Post-exercise Circulatory Occlusion Research Articles

The Effect of Menopause Status on the Skeletal Muscle Metaboreflex.

IntroductionIt is well established that the exercise pressor reflex contributes to cardiovascular control (e.g. mean arterial pressure (MAP)) during exercise. One arm of the exercise pressor reflex includes the metabolically sensitive group IV afferents (i.e. metaboreflex). The metaboreflex‐induced cardiovascular responses to exercise are incompletely understood, especially in women across the aging spectrum. For example, post‐menopausal women have greater increases in MAP and systemic vascular resistance (SVR) during locomotor muscle exercise compared to pre‐menopausal women. However, it is unclear if an exaggerated metaboreflex arising from the locomotor muscles is contributing to these cardiovascular adjustments with exercise in post‐menopausal women. We hypothesized that 1) post‐menopausal women will have an augmented MAP response with isolated metaboreflex activation compared to pre‐menopausal women and 2) the exaggerated increase in MAP in the post‐menopausal women will be primarily due to greater increases in SVR.MethodsPre‐ (n= 10, 25±3yrs, 24±3 kg/m2) and post‐menopausal women (n=12, 58±4yrs, 24±3 kg/m2) performed 2 sessions of cycling exercise at 20 W for 5 min with bilateral upper thigh pressure tourniquets inflated to 90 mmHg. At end exercise, the recovery was randomized to post‐exercise circulatory occlusion (PECO) to isolate the metaboreflex (via bilateral upper thigh pressure tourniquets rapidly inflated to suprasystolic pressure for 2 min) or normal recovery (NR) without intervention. Systolic and diastolic blood pressure were measured via manual sphygmomanometry and MAP was calculated. Cardiac output was measured via open circuit acetylene wash‐in and systemic vascular resistance (SVR) was calculated. Data is reported as the absolute change from rest to recovery.ResultsMAP was elevated during PECO compared to NR in both groups (p<0.05), while MAP during PECO was greater in post‐ compared to pre‐menopausal women (20±9 vs. 13±5 mmHg, respectively) (p<0.05). Similarly, SVR was elevated during PECO compared to NR in both groups (p<0.05), while SVR was greater during PECO in post‐ compared to pre‐menopausal women (5±3 vs. 3±1 mmHg/L/min, respectively) (p<0.05). In contrast, cardiac output was not different between NR and PECO in either pre‐ (NR: 0.3±1 vs. PECO: −0.2±1 L/min) and post‐menopausal (NR: −0.1±1 vs. PECO: −0.7±0.9 L/min) (all, p>0.05).ConclusionThese data demonstrate that isolated metaboreflex stimulation following whole‐body exercise results in exaggerated increases in MAP and SVR in post‐ compared to pre‐menopausal women. These data suggest that exercise pressor reflex‐mediated control of MAP during exercise is accentuated in post‐menopausal women with menopause status.

Sympathetic Activation to Limb Venous Distension is Preserved during Muscle Metaboreceptor Stimulation

Venous saline infusions in an arterially occluded forearm evokes reflex increases in muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in humans (venous distension reflex). Animal studies suggest that venous distension increases the discharge of Group III and IV afferent nerve endings in peripheral veins. Exercise also activates the Group III and IV afferent nerves in exercising muscles. It is unclear if the venous distension reflex contributes to BP regulation during exercise. We hypothesized that muscle metaboreceptor stimulation might alter the venous distension reflex response. BP (Finapres), heart rate (ECG), and MSNA (microneurography) were assessed in 18 young healthy subjects (13 M, 5 F, 26 ± 1 yrs). In trial 1, saline (5% forearm volume) was infused into veins of an arterially occluded arm (non‐handgrip trial). In the second experiment, subjects performed 2 min static handgrip followed by post exercise circulatory occlusion (PECO) of the arm. During PECO, saline was infused into veins of the arm (handgrip trial). In trial 1, infusion increased MSNA (18.5 ± 1.6 to 29.1 ± 2.4 bursts/min, P < 0.001) and BP (P <0.001) as expected. Handgrip significantly raised MSNA (19.8 ± 1.6 to 28.0 ± 1.8 bursts/min, P < 0.001), BP (P < 0.001) and venous lactic acid (1.0 ± 0.1 to 3.1 ± 0.4, mmol/L, P < 0.001). Venous saline infusion during PECO further raised MSNA (prior infusion vs. end of infusion, 29.0 ± 2.4 to 37.7±2.7 bursts/min, P= 0.001) and BP (P < 0.001). The changes in MSNA evoked by infusion during PECO were not significantly different from the rises in the non‐handgrip trial (delta 8.6 ± 1.5 to delta 10.6 ± 1.8 bursts/min, P = 0.258). The BP responses to the infusion were not different in the two trials. These observations indicate that venous distension reflex responses are preserved during the sympathetic activation mediated by the muscle metaboreceptor stimulation. These data may suggest that venous distension reflex contributes to the BP regulation during exercise.Support or Funding InformationSupported by NIH R01 HL144781 (Cui and Sinoway) and UL1 TR002014 (Sinoway), and Pennsylvania Department of Health Tobacco CURE Funds SAP#4100079742 (Cui).

Baroreflex Resetting of Sympathetic Action Potential Subpopulations During Fatiguing Isometric Handgrip and Post‐Exercise Circulatory Occlusion

The arterial baroreflex exerts heterogeneous control over the varying‐sized action potential (AP) subpopulations active within human muscle sympathetic nerve activity (MSNA) under baseline conditions. How baroreflex control of sympathetic AP discharge becomes reset to facilitate sympathoexcitation during physical exercise remains to be investigated. Therefore, we quantified the baroreflex gain for each sympathetic AP cluster (i.e., reflecting different c‐fibres) within the MSNA filtered neurogram (microneurography and continuous wavelet transform) during baseline conditions (BSL), the last 2‐min of a 5‐min fatiguing isometric handgrip (20% of max; IHG), and during post‐exercise circulatory occlusion (PECO) in six healthy young participants (3 females, 23–31 years). Baroreflex gain was measured as the slope of the linear function between AP probability (%) versus diastolic blood pressure (DBP; Finometer). We classified AP clusters based on peak‐to‐peak amplitude using the following allocations: small (clusters 1–2), medium (clusters 3–8) and large (clusters 9–15). During BSL, medium AP clusters (e.g., cluster 3: −9.4 ± 2.7 %/mmHg) expressed the greatest baroreflex gains while small (e.g., cluster 1: −1.9 ± 0.4 %/mmHg) and large (e.g., cluster 9: −2.4 ± 0.9 %/mmHg) clusters expressed lesser gains (both P < 0.05 vs. cluster 3). Compared to BSL, baroreflex functions for most AP clusters during IHG and PECO were reset upwards to greater firing probabilities (both Condition‐by‐Cluster Interactions: P < 0.05) and rightwards to higher DBP (BSL: 69 ± 4, IHG: 81 ± 3, PECO: 79 ± 2 mmHg; both P < 0.05 vs. BSL). However, compared to BSL, the gains of the AP cluster baroreflex functions remained unchanged with IHG (e.g., cluster 1: −1.6 ± 0.4, cluster 3: −8.2 ± 2.9, cluster 9: −4.3 ± 1.8 %/mmHg, Main Effect: P > 0.05). Nonetheless, AP cluster gains were augmented above BSL during PECO (e.g., cluster 1: −2.6 ± 1.0, cluster 3: −16.0 ± 4.4, cluster 9: −5.5 ± 1.8 %/mmHg; Main Effect: P < 0.05). IHG (e.g., cluster 15: −1.6 ± 0.5 %/mmHg) and PECO (e.g., cluster 15: −0.6 ± 0.3 %/mmHg) recruited a subpopulation of previously silent larger and faster conducting APs that expressed weak baroreflex gains. These data suggest that during fatiguing isometric handgrip exercise the interaction between the central command feature and the skeletal muscle metaboreflex resets baroreflex control of discrete AP subpopulations to higher blood pressures and greater levels of discharge. In addition to resetting the baroreflex functions, independent activation of the muscle metaboreflex augments the strength of baroreflex control over subpopulations of previously active APs.Support or Funding InformationSupported by the Natural Sciences and Engineering Research Council (NSERC) of Canada.

Muscle metaboreflex activation increases ventilation and heart rate during dynamic exercise in humans.

What is the central question of this study? Classically, the stimulation of thin-fibre skeletal muscle afferents, via the application of postexercise circulatory occlusion (PECO) at rest, fails to generate ventilatory responses. We used a new experimental protocol to examine whether the involvement of these metabosensitive afferents in ventilatory control can only be revealed during exercise, when other potentially synergistic inputs that increase central respiratory drive are activated. What is the main finding and its importance? We found that PECO of one leg augmented the ventilatory and heart rate responses to single-legged exercise of the contralateral leg, suggesting that metaboreceptive muscle afferents contribute to the control of the exercise hyperpnoea. Inhibition of thin-fibre skeletal muscle afferent neurotransmission attenuates ventilatory and cardiovascular responses to exercise. However, stimulation of muscle metaboreceptive afferents at rest, via postexercise circulatory occlusion (PECO), classically fails to generate increases in ventilation or heart rate. It is possible that the involvement of muscle afferent feedback in ventilatory control can only be revealed during exercise, when other potentially synergistic inputs that increase central respiratory drive are activated. Therefore, we assessed the cardiorespiratory responses to single-legged cycling exercise with or without PECO of the contralateral leg. Thirteen healthy participants performed left-legged cycling exercise (40 or 60W) followed by either: (i) no PECO (Con trial); or (ii) PECO (PECO trial) of the left leg for 3min. During this 3min period, right-legged cycling exercise was performed at the same workload as the preceding left-legged exercise (40 or 60W). During 60W right-legged cycling, ventilation relative to baseline was significantly higher in the PECO versus Con trial (22.9±2 versus 18.7±1.8lmin-1 ; P<0.05), but there was no difference between the trials performed at 40W. The change in heart rate was significantly greater during right-legged cycling in the PECO versus Con trial in the 40 (41.2±4 versus 34.1±3.1beatsmin-1 ; P<0.05) and 60W trials (49.7±2.7versus 43.4±3.7beatsmin-1 ; P<0.05). There were no differences in oxygen uptake, carbon dioxide production and ratings of perceived exertion between trials. These findings suggest that stimulation of muscle metaboreceptive afferents can drive increases in ventilation and heart rate during dynamic exercise.

Interaction between the muscle metaboreflex and central command - A clearer picture of cardiorespiratory control during exercise.

Neural control of the circulatory and ventilatory responses to exercise has been an intriguing area of investigation for well over 100 years. However, development of experimental protocols that clarify mechanisms and their relative importance has proved difficult because of the likelihood of redundancy and the complexity of central integration. In this issue of Experimental Physiology, Lam, Greenhough, Nazari, White, & Bruce (2019) met this challenge with an elegant and cleverly designed study in humans that improves our understanding of the contribution of metabolically sensitive neural feedback from active skeletal muscle to the cardiorespiratory response to dynamic exercise. Ventilation and heart rate responses to exercise occur rapidly to a level well matched to the workload. Descending neural signals from higher brain centres (i.e. central command) have a prominent role in increasing ventilation and heart rate in proportion to the effort exerted (Goodwin, McCloskey, & Mitchell, 1972). When examining the contribution of metabolically sensitive neural feedback from active skeletal muscle (i.e. the metaboreflex) in isolation after exercise, which effectively increases blood pressure, the ventilatory and heart rate responses generally trend towards resting values. Given this, the observation that ventilation and heart rate rapidly return towards resting levels during metaboreflex isolation (i.e. postexercise ischaemia) has led some to suggest that the muscle metaboreflex has little influence on both ventilation and heart rate. Countering evidence shows a contribution of the afferent feedback from contracting skeletal muscle to the ventilatory and heart rate response to dynamic leg exercise that is attenuated by pharmacological blockade (Amann et al. 2010). These findings seem to suggest that the metaboreflex can contribute to the ventilatory response to exercise, but only in certain conditions. The study by Lam et al. (2019) provides insight into this mechanism by demonstrating metaboreflex control of exercise ventilation and heart rate only when central command is engaged, i.e. during exercise. To demonstrate this, the authors used an innovative and creative study protocol, in which cardiorespiratory responses to left-legged cycling were followed by right-legged cycling with and without left leg postexercise circulatory occlusion (PECO). Relative to baseline, ventilation was elevated during leg cycling, as expected, but was heightened further during concomitant PECO, particularly at higher workloads. Indeed, ventilation returned to baseline when PECO was performed in a separate protocol without right-legged cycling. Central respiratory drive is modified by many afferent inputs during exercise. However, chemosensitive structures in the medulla and carotid bodies responsible for ventilatory responses to hypoxia and hypercapnia probably make a small contribution to the ventilatory response to mild- and moderate-intensity exercise because arterial , and pH remain relatively constant. Indeed, end-tidal CO2 () was not increased with higher intensity single-legged cycling. In fact, single-legged cycling combined with PECO significantly reduced , probably as a result of greater ventilation relative to CO2 production. Thus, if lower arterial were to be confirmed ( is not necessarily equivalent to arterial ), it would suggest opposite signalling from the muscle metaboreflex and central chemoreflex and perhaps an overall underestimation of metaboreflex-mediated increases in ventilation. However, little is known regarding the potential interaction between the muscle metaboreflex and central and peripheral chemoreceptor input to modulate exercise ventilation. Advancements in the field often create more questions than answers, and the study by Lam et al. (2019) is no exception. An exaggerated ventilatory response to exercise is characteristic of patients with heart failure, chronic obstructive pulmonary disease and pulmonary hypertension. The obvious question is, to what extent does the metaboreflex contribute? Also, exaggerated sympathetic responses (not assessed in the study by Lam et al., 2019) to isolated muscle metaboreflex activation have been documented in patient populations with high prevalence, such as hypertension, heart failure and diabetes. Future studies are needed to determine the extent to which the interaction between the metaboreflex and central command augments the sympathetic response beyond what is observed during isolated metaboreflex activation in these patient populations. To this end, the authors are to be commended on moving a step forwards in our understanding of the role of the skeletal muscle metaboreflex in controlling ventilation and heart rate during exercise in healthy humans.

Sex differences in blood pressure regulation during ischemic isometric exercise: the role of the β-adrenergic receptors.

We sought to investigate whether the β-adrenergic receptors play a pivotal role in sex-related differences in arterial blood pressure (BP) regulation during isometric exercise. Sixteen volunteers (8 women) performed 2 min of ischemic isometric handgrip exercise (IHE) and 2 min of postexercise circulatory occlusion (PECO). Heart rate (HR) and beat-to-beat arterial BP were continuously measured. Beat-to-beat estimates of stroke volume (ModelFlow) were obtained and matched with HR to calculate cardiac output (Q̇) and total peripheral resistance (TPR). Two trials were randomly conducted between placebo and nonselective β-adrenergic blockade (40 mg propranolol). Under the placebo condition, the magnitude of the BP response in IHE was lower in women compared with men. During PECO, the BP remained elevated and the sex differences persisted. The β-blockade attenuated the BP response during IHE in men (∆57 ± 4 vs. ∆45 ± 7 mmHg, P = 0.025) due to a reduction in Q̇ (∆3.7 ± 0.5 vs. ∆1.8 ± 0.2 L/min, P = 0.012) while TPR was not affected. In women, however, the BP response during IHE was unchanged (∆27 ± 3 vs. ∆28 ± 3 mmHg, P = 0.889), despite attenuated Q̇ (∆2.7 ± 0.4 vs. ∆1.3 ± 0.2 L/min, P = 0.012). These responses were mediated by a robust increase in TPR under β-blockade (∆-0.2 ± 0.4 vs. ∆2.2 ± 0.7 mmHg·L-1·min, P = 0.012). These findings demonstrate that the sex differences in arterial BP regulation during ischemic IHE are mediated by β-adrenergic receptors.NEW & NOTEWORTHY We found that the blood pressure response during isometric exercise in women is mediated by increases in cardiac output, whereas in men it is mediated by increases in both cardiac output and total peripheral resistance. In addition, women showed a robust increase in total peripheral resistance under β-blockade during isometric exercise and muscle metaboreflex activation. These findings demonstrate that sex differences in blood pressure regulation during isometric exercise are mediated by β-adrenergic receptors.

Cardiovascular Responses to the Exercise Pressor Reflex in Pediatric Heart Transplant Recipients

Pediatric heart transplant recipients (HTR) have reduced exercise tolerance despite normal systolic ventricular function. A slower heart rate adaptation to exercise in HTR due to cardiac denervation is commonly observed in HTR patients, which explains, in part, the exercise intolerance. We tested the hypothesis that the cardiovascular response to exercise pressor reflex activation from handgrip exercise would be blunted in HTR.MethodsSix pediatric HTR (3f/3m; mean±SD, 10±3 yrs) and five healthy‐matched controls (CTL; 3f/2m; 10±2 yrs) were studied. After 3 min of resting baseline, subjects performed 2 min of isometric handgrip (HG) exercise at 40% maximal voluntary contraction, followed by 3 min post‐exercise circulatory occlusion (PECO). Beat‐by‐beat mean arterial pressure, heart rate, and modelflow stroke volume and cardiac output were recorded. Data were analysed as the change (Δ) from rest using two‐way repeated measures ANOVA (2 × 3; group × condition) and Holm‐Sidak multiple comparisons analysis. Significance was accepted at P&lt;0.05.ResultsMean arterial pressure increased in HTR (Δ17±15 mmHg) and CTL (Δ13±16 mL) during HG (P&lt;0.001) and remained elevated above baseline during PECO (HTR: Δ10±10 mmHg; CTL: Δ11±9 mmHg; P&lt;0.05), with no between group differences. Heart rate did not significantly increase during HG in HTR (Δ4±5 bpm, P=0.235) but did in CTL (Δ14±11 bpm, P&lt;0.001), and was 9 bpm lower in HTR vs CTL (P=0.005). Heart rate was not different during PECO from rest in HTR and CTL. Stroke volume increased in HTR (Δ3±1 mL) and CTL (Δ3±3 mL) during HG (P&lt;0.001) and remained elevated above baseline during PECO (HTR: Δ3±2 mL; CTL: Δ4±3 mL; P&lt;0.001), with no between group differences. Cardiac output did not significantly increase during HG in HTR (Δ0.34±0.21 L/min, P=0.074) but did in CTL (Δ0.71±0.54 L/min, P&lt;0.001), and was 0.37 L/min lower in HTR vs CTL (P=0.035). Cardiac output was not different during PECO from rest in HTR and CTL.ConclusionsOwing to the impaired heart rate response during handgrip exercise, cardiac output was lower in pediatric HTR compared to healthy‐matched controls in response to exercise pressor reflex activation.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Sex Differences in Blood Pressure Regulation During Ischemic Isometric Exercise: The Role of the β‐Adrenergic Receptors

Sex differences have been reported in the respective contribution of cardiac output (Q̇) and vascular constriction to the pressor response to isometric handgrip exercise (IHE). Differently from men, the majority of the blood pressure (BP) response to IHE in young women is due to elevated Q̇ rather than elevations in total peripheral resistance (TPR). The underlying mechanisms for these differences are unknown, but previous data suggest that the β‐adrenergic receptors offset α‐adrenergic vasoconstriction in young women under resting condition. Whether this could be extended to an exercise condition remains to be determined. Given this, the aim of the present study was to investigate whether the β‐adrenergic receptors play a pivotal role in sex‐related differences in the BP regulation during ischemic IHE. Ten men (21 ± 0.6 years) and 9 women (23 ± 1.3 years) healthy and physically active volunteers were recruited. All women were non‐oral contraceptives users and performed experiments in the early follicular phase of the menstrual cycle. To make the forearm ischemic prior to exercise, a 3 min period of circulatory arrest was achieved by inflating an upper arm cuff to supra systolic pressure. This cuff remained inflated for 2 min of isometric exercise at 30% of maximal voluntary contraction force, and 2 min of post‐exercise circulatory occlusion (PECO). Beat‐to‐beat heart rate (HR) (electrocardiography) and arterial BP (finger photopletysmography) were continuously measured. Beat‐to‐beat changes in stroke volume (SV) was obtained with Modelflow method and matched with the responses of heart rate (HR) to estimate Q̇ (Q̇=SV x HR) and TPR (TPR=Mean BP/Q). The exercise and PECO responses were analyzed using the peak change. Two trials were randomly conducted in different days either placebo or non‐selective β‐adrenergic blockade (40mg propranolol). During ischemic IHE under placebo condition, mean BP increased from rest in both men and women, however the magnitude of these responses was greater in men. During PECO, the mean BP remained elevated and the sex differences persisted. The β‐adrenergic blockade attenuated the mean BP response during ischemic IHE from rest in men (Δ 51 ± 6 mmHg vs Δ 39 ± 6 mmHg, P&lt;0.01) but not in women (Δ 28 ± 5 mmHg vs Δ 32 ± 5mmHg, P=0.17). This attenuated mean BP response observed in men under β‐blockade could be explained by a reduction in Q̇ (Δ 3.0 ± 0.4l/min vs Δ 1.2 ± 0.2 l/min, P&lt;0.01). This was less pronounced in women (Δ 2.0 ± 0.4 l/min vs Δ 1.0 ± 0.2 l/min, P=0.05). In addition, vascular constriction was increased during ischemic IHE and PECO in men and these responses were not affected by β‐blockade. In contrast, increases in TPR were greater in women under β‐adrenergic blockade during both ischemic IHE (Δ 1.2 ± 0.7 mmHg.L‐1.min vs Δ 3.3 ± 0.9 mmHg.L‐1.min, P=0.03) and PECO (Δ 4.5 ± 0.9 mmHg.L‐1.min vs Δ 6.8 ± 1.1 mmHg.L‐1.min, P=0.04). These findings demonstrate for the first time that the sex differences in arterial BP regulation during ischemic IHE are mediated by β‐adrenergic receptors.Support or Funding InformationFunding: CNPq, FAPDF, CAPES and an American Physiological Society Arthur C. Guyton Awards for Excellence in Integrative Physiology (to L.C. Vianna).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Lower baroreflex sensitivity during muscle metaboreflex activation in children and adolescents with the Fontan circulation and single ventricle physiology

Individuals with the Fontan circulation and single ventricle physiology have elevated sympathetic nerve activity at rest and during muscle metaboreflex activation that is consistent with autonomic dysfunction. Adults with the Fontan circulation also show reduced baroreflex sensitivity (BRS); however, there is limited understanding of BRS in children or adolescents with the Fontan circulation. In healthy adults, BRS decreases with increased sympathetic nerve activity during isometric handgrip exercise, but not during isolated muscle metaboreflex activation. The effect of handgrip exercise and muscle metaboreflex activation on BRS in children and adolescents with the Fontan circulation is currently unknown.PURPOSEWe tested the hypothesis that BRS is lower at rest and less responsive during handgrip exercise and post‐exercise circulatory occlusion (PECO) in children/adolescents with the Fontan circulation compared to healthy controls.METHODSEight children/adolescents with the Fontan circulation (12 ± 2 yrs; 3 males) and 8 healthy controls (13 ± 4 yrs; 5 males) were studied. Continuous heart rate (ECG) and non‐invasive blood pressure (Finometer® MIDI) were recorded during 3‐min of resting baseline, 2‐min of isometric handgrip exercise at 30% of maximal voluntary contraction, and 3‐min of PECO. Continuous heart rate, systolic blood pressure, and diastolic blood pressure signals were analyzed using the BRS Analysis software (Nevrokard, Slovenia, 2018) to yield average BRS values during rest, handgrip, and PECO for each group. Differences between groups and across conditions were assessed using two‐way repeated measures (2 × 3, group × condition) ANOVA. P&lt;0.05 was considered significant.RESULTSThere was a significant group × condition interaction for BRS (P&lt;0.001). BRS was lower in children/adolescents with the Fontan circulation vs. healthy controls at rest (13 ± 8 vs. 38 ± 10 ms/mmHg; P&lt;0.001) and during PECO (18 ± 17 vs. 37 ± 18 ms/mmHg; P=0.044), but not during handgrip (13 ± 10 vs. 14 ± 6 ms/mmHg; P=0.843). BRS in children/adolescents with the Fontan circulation did not change across conditions (P=0.188).CONCLUSIONOur findings suggest that BRS is lower at rest and has a blunted response during sympatho‐excitation in children/adolescents with the Fontan circulation compared to healthy controls. Collectively, our findings indicate potential autonomic dysfunction in children/adolescents with the Fontan circulation.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Sensitivity of the human ventilatory response to muscle metaboreflex activation during concurrent mild hypercapnia.

What is the central question of this study? What is the relationship between the level of systemic hypercapnia and the magnitude of the additional hyperpnoea produced in response to a standardized level of muscle metaboreflex activation? What is the main finding and its importance? When a standardized activation of the muscle metaboreflex was combined with exposure to increasing levels of hypercapnia, the hyperpnoea this caused increased linearly. The concept of a synergistic interaction between the muscle metaboreflex and the central chemoreflex in humans is supported by this finding. Ventilation increases during muscle metaboreflex activation when postexercise circulatory occlusion (PECO) traps metabolites in resting human muscle, but only in conditions of concurrent systemic hypercapnia. We hypothesize that a linear relationship exists between the level of hypercapnia and the magnitude of the additional hyperpnoea produced in response to a standardized level of muscle metaboreflex activation. Fifteen male subjects performed four trials, in which the end-tidal partial pressure of carbon dioxide ( ) was elevated by 1, 3, 7 or 10mmHg above resting values using a dynamic end-tidal forcing system. In each trial, subjects were seated in an isometric dynamometer designed to measure ankle plantar flexor force. Rest for 2 min in room air was followed by 15min of exposure to one of the four levels ofhypercapnia, at which 5min further rest was followed by 2 min of sustained isometric calf muscle contraction at 50% of predetermined maximal voluntary strength. Immediately before cessation of exercise, a cuff around the upper leg was inflated to a suprasystolic pressure to cause PECO for 3min, before its deflation and a further 5min of rest, concluding exposure to hypercapnia. The PECO consistently elevated mean arterial blood pressure by ∼10mmHg in all trials, indicating similar levels of metaboreflex activation. Increased ventilation during PECO was related to as described by the following linear regression equation: Change in minute ventilation (lmin-1 )=0.85× (mmHg)+0.80 (lmin-1 ). This finding supports our hypothesis and furthers the idea of a synergistic interaction between muscle metaboreflex activation and central chemoreflex stimulation.

TRPV1 and BDKRB2 receptor polymorphisms can influence the exercise pressor reflex.

The mechanisms responsible for the high inter-individual variability in blood pressure responses to exercise remain unclear. Common genetic variants of genes related to the vascular transduction of sympathetic outflow have been investigated, but variants influencing skeletal muscle afferent feedback during exercise have not been explored. Single nucleotide polymorphisms in TRPV1 rs222747 and BDKRB2 rs1799722 receptors present in skeletal muscle were associated with differences in the magnitude of the blood pressure response to static handgrip exercise but not mental stress. The combined effects of TRPV1 rs222747 and BDKRB2 rs1799722 on blood pressure and heart rate responses during exercise were additive, and primarily found in men. Genetic differences in skeletal muscle metaboreceptors may be a risk factor for exaggerated blood pressure responses to exercise. Exercise blood pressure (BP) responses demonstrate high inter-individual variability, which could relate to differences in metabolically sensitive afferent feedback from the exercising muscle. We hypothesized that single-nucleotide polymorphisms (SNPs) in genes encoding metaboreceptors present in group III/IV skeletal muscle afferents can influence the exercise pressor response. Two hundred men and women underwent measurements of continuous BP and heart rate at baseline and during 2min of static handgrip exercise (30% maximal volitional contraction), post-exercise circulatory occlusion and mental stress (serial subtraction; internal control). Participants were genotyped for SNPs in TRPV1 (rs222747; G/C), ASIC3 (rs2288645; G/A), BDKRB2 (rs1799722; C/T), PTGER2 (rs17197; A/G) and P2RX4 (rs25644; A/G). Exercise systolic BP (19± 10 vs. 22± 10mmHg, P= 0.03) was lower in GG versus GC/CC minor allele carriers for TRPV1 rs222747, while exercise diastolic BP (14± 7 vs. 17± 7mmHg, P= 0.007) and heart rate (12± 8 vs. 15± 9beatsmin-1 , P= 0.03) were lower in CC versus CT/TT minor allele carriers for BDKRB2 rs1799722. Individuals carrying both minor alleles for TRPV1 rs222747 and BDKRB2 rs1799722 had greater systolic (22± 11 vs. 17± 10mmHg, P= 0.04) and diastolic (18± 7 vs. 14± 7mmHg, P= 0.01) BP responses than those with no minor alleles; these differences were larger in men. No differences in BP or heart rate responses were detected during static handgrip with ASIC3 rs2288645, PTGER2 rs17197 or P2RX4 rs25644. None of the selected SNPs were associated with differences during mental stress. These findings demonstrate that variants in TRPV1 and BDKRB2 receptors can contribute to BP differences during static exercise in an additive manner.

Metaboreceptor activation in heart failure with reduced ejection fraction: Linking cardiac and peripheral vascular haemodynamics.

What is the central question of this research? Do patients with heart failure with reduced ejection fraction (HFrEF) exhibit a greater dependence on cardiac or peripheral vascular haemodynamics across multiple levels of muscle metaboreflex activation provoked by postexercise circulatory occlusion? What is the main finding and its importance? The metaboreflex-induced pressor response in HFrEF patients is governed almost entirely by the peripheral circulation, which places a substantial haemodynamic load on the failing heart. This maladaptive response exacerbates the disease-related impairment of systolic function that is a hallmark feature of HFrEF and may therefore contribute to exercise intolerance in this patient group. We sought to evaluate the muscle metaboreflex in heart failure with reduced ejection fraction (HFrEF) patients, with an emphasis on the interaction between cardiac and peripheral vascular haemodynamics across multiple levels of metaboreceptor activation. In 23HFrEF patients (63±2years of age) and 15 healthy control subjects (64±3years of age), we examined changes in mean arterial pressure, cardiac output, systemic vascular conductance, effective arterial elastance, stroke work and forearm deoxyhaemoglobin concentration during metaboreceptor activation elicited by postexercise circulatory occlusion (PECO) after three levels of static-intermittent handgrip exercise (15, 30 and 45% maximal voluntary contraction). Across workloads, the metaboreflex-induced increase in deoxyhaemoglobin and mean arterial pressure were similar between groups. However, in control subjects, the pressor response was driven by changes (Δ) in cardiac output(Δ495±155, Δ564±156 and Δ666±217mlmin-1 ), whereas this change was accomplished by intensity-dependent reductions in systemic vascular conductance in patients with HFrEF (Δ-4.9 ±1.5, Δ-9.1 ±1.9 and Δ-12.7 ±1.8mlminmmHg-1 ). This differential response contributed to the exaggerated increases in effective arterial elastance in HFrEF patients compared with control subjects, coupled with a blunted response in stroke work in the HFrEF patients. Together, these findings indicate a preserved role of the metaboreflex-induced pressor response in HFrEF but suggest that this response is governed by changes in the peripheral circulation. The net effect of this response appears to be maladaptive, as it places a substantial haemodynamic load on the left ventricle that may exacerbate left ventricular systolic dysfunction and contribute to exercise intolerance in this patient population.

The Ventilatory Response to Muscle Metaboreflex Activation During Concurrent Hypercapnia is Attenuated by Local Muscle Training

Increased ventilation during post‐exercise circulatory occlusion (PECO) with concurrent hypercapnia suggests a synergistic interaction between muscle metaboreflex activation and chemoreflex stimulation. The exercise pressor reflex (EPR) response to contraction of a human calf muscle and subsequent PECO can be attenuated by training, indicating a decreased activation of muscle metaboreceptive afferents driving the EPR. We hypothesised that 6 weeks of one legged calf raise training would attenuate metaboreceptor activity, the EPR and if these afferents provide a drive to breathe, the ventilatory response seen during PECO when combined with mild hypercapnia. In the contralateral limb there would be no effect on muscle afferent input to the cardiovascular or respiratory control systems so no change in EPR or breathing would be expected during PECO.Eleven male subjects aged 19.5 ± 0.8 years (mean±SD) gave informed consent to participate in the study, approved by the local ethics committee. A standardized test of the cardiovascular and respiratory responses to isometric contraction of the calf muscle at 50% of maximum voluntary force (MVC) for 2 min was followed by 3 min of PECO. In random order left and right legs were tested separately under two conditions, 1) breathing room air 2) hypercapnia, 5% CO2 above end tidal level. A dynamic end tidal forcing system controlled the inspired gas composition and monitored ventilation. Heart rate (HR) and blood pressure (MAP) were measured by ECG and Portapres respectively. Right leg training consisted of 120 calf raises to maximum height in 4 sets of 30, one heel raise and lower per second, one minute rest between sets. Whenever 4 sets could be achieved loading of 10%, then increments of 5% body mass was added. After 6 weeks of training the initial tests were repeated.MVC did not change after training in either leg. During exercise of the trained leg during hypercapnia, average MAP rise from baseline was reduced from 18.1± 1.4, to 15.6±1.4 mmHg (mean±SEM), p&lt;0.05 after, training. Ventilation change from the hypercapnic baseline was also reduced from 17.5± 2.8 to 12.1±2.6 l.min−1, p&lt;0.05 after training.Table 1 shows the data from each leg in the PECO phase of the trials, performed before and after the training. In the room air and hypercapnia trials, the EPR was significantly reduced from control values in the trained leg. The increase in ventilation from baseline was reduced, by ~45%, in the trained limb during the hypercapnia trial. There were no alterations in the cardiovascular or ventilatory responses to PECO, during hypercapnia or room air breathing trials in the untrained limb, ruling out any central or peripheral adaptation in this leg, induced by the training period. In the trained leg the MAP data shows clear evidence of a decrease in the EPR after training, indicating reduced muscle metaboreflex activation during PECO. This is despite generating the same force‐time integral during the exercise period as before training. We conclude that in the trained limb the marked decrease in ventilation during PECO in the hypercapnia condition must be due to a decreased drive to breathe arising from metabosensitive muscle afferents.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Oral Contraceptives Attenuate Metaboreflex in Young Women

BackgroundSkeletal muscle afferent feedback (group III/IV) increases mean arterial pressure (MAP) and heart rate (HR) during exercise. Evidence suggests that oral contraceptive (OC) use can increase resting blood pressure. The influence of OC on MAP and HR when activating group III/IV afferents is unclear.ObjectiveTo determine if women taking OCs have greater cardiovascular responses to activating group III/IV afferents and if phases of menstrual cycle influence this response.MethodsTwelve women (means ± SD; 24±2 yrs, 7 taking OCs) attended two identical experimental visits, once during early follicular (low estrogen, days 1–4, LE) and once during ovulation (high estrogen, days 10–14, HE). Visits included 1) 3 min of rest and 3 min of passive knee flexion (HUMAC Norm, CSMI, Stoughton, MA) to activate the mechanoreflex and 2) steady state cycling (5 min) with bilateral post exercise circulatory occlusion (PECO) (2 min) of the vastus lateralis to activate the metaboreflex. Continuous noninvasive blood pressure (Nexfin, Edward Lifesciences, Irvine, CA) and a 3 lead ECG (AD Instruments, Coloroado Springs, CO) measured MAP and HR, respectively.ResultsResting MAP was similar in women taking OC (90±4 mmHg) vs. no OC (87±8 mmHg, p=0.24). Mechanoreceptor activation did not increase MAP (OC: 90±6 mmHg and no OC: 88±8 mmHg) or HR (OC: 64±7 bpm and no OC: 67±12 bpm, p&lt;0.05) in either group. MAP and HR were similar in women during both LE and HE phases with mechanoreflex activation (p&gt;0.05). Metaboreflex activation increased MAP in women not taking OCs (steady state 95±23 mmHg vs. PECO 105±24 mmHg). On the other hand, MAP decreased with metaboreceptor activation in women taking OCs (steady state 94±12 mmHg vs. PECO 89±16 mmHg, p=0.032). Resting HR was greater in women not taking OCs (136±11 bpm) vs. OCs (107±32 bpm, p&lt;0.05). HR declined with metaboreflex activation in both OC and no OC group irrespective of LE and HE phase (p&lt;0.05).ConclusionsAlthough mechanoreflex activation did not influence MAP for either group of women, women taking OCs had an attenuated MAP with metaboreflex activation. This is in contrast to evidence suggesting that OCs can increase MAP at rest and may indicate that during exercise OC use can be beneficial in lowering blood pressure in women.Support or Funding InformationNo funding to disclose.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Interindividual variability in muscle sympathetic responses to static handgrip in young men: evidence for sympathetic responder types?

Negative and positive muscle sympathetic nerve activity (MSNA) responders have been observed during mental stress. We hypothesized that similar MSNA response patterns could be identified during the first minute of static handgrip and contribute to the interindividual variability throughout exercise. Supine measurements of multiunit MSNA (microneurography) and continuous blood pressure (Finometer) were recorded in 29 young healthy men during the first (HG1) and second (HG2) minute of static handgrip (30% maximal voluntary contraction) and subsequent postexercise circulatory occlusion (PECO). Responders were identified on the basis of differences from the typical error of baseline total MSNA: 7 negative, 12 positive, and 10 nonresponse patterns. Positive responders demonstrated larger total MSNA responses during HG1 ( P < 0.01) and HG2 ( P < 0.0001); however, the increases in blood pressure throughout handgrip exercise were similar between all groups, as were the changes in heart rate, stroke volume, cardiac output, total vascular conductance, and respiration (all P > 0.05). Comparing negative and positive responders, total MSNA responses were similar during PECO ( P = 0.17) but opposite from HG2 to PECO (∆40 ± 46 vs. ∆-21 ± 62%, P = 0.04). Negative responders also had a shorter time-to-peak diastolic blood pressure during HG1 (20 ± 20 vs. 44 ± 14 s, P < 0.001). Total MSNA responses during HG1 were associated with responses to PECO ( r = 0.39, P < 0.05), the change from HG2 to PECO ( r = -0.49, P < 0.01), and diastolic blood pressure time to peak ( r = 0.50, P < 0.01). Overall, MSNA response patterns during the first minute of static handgrip contribute to interindividual variability and appear to be influenced by differences in central command, muscle metaboreflex activation, and rate of loading of the arterial baroreflex.

Ischemic preconditioning does not alter muscle sympathetic responses to static handgrip and metaboreflex activation in young healthy men.

Ischemic preconditioning (IPC) has been hypothesized to elicit ergogenic effects by reducing feedback from metabolically sensitive group III/IV muscle afferents during exercise. If so, reflex efferent neural outflow should be attenuated. We investigated the effects of IPC on muscle sympathetic nerve activity (MSNA) during static handgrip (SHG) and used post‐exercise circulatory occlusion (PECO) to isolate for the muscle metaboreflex. Thirty‐seven healthy men (age: 24 ± 5 years [mean ± SD]) were randomized to receive sham (n = 16) or IPC (n = 21) interventions. Blood pressure, heart rate, and MSNA (microneurography; sham n = 11 and IPC n = 18) were collected at rest and during 2 min of SHG (30% maximal voluntary contraction) and 3 min of PECO before (PRE) and after (POST) sham or IPC treatment (3 × 5 min 20 mmHg or 200 mmHg unilateral upper arm cuff inflation). Resting mean arterial pressure was higher following sham (79 ± 7 vs. 83 ± 6 mmHg, P < 0.01) but not IPC (81 ± 6 vs. 82 ± 6 mmHg, P > 0.05), while resting MSNA burst frequency was unchanged (P > 0.05) with sham (18 ± 7 vs. 19 ± 9 bursts/min) or IPC (17 ± 7 vs. 19 ± 7 bursts/min). Mean arterial pressure, heart rate, stroke volume, cardiac output, and total vascular conductance responses during SHG and PECO were comparable PRE and POST following sham and IPC (All P > 0.05). Similarly, MSNA burst frequency, burst incidence, and total MSNA responses during SHG and PECO were comparable PRE and POST with sham and IPC (All P > 0.05). These findings demonstrate that IPC does not reduce hemodynamic responses or central sympathetic outflow directed toward the skeletal muscle during activation of the muscle metaboreflex using static exercise or subsequent PECO.

Cardiac Baroreflex Variability and Resetting during Sustained Mild Effort.

This exploratory study assessed the pattern of closed-loop baroreflex resetting using multi-logistic-curve analysis. Operating point gain and ranges of RR-interval (RRI) and systolic blood pressure (SBP) are derived to examine how these relate to sympathetic activation. Sustained low-intensity isometric handgrip exercise, with a period of post-exercise circulatory occlusion (PECO), provided a model to study baroreflex resetting because the progression toward fatigue at constant tension induces a continuous increase in volitional contribution to neuro-cardiovascular control. Continuous measurements of muscle sympathetic nerve activity (MSNA), blood pressure, and RRI were made simultaneously throughout the experimental session. Spontaneous sequence analysis was used to detect episodes of baroreflex “engagements”, but the results are examined with a view to the fundamental difference between experimental conditions that isolate the carotid sinus (open-loop) and intact physiological conditions (closed-loop). While baroreflex function under open-loop conditions can be described in terms of a single logistic curve, intact physiologic conditions require a family of logistic curves. The results suggest that the baroreflex is in a “floating” state whereby it is continuously resetting during the timeline of the experiment but with minute-by-minute average values that mimic the less complex step-wise resetting pattern reported under open-loop conditions. Furthermore, the results indicate that baroreflex function and resetting of the operating point gain is reflected not in terms of change in the values of blood pressure or RR-interval but in terms of change in the range of values of these variables prevailing under different experimental conditions.

The effect of slow-loaded breathing training on the blood pressure response to handgrip exercise in patients with isolated systolic hypertension.

Isolated systolic hypertension (ISH) is the most common form of hypertension in older people. It is characterized by increased resting systolic blood pressure (sBP) and increased sBP in response to exercise. It has previously been shown that slow breathing training reduces resting sBP, and the objective of the present study was to determine whether it also reduced the blood pressure response to static handgrip exercise. ISH patients aged between 60 and 74 years were randomly divided into a control group (10 subjects, 4 of which were male) that breathed normally and a trained group (10 subjects, 4 of which were male) that trained daily for 8 weeks by slow breathing against an inspiratory resistance of 18 cmH2O. Before and immediately after training, subjects underwent a 2-min handgrip test (30% max) followed by 2 min of post-exercise circulatory occlusion (PECO) to assess metaboreflex activity. Training reduced sBP by 10.6 mm Hg (95% confidence interval (CI), -16 to -5 mm Hg, P=0.004), but changes were not observed in the control group. The peak exercise sBP was reduced by 23 mm Hg (95% CI, -16 to -31 mm Hg, P<0.001), while the increase in the sBP above resting was reduced by 12.6 mm Hg (95% CI, -6.9 to -18.2 mm Hg, P=0.002). The sBP during PECO was reduced by 8.9 mm Hg (95% CI, -4 to -14 mm Hg, P=0.008), which is indicative of reduced metaboreflex activity; no such change was observed in the control group. The results demonstrate that conventional treatment of older patients with ISH may be improved in two ways by slow breathing training: resting sBP may be reduced by 10 mm Hg, more than can be achieved by conventional pharmacological therapies, while the response to static exercise may be reduced by approximately twice this value.

Evidence of an Exaggerated Muscle Metaboreflex Response in Heart Failure with Preserved Ejection Fraction

BackgroundExercise intolerance is the primary chronic symptom in heart failure patients with preserved ejection fraction (HFpEF), and often persists even with optimized treatment. Though there are many mechanisms that may contribute to this deficit, disease‐related changes in the muscle metaboreflex may play a role. Indeed, it has been previously shown that in heart failure with reduced ejection fraction (HFrEF), input from group III/IV muscle afferents contributes to the development of fatigue and exercise intolerance. Therefore, the purpose of this study was to examine metaboreflex modulation of heart rate (HR) and mean arterial pressure (MAP) in HFpEF patients.MethodsEight HFpEF patients (6M, 2F; age 67 ± 4 yrs; BMI 35 ± 3 kg/m2; ejection fraction 63 ± 3%) and seven healthy controls (4M, 3F; age 59 ± 3 yrs; BMI 30 ± 1 kg/m2) participated in this study. Patients were studied under their normal pharmacotherapy. After 30 min of supine rest, participants performed 2 min of isometric handgrip exercise at 30% and 40% of maximal voluntary contraction (MVC), followed by 2 min of post‐exercise circulatory occlusion (PECO) to isolate the muscle metaboreflex response. HR (3‐lead ECG) and arterial blood pressure (Finapres Medical Systems BV) were measured continuously, and the last 30 sec of exercise and PECO was averaged to determine peak changes in HR and MAP.ResultsBaseline HR and MAP were not different between HFpEF and controls (70 ± 7 vs. 68 ± 5 bpm; 97 ± 4 vs. 103 ± 5 mmHg, respectively). At 30% MVC, comparable ΔHR were observed between groups during handgrip (6 ± 1 vs. 4 ± 2 bpm, HFpEF vs. control) and PECO (2 ± 1 vs. 2 ± 1 bpm, HFpEF vs. control). While ΔMAP was similar between groups during handgrip (15 ± 2 vs. 14 ± 3 mmHg, HFpEF vs. control), HFpEF patients exhibited a greater ΔMAP during PECO (16 ± 2 vs. 8 ± 3 mmHg, HFpEF vs. control, p&lt;0.05). At 40% MVC, ΔHR was not significantly different between HFpEF and controls during handgrip (7 ± 3 vs. 12 ± 2 bpm, respectively) or PECO (1 ± 1 vs. 1 ± 2 bpm, respectively). Similarly, ΔMAP at 40% MVC was comparable between the groups during handgrip (24 ± 5 vs. 24 ± 2 mmHg, HFpEF vs. control), whereas there was a trend towards a greater ΔMAP during PECO in the HFpEF patients (24 ± 5 vs. 16 ± 3 mmHg, p=0.16).ConclusionsWhile the overall pressor response during handgrip was comparable between groups, a notable elevation in blood pressure was observed during PECO in the HFpEF patients. It is important to note that these differences occurred with the patients maintaining their normal pharmacotherapy, which often includes antihypertensive agents. These preliminary findings suggest that the muscle metaboreflex is exaggerated in patients with HFpEF, and this may be involved in the exercise intolerance observed in this patient population.Support or Funding InformationFunded in part by the National Institutes of Health (HL118313) and the U.S. Department of Veterans Affairs (RX001697, RX001418, E6910R)

Central vs. peripheral determinants of sympathetic neural recruitment: insights from static handgrip exercise and postexercise circulatory occlusion

Sympathetic outflow is modified during acute homeostatic stress through increased firing of low-threshold axons, recruitment of latent axons, and synaptic delay modifications. However, the role of central mechanisms versus peripheral reflex control over sympathetic recruitment remains unknown. Here, we examined sympathetic discharge patterns during fatiguing static handgrip (SHG) exercise and postexercise circulatory occlusion (PECO) to study the central vs. peripheral reflex elements of sympathetic neural coding. Muscle sympathetic nerve activity (MSNA; microneurography) was measured in six males (25 ± 3 yr) at baseline (3 min) and during 5 min of SHG exercise completed at 20% maximal voluntary contraction. Isolation of the peripheral metaboreflex component was achieved by PECO for 3 min. Action potential (AP) patterns were studied using wavelet-based methodology. Compared with baseline, total MSNA increased by minute 3 of SHG, remaining elevated throughout the duration of exercise and PECO (all P < 0.05). The AP content per burst increased above baseline by minute 4 of SHG (Δ4 ± 2), remaining elevated at minute 5 (Δ6 ± 4) and PECO (Δ4 ± 4; all P < 0.05). Similarly, total AP clusters increased by minute 4 of SHG (Δ5 ± 5) and remained elevated at minute 5 (Δ6 ± 3) and PECO (Δ7 ± 5; all P < 0.01), indicating recruitment of latent subpopulations. Finally, the AP cluster size-latency profile was shifted downward during minutes 4 (-32 ± 22 ms) and 5 (-49 ± 17 ms; both P < 0.05) of SHG but was not different than baseline during PECO (P > 0.05). Our findings suggest that central perceptual factors play a specific role in the synaptic delay aspect of sympathetic discharge timing, whereas peripheral reflex mechanisms affect recruitment of latent axons.