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Skeletal muscle interstitial P2Y2 receptor content and localization                                A, P2Y2 receptor content in vastus lateralis muscle before and after 14 days of immobilization of one leg and 5 weeks of exercise training of the other leg. †Different from the control leg, P < 0.05; #different from the immobilized leg, P < 0.05. B, immunohistochemical localization of purinergic P2Y2 receptors in human skeletal muscle. Positive staining for P2Y2 and endothelium superimposed. P2Y2 purinergic receptors were evident in endothelial cells of capillaries and microvessels (white arrow), and in vascular smooth muscle cells (white arrowhead). Modified from Mortensen et al. 2009a, 2012.

Skeletal muscle interstitial P2Y2 receptor content and localization  A, P2Y2 receptor content in vastus lateralis muscle before and after 14 days of immobilization of one leg and 5 weeks of exercise training of the other leg. †Different from the control leg, P < 0.05; #different from the immobilized leg, P < 0.05. B, immunohistochemical localization of purinergic P2Y2 receptors in human skeletal muscle. Positive staining for P2Y2 and endothelium superimposed. P2Y2 purinergic receptors were evident in endothelial cells of capillaries and microvessels (white arrow), and in vascular smooth muscle cells (white arrowhead). Modified from Mortensen et al. 2009a, 2012.

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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...

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... 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 affected by the level of physical activity ( Fig. 4; Mortensen et al. 2012). The origin of plasma ATP has been proposed to be endothelial and red blood cells (Mortensen et al. 2011), whereas the skeletal muscle is the main source of interstitial ATP ( Tu et al. ...

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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...

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... 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. ...
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Skeletal muscle is one of the most dynamic metabolic organs as evidenced by increases in metabolic rate of >150-fold from rest to maximal contractile activity. Because of limited intracellular stores of ATP, activation of metabolic pathways is required to maintain the necessary rates of ATP re-synthesis during sustained contractions. During the very early phase, phosphocreatine hydrolysis and anaerobic glycolysis prevails but as activity extends beyond ∼1 min, oxidative phosphorylation becomes the major ATP-generating pathway. Oxidative metabolism of macronutrients is highly dependent on the cardiovascular system to deliver O2 to the contracting muscle fibres, which is ensured through a tight coupling between skeletal muscle O2 utilization and O2 delivery. However, to what extent O2 delivery is ideal in terms of enabling optimal metabolic and contractile function is context-dependent and determined by a complex interaction of several regulatory systems. The first part of the review focuses on local and systemic mechanisms involved in the regulation of O2 delivery and how integration of these influences the matching of skeletal muscle O2 demand and O2 delivery. In the second part, alterations in cardiovascular function and structure associated with aging and heart failure, and how these impact metabolic and contractile function, will be addressed. Where applicable, the potential of exercise training to offset/reverse age- and disease-related cardiovascular declines will be highlighted in the context of skeletal muscle metabolic function. The review focuses on human data but also covers animal observations.
... 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]. ...
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Aging is associated with a decline in physiological function and exercise performance. These effects are mediated, at least in part, by an age-related decrease in the bioavailability of nitric oxide (NO), a ubiquitous gasotransmitter and regulator of myriad physiological processes. The decrease in NO bioavailability with aging is especially apparent in sedentary individuals, whereas older, physically active individuals maintain higher levels of NO with advancing age. Strategies which enhance NO bioavailability (including nutritional supplementation) have been proposed as a potential means of reducing the age-related decrease in physiological function and enhancing exercise performance and may be of interest to a range of older individuals including those taking part in competitive sport. In this brief review we discuss the effects of aging on physiological function and endurance exercise performance, and the potential role of changes in NO bioavailability in these processes. We also provide a summary of current evidence for dietary supplementation with substrates for NO production — including inorganic nitrate and nitrite, l-arginine and l-citrulline — for improving exercise capacity/performance in older adults. Additionally, we discuss the (limited) evidence on the effects of (poly)phenols and other dietary antioxidants on NO bioavailability in older individuals. Finally, we provide suggestions for future research.
... 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). ...
Article
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). ...
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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 (8-10). 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). ...
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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. ...
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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.
... Redistribution of peripheral blood flow/volume is vital during exercise to maintain cardiac filling pressure and optimize oxygen delivery to active skeletal muscles from non-active tissues (Saltin & Mortensen, 2012), with recent evidence highlighting α-adrenergic receptor-signalling as the primary mechanism at sea level (Hansen et al., 2020). To identify whether polycythaemia causes adaptations to physiological α-adrenergic vasoconstriction in non-active skeletal muscle during exercise, we determined the forearm vasoconstrictor response to moderate intensity (i.e. ...
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Key points: Humans suffering from polycythaemia undergo multiple circulatory adaptations including changes in blood rheology and structural and functional vascular adaptations to maintain normal blood pressure and vascular shear stresses, despite high blood viscosity. During exercise, several circulatory adaptations are observed, especially involving adrenergic and non-adrenergic mechanisms within non-active and active skeletal muscle to maintain exercise capacity, which is not observed in animal models. Despite profound circulatory stress, i.e., polycythaemia, several adaptations can occur to maintain exercise capacity, therefore making early identification of the disease difficult without overt symptomology. Pharmacological treatment of the background heightened sympathetic activity may impair the adaptive sympathetic response needed to match local oxygen delivery to active skeletal muscle oxygen demand and therefore inadvertently impair exercise capacity. Abstract: Excessive haematocrit and blood viscosity can increase blood pressure, cardiac work and reduce aerobic capacity. However, past clinical investigations have demonstrated that certain human high-altitude populations suffering from excessive erythrocytosis, Andeans with chronic mountain sickness, appear to have phenotypically adapted to life with polycythaemia, as their exercise capacity is comparable to healthy Andeans and even with sea level inhabitants residing at high altitude. By studying this unique population, which has adapted thru natural selection, this study aimed to describe how humans can adapt to life with polycythaemia. Experimental studies included Andeans with (n = 19) and without (n = 17) chronic mountain sickness, documenting exercise capacity, and characterizing the transport of oxygen thru blood rheology, including haemoglobin mass, blood and plasma volume & blood viscosity, cardiac output, blood pressure and changes in total and local vascular resistances thru pharmacological dissected of α-adrenergic signalling pathways within non-active and active skeletal muscle. At rest, Andeans with chronic mountain sickness had a substantial plasma volume contraction, which alongside a higher red blood cell volume, caused an increase in blood viscosity yet similar total blood volume. Moreover, both morphological and functional alterations in the periphery normalized vascular shear stress and blood pressure despite high sympathetic nerve activity. During exercise, blood pressure, cardiac work and global oxygen delivery increased similar to healthy Andeans but were sustained by modifications in both non-active and active skeletal muscle vascular function. These findings highlight widespread physiological adaptations that can occur in response to polycythaemia, which allow the maintenance of exercise capacity. This article is protected by copyright. All rights reserved.
... Although extensively studied, the sympatholytic compounds responsible for functional sympatholysis and their mechanism(s) of action are not well understood. Nevertheless, accumulating evidence supports a significant contribution played by ATP (Rosenmeier et al., 2004;Saltin and Mortensen, 2012), which appears to mediate its effect, in part, by attenuating the sensitivity of α-adrenergic receptors (Mortensen et al., 2009). Although less clear, NO also appears to contribute (Thomas and Victor, 1998), but its role may depend on the presence of other compounds such as prostacyclin (Dinenno and Joyner, 2004;Mortensen et al., 2007). ...
... In addition to sympathetic control, non-adrenergic vasoconstrictor and vasodilatory compounds also contribute to the regulation of contracting skeletal muscle BF (Saltin and Mortensen, 2012;Holwerda et al., 2015). These can be released by skeletal muscle, endothelial cells, nerve terminals, and circulating erythrocytes in response to increased mechanical stimuli and metabolic activity during exercise. ...
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Emerging evidence suggests that type 2 diabetes (T2D) may impair the ability to properly adjust the circulation during exercise with augmented blood pressure (BP) and an attenuated contracting skeletal muscle blood flow (BF) response being reported. This review provides a brief overview of the current understanding of these altered exercise responses in T2D and the potential underlying mechanisms, with an emphasis on the sympathetic nervous system and its regulation during exercise. The research presented support augmented sympathetic activation, heightened BP, reduced skeletal muscle BF, and impairment in the ability to attenuate sympathetically mediated vasoconstriction (i.e., functional sympatholysis) as potential drivers of neurovascular dysregulation during exercise in T2D. Furthermore, emerging evidence supporting a contribution of the exercise pressor reflex and central command is discussed along with proposed future directions for studies in this important area of research.
... Impaired systemic vasodilation can also lower V O 2 peak 27 . Potential mechanisms for this impediment include augmented sympathetic outflow, diminished flow-mediated dilation as a consequence of impaired endothelial function, and their interaction, i.e., attenuated 'functional sympatholysis' 91 . We hypothesize that the latter will assume greater prominence in HFpEF than in HFrEF, due to the higher prevalence in such patients of co-morbidities known to compromise endothelial function 6 . ...
Article
In heart failure with reduced ejection fraction (HFrEF), diminished tonic and reflex vagal heart rate modulation and exaggerated sympathetic outflow and neural norepinephrine release are evident from disease inception. Each of these disturbances of autonomic regulation has been associated independently with foreshortened survival; β-adrenoceptor antagonism and therapeutic autonomic modulation by other means have been demonstrated, in clinical trials, to lessen symptoms and prolong survival. In contrast, data concerning the autonomic status of patients with heart failure with preserved ejection fraction (HFpEF) are comparatively sparse, little is known concerning the prognostic consequences of autonomic dysregulation in such individuals, and therapies applied with success in HFrEF have in most trials failed to improve symptoms or survival of those with HFpEF. A recent HFpEF Expert Scientific Panel report emphasized that without a deeper understanding of the pathophysiology of HFpEF, establishing effective treatment will be challenging. One aspect of such pathology may be cardiovascular autonomic disequilibrium, often worsened by acute exercise or routine daily activity. This review aims to: summarize existing knowledge concerning parasympathetic and sympathetic function of patients with HFpEF; consider potential mechanisms and specific consequences of autonomic disturbances thus far identified; and propose hypotheses for future investigation.
... Additionally, evidence also demonstrates blood flow can be redistributed from vascular beds in less active to more active fibers within the same skeletal muscle (23). Within the vasculature of contracting skeletal muscle, sympathetic-mediated vasoconstriction is blunted through a complex integration of vasodilatory and vasoconstrictor substances helping to ensure adequate perfusion to the metabolically active tissue while maintaining mean arterial pressure (19,55). This unique ability of contracting skeletal muscle to blunt sympathetically mediated vasocon-striction, termed functional sympatholysis (50), has gained considerable attention in recent years (19,41,65). ...
... Another point of consideration is erythrocyte-derived ATP (55). In response to hypoxia and/or mechanical deformation (e.g., exercise), erythrocytes release ATP to evoke vasodilatation in contracting skeletal muscle (10). ...
Article
Patients with type 2 diabetes mellitus (T2DM) exhibit diminished exercise capacity likely attributable to reduced skeletal muscle blood flow (i.e., exercise hyperemia). A potential underlying mechanism of the impaired hyperemic response to exercise could be inadequate blunting of sympathetic-mediated vasoconstriction (i.e., poor functional sympatholysis). Therefore, we studied the hyperemic and vasodilatory responses to hand grip exercise in patients with T2DM as well as vasoconstriction to selective α-agonist infusion. Forearm blood flow (FBF) and vascular conductance (FVC) were examined in patients with T2DM (n=30) as well as nondiabetic controls (n=15) with similar age (59±9 vs. 60±9yrs, P=0.69) and body mass index (31.4±5.2 vs. 29.5±4.6kg·m ⁻² , P=0.48). Intra-arterial infusion of phenylephrine (α 1 -agonist) and dexmedetomidine (α 2 -agonist) were used to induce vasoconstriction: ((FVC with drug -FVC pre-drug )/FVC pre-drug x100%). Subjects completed rest and dynamic hand grip exercise (20% of maximum) trials per α-agonist. Patients with T2DM had smaller increases (Δ from rest) in FBF (147±71 vs. 199±63ml·min ⁻¹ ) and FVC (126±58 vs. 176±50ml·min ⁻¹ ·100mmHg ⁻¹ , P<0.01 for both) during exercise compared to controls, respectively. During exercise, patients with T2DM had greater α 1 - (-16.9±5.9 vs. -11.3±3.8%) and α 2 -mediated vasoconstriction (-23.5±7.1 vs. -19.0±6.5%, P<0.05 for both) versus controls. The magnitude of sympatholysis (Δ in %vasoconstriction between exercise and rest) for PE was lower (worse) in patients with T2DM versus controls (14.9±12.2 vs. 23.1±8.1%, P<0.05) whereas groups were similar during DEX trials (24.6±12.3 vs. 27.6±13.4%, P=0.47). Our data suggest patients with T2DM have attenuated hyperemic and vasodilatory responses to exercise which could be attributable to greater α 1 -mediated vasoconstriction in contracting skeletal muscle.