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Percentage change in leg blood flow and vascular conductance when tyramine was infused during one-legged knee extensor exercise with a control, detrained and trained leg (A) and in young, sedentary elderly and trained elderly (right panel) A, †Different from control leg; P < 0.05, #different from immobilized leg. B, P < 0.05, *different from young men, P < 0.05; §different from sedentary elderly men, P < 0.05. Modified from Mortensen et al. 2012a, 2012b.
Source publication
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...
Contexts in source publication
Context 1
... not appear to cross into the interstitial space of the muscle (Mortensen et al. 2009b). We recently found that 2 weeks of leg immobilization markedly lower interstitial ATP concentrations during exercise (S. P. Mortensen, J. H. Svendsen, Y. Hellsten, N. H. Secher & B. Saltin, in review) in association with an impaired functional sympatholysis ( Fig. 3A; Mortensen et al. 2012). This opens up the possibility that interstitial ATP interacts directly with the α-receptor possibly via P2Y receptors or via end- othelial P2Y receptors (Mortensen et al. 2009a). A likely scenario could be that luminal and interstitial ATP operate synergistically via P2 receptors, which are also markedly ...
Context 2
... Koch et al. 2003;Dinenno et al. 2005;Kirby et al. 2011). A link between the reduced exercise hyperaemia and impaired functional sympatholysis remains to be established, but we have recently observed that chronically endurance trained elderly can maintain an intact functional sympatholysis and sufficient blood flow to maintain aerobic metabolism ( Fig. 3A; S. P. Mortensen, M. Nyberg, K. Winding & B. Saltin, in review). In contrast, a similar leg blood flow in chronically sedentary elderly was associated with a lower aerobic metabolism, increased lactate release and impaired functional sympatholysis. These observations illustrate the need for local determination of muscle perfusion and ...
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Purpose
ATP could play an important role in skeletal muscle blood flow regulation by inducing vasodilation via purinergic P2 receptors. This study investigated the role of P2 receptors in exercise hyperemia in miniature swine.
Methods
We measured regional blood flow with radiolabeled-microsphere technique and systemic hemodynamics before and aft...
Citations
... Prior work has reported racial differences in exercise hyperemia without a difference in functional sympatholysis (52), highlighting that these outcomes can be dissociated. Functional sympatholysis has been identified as an underappreciated cause of poor contracting muscle perfusion (53) and may result in functional changes in exercise capacity (12). It has been shown that a high-fat diet can decrease aerobic exercise capacity (54). ...
A single high-fat Western meal transiently reduces endothelium-dependent vasodilation at rest but the interaction with sympathetic vasoconstrictor activity during exercise remains unknown. Herein, we tested the hypothesis that a single high-fat Western meal would impair the ability of contracting skeletal muscle to offset vascular responsiveness to sympathetic activation during exercise, termed functional sympatholysis. In 18 (10F/8M) healthy young adults, forearm blood flow (Doppler ultrasound) and beat-to-beat arterial pressure (photoplethysmography) were measured during lower-body negative pressure (LBNP; -20 mmHg) applied at rest and simultaneously during low- (15% maximum contraction) and moderate-intensity (30% maximum contraction) rhythmic handgrip. The magnitude of sympatholysis was calculated as the difference of LBNP-induced changes in forearm vascular conductance (FVC) between handgrip and rest. Experiments were performed preprandial and 1h, 2h, and 3h after a high- or low-fat meal. In the preprandial state, LBNP decreased resting FVC (∆-54±10%), and these responses were attenuated during low- (∆-17±7%) and moderate-intensity handgrip (∆-8±6%). Following a high-fat meal, LBNP induced attenuated decreases in resting FVC (3h postprandial: ∆-47±10%, P=0.002 vs. preprandial), and blunted attenuation of FVC during low- (3h postprandial: ∆-23±8%, P=0.001 vs. preprandial) and moderate-intensity handgrip (3h postprandial: ∆-16±6%, P<0.001 vs. preprandial). The high-fat meal attenuated the magnitude of sympatholysis during low- (preprandial: 38±7% vs. 3h postprandial: 23±8%, P<0.001) and moderate-intensity handgrip (preprandial: 46±11% vs. 3h postprandial: 31±10%, P<0.001). The low-fat meal had no impact on these responses. In conclusion, a single high-fat Western meal modulates sympathetic vasoconstriction at rest and during low- and moderate-intensity handgrip exercise in young healthy adults.
... Specifically, exercise-induced increases in sympathetic vasoconstrictor discharge promotes venous return to the heart which supports increases in left ventricular (LV) cardiac output ( _ Q c ), and vasoconstriction in non-active tissues serves to redistribute blood flow toward active skeletal muscle to meet the metabolic demands of exercise (1). Conversely, locally released metabolic by-products within active skeletal muscle offset sympathetically-mediated vasoconstriction (i.e., functional sympatholysis) to ensure blood supply matches the metabolic requirements of active muscle (2,3). This phenomenon is particularly important in the resistance arterioles of the muscle microcirculation (4). ...
... The concept of functional sympatholysis is the ability of active skeletal muscle to override sympathetic vasoconstrictor drive, ensuring adequate oxygen delivery to the muscle (2,3). While this physiological response is well-established in healthy humans, it is attenuated in diseases like elevated sympathetic activity (3). ...
Excessive sympathetic activity during exercise causes heightened peripheral vasoconstriction, which can reduce oxygen delivery to active muscles, resulting in exercise intolerance. Although both patients suffering from heart failure with preserved and reduced ejection fraction (HFpEF and HFrEF, respectively) exhibit reduced exercise capacity, accumulating evidence suggests that the underlying pathophysiology may be different between these two conditions. Unlike HFrEF, which is characterized by cardiac dysfunction with lower peak oxygen uptake, exercise intolerance in HFpEF appears to be predominantly attributed to peripheral limitations involving inadequate vasoconstriction rather than cardiac limitations. However, the relationship between systemic hemodynamics and the sympathetic neural response during exercise in HFpEF is less clear. This mini review summarizes the current knowledge on the sympathetic (i.e., muscle sympathetic nerve activity, plasma norepinephrine concentration) and hemodynamic (i.e., blood pressure, limb blood flow) responses to dynamic and static exercise in HFpEF compared to HFrEF, as well as non-HF controls. We also discuss the potential of a relationship between sympathetic over-activation and vasoconstriction leading to exercise intolerance in HFpEF. The limited body of literature indicates that higher peripheral vascular resistance, perhaps secondary to excessive sympathetically mediated vasoconstrictor discharge compared to non-HF and HFrEF, drives exercise in HFpEF. Excessive vasoconstriction also may primarily account for over elevations in blood pressure and concomitant limitations in skeletal muscle blood flow during dynamic exercise, resulting in exercise intolerance. Conversely, during static exercise, HFpEF exhibit relatively normal sympathetic neural reactivity compared to non-HF, suggesting that other mechanisms beyond sympathetic vasoconstriction dictate exercise intolerance in HFpEF.
... The parallel increase in norepinephrine and epinephrine observed in the study by Shim et al. [37] supports the view that both RAAS and sympathoadrenal system mutually interact in determining BP changes during physical exercise. The increased activity of both systems leading to peripheral arterial vasoconstriction may contribute to EBPR during exercise [38]. In this regard, studies conducted in hypertensive patients, in individuals with high-normal BP as well as in elderly men have suggested that hyper-activation of muscle chemoreceptors may attenuate functional sympatholysis, enhancing the vasoconstriction, which, in combination with increased cardiac output, is responsible of EBPR [39,40]. ...
The hypertensive response to exercise testing, defined as exaggerated blood pressure response (EBPR), has been documented to be independently associated with unhealthy conditions, carrying an increased risk of future hypertension, cardiovascular (CV) morbidity and mortality. In treated hypertensives, EBPR is a marker of uncontrolled hypertension, a condition previously undetected by office blood pressure (BP) measurements at rest; EBPR may also detect masked hypertension, a phenotype characterized by normal BP values in the medical environment but elevated home or ambulatory BP monitoring (ABPM). The aim of the present review is to provide a comprehensive and up-dated information on the clinical importance of EBPR targeting the following issues: (I) definition and prevalence; (II) underlying mechanisms; (III) clinical correlates and association with subclinical organ damage; (IV) predictive value; (V) clinical decision making.
... The mechanisms of local limb vasodilation after tennis services may involve functional sympatholysis. 19,20 Functional sympatholysis is a local vasodilation mechanism that may be evoked by an accumulation of metabolites, such as nitric oxide and adenosine triphosphate, in skeletal muscle vasculature. 21 Our tennis service protocols may have led to the accumulation of metabolic products in the dominant arm, resulting in local vasodilation with increased brachial BF, mean SR, and VC. ...
Objectives
This study aimed to examine the influences of tennis service exercise on cardiac output (CO) and bilateral brachial hemodynamics in young tennis players.
Design
Experimental study.
Methods
Ten young male tennis players (21 ± 2 years of age) participated. Each performed 100 tennis services without a return shot for experimental tennis exercise. Cardiovascular hemodynamic variables, including bilateral brachial blood flow (BF), shear rate (SR), blood pressure, and CO, were collected under three conditions: 1) baseline, 2) immediately after the tennis services (post), and 3) 1 h after the tennis services (1-h). The positive incremental area under the curve (iAUC) for brachial hemodynamic variables was calculated.
Results
Immediately after the 100 tennis services, CO, brachial BF, SR, and brachial vascular conductance (VC) in the dominant and non-dominant arms increased (p < 0.05). At the 1-h condition, CO returned to baseline; the brachial BF, SR, and VC in the non-dominant arm returned to baseline levels, whereas the same variables in the dominant arm remained increased. The iAUC for brachial BF and VC in the dominant arm was higher than that in the non-dominant arm. Furthermore, the brachial BF/CO ratio index in the dominant arm increased at the post and 1-h conditions, whereas that in the non-dominant arm was unchanged.
Conclusion
Tennis service exercise specifically increases brachial BF, SR, and VC in the dominant arm, independent of increased CO. Our findings contribute to unveiling the underlying mechanisms of brachial artery adaptations in tennis players.
... This observation may relate to the capacity of intravascular ATP to override sympathetic vasoconstrictor activity (Rosenmeier et al., 2004;Mortensen et al., 2012b). During exercise, sympathetic activity reduces perfusion of inactive muscles whereas this effect is blunted in contracting muscle (termed functional sympatholysis), thus directing blood flow away from areas of lower metabolic activity and toward areas of higher metabolic demand (Remensnyder et al., 1962;Saltin and Mortensen, 2012). Importantly, the vasoconstrictor effects of muscle sympathetic nervous activity are not abolished (Remensnyder et al., 1962;, and sympathetic restraint of blood flow remains even in highly active skeletal muscle (Joyner et al., 1992;. ...
... In the kidney and liver, sympathetic vasoconstriction can reduce perfusion by~75% during intense exercise in humans, thus allowing for~10% of maximal cardiac output (~2 L min −1 ) to be redistributed . In active skeletal muscle, the magnitude of decrease in vascular conductance and blood flow is dependent on muscle sympathetic nervous activity, metabolic activity, and the ability of the muscle for functional sympatholysis with respiratory muscles being less affected than limb skeletal muscles (Remensnyder et al., 1962;Saltin, 2007;Saltin and Mortensen, 2012). Depending on the extent of vascular restraint, matching of skeletal muscle O 2 delivery and demand may be altered to an extent that will affect metabolic performance as discussed in the following sections. ...
Skeletal muscle is one of the most dynamic metabolic organs as evidenced by increases in metabolic rate of >150-fold from rest to maximal contractile activity. Because of limited intracellular stores of ATP, activation of metabolic pathways is required to maintain the necessary rates of ATP re-synthesis during sustained contractions. During the very early phase, phosphocreatine hydrolysis and anaerobic glycolysis prevails but as activity extends beyond ∼1 min, oxidative phosphorylation becomes the major ATP-generating pathway. Oxidative metabolism of macronutrients is highly dependent on the cardiovascular system to deliver O2 to the contracting muscle fibres, which is ensured through a tight coupling between skeletal muscle O2 utilization and O2 delivery. However, to what extent O2 delivery is ideal in terms of enabling optimal metabolic and contractile function is context-dependent and determined by a complex interaction of several regulatory systems. The first part of the review focuses on local and systemic mechanisms involved in the regulation of O2 delivery and how integration of these influences the matching of skeletal muscle O2 demand and O2 delivery. In the second part, alterations in cardiovascular function and structure associated with aging and heart failure, and how these impact metabolic and contractile function, will be addressed. Where applicable, the potential of exercise training to offset/reverse age- and disease-related cardiovascular declines will be highlighted in the context of skeletal muscle metabolic function. The review focuses on human data but also covers animal observations.
... Skeletal muscle oxygen delivery, in turn, is largely determined by skeletal muscle blood flow, i.e., exercise hyperemia. Exercise hyperemia is dependent upon the activity of vasoactive substances acting "locally" in the vascular beds supplying active skeletal muscle to cause vasodilation and oppose the systemic, vasoconstrictive stimulus of sympathetic nervous system in a process termed 'functional sympatholysis.' [31] Key vasoactive molecules produced either by the active skeletal muscle and/or the vascular endothelium that help increase blood flow to active muscle during exercise include adenosine, ATP, potassium ions, prostacyclin and NO [32]. The bioactivity of many of these vasodilators during exercise has been shown to be reduced with aging [33][34][35], which, in turn, likely contributes to a decrease in exercise hyperemia [36] and reduced functional sympatholysis characterized by a relative increase in sympathetically-mediated vasoconstriction of vascular beds supplying active skeletal muscle in older relative to young adults [37,38]. ...
Aging is associated with a decline in physiological function and exercise performance. These effects are mediated, at least in part, by an age-related decrease in the bioavailability of nitric oxide (NO), a ubiquitous gasotransmitter and regulator of myriad physiological processes. The decrease in NO bioavailability with aging is especially apparent in sedentary individuals, whereas older, physically active individuals maintain higher levels of NO with advancing age. Strategies which enhance NO bioavailability (including nutritional supplementation) have been proposed as a potential means of reducing the age-related decrease in physiological function and enhancing exercise performance and may be of interest to a range of older individuals including those taking part in competitive sport. In this brief review we discuss the effects of aging on physiological function and endurance exercise performance, and the potential role of changes in NO bioavailability in these processes. We also provide a summary of current evidence for dietary supplementation with substrates for NO production — including inorganic nitrate and nitrite, l-arginine and l-citrulline — for improving exercise capacity/performance in older adults. Additionally, we discuss the (limited) evidence on the effects of (poly)phenols and other dietary antioxidants on NO bioavailability in older individuals. Finally, we provide suggestions for future research.
... In contrast, during active muscle contractions Remensnyder and colleagues (Remensnyder et al., 1962) documented the relatively attenuated vasoconstrictor response to a sympathetic stimulus and the term functional sympatholysis was coined. Although sympatholysis has been studied extensively with theoretical models (Roy et al., 2014,), in animals (Buckwalter et al., 2004), and in young healthy humans (Tschakovsky et al., 2002), the exact mechanisms responsible for this process are still not completely understood (Saltin et al., 2012). ...
... In contrast, during active muscle contractions Remensnyder and colleagues (Remensnyder et al., 1962) documented the relatively attenuated vasoconstrictor response to a sympathetic stimulus and the term functional sympatholysis was coined. Although sympatholysis has been studied extensively with theoretical models (Roy et al., 2014,), in animals (Buckwalter et al., 2004), and in young healthy humans (Tschakovsky et al., 2002), the exact mechanisms responsible for this process are still not completely understood (Saltin et al., 2012). ...
... It is well recognized that the autonomic nervous system plays a profound and somewhat complicated role in local blood flow regulation during exercise (Fadel, 2013;Saltin et al., 2012). Certainly, MSNA is modulated, at least in part, by the parallel activation of central somatomotor and sympathetic pathways, known as central command and by feedback that arises from the stimulation of mechano-and metabo-receptors in the exercising muscle (Amann et al., 2015;Friedman et al., 1990;Venturelli et al., 2017). ...
Please cite this article as: M. Venturelli, M.J. Rossman, S.J. Ives, et al., Passive leg movement-induced vasodilation and exercise-induced sympathetic vasoconstriction, Abstract The role of nitric oxide (NO) as a modulator of functional sympatholysis has been debated in the literature, but the preponderance of evidence suggests that the magnitude of NO-mediated dilation is restrained by sympathetic vasoconstriction. Therefore, we hypothesized that passive leg movement (PLM)-induced vasodilation, which is predominantly NO-mediated, would be attenuated by an exercise-induced increase in muscle sympathetic nerve activity (MSNA). To test this hypothesis, MSNA, leg blood flow (LBF), and mean arterial blood pressure (MAP) were measured and leg vascular conductance (LVC) calculated in 9 healthy subjects (30±3 yr), during PLM with and without sympathoexcitation evoked by arm-cranking exercise (ACE), at 25, 50, and 75% of maximal capacity. During this incremental intensity ACE, MSNA increased significantly (26±2, 34±3, and 41±5 bursts/100 HB, respectively). LVC during PLM fell markedly (~1.2 ml/min/mmHg) with each increase in ACE intensity, and there was a strong relationship (r = 0.92; p < 0.05) between ∆MSNA and ∆Peak LVC induced by the three intensities of ACE. Thus, as anticipated, this study reveals that the, NO-mediated, PLM-induced vasodilation, is significantly and proportionally attenuated by exercise-induced MSNA. This finding highlights the dominant role of MSNA in regulating skeletal muscle vascular conductance.
... Taken together, SNSA likely encourages vasoconstriction to a greater extent in men, and thus, men may be more reliant on functional sympatholytic (inhibition of sympathetic mediated vasomotor actions) to meet metabolic demands. Functional sympatholytic has previously been reported to mainly be mediated by ATP (Kirby et al., 2013;Saltin and Mortensen, 2012), and Kirby et al. (2013) have shown that the origin of intravascular ATP was sourced from red blood cells, which were ultimately responsible for the augmentation and maintenance of elevated plasma ATP during exercise. However, if mechanical compression of vasculature is present such as during sustain IHG tasks, it would be expected that there would be reduced muscle perfusion/blood flow (red blood cells), and consequentially, a reduction in the ability to express functional symphysis (Kirby et al., 2013). ...
Women exhibit an attenuated exercise pressor reflex (EPR) when compared to men. The influence of sex-specific mechanisms related to the EPR and performance fatigability remain to be fully elucidated. The purpose was to determine the impact of oxygenation and metabolic efficiency on sex-specific performance fatigability and increases in mean arterial pressure (MAP) resulting from a fatiguing isometric handgrip (IHG). Twenty-four adults volunteered to perform an IHG at 25% at maximal voluntary isometric contractions (MVICs). Pre- and posttest MVICs were conducted to quantify performance fatigability. MAP was collected at 3 timepoints. A near-infrared spectroscopy device was attached to the forearm to derive the following signals: oxy[haem], deoxy[haem], total[haem], and diff[haem]. These values were normalized and examined across time in 5% segments of time-to-task-failure. Metabolic efficiency was defined as the ratio force:deoxy[haem]. During the IHG, there was a decline in oxy[haem] for the men (b = −0.075), whereas the women demonstrated an increase (b = 0.117). For the men, the diff[haem] tracked the mean oxy[haem] response, but there was no change for the women. The men exhibited greater declines in metabolic efficiency, yet there were no sex differences in PF (46.6 ± 9.7% vs. 45.5 ± 14.2%). For relative MAP, the men (24.5 ± 15.1%) exhibited a greater (p = .03) increase than the women (11.0 ± 17.6%). These results indicated the EPR was more prominent for the men, perhaps due to differences in mechanical stimuli and a lack of ability to maintain metabolic efficiency. However, these physiological differences did not induce a sex difference in performance fatigability.
... Exaggerated exercise SBP response is partially due to the inability of the endothelium to counteract sympathetic-mediated vasoconstriction, likely attributed to decreased nitric oxide (NO) bioavailability (8)(9)(10). Functional sympatholysis, the process of attenuating sympathetic-mediated vasoconstriction via local vasodilation induced by metabolites within the exercising muscles, is diminished in hypertensive adults (11), hindering skeletal muscle perfusion (12). Previous research has shown that an exaggerated SBP response to dynamic plantarflexion exercise is associated with the inability to counteract sympathetic-mediated vasoconstriction in old females, likely attributed to impaired functional sympatholysis (3). ...
Purpose:
Hypertensive postmenopausal women (PMW) have exaggerated exercise systolic blood pressure (BP) due to impaired functional sympatholysis. L-Citrulline (CIT) supplementation attenuates aortic systolic BP (SBP) responses to cold pressor test (CPT) induced vasoconstriction in young men. We hypothesized that acute CIT ingestion would attenuate aortic SBP and leg hemodynamic responses during exercise and CPT (EX+CPT).
Methods:
Fifteen hypertensive PMW (61 ± 7 years) were randomly assigned to consume either 6g of CIT or placebo (PL) separated by a minimum 3-day washout phase. Brachial and aortic BP, femoral artery blood flow (FBF), and vascular conductance (FVC) were measured at rest and during 5 minutes of unilateral plantarflexion exercise with a CPT applied during minutes 4 and 5.
Results:
No differences between conditions were found in FBF, FVC, brachial and aortic BP at rest and during exercise alone. Changes in brachial SBP (CIT 29 ± 12 mmHg vs. PL 40 ± 10 mmHg) and mean arterial pressure (MAP) (CIT 21 ± 10 mmHg vs PL 33 ± 11 mmHg), and aortic SBP (CIT 27 ± 11 mmHg vs PL 38 ± 9 mmHg) and MAP (CIT 23 ± 9 mmHg vs PL 33 ± 11 mmHg) to EX+CPT were lower in the CIT vs. PL condition (P < 0.05). FBF, FVC, and functional sympatholysis (%ΔFVC) were not significant different between conditions.
Conclusions:
Acute CIT ingestion attenuated aortic SBP response to exercise and cold-induced sympathetic activation that may prevent left ventricle overload in hypertensive PMW.
... In theory, all factors influencing the cardiovascular and autonomic responses to metaboreflex [please refer to (Grotle et al. 2020) for additional reading] may be modulated by chronic exercise. Accordingly, exercise-related improvements may result from a wide spectrum of adaptations, as the sensitivity or expression of channels and receptors (i.e., ASICs channels, TRPv1, P2 and COX-2 receptors) (Antunes-Correa et al. 2014;Wang et al. 2012), muscle oxidative stress and antioxidant capacity (de Sousa et al. 2017;Powers et al. 2016), metabolite accumulation within exercising muscles (McAllister et al. 1996;Deer and Heaps 2013;Keytsman et al. 2019;Devereux et al. 2012), or functional sympatholysis (Mizuno et al. 2014;Jendzjowsky and Delorey 2013;Saltin and Mortensen 2012). ...
... Increasing the net effect of those vasodilatory substances would contribute to exercise hyperemia by inducing local vasodilation and overriding sympathetic vasoconstrictor activity during exercise (functional sympatholysis) (Munch et al. 2018). Exercise training (in particular aerobic) seems to enhance functional sympatholysis by increasing the release of those vasodilatory substances (Mizuno et al. 2014;Jendzjowsky and Delorey 2013;Saltin and Mortensen 2012) -which adaptation was diminished by NO blockade (Mizuno et al. 2014). Taken together, those vascular adaptations to exercise training (Ashor et al. 2015) may prevent or postpone the critical accumulation of metabolites, therefore, favoring the muscle metaboreflex. ...
Abnormalities in the muscle metaboreflex concur to exercise intolerance and greater cardiovascular risk. Exercise training benefits neurocardiovascular function at rest and during exercise, but its role in favoring muscle metaboreflex in health and disease remains controversial. While some authors demonstrated that exercise training enhanced the sensitization of muscle metabolically afferents and improved neurocardiovascular responses to muscle metaboreflex activation, others reported unaltered responses. This narrative review aimed to: (a) highlight the current evidence on the effects of exercise training upon cardiovascular and autonomic responses to muscle metaboreflex activation; (b) analyze the role of training components and indicate potential mechanisms of metaboreflex adaptations; and (c) address key methodological features for future research. Though limited, accumulated evidence suggests that muscle metaboreflex adaptations depend on the individual clinical status, exercise modality, and training duration. In healthy populations, most trials negated the hypothesis of metaboreflex improvement due to chronic exercise, irrespective of the training duration. Favorable changes in patients with impaired metaboreflex, particularly chronic heart failure, mostly resulted from long-term interventions (> 16 weeks) including aerobic exercise of moderate to high intensity, performed in isolation or within multimodal training. Potential mechanisms of metaboreflex improvements include enhanced sensitivity of channels and receptors, greater antioxidant capacity, lower metabolite accumulation, increased functional sympatholysis, and muscle perfusion. Future research should investigate: (1) the dose–response relationship of training components within different exercise modalities to elicit improvements in individuals showing intact or impaired muscle metaboreflex; and (2) potential and specific underlying mechanisms of metaboreflex improvements in individuals with different medical conditions.
