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Dietary nitrate supplementation has been shown to reduce pulmonary O 2 uptake during submaximal exercise and enhance exercise performance. However, the effects of nitrate supplementation on local metabolic and haemodynamic regulation in contracting human skeletal muscle remain unclear. To address this, eight healthy young male sedentary subjects were assigned in a randomized, double-blind, crossover design to receive nitrate-rich beetroot juice (NO3, 9 mmol) and placebo (PLA) 2.5 h prior to the completion of a double-step knee-extensor exercise protocol that included a transition from unloaded to moderate-intensity exercise (MOD) followed immediately by a transition to intense exercise (HIGH). Compared with PLA, NO3 increased plasma levels of nitrate and nitrite. During MOD, leg V ̇ O 2 and leg blood flow (LBF) were reduced to a similar extent (∼9%-15%) in NO3. During HIGH, leg V ̇ O 2 was reduced by ∼6%-10% and LBF by ∼5%-9% (did not reach significance) in NO3. Leg V ̇ O 2 kinetics was markedly faster in the transition from passive to MOD compared with the transition from MOD to HIGH both in NO3 and PLA with no difference between PLA and NO3. In NO3, a reduction in nitrate and nitrite concentration was detected between arterial and venous samples. No difference in the time to exhaustion was observed between conditions. In conclusion, elevation of plasma nitrate and nitrate reduces leg skeletal muscle V ̇ O 2 and blood flow during exercise. However, nitrate supplementation does not enhance muscle V ̇ O 2 kinetics during exercise, nor does it improve time to exhaustion when exercising with a small muscle mass. KEY POINTS: Dietary nitrate supplementation has been shown to reduce systemic O 2 uptake during exercise and improve exercise performance. The effects of nitrate supplementation on local metabolism and blood flow regulation in contracting human skeletal muscle remain unclear. By using leg exercise engaging a small muscle mass, we show that O 2 uptake and blood flow are similarly reduced in contracting skeletal muscle of humans during exercise. Despite slower V ̇ O 2 kinetics in the transition from moderate to intense exercise, no effects of nitrate supplementation were observed for V ̇ O 2 kinetics and time to exhaustion. Nitrate and nitrite concentrations are reduced across the exercising leg, suggesting that these ions are extracted from the arterial blood by contracting skeletal muscle., (© 2021 The Authors. The Journal of Physiology © 2021 The Physiological Society.)

Key Points: Increased insulin action is an important component of the health benefits of exercise, but its regulation is complex and not fully elucidated. Previous studies of insulin-stimulated GLUT4 translocation to the skeletal muscle membrane found insufficient increases to explain the increases in glucose uptake. By determination of leg glucose uptake and interstitial muscle glucose concentration, insulin-induced muscle membrane permeability to glucose was calculated 4 h after one-legged knee-extensor exercise during a submaximal euglycaemic-hyperinsulinaemic clamp. It was found that during submaximal insulin stimulation, muscle membrane permeability to glucose in humans increases twice as much in previously exercised vs. rested muscle and outstrips the supply of glucose, which then becomes limiting for glucose uptake. This methodology can now be employed to determine muscle membrane permeability to glucose in people with diabetes, who have reduced insulin action, and in principle can also be used to determine membrane permeability to other substrates or metabolites., Abstract: Increased insulin action is an important component of the health benefits of exercise, but the regulation of insulin action in vivo is complex and not fully elucidated. Previously determined increases in skeletal muscle insulin-stimulated GLUT4 translocation are inconsistent and mostly cannot explain the increases in insulin action in humans. Here we used leg glucose uptake (LGU) and interstitial muscle glucose concentration to calculate insulin-induced muscle membrane permeability to glucose, a variable not previously possible to quantify in humans. Muscle membrane permeability to glucose, measured 4 h after one-legged knee-extensor exercise, increased ∼17-fold during a submaximal euglycaemic-hyperinsulinaemic clamp in rested muscle (R) and ∼36-fold in exercised muscle (EX). Femoral arterial infusion of N G -monomethyl l-arginine acetate or ATP decreased and increased, respectively, leg blood flow (LBF) in both legs but did not affect membrane glucose permeability. Decreasing LBF reduced interstitial glucose concentrations to ∼2 mM in the exercised but only to ∼3.5 mM in non-exercised muscle and abrogated the augmented effect of insulin on LGU in the EX leg. Increasing LBF by ATP infusion increased LGU in both legs with uptake higher in the EX leg. We conclude that it is possible to measure functional muscle membrane permeability to glucose in humans and it increases twice as much in exercised vs. rested muscle during submaximal insulin stimulation. We also show that muscle perfusion is an important regulator of muscle glucose uptake when membrane permeability to glucose is high and we show that the capillary wall can be a significant barrier for glucose transport., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

Key Points: Training with blood flow restriction (BFR) is a well-recognized strategy for promoting muscle hypertrophy and strength. However, its potential to enhance muscle function during sustained, intense exercise remains largely unexplored. In the present study, we report that interval training with BFR augments improvements in performance and reduces net K + release from contracting muscles during high-intensity exercise in active men. A better K + regulation after BFR-training is associated with an elevated blood flow to exercising muscles and altered muscle anti-oxidant function, as indicated by a higher reduced to oxidized glutathione (GSH:GSSG) ratio, compared to control, as well as an increased thigh net K + release during intense exercise with concomitant anti-oxidant infusion. Training with BFR also invoked fibre type-specific adaptations in the abundance of Na + ,K + -ATPase isoforms (α 1 , β 1 , phospholemman/FXYD1). Thus, BFR-training enhances performance and K + regulation during intense exercise, which may be a result of adaptations in anti-oxidant function, blood flow and Na + ,K + -ATPase-isoform abundance at the fibre-type level., Abstract: We examined whether blood flow restriction (BFR) augments training-induced improvements in K + regulation and performance during intense exercise in men, and also whether these adaptations are associated with an altered muscle anti-oxidant function, blood flow and/or with fibre type-dependent changes in Na + ,K + -ATPase-isoform abundance. Ten recreationally-active men (25 ± 4 years, 49.7 ± 5.3 mL kg -1  min -1 ) performed 6 weeks of interval cycling, where one leg trained without BFR (control; CON-leg) and the other trained with BFR (BFR-leg, pressure: ∼180 mmHg). Before and after training, femoral arterial and venous K + concentrations and artery blood flow were measured during single-leg knee-extensor exercise at 25% (Ex1) and 90% of thigh incremental peak power (Ex2) with i.v. infusion of N-acetylcysteine (NAC) or placebo (saline) and a resting muscle biopsy was collected. After training, performance increased more in BFR-leg (23%) than in CON-leg (12%, P < 0.05), whereas K + release during Ex2 was attenuated only from BFR-leg (P < 0.05). The muscle GSH:GSSG ratio at rest and blood flow during exercise was higher in BFR-leg than in CON-leg after training (P < 0.05). After training, NAC increased resting muscle GSH concentration and thigh net K + release during Ex2 only in BFR-leg (P < 0.05), whereas the abundance of Na + ,K + -ATPase-isoform α 1 in type II (51%), β 1 in type I (33%), and FXYD1 in type I (108%) and type II (60%) fibres was higher in BFR-leg than in CON-leg (P < 0.05). Thus, training with BFR elicited greater improvements in performance and reduced thigh K + release during intense exercise, which were associated with adaptations in muscle anti-oxidant function, blood flow and Na + ,K + -ATPase-isoform abundance at the fibre-type level., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

Key Points: Animal models have shown that beta 2 -adrenoceptor stimulation increases protein synthesis and attenuates breakdown processes in skeletal muscle. Thus, the beta 2 -adrenoceptor is a potential target in the treatment of disuse-, disease- and age-related muscle atrophy. In the present study, we show that a few days of oral treatment with the commonly prescribed beta 2 -adrenoceptor agonist, salbutamol, increased skeletal muscle protein synthesis and breakdown during the first 5 h after resistance exercise in young men. Salbutamol also counteracted a negative net protein balance in skeletal muscle after resistance exercise. Changes in protein turnover rates induced by salbutamol were associated with protein kinase A-signalling, activation of Akt2 and modulation of mRNA levels of growth-regulating proteins in skeletal muscle. These findings indicate that protein turnover rates can be augmented by beta 2 -adrenoceptor agonist treatment during recovery from resistance exercise in humans., Abstract: The effect of beta 2 -adrenoceptor stimulation on skeletal muscle protein turnover and intracellular signalling is insufficiently explored in humans, particularly in association with exercise. In a randomized, placebo-controlled, cross-over study investigating 12 trained men, the effects of beta 2 -agonist (6 × 4 mg oral salbutamol) on protein turnover rates, intracellular signalling and mRNA response in skeletal muscle were investigated 0.5-5 h after quadriceps resistance exercise. Each trial was preceded by a 4-day lead-in treatment period. Leg protein turnover rates were assessed by infusion of [ 13 C 6 ]-phenylalanine and sampling of arterial and venous blood, as well as vastus lateralis muscle biopsies 0.5 and 5 h after exercise. Furthermore, myofibrillar fractional synthesis rate, intracellular signalling and mRNA response were measured in muscle biopsies. The mean (95% confidence interval) myofibrillar fractional synthesis rate was higher for salbutamol than placebo [0.079 (95% CI, 0.064 to 0.093) vs. 0.066 (95% CI, 0.056 to 0.075%) × h -1 ] (P < 0.05). Mean net leg phenylalanine balance 0.5-5 h after exercise was higher for salbutamol than placebo [3.6 (95% CI, 1.0 to 6.2 nmol) × min -1  × 100 g Leg Lean Mass -1 ] (P < 0.01). Phosphorylation of Akt2, cAMP response element binding protein and PKA substrate 0.5 and 5 h after exercise, as well as phosphorylation of eEF2 5 h after exercise, was higher (P < 0.05) for salbutamol than placebo. Calpain-1, Forkhead box protein O1, myostatin and Smad3 mRNA content was higher (P < 0.01) for salbutamol than placebo 0.5 h after exercise, as well as Forkhead box protein O1 and myostatin mRNA content 5 h after exercise, whereas ActivinRIIB mRNA content was lower (P < 0.01) for salbutamol 5 h after exercise. These observations suggest that beta 2 -agonist increases protein turnover rates in skeletal muscle after resistance exercise in humans, with concomitant cAMP/PKA and Akt2 signalling, as well as modulation of mRNA response of growth-regulating proteins., (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)

Key Points: Exercise training effectively improves vascular and skeletal muscle function; however, these effects of training may be blunted in postmenopausal women as a result of the loss of oestrogens. Accordingly, the capacity to deliver oxygen to the active muscles may also be impaired in postmenopausal women. In both premenopausal and recent postmenopausal women, exercise training was shown to improve leg vascular and skeletal muscle mitochondrial function. Interestingly, these effects were more pronounced in postmenopausal women. Skeletal muscle oxygen supply and utilization were similar in the two groups of women. These findings suggest that the early postmenopausal phase is associated with an enhanced capacity of the leg vasculature and skeletal muscle mitochondria to adapt to exercise training and that the ability to deliver oxygen to match the demand of the active muscles is preserved in the early phase following the menopausal transition., Abstract: Exercise training leads to favourable adaptations within skeletal muscle; however, this effect of exercise training may be blunted in postmenopausal women as a result of the loss of oestrogens. Furthermore, postmenopausal women may have an impaired vascular response to acute exercise. We examined the haemodynamic response to acute exercise in matched pre- and postmenopausal women before and after 12 weeks of aerobic high intensity exercise training. Twenty premenopausal and 16 early postmenopausal (mean ± SEM: 3.1 ± 0.5 years after final menstrual period) women only separated by 4 years of age (mean ± SEM: 50 ± 0 years vs. 54 ± 1 years) were included. Before training, leg blood flow, O 2 delivery, O 2 uptake and lactate release during knee-extensor exercise were similar in pre- and postmenopausal women. Exercise training reduced (P < 0.05) leg blood flow, O 2 delivery, O 2 uptake, lactate release, blood pressure and heart rate during the same absolute workloads in postmenopausal women. These effects were not detected in premenopausal women. Quadriceps muscle protein contents of mitochondrial complex II, III and IV; endothelial nitric oxide synthase (eNOS); cyclooxygenase (COX)-1; COX-2; and oestrogen-related receptor α (ERRα) were increased (P < 0.05) with training in postmenopausal women, whereas only the levels of mitochondrial complex V, eNOS and COX-2 were increased (P < 0.05) in premenopausal women. These findings demonstrate that vascular and skeletal muscle mitochondrial adaptations to aerobic high intensity exercise training are more pronounced in recent post- compared to premenopausal women, possibly as an effect of enhanced ERRα signalling. Also, the hyperaemic response to acute exercise appears to be preserved in the early postmenopausal phase., (© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.)

The ability to sustain a given absolute submaximal workload declines with advancing age, likely to be due to a lower level of blood flow and O2 delivery to the exercising muscles. Given that physical inactivity mimics many of the physiological changes associated with ageing, separating the physiological consequences of ageing and physical inactivity can be challenging; yet, observations from cross-sectional and longitudinal studies on the effects of physical activity have provided some insight. Physical activity has the potential to offset the age-related decline in blood flow to contracting skeletal muscle during exercise where systemic blood flow is not limited by cardiac output, thereby improving O2 delivery and allowing for an enhanced energy production from oxidative metabolism. The mechanisms underlying the increase in blood flow with regular physical activity include improved endothelial function and the ability for functional sympatholysis - an attenuation of the vasoconstrictor effect of sympathetic nervous activity. These vascular adaptations with physical activity are likely to be an effect of improved nitric oxide and ATP signalling. Collectively, precise matching of blood flow and O2 delivery to meet the O2 demand of the active skeletal muscle of aged individuals during conditions where systemic blood flow is not limited by cardiac output seems to a large extent to be related to the level of physical activity., (© 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.)

Essential hypertension is linked to an increased sympathetic vasoconstrictor activity and reduced tissue perfusion. We investigated the role of exercise training on functional sympatholysis and postjunctional α-adrenergic responsiveness in individuals with essential hypertension. Leg haemodynamics were measured before and after 8 weeks of aerobic training (3-4 times per week) in eight hypertensive (47 ± 2 years) and eight normotensive untrained individuals (46 ± 1 years) during arterial tyramine infusion, arterial ATP infusion and/or one-legged knee extensions. Before training, exercise hyperaemia and leg vascular conductance (LVC) were lower in the hypertensive individuals (P < 0.05) and tyramine lowered exercise hyperaemia and LVC in both groups (P < 0.05). Training lowered blood pressure in the hypertensive individuals (P < 0.05) and exercise hyperaemia was similar to the normotensive individuals in the trained state. After training, tyramine did not reduce exercise hyperaemia or LVC in either group. When tyramine was infused at rest, the reduction in blood flow and LVC was similar between groups, but exercise training lowered the magnitude of the reduction in blood flow and LVC (P < 0.05). There was no difference in the vasodilatory response to infused ATP or in muscle P2Y2 receptor content between the groups before and after training. However, training lowered the vasodilatory response to ATP and increased skeletal muscle P2Y2 receptor content in both groups (P < 0.05). These results demonstrate that exercise training improves functional sympatholysis and reduces postjunctional α-adrenergic responsiveness in both normo- and hypertensive individuals. The ability for functional sympatholysis and the vasodilator and sympatholytic effect of intravascular ATP appear not to be altered in essential hypertension., (© 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.)

Ageing is thought to be associated with decreased vascular function partly due to oxidative stress. Resveratrol is a polyphenol, which in animal studies has been shown to decrease atherosclerosis, and improve cardiovascular health and physical capacity, in part through its effects on Sirtuin 1 signalling and through an improved antioxidant capacity. We tested the hypothesis that resveratrol supplementation enhances training-induced improvements in cardiovascular health parameters in aged men. Twenty-seven healthy physically inactive aged men (age: 65 ± 1 years; body mass index: 25.4 ± 0.7 kg m(-2); mean arterial pressure (MAP): 95.8 ± 2.2 mmHg; maximal oxygen uptake: 2488 ± 72 ml O2 min(-1)) were randomized into 8 weeks of either daily intake of either 250 mg trans-resveratrol (n = 14) or of placebo (n = 13) concomitant with high-intensity exercise training. Exercise training led to a 45% greater (P < 0.05) increase in maximal oxygen uptake in the placebo group than in the resveratrol group and to a decrease in MAP in the placebo group only (-4.8 ± 1.7 mmHg; P < 0.05). The interstitial level of vasodilator prostacyclin was lower in the resveratrol than in the placebo group after training (980 ± 90 vs. 1174 ± 121 pg ml(-1); P < 0.02) and muscle thromboxane synthase was higher in the resveratrol group after training (P < 0.05). Resveratrol administration also abolished the positive effects of exercise on low-density lipoprotein, total cholesterol/high-density lipoprotein ratio and triglyceride concentrations in blood (P < 0.05). Resveratrol did not alter the effect of exercise training on the atherosclerosis marker vascular cell adhesion molecule 1 (VCAM-1). Sirtuin 1 protein levels were not affected by resveratrol supplementation. These findings indicate that, whereas exercise training effectively improves several cardiovascular health parameters in aged men, concomitant resveratrol supplementation can blunt these effects.

During exercise, oxygen delivery to skeletal muscle is elevated to meet the increased oxygen demand. The increase in blood flow to skeletal muscle is achieved by vasodilators formed locally in the muscle tissue, either on the intraluminal or on the extraluminal side of the blood vessels. A number of vasodilators have been shown to bring about this increase in blood flow and, importantly, interactions between these compounds seem to be essential for the precise regulation of blood flow. Two compounds stand out as central in these vasodilator interactions: nitric oxide (NO) and prostacyclin. These two vasodilators are both stimulated by several compounds, e.g. adenosine, ATP, acetylcholine and bradykinin, and are affected by mechanically induced signals, such as shear stress. NO and prostacyclin have also been shown to interact in a redundant manner where one system can take over when formation of the other is compromised. Although numerous studies have examined the role of single and multiple pharmacological inhibition of different vasodilator systems, and important vasodilators and interactions have been identified, a large part of the exercise hyperaemic response remains unexplained. It is plausible that this remaining hyperaemia may be explained by cAMP- and cGMP-independent smooth muscle relaxation, such as effects of endothelial derived hyperpolarization factors (EDHFs) or through metabolic modulation of sympathetic effects. The nature and role of EDHF as well as potential novel mechanisms in muscle blood flow regulation remain to be further explored to fully elucidate the regulation of exercise hyperaemia.

Ageing is associated with an impaired ability to modulate sympathetic vasoconstrictor activity (functional sympatholysis) and a reduced exercise hyperaemia. The purpose of this study was to investigate whether a physically active lifestyle can offset the impaired functional sympatholysis and exercise hyperaemia in the leg and whether ATP signalling is altered by ageing and physical activity. Leg haemodynamics, interstitial [ATP] and P2Y(2) receptor content was determined in eight young (23 ± 1 years), eight lifelong sedentary elderly (66 ± 2 years) and eight lifelong active elderly (62 ± 2 years) men at rest and during one-legged knee extensions (12 W and 45% maximal workload (WL(max))) and arterial infusion of ACh and ATP with and without tyramine. The vasodilatory response to ACh was lowest in the sedentary elderly, higher in active elderly (P < 0.05) and highest in the young men (P < 0.05), whereas ATP-induced vasodilatation was lower in the sedentary elderly (P < 0.05). During exercise (12 W), leg blood flow, vascular conductance and VO2 was lower and leg lactate release higher in the sedentary elderly compared to the young (P < 0.05), whereas there was no difference between the active elderly and young. Interstitial [ATP] during exercise and P2Y(2) receptor content were higher in the active elderly compared to the sedentary elderly (P < 0.05). Tyramine infusion lowered resting vascular conductance in all groups, but only in the sedentary elderly during exercise (P < 0.05). Tyramine did not alter the vasodilator response to ATP infusion in any of the three groups. Plasma [noradrenaline] increased more during tyramine infusion in both elderly groups compared to young (P < 0.05). A lifelong physically active lifestyle can maintain an intact functional sympatholysis during exercise and vasodilator response to ATP despite a reduction in endothelial nitric oxide function. A physically active lifestyle increases interstitial ATP levels and skeletal muscle P2Y(2) receptor content.

Ageing has been proposed to be associated with increased levels of reactive oxygen species (ROS) that scavenge nitric oxide (NO). In eight young sedentary (23 ± 1 years; Y), eight older lifelong sedentary (66 ± 2 years; OS) and eight older lifelong physically active subjects (62 ± 2 years; OA), we studied the effect of ROS on systemic and skeletal muscle NO bioavailability and leg blood flow by infusion of the antioxidant N-acetylcysteine (NAC). Infusion of NAC increased the bioavailability of NO in OS, as evidenced by an increased concentration of stable metabolites of NO (NOx) in the arterial and venous circulation and in the muscle interstitium. In OA, infusion of NAC only increased NOx concentrations in venous plasma whereas in Y, infusion of NAC did not affect NOx concentrations. Skeletal muscle protein levels of endothelial and neuronal NO synthase were 32% and 24% higher, respectively, in OA than in OS. Exercise at 12 W elicited a lower leg blood flow response that was associated with a lower leg oxygen uptake in OS than in Y. The improved bioavailability of NO in OS did not increase blood flow during exercise. These data demonstrate that NO bioavailability is compromised in the systemic circulation and in the musculature of sedentary ageing humans due to increased oxidative stress. Lifelong physical activity opposes this effect within the trained musculature and in the arterial circulation. The lower blood flow response to leg exercise in ageing humans is not associated with a reduced NO bioavailability.

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.

Passive leg movement is associated with a ∼3-fold increase in blood flow to the leg but the underlying mechanisms remain unknown. The objective of the present study was to examine the role of nitric oxide (NO) for the hyperaemia observed during passive leg movement. Leg haemodynamics and metabolites of NO production (nitrite and nitrate; NOx) were measured in plasma and muscle interstitial fluid at rest and during passive leg movement with and without inhibition of NO formation in healthy young males. The hyperaemic response to passive leg movement and to ACh was also assessed in elderly subjects and patients with peripheral artery disease. Passive leg movement (60 r.p.m.) increased leg blood flow from 0.3 ± 0.1 to 0.9 ± 0.1 litre min(-1) at 20 s and 0.5 ± 0.1 litre min(-1) at 3 min (P < 0.05). Mean arterial pressure remained unchanged during the trial. When passive leg movement was performed during inhibition of NO formation (N(G)-mono-methyl-l-arginine; 29-52 mg min(-1)), leg blood flow and vascular conductance were increased after 20 s (P < 0.05) and then returned to baseline levels, despite an increase in arterial pressure (P < 0.05). Passive leg movement increased the femoral venous NOx levels from 35 ± 5 at baseline to 62 ± 11 μmol l(-1) during passive leg movement (P < 0.05), whereas muscle interstitial NOx levels remained unchanged. The hyperaemic response to passive leg movement were correlated with the vasodilatation induced by ACh (r(2) = 0.704, P < 0.001) and with age (r(2) = 0.612, P < 0.001). Leg blood flow did not increase during passive leg movement in individuals with peripheral arterial disease. These results suggest that the hypaeremia induced by passive leg movement is NO dependent and that the source of NO is likely to be the endothelium. Passive leg movement could therefore be used as a non-invasive tool to evaluate NO dependent endothelial function of the lower limb.

We examined the role of nitric oxide (NO) and prostanoids in the regulation of leg blood flow and systemic blood pressure before and after 8 weeks of aerobic high-intensity training in individuals with essential hypertension (n = 10) and matched healthy control subjects (n = 11). Hypertensive subjects were found to have a lower (P < 0.05) blood flow to the exercising leg than normotensive subjects (30 W: 2.92 ± 0.16 vs. 3.39 ± 0.37 l min(−1)). Despite the lower exercise hyperaemia, pharmacological inhibition of the NO and prostanoid systems reduced leg blood flow to a similar extent during exercise in the two groups and vascular relaxation to the NO-dependent vasodilator acetylcholine was also similar between groups. High-intensity aerobic training lowered (P < 0.05) resting systolic (∼9 mmHg) and diastolic (∼12 mmHg) blood pressure in subjects with essential hypertension, but this effect of training was abolished when the NO and prostanoid systems were inhibited. Skeletal muscle vascular endothelial NO synthase uncoupling, expression and phosphorylation status were similar in the two groups before and after training. These data demonstrate that a reduction in exercise hyperaemia in hypertensive subjects is not associated with a reduced capacity of the NO and prostanoid systems to induce vasodilatation or with altered acetylcholine-induced response. However, our data suggest that the observed reduction in blood pressure is related to a training-induced change in the tonic effect of NO and/or prostanoids on vascular tone.

Intraluminal ATP could play an important role in the local regulation of skeletal muscle blood flow, but the stimuli that cause ATP release and the levels of plasma ATP in vessels supplying and draining human skeletal muscle remain unclear. To gain insight into the mechanisms by which ATP is released into plasma, we measured plasma [ATP] with the intravascular microdialysis technique at rest and during dynamic exercise (normoxia and hypoxia), passive exercise, thigh compressions and arterial ATP, tyramine and ACh infusion in a total of 16 healthy young men. Femoral arterial and venous [ATP] values were 109 ± 34 and 147 ± 45 nmol l(−1) at rest and increased to 363 ± 83 and 560 ± 111 nmol l(−1), respectively, during exercise (P < 0.05), whereas these values did not increase when exercise was performed with the other leg. Hypoxia increased venous plasma [ATP] at rest compared to normoxia (P < 0.05), but not during exercise. Arterial ATP infusion (≤1.8 μmol min(−1) increased arterial plasma [ATP] from 74 ± 17 to 486 ± 82 nmol l(−1) (P < 0.05), whereas it remained unchanged in the femoral vein at ∼150 nmol l(−1). Both arterial and venous plasma [ATP] decreased during acetylcholine infusion (P < 0.05). Rhythmic thigh compressions increased arterial and venous plasma [ATP] compared to baseline conditions, whereas these values did not change during passive exercise or tyramine infusion. These results demonstrate that ATP is released locally into arterial and venous plasma during exercise and during hypoxia at rest. Compression of the vascular system could contribute to the increase during exercise whereas there appears to be little ATP release in response to increased blood flow, vascular stretch or sympathetic ATP release. Furthermore, the half-life of arterially infused ATP is <1 s.