Interstitial pH, K+, lactate, and phosphate  determined with MSNA during exercise in humans

The purpose of the present study was to use the microdialysis technique to simultaneously measure the interstitial concentrations of several putative stimulators of the exercise pressor reflex during 5 min of intermittent static quadriceps exercise in humans ( n = 7). Exercise resulted in approximately a threefold ( P < 0.05) increase in muscle sympathetic nerve activity (MSNA) and 13 ± 3 beats/min ( P < 0.05) and 20 ± 2 mmHg ( P < 0.05) increases in heart rate and blood pressure, respectively. During recovery, all reflex responses quickly returned to baseline. Interstitial lactate levels were increased ( P < 0.05) from rest (1.1 ± 0.1 mM) to exercise (1.6 ± 0.2 mM) and were further increased ( P < 0.05) during recovery (2.0 ± 0.2 mM). Dialysate phosphate concentrations were 0.55 ± 0.04, 0.71 ± 0.05, and 0.48 ± 0.03 mM during rest, exercise, and recovery, respectively, and were significantly elevated during exercise. At the onset of exercise, dialysate K+ levels rose rapidly above resting values (4.2 ± 0.1 meq/l) and continued to increase during the exercise bout. After 5 min of contractions, dialysate K+ levels had peaked with an increase ( P < 0.05) of 0.6 ± 0.1 meq/l and subsequently decreased during recovery, not being different from rest after 3 min. In contrast, H+ concentrations rapidly decreased ( P < 0.05) from resting levels (69.4 ± 3.7 nM) during quadriceps exercise and continued to decrease with a mean decline ( P < 0.05) of 16.7 ± 3.8 nM being achieved after 5 min. During recovery, H+ concentrations rapidly increased and were not significantly different from baseline after 1 min. This study represents the first time that skeletal muscle interstitial pH, K+, lactate, and phosphate have been measured in conjunction with MSNA, heart rate, and blood pressure during intermittent static quadriceps exercise in humans. These data suggest that interstitial K+ and phosphate, but not lactate and H+, may contribute to the stimulation of the exercise pressor reflex.

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Cardiovascular regulation by skeletal muscle reflexes in health and disease

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00208.2011 ◽

2011 ◽

Vol 301 (4) ◽

pp. H1191-H1204 ◽

Cited By ~ 81

Author(s):

Megan N. Murphy ◽

Masaki Mizuno ◽

Jere H. Mitchell ◽

Scott A. Smith

Keyword(s):

Blood Pressure ◽

Cardiovascular Disease ◽

Skeletal Muscle ◽

Heart Rate ◽

Sympathetic Nerve ◽

Sympathetic Nerve Activity ◽

Nerve Activity ◽

Group Iii ◽

Exercise Pressor Reflex ◽

Pressor Reflex

Heart rate and blood pressure are elevated at the onset and throughout the duration of dynamic or static exercise. These neurally mediated cardiovascular adjustments to physical activity are regulated, in part, by a peripheral reflex originating in contracting skeletal muscle termed the exercise pressor reflex. Mechanically sensitive and metabolically sensitive receptors activating the exercise pressor reflex are located on the unencapsulated nerve terminals of group III and group IV afferent sensory neurons, respectively. Mechanoreceptors are stimulated by the physical distortion of their receptive fields during muscle contraction and can be sensitized by the production of metabolites generated by working skeletal myocytes. The chemical by-products of muscle contraction also stimulate metaboreceptors. Once activated, group III and IV sensory impulses are transmitted to cardiovascular control centers within the brain stem where they are integrated and processed. Activation of the reflex results in an increase in efferent sympathetic nerve activity and a withdrawal of parasympathetic nerve activity. These actions result in the precise alterations in cardiovascular hemodynamics requisite to meet the metabolic demands of working skeletal muscle. Coordinated activity by this reflex is altered after the development of cardiovascular disease, generating exaggerated increases in sympathetic nerve activity, blood pressure, heart rate, and vascular resistance. The basic components and operational characteristics of the reflex, the techniques used in human and animals to study the reflex, and the emerging evidence describing the dysfunction of the reflex with the advent of cardiovascular disease are highlighted in this review.

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Chronic femoral artery ligation exaggerates the pressor and sympathetic nerve responses during dynamic skeletal muscle stretch in decerebrate rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00498.2017 ◽

2018 ◽

Vol 314 (2) ◽

pp. H246-H254 ◽

Cited By ~ 6

Author(s):

Evan A. Kempf ◽

Korynne S. Rollins ◽

Tyler D. Hopkins ◽

Alec L. Butenas ◽

Joseph M. Santin ◽

...

Keyword(s):

Blood Pressure ◽

Peripheral Artery Disease ◽

Sympathetic Nerve ◽

Sympathetic Nerve Activity ◽

Peripheral Artery ◽

Nerve Activity ◽

Exercise Pressor Reflex ◽

Pressor Reflex ◽

Artery Disease ◽

Dynamic Stretch

Mechanical and metabolic signals arising during skeletal muscle contraction reflexly increase sympathetic nerve activity and blood pressure (i.e., the exercise pressor reflex). In a rat model of simulated peripheral artery disease in which a femoral artery is chronically (~72 h) ligated, the mechanically sensitive component of the exercise pressor reflex during 1-Hz dynamic contraction is exaggerated compared with that found in normal rats. Whether this is due to an enhanced acute sensitization of mechanoreceptors by metabolites produced during contraction or involves a chronic sensitization of mechanoreceptors is unknown. To investigate this issue, in decerebrate, unanesthetized rats, we tested the hypothesis that the increases in mean arterial blood pressure and renal sympathetic nerve activity during 1-Hz dynamic stretch are larger when evoked from a previously “ligated” hindlimb compared with those evoked from the contralateral “freely perfused” hindlimb. Dynamic stretch provided a mechanical stimulus in the absence of contraction-induced metabolite production that closely replicated the pattern of the mechanical stimulus present during dynamic contraction. We found that the increases in mean arterial blood pressure (freely perfused: 14 ± 1 and ligated: 23 ± 3 mmHg, P = 0.02) and renal sympathetic nerve activity were significantly greater during dynamic stretch of the ligated hindlimb compared with the increases during dynamic stretch of the freely perfused hindlimb. These findings suggest that the exaggerated mechanically sensitive component of the exercise pressor reflex found during dynamic muscle contraction in this rat model of simulated peripheral artery disease involves a chronic sensitizing effect of ligation on muscle mechanoreceptors and cannot be attributed solely to acute contraction-induced metabolite sensitization. NEW & NOTEWORTHY We found that the pressor and sympathetic nerve responses during dynamic stretch were exaggerated in rats with a ligated femoral artery (a model of peripheral artery disease). Our findings provide mechanistic insights into the exaggerated exercise pressor reflex in this model and may have important implications for peripheral artery disease patients.

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Disruption of phase synchronization between blood pressure and muscle sympathetic nerve activity in postural vasovagal syncope

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00415.2013 ◽

2013 ◽

Vol 305 (8) ◽

pp. H1238-H1245 ◽

Cited By ~ 12

Author(s):

Christopher E. Schwartz ◽

Elisabeth Lambert ◽

Marvin S. Medow ◽

Julian M. Stewart

Keyword(s):

Blood Pressure ◽

Heart Rate ◽

Sympathetic Nerve ◽

Sympathetic Nerve Activity ◽

Phase Synchronization ◽

Vasovagal Syncope ◽

Muscle Sympathetic Nerve Activity ◽

Nerve Activity ◽

Control Subjects ◽

Late Stages

Withdrawal of muscle sympathetic nerve activity (MSNA) may not be necessary for the precipitous fall of peripheral arterial resistance and arterial pressure (AP) during vasovagal syncope (VVS). We tested the hypothesis that the MSNA-AP baroreflex entrainment is disrupted before VVS regardless of MSNA withdrawal using the phase synchronization between blood pressure and MSNA during head-up tilt (HUT) to measure reflex coupling. We studied eight VVS subjects and eight healthy control subjects. Heart rate, AP, and MSNA were measured during supine baseline and at early, mid, late, and syncope stages of HUT. Phase synchronization indexes, measuring time-dependent differences between MSNA and AP phases, were computed. Directionality indexes, indicating the influence of AP on MSNA (neural arc) and MSNA on AP (peripheral arc), were computed. Heart rate was greater in VVS compared with control subjects during early, mid, and late stages of HUT and significantly declined at syncope ( P = 0.04). AP significantly decreased during mid, late, and syncope stages of tilt in VVS subjects only ( P = 0.001). MSNA was not significantly different between groups during HUT ( P = 0.700). However, the phase synchronization index significantly decreased during mid and late stages in VVS subjects but not in control subjects ( P < .001). In addition, the neural arc was significantly affected more than the peripheral arc before syncope. In conclusion, VVS is accompanied by a loss of the synchronous AP-MSNA relationship with or without a loss in MSNA at faint. This provides insight into the mechanisms behind the loss of vasoconstriction and drop in AP independent of MSNA at the time of vasovagal faint.

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Abstract 529: Muscle Sympathetic Nerve Activity is Higher in Winter than Other Seasons

Hypertension ◽

10.1161/hyp.62.suppl_1.a529 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Jian Cui ◽

Matthew D Muller ◽

Allen R Kunselman ◽

Cheryl Blaha ◽

Lawrence I Sinoway

Keyword(s):

Blood Pressure ◽

Heart Rate ◽

Sympathetic Nerve ◽

Sympathetic Nerve Activity ◽

Muscle Sympathetic Nerve Activity ◽

Epidemiological Data ◽

Repeated Measurements ◽

Nerve Activity ◽

Cardiovascular Morbidity And Mortality ◽

Significant Difference

Epidemiological data suggest that blood pressure tends to be higher in winter and lower in summer, particularly in the elderly. Moreover, hospitalization and mortality rates due to cardiovascular disease have higher rates in winter than summer. Whether autonomic adjustment including muscle sympathetic nerve activity (MSNA) varies with season is unclear. To test the hypothesis that resting MSNA varies along the seasons, we retrospectively analyzed the supine baseline (6 min) MSNA and heart rate (from ECG) of 57 healthy subjects (33M, 24F, 29 ± 1 yrs, range 22-64 yrs) from studies in our laboratory (room temperature ~23 °C). Each of these subjects from central Pennsylvania was studied during 2 or more seasons (total 231 visits). A linear-mixed effects model, which is an extension of the analysis of variance model accounting for repeated measurements (i.e. season) per subject, was used to assess the association of season with the cardiovascular outcomes. The Tukey-Kramer procedure was used to account for multiple comparisons testing between the seasons. MSNA burst rate in winter (21.3 ± 1.0 burst/min) was significantly greater than in summer (13.7 ± 1.0 burst/min, P < 0.001), spring (17.5 ± 1.6 burst/min, P = 0.04) and fall (17.0 ± 1.2 burst/min, P < 0.002). There was no significant difference in MSNA in other comparisons (spring vs. summer, P = 0.12; spring vs. fall, P = 0.99; summer vs. fall, P = 0.054). Heart rate (63.6 ± 1.1 vs. 60.8 ± 1.2 beats/min, P = 0.048) was significantly greater in winter compared to summer. Blood pressure (automated sphygmomanometry of the brachial artery) was not significantly different between seasons. The results suggest that baseline sympathetic nerve activity varies along the seasons, with peak levels evident in winter. We speculate that the seasonal MSNA variation may contribute to seasonal variations in cardiovascular morbidity and mortality.

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Baroreflex control of muscle sympathetic nerve activity during skin surface cooling

Journal of Applied Physiology ◽

10.1152/japplphysiol.00115.2007 ◽

2007 ◽

Vol 103 (4) ◽

pp. 1284-1289 ◽

Cited By ~ 20

Author(s):

Jian Cui ◽

Sylvain Durand ◽

Craig G. Crandall

Keyword(s):

Blood Pressure ◽

Heart Rate ◽

Arterial Blood Pressure ◽

Sympathetic Nerve Activity ◽

Muscle Sympathetic Nerve Activity ◽

Skin Surface ◽

Surface Cooling ◽

Nerve Activity ◽

Baroreflex Control ◽

Arterial Blood

Skin surface cooling improves orthostatic tolerance through a yet to be identified mechanism. One possibility is that skin surface cooling increases the gain of baroreflex control of efferent responses contributing to the maintenance of blood pressure. To test this hypothesis, muscle sympathetic nerve activity (MSNA), arterial blood pressure, and heart rate were recorded in nine healthy subjects during both normothermic and skin surface cooling conditions, while baroreflex control of MSNA and heart rate were assessed during rapid pharmacologically induced changes in arterial blood pressure. Skin surface cooling decreased mean skin temperature (34.9 ± 0.2 to 29.8 ± 0.6°C; P < 0.001) and increased mean arterial blood pressure (85 ± 2 to 93 ± 3 mmHg; P < 0.001) without changing MSNA ( P = 0.47) or heart rate ( P = 0.21). The slope of the relationship between MSNA and diastolic blood pressure during skin surface cooling (−3.54 ± 0.29 units·beat−1·mmHg−1) was not significantly different from normothermic conditions (−2.94 ± 0.21 units·beat−1·mmHg−1; P = 0.19). The slope depicting baroreflex control of heart rate was also not altered by skin surface cooling. However, skin surface cooling shifted the “operating point” of both baroreflex curves to high arterial blood pressures (i.e., rightward shift). Resetting baroreflex curves to higher pressure might contribute to the elevations in orthostatic tolerance associated with skin surface cooling.

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Chemoreflex and metaboreflex control during static hypoxic exercise

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01043.2004 ◽

2005 ◽

Vol 288 (4) ◽

pp. H1724-H1729 ◽

Cited By ~ 26

Author(s):

Anne Houssiere ◽

Boutaina Najem ◽

Agniezka Ciarka ◽

Sonia Velez-Roa ◽

Robert Naeije ◽

...

Keyword(s):

Blood Pressure ◽

Heart Rate ◽

Sympathetic Nerve Activity ◽

Muscle Sympathetic Nerve Activity ◽

Circulatory Arrest ◽

Handgrip Exercise ◽

Isometric Handgrip ◽

Isometric Handgrip Exercise ◽

Baseline Values ◽

Hypoxic Exercise

To investigate the effects of muscle metaboreceptor activation during hypoxic static exercise, we recorded muscle sympathetic nerve activity (MSNA), heart rate, blood pressure, ventilation, and blood lactate in 13 healthy subjects (22 ± 2 yr) during 3 min of three randomized interventions: isocapnic hypoxia (10% O2) (chemoreflex activation), isometric handgrip exercise in normoxia (metaboreflex activation), and isometric handgrip exercise during isocapnic hypoxia (concomitant metaboreflex and chemoreflex activation). Each intervention was followed by a forearm circulatory arrest to allow persistent metaboreflex activation in the absence of exercise and chemoreflex activation. Handgrip increased blood pressure, MSNA, heart rate, ventilation, and lactate (all P < 0.001). Hypoxia without handgrip increased MSNA, heart rate, and ventilation (all P < 0.001), but it did not change blood pressure and lactate. Handgrip enhanced blood pressure, heart rate, MSNA, and ventilation responses to hypoxia (all P < 0.05). During circulatory arrest after handgrip in hypoxia, heart rate returned promptly to baseline values, whereas ventilation decreased but remained elevated ( P < 0.05). In contrast, MSNA, blood pressure, and lactate returned to baseline values during circulatory arrest after hypoxia without exercise but remained markedly increased after handgrip in hypoxia ( P < 0.05). We conclude that metaboreceptors and chemoreceptors exert differential effects on the cardiorespiratory and sympathetic responses during exercise in hypoxia.

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Cardiac and Sympathetic Baroreflexes Remain Functional During Local Anesthesia With Vasoconstrictor-free Mepivacaine in Humans

10.21203/rs.3.rs-118455/v1 ◽

2020 ◽

Author(s):

Chiaki Furutani ◽

Kazushige Isono ◽

Hironao Asahina ◽

Yudai Higuchi ◽

Kota Miyahara ◽

...

Keyword(s):

Blood Pressure ◽

Heart Rate ◽

Local Anesthesia ◽

Baroreflex Sensitivity ◽

Sympathetic Nerve Activity ◽

Muscle Sympathetic Nerve Activity ◽

Nerve Activity ◽

Mandibular Foramen ◽

Pressor Responses ◽

Operating Points

Abstract Local anesthesia with vasoconstrictor-free mepivacaine is known to not evoke pressor responses. However, it is unknown whether baroreflex function and blood pressure (BP) fluctuations are preserved by using mepivacaine. We tested the hypothesis that mepivacaine reduces baroreflex sensitivity (BRS) without changing its operating point. Beat-by-beat BP, heart rate (HR), and muscle sympathetic nerve activity (MSNA) were measured upon injection of either saline (CNT) or 3% mepivacaine (MPV) in the apical regions of the premolars and around the mandibular foramen in 10 healthy young men [23±5 (SD) years]. Cardiac and sympathetic BRSs were assessed by bolus injections of sodium nitroprusside followed by phenylephrine HCl, and then determined from the slopes of regression lines between systolic BP and HR and between diastolic BP and MSNA, respectively. HR was significantly higher in MPV than CNT (P<0.05), while there were no significant differences in MSNA, the operating points, or BP fluctuations between MPV and CNT (all P>0.05). Moreover, neither cardiac nor sympathetic BRS in CNT were altered by MPV (−0.71±0.13 vs. −0.78±0.33 beats·min−1·mmHg−1, P=0.41; −0.98±0.35 vs. −0.92±0.16 units･beat−1･ mmHg−1, P=0.73). Cardiac and sympathetic baroreflex functions were preserved and BP fluctuation may be well maintained under local anesthesia using vasoconstrictor-free 3% mepivacaine.

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Effects of hindlimb contraction on pressor and muscle interstitial metabolite responses in the cat

Journal of Applied Physiology ◽

10.1152/jappl.1998.85.4.1583 ◽

1998 ◽

Vol 85 (4) ◽

pp. 1583-1592 ◽

Cited By ~ 30

Author(s):

Dave A. MacLean ◽

Kathryn F. LaNoue ◽

Kristen S. Gray ◽

Lawrence I. Sinoway

Keyword(s):

Muscle Afferents ◽

Decerebrate Cat ◽

Exercise Pressor Reflex ◽

Interstitial Concentration ◽

Pressor Responses ◽

Pressor Reflex ◽

Lactate Levels ◽

First Time ◽

Made In ◽

Stimulation Of

We used the microdialysis technique to measure the interstitial concentration of several putative metabolic stimulants of the exercise pressor reflex during 3- and 5-Hz twitch contractions in the decerebrate cat. The peak increases in heart rate and mean arterial pressure during contraction were 20 ± 5 beats/min and 21 ± 8 mmHg and 27 ± 9 beats/min and 37 ± 12 mmHg for the 3- and 5-Hz stimulation protocols, respectively. All variables returned to baseline after 10 min of recovery. Interstitial lactate rose ( P < 0.05) by 0.41 ± 0.15 and 0.56 ± 0.16 mM for the 3- and 5-Hz stimulation protocols, respectively, and were not statistically different from one another. Interstitial lactate levels remained above ( P < 0.05) baseline during recovery in the 5-Hz group. Dialysate phosphate concentrations (corrected for shifts in probe recovery) rose with stimulation ( P < 0.05) by 0.19 ± 0.08 and 0.11 ± 0.03 mM for the 3- and 5-Hz protocols. There were no differences between groups. The resting dialysate K+ concentrations for the 3- and 5-Hz conditions were 4.0 ± 0.1 and 3.9 ± 0.1 meq/l, respectively. During stimulation the dialysate K+ concentrations rose steadily for both conditions, and the increase from rest to stimulation ( P < 0.05) was 0.57 ± 0.19 and 0.81 ± 0.06 meq/l for the 3- and 5-Hz conditions, respectively, with no differences between groups. Resting dialysate pH was 6.915 ± 0.055 and 6.981 ± 0.032 and rose to 7.013 ( P < 0.05) and 7.053 ( P < 0.05) for the 3- and 5-Hz conditions, respectively, and then became acidotic (6.905, P < 0.05) during recovery (5 Hz only). This study represents the first time simultaneous measurements of multiple skeletal muscle interstitial metabolites and pressor responses to twitch contractions have been made in the cat. These data suggest that interstitial K+ and phosphate, but not lactate and H+, may contribute to the stimulation of thin fiber muscle afferents during contraction.

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Dissection of carotid sinus hypersensitivity: the timing of vagal and vasodepressor effects and the effect of body position

Clinical Science ◽

10.1042/cs20100607 ◽

2011 ◽

Vol 121 (9) ◽

pp. 389-396 ◽

Cited By ~ 8

Author(s):

C. T. Paul Krediet ◽

David L. Jardine ◽

Wouter Wieling

Keyword(s):

Blood Pressure ◽

Heart Rate ◽

Cardiac Output ◽

Total Peripheral Resistance ◽

Sympathetic Nerve Activity ◽

Carotid Sinus ◽

Body Position ◽

Muscle Sympathetic Nerve Activity ◽

Peripheral Resistance ◽

Head Up Tilt

We assessed the timing of vagal and sympathetic factors that mediate hypotension during CSM (carotid sinus massage) in patients with carotid sinus hypersensitivity. We hypothesized that a fall in cardiac output would precede vasodepression, and that vasodepression would be exaggerated by head-up tilt. We performed pulse contour analyses on blood pressure recordings during CSM in syncope patients during supine rest and head-up tilt. In a subset we simultaneously recorded muscle sympathetic nerve activity supine. During supine rest, systolic blood pressure decreased from 150±7 to 107±7 mmHg (P<0.001) and heart rate from 64±2 to 39±3 beats/min (P<0.01). Cardiac output decreased with heart rate to nadir (66±6% of baseline), 3.1±0.4 s after onset of bradycardia. In contrast, total peripheral resistance reached nadir (77±3% of baseline) after 11±1 s. During head-up-tilt, systolic blood pressure fell from 149±10 to 90±11 mmHg and heart rate decreased from 73±4 to 60±7 beats/min. Compared with supine rest, cardiac output nadir was lower (60±8 compared with 83±4%, P<0.05), whereas total peripheral resistance nadir was similar (81±6 compared with 80±3%). The time to nadir from the onset of bradycardia did not differ from supine rest. At the onset of bradycardia there was an immediate withdrawal of muscle-sympathetic nerve activity while total peripheral resistance decay occurred much later (6–8 s). The haemodynamic changes following CSM have a distinct temporal pattern that is characterized by an initial fall in cardiac output (driven by heart rate), followed by a later fall in total peripheral resistance, even though sympathetic withdrawal is immediate. This pattern is independent of body position.

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