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Exercise training modulates functional sympatholysis and α-adrenergic vasoconstrictor responsiveness in hypertensive and normotensive individuals

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Abstract

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

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... It has been suggested that high-intensity training leads to a reduction in the α-adrenergic responsiveness and improves functional sympatholysis at rest [32,33]. Kruse et al. [34] concluded that faster compared to slower volume-matched muscle contractions led to improved functional sympatholysis muscle contractions in humans. ...
... It has been demonstrated that intravascular [ATP] draining active skeletal muscle increases progressively with exercise intensity in young healthy adults [2,31], and has an intensity-dependent ability to limit α 1 -mediated vasoconstriction [8]. 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]. ...
... 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. ...
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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.
... Previous studies have reported that 16 weeks of aerobic exercise training decreases SBP during treadmill exercise in hypertensive 12) and borderline or mildly hypertensive 13) men. Aerobic training improves vascular load (i.e., arterial stiffness 4,14,15) and vascular conductance 14, 16) ) and blunts sympathetic vasoconstriction during exercise (functional sympatholysis) 17) . It has also been reported that endurance-trained athletes 18,19) and physically active men with autism spectrum disorder 20) have lower arterial stiffness. ...
... Arterial stiffening in strength-trained individuals may be associated with higher levels of plasma endothelin-1, a vasoconstrictor peptide 19) . On the other hand, aerobic training, which does not require intense muscle contractions, decreases vascular load [14][15][16] and increases functional sympatholysis 17) . Therefore, we investigated the effects of daily physical activity levels and aerobic training on SBP during resistance exercise in middle-aged and older individuals 4) . ...
... Indeed, plasma concentrations of soluble LOX-1 were correlated with arterial stiffness 30) . 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) . ...
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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.
... Inhibition of NO and prostaglandin formation abolishes ATPinduced vasodilatation in this model suggesting that the effect of interstitial ATP is mediated by the formation of these vasodilators, most likely via purinergic receptors on the endothelium (313). Somewhat unexpectedly, endurance training leads to a reduced sensitivity to arterially infused ATP (293), whereas immobilization of the leg leads to an increased sensitivity to infused ATP (292). This may seem counterintuitive; however, it may suggest that the relative importance of the different vasoactive compounds can change with training status. ...
... This residual effect of acute exercise indicates that exercise training is central for stimulating the signaling pathways that are important for functional sympatholysis. In accordance, data obtained from both longitudinal (209,292,293) and cross-sectional (295) Figure 7 Femoral arterial blood flow during knee-extensor exercise without and with arterial infusion of tyramine (induces a release of norepinephrine from sympathetic nerve endings) with a previously immobilized, untrained, and trained limb. Immobilization lasted for two weeks and was achieved by casting. ...
... The mechanisms underlying the effect of training on functional sympatholysis are still unresolved, but data obtained from the human leg indicates that a reduced α-adrenergic responsiveness may be important (293), whereas rodent data suggest that functional sympatholysis is augmented through a NO-dependent mechanism in an intensity-dependent manner (209). In regard to the latter study, a more pronounced vasoconstrictor effect of sympathetic stimulation was observed in trained rats at rest. ...
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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 released ATP acts on P2 receptors on endothelial cells mainly in response to shear stress and hypoxia to act on P2Y1, P2Y2, and sometimes P2Y4, P2Y11 P2X1, P2X2, P2X3, and P2X4 receptors, leading to vasodilation. Adenosine is also formed and stimulates the formation of NO and prostaglandins, besides that stimulates vasodilation directly through P1 receptors, mainly A2 receptors on vascular smooth muscle cells [18,25]. In the skeletal muscle interstitium, there is a marked increase in the concentration of ATP and adenosine, and this increase is tightly coupled to the increase in blood flow. ...
... In the skeletal muscle interstitium, there is a marked increase in the concentration of ATP and adenosine, and this increase is tightly coupled to the increase in blood flow. The sources of interstitial ATP and adenosine are thought to be skeletal muscle cells and endothelial cells [25]. ...
... About P2X receptors, in a study with hypertensive humans undergoing chronic cycling ergometer training, Mortensen et al. [25] found that, before training, P2X1 content in skeletal muscle did not differ between hypertensive and normotensive subjects. However, training increases P2X1 expression in normotensive, but not in the hypertensive group. ...
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In the last years, it has become evident that both acute and chronic physical exercise trigger responses/adaptations in the purinergic signaling and these adaptations can be considered one important mechanism related to the exercise benefits for health improvement. Purinergic system is composed of enzymes (ectonucleotidases), receptors (P1 and P2 families), and molecules (ATP, ADP, adenosine) that are able to activate these receptors. These components are widely distributed in almost all cell types, and they respond/act in a specific manner depending on the exercise types and/or intensities as well as the cell type (organ/tissue analyzed). For example, while acute intense exercise can be associated with tissue damage, inflammation, and platelet aggregation, chronic exercise exerts anti-inflammatory and anti-aggregant effects, promoting health and/or treating diseases. All of these effects are dependent on the purinergic signaling. Thus, this review was designed to cover the aspects related to the relationship between physical exercise and purinergic signaling, with emphasis on the modulation of ectonucleotidases and receptors. Here, we discuss the impact of different exercise protocols as well as the differences between acute and chronic effects of exercise on the extracellular signaling exerted by purinergic system components. We also reinforce the concept that purinergic signaling must be understood/considered as a mechanism by which exercise exerts its effects.
... blood flow, particularly during exercise, are apparent after a single skeletal muscle contraction (6,7,9,19,21) and persist under steady-state conditions (8,23,33,34,36). Blunted skeletal muscle blood flow responses in older adults have been attributed to alterations in local vasodilatory mechanisms, elevations in sympathetic vasoconstrictive activity, or an impaired ability to modulate sympathetic vasoconstriction during exercise (13,17,22,26,42). Collectively, these adverse changes in the vasculature and decreased limb blood flow can potentially lead to an inadequate matching of oxygen delivery to the metabolic demand of the contracting muscle (1,23,40). ...
... Chronic exercise training has been shown to ameliorate many age-associated changes in vascular function (26,28,43), while physical inactivity is a risk factor for the development of chronic diseases (5,32). Indeed, there is a strong inverse relationship between cardiorespiratory fitness (e.g., maximal oxygen consumption) and overall mortality (4,15), highlighting the benefits of lifelong exercise and high levels of physical activity. ...
... 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. ...
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.
... Perfusion of the capillary bed is a critical determinant of maximal tissue metabolism as it sets the capacity for substrate uptake (Wagner, 1996;Bassett and Howley, 2000;Sarelius and Pohl, 2010). This dependence manifests with endurance training when most subjects demonstrate compensatory adaptations within the capillary bed of skeletal muscle, such as enhanced endothelium-dependent vasodilatation of arterioles and increased capillarisation (Egginton, 2009;Mortensen et al., 2014). The regulatory processes being implicated in exerciseinduced vascular adaptations comprise a rapidly increased blood flow with the onset of muscle contractions (Clifford and Hellsten, 2004;Egginton, 2009). ...
... The findings indicate that additional factors, or confounders, which affect the ACE system and water homeostasis must play a role of regulation of ACE, such as prior exercise, thermal environment and water intake (Kosunen et al., 1976;Staessen et al., 1987;Danser et al., 2007). The endurance training state is possibly an important confounder, because it affects the capacity for exercise-induced muscle perfusion through an improvement in exercise-induced vasodilatation and increase of the capillary bed (Egginton et al., 1998;Flück and Hoppeler, 2003;Mortensen et al., 2014). In fact, endurance training state is an important factor, which affects the angiogenic response to exercise (Busso and Flück, 2013;Hoier et al., 2013), in association with improved vasodilatative and capacitive mechanism of muscle perfusion and aerobic metabolism (reviewed in Flück and Hoppeler, 2003;Clifford and Hellsten, 2004;Egginton, 2009;Korthuis, 2011;Mortensen et al., 2014). ...
... The endurance training state is possibly an important confounder, because it affects the capacity for exercise-induced muscle perfusion through an improvement in exercise-induced vasodilatation and increase of the capillary bed (Egginton et al., 1998;Flück and Hoppeler, 2003;Mortensen et al., 2014). In fact, endurance training state is an important factor, which affects the angiogenic response to exercise (Busso and Flück, 2013;Hoier et al., 2013), in association with improved vasodilatative and capacitive mechanism of muscle perfusion and aerobic metabolism (reviewed in Flück and Hoppeler, 2003;Clifford and Hellsten, 2004;Egginton, 2009;Korthuis, 2011;Mortensen et al., 2014). In turn this affects shear stress and tissue oxygenationmediated control of angiogenic factor expression and action (Zumstein et al., 1983;Wibom et al., 1992;Egginton et al., 2001;Dapp et al., 2006;Williams et al., 2006). ...
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The insertion/deletion polymorphism in the gene for the regulator of vascular tone, angiotensin-converting enzyme (ACE), is the prototype of a genetic influence on physical fitness and this involves an influence on capillary supply lines and dependent aerobic metabolism in skeletal muscle. The respective interaction of ACE-I/D genotype and training status on local metabolic and angiogenic reactions in exercised muscle is not known. Toward this end we characterized the metabolomic and angiogenic response in knee extensor muscle, m. vastus lateralis, in 18 untrained and 34 endurance-trained (physically active, V.O2max > 50 mL min⁻¹ kg⁻¹) white British men to an exhaustive bout of one-legged cycling exercise. We hypothesized that training status and ACE-I/D genotype affect supply-related muscle characteristics of exercise performance in correspondence to ACE expression and angiotensin 2 levels. ACE-I/D genotype and training status developed an interaction effect on the cross-sectional area (CSA) of m. vastus lateralis and mean CSA of slow type fibers, which correlated with peak power output (r ≥ 0.44). Genotype × training interactions in muscle also resolved for exercise-induced alterations of 22 metabolites, 8 lipids, glycogen concentration (p = 0.016), ACE transcript levels (p = 0.037), and by trend for the pro-angiogenic factor tenascin-C post exercise (p = 0.064). Capillary density (p = 0.001), capillary-to-fiber ratio (p = 0.010), systolic blood pressure (p = 0.014), and exercise-induced alterations in the pro-angiogenic protein VEGF (p = 0.043) depended on the ACE-I/D genotype alone. Our observations indicate that variability in aerobic performance in the studied subjects was in part reflected by an ACE-I/D-genotype-modulated metabolic phenotype of a major locomotor muscle. Repeated endurance exercise appeared to override this genetic influence in skeletal muscle by altering the ACE-related metabolic response and molecular aspects of the angiogenic response to endurance exercise. © 2017 Valdivieso, Vaughan, Laczko, Brogioli, Waldron, Rittweger and Flück.
... 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. ...
... An interesting observation was that exercise training lowered the a-adrenergic responsiveness in both groups at rest. Mortensen et al 11 reported that normotensive and hypertensive middle-aged men and women demonstrated lower a-adrenergic responsiveness after a training period; however, to the best of our knowledge, this is the first evidence that exercise training reduces a-adrenergic responsiveness in older men. There was some discrepancy between the older and the young group in that the older group experienced lower a-adrenergic responsiveness at the medium tyramine infusion dose only, whereas the young group showed a lower a-adrenergic responsiveness at the highest infusion dose. ...
... The mechanisms responsible for the reduction in a-adrenergic responsiveness observed with training are currently unknown. Similar to the findings by Mortensen et al, 11 tyramine-induced NE release at rest was not affected by training in the current study, which rules out the possibility that the lower change in LVC with tyramine after training was caused by a lowering of NE release. ...
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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.
... Endothelial hyperpolarization conducts in both directions via gap junctions and may also by conducted directly to adjacent smooth muscle cells via myoendothelial gap junctions (not shown). Recent findings in humans show that the functional sympatholytic ability is improved after a period of exercise training in different populations [74][75][76]. ...
... Functional sympatholysis can be assessed by the ability of acute exercise to oppose the vasoconstriction induced by infusion of tyramine, a compound which induces release of noradrenalin from the nerve terminal. Recent findings in humans show that the ability for functional sympatholysis is improved after a period of exercise training in young healthy individuals [74] and in individuals with cardiovascular disease [75,76]. Previous findings have also shown that it is preserved with lifelong physical activity in older adults [24]. ...
... The mechanisms underlying the improvements are incompletely understood, but ATP, which is a sympatholytic compound in humans [5], has been shown to be higher in lifelong physically active men than in sedentary individuals [24], and lowered with a period of immobilization concomitant with changes in the ability for functional sympatholysis [77]. In addition, a lower constrictive effect of sympathetic activity after training may also be explained by a reduction in a-adrenergic responsiveness to noradrenalin in trained muscle, as examined by infusion of tyramine at rest [75]. In rodents, the improvement in functional sympatholysis with training has been convincingly coupled to NO [72,73]. ...
Article
A number of mechanisms govern the rapid and precise changes in blood flow which occur in skeletal muscle with alterations in metabolic demand. Such mechanisms include sympathetic activity, functional sympatholysis, conducted vasodilation, flow mediated dilation, and compounds which stimulate formation of endothelium derived vasodilators. Compounds identified to be of importance in vasodilation include nitric oxide, prostacyclin, potassium, and nucleotides. In this review, we briefly describe some of the basic mechanisms and present selected contemporary contributions to the field. The main focus is on basic regulation of exercise hyperemia but aspects of training, age and sex have also been included.
... In animal studies, blunting of sympathetic vasoconstriction during exercise (functional sympatholysis) was enhanced through a NO-dependent mechanism (Jendzjowsky and Delorey, 2013;Mizuno et al., 2014). Human studies have reported that aerobic training increases plasma concentrations of nitrite/nitrate (NOx, end products of NO) (Maeda et al., 2004;Fujie et al., 2014Fujie et al., , 2015 and improves functional sympatholysis (Mortensen et al., 2014). In addition, decreases in resistance exercise SBP by aerobic training are correlated with decreases in arterial stiffness (Otsuki et al., 2016); NO is a potent regulator of arterial stiffness (Wilkinson et al., 2002;Sugawara et al., 2007). ...
... 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). ...
... 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). Vasodilation mediated by NO in contracting muscles might be a mechanism through which increases in NOx concentrations lead to decreases in resistance exercise SBP. ...
Article
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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.
... However, uncertainty remains regarding the relevance of such an antihypertensive effect beyond a few hours, the impact of consuming amaranth hydrolysate on blood pressure in normotensive cases, and the magnitude of the antihypertensive effect compared to lifestyle interventions such as physical activity. Increasing physical activity helps to prevent and control blood pressure [7][8][9], in part by promoting the exercise-induced attenuation of sympathetic vasoconstriction [10][11][12]. In fact, a physical activity program of at least 30 min five times per week is an inexpensive and effective intervention that helps to control blood pressure [13]. ...
... Compelling evidence suggests that exercise stimuli increase the endothelial function and that this biological event increases the activity of endothelial nitric oxide synthases [40,41]. As a mediator of functional sympatholysis, nitric oxide promotes the exercise-induced attenuation of sympathetic vasoconstriction [11,12]. As stated by others [19,42], our results show that a low-intensity aerobic exercise routine can lower the SBP in SHR and that the antihypertensive effect can be sustained as the physical activity is conducted. ...
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Background and objectives: Both antihypertensive peptide intake and physical activity help to control blood pressure. Our aim was to evaluate the impact of consuming amaranth antihypertensive peptides on systolic blood pressure (SBP) in normotensive rats and the magnitude and relevance of the peptide-induced antihypertensive effect in spontaneously hypertensive rats (SHR). Materials and Methods: Treatments (alcalase-generated amaranth protein hydrolysate, captopril, or water) were given by gavage and the SBP measured by the tail-cuff method. Physical activity was performed five days/week (for twenty weeks). Results: The normotensive rats' SBP (mmHg, average/group) remained unaffected after amaranth antihypertensive peptide supplementation (121.8) (p > 0.05 vs controls). In SHR, the SBP was lowered by 24.6 (sedentary/supplemented at two weeks), 42.0 (sedentary/supplemented at eight weeks), and 31.5 (exercised/non-supplemented at eight weeks) (p < 0.05 vs sedentary/non-supplemented). The combination of supplementation and physical activity lowered the SBP by 36.2 and 42.7 (supplemented/exercised at two weeks and eight weeks, respectively) (p < 0.05 vs sedentary/non-supplemented), but it did not have additional antihypertensive benefits (p > 0.05 vs sedentary/supplemented at eight weeks or exercised/non-supplemented at eight weeks). Conclusions: Amaranth antihypertensive peptide supplementation has no impact on SBP in normotensive rats. This supplementation develops sustained antihypertensive benefits in SHR, which are similar to the antihypertensive effect developed after eight-or twenty-week low-intensity physical activity. These findings have implications for developing safe and effective peptide-based functional foods.
... On one testing day, assessment of body composition (bioelectrical impedance analysis; Bodystat 1500, Bodystat, Douglas, Isle of Man) and measurement of arterial stiffness were followed by a maximal incremental exercise test. On the other testing (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40) Values are means (95% confidence interval). BMI, body mass index; DBP, diastolic blood pressure; SBP, systolic blood pressure; V O2peak, peak oxygen consumption. ...
... Changes to efferent neurotransmission may also mediate upward vascular sympathetic baroreflex setting. Short-term exercise training reduces ␣-adrenergic vasoconstrictor responsiveness (35), and a reduction of sympathetic vascular transduction has been proposed to contribute to orthostatic intolerance observed in some highly trained individuals (52). Vasoconstrictor responsiveness to noradrenaline declines with advancing age (10), which may counteract the effects of elevated MSNA burst frequency (16). ...
Article
This study focused on the influence of habitual endurance exercise training (i.e., committed runner or nonrunner) on the regulation of muscle sympathetic nerve activity (MSNA) and arterial pressure in middle-aged (50 to 63 yr, n = 23) and younger (19 to 30 yr; n = 23) normotensive men. Hemodynamic and neurophysiological assessments were performed at rest. Indices of vascular sympathetic baroreflex function were determined from the relationship between spontaneous changes in diastolic blood pressure (DBP) and MSNA. Large vessel arterial stiffness and left ventricular stroke volume also were measured. Paired comparisons were performed within each age category. Mean arterial pressure and basal MSNA bursts/min were not different between age-matched runners and nonrunners. However, MSNA bursts/100 heartbeats, an index of baroreflex regulation of MSNA (vascular sympathetic baroreflex operating point), was higher for middle-aged runners (P = 0.006), whereas this was not different between young runners and nonrunners. The slope of the DBP-MSNA relationship (vascular sympathetic baroreflex gain) was not different between groups in either age category. Aortic pulse wave velocity was lower for runners of both age categories (P < 0.03), although carotid β-stiffness was lower only for middle-aged runners (P = 0.04). For runners of both age categories, stroke volume was larger, whereas heart rate was lower (both P < 0.01). In conclusion, we suggest that neural remodeling and upward setting of the vascular sympathetic baroreflex compensates for cardiovascular adaptations after many years committed to endurance exercise training, presumably to maintain arterial blood pressure stability. NEW & NOTEWORTHY Exercise training reduces muscle sympathetic burst activity in disease; this is often extrapolated to infer a similar effect in health. We demonstrate that burst frequency of middle-aged and younger men committed to endurance training is not different compared with age-matched casual exercisers. Notably, well-trained, middle-aged runners display similar arterial pressure but higher sympathetic burst occurrence than untrained peers. We suggest that homeostatic plasticity and upward setting of the vascular sympathetic baroreflex maintains arterial pressure stability following years of training.
... For example, resistance training on a regular basis increases arterial stiffness, a determinant of blood pressure (5,17). However, habitual exercise that does not require intense muscle contraction (e.g., increased levels of daily physical activity and aerobic exercise training) may attenuate blood pressure elevation during resistance exercise, because aerobic exercise training improves arterial stiffness (5,36), vascular conductance (5,26), and blunting of sympathetic vasoconstriction during exercise (20). ...
... functional sympatholysis is impaired in older individuals with a sedentary lifestyle (8,10). 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. ...
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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.
... Although performed at a much higher intensity and duration, IPC is not dissimilar to the ischemic component of IRT. Furthermore, Kimura et al. 28 observed improved blood flow and hence FS within the contralateral limb following IPC, suggesting a possible systemic effect. It is also thought that stimulation of ATP activated potassium channels (K ATP ) may contribute to improved FS and this has previously been shown to be one of the effects of IPC exercise 3,27 . ...
... Therefore, it is plausible that repeated exposure to an ischemia-reperfusion stimulus using IRT may enhance FS via improved K ATP channel activity. Although these purported mechanisms are speculative, at this time the data presented in this study suggest that IRT may improve vascular function which has been previously reported to be enhanced through improved FS 28,29 . However, additional research needs to be undertaken to further explore these possible mechanisms and the reported reductions seen in MBPS following IRT. ...
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Despite the reported association between diurnal variations in ambulatory blood pressure (BP) and elevated cardiovascular disease risk, little is known regarding the effects of isometric resistance training (IRT), a practical BP-lowering intervention, on ambulatory BP and morning BP surge (MBPS). Thus, we investigated whether (i) IRT causes reductions in ambulatory BP and MBPS, in young normotensives, and (ii) if there are any sex differences in these changes. Twenty normotensive individuals (mean 24-h SBP = 121 ± 7, DBP = 67 ± 6 mmHg) undertook 10-weeks of bilateral-leg IRT (4 × 2-min/2-min rest, at 20% maximum voluntary contraction (MVC) 3 days/week). Ambulatory BP and MBPS (mean systolic BP (SBP) 2 h after waking minus the lowest sleeping 1 h mean SBP) was measures pre- and post-training. There were significant reductions in 24-h ambulatory SBP in men (− 4 ± 2 mmHg, P = 0.0001) and women (− 4 ± 2 mmHg, P = 0.0001) following IRT. Significant reductions were also observed in MBPS (− 6 ± 8 mmHg, p = 0.044; − 6 ± 7 mmHg, P = 0.019), yet there were no significant differences between men and women in these changes, and 24-h ambulatory diastolic BP remained unchanged. Furthermore, a significant correlation was identified between the magnitude of the change in MBPS and the magnitude of changes in the mean 2-h SBP after waking for both men and women (men, r = 0.89, P = 0.001; women, r = 0.74, P = 0.014). These findings add further support to the idea that IRT, as practical lifestyle intervention, is effective in significantly lowering ambulatory SBP and MBPS and might reduce the incidence of adverse cardiovascular events that often occur in the morning.
... The reductions of BP after acute exercise are instantaneous and remain for up to 24 h after the exercise bout [35]; this is the socalled post-exercise hypotension (PEH) [21,36,37]. Histamine receptor activation seems to be the physiological cause of PEH, although more research is needed in this regard [38]. ...
... Hypertensive men show attenuated functional sympatholysis during exercise and exaggerated sympathetic vasoconstriction [87]. It has been shown that exercise training improves functional sympatholysis in hypertensive subjects by lowering the sensitivity of adrenergic receptors on vascular smooth muscle [37]. ...
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.
... Leg blood flow (LBF) in the common femoral artery was measured using Doppler ultrasound. LBF was measured at rest and during 1 minute of passive leg movements followed by 3-minute leg kicking at 12 W. 17,18 statistical methods Effects within training groups were analyzed using a paired t-test, and differences between groups with Student's t-test comparing the mean change from baseline, but where the assumption of normality was not met, we used the Wilcoxon and Mann-Whitney U-tests. LBF measured at different time points was analyzed using a two-way analysis of variance with repeated measures (Holm-Sidak post hoc). ...
... The ability to override sympathetic vasoconstrictor activity during exercise, termed functional sympatholysis, appears to impair leg muscle blood flow in patients with essential hypertension, while exercise training improves exercise hyperemia and functional sympatholysis. 17 ...
Article
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Introduction Exercise is an important countermeasure to limb muscle dysfunction in COPD. The two major training modalities in COPD rehabilitation, endurance training (ET) and resistance training (RT), may both be efficient in improving muscle strength, exercise capacity, and health-related quality of life, but the effects on quadriceps muscle characteristics have not been thoroughly described. Methods Thirty COPD patients (forced expiratory volume in 1 second: 56% of predicted, standard deviation [SD] 14) were randomized to 8 weeks of ET or RT. Vastus lateralis muscle biopsies were obtained before and after the training intervention to assess muscle morphology and metabolic and angiogenic factors. Symptom burden, exercise capacity (6-minute walking and cycle ergometer tests), and vascular function were also assessed. Results Both training modalities improved symptom burden and exercise capacity with no difference between the two groups. The mean (SD) proportion of glycolytic type IIa muscle fibers was reduced after ET (from 48% [SD 11] to 42% [SD 10], P<0.05), whereas there was no significant change in muscle fiber distribution with RT. There was no effect of either training modality on muscle capillarization, angiogenic factors, or vascular function. After ET the muscle protein content of phosphofructokinase was reduced (P<0.05) and the citrate synthase content tended increase (P=0.08) but no change was observed after RT. Conclusion Although both ET and RT improve symptoms and exercise capacity, ET induces a more oxidative quadriceps muscle phenotype, counteracting muscle dysfunction in COPD.
... One important adaptation is an increase in peripheral fractional O 2 extraction, and a lowering of blood flow to the exercising limb when exercise is performed submaximally at the same workload. [21][22][23] This effect of training is thought to be, at least in part, attributed to a parallel increase in skeletal muscle capillarization. 24 An increase in skeletal muscle capillarization can prolong mean erythrocyte transit time, and reduce diffusion distance, improving conditions for O 2 diffusion, 25 although some data also suggest that an increase in capillary density does not affect muscle O 2 diffusing capacity 26 and that diffusing distance may not be a major limiting factor. ...
... 9,38 It is known that a period of exercise training can increase fractional O 2 extraction and lower blood flow in the muscle during submaximal exercise. [21][22][23] As increased skeletal muscle capillarization and increased muscle oxidative capacity are common adaptations to aerobic exercise training, it has been assumed that the increased fractional O 2 extraction has been a result of these adaptations. However, no in vivo study in either animals or humans has directly demonstrated the lone effect of increasing capillarization on muscle fractional oxygen extraction and blood flow. ...
Article
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Aim: To investigate the effect of elevated basal shear stress on angiogenesis in humans, and the role of enhanced skeletal muscle capillarisation on blood flow and O2 extraction. Methods: Limb haemodynamics and O2 extraction was measured at rest and during one-leg knee-extensor exercise (12 and 24W) in 10 healthy untrained young men before and after 4 weeks treatment with an α1 receptor-antagonist (Terazosin, 1-2 mg day(-1) ). Corresponding biopsies were taken from the m. vastus lateralis. Results: Resting leg blood flow was increased by 57% 6 hours following Terazosin treatment (P<0.05), while basal capillary-to-fibre ratio was 1.69±0.08 and increased to 1.90±0.08 after treatment (P<0.05). Leg O2 extraction during knee-extensor exercise was higher (4-5%; P<0.05), leg blood flow and venous lactate levels lower (6-7%; P<0.05), while leg VO2 was not different after Terazosin treatment. Conclusions: These results demonstrate that daily treatment with an α-adrenergic receptor blocker induces capillary growth in human skeletal muscle, likely due to increased shear stress. The increase in capillarisation resulted in an increased fractional O2 extraction, a lower blood flow and venous lactate levels in the exercising leg. The increase in capillarisation, and concomitant functional readouts in the exercising leg, may provide a basis for novel angiotherapy. This article is protected by copyright. All rights reserved.
... This is combined with exaggerated SNA responses to exercise, leading to reductions in muscle perfusion and increased metabolites that activate the metaboreflex. 18,31,32 Therefore, an impaired functional sympatholysis could also explain exaggerated metaboreflex sensitivity in treated-controlled hypertension. It could be postulated that standard first-line antihypertensive medications (eg, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, or thiazide-like diuretic 33 ) do not directly affect functional sympatholysis or metaboreflex sensitivity during exercise. ...
... Putting the overt cardiovascular risk of acute exercise aside demonstrated herein, long-term aerobic training (3-4× per week) has improved functional sympatholysis in the femoral artery and subsequently the BP response to exercise of untreated hypertensive patients. 32 Improvement of longterm cardiovascular fitness could be an effective method for improving the autonomic response to exercise in treated and untreated hypertension. However, adherence to exercise regimes is typically poor, highlighting the need for improved strategies to promote exercise training or physical activity in the community. ...
Article
An exaggerated blood pressure (BP) response to maximal exercise is an independent risk factor for cardiovascular events and mortality. It is unclear whether treating BP to guideline recommended levels could normalize the rise in BP during exercise, which is mediated by the metaboreflex. We aimed to assess the BP response to incremental exercise testing and metaboreflex activation in treated-controlled hypertension (n=16), treated-uncontrolled hypertension (n=16), and untreated hypertension (n=11) and 16 control participants with normal BP (n=16). All groups were matched for age and body mass index. BP was measured during an incremental Vo2 peak test on a cycle ergometer and during metaboreflex isolation using postexercise ischemia. Data were analyzed using 2-way ANOVA with Tukey test for multiple comparisons. Aerobic fitness was similar among groups (P=0.97). The rise in absolute systolic BP from baseline at peak exercise was similar in controlled, uncontrolled, and untreated hypertension but greater compared with normotensive controls (Δ71±3, 81±7, 79±8.5 versus 47±5 mm Hg; P=0.0001). Metaboreflex sensitivity was also similar in controlled, uncontrolled, and untreated hypertension but augmented compared with normotensive controls (Δsystolic BP: 21±2, 28±2, 25±3 versus 12±2 mm Hg; P<0.0001). An amplified pressor response to exercise occurred in patients taking antihypertensive medication, despite having controlled BP at rest and was potentially caused (in part) by enhanced metaboreflex sensitivity. Poor BP control during exercise, partially mediated by the metaboreflex, may contribute to the heightened risk of an adverse cardiovascular event even in treated-controlled patients.
... Related to the chronic effects of physical exercise in purinergic system components, Mortensen et al. [234] investigated aerobic training for 8 weeks in hypertensive and normotensive individuals. They aimed to examine whether functional sympatholytic and ATP signaling are impaired in the leg of hypertensive individuals and to determine the effect of aerobic training on these parameters. ...
... However, the training reduced the vasodilatory response to ATP and increased the skeletal muscle P2Y 2 R content in both groups. These results indicate that exercise training improves functional sympatholysis and reduces postjunctional α-adrenergic responsiveness in both normo-and hypertensive individuals [234]. ...
Article
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Diabetes mellitus (DM) and hypertension are highly prevalent worldwide health problems and frequently associated with severe clinical complications, such as diabetic cardiomyopathy, nephropathy, retinopathy, neuropathy, stroke, and cardiac arrhythmia, among others. Despite all existing research results and reasonable speculations, knowledge about the role of purinergic system in individuals with DM and hypertension remains restricted. Purinergic signaling accounts for a complex network of receptors and extracellular enzymes responsible for the recognition and degradation of extracellular nucleotides and adenosine. The main components of this system that will be presented in this review are: P1 and P2 receptors and the enzymatic cascade composed by CD39 (NTPDase; with ATP and ADP as a substrate), CD73 (5′-nucleotidase; with AMP as a substrate), and adenosine deaminase (ADA; with adenosine as a substrate). The purinergic system has recently emerged as a central player in several physiopathological conditions, particularly those linked to inflammatory responses such as diabetes and hypertension. Therefore, the present review focuses on changes in both purinergic P1 and P2 receptor expression as well as the activities of CD39, CD73, and ADA in diabetes and hypertension conditions. It can be postulated that the manipulation of the purinergic axis at different levels can prevent or exacerbate the insurgency and evolution of diabetes and hypertension working as a compensatory mechanism.
... It is possible that the older hypertensive group in the current study is part of an angiogenic nonresponder population that does not experience increases in capillary density in response to endurance training (40). In contrast to our finding, studies in younger hypertensive adults have shown improvements in capillarization and capillary ultrastructure (41) and improvements in functional sympatholysis (42) after endurance exercise training. Increased peripheral vascular resistance associated with hypertension may have limited the changes in microvascular function. ...
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.
... 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. ...
... However, recent findings suggest that exercise training reduces blood pressure only in hypertensive individuals whereas sympathetic activity is reduced in both normotensive and hypertensive individuals, indicating that a reduced sympathetic activity is not the underlying cause (5). An alternative mechanism behind the effect of exercise training on blood pressure could be a reduced sensitivity to noradrenaline, as previously shown (6). However, the mechanism underlying this reduced sensitivity remains unknown. ...
Article
Introduction: Regular exercise training reduces arterial blood pressure but the underlying mechanisms are unclear. Here, we evaluated the potential involvement of Pannexin-1, an ATP releasing channel, in the blood pressure-reducing effect of training. Methods: Middle-aged men; 13 normotensive and 14 non-medicated stage 1 hypertensive, completed 8 weeks of intensive aerobic cycle training. Before and after training, blood pressure and changes in leg vascular conductance, induced by femoral arterial infusion of tyramine (induces endogenous noradrenaline release), acetylcholine or sodium nitroprusside were measured during control conditions and after acute Pannexin-1 inhibition by probenecid. A skeletal muscle biopsy was obtained from the thigh, pre- and post-training. Results: Exercise training reduced mean systolic and diastolic blood pressure by ~5 (P = 0.013) and 5 mmHg (P < 0.001), respectively, in the hypertensive group only. The reduction in blood pressure was not related to changes in Pannexin-1 function since mean arterial blood pressure and tyramine-induced vasoconstriction remain unaltered by Pannexin-1 inhibition after training in both groups. After training, Pannexin-1 inhibition enhanced leg vascular conductance in the normo- and hypertensive groups at baseline (41.5%, P = 0.0036 and 37.7%, P = 0.024, respectively) and in response to sodium nitroprusside infusion (275%, P = 0.038 and 188%, P = 0.038, respectively). Training did not alter the Pannexin-1 protein expression in skeletal muscle. Training enhanced the vasodilator response to acetylcholine infusion, and increased the expression of microvascular function-relevant proteins. Conclusions: The exercise training-induced lowering of arterial blood pressure in non-medicated hypertensive men, does not involve an altered function of Pannexin-1.
... augmented group III and IV skeletal muscle afferent stimulation per se, alterations in their sensitivity, for example via an upregulation of purinergic [23] and TRPV1 [21] signaling pathways, may also be important. Impaired functional sympatholysis may augment neural-vascular transduction in hypertension [24], although this is not a consistent observation [25]. Finally, alterations in central autonomic reflex control may also be influential, with diminished nitric oxide signaling and augmented oxidative stress at the nucleus tractus solitarius shown to be important for the overactive muscle mechanoreflex observed in the hypertensive rat [26]. ...
... The trend toward a larger attenuation in cardiac BRS during active cycling in the high-fitness group may support this concept. As MSNA did not differ between the normal-and high-fitness groups, the greater increase in total vascular conductance may be associated with enhanced endothelium-dependent smooth muscle function, or functional sympatholysis (28,30). Future work is required to prospectively test the influence of exercise training on central command and its influence on MSNA responses. ...
Article
The contribution of central command to the peripheral vasoconstrictor response during exercise has been investigated using primarily handgrip exercise. The purpose of the present study was to compare muscle sympathetic nerve activity (MSNA) responses during passive (involuntary) and active (voluntary) zeroload cycling to gain insight into the effects of central command on sympathetic outflow during dynamic exercise. Hemodynamic measurements and contralateral leg MSNA (microneurography) were collected in eighteen young healthy participants at rest and during 2 minutes of passive and active zeroload one-legged cycling. Arterial baroreflex control of MSNA burst occurrence and burst area were calculated separately in the time-domain. Blood pressure and stroke volume increased during exercise (p<0.0001) but were not different between passive and active cycling (p>0.05). In contrast, heart rate, cardiac output, and total vascular conductance were all greater during the first and second minute of active cycling (p<0.001). MSNA burst frequency and incidence decreased during passive and active cycling (p<0.0001) but no differences were detected between exercise modes (p>0.05). Reductions in total MSNA were attenuated during the first (p<0.0001) and second (p=0.0004) minute of active compared to passive cycling, in concert with increased MSNA burst amplitude (p=0.02 and p=0.005, respectively). Compared to passive cycling, the sensitivity of arterial baroreflex control of MSNA burst occurrence was lower during active cycling (p=0.01), while control of MSNA burst strength was unchanged (p>0.05). These results suggest that central feedforward mechanisms are involved primarily with modulating the strength but not occurrence of a sympathetic burst during low intensity dynamic leg exercise.
... Cependant, Enko et collègues ont démontré qu'un traitement de RIPC appliqué au bras gauche entraîne une vasodilatation (indépendante du NO) de l'artère brachiale du bras droit qui s'expliquerait par une hausse de l'activité parasympathique 250 . En somme, bien que les mécanismes à l'origine des modulations de la fonction endothéliale à la suite du RIPC demeurent énigmatiques, ce type de conditionnement favorise le débit sanguin dans le muscle squelettique en induisant une vasodilatation 250 et en favorisant la sympatholyse fonctionnelle 251(atténuation ou abolition de l'augmentation de l'activité vasoconstrictrice sympathique lors de la contraction musculaire252,253 ). ...
... However, sympathetic vasoconstrictor activity is higher at high-intensity exercise and may dominate over ATP-mediated vasodilation, even if exercise training also has been shown to improve functional sympatholysis. 13,63 However, to study the mechanisms regulating skeletal muscle blood flow was beyond the scope of the present investigation. ...
Article
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When exercising with a small muscle mass, the mass-specific O2 delivery exceeds the muscle oxidative capacity resulting in a lower O2 extraction compared to whole-body exercise. We elevated the muscle oxidative capacity and tested its impact on O2 extraction during small muscle mass exercise. Nine individuals conducted six weeks of one-legged knee extension (1L-KE) endurance training. After training, the trained leg (TL) displayed 45% higher citrate synthase and COX-IV protein content in vastus lateralis and 15-22% higher pulmonary oxygen uptake (VO2peak ) and peak power output (Wpeak ) during 1L-KE than the control leg (CON; all P<0.05). Leg O2 extraction (catheters) and blood flow (ultrasound Doppler) were measured while both legs exercised simultaneously during 2L-KE at the same submaximal power outputs (real-time feedback-controlled). TL displayed higher O2 extraction than CON (main effect: 1.7±1.6%-points; P=0.010; 40-83% of Wpeak ) with the largest between-leg difference at 83% of Wpeak (O2 extraction: 3.2±2.2%-points; arteriovenous O2 difference: 7.1±4.8 mL·L-1 ; P<0.001). At 83% of Wpeak , muscle O2 conductance (DMO2 ; Fick law of diffusion) and the equilibration index Y were higher in TL (P<0.01), indicating reduced diffusion limitations. The between-leg difference in O2 extraction correlated with the between-leg ratio of citrate synthase and COX-IV (r=0.72-0.73; P=0.03), but not with the difference in the capillary-to-fibre ratio (P=0.965). In conclusion, endurance training improves O2 extraction during small muscle mass exercise by elevating the muscle oxidative capacity and the recruitment of DMO2 ; especially evident during high-intensity exercise exploiting a larger fraction of the muscle oxidative capacity.
... Exercise training lower the response to arterially infused tyramine of hypertensive individuals. The training-induced lowering occur without alterations in norepinephrine concentration, suggesting that tyramine-induced norepinephrine release was not affected by exercise training (26). ...
Article
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The goal of this study was to examine vascular control after sympathetic stimulation by tyramine infusion in hypertensive rats submitted to swimming training. To this end, male rats were assigned to the following groups: sedentary (SN) and trained normotensive (TN), sedentary (SH) and trained hypertensive (TH). Arterial pressure (AP), heart rate (HR), HR variability (HRV), AP variability (APV), and cardiac autonomic function were recorded. Following, infusion of tyramine was administrated. The TN and TH showed a lower resting HR compared with their respective sedentary groups (p < .05). Pressure levels were less in TH than SH (p < .05). The TH showed a higher HRV together with a lower APV in comparison to SH (p < .05). The sympathetic modulation of HRV and APV was lower in TH than in SH (p < .05). Both trained groups presented an increased parasympathetic modulation of HRV compared with their respective sedentary groups (p < .05). The TN and TH groups had a higher vagal effect in comparison with their respective sedentary groups (p < .001). The sympathetic effect was lower in TH than in SH (p < .001). Pressor and HR responses to tyramine in different doses were attenuated in TH (p < .001). Further analysis showed a significant association between infusion of tyramine and normalized LF component of HRV (r = 0.84, p < .001), systolic APV (r = 0.58, p < .001) and diastolic APV (r = 0.49, p < .001). In conclusion, exercise training provokes less pressor response variation by tyramine infusion in hypertensive animals suggesting sympathetic nerve endings adjustments and decrease of the vasoconstrictor effect attenuates injury caused by hypertension improving cardiovascular autonomic dysfunction, which can be associated with sympathetic attenuation. ARTICLE HISTORY
... This reduced vasoconstriction during contraction (functional sympatholysis) allows adequate O 2 delivery to the active fibers. As a result, there is a decrease in α-adrenergic responsiveness on the smooth muscle cells, promoting a physical exercise-induced sympatholysis [113]. Accordingly, Heinonen and colleagues found that the inhibition of α-adrenergic tone disturbed the perfusion of blood flow to contracting muscles by directing it to the inactive muscle fibers as well [114]. ...
Article
The tumor vessel network has been investigated as a precursor of an inhospitable tumor microenvironment, including its repercussions in tumor perfusion, oxygenation, interstitial fluid pressure, pH, and immune response. Dysfunctional tumor vasculature leads to the extravasation of blood to the interstitial space, hindering proper perfusion and causing interstitial hypertension. Consequently, the inadequate delivery of oxygen and clearance of by-products of metabolism promote the development of intratumoral hypoxia and acidification, hampering the action of immune cells and resulting in more aggressive tumors. Thus, pharmacological strategies targeting tumor vasculature were developed, but the overall outcome was not satisfactory due to its transient nature and the higher risk of hypoxia and metastasis. Therefore, physical exercise emerged as a potential favorable modulator of tumor vasculature, improving intratumoral vascularization and perfusion. Indeed, it seems that regular exercise practice is associated with lasting tumor vascular maturity, reduced vascular resistance, and increased vascular conductance. Higher vascular conductance reduces intratumoral hypoxia and increases the accessibility of circulating immune cells to the tumor milieu, inhibiting tumor development and improving cancer treatment. The present paper describes the implications of abnormal vasculature on the tumor microenvironment and the underlying mechanisms promoted by regular physical exercise for the re-establishment of more physiological tumor vasculature.
... A saúde mental por sua vez, relaciona-se ao estado do sistema imunológico (86)(87)(88). De acordo com a literatura, os mecanismos psicológicos relacionados à prática de exercícios favorecem os estados de humor, que podem ser decorrentes da distração e/ou da autoeficácia (84,86) e, ainda, reduz a inflamação por meio de vários processos fisiológicos diferentes(86) promovendo melhora da função endotelial(89) e protegendo o sistema cardiocirculatório (90,91) bem como melhora o funcionamento do cérebro e a cognição (92). E tem sido recomendada por cientistas para melhorar a saúde das populações, bem como o sistema imunológico, face à pandemia de CoViD-19 (93,94). ...
Article
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Introdução: No início de janeiro de 2020, surgiram notícias difusas a respeito de uma nova doença, que logo se transformou em pandemia.Objetivo: Examinar o desenrolar histórico desse agravo à saúde e identificar possíveis efeitos sobre a prática de atividade física.Métodos: Foi feita busca nos termos “CoViD-19 or SARS-Cov2 or coronavirus” “WHO” “2020” compuseram o estudo artigos científicos, recomendações da Organização Mundial da Saúde (OMS) e notícias de jornais.Resultados e Discussão: Os primeiros meses do ano configuraram-se em um período de grande apreensão, face ao enfrentamento da nova, e potencialmente mortal, doença. Com o desenvolvimento do conhecimento clínico e experimental, os mecanismos da doença foram sendo desvendados e as formas de tratar/prevenir a CoViD-19 foram sendo estabelecidas. Recomendações da OMS quanto ao uso de máscaras de proteção durante a prática de atividade física foram identificadas.Conclusão: As consequências da pandemia atingiram todos os setores da vida humana, afetando a produtividade. É provável que a prevalência de sedentarismo tenha aumentado em todas as partes do globo, porém, os impactos sobre a prática de atividade física, cujos benefícios à saúde são bem estabelecidos na literatura, ainda não foram examinados.
... Le couplage ventriculo-artériel permet de calculer des indices fiables des fonctions vasculaires, mais il serait également intéressant de réaliser des mesures spécifiques aux vaisseaux, comme le calcul du rapport intima-média ou encore de la vitesse de l'onde de pouls [212]. De plus, une mesure du tonus autonomique exercé sur les vaisseaux pourrait apporter des résultats intéressants pour évaluer les e ets vasculaires de l'entraînement [349]. ...
Thesis
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Cette thèse visait à explorer trois limites des adaptations cardiovasculaires des sportifs endurants. Les athlètes endurants bradycardes ont-ils un risque augmenté de présenter des syncopes réflexes et des particularités électrocardiographiques par rapport à leurs homologues non bradycardes ? Commencer un entraînement après 40 ans est-il trop tard pour espérer améliorer sa santé cardiovasculaire ? La fatigue cardiaque retrouvée à l’issue d’efforts longs et intenses chez les coureurs à pied est-elle également induite par des efforts pratiqués essentiellement avec les bras comme le canoë-kayak ou par les efforts pratiqués par les militaires durant leurs stages intensifs ? Tout d’abord, l’étude BRADY suggère que chez des athlètes endurants de même niveau qui diffèrent uniquement par leur FC de repos (44 vs 61 batt.min-1) les bradycardes ne sont pas plus à risque de syncopes réflexes ni de particularités électrocardiographiques que les non bradycardes. L’hypertrophie cardiaque, plus importante chez les bradycardes, pourrait jouer un rôle central dans le développement de la bradycardie du sportif. Deuxièmement, l’étude COSS suggère que commencer un entraînement en endurance après 40 ans n’est pas trop tard pour être en meilleure santé cardiovasculaire à 60 ans. En effet le VO2max, la FC de repos ainsi que la balance sympathovagal ne diffèrent pas chez des seniors de 60 ans ayant commencé à s’entraîner avant 30 ans de chez ceux ayant commencé après 40 ans. Ces indices de la santé cardiovasculaire étaient meilleurs dans ces deux groupes par rapport aux personnes n’ayant jamais suivi un entraînement en endurance. Seul un entraînement initié avant 30 ans semble cependant apporter certains bénéfices vasculaires à l’effort, non retrouvés chez les seniors ayant commencé après 40 ans. Enfin, l’étude FACEFI visait à évaluer les conséquences cardiaques de 3 types d’efforts : 3 semaines d’entraînements intenses en canoë-kayak au pôle France de Cesson-Sévigné, 24h d’un stage d’aguerrissement chez des élèves des Écoles de Saint-Cyr Coëtquidan, et 4 jours d’un stage chez les Commandos de Marine. Seule une partie des résultats obtenus chez les Commandos de Marine a été analysée. Ils indiquent que 3 jours et 3 nuits d’un stage commando, finalisés par une marche forcée de 20 km en portant une charge de 20 kg, ne semblent pas altérer ni les dimensions ni les fonctions cardiaques. La durée relativement faible de l’effort (< 2h45), le très bon niveau d’entraînement des sujets, ainsi que la composante en résistance importante des efforts réalisés, peuvent expliquer ce résultat.
... Impaired ability to modulate sympathetic vasoconstrictor activity (functional sympatholysis) and a reduced exercise hyperemia are also characteristics of aging. Again, regular PA was shown to offset these impairments [22]. ...
Article
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Regular physical exercise and a healthy diet are major determinants of a healthy lifespan. Although aging is associated with declining endurance performance and muscle function, these components can favorably be modified by regular physical activity and especially by exercise training at all ages in both sexes. In addition, age-related changes in body composition and metabolism, which affect even highly trained masters athletes, can in part be compensated for by higher exercise metabolic efficiency in active individuals. Accordingly, masters athletes are often considered as a role model for healthy aging and their physical capacities are an impressive example of what is possible in aging individuals. In the present review, we first discuss physiological changes, performance and trainability of older athletes with a focus on sex differences. Second, we describe the most important hormonal alterations occurring during aging pertaining regulation of appetite, glucose homeostasis and energy expenditure and the modulatory role of exercise training. The third part highlights nutritional aspects that may support health and physical performance for older athletes. Key nutrition-related concerns include the need for adequate energy and protein intake for preventing low bone and muscle mass and a higher demand for specific nutrients (e.g., vitamin D and probiotics) that may reduce the infection burden in masters athletes. Fourth, we present important research findings on the association between exercise, nutrition and the microbiota, which represents a rapidly developing field in sports nutrition.
... tness blunts neurovascular coupling and/or post-synaptic sympathetic vasoconstrictor responsiveness(Notarius et al. 2012). The effect of exercise training on non-adrenergic receptor mediated vasoconstriction has not been investigated. The effects of exercise training on the expression of post-synaptic sympathetic receptors are also largely unknown.Mortensen et al (2014b) reported a small, but statistically significant, increase in skeletal muscle P2x receptor expression following 8 weeks of aerobic exercise training in middle-aged, normotensive men and women, suggesting that post-synaptic receptor expression may be responsive to exercise training. However, further investigation is required to determine ...
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.
... 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.
Article
Exercise training (ET) increases sympathetic vasoconstrictor responsiveness and enhances contraction-mediated inhibition of sympathetic vasoconstriction (i.e., sympatholysis) through a nitric oxide (NO)-dependent mechanism. Changes in α2-adrenoreceptor vasoconstriction mediate a portion of these training adaptations, however the contribution of other postsynaptic receptors remains to be determined. Therefore, the purpose of this study was to investigate the effect of ET on α1-adrenoreceptor-mediated vasoconstriction in resting and contracting muscle. It was hypothesized that α1-adrenoreceptor-mediated sympatholysis would be enhanced following ET. Male Sprague Dawley rats were randomized to sedentary (S; n = 12) or heavy-intensity treadmill ET (n = 11) groups. Subsequently, rats were anesthetized and instrumented for lumbar sympathetic chain stimulation and measurement of femoral vascular conductance (FVC) at rest and during muscle contraction. The percentage change in FVC in response to sympathetic stimulation was measured in control, α1-adrenoreceptor blockade (Prazosin; 20 lg, IV), and combined α1 and NO synthase (NOS) blockade (L-NAME; 5 mg·kg-1 IV) conditions. Sympathetic vasoconstrictor responsiveness was increased (P < 0.05) in ET compared to S rats at low, but not high (P > 0.05) stimulation frequencies at rest (S: 2 Hz: -25 ± 4%; 5 Hz: -45 ± 5 %; ET: 2 Hz: -35 ± 7%, 5 Hz: -52 ± 7%), whereas sympathetic vasoconstrictor responsiveness was not different (P > 0.05) between groups during contraction (S: 2 Hz: -11 ± 8%; 5 Hz: -26 ± 11%; ET: 2 Hz: -10 ± 7%, 5 Hz: -27 ± 12%). Prazosin blunted (P < 0.05) vasoconstrictor responsiveness in S and ET rats at rest and during contraction, and abolished group differences in vasoconstrictor responsiveness. Subsequent NOS blockade increased vasoconstrictor responses (P < 0.05) in S at rest and during contraction, whereas in ET vasoconstriction was increased (P < 0.05) in response to sympathetic stimulation at 2 Hz at rest and unchanged (P > 0.05) during contraction. ET enhanced (P < 0.05) sympatholysis, however the training-mediated improvements in sympatholysis were abolished by α1-adrenoreceptor blockade. Subsequent NOS inhibition did not alter (P > 0.05) sympatholysis in S or ET rats. In conclusion, ET augmented α1-adrenoreceptor-mediated vasoconstriction in resting skeletal muscle and enhanced α1-adrenoreceptor-mediated sympatholysis. Furthermore, these data suggest that NO is not required to inhibit α2-adrenoreceptor- and nonadrenoreceptor-mediated vasoconstriction during exercise.
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.
Article
During both dynamic (e.g. endurance) and static (e.g. strength) exercise there are exaggerated cardiovascular responses in hypertension. This includes greater increases in blood pressure, heart rate, and efferent sympathetic nerve activity than in normals. Two of the known neural factors which contribute to this abnormal cardiovascular response are the exercise pressor reflex (EPR) and functional sympatholysis. The EPR originates in contracting skeletal muscle and reflexly increases sympathetic efferent nerve activity to the heart and blood vessels as well as decreases parasympathetic efferent nerve activity to the heart. These changes in autonomic nerve activity cause an increase in blood pressure, heart rate, left ventricular contractility, and vasoconstriction in the arterial tree. However, arterial vessels in the contracting skeletal muscle have a markedly diminished vasoconstrictor response. The markedly diminished vasoconstriction in contracting skeletal muscle has been termed functional sympatholysis. It has been shown in hypertension that there is an enhanced EPR, including both its mechanoreflex and metaboreflex components, and an impaired functional sympatholysis. These conditions set up a positive feedback or vicious cycle situation which causes a progressively greater decrease in the blood flow to the exercising muscle. Thus, these two neural mechanisms contribute significantly to the abnormal cardiovascular response to exercise in hypertension. In addition, exercise training in hypertension decreases the enhanced EPR, including both mechanoreflex and metaboreflex function, and improves the impaired functional sympatholysis. These two changes, caused by exercise training, improve the muscle blood flow to exercising muscle and cause a more normal cardiovascular response to exercise in hypertension.
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.
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
Breathlessness during daily activities is the primary symptom in patients with heart failure (HF). Poor correlation between the hemodynamic parameters of left ventricular performance and perceived symptoms suggests that other factors such as skeletal muscle function plays a role in determining exercise capacity. We investigated the effect of six weeks of high-intensity one-legged cycling (HIC; 8x4 at 90% one-legged cycling max) on: 1) the ability to override sympathetic vasoconstriction (arterial infusion of tyramine) during one-legged knee-extensor exercise (KEE); 2) vascular function (arterial infusion of ACh, SNP, tyramine and ATP); 3) exercise capacity in HF patients with reduced ejection fraction (n=8) compared with healthy individuals (n=6). Arterial tyramine infusion lowered leg blood flow and leg vascular conductance at rest and during KEE before the training intervention in both groups (P<0.05), but not during KEE after the training intervention. There was no difference between groups. The peak vasodilatory response to ATP was blunted in the HF patients. (P<0.05), whereas there was no difference in ACh- and SNP- induced vasodilation between HF patients and healthy individuals. ACh induced vasodilation increased in the HF patients after the training intervention (P<0.05). HIC improved aerobic capacity in both groups (P<0.05), whereas only the HF patients improved six min walking distance (P<0.05). These results suggest that exercise hyperemia and functional sympatholysis is not altered in HF patients, and that functional sympatholysis is improved with HIC in both HF patients and healthy individuals. Moreover, these results suggest that the peak vasodilatory response to ATP is blunted.
Article
Objective: We analyzed the driving component between the periods of adjacent heartbeats (R-R intervals) and vastus lateralis-deoxygenation (%HHb) during incremental cycling. Considering a tight matching of local metabolism with systemic and local perfusion, a coupling between indices of cardiovascular control (R-R variability) and %HHb is suggested. Further, an intensity-dependent coupling between R-R variability and %HHb was hypothesized, because a multitude of feedback and feedforward mechanisms to autonomic cardiovascular control as well as local vasodilating mechanisms are associated with muscle metabolism and thus exercise intensity. Approach: Ten male triathletes (age: 34 ± 8 years) completed a test, including baseline (BAS, 50 W), a 25 W * min-1 ramp incremental phase until exhaustion and a recovery period (REC, 50 W). R-R intervals, %HHb and respiratory responses were simultaneously recorded. Five corresponding data segments were selected: BAS, before the first ventilatory threshold (preGET), between GET and the respiratory compensation point (preRCP), above RCP (postRCP), and REC. Bivariate transfer entropy (BTE) was applied to determine the signal coupling between R-R and %HHb. Main results: During preGET and preRCP, the analysis yielded the dominating direction from %HHb to R-R intervals, while for postRCP the direction was reversed. No significant signal coupling was detectable for the BAS and REC segments. Significance: Assuming that %HHb is related to the metabolic state of the working muscle, BTE results support the role of metaboreceptors in the systemic blood flow regulation at lower exercise intensities, while other mechanisms (e.g. baroreceptor and mechanoreceptor feedback, central command) that modulate cardiovascular control may override this coupling at higher intensities.
Article
Patients with end-stage renal disease (ESRD) have decreased exercise capacity and exercise intolerance that contribute to cardiovascular risk. One potential mechanism underlying exercise intolerance in ESRD is impaired ability to oppose sympathetically mediated vasoconstriction within exercising skeletal muscle (i.e., functional sympatholysis, FS). We hypothesized that ESRD patients have impaired FS compared with healthy (CON) and hypertensive (HTN) controls and that impaired FS is related to circulating levels of the uremic toxin asymmetric dimethyl arginine (ADMA), an endogenous nitric oxide synthase inhibitor. Near-infrared spectroscopy-derived oxygen tissue saturation index (TSI) of the forearm muscle was measured continuously in 33 participants (9 CON, 14 HTN, 10 ESRD) at rest and during low-dose (-20 mmHg) lower body negative pressure (LBNP), moderate rhythmic handgrip exercise, and LBNP with concomitant handgrip exercise (LBNP+handgrip). Resting muscle TSI was lower in ESRD than in CON and HTN groups (CON = 67.8 ± 1.9%, HTN = 67.2 ± 1.1%, ESRD = 62.7 ± 1.5%, P = 0.03). Whereas CON and HTN groups had an attenuation in sympathetically mediated reduction in TSI during LBNP + handgrip compared with LBNP alone (P ≤ 0.05), this response was not present in ESRD (P = 0.71), suggesting impaired FS. There was no difference in plasma [ADMA] between groups (CON = 0.47 ± 0.05 µmol/l, HTN = 0.42 ± 0.06 µmol/l, ESRD = 0.63 ± 0.14 µmol/l, P = 0.106) and no correlation between plasma [ADMA] and resting muscle TSI (P = 0.84) or FS (P = 0.75). Collectively, these findings suggest that ESRD patients have lower muscle perfusion at rest and impaired FS but that these derangements are not related to circulating [ADMA].
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
Weightlessness in space induces a fluid shift from the dependent to the cephalad parts of the body leading to distension of the cardiac chambers and an accumulation of blood in the veins of the head and neck. Surprisingly, central venous pressure (CVP) during the initial hours of spaceflight decreases compared to being horizontal supine on the ground. The explanation is that the thorax is expanded by weightlessness leading to a decrease in inter-pleural pressure (IPP), which exceeds the measured decrease in CVP. Thus, transmural CVP (TCVP = CVP - IPP) is increased indicating an augmented cardiac preload. Simultaneously, stroke volume and cardiac output (CO) are increased by 18 - 26 % within the initial weeks and more so by 35 - 56 % during the subsequent months of flight relative to in the upright posture on the ground. Mean arterial pressure (MAP) is decreased indicating a lower systemic vascular resistance (MAP/CO). It is therefore a surprise that sympathetic nerve activity is not suppressed in space and thus cannot be a mechanism for the systemic vasodilation, which still needs to be explored. Recent observations indicate that the fluid shift during long duration (months) flights is associated with increased retinal thickness that sometimes leads to optical disc edema. Ocular and cerebral structural changes, increases in left atrial size and decreased flows with thrombi formation in the left Internal Jugular Vein have also been observed. This is of concern for future long duration deep space missions, because the health implications are unknown.
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.
Article
During 1-leg cycling, contralateral muscle sympathetic nerve activity (MSNA) falls in healthy adults but increases in most with reduced ejection fraction heart failure (HFrEF). We hypothesized that their peak oxygen uptake (V̇O 2peak ) relates inversely to their MSNA response to exercise. Twenty-nine patients (6 women; 63 ± 9 years; left ventricular ejection fraction: 30 ± 7%; V̇O 2peak : 78 ± 23 percent age-predicted (%V̇O 2peak ); mean ± SD) and 21 healthy adults (9 women; 58 ± 7 years; 115 ± 29%V̇O 2peak ) performed 2 min of mild- (“loadless”) and moderate-intensity (“loaded”) 1-leg cycling. Heart rate, blood pressure (BP), contralateral leg MSNA and perceived exertion rate (RPE) were recorded. Resting MSNA burst frequency (BF) was higher (p < 0.01) in HFrEF (51 ± 11 vs 44 ± 7 bursts·min ⁻¹ ). Exercise heart rate, BP and RPE responses at either intensity were similar between groups. In minute 2 of “loadless” and “loaded” cycling, group mean BF fell from baseline values in controls (−5 ± 6 and −7 ± 7 bursts·min ⁻¹ , respectively) but rose in HFrEF (+5 ± 7 and +5 ± 10 bursts·min ⁻¹ ). However, in 10 of the latter cohort, BF fell, similarly to controls. An inverse relationship between ΔBF from baseline to “loaded” cycling and %V̇O 2peak was present in patients (r = −0.43, p < 0.05) but absent in controls (r = 0.07, p = 0.77). In HFrEF, ∼18% of variance in %V̇O 2peak can be attributed to the change in BF elicited by exercise. Novelty: Unlike healthy individuals, in the majority of heart failure patients with reduced ejection fraction (HFrEF), 1-leg cycling increases muscle sympathetic nerve activity (MSNA). In HFrEF, ∼18% of age-predicted peak oxygen uptake (V̇O 2peak ) can be attributed to changes in MSNA elicited by low-intensity exercise. This relationship is absent in healthy adults.
Thesis
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This thesis includes four research papers, based on four separate studies aiming to elucidate the importance of O2 extraction and blood volume (BV) for maximal O2 uptake (VO2max). In study I, twelve untrained subjects (VO2max: 44 ml · kg-1 · min-1) completed ten weeks of supervised endurance training (three sessions per week). VO2max and maximal cardiac output (Qmax) were measured during upright and supine cycling before and after training, as well as immediately after the training-induced gain in BV was reversed by blood withdrawal. The supine position increases venous return to the heart and may thus counteract potential adverse effects of blood withdrawal. The BV increased by 4% (~2 dl) with training. After reversing BV to the pre-training level, VO2max and Qmax remained 11% and 9% higher than before training, respectively, regardless of exercise position. By using the Fick principle (VO2 = Q × a-v ̅O2diff), it was calculated that 30% and 70% of the increase in VO2max was attributed to increased O2 content difference between arterial and mixed venous blood (a-v ̅O2diff) and increased Qmax, respectively. These improvements coincided with increased protein content of mitochondrial enzymes, a small increase in the capillary-to-fibre ratio (m. vastus lateralis) and an increased left ventricular mass (echocardiography). Thus, VO2max may increase with endurance training independent of BV expansion, caused by combined central and peripheral adaptations. In study II, thirteen subjects (VO2max: 63 ml · kg-1 · min-1) performed maximal exercise on a cycle ergometer in three experimental conditions: with normal BV and immediately after acute BV reductions of 150 ml and 450 ml, representing 2.5% and 7.6% of the total BV (6.0 l), respectively. After the 150 ml reduction, VO2max was preserved compared with the control test (non-significant reduction of 1%), likely caused by a rapid plasma volume (PV) restoration (calculated from changes in haematocrit and haemoglobin concentration). After the 450 ml BV reduction, VO2max was reduced by 7% despite partial PV restoration, increased maximal heart rate and increased leg O2 extraction as indicated by near-infrared spectroscopy. The reduction in VO2max was 2.5-fold larger after withdrawing 450 compared with 150 ml blood after normalising to the BV removed. Therefore, the body may cope with small but not moderate blood loss to preserve VO2max. These data may enhance our understanding regarding the impact of, e.g., acute BV manipulations, PV reduction following dehydration induced by prolonged exercise or hyperthermia, or daily oscillations of PV. In study III, the muscle oxidative capacity in one leg was increased by six weeks of one-legged endurance training (3-4 sessions per week) in nine subjects (VO2max: 56 ml · kg-1 · min-1). The impact on leg O2 extraction fraction (arterial and femoral venous catheters) vs the untrained control leg was investigated during dynamic two-legged knee extension exercise with both legs performing the same power output. This exercise model involves a small muscle mass, does not tax Qmax and is thus not perfusion limited. Therefore, the muscle oxidative capacity may potentially be the principal limiting factor for O2 extraction and VO2 before training. At low to moderate exercise intensities, O2 extraction fraction was similar in both legs. At higher exercise intensities, which are associated with greater mitochondrial activation and lower time for haemoglobin-O2 off-loading, the O2 extraction fraction was increased in the trained leg. The between-leg difference in O2 extraction correlated with the between-leg difference in mitochondrial protein content (m. vastus lateralis). Therefore, our data suggest that endurance training improves O2 extraction in exercise models where the mitochondria do not possess an apparent excess oxidative capacity over O2 delivery, particularly when the exercise intensity is close to maximal. In study IV, the relationships between pulmonary VO2max and systemic and leg O2 extraction fractions were investigated by statistically analysing data from 43 previously published catheterisation studies, comprising 377 subjects. It was observed that a-v ̅O2diff (mostly calculated by the Fick principle, and Qmax measured by the indicator-dilution method) increased curvilinearly and reached its maximum at ~4.5 l · min-1 in VO2max (moderately trained subjects), and was, if anything, slightly lower in those subjects with the highest VO2max (> 5 l · min-1). However, after accounting for the hypoxemia-induced lowering of arterial O2 content (CaO2) with increasing VO2max, the calculated systemic O2 extraction fraction (a-v ̅O2diff / CaO2) increased with VO2max up to ~4.5-5.0 l · min-1 and approached a plateau at ~90%. This pattern was strengthened by the direct measurements using arterial and femoral venous catheters, with leg O2 extraction fraction increasing progressively with VO2max until reaching ~90-95%. These analyses emphasise that a-v ̅O2diff and systemic O2 extraction fraction cannot be used interchangeably, and that the systemic and peripheral O2 extraction fractions improves with increasing VO2max and training status. By using the theoretical model of Piiper and Scheid, it appeared that the limiting factors to VO2max change with increasing VO2max: untrained, but healthy individuals display mixed perfusion-diffusion limitations, and this diffusion limitation reduces as VO2max increase.
Article
The precise matching of blood flow to skeletal muscle during exercise remains an important area of investigation. Release of adenosine triphosphate (ATP) from red blood cells (RBCs) is postulated to mediate peripheral vascular tone in response to shear stress, hypoxia, and mechanical deformation. We tested the following hypotheses: 1) RBCs of different densities contain different quantities of ATP; 2) hypoxia is a stimulus for ATP release from RBCs; and 3) hypoxic ATP release from RBCs is related to RBC lysis. Human blood was drawn from male and female volunteers (n=11); the RBCs were isolated and washed. A Percoll gradient was used to separate RBCs by cellular density. Density groups were then re-suspended to 4% hematocrit and exposed to normoxia or hypoxia in a tonometer. Equilibrated samples were drawn and centrifuged; paired analyses of ATP (luminescence via a luciferase-catalyzed reaction) and hemolysis (Harboe spectrophotometric absorbance assay) were measured in the supernatant. ATP release was not different among low-density (LD) cells versus middle-density (MD) versus high-density (HD) cells. Similarly, hemoglobin (Hb) release was not different among the RBC subsets. No difference was found for either ATP release or Hb release following matched exposure to normoxic or hypoxic gas. [ATP] and [Hb] for all subsets combined were linearly correlated (r=0.59, p<0.001). With simultaneous probing for Hb and ATP in the supernatant of each sample, we conclude that ATP release from RBCs can be explained by hemolysis and that hypoxia per se does not stimulate either ATP release or Hb release from RBCs.
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Key points The increase in blood pressure observed during physical activities is exaggerated in patients with hypertension, exposing them to a higher cardiovascular risk. Neural signals from the skeletal muscles appear to be overactive, resulting in this abnormal response in hypertensive patients. In the present study, we tested whether the attenuation of these neural signals in hypertensive patients could normalize their abnormal increase in blood pressure during physical activity. Attenuation of the neural signals from the leg muscles with intrathecal fentanyl injection reduced the blood pressure of hypertensive men during cycling exercise to a level comparable to that of normotensive men. Skeletal muscle afferent overactivity causes the abnormal cardiovascular response to exercise and was reverted in this experimental model, appearing as potential target for treatment.
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Contracting skeletal muscle can overcome sympathetic vasoconstrictor activity (functional sympatholysis), which allows for a blood supply that matches the metabolic demand. This ability is thought to be mediated by locally released substances that modulate the effect of noradrenaline (NA) on the α-receptor. Tyramine induces local NA release and can be used in humans to investigate the underlying mechanisms and physiological importance of functional sympatholysis in the muscles of healthy and diseased individuals as well as the impact of the active muscles' training status. In sedentary elderly men, functional sympatholysis and muscle blood flow are impaired compared to young men, but regular physical activity can prevent these age related impairments. In young subjects, two weeks of leg immobilization causes a reduced ability for functional sympatholysis, whereas the trained leg maintained this function. Patients with essential hypertension have impaired functional sympatholysis in the forearm, and reduced exercise hyperaemia in the leg, but this can be normalized by aerobic exercise training. The effect of physical activity on the local mechanisms that modulate sympathetic vasoconstriction is clear, but it remains uncertain which locally released substance(s) block the effect of NA and how this is accomplished. NO and ATP have been proposed as important inhibitors of NA mediated vasoconstriction and presently an inhibitory effect of ATP on NA signaling via P2 receptors appears most likely.
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Evidence assembled in this review indicates that sympathetic nervous system dysfunction is crucial in the development of heart failure and essential hypertension. This takes the form of persistent and adverse activation of sympathetic outflows to the heart and kidneys in both conditions. An important goal for clinical scientists is translation of the knowledge of pathophysiology, such as this, into better treatment for patients. The achievement of this 'mechanisms to management' transition is at different stages of development with regard to the two disorders. Clinical translation is mature in cardiac failure, knowledge of cardiac neural pathophysiology having led to the introduction of beta-adrenergic blockers, an effective therapy. With essential hypertension perhaps we are on the cusp of effective translation, with recent successful testing of selective catheter-based renal sympathetic nerve ablation in patients with resistant hypertension, an intervention firmly based on the demonstration of activation of the renal sympathetic outflow. Additional evidence in this regard is provided by the results of pilot studies exploring the possibility to reduce blood pressure in resistant hypertensives through electrical stimulation of the area of carotid baroreceptors. Despite the general importance of the sympathetic nervous system in blood pressure regulation, and the specific demonstration that the blood pressure elevation in essential hypertension is commonly initiated and sustained by sympathetic nervous activation, drugs antagonizing this system are currently underutilized in the care of patients with hypertension. Use of beta-adrenergic blocking drugs is waning, given the propensity of this drug class to have adverse metabolic effects, including predisposition to diabetes development. The blood pressure lowering achieved with carotid baroreceptor stimulation and with the renal denervation device affirms the importance of the sympathetic nervous system in hypertension pathogenesis, and perhaps suggests a wider role for anti-adrenergic antihypertensives, such as the imidazoline drug class (moxonidine, rilmenidine) which act within the CNS to inhibit central sympathetic outflow, although the lack of large-scale outcome trials with this drug class remains a very material deficiency.
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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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The autonomic nervous system and its sympathetic arm play important roles in the regulation of blood pressure.1–3⇓⇓ Their role in the short-term regulation of blood pressure, especially in responses to transient changes in arterial pressure, via baroreflex mechanisms is well known.4 However, the role of the sympathetic branch in longer-term (days, months, and years) blood pressure regulation has been a focus of debate since at least the 1970s.1,4⇓ Our goal in this Hypertension Highlights is to summarize and integrate our ideas on the role of the sympathetic nervous system in long-term blood pressure regulation in humans.1–3,5–9⇓⇓⇓⇓⇓⇓⇓ We will focus primarily on information from studies conducted in humans and use data from animal studies to emphasize key points. In this context, we want to address 4 key questions. The first 3 focus on our recent work. The final issue is an emerging one and more speculative. First, what is the role of the sympathetic nervous system in long-term blood pressure regulation in young (18- to 40-year–old) normotensive men? Second, does the role of the sympathetic nervous system in long-term blood pressure regulation change as a function of age in men? Third, does sex influence the role of the sympathetic nervous system in long-term blood pressure regulation, and are sex differences modified by aging? Fourth, are we entering an era of sympathetically driven hypertension? Before we address these questions, we share a few thoughts about how to assess the overall activity of sympathetic nerves in humans. Various approaches used to assess sympathetic activity in humans have been reviewed recently by Grassi.10 We focus primarily on studies that use direct measurements of muscle sympathetic nerve activity (MSNA) as an overall marker of sympathetic outflow in humans and, to …
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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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Multiple components of vascular alpha adrenergic responsiveness were investigated in twenty-four men with mild hypertension and eighteen age- and weight-matched normotensive controls. Arterial plasma norepinephrine (paNE), an index of sympathetic drive, was increased in hypertensives compared to normotensives (mean +/- SE), 199 +/- 24 vs. 134 +/- 11 pg/ml, P less than 0.02. The effective concentration of intra-arterial (iaNE) increasing forearm vascular resistance (FAVR) 30% (NE-EC30, an index of vascular alpha-receptor sensitivity) was similar in normotensives and hypertensives, 9 +/- 1 vs. 13 +/- 3 ng/100 ml per min, respectively, P greater than 0.3. The phentolamine induced reduction in FAVR, an index of vascular alpha-tone, was greater in hypertensives, -21.3 +/- 1.8 vs. normotensives, -14.9 +/- 1.2 U, P less than 0.02. We interpret these data as evidence for normal vascular alpha-receptor sensitivity to norepinephrine in mild hypertensives. Consequently, the increased sympathetic drive in mild hypertensives explains the elevated vascular alpha-tone. Although vascular alpha-receptor sensitivity to iaNE was normal, the FAVR responses at high doses (reactivity) were greater in hypertensives to regional infusion of both NE and angiotensin II. This "nonspecific" enhancement of vascular reactivity is probably explained by structural vascular changes in hypertensives.
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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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Nitric oxide (NO) attenuates alpha-adrenergic vasoconstriction in contracting rodent skeletal muscle, but it is unclear if NO plays a similar role in human muscle. We therefore hypothesized that in humans, NO produced in exercising skeletal muscle blunts the vasoconstrictor response to sympathetic activation. We assessed vasoconstrictor responses in the microcirculation of human forearm muscle using near-infrared spectroscopy to measure decreases in muscle oxygenation during reflex sympathetic activation evoked by lower body negative pressure (LBNP). Experiments were performed before and after NO synthase inhibition produced by systemic infusion of N(G)-nitro-L-arginine methyl ester (L-NAME). Before L-NAME, LBNP at -20 mmHg decreased muscle oxygenation by 20 +/- 2 % in resting forearm and by 2 +/- 3 % in exercising forearm (n = 20), demonstrating metabolic modulation of sympathetic vasoconstriction. As expected, L-NAME increased mean arterial pressure by 17 +/- 3 mmHg, leading to baroreflex-mediated suppression of baseline muscle sympathetic nerve activity (SNA). The increment in muscle SNA in response to LBNP at -20 mmHg also was attenuated after L-NAME (before, +14 +/- 2; after, +8 +/- 1 bursts min(-1); n = 6), but this effect of L-NAME was counteracted by increasing LBNP to -40 mmHg (+19 +/- 2 bursts min(-1)). After L-NAME, LBNP at -20 mmHg decreased muscle oxygenation similarly in resting (-11 +/- 3 %) and exercising (-10 +/- 2 %) forearm (n = 12). Likewise, LBNP at -40 mmHg decreased muscle oxygenation both in resting (-19 +/- 4 %) and exercising (-21 +/- 5 %) forearm (n = 8). These data advance the hypothesis that NO plays an important role in modulating sympathetic vasoconstriction in the microcirculation of exercising muscle, because such modulation is abrogated by NO synthase inhibition with L-NAME.
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Extracellular ATP and other purines play a crucial role in the vasculature, and their turnover is selectively governed by a network of ectoenzymes expressed both on endothelial and hematopoietic cells. By studying the whole pattern of purine metabolism in human serum, we revealed the existence of soluble enzymes capable of both inactivating and transphosphorylating circulating purines. Evidence for this was obtained by using independent assays, including chromatographic analyses with 3H-labeled and unlabeled nucleotides and adenosine, direct transfer of gamma-terminal phosphate from [gamma-32P]ATP to NDP/AMP, and bioluminescent measurement of ATP metabolism. Based on substrate-specificity and competitive studies, we identified three purine-inactivating enzymes in human serum, nucleotide pyrophosphatase (EC 3.6.1.9), 5'-nucleotidase (EC 3.1.3.5), and adenosine deaminase (EC 3.5.4.4), whereas an opposite ATP-generating pathway is represented by adenylate kinase (EC 2.7.4.3) and NDP kinase (EC 2.7.4.6). Comparative kinetic analysis revealed that the Vmax values for soluble nucleotide kinases significantly exceed those of counteracting nucleotidases, whereas the apparent Km values for serum enzymes were fairly comparable and varied within a range of 40-70 micro mol/l. Identification of soluble enzymes contributing, along with membrane-bound ectoenzymes, to the active cycling between circulating ATP and other purines provides a novel insight into the regulatory mechanisms of purine homeostasis in the blood.
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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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Purinergic signaling plays important roles in control of vascular tone and remodeling. There is dual control of vascular tone by ATP released as a cotransmitter with noradrenaline from perivascular sympathetic nerves to cause vasoconstriction via P2X1 receptors, whereas ATP released from endothelial cells in response to changes in blood flow (producing shear stress) or hypoxia acts on P2X and P2Y receptors on endothelial cells to produce nitric oxide and endothelium-derived hyperpolarizing factor, which dilates vessels. ATP is also released from sensory-motor nerves during antidromic reflex activity to produce relaxation of some blood vessels. In this review, we stress the differences in neural and endothelial factors in purinergic control of different blood vessels. The long-term (trophic) actions of purine and pyrimidine nucleosides and nucleotides in promoting migration and proliferation of both vascular smooth muscle and endothelial cells via P1 and P2Y receptors during angiogenesis and vessel remodeling during restenosis after angioplasty are described. The pathophysiology of blood vessels and therapeutic potential of purinergic agents in diseases, including hypertension, atherosclerosis, ischemia, thrombosis and stroke, diabetes, and migraine, is discussed.
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In young healthy humans, sympathetic vasoconstriction is markedly blunted during exercise to optimize blood flow to the metabolically active muscle. This phenomenon known as functional sympatholysis is impaired in hypertensive humans and rats by angiotensin II-dependent mechanisms, involving oxidative stress and inactivation of nitric oxide (NO). Nebivolol is a β1-adrenergic receptor blocker that has NO-dependent vasodilatory and antioxidant properties. We therefore asked whether nebivolol would restore functional sympatholysis in hypertensive humans. In 21 subjects with stage 1 hypertension, we measured muscle oxygenation and forearm blood flow responses to reflex increases in sympathetic nerve activity evoked by lower body negative pressure at rest, and during rhythmic handgrip exercise at baseline, after 12 weeks of nebivolol (5-20 mg/d) or metoprolol (100-300 mg/d), using a double-blind crossover design. We found that nebivolol had no effect on lower body negative pressure-induced decreases in oxygenation and forearm blood flow in resting forearm (from -29±5% to -30±5% and from -29±3% to -29±3%, respectively; P=NS). However, nebivolol attenuated the lower body negative pressure-induced reduction in oxygenation and forearm blood flow in exercising forearm (from -14±4% to -1±5% and from -15±2% to -6±2%, respectively; both P<0.05). This effect of nebivolol on oxygenation and forearm blood flow in exercising forearm was not observed with metoprolol in the same subjects, despite a similar reduction in blood pressure. Nebivolol had no effect on sympathetic nerve activity at rest or during handgrip, suggesting a direct effect on vascular function. Thus, our data demonstrate that nebivolol restored functional sympatholysis in hypertensive humans by a mechanism that does not involve β1-adrenergic receptors.Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01502787.
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Endothelin-1 has potent constrictor and proliferative activity in vascular smooth muscle, and essential hypertension and aging are associated with increased endothelin-1-mediated vasoconstrictor tone. The aim of this study was to investigate the effect of physical activity, hypertension and age on endothelin-1 levels in plasma and skeletal muscle and endothelin receptors in skeletal muscle in human subjects. In study 1, normotensive (46 ± 1 years, n = 11) and hypertensive (47 ± 1 years, n = 10) subjects were studied before and after 8 weeks of aerobic exercise training. In study 2, young (23 ± 1 years, n = 8), older lifelong sedentary (66 ± 2 years, n = 8) and older lifelong endurance-trained (62 ± 2 years, n = 8) subjects were studied in a cross-sectional design. Skeletal muscle and plasma endothelin-1 levels were increased with age and plasma endothelin-1 levels were higher in hypertensive than normotensive individuals. Eight weeks of exercise training normalized plasma endothelin-1 levels in the hypertensive subjects and increased the protein expression of the ETA receptor in skeletal muscle of normotensive subjects. Similarly, individuals that had performed lifelong physical activity had similar plasma and muscle endothelin-1 levels as the young controls and had higher ETA receptor levels. Our findings suggest that aerobic exercise training opposes the age-related increase in skeletal muscle and plasma endothelin-1 levels and normalizes plasma endothelin-1 levels in individuals with essential hypertension. This effect may explain some of the beneficial effects of training on the cardiovascular system in older and hypertensive subjects.
Article
During exercise, oxygen delivery to skeletal muscle is elevated to meet the increased oxygen demand. The increase in blood flow to skeletal muscle is achieved by vasodilators formed locally in the muscle tissue, either on the intraluminal or the extraluminal side of the blood vessels. A number of vasodilators have been shown to bring about this increase in blood flow and, importantly, interactions between these compounds seem to be essential for the precise regulation of blood flow. Two compounds stand out as central in these vasodilator interactions; nitric oxide (NO) and prostacyclin. These two vasodilators are both stimulated by several compounds, eg. adenosine, ATP, acetylcholine, bradykinin, and are affected by mechanically induced signals, such as shear stress. NO and prostacyclin have also been shown to interact in a redundant manner where one system can take over when formation of the other is compromised. Although numerous studies have examined the role of single and multiple pharmacological inhibition of different vasodilator systems, and important vasodilators and interactions have been identified, a large part of the exercise hyperemic response remains unexplained. It is plausible that this remaining hyperemia may be explained by cAMP and cGMP independent smooth muscle relaxation, such as effects of endothelial derived hyperpolarization factors (EDHFs) or through metabolic modulation of sympathetic effects. The nature and role of EDHF as well as potential novel mechanisms in muscle blood flow regulation remain to be further explored to fully elucidate the regulation of exercise hyperemia.
Article
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.
Article
: This study examined vascular function and the adenosine system in skeletal muscle of patients diagnosed with essential hypertension (n = 10) and of normotensive (n = 11) patients, before and after aerobic training. : Before and after 8 weeks of aerobic training, the patients completed experiments in which leg blood flow was determined during infusion of adenosine, acetylcholine and during exercise (20 W); muscle interstitial fluid and femoral venous plasma were sampled via microdialysis probes during baseline conditions, exercise and adenosine infusion and resting muscle biopsies were obtained from muscle vastus lateralis. : Before training, leg vascular conductance in response to arterial adenosine infusion was similar in the hypertensive and normotensive groups and the individual vascular response was positively correlated to that of both acetylcholine infusion (r  = 0.66, P < 0.001) and exercise (r  = 0.72, P < 0.001). Before training, interstitial adenosine concentrations during exercise and prostacyclin (PGI2) concentrations after adenosine infusion were lower in the hypertensive than the normotensive group (P < 0.05). In the hypertensive group, training did not affect the vasodilatory response to arterially infused adenosine but increased the formation of interstitial adenosine and PGI2 and lowered blood pressure. In the normotensive group, training resulted in lower (P < 0.05) leg vascular conductance in response to arterial adenosine infusion. : The present data suggest that essential hypertension is associated with a reduced capacity to form adenosine and PGI2 at the skeletal muscle microcirculatory level, which is likely to contribute to the increased peripheral vascular resistance related to the disease. This impairment in vasodilator formation can be normalized by aerobic training.
Article
Ageing has been proposed to be associated with increased levels of reactive oxygen species (ROS) that scavenge nitric oxide (NO). In eight young sedentary (23±1 years; Y), eight older lifelong sedentary (66±2 years; OS) and eight older lifelong physically active subjects (62±2 years; OA), we studied the effect of ROS on systemic and skeletal muscle NO bioavailability and leg blood flow by infusion of the antioxidant N-acetylcysteine (NAC). Infusion of NAC increased the bioavailability of NO in OS, as evidenced by an increased concentration of stable metabolites of NO (NOx) in the arterial and venous circulation and in the muscle interstitium. In OA, infusion of NAC only increased NOx concentrations in venous plasma whereas in Y, infusion of NAC did not affect NOx concentrations. Skeletal muscle protein levels of endothelial and neuronal NO synthase were 32% and 24% higher, respectively, in OA than in OS. Exercise at 12 W elicited a lower leg blood flow response that was associated with a lower leg oxygen uptake in OS than in Y. The improved bioavailability of NO in OS did not increase blood flow during exercise. These data demonstrate that NO bioavailability is compromised in the systemic circulation and in the musculature of sedentary ageing humans due to increased oxidative stress. Lifelong physical activity opposes this effect within the trained musculature and in the arterial circulation. The lower blood flow response to leg exercise in ageing humans is not associated with a reduced NO bioavailability.
Article
Circulating ATP possesses unique vasomotor properties in humans and has been hypothesized to play a role in vascular control under a variety of physiological conditions. However, the primary downstream signaling mechanisms underlying ATP-mediated vasodilatation remain unclear. The purpose of the present experiment was to determine whether ATP-mediated vasodilatation is independent of nitric oxide (NO) and prostaglandin (PG) synthesis and occurs primarily via the activation of Na+/K+-ATPase and inwardly-rectifying potassium (KIR) channels in humans. In all protocols, young healthy adults were studied and forearm vascular conductance (FVC) was calculated from forearm blood flow (measured via venous occlusion plethysmography) and intra-arterial blood pressure to quantify local vasodilatation. Vasodilator responses (%ΔFVC) during intra-arterial ATP infusions were unchanged following combined inhibition of NO and PGs (n=8; P>0.05) whereas the responses to KCl were greater (P<0.05). Combined infusion of ouabain (to inhibit Na+/K+-ATPase) and barium chloride (BaCl2; to inhibit KIR channels) abolished KCl-mediated vasodilatation (n=6; %ΔFVC=134±13 vs 4±5%; P<0.05), demonstrating effective blockade of direct vascular hyperpolarization. The vasodilator responses to 3 different doses of ATP were inhibited on average 56±5% (n=16) following combined ouabain+BaCl2 infusion. In follow-up studies, BaCl2 alone inhibited the vasodilator responses to ATP on average 51±3% (n=6), which was not different than that observed for combined ouabain+BaCl2 administration. Our novel results indicate that the primary mechanism of ATP-mediated vasodilatation is vascular hyperpolarization via activation of KIR channels. These observations translate in vitro findings to humans in vivo and may help explain the unique vasomotor properties of intravascular ATP in the human circulation.
Article
Abstract  In healthy human beings, blood flow to dynamically contracting skeletal muscle is regulated primarily to match oxygen (O(2)) delivery closely with utilisation. This occurs across a wide range of exercise intensities, as well as when exercise is combined with conditions that modify blood O(2) content. The red blood cells (RBCs), the primary O(2) carriers in the blood, contribute to the regulation of the local processes matching O(2) supply and demand. This is made possible by the ability of RBCs to release the vasoactive substance adenosine triphosphate (ATP) in response to reductions in erythrocyte and plasma O(2), as well as to other adjuvant metabolic and mechanical stimuli. The regulatory role of RBCs in human beings is supported by the observations that, i) exercising skeletal muscle blood flow responds primarily to changes in the amount of O(2) bound to the erythrocyte haemoglobin molecules, rather than the amount of O(2) in plasma, and ii) exercising muscle blood flow can almost double (from 260 to 460 ml min(-1) 100 g(-1)) with alterations in blood O(2) content, such that O(2) delivery and are kept constant. Besides falling blood O(2) content, RBCs release ATP when exposed to increased temperature, reduced pH, hypercapnia, elevated shear stress and augmented mechanical deformation, i.e. conditions that exist in the microcirculation of active skeletal muscle. ATP is an attractive mediator signal for skeletal muscle blood flow regulation, not only because it can act as a potent vasodilator, but also because of its sympatholytic properties in the human limb circulations. These properties are essential to counteract the vasoconstrictor effects of concurrent increases in muscle sympathetic nerve activity and circulating vasoconstrictor substances during exercise. Comparison of the relative vasoactive potencies and sympatholytic properties of ATP, other nucleotides, and adenosine in human limbs, suggests that intravascular ATP exerts its vasodilator and sympatholytic effects directly, and not via its degradation compounds. In conclusion, current evidence clearly indicates that RBCs are involved directly in the regulation of O(2) supply to human skeletal muscle during dynamic exercise. Further, intravascular ATP might be an important mediator in local metabolic sensing and signal transduction between the RBCs and the endothelial and smooth muscle cells in the vascular beds of skeletal muscle.
Article
Abstract  The maintenance of adequate tissue O(2) levels in skeletal muscle is vital for normal physiology and requires a well regulated and appropriately distributed convective O(2) supply. Inherent in this fundamental physiological process is the requirement for a mechanism which both senses tissue O(2) need and locally adjusts flow to appropriately meet that need. Over the past several years we and others have suggested that, in skeletal muscle, O(2) carrying erythrocytes participate in the regulation of total blood flow and its distribution by releasing ATP. Importantly, the release of this vasoactive molecule must be both rapid and well controlled if it is to serve an important physiological role. Here we provide insights into three distinct regulated signalling pathways within the erythrocyte that are activated by exposure to reduced O(2) tension or in response to binding of agonists to the prostacyclin or β-adrenergic receptors. Although much has been learned about the role of the erythrocyte in perfusion of skeletal muscle, much remains to be understood. However, what is clear is that the long established passive carrier of O(2) also contributes to the regulation of the distribution of microvascular perfusion in skeletal muscle by virtue of its capacity to release ATP.
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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.
Article
Sympathetic vasoconstriction is normally attenuated in exercising muscle, but this functional sympatholysis is impaired in rats with hypertension or heart failure due to elevated levels of reactive oxygen species (ROS) in muscle. Whether ROS have a similar effect in the absence of cardiovascular disease or whether these findings extend to humans is not known. We therefore tested the hypothesis that chronic treatment with nitroglycerin (NTG) to induce nitrate tolerance, which is associated with excessive ROS production, impairs functional sympatholysis in healthy rats and humans. NTG treatment increased ethidium fluorescence in rat muscles and urinary F(2)-isoprostanes in humans, demonstrating oxidative stress. In vehicle-treated rats, sympathetic nerve stimulation (1 to 5 Hz) evoked decreases in femoral vascular conductance at rest (range, -30 to -63%) that were attenuated during hindlimb contraction (range, -2 to -31%; P < 0.05). In NTG-treated rats, vasoconstrictor responses were similar at rest, but were enhanced during contraction (range, -17 to -50%; P < 0.05 vs. vehicle). Infusion of the ROS scavenger tempol restored sympatholysis in these rats. In humans, reflex sympathetic activation during lower body negative pressure (LBNP) evoked decreases in muscle oxygenation in resting forearm (-12 ± 1%) that were attenuated during handgrip exercise (-3 ± 1%; P < 0.05). When these subjects became nitrate tolerant, LBNP-induced decreases in muscle oxygenation were unaffected at rest, but were enhanced during exercise (-9 ± 1%; P < 0.05 vs. before NTG). Collectively, these data indicate that functional sympatholysis is impaired in otherwise healthy nitrate-tolerant rats and humans by a mechanism probably involving muscle oxidative stress.