Journal Logo


Muscle Metaboreflex Control of Sympathetic Activity in Obstructive Sleep Apnea


Author Information
Medicine & Science in Sports & Exercise: July 2017 - Volume 49 - Issue 7 - p 1424-1431
doi: 10.1249/MSS.0000000000001242
  • Free


Obstructive sleep apnea (OSA) is characterized by repetitive airway obstruction that results in intermittent hypoxia, hypercapnia, intrathoracic pressure swings, and sleep fragmentation, which in turn lead to sympathetic activation and endothelial dysfunction. Hypoxia and hypercapnia, acting through the chemoreflexes, elicited increases in blood pressure (BP) levels and muscle sympathetic nerve activity (MSNA), especially during the end of a sleep apnea event (40). In contrast with healthy subjects who have a decrease in sympathetic activity during sleep (39), patients with OSA experience repetitive surges of MSNA associated with obstructive events during sleep. Patients with OSA have increased MSNA while awake during resting conditions (3), indicating that sympathetic overactivity during sleep has after effects during the daytime.

During exercise, the changes in autonomic neural outflow are mediated via integration of the central and peripheral neural mechanisms (45) with further modulation provided by the arterial baroreflex (17,31). There is evidence that muscle afferents of both the pressor reflex and central command contribute directly to cardiovascular adjustments to static exercise in humans (23). The sensory component of this pressor reflex comprises group III skeletal muscle afferents that are primarily responsive to mechanical (mechanoreflex) stimuli and group IV skeletal muscle afferents that respond to metabolic (metaboreflex) stimuli (i.e., lactate, K+, and H+) from contracting muscles (6,19). The skeletal muscle metaboreflex is thought to play an important role in the sympathetic response during static exercise (37).

The metaboreflex is measured during post-handgrip muscle ischemia (PHMI) that induces a reflex increase in systemic arterial pressure, HR, and sympathetic outflow in an attempt to maintain adequate perfusion of exercising muscle (28). Post-handgrip muscle ischemia causes the metabolites produced during exercise to become trapped in the forearm, stimulating the chemically sensitive muscle afferents of the exercise pressor reflex, eliminating the input from mechanically sensitive afferents and central command (6). Investigations in humans assessing metaboreflex control in disease have produced conflicting results, reporting both reductions and enhancements in metaboreflex sensitivity. Previously, studies conducted in our laboratory showed that muscle metaboreflex control of MSNA is blunted in obesity (26), hypertension (33), and heart failure (1,38). In contrast, other authors showed that metaboreflex control of MSNA is exaggerated in hypertension (6,35) and heart failure (30).

It must be noted, however, that other factors, such as age, level of physical conditioning, obesity, presence of comorbidities, stage of disease, and use of medications may have contributed to the disparate results in the metaboreflex in humans. A previous study investigating metaboreflex in hypertension (35) included vasoactive drugs and antihypertensive therapies. These may alter the magnitude of the BP response during metaboreflex activation when compared to never-treated patients with hypertension (33). Others (1) included patients using ß-blockers to investigate metaboreflex in patients with heart failure. We can assume that use of ß-blockers can affect metaboreflex hyperactivation, reducing the sympathetic responses compared to the non-use of ß-blockers (30). The stage of the disease may also have contributed to the disparate results of metaboreflex in patients with heart failure. The abnormal metaboreflex of MSNA was observed in patients with more severe heart failure compared with mild heart failure (26). Studies that investigated metaboreflex in hypertension (6,35) and heart failure (1,30) also included obese patients. Narkiewicz et al. (25) reported that MSNA is increased when obesity and OSA coexist, but it is not affected by obesity alone. Therefore, we do not know whether OSA is a confounding variable or OSA is independently associated with improved metaboreflex sensitivity.

We therefore hypothesized that metaboreflex control of MSNA is augmented in patients with OSA, and the metaboreflex response of MSNA in patients with OSA is associated with markers of intermittent hypoxia and severity of nocturnal hypoxemia. To this end, we compared neurovascular control during sustained moderate handgrip exercise followed by PHMI in middle age, sedentary patients with OSA with no other comorbidities and no use of medications with a matched control group.


Study population

Male and female individuals, age 40 to 65 yr from the Sleep Laboratory of InCor-HCFMUSP who had recently undergone a sleep study, were recruited for this protocol. The study controls were recruited from the Heart Institute Hospital staff or relatives and friends. All subjects were without comorbidities as confirmed by medical history and physical examinations, echocardiographic evaluation, and were not taking medications. All premenopausal women were studied between the first and the fifth day after the onset of menstruation, because hormonal variability during the regular menstrual cycle may affect BP. Patients with hypertension (resting BP higher than 140/90 mm Hg) were excluded. Study subjects who had body mass index (BMI) greater than 40 kg·m−2, cardiopulmonary disease, chronic renal disease, diabetes mellitus, atrial fibrillation, a pacemaker, renal failure, echocardiographic evidence of impaired left ventricular (LV) function, history of psychiatric or neurodegenerative disorders, smoking, or alcohol abuse (two or more drinks per day), any sleep apnea treatment, or circadian desynchrony (e.g., shift workers) were excluded from the study. All subjects were sedentary adults who had not exercised regularly for at least 3 months before enrolling in this study. The institutional committee (0833/10) on human research of InCor-HCFMUSP approved the study, and all subjects gave written informed consent.


Brachial BP

Clinical BP readings were obtained from the left arm of subjects while seated, after 5 min of quiet rest, with a mercury sphygmomanometer. All subjects had at least three office BP measurements obtained on separate occasions taken by one investigator. Systolic and diastolic BPs were recorded at the first appearance and disappearance (phase I and V, respectively) of Korotkoff sounds. The three office BP measurements were averaged to determine the clinical BP. To exclude masked hypertension, all subjects performed several out-of-office BP measurements. The subjects were classified as normotensive if the average systolic and diastolic BP levels were ≤140 or 90 mm Hg (4).

Sleep study

All participants underwent overnight polysomnography (Embla N7000, Medcare Flaga, Reykjavik, Iceland), as previously described (10,11). Sleep stages, apneas, hypopneas, and arousals were defined and scored, as previously described (8,11).


The echocardiographic studies were performed using Vivid E9 machines (GE Healthcare, Horten, Norway) with offline data analyses (EchoPac® version 112; GE Healthcare). Maximal wall thickness was measured from all LV segments from the base to the apex of the LV in parasternal short-axis view. Left ventricular end-diastolic diameter and LV end-systolic diameter were measured by M-mode imaging. Left ventricular ejection fraction was calculated using Teichholz’s method. Normal systolic function was defined as LV ejection fraction > 50%. The measurement was conducted by a single investigator, blinded to the study protocol.

Bioelectrical impedance

Bioelectrical impedance was measured using the Quantum-II Desktop (RJL Systems, Clinton Township, MI). Briefly, two signaling electrodes were placed on the dorsal surface of the right foot between the second and third toe, as well as the dorsal surface of the right hand between the second and third digits. Two sensor electrodes were placed on the right hand and right ankle. Participants were asked to remain motionless in the supine position with legs and arms slightly abducted so there was no contact between the extremities and torso. Data output included reactance, resistance, and impedance. Data were entered into the software program provided by the manufacturer (Cypress, RLJ Systems). Data output included fat mass (%) and fat-free mass (%).


The MSNA was directly recorded from the peroneal nerve of the leg by using microneurography (662C-4; Nerve Traffic Analysis System, The University of Iowa, Iowa City, IA), as described elsewhere (11,27). All recordings of MSNA met previously established and described criteria (44). Muscle sympathetic bursts were identified by visual inspection conducted by a single investigator, blinded to the study protocol, and were expressed as burst frequency (bursts per min) and burst incidence (bursts per 100 heartbeats).

Forearm blood flow

Venous occlusion plethysmography (AI6; Hokanson, Bellevue, WA) was used to determine forearm blood flow, as previously described (7). Briefly, the nondominant arm was elevated above the heart level. A suitable strain gauge (Hokanson) is placed around the forearm and connected to a plethysmograph. An inflating cuff (SC12D; Hokanson) was placed around the participant’s bicep to occlude venous blood flow and connected to a rapid cuff inflator (Hokanson). To exclude hand circulation, which contains a large number of arteriovenous shunts, a segmental pressure cuff (TMC7; Hokanson) was placed around the wrist and inflated to supra-arterial pressure immediately before testing commenced. At 20-s intervals, the upper arm cuff was inflated above venous pressure for 10 s. Forearm blood flow (mL·min−1 per 100 g of tissue) per minute was determined based on three separate readings.

HR and ankle BP

Heart rate was continuously evaluated by electrocardiography. BP was monitored noninvasively with an automatic ankle BP cuff with an automated oscillometric device (DX 2022; Dixtal Biomedics, Manaus, AM, Brazil). The systolic, diastolic, and mean BPs were registered every minute of the protocol.

Handgrip static exercise

To determine the relative handgrip exercise intensity, maximal voluntary contraction (MVC) of the dominant forearm was performed using a mechanical handgrip dynamometer three times at a maximal effort. Then, the workload for handgrip static exercise was calculated as 30% of each subject’s MVC. The target force was displayed on the handgrip device to assist the subjects in achieving and maintaining the prescribed workload.

Experimental Protocol

The experimental protocol was performed in a thermoneutral room at approximately the same time each day. The subject was placed in a supine position, and electrocardiogram leads were placed on the chest. The leg was positioned for microneurography. The cuff for ankle BP measurement was placed on the opposite leg. After an adequate nerve-recording site was obtained, the subject rested quietly for 10 min. Baseline MSNA, ankle BP, HR, and forearm blood flow were then recorded continuously for 4 min at baseline, for a 3-min period of moderate sustained handgrip exercise, followed by 2 min of forearm circulatory arrest.

Moderate sustained handgrip exercise

The purpose of this experiment was to determine MSNA, BP, HR, and forearm blood flow values during activation of central command, mechanoreceptors, and metaboreceptors in normotensive patients with OSA. After obtaining MVC, all participants rested for 15 min. After this period, baseline MSNA, forearm blood flow, BP, and HR were recorded for 4 min. The handgrip exercise was performed with the dominant arm at an intensity of 30% MVC for 3 min, as described elsewhere (26,27,33). To help participants achieve and maintain the workload prescribed, each subject received continuous feedback during the handgrip exercise. The subjects were instructed to breathe normally during exercise to avoid inadvertent performance of a Valsalva maneuver.

Muscle metaboreflex control

The purpose of this experiment was to determine the magnitude of change in MSNA, BP, and forearm blood flow during isolated metaboreflex activation in normotensive OSA patients. Ten seconds before the release of 30% of MVC of the handgrip exercise, the circulation to the exercising forearm was arrested (muscle ischemia) by inflation of the upper arm occlusion cuff (240 mm Hg) for 2 min. Metaboreflex response was estimated using changes in MSNA from baseline to PHMI, as described elsewhere (26,27,33).

Statistical Analysis

The data are presented as mean ± SEM. A χ2, unpaired Student t test, or Mann–Whitney test was used to compare differences between groups. A χ2 (sex), unpaired Student t test (physical, cardiovascular, and force parameters), or Mann–Whitney U (arousal index) test was used to compare differences between groups. Two-way analysis of variance with repeated measures was used to compare within- and between-group differences at baseline, handgrip exercise, and during PHMI for MSNA, forearm blood flow, HR, and BP variables. In the case of significance, post hoc comparisons were performed using the Duncan multiple range test. Pearson regression analysis was used to examine the association between metaboreflex responses and sleep severity. P ≤ 0.05 was considered statistically significant. All statistical analyses were performed using STATISTICA 12 (StatSoft Inc., Tulsa, OK) software.


From a total of 36 subjects who were initially selected to participate in the study, five patients were excluded: one patient due to the presence of asymptomatic systolic ventricular dysfunction; one patient did not complete the evaluations and began OSA treatment with continuous positive airway pressure; three patients due to the inadequate nerve recording obtained. Thus, 14 control subjects and 17 patients with OSA completed the protocol measurements. Characteristics of OSA and control groups are shown in Table 1. No significant differences existed between groups in sex, age, BMI, fat mass, and fat-free mass. Four premenopausal women (control, n = 2 and with OSA, n = 2) were studied between the first and the fifth day after the onset of menstruation ruling out potential confounding influences of sex hormones. Regarding sleep patterns, no differences were noted in total sleep time. Apnea-hypopnea index (AHI) and arousal index were higher and minimum O2 saturation was lower in the OSA group compared with that in the control group. HR, BP, LV ejection fraction parameters did not differ between groups. The baseline MSNA in burst frequency or burst incidence was higher in OSA patients compared with that in controls. Figure 1 shows examples of MSNA in controls and patients with OSA at baseline and PHMI. No significant (P > 0.05) differences occurred in baseline forearm blood flow between groups. The production of force during the MVC was not different between groups (26 ± 2 vs 31 ± 3 kg, P = 0.15), and the absolute force produced during the activation of metaboreflex via static contraction at 30% of MVC was similar between groups (8 ± 1 vs 9 ± 2 kg, P = 0.16).

Baseline characteristics in controls and patients with OSA.
Sympathetic neurograms at baseline and PHMI in control subjects and patients with OSA.

Moderate static handgrip exercise

During peak 30% handgrip exercise, the MSNA in burst/min or burst/100 heartbeats increased significantly in both control and OSA groups. However, the MSNA value was higher at baseline and remained significantly higher during peak 30% handgrip in OSA compared with controls (Figs. 2A, B). Further analysis showed that the changes (peak 30% handgrip-baseline) in MSNA burst frequency during peak 30% handgrip exercise was higher in OSA patients compared with that in controls (interaction effects, P < 0.001). During peak 30% exercise, mean BP and HR similarly increased in both control and OSA groups (Figs. 2C, D). The level of forearm blood flow increased significantly during peak 30% exercise in both groups (Fig. 2E).

A, Muscle sympathetic nerve activity (MSNA) burst frequency; (B) MSNA burst incidence; (C) Mean BP; (D) HR, (E) Forearm blood flow (baseline, handgrip, and during 2 min of PHMI [PHMI: I1-I2]) in controls and patients with OSA. *P < 0.05 between-group comparisons; †P < 0.05 within-group comparisons versus baseline; ‡P < 0.05 within-group comparisons versus handgrip. HB, heartbeats; Hg, peak 30% handgrip exercise.

Muscle metaboreflex control

During PHMI, when the muscle metaboreflex was isolated, MSNA burst frequency and burst incidence levels remained significantly elevated in relation to baseline in the control group (Figs. 2A, B). In contrast, MSNA burst frequency and burst incidence returned to baseline values in patients with OSA. MSNA during PHMI was significantly (P < 0.05) different between controls and patients with OSA.

Mean BP remained significantly elevated in relation to baseline during 2 min of PHMI in control and OSA groups (Fig. 2C). There was no group difference in mean BP during PHMI (P > 0.05). Hear rate and forearm blood flow returned toward baseline during PHMI in both groups (Figs. 2D, E). There was a significant decrease in HR and blood flow during PHMI compared with that during the peak handgrip exercise (P < 0.05). There were no group differences in HR and forearm blood flow during PHMI (P > 0.05). Further analysis showed a significant inverse correlation between changes in MSNA due to PHMI and AHI (r = −0.61, P < 0.001; Fig. 3A) and a positive correlation with minimum O2 saturation (r = 0.70, P < 0.001, Fig. 3B).

Group data correlations between metaboreflex responses and apnea–hypopnea index (A); and minimum O2 saturation (B). Open circle are controls, and dark circles are patients with OSA.


The main and new findings of the present study are, first, PHMI elicited an increase in MSNA in the control group and a decrease in MSNA to baseline values in the OSA group. Second, there was an inverse correlation between MSNA responses during PHMI with AHI, and a positive correlation between changes in MSNA due to PHMI and AHI. Third, muscle vasodilation during sustained handgrip exercise was preserved in patients with OSA.

A recent report using MSNA and functional magnetic resonance imaging to analyze changes in cortical and brain stem control during PHMI showed that ischemia did not depend on central command, whereas metaboreflex mediated by the medulla is responsible for an increase in neural activity during ischemia (34). In the present study, PHMI elicited a significant increase in MSNA in the control group. In contrast, MSNA decreased to baseline values in patients with OSA, suggesting an association between OSA and impaired muscle metaboreflex control of MSNA.

Our data also indicate that patients with OSA exhibit elevated levels of MSNA during sustained handgrip exercise. During peak 30% handgrip exercise, MSNA increased significantly in both control subjects and patients with OSA, but MSNA responses were higher in patients with OSA. One possible mechanism that could explain increased MSNA during peak 30% handgrip exercise in OSA is the overactivation of metaboreceptors, which along with the central mechanism process (46) are activated during muscle contraction. Because we found diminished metaboreflex control of MSNA, other potential mechanisms for the sympatho-excitation in OSA during moderate sustained handgrip exercise include impaired baroreceptor restraint of sympathetic tone (42), increased sympathetic peripheral and central chemoreflex (43), impaired central process, and increased mechanoreflex.

An increase in MSNA during handgrip exercise before cuff inflation could suggest an augmented mechanoreflex in OSA patients. Previous studies that isolate the contribution of the mechanical component of the exercise pressor reflex found an increase in MSNA during activation of mechanoreceptors/central command in severe heart failure patients (26) and in obese individuals (27) compared with controls. In these previous studies, changes in MSNA were not different from those in respective control groups. It should be noted that in our study all participants had a BMI > 25 kg·m−2 and therefore were overweight or obese. However, there was no significant difference in BMI between OSA and control groups.

In the present study, we do not address or isolate the contribution of the mechanical component of the exercise pressor reflex control of MSNA in OSA patients. However, we do not rule out possible OSA-related differences in the mechanical component of the exercise pressor reflex. Future studies examining the mechanical component of the exercise pressor reflex in patients with OSA are warranted.

Other studies examining alterations in the central process have reported that the elevated muscle vasoconstrictor drive that occurs in patients with OSA may be driven by changes in higher brain cortical regions (15), and brainstem sites that project to the rostral ventrolateral medulla can mediate significant changes in MSNA (9,22), possibly through influencing brainstem regulatory nuclei. Regions of the thalamus (involved in the integration of afferent baroreceptor information) stimulated during central command appear to be involved in the pathway from higher brain regions during moderate handgrip exercise (46). Furthermore, signals from the chemoreceptors can be relayed to central command for integration, which could then modulate other reflexes/signals. These mechanisms can be upregulated or downregulated in response to physiological stimuli or pathophysiological conditions (5). The application of experimental approaches using concurrent recordings of sympathetic nerve activity and neuroimaging promises to reveal much new information about the integration of these mechanisms into OSA.

Evidence that sympathoexcitatory stimulation increases in patients with OSA independent of the type IV neural afferent has also been shown in our previous study (11) in which MSNA increased during mental stress compared with that in patients without OSA. This previous work reinforces the notion that the selective activation metaboreflex control of MSNA is diminished in patients with moderate to severe OSA despite increased MSNA at rest and during peak 30% handgrip exercise. One hypothesis is that the mechanism for chronic hypoxia-reoxygenation triggered by apneic events may be one of the factors responsible for desensitization of metaboreceptors in patients with OSA. The significant correlations between muscle metaboreflex responses and severity of sleep (AHI and minimum O2 saturation, Figs. 3A, B) found in this study may also reinforce this hypothesis.

Blood pressure increased in relation to that at baseline similarly in control and OSA groups during peak 30% handgrip exercise. BP remained significantly higher for both groups during PHMI. In the current study, BP levels were similar between controls and patients with OSA and were consistent with that reported in a previous study (33). The BP response to exercise is mediated by activation of central command and exercise pressor reflex, with further modulation provided by arterial baroreflex (31,45).

In the present study, despite high basal sympathetic vasoconstrictor tone and increased MSNA during peak 30% handgrip static exercise, muscle vasodilation during handgrip was preserved in patients with OSA. The finding of preserved vasodilation during moderate handgrip exercise would seem to contradict earlier reports of reduced flow-mediated vasodilation in patients with OSA (13,14,18). However, this finding is consistent with the previous study that found a similar increase in brachial artery blood flow measured during hypoxia before and after regional α-adrenergic block with phentolamine in patients with OSA and controls (24).

During handgrip exercise, there is a greater production and accumulation of skeletal muscle metabolites (i.e., lactate, K+, and H+) that activate muscle afferent nerve endings to cause the exercise pressor reflex. When the metabolic activity increases, the chemical mediators increase regional blood flow that depends on the direct effect of metabolites and endothelial factors on vascular smooth muscle. There is also a continuous interaction between the neural and metabolic mechanisms that determine appropriate pressures and flow proportional to metabolic activity of tissue. In fact, the previous study using pharmacological blockade showed that β-adrenergic mechanisms and local nitric oxide release contribute to the forearm blood flow dilatation during contralateral hand gripping to fatigue and postexercise ischemia in healthy individuals (32). Repetitive episodes of hypoxia/reoxygenation affect the vascular endothelium by promoting inflammation and oxidative stress while decreasing bioavailability of the endothelium-derived vasodilator nitric oxide (16). The constrictors endothelin-1, activation of the renin–angiotensin aldosterone system, and thromboxane A2 could also contribute to impaired responses to vasodilator mechanisms in OSA (2,20,29).

The metabolic vasodilator mechanisms might be upregulated in patients with OSA (24). Alternative adaptive mechanism including elevated serum levels of vascular endothelial growth factor was found in patients with severe hypoxia, related to the degree of nocturnal oxygen desaturation (36). The metabolic vasodilator mechanisms may contribute to the survival of the cell to provide the perfusion pressure at an appropriate level and preventing excessive cardiac work and risk of structural damage to the heart and blood vessels. Thus, it might be speculated that the preserved forearm vasodilation during handgrip static exercise may be related to a protective factor for sympathetic overactivation and other vasoconstrictors during physiological maneuvers and hypoxic events in patients with OSA. Further investigations are needed to specifically study the metabolic vasodilator mechanisms in OSA.

The finding of greater MSNA in patients with OSA with no difference in the BP or blood flow during handgrip and PHMI between groups suggests a reduction in neurovascular transduction. A recent study (41) showed that despite the markedly higher sympathetic activity, sympathetic transduction (evaluated by relation of sympathetic activity to resistance, conductance, and via an adaptation of Poseuille’s relation, including pressure, sympathetic activity, and flow) was similar between OSA and healthy controls. The authors demonstrated that OSA does not impact neurovascular transduction in response to handgrip exercise and is not augmented by continuous positive airway pressure treatment. The reduction of sympathetic neurovascular transduction found in our results can be explained by downregulation of vascular sympathoadrenergic receptors in patients with OSA (12). Sympathetic neurovascular transduction may provide a tool to further explore the physiology of regional vascular control during physiological maneuvers in patients with OSA.

Our study has strengths and limitations. In this study, we did not measure the amount of muscle metabolites produced during exercise. Because the production of force during MVC was similar between groups (P > 0.05) and the absolute force produced during the activation of metaboreflex via static contraction at 30% of MVC was not different between control and OSA groups (P > 0.05), we assumed that it resulted in the production of muscle metabolites similarly in both groups. The potential influence of pain during arm circulatory arrest cannot be excluded, and our results must be viewed in light of this limitation. We also recognize that measurement of BP every minute is not sensitive enough to detect differences in BP between the OSA and control groups during handgrip exercise. However, it was impossible to use beat-by-beat BP measurements during exercise, because the dominant arm was used for handgrip exercise and the nondominant arm was used for continuous measurement of forearm blood flow with venous occlusion plethysmography. However, important strengths of our study are, first, that all participants were free of medications. Second, control subjects were matched for age, BMI, fat mass, fat-free mass, and sedentary lifestyle, thus ruling out any potential confounding influence of age, obesity, and physical activity status on our data. Third, all patients with OSA were free of other known diseases, were newly diagnosed, and had never been treated for sleep apnea. The common use of anti-hypertensive agents in patients with OSA, such as ß-blockers, calcium-channel blockers, angiotensin-converting enzyme inhibitors, diuretics, and angiotensin receptor agonist can directly influence the hypertensive response of exercise pressor reflex. The use of ß-blockers in particular would require a greater reduction in BP and sympathetic response (21) during the exercise pressor reflex in patients with OSA who have hypertension.

In conclusion, patients with OSA experience MSNA overactivation during moderate static exercise and decreased muscle metaboreflex control of MSNA. Muscle vasodilation during sustained handgrip exercise is preserved in patients with OSA.

This study was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 2010/15064-6) and in part by Pro-Reitoria de Pesquisa da Universidade de São Paulo to Dra. Linda M. Ueno Pardi. The authors have no conflicts of interest to declare. The results of the study are presented honestly, and without fabrication, or falsification. The results of the present study do not constitute endorsement by ACSM.

Trial Information: Clinical Trials (service of NIH); Registration number: NCT002289625; URL:


1. Antunes-Correa LM, Nobre TS, Groehs RV, et al. Molecular basis for the improvement in muscle metaboreflex and mechanoreflex control in exercise-trained humans with chronic heart failure. Am J Physiol Heart Circ Physiol. 2014;307(11):H1655–66.
2. Barceló A, Elorza MA, Barbé F, Santos C, Mayoralas LR, Agusti AG. Angiotensin converting enzyme in patients with sleep apnoea syndrome: plasma activity and gene polymorphisms. Eur Respir J. 2001;17(4):728–32.
3. Carlson JT, Hedner J, Elam M, Ejnell H, Sellgren J, Wallin BG. Augmented resting sympathetic activity in awake patients with obstructive sleep apnea. Chest. 1993;103(6):1763–8.
4. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42(6):1206–52.
5. Dampney RA, Tagawa T, Horiuchi J, Potts PD, Fontes M, Polson JW. What drives the tonic activity of presympathetic neurons in the rostral ventrolateral medulla? Clin Exp Pharmacol Physiol. 2000;27(12):1049–53.
6. Delaney EP, Greney JL, Edwards DG, Rose WC, Fadel PJ, Farquhar WB. Exaggerated sympathetic and pressor responses to handgrip exercise in older hypertensive humans: role of the muscle metaboreflex. Am J Physiol Heart Circ Physiol. 2010;299(5):H1318–27.
7. Dos Santos MR, Sayegh AL, Bacurau AV, et al. Effect of exercise training and testosterone replacement on skeletal muscle wasting in patients with heart failure with testosterone deficiency. Mayo Clin Proc. 2016;91(5):575–86.
8. Drager LF, Ueno LM, Lessa PS, Negrão CE, Lorenzi-Filho G, Krieger EM. Sleep-related changes in hemodynamic and autonomic regulation in human hypertension. J Hypertens. 2009;27(8):1655–63.
9. Fatouleh RH, Hammam E, Lundblad LC, et al. Functional and structural changes in the brain associated with the increase in muscle sympathetic nerve activity in obstructive sleep apnoea. Neuroimage Clin. 2014;6:275–83.
10. Garcia CE, Drager LF, Krieger EM, et al. Arousals are frequent and associated with exacerbated blood pressure response in patients with primary hypertension. Am J Hypertens. 2013;26(5):617–23.
11. Goya TT, Silva RF, Guerra RS, et al. Increased muscle sympathetic nerve activity and impaired executive performance capacity in obstructive sleep apnea. Sleep. 2016;39(1):25–33.
12. Grote L, Kraiczi H, Hedner J. Reduced alpha- and beta(2)-adrenergic vascular response in patients with obstructive sleep apnea. Am J Respir Crit Care Med. 2000;162(4 Pt 1):1480–7.
13. Imadojemu VA, Gleeson K, Quraishi SA, Kunselman AR, Sinoway LI, Leuenberger UA. Impaired vasodilator responses in obstructive sleep apnea are improved with continuous positive airway pressure therapy. Am J Respir Crit Care Med. 2002;165(7):950–3.
14. Ip MS, Tse HF, Lam B, Tsang KW, Lam WK. Endothelial function in obstructive sleep apnea and response to treatment. Am J Respir Crit Care Med. 2004;169(3):348–53.
15. James C, Macefield VG, Henderson LA. Real-time imaging of cortical and subcortical control of muscle sympathetic nerve activity in awake human subjects. Neuroimage. 2013;15(70):59–65.
16. Jelic S, Padeletti M, Kawut SM, et al. Inflammation, oxidative stress, and repair capacity of the vascular endothelium in obstructive sleep apnea. Circulation. 2008;117(17):2270–8.
17. Joyner MJ. Baroreceptor function during exercise: resetting the record. Exp Physiol. 2006;91(1):27–36.
18. Kato M, Roberts-Thomson P, Phillips BG, et al. Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea. Circulation. 2000;102(21):2607–10.
19. Kaufman MP, Longhurst JC, Rybicki KJ, Wallach JH, Mitchell JH. Effects of static muscular contraction on impulse activity of groups III and IV afferents in cats. J Appl Physiol Respir Environ Exerc Physiol. 1983;55(1 Pt 1):105–12.
20. Kimura H, Niijima M, Abe Y, et al. Compensatory excretion of prostacyclin and thromboxane metabolites in obstructive sleep apnea syndrome. Intern Med. 1998;37(2):127–33.
21. Kraiczi H, Hedner J, Peker Y, Grote L. Comparison of atenolol, amlodipine, enalapril, hydrochlorothiazide, and losartan for antihypertensive treatment in patients with obstructive sleep apnea. Am J Respir Crit Care Med. 2000;161(5):1423–8.
22. Lundblad LC, Fatouleh RH, Hammam E, McKenzie DK, Macefield VG, Henderson LA. Brainstem changes associated with increased muscle sympathetic drive in obstructive sleep apnoea. Neuroimage. 2014;103:258–66.
23. Mark AL, Victor RG, Nerhed C, Wallin BG. Microneurographic studies of the mechanisms of sympathetic nerve responses to static exercise in humans. Circ Res. 1985;57(3):461–9.
24. Moradkhan R, Spitnale B, McQuillan P, Hogeman C, Gray KS, Leuenberger UA. Hypoxia-induced vasodilation and effects of regional phentolamine in awake patients with sleep apnea. J Appl Physiol (1985). 2010;108(5):1234–40.
25. Narkiewicz K, van de Borne PJ, Cooley RL, Dyken ME, Somers VK. Sympathetic activity in obese subjects with and without obstructive sleep apnea. Circulation. 1998;98(8):772–6.
26. Negrão CE, Rondon MU, Tinucci T, et al. Abnormal neurovascular control during exercise is linked to heart failure severity. Am J Physiol Heart Circ Physiol. 2001;280(3):H1286–92.
27. Negrão CE, Trombetta IC, Batalha LT, et al. Muscle metaboreflex control is diminished in normotensive obese women. Am J Physiol Heart Circ Physiol. 2001;281(2):H469–75.
28. O'Leary DS. Autonomic mechanisms of muscle metaboreflex control of heart rate. J Appl Physiol (1985). 1993;74(4):1748–54.
29. Phillips BG, Narkiewicz K, Pesek CA, Haynes WG, Dyken ME, Somers VK. Effects of obstructive sleep apnea on endothelin-1 and blood pressure. J Hypertens. 1999;17(1):61–6.
30. Piepoli M, Ponikowski P, Clark AL, Banasiak W, Capucci A, Coats AJ. A neural link to explain the “muscle hypothesis” of exercise intolerance in chronic heart failure. Am Heart J. 1999;137(6):1050–6.
31. Raven PB, Fadel PJ, Ogoh S. Arterial baroreflex resetting during exercise: a current perspective. Exp Physiol. 2006;91(1):37–49.
32. Reed AS, Tschakovsky ME, Minson CT, et al. Skeletal muscle vasodilatation during sympathoexcitation is not neurally mediated in humans. J Physiol. 2000;525(Pt 1):253–62.
33. Rondon MU, Laterza MC, de Matos LD, et al. Abnormal muscle metaboreflex control of sympathetic activity in never-treated hypertensive subjects. Am J Hypertens. 2006;19(9):951–7.
34. Sander M, Macefield VG, Henderson LA. Cortical and brain stem changes in neural activity during static handgrip and postexercise ischemia in humans. J Appl Physiol (1985). 2010;108(6):1691–1700.
35. Sausen MT, Delaney EP, Stillabower ME, Farquhar WB. Enhanced metaboreflex sensitivity in hypertensive humans. Eur J Appl Physiol. 2009;105(3):351–6.
36. Schulz R, Hummel C, Heinemann S, Seeger W, Grimminger F. Serum levels of vascular endothelial growth factor are elevated in patients with obstructive sleep apnea and severe nighttime hypoxia. Am J Respir Crit Care Med. 2002;165(1):67–70.
37. Sinoway L, Prophet S, Gorman I, et al. Muscle acidosis during static exercise is associated with calf vasoconstriction. J Appl Physiol (1985). 1989;66(1):429–36.
38. Sterns DA, Ettinger SM, Gray KS, et al. Skeletal muscle metaboreceptor exercise responses are attenuated in heart failure. Circulation. 1991;84(5):2034–9.
39. Somers VK, Dyken ME, Mark AL, Abboud FM. Sympathetic-nerve activity during sleep in normal subjects. N Engl J Med. 1993;328(5):303–7.
40. Somers VK, Dyken ME, Mark AL, Abboud FM. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest. 1995;96(4):1897–1904.
41. Tamisier R, Tan CO, Pepin JL, Levy P, Taylor JA. Blood pressure increases in OSA due to maintained neurovascular sympathetic transduction: impact of CPAP. Sleep. 2015;38(12):1973–80.
42. Toschi-Dias E, Trombetta IC, Dias da Silva VJ, et al. Time delay of baroreflex control and oscillatory pattern of sympathetic activity in patients with metabolic syndrome and obstructive sleep apnea. Am J Physiol Heart Circ Physiol. 2013;304(7):H1038–44.
43. Trombetta IC, Maki-Nunes C, Toschi-Dias E, et al. Obstructive sleep apnea is associated with increased chemoreflex sensitivity in patients with metabolic syndrome. Sleep. 2013;36(1):41–9.
44. Vallbo AB, Hagbarth KE, Torebjörk HE, Wallin BG. Somatosensory, proprioceptive, and sympathetic activity in human peripheral nerves. Physiol Rev. 1979;59(4):919–57.
45. Williamson JW, Fadel PJ, Mitchell JH. New insights into central cardiovascular control during exercise in humans: a central command update. Exp Physiol. 2006;91(1):51–8.
46. Williamson JW, McColl R, Mathews D. Evidence for central command activation of the human insular cortex during exercise. J Appl Physiol (1985). 2003;94(5):1726–34.


© 2017 American College of Sports Medicine