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Lifelong physical activity preserves functional sympatholysis and purinergic signalling in the ageing human leg

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Abstract

Ageing is associated with an impaired ability to modulate sympathetic vasoconstrictor activity (functional sympatholysis) and a reduced exercise hypaeremia. 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 signaling is altered by ageing and physical activity. Leg haemodynamics, intersitial [ATP] and P2Y2 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 (WLmax)) 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 vasodilation 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 P2Y2 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 physical active lifestyle can maintain an intact functional sympatholysis during exercise and vasodilator response to ATP despite a reduction in endothelial nitriic oxide function. A physical active lifestyle increases interstitial ATP levels and skeletal muscle P2Y2 receptor content.

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... The importance of this matching between O 2 supply and utilization is further underscored by the great degree of redundancy that exists between vasodilator systems regulating skeletal muscle blood flow that allows for preservation of blood flow in conditions where one or more vasoactive systems may be compromised (Hellsten and Nyberg, 2015;Joyner and Casey, 2015). At moderate intensity, there even appears to be hyperperfusion of the exercising knee-extensors as a pharmacologically induced reduction in leg blood flow and O 2 delivery of~10%-25% is compensated by increased O 2 extraction so that skeletal muscle O 2 utilization is maintained (Nyberg et al., 2010;Mortensen et al., 2012b;Nyberg et al., 2015a). ...
... Interestingly, when blood flow was increased through arterial ATP infusion during intense exercise, O 2 uptake was found to be reduced after 30 s and until predetermined exercise termination at 4 min (Nyberg et al., 2014). This observation may relate to the capacity of intravascular ATP to override sympathetic vasoconstrictor activity (Rosenmeier et al., 2004;Mortensen et al., 2012b). During exercise, sympathetic activity reduces perfusion of inactive muscles whereas this effect is blunted in contracting muscle (termed functional sympatholysis), thus directing blood flow away from areas of lower metabolic activity and toward areas of higher metabolic demand (Remensnyder et al., 1962;Saltin and Mortensen, 2012). ...
... These initial observations suggest that skeletal muscle O 2 delivery is not limiting for O 2 utilisation in the initial phase of low-and moderate-intensity exercise engaging only the kneeextensors. Skeletal muscle vascular conductance, blood flow, and O 2 delivery have been reported to be lower in older individuals during steady state knee-extensor exercise, which may be a consequence of impaired endothelial function, functional sympatholysis, cGMP signalling and/or endothelin A mediated vasoconstriction (Donato et al., 2006;Mortensen et al., 2012b;Nyberg et al., 2012;Barrett-O'Keefe et al., 2015;Nyberg et al., 2015b). To what extent the attenuation in O 2 delivery has consequences for the rate of O 2 utilisation is currently unclear. ...
Article
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Skeletal muscle is one of the most dynamic metabolic organs as evidenced by increases in metabolic rate of >150-fold from rest to maximal contractile activity. Because of limited intracellular stores of ATP, activation of metabolic pathways is required to maintain the necessary rates of ATP re-synthesis during sustained contractions. During the very early phase, phosphocreatine hydrolysis and anaerobic glycolysis prevails but as activity extends beyond ∼1 min, oxidative phosphorylation becomes the major ATP-generating pathway. Oxidative metabolism of macronutrients is highly dependent on the cardiovascular system to deliver O2 to the contracting muscle fibres, which is ensured through a tight coupling between skeletal muscle O2 utilization and O2 delivery. However, to what extent O2 delivery is ideal in terms of enabling optimal metabolic and contractile function is context-dependent and determined by a complex interaction of several regulatory systems. The first part of the review focuses on local and systemic mechanisms involved in the regulation of O2 delivery and how integration of these influences the matching of skeletal muscle O2 demand and O2 delivery. In the second part, alterations in cardiovascular function and structure associated with aging and heart failure, and how these impact metabolic and contractile function, will be addressed. Where applicable, the potential of exercise training to offset/reverse age- and disease-related cardiovascular declines will be highlighted in the context of skeletal muscle metabolic function. The review focuses on human data but also covers animal observations.
... 2,3 A lifelong sedentary lifestyle has been shown to be associated with reduced vascular responsiveness to intravascular ATP in skeletal muscle; however, this reduction is not present in lifelong physically active subjects. 6 To what extent a period of exercise training can reverse a potential age-related dysregulation of plasma and interstitial ATP signaling in skeletal muscle remains unknown. ...
... (µmol/L) 6 ...
... In line with this effect of training on interstitial ATP levels, lifelong physical activity has been shown to be associated with increased levels of ATP in the interstitium of contracting skeletal muscle. 6 It cannot be excluded that the enhanced levels of interstitial ATP after training in the older group could influence the parallel lower plasma levels, as intravascular and interstitial ATP share common pathways in that their vasodilatory effect is mediated via NO and prostanoid formation. 18,19 It is noteworthy that findings in the human forearm differ from our observations in the leg in that they show an agerelated attenuation in venous plasma ATP levels during exercise 8 as well as an unaltered vascular response to arterial ATP infusion. ...
Article
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The study examined the effect of 8 weeks of exercise training on ATP signalling in human skeletal muscle of 15 young (25±1 years) and 15 older (72±1 years) recreationally active male subjects. Before training, femoral venous plasma [ATP] was higher (P<0.05) during low‐intensity knee‐extensor exercise in the older than the young group. During moderate intensity exercise, phosphodiesterase‐5 (PDE5) inhibition (to increase cGMP signalling) led to a greater increase (P<0.05) in plasma [ATP] in the older group. The vasodilator response to arterial ATP infusion was lower (P<0.05) in the older group. After training, plasma [ATP] was similar in the two groups during exercise at both workloads and PDE5 inhibition did not change plasma [ATP] in either group. The vasodilator response to ATP infusion was enhanced with exercise training in the older group only. These findings provide novel evidence for altered regulation of plasma [ATP] during moderate intensity knee‐extensor exercise in aging which can be reversed by exercise training. The observed effect of PDE5 inhibition suggests that altered cGMP signalling may be one underlying mechanism. Lastly, exercise training can reverse the age‐related reduction in the vasodilator response to intravascular ATP. This article is protected by copyright. All rights reserved.
... The ability of contracting skeletal muscle to attenuate sympathetic vasoconstriction during exercise, so-called functional sympatholysis, is well documented. [1][2][3][4] However, in older human subjects, functional sympatholysis has been found to be impaired, [4][5][6] potentially contributing to the reduced skeletal muscle perfusion observed in aging muscles. 7,8 Interestingly, recent studies have provided evidence for that functional sympatholysis to a large extent may be related to the training status of the skeletal muscle. ...
... The ability of contracting skeletal muscle to attenuate sympathetic vasoconstriction during exercise, so-called functional sympatholysis, is well documented. [1][2][3][4] However, in older human subjects, functional sympatholysis has been found to be impaired, [4][5][6] potentially contributing to the reduced skeletal muscle perfusion observed in aging muscles. 7,8 Interestingly, recent studies have provided evidence for that functional sympatholysis to a large extent may be related to the training status of the skeletal muscle. ...
... 7,8 Interestingly, recent studies have provided evidence for that functional sympatholysis to a large extent may be related to the training status of the skeletal muscle. 4,[9][10][11][12] This indicates that the impaired functional sympatholysis in elderly is caused primarily by lack of physical activity over a long time rather than aging per se. 7 The effect of a period of exercise training on functional sympatholysis has not been investigated in older men. ...
Article
Full-text available
The ability of contracting skeletal muscle to attenuate sympathetic vasoconstriction during exercise, termed functional sympatholysis, can be improved by exercise training. However, to what extent age affects functional sympatholysis is unclear. Thus, the current study examined the effect of 8 weeks of high-intensity exercise training on α-adrenergic responsiveness at rest and on functional sympatholysis in a group of young (n=15; 25 ± 1 years) and older (n=15; 72 ± 1 years) habitually active, healthy male subjects. Before and after the exercise training, all subjects participated in an experimental day in which leg hemodynamics and venous plasma norepinephrine were assessed at rest and during knee-extensor exercise without and with tyramine infusion. The results of the study show that before exercise training, the young and older subjects had similar α-adrenergic responsiveness at rest and similar incomplete functional sympatholysis during knee-extensor exercise. Exercise training resulted in a reduction in α-adrenergic responsiveness at rest in both groups, whereas functional sympatholysis was improved in the young group only. The improvement in functional sympatholysis in the young but not the older subjects despite a reduced α-adrenergic responsiveness at rest suggest that improving sympatholytic capacity by training may be a slower process in aged than in young.
... The age-related haemodynamic responses are less consistent among men, possibly, at least in part, due to a positive modulatory influence of fitness level that is observed in older men but not in older women (Parker et al. 2010). While peak and/or submaximal blood flow and vascular conductance responses appear to be reduced in both sedentary or chronically endurance-trained older men compared with activity-matched young counterparts during graded cycling (Beere et al. 1999;Poole et al. 2003;Proctor et al. 1998), graded single leg knee extensor exercise Mortensen et al. 2012) and graded handgrip exercise (Casey and Joyner 2012); in contrast, normally active older men have displayed a preservation in peak and submaximal blood flow and vascular conductance responses during graded cycling (Proctor et al. 2003b), graded single leg knee extension (Parker et al. 2008) as well as graded handgrip exercise (Donato et al. 2006;Jasperse et al. 1994;Limberg et al. 2012). It should be noted that in the study by Donato et al. (2006) the normally active older men who showed similar FBF and FVC responses to young men during handgrip exercise also demonstrated an attenuation in femoral artery LBF and LVC responses during knee extension exercise in contrast with findings by Parker et al. (Parker et al. 2008); thus, indicating that ageing induces limb specific alterations in blood flow regulation during exercise at least in men (Donato et al. 2006). ...
... In fact, using a similar study design to that employed in the present study, albeit employing the dynamic single knee extension exercise mode, Parker et al. (2008) reported preserved or even slightly augmented peak LBF and LVC responses and larger slopes of the hyperaemic and vasodilatory responses expressed at absolute workloads (W) in older compared with young men (Parker et al. 2008). In contrast, in much more sedentary male cohorts LBF and LVC responses have been shown to be attenuated due to ageing during cycling Beere et al. 1999) and knee-extension exercise Mortensen et al. 2012), and FBF and FVC during handgrip exercise (Casey and Joyner 2012). Attenuated LBF and LVC responses were also observed in chronically endurance trained older participants during graded cycling (Proctor et al. 1998). ...
... Studies that reported attenuated limb blood flow and vascular conductance responses in ageing have attributed them to blunted nitric oxide signalling responses (Casey et al. 2015), reductions in plasma ATP and erythrocytemediated ATP release (Mortensen et al. 2012;Kirby et al. 2012), blunted functional sympatholysis (Casey and Joyner 2012) or impaired endothelial-dependent vasodilation (Kirby et al. 2009). However, it should be noted that in these studies participants were sedentary to moderately active, and apart from the study by Mortensen et al. (2012) (which employed the knee-extension exercise model in men) used the handgrip exercise model in mixed groups of men and women and employed relative exercise intensities (i.e. based on % MVC) where MVC responses were always larger (between ~ 6 and ~ 25%) in young participants. ...
Article
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PurposeAge-related exercising leg blood flow (LBF) responses during dynamic knee-extension exercise and forearm blood flow responses during handgrip exercise are preserved in normally active men but attenuated in activity-matched women. We explored whether these age- and sex-specific effects are also apparent during isometric calf plantar-flexion incremental exercise. Methods Normally active young men (YM, n = 15, 24 ± 2 years), young women (YW, n = 8, 22 ± 1 years), older men (OM, n = 13, 70 ± 7 years) and older women (OW, n = 10, 64 ± 7 years) were tested. LBF was measured between contractions using venous occlusion plethysmography. ResultsPeak force obtained was higher (P < 0.05) in men compared with women and in young compared with older individuals. However, peak LBF (YM; 971 ± 328 ml min−1, OM; 985 ± 504 ml min−1, YW; 844 ± 366 ml min−1, OW; 960 ± 244 ml min−1) and peak leg vascular conductance [LVC = LBF/(MAP + hydrostatic pressure)] responses (YM; 6.0 ± 1.8 ml min−1 mmHg−1, OM; 5.5 ± 2.8 ml min−1 mmHg−1, YW; 5.3 ± 2.1 ml min−1 mmHg−1, OW; 5.5 ± 1.6 ml min−1 mmHg−1) were similar among the four groups. Furthermore, the hyperaemic (YM; 8.8 ± 3.7 ml min−1 %Fpeak−1 OM; 8.3 ± 5.4 ml min−1 %Fpeak−1, YW; 8.2 ± 3.5 ml min−1 %Fpeak−1, OW; 9.6 ± 2.2 ml min−1 %Fpeak−1) and vasodilatory responses (YM; 0.053 ± 0.020 ml min−1 mmHg−1 %Fpeak−1, OM; 0.048 ± 0.028 ml min−1 mmHg−1 %Fpeak−1, YW; 0.051 ± 0.019 ml min−1 mmHg−1 %Fpeak−1, OW; 0.055 ± 0.014 ml min−1 mmHg−1 %Fpeak−1) were not different among the four groups. These results were accompanied by similar resting LBF responses among groups and were not affected when data were normalised to estimated leg muscle mass. Conclusions Our results demonstrate that exercising LBF responses during isometric incremental calf muscle exercise are preserved in older men and women, suggesting that the previously observed age-related attenuations in leg and forearm hyperaemia among women may be muscle-group specific.
... A meta-analysis was conducted for body fat% for studies that made direct comparisons with master endurance athletes (Fig. 2); this allowed for the greatest number of within-study comparisons to be incorporated into the statistical analysis. Twenty-nine studies (Aagaard et al., 2007;Arbab-Zadeh et al., 2004;Ari et al., 2004;Bjork et al., 2012;Buford et al., 2010;Buyukyazi, 2004;Carrick-Ranson et al., 2014b;Cristea et al., 2008;DubÉ et al., 2016;Hawkins et al., 2001;Hayes et al., 2015;Katzel et al., 1998;Korhonen et al., 2006;Korhonen et al., 2012;Marcell et al., 2003;Marcell et al., 2014;Matelot et al., 2016;Mortensen et al., 2012;Nyberg et al., 2012;Ojanen et al., 2007;Pollock et al., 2015;Proctor and Joyner, 1997;Sallinen et al., 2008;Sanada et al., 2009;Schmidt et al., 2015;Tarpenning et al., 2004a;Trappe et al., 2013;Witkowski et al., 2010;Yataco et al., 1997) reported data for body fat percentage measured using bioelectrical impedance, DXA, hydrostatic weighing or multiple-site skinfold. Thirty study groups included master endurance athletes (19.7 ± 3.8%, n = 594), 11 study groups included master strength/power athletes (16.4 ± 4.4%, n = 136), 19 study groups older control (24.5 ± 4.6%, n = 361), 5 study groups included young endurance trained (15.4 ± 5.2%, n = 63), 2 study groups included young strength/power trained individuals (14.1 ± 3.5%, n = 42) and 8 study groups included young controls (17.4 ± 3.0%, n = 126). ...
... A meta-analysis was conducted for VO 2max for studies that made direct comparisons with master endurance athletes (Fig. 3); this allowed for the greatest number of within-study comparisons to be incorporated into the statistical analysis. VO 2max was measured in 43 studies (Aagaard et al., 2007;Anselme et al., 1994;Arbab-Zadeh et al., 2004;Ari et al., 2004;Bhella et al., 2014;Bjork et al., 2012;Buford et al., 2010;Buyukyazi, 2004;Carrick-Ranson et al., 2014b;DubÉ et al., 2016;Franzoni et al., 2005;Galetta et al., 2005;Galetta et al., 2006;Hawkins et al., 2001;Hayes et al., 2015;Katzel et al., 1998;Katzel et al., 2001;Mackey et al., 2014;Marcell et al., 2003;Marcell et al., 2014;Matelot et al., 2016;Mikkelsen et al., 2013;Molmen et al., 2012;Mortensen et al., 2012;Mucci et al., 1999;Nyberg et al., 2012;Ojanen et al., 2007;Pollock et al., 2015;Prasad et al., 2007;Prefaut et al., 1994;Proctor and Joyner, 1997;Rivier et al., 1994;Sanada et al., 2009;Schmidt et al., 2015;Shibata and Levine, 2012;Sundstrup et al., 2010;Suominen and Rahkila, 1991;Tarpenning et al., 2004a;Thomas et al., 2013;Trappe et al., 2013;Witkowski et al., 2010;Yataco et al., 1997) using treadmill or cycle/rowing ergometer protocols. All studies reported the data relative to bodyweight (ml kg −1 min −1 ). ...
... training intensity and volume) (Eskurza et al., 2002;Fitzgerald et al., 1997), which may underpin the accelerated rate of decline in VO 2max observed (Eskurza et al., 2002;Tanaka et al., 1997). However, the studies included in the current review highlighted no observable difference in training frequency (Aagaard et al., 2007;Bhella et al., 2014;Buyukyazi, 2004 2016; Franzoni et al., 2005;Galetta et al., 2005;Galetta et al., 2006;Korhonen et al., 2006;Korhonen et al., 2012;Larsson et al., 1997;Marcell et al., 2003;Marcell et al., 2014;Molmen et al., 2012;Ojanen et al., 2007;Power et al., 2010b;Sallinen et al., 2008;Sanada et al., 2009;Sipila and Suominen, 1991;Sundstrup et al., 2010;Witkowski et al., 2010;Yataco et al., 1997;Zampieri et al., 2015), distance (Arbab-Zadeh et al., 2004;Couppe et al., 2014;Hawkins et al., 2001;Mackey et al., 2014;Marcell et al., 2003;Marcell et al., 2014;Mikkelsen et al., 2013;Power et al., 2010b;Shibata and Levine, 2012;Stenroth et al., 2016;Suominen and Rahkila, 1991;Tarpenning et al., 2004a;Thomas et al., 2013;Witkowski et al., 2010) and session duration (Ari et al., 2004;Bjork et al., 2012;Buford et al., 2010;Buyukyazi, 2004;Carrick-Ranson et al., 2014b;Couppe et al., 2014;Korhonen et al., 2006;Korhonen et al., 2012;Matelot et al., 2016;Mortensen et al., 2012;Mosole et al., 2014;Mucci et al., 1999;Nyberg et al., 2012;Proctor and Joyner, 1997;Rantalainen et al., 2014;Rivier et al., 1994;Sanada et al., 2009;Schmidt et al., 2015;Stenroth et al., 2016;Suominen and Rahkila, 1991;Trappe et al., 2013;Zampieri et al., 2015) between younger and older endurance athletes; although alterations to training intensity cannot be excluded as none were reported. VO 2max values included in this meta-analysis were ∼32% lower in master endurance athletes (42 ± 6.6 ml kg −1 min −1 ) than young endurance trained individuals (62.0 ± 5.4 ml kg −1 min −1 ), which is supported by recent research demonstrating an inescapable reduction in VO 2max in master endurance athletes, despite continuous levels of endurance exercise training (Everman et al., 2018). ...
Article
Introduction: The extent to which chronic exercise training preserves age-related decrements in physical function, muscle strength, mass and morphology is unclear. Our aim was to conduct a systematic review of the literature to determine to what extent chronically trained master athletes (strength/power and endurance) preserve levels of physical function, muscle strength, muscle mass and morphology in older age, compared with older and younger controls and young trained individuals. Methods: The systematic data search included Medline, EMBASE, SPORTDiscus, CINAHL and Web of Science databases. Inclusion criteria: i) master athletes mean exercise training duration ≥20 years ii) master athletes mean age of cohort >59 years) iii) at least one measurement of muscle mass/volume/fibre-type morphology and/or strength/physical function. Results: Fifty-five eligible studies were identified. Meta-analyses were carried out on maximal aerobic capacity, maximal voluntary contraction and body composition. Master endurance athletes (42.0 ± 6.6 ml kg-1 min-1) exhibited VO2max values comparable with young healthy controls (43.1 ± 6.8 ml kg-1 min-1, P = 0.84), greater than older controls (27.1 ± 4.3 ml.kg-1 min-1, P < 0.01) and master strength/power athletes (26.5 ± 2.3 ml.kg-1.min-1, P < 0.01), and lower than young endurance trained individuals (60.0 ± 5.4 ml kg-1 min-1, P < 0.01). Master strength/power athletes (0.60 (0.28 to 0.93) P < 0.01) and young controls (0.71 (0.06 to 1.36) P < 0.05) were significantly stronger compared with the other groups. Body fat % was greater in master endurance athletes than young endurance trained (-4.44% (-8.44 to -0.43) P < 0.05) but lower compared with older controls (7.11% (5.70 to 8.52) P < 0.01). Conclusion: Despite advancing age, this review suggests that chronic exercise training preserves physical function, muscular strength and body fat levels similar to that of young, healthy individuals in an exercise mode-specific manner.
... Measurements of ATP in the muscle interstitium have revealed inconsistent findings. In aged men, ATP levels have been reported to be higher in life-long trained compared to sedentary men (295) whereas in hypertensive individuals reduced interstitial ATP levels were observed after training (161). Moreover, in young healthy men, a period of immobilization by casting of one leg was shown to reduce the exercise-induced increase in inerstitial ATP levels (292). ...
... In inactive tissues, the increase in sympathetic drive causes vasoconstriction (32,368). However, in young healthy individuals the vasoconstrictor effect of an increase in sympathetic nervous activity, induced by lower body negative pressure (162,447), or by an increase in norepinephrine release from sympathetic nervous endings induced by tyramine infusion (292,295,314,364,437), can be attenuated or even abolished in skeletal muscle during contraction. This phenomenon, termed functional sympatholysis (351), is thought to allow adequate perfusion and oxygen delivery to the contracting fibers (379). ...
... Importantly, blood flow and oxygen delivery is of paramount importance for skeletal muscle performance, and the observation that similar sympathetic stimulation elicited a comparable constrictor response during contractions in the trained and untrained animals indicates that the augmented functional sympatholysis may have served to counteract the increased sympathetic responsiveness. Conversely, human data have provided evidence for that the vasoconstrictor response to a similar release of norepinephrine from sympathetic nerve endings with infusion of tyramine during contractions is attenuated with exercise training (293,295). Furthermore, NO has been shown to mediate functional sympatholysis in rat skeletal muscle (431) and NO has been suggested to play an important role in modulating sympathetic vasoconstriction in the microcirculation of human contracting forearm muscle (59,382). However, infusion of a NO donor does not blunt sympathetic vasoconstriction in the forearm of young men (363) and increasing NO availability in older men with impaired functional sympatholysis does not increase leg exercise hyperemia (295,314). ...
Article
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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. (C) 2016 American Physiological Society.
... The decline in exercise blood flow with aging is presumably due to an imbalance between local vasodilator and vasoconstrictor signaling, elevated sympathetic vasoconstrictive tone, as well as an impaired ability to blunt sympathetic vasoconstriction within the contracting muscle (12, 13, 20 -22, 42). Conversely, lifelong physical activity (27) as well as exercise interventions (26) appear to preserve the ability to blunt sympathetic vasoconstrictive tone (functional sympatholysis) in the leg of older adults and maintain sufficient oxygen delivery in older adults (38,50). However, it should be noted that the documented benefits of lifelong physical activity or chronic exercise training on the regulation of muscle blood flow during exercise may be sex specific. ...
... Previous evidence from our laboratory demonstrates that age-related impairments in contraction-induced ROV in the arm are in part due to a reduction in NO bioavailability or signaling, as well as an increase in sympathetic vasoconstriction (7,9). In this context, evidence from habitually exercising older adults indicates that lifelong exercise training preserves both NO signaling (28,46) as well as functional sympatholysis within the leg vasculature in older individuals (27). Therefore it is plausible that the mechanisms by which chronic exercise training offsets age-related attenuation of ROV in older adults are similar to those observed under steady-state conditions during submaximal dynamic exercise. ...
Article
Aging is associated with attenuated contraction-induced rapid onset vasodilation (ROV). We sought to examine whether chronic exercise training would improve ROV in older adults. Additionally, we examined whether a relationship between cardiorespiratory fitness and ROV exists in young and older adults. Chronically exercise trained older adults (n=16; 66±2yr) performed single muscle contractions in the forearm and leg at various intensities. Brachial and femoral artery diameter and blood velocity were measured using Doppler ultrasound. Vascular conductance (VC) was calculated as the quotient of blood flow (ml·min(-1)) and mean arterial pressure (mmHg). These data were compared with our previously published work from an identical protocol in 16 older untrained (66±1yr) and 14 young (23±1yr) adults. Peak (ΔVCpeak) and total vasodilator (VCtotal) responses were greater in trained compared to untrained older adults across leg exercise intensities (P<0.05). There were no differences in responses between trained older and young adults in the arm or leg at any exercise intensity (P>0.05). Comparison of ΔVCpeakin a subset of subjects at an absolute workload in the leg revealed that trained older adults exhibited augmented responses relative to untrained older adults. Exercise capacity (VO2peak) was associated with ΔVCpeakand VCtotall across arm (r=0.59-0.64) and leg exercise intensities (r=0.55-0.68; P<0.05) in older adults. Our data demonstrate that 1) chronic exercise training improves ROV in the arm and leg of trained older adults, such that age-related differences in ROV are abolished; and 2) VO2peak is associated with ΔVCpeakresponses in both limbs of older adults.
... Moreover, in young individuals the increased sympathetic vasoconstrictor activity that occurs with exercise is counteracted (a phenomenon known as functional 'sympatholysis') to redistribute blood flow to contracting muscles [82]. By contrast, older adults have a reduced vasodilatory capacity and an impaired functional sympatholysis during exercise, which might compromise O 2 supply and reduce V O 2max [83]. It has been recently reported that the impaired vasodilatory capacity and functional sympatholysis observed in the older people might be due, at least partly, to a reduction in the deformability of red blood cells, which is associated with an impaired release of ATP-a vasoactive molecule that stimulates vasodilatationin response to hemoglobin deoxygenation [84]. ...
... Shibata et al. [92] recently reported in individuals aged > 60 years that those who had trained ≥ 4 to 5 sessions/week at high intensities during the last > 25 yearsbut not those who had trained less-had a lower central arterial stiffness than their inactive counterparts, although lower training doses (2-3 sessions/week) were enough to observe benefits in carotid artery stiffness and central blood pressure [92]. Moreover, Mortensen et al. [83] showed that lifelong endurance exercise (> 5 h of training per week during the last 30 years in individuals aged ~ 66 years) preserved functional sympatholysis and attenuated the age-related deterioration in endothelial function and vasodilatory capacity, which could result in an improved blood flow and O 2 supply to working muscles. Groot et al. [93] observed that older adults (mean age of 71-72 years) who performed more than either 30 or 60 min/day of moderate-vigorous PA, respectively, had a preserved vasodilatory capacity compared with their sedentary age-matched controls. ...
Article
Maximum oxygen consumption (VO2max) is not only an indicator of endurance performance, but also a strong predictor of cardiovascular disease and mortality. This physiological parameter is known to decrease with aging. In turn, physical exercise might attenuate the rate of aging-related decline in VO2max, which in light of the global population aging is of major clinical relevance, especially at advanced ages. In this narrative review, we summarize the evidence available from masters athletes about the role of lifelong endurance exercise on aging-related VO2max decline, with examples of the highest VO2max values reported in the scientific literature for athletes across different ages (e.g., 35 ml·kg-1·min-1 in a centenarian cyclist). These data suggest that a linear decrease in VO2max might be possible if physical exercise loads are kept consistently high through the entire life span, with VO2max values remaining higher than those of the general population across all ages. We also summarize the main physiological changes that occur with inactive aging at different system levels-pulmonary and cardiovascular function, blood O2 carrying capacity, skeletal muscle capillary density and oxidative capacity-and negatively influence VO2max, and review how lifelong exercise can attenuate or even prevent most-but apparently not all (e.g., maximum heart rate decline)-of them. In summary, although aging seems to be invariably associated with a progressive decline in VO2max, maintaining high levels of physical exercise along the life span slows the multi-systemic deterioration that is commonly observed in inactive individuals, thereby attenuating age-related VO2max decline.
... Equally recognized is the central role of exercise in the treatment of a vast number of chronic diseases (Pedersen and Saltin 2015). Some of the recent data on the cardiovascular effects of lifelong exercise training show remarkable preservation of cardiac and vascular function (Mortensen et al. 2012;Nyberg et al. 2013;Steding-Ehrenborg et al. 2015;Maessen et al. 2017). Advances have been made in further identifying specific and redundant pathways for muscle vasodilation during exercise (Joyner and Casey 2014). ...
Article
This perspective document summarizes discussions held at the CSEP Annual Meeting in Winnipeg on October 27, 2017 when an expert panel was assembled to discuss the key questions and challenges for future research in cardiovascular exercise physiology. We were inspired by the example of the late Dr. Mike Sharratt, an accomplished and impactful Professor in the Faculty of Kinesiology at the University of Waterloo. Dr. Sharratt had a unique ability to bring experts together and translate theory into action, with a central goal of optimizing the health benefits of exercise, particularly in the fields of cardiac rehabilitation and aging (University of Waterloo Applied Health Science Dept., 2016).
... Elevated hydrogen peroxide (H2O2) in ECs activates K ϩ channels in the plasma membrane, thereby increasing K ϩ efflux and attenuating the spread of hyperpolarization and reducing CVD and AVD (as depicted in Fig. 1C) early studies of human subjects during cycling exercise (109) and have remained an active area of investigation (24,43,45). A recent study found that lifelong physical activity preserves functional sympatholysis in older individuals compared with those having a sedentary lifestyle (61). Thus regular exercise may help maintain exercise capacity by promoting functional hyperemia throughout the life span. ...
Article
Effective oxygen delivery to active muscle fibers requires that vasodilation initiated in distal arterioles, which control flow distribution and capillary perfusion, ascends the resistance network into proximal arterioles and feed arteries, which govern total blood flow into the muscle. With exercise onset, ascending vasodilation reflects initiation and conduction of hyperpolarization along endothelium from arterioles into feed arteries. Electrical coupling of endothelial cells to smooth muscle cells evokes the rapid component of ascending vasodilation, which is sustained by ensuing release of nitric oxide during elevated luminal shear stress. Concomitant sympathetic neural activation inhibits ascending vasodilation by stimulating α-adrenoreceptors on smooth muscle cells to constrict the resistance vasculature. We hypothesized that compromised muscle blood flow during advanced age reflects impaired ascending vasodilation through actions on both cell layers of the resistance network. In the gluteus maximus muscle of old (24 months) vs. young (4 months) male mice (corresponding to mid-60s vs. early 20s in humans), inhibiting α-adrenoreceptors in old mice restored ascending vasodilation while even minimal activation of α-adrenoreceptors in young mice attenuated ascending vasodilation in the manner seen with aging. Conduction of hyperpolarization along the endothelium is impaired in old vs. young mice due to "leaky" membranes resulting from the activation of potassium channels by hydrogen peroxide released from endothelial cells. Exposing the endothelium of young mice to hydrogen peroxide recapitulates this effect of aging. Thus, enhanced α-adrenoreceptor activation of smooth muscle in concert with electrically leaky endothelium restricts muscle blood flow by impairing ascending vasodilation during advanced age.
... Regarding locally formed vasodilators, there is an age-related decline in both endothelial and prostanoid system function [64,65]. The effect of decreased/declined endothelial function translates into a lower nitric oxide (NO) synthesis and availability. ...
Article
In the ageing muscle, many changes occur. Some are on an architectural level, like alterations in muscle composition, or modifications in the characteristics of the muscle fiber itself, where muscle fiber length, orientation and type change. Other changes are neuronal, which occur on all levels, from the central activation over the spinal properties down to the level of the motor unit and the neuromuscular junction. There are also hormonal factors that undergo agerelated concentration variations. All these alterations in the muscle have an effect on both strength and function. In this matter, they contribute to the process of sarcopenia. Although many different components are identified, it is still unclear to what degree these components contribute to the loss of muscle mass, strength and function. This review summarizes the occurring physiological and anatomical changes within the ageing muscle and links them to outcomes such as strength and function.
... We observed lower blood flow in the older men during exercise, this is very likely due to an age-related decline in regulatory pathways of vasodilatation by e.g. reduced endotheliumdependent vasodilation (nitric oxide) (Taddei et al., 2001), increased endothelin-1 activity (Donato et al., 2009), and/or overactive sympathetic vasoconstriction (Mortensen et al., 2012). Furthermore, we observed an age-related difference in leg O 2 uptake during the exercise bout with the young men having higher leg VO 2 . ...
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Key points: This study aimed to provide molecular insight into the differential effects of age and physical inactivity on the regulation of substrate metabolism during moderate-intensity exercise. Using the arteriovenous balance technique, we studied the effect of immobilization of one leg for 2 weeks on leg substrate utilization in young and older men during two-legged dynamic knee-extensor moderate-intensity exercise, as well as changes in key proteins in muscle metabolism before and after exercise. Age and immobilization did not affect relative carbohydrate and fat utilization during exercise, but the older men had higher uptake of exogenous fatty acids, whereas the young men relied more on endogenous fatty acids during exercise. Using a combined whole-leg and molecular approach, we provide evidence that both age and physical inactivity result in intramuscular lipid accumulation, but this occurs only in part through the same mechanisms. Abstract: Age and inactivity have been associated with intramuscular triglyceride (IMTG) accumulation. Here, we attempt to disentangle these factors by studying the effect of 2 weeks of unilateral leg immobilization on substrate utilization across the legs during moderate-intensity exercise in young (n = 17; 23 ± 1 years old) and older men (n = 15; 68 ± 1 years old), while the contralateral leg served as the control. After immobilization, the participants performed two-legged isolated knee-extensor exercise at 20 ± 1 W (∼50% maximal work capacity) for 45 min with catheters inserted in the brachial artery and both femoral veins. Biopsy samples obtained from vastus lateralis muscles of both legs before and after exercise were used for analysis of substrates, protein content and enzyme activities. During exercise, leg substrate utilization (respiratory quotient) did not differ between groups or legs. Leg fatty acid uptake was greater in older than in young men, and although young men demonstrated net leg glycerol release during exercise, older men showed net glycerol uptake. At baseline, IMTG, muscle pyruvate dehydrogenase complex activity and the protein content of adipose triglyceride lipase, acetyl-CoA carboxylase 2 and AMP-activated protein kinase (AMPK)γ3 were higher in young than in older men. Furthermore, adipose triglyceride lipase, plasma membrane-associated fatty acid binding protein and AMPKγ3 subunit protein contents were lower and IMTG was higher in the immobilized than the contralateral leg in young and older men. Thus, immobilization and age did not affect substrate choice (respiratory quotient) during moderate exercise, but the whole-leg and molecular differences in fatty acid mobilization could explain the age- and immobilization-induced IMTG accumulation.
... In addition, epinephrine release in response to physical activity may modulate the sympathetic vasoconstrictor activity by enhancing vasodilator response, thus maintaining optimal tissue oxygen delivery in the brain [38]. There is increasing evidence that the serotonergic system is severely affected by the pathology of Alzheimer's disease. ...
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Behavioral and psychological symptoms of dementia (BPSD), also known as neuropsychiatric or non-cognitive symptoms are common and often distressing features of Alzheimer's Dementia. BPSD significantly increase patient suffering, early institutionalization and caregiver's burden. The clinical management of BPSD is dominated by a pharmacological approach, although these medications often come with serious adverse side-effects. There are only few non-pharmacological treatment strategies for BPSD. A substantial amount of intervention studies that have investigated non-pharmacological treatment options for BPSD have focused on physical exercise. Although these studies are very heterogeneous in terms of type and severity of dementia, as well as type and duration of the exercise intervention, the overall picture shows a positive effect of physical exercise in alleviating BPSD. There is evidence that numerous mechanisms contribute to the positive effect of physical exercise on BPSD. No attempt has been undertaken so far to give an overview of the existing knowledge regarding these mechanisms. Therefore, the current review aims to integrate the existing evidence on psychological and neurobiological mechanisms that contribute to the beneficial effects of physical exercise in ameliorating BPSD in Alzheimer's dementia. A discussion of psychological mechanisms such as improved sleep and stress reduction will be followed by a discussion of neurobiological mechanisms including the exercise induced change in neurotransmitter concentrations, increased synthesis of neurotrophins and immune activation. The review closes with recommendations for future research to overcome the shortcomings of existing studies and broaden the current knowledge on the positive effects of physical exercise on BPSD.
... Aerobic exercise training improves endothelial function (1,28) and functional sympatholysis (20). In addition, Mortensen et al. (21) reported that functional sympatholysis was preserved in physically active older individuals. A decrease in vasoconstriction due to endothelial function lowers blood pressure via reduction of vascular resistance. ...
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Since aerobic exercise (e.g., walking) and resistance exercise (e.g., lifting objects and mopping) are both parts of activities of daily living, an exaggerated elevation in systolic blood pressure (SBP) during aerobic and resistance exercise is an early marker of cardiovascular disease. This study investigated the effects of habitual exercise on SBP during low-intensity resistance exercise using both cross-sectional and interventional approaches. First, in 57 normotensive women (61.9±1.0 years of age) daily physical activity level as assessed by triaxial accelerometry was correlated with SBP during resistance exercise at 20% and 40% of the one-repetition maximum (r=-0.408 and r=-0.348, respectively). Maximal oxygen uptake was correlated with SBP during exercise at 20% (r=-0.385) and 40% (r=-0.457). Physical activity level or maximal oxygen uptake was identified as a predictor of SBP during the exercise in stepwise regression analysis, independent of SBP at rest and other factors (R(2)=0.729 to 0.781). Second, 66 men and women (64.6±0.9 years of age) participated in a 6-week intervention as a part of the training (walking, 4.3±0.3 d/wk, 55.6±4.1 min/d, 70.7±1.2% of maximal heart rate) or control group. SBP during resistance exercise in the training group decreased after the intervention (before vs. after: 20%, 143±4 vs. 128±4 mmHg; and 40%, 148±5 vs. 134±4 mmHg). In the control group, there were no significant differences in SBP before and after the intervention. SBP during resistance exercise after the intervention was lower in the training group relative to the control group. These results suggest that habitual exercise decreases SBP during low-intensity resistance exercise.
... 9 Moreover, exercise training can preserve functional sympatholysis with aging by improving blood flow distribution within the active muscle associated with increased aerobic metabolism. 23 However, none of the studies to our knowledge have compared the response of acute isometric exercise on muscle vasodilation between sedentary and physically active older adults. Curiously, in this study, baseline resting muscle blood flow of active older adults showed no difference when compared to sedentary older adults. ...
Article
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The objective of this study was to evaluate cardiac autonomic control and muscle vasodilation response during isometric exercise in sedentary and physically active older adults. Twenty healthy participants, 10 sedentary and 10 physically active older adults, were evaluated and paired by gender, age, and body mass index. Sympathetic and parasympathetic cardiac activity (spectral and symbolic heart rate analysis) and muscle blood flow (venous occlusion plethysmography) were measured for 10 minutes at rest (baseline) and during 3 minutes of isometric handgrip exercise at 30% of the maximum voluntary contraction (sympathetic excit-atory maneuver). Variables were analyzed at baseline and during 3 minutes of isometric exercise. Cardiac autonomic parameters were analyzed by Wilcoxon and Mann–Whitney tests. Muscle vasodilatory response was analyzed by repeated-measures analysis of variance followed by Tukey's post hoc test. Sedentary older adults had higher cardiac sympathetic activity compared to physically active older adult subjects at baseline (63.13±3.31 vs 50.45±3.55 nu, P=0.02). The variance (heart rate variability index) was increased in active older adults (1,438.64±448.90 vs 1,402.92±385.14 ms, P=0.02), and cardiac sympathetic activity (symbolic analysis) was increased in sedentary older adults (5,660.91±1,626.72 vs 4,381.35±1,852.87, P=0.03) during isometric handgrip exercise. Sedentary older adults showed higher cardiac sympathetic activity (spectral analysis) (71.29±4.40 vs 58.30±3.50 nu, P=0.03) and lower parasympathetic modulation (28.79±4.37 vs 41.77±3.47 nu, P=0.03) compared to physically active older adult subjects during isometric handgrip exercise. Regarding muscle vasodilation response, there was an increase in the skeletal muscle blood flow in the second (4.1±0.5 vs 3.7±0.4 mL/min per 100 mL, P=0.01) and third minute (4.4±0.4 vs 3.9±0.3 mL/min per 100 mL, P=0.03) of handgrip exercise in active older adults. The results indicate that regular physical activity improves neurovascular control of muscle blood flow and cardiac autonomic response during isometric handgrip exercise in healthy older adult subjects.
... Moreover, few substances that act as selective agonists and/or antagonists in relation to the ATP receptors have been identified, which contributes to the lack of information. One function may be an involvement in brain plasticity and nociception because the damaged tissues release ATP, which has reparatory, nociceptive effects, as a consequence of the intensification of LTP and the activation of myelin-free afferent nerve endings, which comprise P2X receptors [34]. ...
Article
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The proteolysis of the extracellular matrix as a key role in the synaptic neuroplasticity of the CNS, which results in learning and memory. Proteases from the serine family and metaloproteinases of the extracellular matrix are localized within the synapses and are released into the extracellular space in proportion to the degree of neuronal excitation. These enzymes cause changes in the morphology, shape and size, and the overall number of synapses and synthesize new synaptic connections. The proteinase also change the function of receptors, and consequently, the secretion of neurotransmitter/neuromodulator from the presynaptic glutamatergic and/or purinergic elements are either strongthend or weakened. Neuroglia involved in homeostasis, melanin synthesis and defense of the brain contain different combinations of purinergic receptors, which contribute to many neurotransmitters. This review summarizes a concepts of brain plasticity, the role of ATP and P2 receptors interaction with glutamatergic system during plasticity of the brain in the one handand after physical exercise in the other, which may be triggering phenomena facilitative synaptic plasticity as well as potentiates an personal efficiency to react to biobehavioral adaptation and disorders. Key words: glutamatergic/purinergic system, neuroplasticity, physical exercise, neuroglia dependences
... However, aerobic training improves endothelial function 34,35) and increases functional sympatholysis 17) . In addition, Mortensen et al. reported that functional sympatholysis is preserved in physically active older individuals 36) . In our preliminary study, plasma concentrations of NO end products (NOx) were inversely correlated with SBP during aerobic and resistance exercise (unpublished data). ...
Article
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Blood pressure increases transiently during exercise in proportion to exercise intensity as a response to the increased demand for blood flow to the muscles. However, in addition to exercise intensity, many factors, including age and arterial stiffness, affect blood pressure during exercise. Aerobic exercises such as walking and cycling and resistance exercises such as lifting objects and climbing stairs are part of daily life activities. Therefore, exaggerated blood pressure responses to exercise increase the risk of cardiovascular disease. In this paper, the effects of habitual exercise on blood pressure during aerobic and resistance exercise are reviewed.
... Thus, exercising skeletal muscle reduces the influence of sympathetic nervous system for attenuating local vasoconstriction. Molecular adaptations provoked by exercise training are implicated in functional sympatholysis, and may also help recovering lost function [85,86]. Hypertensive men show attenuated functional sympatholysis during exercise and exaggerated sympathetic vasoconstriction [87]. ...
Article
It was initially assumed that heart rate and arterial blood pressure were modulated by normal respiration and muscle contraction. The arterial baroreflex, an inverse relationship between blood pressure and heart rate, was later reported. Nonetheless, it was then assumed that those responses involved vagal modulation. We summarize available evidence on the modulation of heart rate by acute or chronic aerobic exercise as well as its potential implications on BP control. Numerous studies have tried to clarify whether aerobic exercise modifies neurally-mediated vasoconstriction, but they report contradictory results. In view of these incongruities, the aim of this narrative review is to summarize available evidence on the modulation of heart rate by acute or chronic aerobic exercise as well as its potential implications on blood pressure control. We mainly focus on the effects of aerobic exercise in both heart rate and blood pressure. Heart rate and heart rate variability have been indistinctly considered similar metrics, but they have completely different meanings when properly used. Both are risk markers in cardiac disease, whereas heart rate variability is also an index of sympathovagal modulation of heart rate. On the other hand, heart rate recovery has been also used as an index for mirroring both cardiovascular fitness and autonomic function, and can be used as a measure of vagal reactivation. Importantly, it is now well-known that a reduced rate of heart rate recovery represents a powerful predictor of overall mortality. In this review, due to its complexity, we have included studies in which any of these three parameters have been analyzed.
... Other known positive effects of exercise training on vascular function include an improved ability for functional sympatholysis 94,99 and reduced endothelin levels, 100 but there is a paucity of evidence for the effect of training on these functions in post-menopausal women or in corresponding animal models. However, in a cross-sectional study on sedentary and habitually active post-menopausal women, functional sympatholysis during mild-to-moderate intensity forearm exercise was greater in the habitually active women. ...
... Importantly, ATP is a potent modulator of endothelium-dependent vasodilation in human skin (Wingo et al., 2010;Fujii et al., 2015;Lang et al., 2017), a response that is attenuated in chronic health conditions such as type II diabetes (Fujii et al., 2018a). Although ATP remains a potent vasodilator in healthy older adults, the influence of ageing on ATP-induced vasodilation in conduit arteries and human skin vessels is mixed, with studies showing attenuated or negligible effects (Kirby et al., 2010;Mortensen et al., 2012;Fujii et al., 2018b), or an augmented response relative to young adults . Regardless, the underlying mechanisms that modulate ATP-induced cutaneous vasodilation in healthy older adults remain poorly understood. ...
Article
Objective To examine the contributions of calcium-activated K⁺ (KCa) channels and nitric oxide synthase (NOS) to adenosine triphosphate (ATP)-induced cutaneous vasodilation in healthy older adults. Methods In eleven older adults (69 ± 2 years, 5 females), cutaneous vascular conductance, normalized to maximum vasodilation (%CVCmax) was assessed at four dorsal forearm skin sites that were continuously perfused with either 1) lactated Ringer solution (Control), 2) 50 mM tetraethylammonium (TEA, KCa channel blocker), 3) 10 mM Nω-nitro-L-arginine (L-NNA, NOS inhibitor), or 4) combined 50 mM TEA +10 mM L-NNA, via microdialysis. Local skin temperature was fixed at 33 °C at all sites with local heaters throughout the protocol while the cutaneous vasodilator response was assessed during coadministration of ATP (0.03, 0.3, 3, 30, 300 mM; 20 min per dose), followed by 50 mM sodium nitroprusside and local skin heating to 43 °C to achieve maximum vasodilation (20–30 min). Results Blockade of KCa channels blunted %CVCmax relative to Control from 0.3 to 300 mM ATP (All P < 0.05). A similar response was observed for the combined KCa channel blockade and NOS inhibition site from 3 to 300 mM ATP (All P < 0.05). Conversely, NOS inhibition alone did not influence %CVCmax across all ATP doses (All P > 0.05). Conclusion In healthy older adults, KCa channels play an important role in modulating ATP-induced cutaneous vasodilation, while the NOS contribution to this response is negligible.
... The authors thus concluded that when comparing groups with differing exercise capacities, differences in exercise-induced inhibition of α 1 -adrenergic vasoconstriction between young and old (males) may therefore not be as pronounced as previously reported. However, in contrast to the findings by Wray et al. (2009), Mortensen et al. (2012), using a similar experimental design, demonstrated that both relative and absolute work intensities are similarly effective at modulating functional sympatholysis in the legs of young and older men. In light of these observations we revealed that under exercise conditions using the same absolute mechanical work (i.e. 7 kg) PE-induced sympathetic vasoconstriction occurred to a greater extent in PMW than in YW. ...
Article
Key points: Contraction-mediated blunting of postjunctional α-adrenergic vasoconstriction (functional sympatholysis) is attenuated in skeletal muscle of ageing males, brought on by altered postjunctional α1 - and α2 -adrenergic receptor sensitivity. The extent to which postjunctional α-adrenergic vasoconstriction occurs in the forearms at rest and during exercise in postmenopausal women remains unknown. The novel findings indicate that contraction-mediated blunting of α1 - (via intra-arterial infusion of phenylephrine) but not α2 -adrenergic (via intra-arterial infusion of dexmedetomidine) vasoconstriction was attenuated in postmenopausal women compared to young women. Additional important findings revealed that postjunctional α-adrenergic vasoconstrictor responsiveness at rest does not appear to be affected by age in women. Collectively, these results contribute to our understanding of local neurovascular control at rest and during exercise with age in women. Abstract: Contraction-mediated blunting of postjunctional α-adrenergic vasoconstriction (functional sympatholysis) is attenuated in older males; however, direct confirmation of this effect remains unknown in postmenopausal women (PMW). The present study examined whether PMW exhibit augmented postjunctional α-adrenergic receptor vasoconstriction at rest and during forearm exercise compared to young women (YW). Eight YW (24 ± 1 years) and eight PMW (65 ± 1 years) completed a series of randomized experimental trials: (1) at rest, (2) under high flow (adenosine infusion) conditions and (3) during 6 min of forearm exercise at relative (20% of maximum) and absolute (7 kg) intensities. Phenylephrine (α1 -agonist) or dexmedetomidine (α2 -agonist) was administered during the last 3 min of each trial to elicit α-adrenergic vasoconstriction. Forearm vascular conductance (FVC) was calculated from blood flow and blood pressure. Vasoconstrictor responsiveness was identified as the change in FVC (%) during α-adrenergic agonist infusions from baseline (resting trial) or from steady-state conditions (high flow and exercise trials). During resting and high flow trials, the %FVC during α1 - and α2 -agonist stimulation was similar between YW and PMW. During exercise, α1 -mediated vasoconstriction was blunted in YW vs. PMW at relative (-6 ± 2% vs. -15 ± 3%) and absolute (-4 ± 2% vs. -14 ± 5%) workloads, such that blood flow and FVC were lower in PMW (P < 0.05 for all). Conversely, α2 -mediated vasoconstriction was similar between YW and PMW at relative (-22 ± 3% vs. -22 ± 4%; P > 0.05) and absolute (-19 ± 3% vs. -18 ± 4%; P > 0.05) workloads. Collectively, these findings demonstrate that despite similar α-adrenergic vasoconstrictor responsiveness at rest, PMW have a decreased ability to attenuate α1 -adrenergic vasoconstriction in contracting skeletal muscle.
... Exercise hyperemia is dependent upon the activity of vasoactive substances acting "locally" in the vascular beds supplying active skeletal muscle to cause vasodilation and oppose the systemic, vasoconstrictive stimulus of sympathetic nervous system in a process termed 'functional sympatholysis.' [31] Key vasoactive molecules produced either by the active skeletal muscle and/or the vascular endothelium that help increase blood flow to active muscle during exercise include adenosine, ATP, potassium ions, prostacyclin and NO [32]. The bioactivity of many of these vasodilators during exercise has been shown to be reduced with aging [33][34][35], which, in turn, likely contributes to a decrease in exercise hyperemia [36] and reduced functional sympatholysis characterized by a relative increase in sympathetically-mediated vasoconstriction of vascular beds supplying active skeletal muscle in older relative to young adults [37,38]. ...
Article
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Aging is associated with a decline in physiological function and exercise performance. These effects are mediated, at least in part, by an age-related decrease in the bioavailability of nitric oxide (NO), a ubiquitous gasotransmitter and regulator of myriad physiological processes. The decrease in NO bioavailability with aging is especially apparent in sedentary individuals, whereas older, physically active individuals maintain higher levels of NO with advancing age. Strategies which enhance NO bioavailability (including nutritional supplementation) have been proposed as a potential means of reducing the age-related decrease in physiological function and enhancing exercise performance and may be of interest to a range of older individuals including those taking part in competitive sport. In this brief review we discuss the effects of aging on physiological function and endurance exercise performance, and the potential role of changes in NO bioavailability in these processes. We also provide a summary of current evidence for dietary supplementation with substrates for NO production — including inorganic nitrate and nitrite, l-arginine and l-citrulline — for improving exercise capacity/performance in older adults. Additionally, we discuss the (limited) evidence on the effects of (poly)phenols and other dietary antioxidants on NO bioavailability in older individuals. Finally, we provide suggestions for future research.
... It is important to note that this ex vivo approach does not negate the roles of multiple vasoactive compounds in functional sympatholysis, which are likely to be drivers of the arterial adaptations described in this study. Functional sympatholysis has been described previously in conduit arteries, including the brachial artery, and increased blood flow has been reported in femoral arteries during exercise (Iepsen et al., 2018;Jendzjowsky & Delorey, 2013;Mortensen et al., 2012Mortensen et al., , 2014Nyberg & Hellsten, 2016). Since blood flow is markedly increased in the femoral artery during exercise, it is possible that increased shear stress augments endothelial-derived nitric oxide release, which can stimulate SERCA activity in vascular smooth muscle cells (Clifford & Hellsten, 2004;Cohen et al., 1999;Pohl et al., 1986). ...
Article
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The vasoconstrictive effect of sympathetic activity is attenuated in contracting skeletal muscle (functional sympatholysis), allowing increased blood supply to the working muscle but the underlying mechanisms are incompletely understood. The purpose of this study was to examine α-adrenergic receptor responsiveness in isolated artery segments from non-exercised and exercised mice, using wire myography. Isometric tension recordings performed on femoral artery segments from exercised mice showed decreased α-adrenergic receptor responsiveness compared to non-exercised mice (logEC50 -5.2 ± 0.04 M vs. -5.7 ± 0.08 M, respectively). In contrast, mesenteric artery segments from exercised mice displayed similar α-adrenergic receptor responses compared to non-exercised mice. Responses to the vasoconstrictor serotonin (5-HT) and vasodilator isoprenaline, were similar in femoral artery segments from non-exercised and exercised mice. To study sarcoplasmic reticulum (SR) function, we examined arterial contractions induced by caffeine, which depletes SR Ca2+ and thapsigargin, which inhibits SR Ca2+ -ATPase (SERCA) and SR Ca2+ uptake. Arterial contractions to both caffeine and thapsigargin were increased in femoral artery segment from exercised compared to non-exercised mice. Furthermore, 3D electron microscopy imaging of the arterial wall showed SR volume/length ratio increased 157% in smooth muscle cells of the femoral artery from the exercised mice, whereas there was no difference in SR volume/length ratio in mesenteric artery segments. These results show that in arteries surrounding exercising muscle, the α-adrenergic receptor constrictions are blunted, which can be attributed to swollen smooth muscle cell SR's, likely due to increased Ca2+ content that is possibly reducing free intracellular Ca2+ available for contraction. Overall, this study uncovers a previously unknown mechanism underlying functional sympatholysis.
... Exercise training also could enhance arteriolar vasodilation through increased bioavailability or sensitivity to vasodilators, including nitric oxide (NO), ATP, or potassium. In support, habitual exercise training blunts age-related declines in NO bioavailability (30) and improves functional sympatholysis (37,38). On the other hand, increasing NO in older adults was not associated with lower extremity blood flow, suggesting other factors are predominating (30). ...
Article
Microvascular function is reduced with age, disease, and inactivity. Exercise is well known to improve vascular health and has the potential to improve microvascular function in aging and disease. Purpose: The study aimed to assess changes in peripheral microvascular function in sedentary older adults following aerobic exercise training. Methods: Twenty-three, sedentary older adults (67±5 yrs, BMI=29±5, mean±SD) successfully completed a randomized 12-week graded treadmill walking intervention. The exercise group (EX) performed 40 minutes of uphill walking 4 days a week at 70% heart rate reserve. The control group (CON) maintained a sedentary lifestyle for 12 weeks. MRI measured blood-oxygen-level dependent (BOLD) responses of the soleus were used to evaluate microvascular function; brief (1s) maximal plantar flexion contractions were performed. Separately, blood flow in the popliteal artery was measured by ultrasound following brief contraction. Phosphorus magnetic resonance spectroscopy of the calf was used to examine muscle oxidative capacity and whole body peak oxygen consumption (V[Combining Dot Above]O2peak) was used to confirm training induced cardiorespiratory adaptations. Results: Peak post-contraction BOLD response increased by 33% in EX (PRE:3.3±1.0%, POST:4.4±1.4%) compared to CON (PRE:3.0±1.3%, POST:3.2±1.5%), p<0.05. EX with hypertension tended to show a blunted peak BOLD increase (n=6, 15%) compared to EX normotensive (n=7, 50%), p=0.056. Peak post-contraction blood flow increased by 39% in EX (PRE:217±88 ml[BULLET OPERATOR]min, POST:302±167 ml[BULLET OPERATOR]min) compared to CON (PRE:188±54 ml[BULLET OPERATOR]min, POST:184±44 ml[BULLET OPERATOR]min), p<0.05. EX muscle oxidative capacity (kPCr) improved by 40% (PRE:1.60±0.57 min, POST:2.25 ±0.80 min) compared to CON (PRE:1.69±0.28 min, POST:1.76±0.52 min), p<0.05. V[Combining Dot Above]O2peak increased by 9% for EX (PRE:19.0±3.1 ml[BULLET OPERATOR]kg[BULLET OPERATOR]min, POST:20.8±2.9 ml[BULLET OPERATOR]kg[BULLET OPERATOR]min) compared to a 7% loss in CON (PRE:21.9±3.6 ml[BULLET OPERATOR]kg[BULLET OPERATOR]min, POST:20.4±3.5 ml[BULLET OPERATOR]kg[BULLET OPERATOR]min), p<0.05. Conclusions: Moderate aerobic exercise significantly improved microvascular function of the leg in older adults.
... Importantly, training-induced lowering of the α-adrenergic responsiveness in humans [32] facilitates the increases in muscle blood flow in trained leg muscles during exercise. However, exercise training reduces the vasodilatory response to arterially infused ATP, suggesting that physical activity may alter purinergic P 2 receptor sensitivity and/or ATP degradation in plasma [32,35]. Based on our results showing increased exercise and post-exercise [ATP] during an annual training cycle, we assume that the type of training may influence the physiological mechanisms of ATP release and/or degradation and its influence on muscle vessel dilatation during incremental exercise. ...
Article
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This study aimed to assess the effect of training loads on plasma adenosine triphosphate responsiveness in highly trained athletes in a 1 y cycle. Highly trained futsal players (11 men, age range 20–31 y), endurance athletes (11 men, age range 18–31 y), sprinters (11 men, age range 21–30 y), and control group (11 men, age range 22–34 y) were examined across four characteristic training phases in response to an incremental treadmill test until exhaustion. A considerably higher exercise and post-exercise plasma adenosine triphosphate concentrations were observed in consecutive training phases in highly trained athletes, with the highest values reached after the competitive period. No differences in plasma adenosine triphosphate concentrations were found in the control group during the 1 y cycle. Sprinters showed a higher absolute and net increase in plasma adenosine triphosphate concentration by 60–114% during exercise in consecutive training phases than futsal players (63–101%) and endurance athletes (64–95%). In this study, we demonstrated that exercise-induced adenosine triphosphate concentration significantly changes in highly trained athletes over an annual training cycle. The obtained results showed that high-intensity but not low- to moderate-intensity training leads to an increased adenosine triphosphate response to exercise, suggesting an important role of ATP for vascular plasticity.
... In response to hypoxia and/or mechanical deformation (e.g., exercise), erythrocytes release ATP to evoke vasodilatation in contracting skeletal muscle (10). There is also mounting evidence supporting the idea that ATP interferes with sympathetic vasoconstriction (22,38,47). In the context of T2DM, hemoglobin glycosylation may impair the ability of erythrocytes to release ATP and potentially explain findings from the present study. ...
Article
Patients with type 2 diabetes mellitus (T2DM) exhibit diminished exercise capacity likely attributable to reduced skeletal muscle blood flow (i.e., exercise hyperemia). A potential underlying mechanism of the impaired hyperemic response to exercise could be inadequate blunting of sympathetic-mediated vasoconstriction (i.e., poor functional sympatholysis). Therefore, we studied the hyperemic and vasodilatory responses to hand grip exercise in patients with T2DM as well as vasoconstriction to selective α-agonist infusion. Forearm blood flow (FBF) and vascular conductance (FVC) were examined in patients with T2DM (n=30) as well as nondiabetic controls (n=15) with similar age (59±9 vs. 60±9yrs, P=0.69) and body mass index (31.4±5.2 vs. 29.5±4.6kg·m ⁻² , P=0.48). Intra-arterial infusion of phenylephrine (α 1 -agonist) and dexmedetomidine (α 2 -agonist) were used to induce vasoconstriction: ((FVC with drug -FVC pre-drug )/FVC pre-drug x100%). Subjects completed rest and dynamic hand grip exercise (20% of maximum) trials per α-agonist. Patients with T2DM had smaller increases (Δ from rest) in FBF (147±71 vs. 199±63ml·min ⁻¹ ) and FVC (126±58 vs. 176±50ml·min ⁻¹ ·100mmHg ⁻¹ , P<0.01 for both) during exercise compared to controls, respectively. During exercise, patients with T2DM had greater α 1 - (-16.9±5.9 vs. -11.3±3.8%) and α 2 -mediated vasoconstriction (-23.5±7.1 vs. -19.0±6.5%, P<0.05 for both) versus controls. The magnitude of sympatholysis (Δ in %vasoconstriction between exercise and rest) for PE was lower (worse) in patients with T2DM versus controls (14.9±12.2 vs. 23.1±8.1%, P<0.05) whereas groups were similar during DEX trials (24.6±12.3 vs. 27.6±13.4%, P=0.47). Our data suggest patients with T2DM have attenuated hyperemic and vasodilatory responses to exercise which could be attributable to greater α 1 -mediated vasoconstriction in contracting skeletal muscle.
... Aging decreases NO bioavailability and exaggerates blood pressure responses to sympathetic nervous activity (Koch et al., 2003;Dinenno et al., 2005). However, an increase in NO bioavailability through habitual exercise attenuates the blood pressure response to sympathetic stimuli; functional sympatholysis is greater in physically active individuals compared to sedentary peers (Mortensen et al., 2012;Kruse et al., 2018a) and improves with aerobic training in middle-aged adults (Mortensen et al., 2014). Although functional sympatholysis was not measured in this study, the frequency (4.4 d/wk) and duration (59 min/d) of exercise were comparable to those in a previous study that reported an improvement in functional sympatholysis with aerobic training (3-4 d/wk and 60 min/d, respectively) (Mortensen et al., 2014). ...
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An exaggerated blood pressure response to resistance exercise is a marker of masked hypertension and a risk factor for future essential hypertension. Habitual aerobic exercise decreases systolic blood pressure (SBP) during resistance exercise in older individuals, but the underlying mechanisms have not been explored. This study tested the hypothesis that nitric oxide (NO) mediates a reduction of resistance exercise SBP with aerobic training in older individuals. Normotensive older adults participated in a 6-week program as a part of the aerobic training group (n = 23, exercised for an average of 4.4 d/wk and 59 min/d) or the control group (n = 26, asked not to modify their lifestyle during the experimental period). The aerobic exercise intervention increased plasma concentrations of nitrite/nitrate (NOx, end products of NO) and decreased SBP during a one-hand arm curl exercise at 20% and 40% of one-repetition maximum and brachial-ankle pulse wave velocity (an index of arterial stiffness). In the control group, there were no differences in these measures before and after the experimental period. Changes in plasma NOx concentrations during the study period were correlated with changes in resistance exercise SBP. Stepwise regression revealed that changes in plasma NOx concentrations during the experimental period are a significant factor of changes in resistance exercise SBP, independent of age, sex, and changes in serum lipid profile, maximal oxygen uptake, resting SBP, and other variables. These results suggest that NO is associated with decreases in resistance exercise SBP with aerobic training in older individuals and help us better understand why habitual aerobic exercise prevents cardiovascular disease.
Article
Purpose: We examined whether two weeks of one-leg immobilization would impair leg microvascular function and to what extent a subsequent period of intense aerobic cycle training could restore function. Methods: Study participants were healthy young males (n=12; 20-24 years of age). Leg microvascular function was determined before the intervention, after the immobilization period and after a four-week exercise training period. Microvascular function was assessed as the vasodilator response to intra-arterial infusion of acetylcholine, sodium nitroprusside and as the vasoconstrictor response to endogenous noradrenaline release induced by tyramine infusion. Vasodilator enzymes as well as pro- and antioxidant enzymes were assessed by protein analysis in skeletal muscle samples; endothelial nitric oxide synthase (eNOS), NADPH oxidase (NOXp67 and NOXgp91) and superoxide dismutase 2 (SOD2). Results: The acetylcholine induced change in vascular conductance was reduced after the two weeks of immobilization (P=0.003), tended to increase after the subsequent four weeks of exercise training (P=0.061) and was back to baseline levels. Plasma prostacyclin levels in response to acetylcholine infusion were lower after immobilization than before (P=0.041). The changes in vascular conductance with sodium nitroprusside and tyramine were similar during all conditions. Skeletal muscle protein levels of eNOS in the experimental leg were unchanged with immobilization and subsequent training but increased 47% in the control leg with training (P=0.002). NOXp67, NOXgp91 and SOD2 in the experimental leg remained unaltered with immobilization and SOD2 were higher than pre-immobilization after four weeks of training (P<0.001). Conclusion: The study shows that two weeks of immobilization impairs leg microvascular endothelial function and prostacyclin formation but that four weeks of intense aerobic exercise training restores the function. The underlying mechanism may reside in the prostacyclin system.
Chapter
The autonomic nervous system is important for maintaining cardiovascular homeostasis in daily living. Improper autonomic function (i.e., the set of neurological control systems regulating and maintaining cardiovascular homeostasis, particularly heat rate and blood pressure) can lead to cardiovascular disease such as hypertension. This chapter discusses the role of the autonomic nervous system in hypertension and the effect of exercise on the autonomic nervous system in restoring cardiovascular health. Within, the reader will find a tutorial of the anatomy and physiology of the autonomic nervous system. Various common techniques for assessing autonomic function are also included in this discussion. The chapter finishes with a review of the literature pertaining to the acute (short-term or immediate) and chronic (i.e., long-term or training) effects of exercise on autonomic function.
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Key points: The ability of contracting skeletal muscle to attenuate sympathetic vasoconstriction (functional sympatholysis) is critical to maintain blood flow during exercise-mediated sympathoexcitation. Functional sympatholysis and endothelial function are impaired with ageing, resulting in compromised blood flow and oxygen delivery to contracting skeletal muscle during exercise. In this investigation, intra-arterial infusion of ACh or ATP to augment endothelium-dependent signalling during exercise attenuated α1 -adrenergic vasoconstriction in contracting muscle of older adults. The vascular signalling mechanisms capable of functional sympatholysis are preserved in healthy ageing, and thus the age-related impairment in functional sympatholysis likely results from the loss of a functional signal (e.g. plasma [ATP]) as opposed to an intrinsic endothelial dysfunction. Abstract: The ability of contracting skeletal muscle to attenuate sympathetic α-adrenergic vasoconstriction ('functional sympatholysis') is impaired with age. In young adults increasing endothelium-dependent vasodilatory signalling during mild exercise augments sympatholysis. Here, we tested the hypothesis that increasing endothelium-dependent signalling during exercise in older adults can improve sympatholysis. In 16 older individuals (Protocol 1 n = 8, Protocol 2 n = 8), we measured forearm blood flow (Doppler ultrasound) and calculated changes in vascular conductance (FVC) to local intra-arterial infusion of phenylephrine (PE; α1 -agonist) during 1) infusion of an endothelium-dependent vasodilator alone (Protocol 1: acetylcholine [ACh] or Protocol 2: low dose adenosine triphosphate [ATP], 2) mild handgrip exercise (5% maximum voluntary contraction; MVC), 3) moderate handgrip exercise (15% MVC), and 4) mild or moderate handgrip exercise + infusion of ACh or ATP to augment endothelium-dependent signalling. PE caused robust vasoconstriction in resting skeletal muscle during control vasodilator infusions (ΔFVC: ACh: -31 ± 3 and ATP: -30 ± 4%). PE-mediated vasoconstriction was not attenuated by mild or moderate intensity exercise (ΔFVC: 5% MVC: -30 ± 9; 15% MVC: -33 ± 8%; P > 0.05 vs. control ACh and ATP), indicative of impaired sympatholysis, and ACh or ATP infusion during mild exercise did not impact this response. However, augmentation of endothelium-dependent signalling via infusion of ACh or ATP during moderate intensity exercise attenuated PE-mediated vasoconstriction (ΔFVC: -13 ± 1 and -19 ± 5%, respectively; P < 0.05 vs. all conditions). Our findings demonstrate that given a sufficient stimulus, endothelium-dependent sympatholysis remains intact in older adults. Strategies aimed at activating such pathways represent a viable approach to improving sympatholysis, and thus tissue blood flow and oxygen delivery in older adults. This article is protected by copyright. All rights reserved.
Article
This review provides a pulmonary-focused description of the age-associated changes in the integrative physiology of exercise, including how declining lung function plays a role in promoting multimorbidity in the elderly through limitation of physical function. We outline the ageing of physiological systems supporting endurance activity: 1) coupling of muscle metabolism to mechanical power output; 2) gas transport between muscle capillary and mitochondria; 3) matching of muscle blood flow to its requirement; 4) oxygen and carbon dioxide carrying capacity of the blood; 5) cardiac output; 6) pulmonary vascular function; 7) pulmonary oxygen transport; 8) control of ventilation; and 9) pulmonary mechanics and respiratory muscle function. Deterioration in function occurs in many of these systems in healthy ageing. Between the ages of 25 and 80 years pulmonary function and aerobic capacity each decline by ∼40%. While the predominant factor limiting exercise in the elderly likely resides within the function of the muscles of ambulation, muscle function is (at least partially) rescued by exercise training. The age-associated decline in pulmonary function, however, is not recovered by training. Thus, loss in pulmonary function may lead to ventilatory limitation in exercise in the active elderly, limiting the ability to accrue the health benefits of physical activity into senescence.
Article
Sympathetic vasoconstriction in the skeletal muscle vascular bed is essential for the regulation of vascular resistance and therefore control of blood pressure and muscle blood flow at rest and during exercise. In this article we address the hypothesis that aerobic exercise training alters sympathetic vasoconstrictor responsiveness and enhances contraction mediated inhibition of sympathetic vasoconstriction (functional sympatholysis) through a nitric oxide dependent mechanism. SUMMARY: Aerobic exercise training alters sympathetic vasoconstrictor responsiveness and nitric oxide dependent inhibition of sympathetic vasoconstriction.
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PurposeBlood flow (BF) and vasodilator responses to knee-extension exercise are attenuated in older adults across an exercise transient (onset, kinetics, and steady-state), and reduced nitric oxide bioavailability (NO) has been hypothesized to be a primary mechanism contributing to this attenuation. We tested the hypothesis acute dietary nitrate (NO3−) supplementation (~ 4.03 mmol NO3− and 0.29 mmol NO2−) would improve leg vasodilator responses across an exercise transient during lower limb exercise in older adults.Methods Older (n = 10) untrained adults performed single and rhythmic knee-extension contractions at 20% and 40% work-rate maximum (WRmax) prior to and 2-h after consuming a NO3− or placebo beverage in a double-blind, randomized fashion. Femoral artery BF was measured by Doppler ultrasound. Vascular conductance was calculated using BF and mean arterial pressure.ResultsAcute ingestion of dietary NO3− enhanced plasma [NO3−] and [NO2−] (P < 0.05). Neither dietary NO3− or placebo enhanced vasodilator responses at the onset of exercise or during steady state at 20% and 40% WRmax (P > 0.05). Leg vasodilator kinetics during rhythmic exercise remained unchanged following NO3− and placebo ingestion (P > 0.05).Conclusions The key findings of this study are that despite increasing plasma [NO3−] and [NO2−], acute dietary NO3− intake had no effect on (1) rapid hyperaemic or vasodilator responses at the onset of exercise; (2) hyperaemic and vasodilator responses during steady-state submaximal exercise; or (3) kinetics of vasodilation preceding steady-state responses. Collectively, these findings suggest that low dose dietary NO3− supplementation does not improve hyperaemic and vasodilator responses across an exercise transient in older adults.
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Over the last 50 years, Bengt Saltin's contributions to our understanding of physiology of the circulation, the matching of the circulation to muscle metabolism, and the underlying mechanisms that set the limits for exercise performance were enormous. His research addressed the key questions in the field using sophisticated experimental methods including field expeditions. From the Dallas Bedrest Study to the 1-leg knee model to the physiology of lifelong training, his prodigious body of work was foundational in the field of exercise physiology and his leadership propelled integrative human physiology into the mainstream of biological sciences.
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Contraction-induced rapid vasodilation is attenuated similarly in the upper and lower limbs of older adults. In the forearm, this attenuation is in part due to a greater sympathetic vasoconstriction. We examined whether the age-related reduction in contraction-induced vasodilation in the leg is also due to a sympathetic vasoconstrictive mechanism. Thirteen young (24±1yr) and twelve older adults (67±1yr) performed single leg knee-extension at 20% and 40% of work-rate maximum (WRmax) during control and cold-pressor test (CPT) conditions. Femoral artery diameter and blood velocity were measured using Doppler ultrasound. Vascular conductance (VC; ml·min-1·mmHg-1) was calculated using blood flow (ml·min-1) and mean arterial pressure (mmHg). Peak (ΔVC from baseline) and total VC were blunted in older adults during control conditions across exercise intensities (P<0.05). Peak and total VC were reduced during CPT in both age groups across exercise intensities (P<0.05). The relative change (i.e. % reduction; CPT vs. control) in peak (-25±5% vs. -22±4% at 20% WRmax; and -21±6% vs. -27±5% at 40% WRmax, P=0.42-0.55) and total VC (-28±5% vs. -36±6% at 20% WRmax; and -22±8% vs. -33±5% at 40% WRmax, P=0.23-0.34) were similar between young and older adults. When matched for absolute workload (~10W), age differences persisted in peak VC (P<0.05) under both conditions, with similar relative changes in peak and total VC during CPT. Our data suggest that 1) sympathetic stimulation reduces contraction-induced rapid vasodilation in the leg of young and older adults similarly; and 2) enhanced sympathetic vasoconstriction does not fully explain age-related differences in contraction-induced vasodilation within the leg.
Article
Introduction: The study evaluated the role of life-long physical activity for leg vascular function in post-menopausal women (61±1 years). Method: The study design was cross-sectional with 3 different groups based on their self-reported physical activity level with regard to intensity and volume over the past decade: Inactive (n=14); Moderately active (n=12) and; Very active (n=15). Endothelial dependent and smooth muscle dependent leg vascular function were assessed by ultrasound doppler measurements of the femoral artery during infusion of acetylcholine, the nitric oxide (NO) donor sodium nitroprusside and the prostacyclin analog epoprostenol. Thigh muscle biopsies and venous plasma samples were obtained for assessment of vasodilator systems. Results: The very active group was found to have ~ 76% greater responsiveness to acetylcholine compared to the sedentary group accompanied by a ~200% higher prostacyclin synthesis during ach infusion. Smooth muscle cell responsiveness to sodium nitroprusside and epoprostenol was not different between groups. The protein amount of endothelial nitric oxide synthase and endogenous antioxidant enzymes in muscle tissue was higher in the very active than the inactive group. The moderately active group had a similar endothelial and smooth muscle cell responsiveness as the inactive group. A secondary comparison with a smaller group (n=5) of habitually active young (24±2 yrs) women indicated that smooth muscle cell responsiveness and endothelial responsiveness is affected by age per se. Conclusion: This study shows that leg vascular function, and a greater potential to form prostacyclin and NO in late post-menopausal women, is influenced by the extent of life-long physical activity.
Article
Skeletal muscle blood flow is attenuated in aged humans performing dynamic exercise, which is due, in part, to impaired local vasodilatory mechanisms. Recent evidence suggests that folic acid improves cutaneous vasodilation during localized and whole body heating through nitric oxide-dependent mechanisms. However, it is unclear whether folic acid improves vasodilation in other vascular beds during conditions of increased metabolism (i.e., exercise). The purpose of this study was to test the hypothesis that folic acid ingestion improves skeletal muscle blood flow in aged adults performing graded handgrip and plantar flexion exercise via increased vascular conductance. Nine healthy, aged adults (two men and seven women; age: 68 ± 5 yr) performed graded handgrip and plantar flexion exercise before (control), 2 h after (acute, 5 mg), and after 6 wk (chronic, 5 mg/day) folic acid ingestion. Forearm (brachial artery) and leg (superficial femoral artery) blood velocity and diameter were measured via Duplex ultrasonography and used to calculate blood flow. Acute and chronic folic acid ingestion increased serum folate (both P < 0.05 vs. control). During handgrip exercise, acute and chronic folic acid ingestion increased forearm blood flow (both conditions P < 0.05 vs. control) and vascular conductance (both P < 0.05 vs. control). During plantar flexion exercise, acute and chronic folic acid ingestion increased leg blood flow (both P < 0.05 vs. control), but only acute folic acid ingestion increased vascular conductance ( P < 0.05 vs. control). Taken together, folic acid ingestion increases blood flow to active skeletal muscle primarily via improved local vasodilation in aged adults. NEW & NOTEWORTHY Our findings demonstrate that folic acid ingestion improves blood flow via enhanced vascular conductance in the exercising skeletal muscle of aged humans. These findings provide evidence for the therapeutic use of folic acid to improve skeletal muscle blood flow, and perhaps exercise and functional capacity, in human primary aging. Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/folic-acid-and-exercise-hyperemia-in-aging/ .
Article
This viewpoint is the result of a Horizon Round Table discussion of Exercise and Aging held during the 2017 Saltin International Graduate School in Exercise and Clinical Physiology in Gatineau, Quebec. This expert panel discussed key issues and approaches to future research into aging, across human physiological systems, current societal concerns, and funding approaches. Over the 60-min round table discussion, 3 major themes emerged that the panel considered to be "On the Horizon" of aging research. These themes include (i) aging is a process that extends from womb to tomb; (ii) the importance of longitudinal experimental studies; and (iii) the ongoing need to investigate multiple systems using an integrative approach between scientists, clinicians, and knowledge brokers. With a focus on these themes, we aim to identify critical questions, challenges, and opportunities that face scientists in advancing the understanding of exercise and aging.
Article
Habitual aerobic exercise attenuates elevated vasoconstriction during acute exercise (functional sympatholysis) in older men; however, this effect remains unknown in postmenopausal women (PMW). This study tested the hypothesis that, PMW who participate in habitual aerobic exercise, demonstrate a greater functional sympatholysis compared to their untrained counterparts. Nineteen PMW (untrained, n=9 vs. trained, n=10) performed 5-minutes of steady-state (SS) forearm exercise at relative (10% and 20% of maximum; MVC) and absolute (5 kg) contraction intensities. Lower body negative pressure (LBNP) was used to increase sympathetic vasoconstriction during rest and forearm exercise. Brachial artery diameter and blood velocities (via Doppler ultrasound) determined forearm blood flow (FBF; ml·min-1). Forearm muscle oxygen consumption (VO2m; ml·min-1) and arterio-venous oxygen difference (a-vo2diff) were estimated during SS-exercise and SS-exercise with LBNP. Forearm vascular conductance (FVC; ml·min-1·100mmHg-1) was calculated from FBF and mean arterial pressure (MAP; mmHg). Vasoconstrictor responsiveness was determined as the % change in FVC during LBNP. The reduction in FVC (% change FVC) during LBNP was lower in trained compared to untrained PMW at 10% MVC (-7.3±1.2% vs. -13.0±1.1%; P<0.05), 20% MVC (-4.4±0.8% vs. -8.6±1.4%; P<0.05) and 5kg (-5.3±0.8% vs. -8.9±1.4%; P<0.05) conditions, whereas there were no differences at rest (-32.7±4.4% vs. -33.7±4.0%). Peripheral (FVC, FBF and VO2m) and the magnitude change in systemic hemodynamics (heart rate and MAP) did not differ between groups during exercise. Collectively, the findings present first evidence suggesting that PMW who participate in aerobic exercise demonstrate a greater functional sympatholysis compared to untrained PMW during mild-to-moderate forearm exercise.
Article
Controls: -0.04 ± 0.01 l·min-1·kg leg mass-1, P > 0.05). Compared with age-matched healthy control subjects, the vasodilatory response to ATP is intact in COPD patients and their ability to blunt sympathetic vasoconstriction (functional sympatholysis) as evaluated by intra-arterial Tyramine during exercise or ATP infusion is maintained. NEW & NOTEWORTHY The ability to blunt sympathetic vasoconstriction in exercising muscle and ATP-induced dilation in chronic obstructive pulmonary disease patients remains unexplored. Chronic obstructive pulmonary disease patients demonstrated similar sympathetic vasoconstriction in response to intra-arterial Tyramine during exercise and ATP-induced vasodilation compared with age-matched healthy control subjects.
Article
Key points: Skeletal muscle blood flow responses to hypoxia and exercise are impaired with age. Blunted increases in circulating ATP, a vasodilator, in older adults may contribute to age-related impairments in haemodynamics. Red blood cells (RBCs) are a primary source of circulating ATP, and treating isolated RBCs with a Rho-kinase inhibitor improves age-related impairments in deoxygenation-induced RBC ATP release. In this study, treating healthy older adults systemically with the Rho-kinase inhibitor fasudil improved blood flow and circulating ATP responses during hypoxia and moderate intensity handgrip exercise compared to young adults, and also tended to improve isolated RBC ATP release. Improved blood flow regulation with fasudil was also associated with increased skeletal muscle oxygen delivery during hypoxia and exercise in older adults. This is the first study to demonstrate that Rho-kinase inhibition can significantly improve age-related impairments in haemodynamic and circulating ATP responses to physiological stimuli, which may have therapeutic implications. Abstract: Skeletal muscle haemodynamics and circulating adenosine triphosphate (ATP) responses during hypoxia and exercise are blunted in older (OA) vs young (YA) adults, which may be associated with impaired red blood cell (RBC) ATP release. Rho-kinase inhibition improves deoxygenation-induced ATP release from OA isolated RBCs. We tested the hypothesis that Rho-kinase inhibition (via fasudil) in vivo would improve local haemodynamic and ATP responses during hypoxia and exercise in OA. Healthy YA (25±3yr; n = 12) and OA (65±5yr; n = 13) participated in a randomized, double-blind, placebo-controlled, crossover study on 2 days (≥5d between visits). A forearm deep venous catheter was used to administer saline/fasudil and sample venous plasma ATP ([ATP]V ). Forearm vascular conductance (FVC) and [ATP]V were measured at rest, during isocapnic hypoxia (80% SpO2 ), and during graded rhythmic handgrip exercise that was similar between groups (5, 15, and 25% maximum voluntary contraction (MVC)). Isolated RBC ATP release was measured during normoxia/hypoxia. With saline, ΔFVC was lower (P<0.05) in OA vs YA during hypoxia (∼60%) and during 15 and 25% MVC (∼25-30%), and these impairments were abolished with fasudil. Similarly, [ATP]V and ATP effluent responses from normoxia to hypoxia and rest to 25% MVC were lower in OA vs YA and improved with fasudil (P<0.05). Isolated RBC ATP release during hypoxia was impaired in OA vs YA (∼75%; P<0.05), which tended to improve with fasudil in OA (P = 0.082). These data suggest Rho-kinase inhibition improves haemodynamic responses to hypoxia and moderate intensity exercise in OA, which may be due in part to improved circulating ATP. Abstract figure legend This article is protected by copyright. All rights reserved.
Article
Key points: Red blood cells (RBCs) release ATP in response to deoxygenation, which can increase blood flow to help match oxygen supply with tissue metabolic demand. This release of ATP is impaired in RBCs from older adults, but the underlying mechanisms are unknown. In this study, improving RBC deformability in older adults restored deoxygenation-induced ATP release, whereas decreasing RBC deformability in young adults reduced ATP release to that of older adults. In contrast, treating RBCs with a phosphodiesterase 3 inhibitor did not affect ATP release in either age group, possibly due to intact intracellular signalling downstream of deoxygenation as indicated by preserved cAMP and ATP release responses to pharmacological Gi protein activation in RBCs from older adults. These findings are the first to demonstrate that the age-related decrease in RBC deformability is a primary mechanism of impaired deoxygenation-induced ATP release, which may have implications for treating impaired vascular control with advancing age. Abstract: Red blood cells (RBCs) release ATP in response to haemoglobin deoxygenation, which binds to endothelial purinergic receptors and stimulates vasodilatation. This ATP release is impaired in RBCs from older vs. young adults, but the underlying mechanisms are unknown. Using isolated RBCs from young .(24±1) and older (65±2) adults, we tested the hypothesis that age-related changes in RBC deformability (Study 1) and cAMP signalling (Study 2) contribute to the impairment. RBC ATP release during normoxia (PO2 ∼112 mmHg) and hypoxia (PO2 ∼20 mmHg) was quantified via luciferin-luciferase technique following RBC incubation with either Y-27632 (Rho-kinase inhibitor to increase deformability), diamide (cell-stiffening agent), cilostazol (phosphodiesterase 3 inhibitor), or vehicle control. The mean change in RBC ATP release from normoxia to hypoxia in control conditions was significantly impaired in older vs. young (∼50% vs ∼120%; P<0.05). RBC deformability was also lower in older vs. young as indicated by a higher RBC transit time (RCTT) measured by blood filtrometry (RCTT: 8.541±0.050 vs. 8.234±0.098 a.u., respectively; P<0.05). Y-27632 improved RBC deformability (RCTT: 8.228±0.083) and ATP release (111.7±17.2%) in older and diamide decreased RBC deformability (RCTT: 8.955±0.114) and ATP release (67.4±11.8%) in young (P<0.05), abolishing the age group differences (P>0.05). Cilostazol did not change ATP release in either age group (P>0.05), and RBC cAMP and ATP release to pharmacological Gi protein activation was similar in both groups (P>0.05). We conclude that decreased RBC deformability is a primary contributor to age-related impairments in RBC ATP release, which may have implications for impaired vascular control with advancing age. This article is protected by copyright. All rights reserved.
Article
The sympathetic nervous system (SNS) is a critically important regulator of the cardiovascular system. The SNS controls cardiac output and its distribution, as well as peripheral vascular resistance and blood pressure at rest and during exercise. Aging is associated with increased blood pressure and decreased skeletal muscle blood flow at rest and in response to exercise. The mechanisms responsible for the blunted skeletal muscle blood flow response to dynamic exercise with aging have not been fully elucidated; however, increased muscle sympathetic nerve activity (MSNA), elevated vascular resistance, and a decline in endothelium-dependent vasodilation are commonly reported in older adults. In contrast to aging, exercise training has been shown to reduce blood pressure and enhance skeletal muscle vascular function. Exercise training has been shown to enhance nitric oxide-dependent vascular function and may improve the vasodilatory capacity of the skeletal muscle vasculature; however, surprisingly little is known about the effect of exercise training on the neural control of circulation. The control of blood pressure and skeletal muscle blood flow also differs between men and women. Blood pressure and MSNA appear to be lower in young women than in men. However, females experience a larger increase in MSNA with aging compared with males. The mechanism(s) underlying the altered SNS control of vascular function in females remains to be determined. Novelty: This review summarizes our current understanding of the effects of aging, exercise training, and sex on sympathetic vasoconstriction at rest and during exercise. Areas where additional research is needed are also identified.
Article
Sympathetic nervous system (SNS) vasoconstriction is primarily achieved through the binding of norepinephrine (NE) to α-adrenoreceptors. However, NE may also bind to β-adrenoreceptors and cause vasodilation that may oppose/blunt SNS-mediated vasoconstriction. Therefore, this study investigated the hypothesis that β-adrenoreceptor–mediated vasodilation opposes evoked vasoconstriction in resting and contracting skeletal muscle. Male (n = 9) Sprague–Dawley rats were anesthetized and surgically instrumented for stimulation of the lumbar sympathetic chain and measurement of arterial blood pressure and femoral artery blood flow. The percentage change of femoral vascular conductance in response to sympathetic chain stimulation delivered at 2 and 5 Hz was determined at rest and during triceps surae skeletal muscle contraction before (control) and after β-adrenoreceptor blockade (propranolol; 0.075 mg·kg ⁻¹ , intravenously). β-Adrenoreceptor blockade did not alter (P > 0.05) baseline hemodynamics or the hyperemic response to exercise. At the 2 Hz stimulation frequency, sympathetic vasoconstriction was similar (P > 0.05) in control and β-blockade conditions in resting (control, −34% ± 6%; β-blockade, −33% ± 8%) and contracting (control, −16% ± 6%; β-blockade, −14% ± 7%) muscle. At the 5 Hz stimulation frequency, sympathetic vasoconstrictor responsiveness was reduced (main effect of drug, P < 0.05) following β-blockade (rest: control, −52% ± 7%; β-blockade, −51% ± 9%; contraction: control, −32% ± 11%; β-blockade, −29% ± 13%). Novelty These data indicate that β-adrenoreceptor blockade did not augment sympathetic vasoconstriction at rest or during exercise. The study demonstrates that β-adrenoreceptors do not oppose evoked sympathetic vasoconstriction in resting or contracting skeletal muscle or contribute to functional sympatholysis.
Article
Objective We evaluated the hypothesis that aging attenuates muscarinic, nicotinic, and ATP‐ related cutaneous vasodilation. Methods In 11 young (24±4 years) and 11 older males (61±8 years), cutaneous vascular conductance (CVC) was assessed at three forearm skin sites that were infused with either: 1) methacholine (muscarinic receptor agonist, 5 doses: 0.0125, 0.25, 5, 100, 2000 mM), 2) nicotine (nicotinic receptor agonist, 5 doses: 1.2, 3.6, 11, 33, 100 mM), or 3) adenosine triphosphate (ATP) (purinergic receptor agonist, 5 doses: 0.03, 0.3, 3, 30, 300 mM). Each agonist was administered for 25 min per dose. Results We showed that CVC at all doses of methacholine did not differ between groups. Similarly, no between‐group differences in CVC were observed during nicotine administration at all doses administered. By contrast, while no differences in CVC were measured during the administration of ATP at low (0.03 and 0.3 mM) or high (300 mM) concentrations, CVC was reduced in the older relative to the young males at moderate concentrations of ATP (3mM:23±6 vs. 40±13%max, 30 mM:62 ± 11 vs. 83 ± 8%max, both P≤0.05). Conclusions We show that aging attenuates ATP‐induced, but not muscarinic or nicotinic, cutaneous vasodilation in men. This article is protected by copyright. All rights reserved.
Article
Objectives Heat shock protein 90 (HSP90) contributes to cutaneous vasodilatation during exercise in the heat through nitric oxide synthase (NOS)‐dependent mechanisms in young adults. We hypothesized that similar responses would be observed in older middle‐aged adults. Methods In nineteen habitually‐active older middle‐aged (56±5 years) men (n=9) and women (n=10), cutaneous vascular conductance (CVC) was measured at four forearm skin sites continuously treated with 1) lactated Ringers solution (Control), 2) 10 mM L‐NAME (NOS inhibitor), 3) 178 μM geldanamycin (HSP90 inhibitor), or 4) 10 mM L‐NAME and 178 μM geldanamycin combined. Participants rested in an upright semi‐recumbent position in the heat (35°C) for 70 min, followed by a 50‐min bout of moderate‐intensity cycling (~55% peak oxygen uptake) and a 30‐min recovery period in the heat. Results In both men and women, we observed no significant effects of HSP90 inhibition on CVC throughout rest, exercise, and recovery in the heat (all P>0.27). Conversely, NOS inhibition and dual NOS and HSP90 inhibition attenuated CVC relative to Control throughout the protocol (all P<0.05). Conclusions While NOS mediates cutaneous vasodilatation during rest, exercise, and recovery in the heat, HSP90 does not measurably influence this response in habitually‐active older middle‐aged men or women under these conditions. This article is protected by copyright. All rights reserved.
Article
The vascular endothelium senses and integrates numerous inputs to regulate vascular tone. Recent evidence reveals complex signal processing within the endothelium, yet little is known about how endothelium-dependent stimuli interact to regulate blood flow. We tested the hypothesis that combined stimulation of the endothelium with adenosine triphosphate (ATP) and acetylcholine (ACh) elicits greater vasodilation and attenuates α 1 ‑adrenergic vasoconstriction compared to combination of ATP or ACh with the endothelium-independent dilator sodium nitroprusside (SNP). We assessed forearm vascular conductance (FVC) in young adults (6F, 7M) during local intra-arterial infusion of ATP, ACh, or SNP alone and in the following combinations: ATP+ACh, SNP+ACh, and ATP+SNP wherein the second dilator was co-infused after attaining steady-state with the first dilator. By design, each dilator evoked a similar response when infused separately (ΔFVC, ATP: 48±4; ACh: 57±6; SNP: 53±6 ml·min ⁻¹ ·100 mmHg ⁻¹ ; P≥0.62). Combined infusion of the endothelium-dependent dilators evoked greater vasodilation than combination of either dilator with SNP (ΔFVC from first dilator, ATP+ACh: 45±9 vs. SNP+ACh: 18±7 and ATP+SNP: 26±4 ml·min ⁻¹ ·100 mmHg ⁻¹ , P<0.05). Phenylephrine was subsequently infused to evaluate α 1 ‑adrenergic vasoconstriction. Phenylephrine elicited less vasoconstriction during infusion of ATP or ACh vs. SNP (ΔFVC, -25±3 and -29±4 vs. -48±3%; P<0.05). The vasoconstrictor response to phenylephrine was further diminished during combined infusion of ATP+ACh (-13±3%; P<0.05 vs. ATP or ACh alone) and was less than that observed when either dilator was combined with SNP (SNP+ACh: -26±3%; ATP+SNP: -31±4%; both P<0.05 vs. ATP+ACh). We conclude that endothelium-dependent agonists interact to elicit vasodilation and limit α 1 ‑adrenergic vasoconstriction in humans.
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During exercise, contracting muscles can override sympathetic vasoconstrictor activity (functional sympatholysis). ATP and adenosine have been proposed to play a role in skeletal muscle blood flow regulation. However, little is known about the role of muscle training status on functional sympatholysis and ATP- and adenosine-induced vasodilation. Eight male subjects (22 ± 2 yr, Vo(2max): 49 ± 2 ml O(2)·min(-1)·kg(-1)) were studied before and after 5 wk of one-legged knee-extensor training (3-4 times/wk) and 2 wk of immobilization of the other leg. Leg hemodynamics were measured at rest, during exercise (24 ± 4 watts), and during arterial ATP (0.94 ± 0.03 μmol/min) and adenosine (5.61 ± 0.03 μmol/min) infusion with and without coinfusion of tyramine (11.11 μmol/min). During exercise, leg blood flow (LBF) was lower in the trained leg (2.5 ± 0.1 l/min) compared with the control leg (2.6 ± 0.2 l/min; P < 0.05), and it was higher in the immobilized leg (2.9 ± 0.2 l/min; P < 0.05). Tyramine infusion lowers LBF similarly at rest, but, when tyramine was infused during exercise, LBF was blunted in the immobilized leg (2.5 ± 0.2 l/min; P < 0.05), whereas it was unchanged in the control and trained leg. Mean arterial pressure was lower during exercise with the trained leg compared with the immobilized leg (P < 0.05), and leg vascular conductance was similar. During ATP infusion, the LBF response was higher after immobilization (3.9 ± 0.3 and 4.5 ± 0.6 l/min in the control and immobilized leg, respectively; P < 0.05), whereas it did not change after training. When tyramine was coinfused with ATP, LBF was reduced in the immobilized leg (P < 0.05) but remained similar in the control and trained leg. Training increased skeletal muscle P2Y2 receptor content (P < 0.05), whereas it did not change with immobilization. These results suggest that muscle inactivity impairs functional sympatholysis and that the magnitude of hyperemia and blood pressure response to exercise is dependent on the training status of the muscle. Immobilization also increases the vasodilatory response to infused ATP.
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Plasma ATP is thought to contribute to the local regulation of skeletal muscle blood flow. Intravascular ATP infusion can induce profound limb muscle vasodilatation, but the purinergic receptors and downstream signals involved in this response remain unclear. This study investigated: 1) the role of nitric oxide (NO), prostaglandins, and adenosine as mediators of ATP-induced limb vasodilation and 2) the expression and distribution of purinergic P(2) receptors in human skeletal muscle. Systemic and leg hemodynamics were measured before and during 5-7 min of femoral intra-arterial infusion of ATP [0.45-2.45 micromol/min] in 19 healthy male subjects with and without coinfusion of N(G)-monomethyl-l-arginine (l-NMMA; NO formation inhibitor; 12.3 +/- 0.3 (SE) mg/min), indomethacin (INDO; prostaglandin formation blocker; 613 +/- 12 microg/min), and/or theophylline (adenosine receptor blocker; 400 +/- 26 mg). During control conditions, ATP infusion increased leg blood flow (LBF) from baseline conditions by 1.82 +/- 0.14 l/min. When ATP was coinfused with either l-NMMA, INDO, or l-NMMA + INDO combined, the increase in LBF was reduced by 14 +/- 6, 15 +/- 9, and 39 +/- 8%, respectively (all P < 0.05), and was associated with a parallel lowering in leg vascular conductance and cardiac output and a compensatory increase in leg O(2) extraction. Infusion of theophylline did not alter the ATP-induced leg hyperemia or systemic variables. Real-time PCR analysis of the mRNA content from the vastus lateralis muscle of eight subjects showed the highest expression of P(2Y2) receptors of the 10 investigated P(2) receptor subtypes. Immunohistochemistry showed that P(2Y2) receptors were located in the endothelium of microvessels and smooth muscle cells, whereas P(2X1) receptors were located in the endothelium and the sacrolemma. Collectively, these results indicate that NO and prostaglandins, but not adenosine, play a role in ATP-induced vasodilation in human skeletal muscle. The expression and localization of the nucleotide selective P(2Y2) and P(2X1) receptors suggest that these receptors may mediate ATP-induced vasodilation in skeletal muscle.
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Metabolic products of skeletal muscle contraction activate metaboreceptor muscle afferents that reflexively increase sympathetic nerve activity (SNA) targeted to both resting and exercising skeletal muscle. To determine effects of the increased sympathetic vasoconstrictor drive on muscle oxygenation, we measured changes in tissue oxygen stores and mitochondrial cytochrome a,a3 redox state in rhythmically contracting human forearm muscles with near infrared spectroscopy while simultaneously measuring muscle SNA with microelectrodes. The major new finding is that the ability of reflex-sympathetic activation to decrease muscle oxygenation is abolished when the muscle is exercised at an intensity > 10% of maximal voluntary contraction (MVC). During high intensity handgrip, (45% MVC), contraction-induced decreases in muscle oxygenation remained stable despite progressive metaboreceptor-mediated reflex increases in SNA. During mild to moderate handgrips (20-33% MVC) that do not evoke reflex-sympathetic activation, experimentally induced increases in muscle SNA had no effect on oxygenation in exercising muscles but produced robust decreases in oxygenation in resting muscles. The latter decreases were evident even during maximal metabolic vasodilation accompanying reactive hyperemia. We conclude that in humans sympathetic neural control of skeletal muscle oxygenation is sensitive to modulation by metabolic events in the contracting muscles. These events are different from those involved in either metaboreceptor muscle afferent activation or reactive hyperemia.
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Adenosine has been proposed to be a locally produced regulator of blood flow in skeletal muscle. However, the fundamental questions of to what extent adenosine is formed in skeletal muscle tissue of humans, whether it is present in the interstitium, and where it exerts its vasodilatory effect remain unanswered. The interstitial adenosine concentration was determined in the vastus lateralis muscle of healthy humans via dialysis probes inserted in the muscle. The probes were perfused with buffer, and the dialysate samples were collected at rest and during graded knee extensor exercise. At rest, the interstitial concentration of adenosine was 220+/-100 nmol/L and femoral arterial blood flow (FaBF) was 0.19+/-0.02 L/min. When the subjects exercised lightly, at a work rate of 10 W, there was a markedly higher (1140+/-540 nmol/L; P<0.05) interstitial adenosine concentration and a higher FaBF (2.22+/-0.18 L/min; P<0.05) compared with at rest. When exercise was performed at 20, 30, 40, or 50 W, the concentration of adenosine was moderately greater for each increment, as was the level of leg blood flow. The interstitial concentrations of ATP, ADP, and AMP increased from rest (0.13+/-0.03, 0.07+/-0.03, and 0.07+/-0.02 micromol/L, respectively) to exercise (10 W; 2.00+/-1.32, 2.08+/-1.23, and 1.65+/-0.50 micromol/L, respectively; P<0.05). The present study provides, for the first time, interstitial adenosine concentrations in human skeletal muscle and demonstrates that adenosine and its precursors increase in the exercising muscle interstitium, at a rate associated with intensity of muscle contraction and the magnitude of muscle blood flow.
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The role of nitric oxide (NO) as a regulator of vasomotor tone has been investigated in resting and exercising human skeletal muscle. At rest, NO synthase (NOS) inhibition by intra-arterial infusion of NG-monomethyl-L-arginine decreased femoral artery blood flow (FABF, ultrasound Doppler) from 0.39 +/- 0.08 to 0.18 +/- 0.03 l/min (P < 0. 01), i.e., by approximately 52%, and increased leg O2 extraction from 62.1 +/- 9.8 to 100.9 +/- 4.5 ml/l (P < 0.004); thus leg O2 uptake (VO2, 22 +/- 4 ml/min, approximately 0.75 ml. min-1. 100 g-1) was unaltered [not significant (P = NS)]. Mean arterial pressure (MAP) increased by 8 +/- 2 mmHg (P < 0.01). Heart rate (HR, 53 +/- 3 beats/min) was unaltered (P = NS). The NOS inhibition had, however, no effect on the initial rate of rise or the magnitude of FABF (4.8 +/- 0.4 l/min, approximately 163 ml. min-1. 100 g-1), MAP (117 +/- 3 mmHg), HR (98 +/- 5 beats/min), or leg VO2 (704 +/- 55 ml/min, approximately 24 ml. min-1. 100 g-1, P = NS) during submaximal, one-legged, dynamic knee-extensor exercise. Similarly, FABF (7.6 +/- 1.0 l/min, approximately 258 ml. min-1. 100 g-1), MAP (140 +/- 8 mmHg), and leg VO2 (1,173 +/- 139 ml/min, approximately 40 ml. min-1. 100 g-1) were unaffected at termination of peak effort (P = NS). Peak HR (137 +/- 3 beats/min) was, however, lowered by 10% (P < 0.01). During recovery, NOS inhibition reduced FABF by approximately 34% (P < 0.04), which was compensated for by an increase in the leg O2 extraction by approximately 41% (P < 0.04); thus leg VO2 was unaltered (P = NS). In conclusion, these findings indicate that NO is not essential for the initiation or maintenance of active hyperemia in human skeletal muscle but support a role for NO during rest, including recovery from exercise. Moreover, changes in blood flow during rest and recovery caused by NOS inhibition are accompanied by reciprocal changes in O2 extraction, and thus VO2 is maintained.
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We tested the hypothesis that basal (resting) limb blood flow and vascular conductance are reduced with age in adult humans and that these changes are related to elevations in sympathetic vasoconstrictor nerve activity and reductions in limb oxygen demand. Sixteen young (28+/-1 years; mean+/-SEM) and 15 older (63+/-1 years) healthy normotensive adult men were studied. Diastolic blood pressure and body fat were higher (P<0.005) in the older men, but there were no other age-related differences in subject characteristics. Femoral artery blood flow (Doppler ultrasound) was 26% lower in the older men (P<0.005), despite similar levels of cardiac output (systemic arterial blood flow) in the 2 groups. Femoral artery vascular conductance was 32% lower and femoral vascular resistance was 45% higher in the older men (P<0. 005). Muscle sympathetic nerve activity (peroneal microneurography) was 74% higher in the older men (P<0.001) and correlated with femoral artery blood flow (r=-0.55, P<0.005), vascular conductance (r=-0.65, P<0.001), and vascular resistance (r=0.61, P<0.001). The age-related differences in femoral hemodynamics were no longer significant after correction for the influence of muscle sympathetic nerve activity. There were no significant age-group differences in leg tissue mass (by dual-energy x-ray absorptiometry), but estimated leg oxygen consumption was 15% lower in the older men (P<0.001). Femoral artery blood flow was directly related to estimated leg oxygen consumption (r=0.78, P<0.001). The age-group differences in femoral artery blood flow were no longer significant after correction for estimated leg oxygen consumption by ANCOVA. (1) Basal whole-leg arterial blood flow and vascular conductance are reduced with age in healthy adult men; (2) these changes are associated with elevations in sympathetic vasoconstrictor nerve activity; and (3) the lower whole-limb blood flow is related to a lower oxygen demand that is independent of tissue mass.
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The aim of this study was to investigate the effects of endurance training on skeletal muscle hemodynamics and oxygen consumption. Seven healthy endurance-trained and seven untrained subjects were studied. Oxygen uptake, blood flow, and blood volume were measured in the quadriceps femoris muscle group by use of positron emission tomography and [15O]O2, [15O]H2O, and [15O]CO during rest and one-legged submaximal intermittent isometric exercise. The oxygen extraction fraction was higher (0.49 +/- 0.14 vs. 0.29 +/- 0.12; P = 0.017) and blood transit time longer (0.6 +/- 0.1 vs. 0.4 +/- 0.1 min; P = 0.04) in the exercising muscle of the trained compared with the untrained subjects. The flow heterogeneity by means of relative dispersion was lower for the exercising muscle in the trained (50 +/- 9%) compared with the untrained subjects (65 +/- 13%, P = 0.025). In conclusion, oxygen extraction is higher, blood transit time longer, and perfusion more homogeneous in endurance-trained subjects compared with untrained subjects at the same workload. These changes may be associated with improved exercise efficiency in the endurance-trained subjects.
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Blood flow to contracting skeletal muscle is tightly coupled to the oxygenation state of hemoglobin. To investigate if ATP could be a signal by which the erythrocyte contributes to the regulation of skeletal muscle blood flow and oxygen (O2) delivery, we measured circulating ATP in 8 young subjects during incremental one-legged knee-extensor exercise under conditions of normoxia, hypoxia, hyperoxia, and CO+normoxia, which produced reciprocal alterations in arterial O2 content and thigh blood flow (TBF), but equal thigh O2 delivery and thigh O2 uptake. With increasing exercise intensity, TBF, thigh vascular conductance (TVC), and femoral venous plasma [ATP] augmented significantly (P<0.05) in all conditions. However, with hypoxia, TBF, TVC, and femoral venous plasma [ATP] were (P<0.05) or tended (P=0.14) to be elevated compared with normoxia, whereas with hyperoxia they tended to be reduced. In CO+normoxia, where femoral venous O2Hb and (O2+CO)Hb were augmented compared with hypoxia despite equal arterial deoxygenation, TBF and TVC were elevated, whereas venous [ATP] was markedly reduced. At peak exercise, venous [ATP] in exercising and nonexercising limbs was tightly correlated to alterations in venous (O2+CO)Hb (r2=0.93 to 0.96; P<0.01). Intrafemoral artery infusion of ATP at rest in normoxia (n=5) evoked similar increases in TBF and TVC than those observed during exercise. Our results in humans support the hypothesis that the erythrocyte functions as an O2 sensor, contributing to the regulation of skeletal muscle blood flow and O2 delivery, by releasing ATP depending on the number of unoccupied O2 binding sites in the hemoglobin molecule.
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Despite increases in muscle sympathetic vasoconstrictor activity, skeletal muscle blood flow and O2 delivery increase during exercise in humans in proportion to the local metabolic demand, a phenomenon coupled to local reductions in the oxygenation state of haemoglobin and concomitant increases in circulating ATP. We tested the hypothesis that circulating ATP contributes to local blood flow and O2 delivery regulation by both inducing vasodilatation and blunting the augmented sympathetic vasoconstrictor activity. In eight healthy subjects, we first measured leg blood flow (LBF) and mean arterial pressure (MAP) during three hyperaemic conditions: (1) intrafemoral artery adenosine infusion (vasodilator control), (2) intrafemoral artery ATP infusion (vasodilator), and (3) mild knee-extensor exercise (approximately 20 W), and then compared the responses with the combined infusion of the vasoconstrictor drug tyramine, which evokes endogenous release of noradrenaline from sympathetic nerve endings. In all three hyperaemic conditions, LBF equally increased from approximately 0.5 +/- 0.1 l min(-1) at rest to approximately 3.6 +/- 0.3 l min(-1), with no change in MAP. Tyramine caused significant leg vasoconstriction during adenosine infusion (53 +/- 5 and 56 +/- 5% lower LBF and leg vascular conductance, respectively, P < 0.05), which was completely abolished by both ATP infusion and exercise. In six additional subjects resting in the sitting position, intrafemoral artery infusion of ATP increased LBF and leg vascular conductance 27 +/- 3-fold, despite concomitant increases in venous noradrenaline and muscle sympathetic nerve activity of 2.5 +/- 0.2- and 2.4 +/- 0.1-fold, respectively. Maximal ATP-induced vasodilatation at rest accounted for 78% of the peak LBF during maximal bicycling exercise. Our findings in humans demonstrate that circulating ATP is capable of regulating local skeletal muscle blood flow and O2 delivery by causing substantial vasodilatation and negating the effects of increased sympathetic vasoconstrictor activity.
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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.
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Mitochondrial function has previously been studied in ageing, but never in humans matched for maximal oxygen uptake ((V)·O2max). Furthermore, the influence of ageing on mitochondrial substrate sensitivity is not known. Skeletal muscle mitochondrial respiratory capacity and mitochondrial substrate sensitivity were measured by respirometry in young (23 ± 3 years) and middle-aged (53 ± 3 years) male subjects with similar (V)·O2max. Protocols for respirometry included titration of substrates for complex I (glutamate), complex II (succinate) and both (octanoyl carnitine) for calculation of substrate sensitivity (C(50) ). Myosin heavy chain (MHC) isoforms, citrate synthase (CS) and β-hydroxy-acyl-CoA-dehydrogenase (HAD) activity, mitochondrial DNA (mtDNA) content, protein levels of complexes I-V and antioxidant defence system [manganese superoxide dismutase (MnSOD)] were measured. No differences were found in maximal mitochondrial respiration or C(50) with glutamate (2.0 ± 0.3 and 1.8 ± 0.3 mm), succinate (3.7 ± 0.2 and 3.8 ± 0.4 mm) or octanoyl carnitine (47 ± 8 and 56 ± 7 μm) in young and middle-aged subjects respectively. Normalizing mitochondrial respiration to mtDNA young subjects had a higher (P < 0.05) respiratory capacity per mitochondrion compared to middle-aged subjects. HAD activity and mtDNA per mg tissue were higher in middle-aged compared to young subjects. Middle-aged had a higher MHC I isoform and a lower MHC IIX isoform content compared to young subjects. Mitochondrial substrate sensitivity is not affected by ageing. When young and middle-aged men are carefully matched for (V)·O2max, mitochondrial respiratory capacity is also similar. However, per mitochondrion respiratory capacity was lower in middle-aged compared to young subjects. Thus, when matched for (V)·O2max, middle-aged seem to require a higher mitochondrial content than young subjects.
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Brachial artery flow-mediated dilation (FMD) is a strong predictor of future cardiovascular disease and is believed to represent a "barometer" of systemic endothelial health. Although a recent study [Padilla et al. Exp Biol Med (Maywood) 235: 1287-1291, 2010] in pigs confirmed a strong correlation between brachial and femoral artery endothelial function, it is unclear to what extent brachial artery FMD represents a systemic index of endothelial function in humans. We conducted a retrospective analysis of data from our laboratory to evaluate relationships between the upper (i.e., brachial artery) vs. lower limb (superficial femoral n = 75; popliteal artery n = 32) endothelium-dependent FMD and endothelium-independent glyceryl trinitrate (GTN)-mediated dilation in young, healthy individuals. We also examined the relationship between FMD assessed in both brachial arteries (n = 42). There was no correlation between brachial and superficial femoral artery FMD (r(2) = 0.008; P = 0.46) or between brachial and popliteal artery FMD (r(2) = 0.003; P = 0.78). However, a correlation was observed in FMD between both brachial arteries (r(2) = 0.34; P < 0.001). Brachial and superficial femoral artery GTN were modestly correlated (r(2) = 0.13; P = 0.007), but brachial and popliteal artery GTN responses were not (r(2) = 0.08; P = 0.11). Collectively, these data indicate that conduit artery vasodilator function in the upper limbs (of healthy humans) is not predictive of that in the lower limbs, whereas measurement of FMD in one arm appears to be predictive of FMD in the other. These data do not support the hypothesis that brachial artery FMD in healthy humans represents a systemic index of endothelial function.
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Non-technical summary When muscles contract, a variety of signals interact and ultimately increase blood flow and oxygen delivery to the active muscle. However, when there is simultaneous activation of the sympathetic nervous system, noradrenaline (norepinephrine) is released which tries to cause vasoconstriction in the same blood vessels that are trying to relax (vasodilate). In young adults, we have shown that there is a unique ability of the contracting muscle to limit this vasoconstriction, and also that a circulating factor called ATP mimics the exercise response. In the present study, we demonstrate that older healthy adults have an impaired ability to limit the sympathetic vasoconstrictor signal during exercise; however, this ability is preserved when we administer ATP. Thus, if this impairment in the ability of contracting muscle to limit sympathetic vasoconstriction in older adults is related to ATP, we speculate that circulating levels of ATP may be impaired during exercise.
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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.
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One major unresolved issue in muscle blood flow regulation is that of the role of circulating versus interstitial vasodilatory compounds. The present study determined adenosine-induced formation of NO and prostacyclin in the human muscle interstitium versus in femoral venous plasma to elucidate the interaction and importance of these vasodilators in the 2 compartments. To this end, we performed experiments on humans using microdialysis technique in skeletal muscle tissue, as well as the femoral vein, combined with experiments on cultures of microvascular endothelial versus skeletal muscle cells. In young healthy humans, microdialysate was collected at rest, during arterial infusion of adenosine, and during interstitial infusion of adenosine through microdialysis probes inserted into musculus vastus lateralis. Muscle interstitial NO and prostacyclin increased with arterial and interstitial infusion of adenosine. The addition of adenosine to skeletal muscle cells increased NO formation (fluorochrome 4-amino-5-methylamino-2',7-difluorescein fluorescence), whereas prostacyclin levels remained unchanged. The addition of adenosine to microvascular endothelial cells induced an increase in NO and prostacyclin levels. These findings provide novel insight into the role of adenosine in skeletal muscle blood flow regulation and vascular function by revealing that both interstitial and plasma adenosine have a stimulatory effect on NO and prostacyclin formation. In addition, both skeletal muscle and microvascular endothelial cells are potential mediators of adenosine-induced formation of NO in vivo, whereas only endothelial cells appear to play a role in adenosine-induced formation of prostacyclin.
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The present study was performed to investigate the effect of acidosis on the efflux of ATP from skeletal muscle. Infusion of lactic acid to the perfused hindlimb muscles of anaesthetised rats produced dose-dependent decreases in pH and increases in the interstitial ATP of extensor digitorum longus (EDL) muscle: 10 mM lactic acid reduced the venous pH from 7.22 ± 0.04 to 6.97 ± 0.02 and increased interstitial ATP from 38 ± 8 to 67 ± 11 nM. The increase in interstitial ATP was well-correlated with the decrease in pH (r(2) = 0.93; P < 0.05). Blockade of cellular uptake of lactic acid using α-cyano-hydroxycinnamic acid abolished the lactic acid-induced ATP release, whilst infusion of sodium lactate failed to depress pH or increase interstitial ATP, suggesting that intracellular pH depression, rather than lactate, stimulated the ATP efflux. Incubation of cultured skeletal myoblasts with 10 mM lactic acid significantly increased the accumulation of ATP in the bathing medium from 0.46 ± 0.06 to 0.76 ± 0.08 μM, confirming the skeletal muscle cells as the source of the released ATP. Acidosis-induced ATP efflux from the perfused muscle was abolished by CFTR(inh)-172, a specific inhibitor of the cystic fibrosis transmembrane conductance regulator (CFTR), or glibenclamide, an inhibitor of both K(ATP) channels and CFTR, but it was not affected by atractyloside, an inhibitor of the mitochondrial ATP transporter. Silencing of the CFTR gene using an siRNA abolished the acidosis-induced increase in ATP release from cultured myoblasts. CFTR expression on skeletal muscle cells was confirmed using immunostaining in the intact muscle and Western blotting in the cultured cells. These data suggest that depression of the intracellular pH of skeletal muscle cells stimulates ATP efflux, and that CFTR plays an important role in the release mechanism.
Article
Endothelium-dependent vasodilatation is reduced with advancing age in humans, as evidenced by blunted vasodilator responsiveness to acetylcholine (ACh). Circulating adenosine triphosphate (ATP) has been implicated in the control of skeletal muscle vascular tone during mismatches in oxygen delivery and demand (e.g. exercise) via binding to purinergic receptors (P2Y) on the endothelium evoking subsequent vasodilatation, and ageing is typically associated with reductions in muscle blood flow under such conditions. Therefore, we tested the hypothesis that ATP-mediated vasodilatation is impaired with age in healthy humans. We measured forearm blood flow (venous occlusion plethysmography) and calculated vascular conductance (FVC) responses to local intra-arterial infusions of ACh, ATP, and sodium nitroprusside (SNP) before and during ascorbic acid (AA) infusion in 13 young and 13 older adults. The peak increase in FVC to ACh was significantly impaired in older compared with young adults (262 ± 71% vs. 618 ± 97%; P < 0.05), and this difference was abolished during AA infusion (510 ± 82% vs. 556 ± 71%; not significant, NS). In contrast, peak FVC responses were not different between older and young adults to either ATP (675 ± 105% vs. 734 ± 126%) or SNP (1116 ± 111% vs. 1138 ± 148%) and AA infusion did not alter these responses in either age group (both NS). In another group of six young and six older adults, we determined whether vasodilator responses to adenosine and ATP were influenced by P1-receptor blockade via aminophylline. The peak FVC responses to adenosine were not different in young (350 ± 65%) versus older adults (360 ± 80%), and aminophylline blunted these responses by ∼50% in both groups. The peak FVC responses to ATP were again not different in young and older adults, and aminophylline did not impact the vasodilatation in either group. Thus, in contrast to the observed impairments in ACh responses, the vasodilatory response to exogenous ATP is not reduced with age in healthy humans. Further, our data also indicate that adenosine mediated vasodilatation is not reduced with age, and that ATP-mediated vasodilatation is independent of P1-receptor stimulation in both young and older adults.
Article
Sympathetic vasoconstriction is blunted in the vascular beds of contracting skeletal muscle in humans, presumably due to the action of vasoactive metabolites (functional sympatholysis). Recently, we demonstrated that infusion of ATP into the arterial circulation of the resting human leg increases blood flow and concomitantly blunts alpha-adrenergic vasoconstriction in a similar manner to that during moderate exercise. Here we tested the hypothesis that ATP, rather than its dephosphorylated metabolites, induces vasodilatation and sympatholysis in resting skeletal muscle via activation of ATP/UTP-selective receptors. To this aim, we first measured leg blood flow (LBF), mean arterial pressure (MAP), cardiac output , leg arterial-venous (a-v) O(2) difference, plasma ATP and soluble nucleotidase activities during intrafemoral artery infusion of adenosine, AMP, ADP, ATP or UTP in nine healthy males. Comparison of the doses of nucleotides and adenosine required for a similar increase in LBF from approximately 0.5 l min(-1) at baseline to approximately 3.5 l min(-1) (without altering MAP but increasing Q significantly) revealed the following rank order of vasoactive potency: ATP (100) = UTP (100) > adenosine (5.8) > ADP (2.7) > AMP (1.7). The infusions did not cause any shifts in plasma ATP level or soluble serum nucleotidase activities. Combined infusion of the vasodilatory compounds and the sympathetic vasoconstrictor drug tyramine increased plasma noradrenaline in all hyperaemic conditions, but only caused leg and systemic vasoconstriction and augmented O(2) extraction during adenosine, AMP and ADP infusion (LBF from 3.2 +/- 0.3 to 1.8 +/- 0.2 l min(-1); 3.7 +/- 0.4 to 1.7 +/- 0.2 l min(-1) and 3.3 +/- 0.4 to 2.4 +/- 0.3 l min(-1), respectively, P < 0.05). These findings in humans suggest that the vasodilatory and sympatholytic effects of exogenous ATP in the skeletal muscle vasculature are largely mediated via ATP itself rather than its dephosphorylated metabolites, most likely via binding to endothelial ATP/UTP-selective P2Y(2) receptors. These data are consistent with a role of ATP in skeletal muscle hyperaemia in conditions of increased sympathetic nerve drive such as exercise or hypoxia.
Article
13 male subjects were studied and placed in 3 groups. Each group exercised one leg with sprint (S), or endurance (E) training and the other leg oppositely or not at all (NT). Oxygen uptake (Vo2), heart rate and blood lactate were measured for each leg separately and for both legs together during submaximal and maximal bicycle work before and after 4 weeks of training with 4-5 sessions per week. Muscle samples were obtained from the quadriceps muscle and assayed for succinate dehydrogenase (SDH) activity, and stained for myofibrillar ATPase. In addition, eight of the subjects performed after the training two-legged exercise at 70% Vo2 max for one hour. The measurements included muscle glycogen and lactate concentrations of the two legs as well as the blood flow and the a-v difference for O2, glucose and lactate.
Article
WE measured plasma noradrenaline (NA) levels in about 20 individuals who were to serve as normal control subjects and noted that older subjects tended to have higher NA levels. Extending the study to teenage and elderly subjects revealed that basal levels of plasma NA correlate with age and that the increase in plasma NA in response to stress is similarly related to age. There is considerable evidence that sensitivity to NA and NA metabolism change with increasing age. In rabbits and cats the threshold for cardiovascular response to low levels of NA decreases with old age1. In ageing rats uptake of NA into the heart is greater than in young animals2 and there is a diminished inotropic response of aged rat myocardium to a fixed concentration of NA (ref. 3). Cardiac monoamine oxidase activity increases severalfold during the life span of a rat while dopa decarboxylase decreases during the first year2. In man, propranalol, which blocks β-adrenergic receptors, reduces heart rate and cardiac output during exercise, but this effect is considerably smaller in older subjects4. The response of heart rate to hypoxia and hypercapnia is attenuated in older men5.
Article
Resting sympathetic nervous system activity is increased in heart failure. Whether sympathetic nervous system responses during exercise are increased is controversial. Furthermore, the role of muscle metaboreceptors and central command in regulating sympathetic outflow has been largely unexplored. Muscle sympathetic nerve activity (MSNA, peroneal nerve) was measured in nine heart failure subjects and eight age-matched control subjects during static exercise (30% maximal voluntary contraction) for 2 minutes and during a period of posthandgrip regional circulatory arrest. This maneuver isolates the metaboreceptor contribution to sympathetic nervous system responses. MSNA responses were similar during static exercise in the two groups. During posthandgrip regional circulatory arrest we observed a marked attenuation in MSNA responses in the heart failure subjects (15% increase in heart failure versus 57% increase in control subjects). A cold pressor test demonstrated a normal MSNA response to a potent nonspecific stimulus in the heart failure subjects (heart failure subjects, 141% increase; control subjects, 215% increase; NS). Nuclear magnetic resonance spectroscopy studies in five separate heart failure subjects and five control subjects suggested that the attenuated metaboreceptor response in heart failure was not due to reduced H+ production. Skeletal muscle metaboreceptor responses are impaired in heart failure. Because MSNA responses during static exercise are similar in the two groups, mechanisms aside from metaboreceptor stimulation must be important in increasing sympathetic nervous system activity.
Article
Recent investigations using direct (microneurographic) recordings of MSNA have provided a substantial amount of new information on the regulation of sympathetic nervous system control of nonactive skeletal muscle blood flow during exercise in humans. Some of the new conclusions from these studies discussed in this review include: 1. The direction, pattern and magnitude of the MSNA response to exercise depend on the collective influence of a number of factors, including the mode (isometric or rhythmic), intensity, and duration of the exercise, the size of the contracting muscle mass, and possibly the level of conditioning (physical training) of the exercising muscles. The MSNA response also appears to be tightly coupled with the onset and progression of muscle fatigue, at least during sustained, isometric contractions. 2. Increases in MSNA evoked during exercise with the arms are fairly uniform among different skeletal muscle nerves, and these responses correlate strongly with changes in venous plasma norepinephrine concentrations, limb vascular resistance and arterial blood pressure. Thus, increases in this neural activity during exercise are associated with the expected physiological responses. 3. The MSNA response to the same level of exercise varies markedly among healthy subjects but appears to be consistent over time within a particular subject. 4. The muscle metaboreflex (muscle chemoreflex) is the primary-mechanism by which MSNA is stimulated during small-muscle, isometric exercise in humans. In contrast, central command has a relatively weak influence on MSNA during this type of exercise. 5. Muscle metaboreflex-stimulation of MSNA also occurs during dynamic exercise, but only at or above moderate, submaximal intensities (i.e., not during mild exercise). 6. Muscle metaboreflex-evoked increases in MSNA during exercise are strongly associated with glycogenolysis and the consequent cellular accumulation of hydrogen ions in the contracting muscles. 7. Sympathoinhibitory cardiopulmonary reflexes do not appear to modulate the MSNA responses to isometric exercise in the healthy human. However, arterial baroreflexes exert a potent inhibitory effect on MSNA during this form of exercise. The mechanisms involved in the regulation of MSNA during large-muscle, dynamic leg exercise is an important topic for future investigations, as is the relationship between MSNA and sympathetic outflow to other regional circulations (e.g., heart, viscera, skin) during various forms of exercise.
Article
Five subjects exercised with the knee extensor of one limb at work loads ranging from 10 to 60 W. Measurements of pulmonary oxygen uptake, heart rate, leg blood flow, blood pressure and femoral arterial-venous differences for oxygen and lactate were made between 5 and 10 min of the exercise. Flow in the femoral vein was measured using constant infusion of saline near 0 degrees C. Since a cuff was inflated just below the knee during the measurements and because the hamstrings were inactive, the measured flow represented primarily the perfusion of the knee extensors. Blood flow increased linearly with work load right up to an average value of 5.7 l min-1. Mean arterial pressure was unchanged up to a work load of 30 W, but increased thereafter from 100 to 130 mmHg. The femoral arterial-venous oxygen difference at maximum work averaged 14.6% (v/v), resulting in an oxygen uptake of 0.80 l min-1. With a mean estimated weight of the knee extensors of 2.30 kg the perfusion of maximally exercising skeletal muscle of man is thus in the order of 2.5 l kg-1 min-1, and the oxygen uptake 0.35 l kg-1 min-1. Limitations in the methods used previously to determine flow and/or the characteristics of the exercise model used may explain why earlier studies in man have failed to demonstrate the high perfusion of muscle reported here. It is concluded that muscle blood flow is closely related to the oxygen demand of the exercising muscles. The hyperaemia at low work intensities is due to vasodilatation, and an elevated mean arterial blood pressure only contributes to the linear increase in flow at high work rates. The magnitude of perfusion observed during intense exercise indicates that the vascular bed of skeletal muscle is not a limiting factor for oxygen transport.