.13, 0.58 +/- 0.17, 0.61 +/- 0.11 and 0.71 +/- 0.17 L min(-1), respectively, whereas the leg A-V O(2) difference decreased from 74 +/- 9 to 60 +/- 12, 52 +/- 11, 53 +/- 9 and 45 +/- 7 mL L(-1), respectively (P < 0.05). Mean arterial pressure was unchanged, indicating that the increase in LBF was associated with vasodilatation. The effect of K(+) was totally inhibited by infusion (27 micromol min(-1)) of Ba(2+), an inhibitor of Kir2.1 channels. Simultaneous infusion of ATP and K(+) evoked an increase in LBF equalled to the sum of their effects.
Physiological infusions of K(+) induce significant increases in resting LBF, which are completely blunted by inhibition of the Kir2.1 channels. The present findings in resting skeletal muscle suggest that K(+) released from contracting muscle might be involved in exercise hyperaemia. However, the magnitude of increase in LBF observed with K(+) infusion suggests that K(+) only accounts for a limited fraction of the hyperaemic response to exercise.
Forearm vascular responses to intra-arterial infusions of endothelium-dependent and -independent vasodilators have been thoroughly characterized in humans. While the forearm is a well-established experimental model for studying human vascular function, it is of limited consequence to systemic cardiovascular control owing to its small muscle mass and blood flow requirements. In the present study we determined whether these responses could be generalized to the leg. Based upon blood pressure differences between the leg and arm during upright posture, we hypothesized that the responsiveness to endothelium-dependent vasodilators would be greater in the forearm than the leg. Brachial and femoral artery blood flow (Q, ultrasound Doppler) at rest and during intra-arterial infusions of endothelium-dependent (acetylcholine and substance P) and -independent (sodium nitroprusside) vasodilators were measured in eight healthy men (22-27 years old). Resting blood flows in the forearm before infusion of acetylcholine, substance P or sodium nitroprusside were 25 +/- 4, 30 +/- 7 and 29 +/- 5 ml min(-1), respectively, and in the leg were 370 +/- 32, 409 +/- 62 and 330 +/- 30 ml min(-1), respectively. At the highest infusion rate of acetylcholine (16 microg (100 ml tissue)(-1) min(-1)) there was a greater (P < 0.05) increase in Q to the forearm (1864 +/- 476%) than to the leg (569 +/- 86%). Similarly, at the highest infusion rate of substance P (125 pg (100 ml tissue)(-1) min(-1)) there was a greater (P < 0.05) increase in Q to the forearm (911 +/- 286%) than to the leg (243 +/- 58%). The responses to sodium nitroprusside (1 microg (100 ml tissue)(-1) min(-1)) were also greater (P < 0.05) in the forearm (925 +/- 164%) than in the leg (326 +/- 65%). These data indicate that vascular responses to both endothelium-dependent and -independent vasodilator agents are blunted in the leg compared to the forearm.
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