Sympathetic Vasomotor Outflow Research Articles

Sympathoinhibition during cardiopulmonary baroreceptor loading is attenuated in older females.

The purpose of the present study was to clarify the impact of age on the sympathoinhibitory response to cardiopulmonary baroreceptor loading in females. Nine older females (mean±SD, 70±6 years) and eleven younger females (20±1 years) completed the study. A passive leg raising (PLR) test was performed wherein the participants were positioned supine (baseline, 0º), and their lower limbs were passively lifted at 10º, 20º, 30º, and 40º (3 min at each angle). Muscle sympathetic nerve activity (MSNA) was recorded via microneurography of the left radial nerve. The central venous pressure was estimated based on peripheral venous pressure (eCVP), which was monitored using a cannula in the right large antecubital vein. Baseline MSNA was higher in older females compared to younger females. MSNA burst frequency (BF) decreased during the PLR test in both older and younger females, but the magnitude of the decrease in MSNA BF was smaller in older females than in younger females (older, -3.5±1.5 vs. younger, -6.3±1.5 bursts/min at 40º from baseline, P=0.014). The eCVP increased during the PLR in both groups, and there was no difference in the changes in eCVP between the two groups (older, +1.07±0.37 vs. younger, +1.12±0.33 mmHg at 40º from baseline, P=0.941). These results suggest that inhibition of sympathetic vasomotor outflow during cardiopulmonary baroreceptor loading could be blunted with advancing age in females.

Influence of sex on sympathetic vasomotor outflow responses to passive leg raising in young individuals.

The purpose of this study was to clarify sex differences in the inhibition of sympathetic vasomotor outflow which is caused by the loading of cardiopulmonary baroreceptors. Ten young males and ten age-matched females participated. The participants underwent a passive leg raising (PLR) test wherein they were positioned supine (baseline, 0º), and their lower limbs were lifted passively at 10º, 20º, 30º, and 40º. Each angle lasted for 3min. Muscle sympathetic nerve activity (MSNA) was recorded via microneurography of the left radial nerve. Baseline MSNA was lower in females compared to males. MSNA burst frequency was decreased during the PLR in both males (- 6.2 ± 0.4 bursts/min at 40º) and females (- 6.5 ± 0.4 bursts/min at 40º), but no significant difference was detected between the two groups (P = 0.61). These results suggest that sex has minimal influence on the inhibition of sympathetic vasomotor outflow during the loading of cardiopulmonary baroreceptors in young individuals.

The interactive effects of age and sex on the neuro-cardiovascular responses during fatiguing rhythmic handgrip exercise.

The impact of age on exercise pressor responses is equivocal, likely because of sex-specific neuro-cardiovascular changes with age. However, assessments of the interactive effects of age and sex on muscle sympathetic nerve activity (MSNA) responses to exercise are lacking. We tested the hypothesis that older females would exhibit exaggerated increases in blood pressure (BP) and MSNA discharge patterns during handgrip exercise compared with similarly aged males and young adults. Twenty-five young (25 (2) years; mean (SD)) males (YM; n=12) and females (YF; n=13) and 23 older (71 (5) years) males (OM; n=11) and females (OF; n=12) underwent assessments of BP, total peripheral resistance (TPR; Modelflow) and MSNA action potential (AP) discharge patterns (microneurography) during incremental rhythmic handgrip exercise and post-exercise circulatory occlusion (PECO). OM demonstrated larger ∆BP and ∆TPR from baseline than YM (both P < 0.001) despite smaller increases in ∆APs/burst (OM: 0.4 (3) vs. YM: 5 (3) spikes/burst, P < 0.001) and ∆AP clusters/burst (OM: 0.1 (1) vs. YM: 1.8 (1) clusters/burst, P < 0.001) during exercise. Testosterone was lower in OM than YM (P < 0.001) and was inversely related to ∆BP but positively related to ∆AP clusters/burst in males (both P=0.03). Conversely, YF and OF demonstrated similar ∆BP and ∆AP discharge during exercise (range: P=0.75-0.96). Age and sex did not impact haemodynamics or AP discharge during PECO (range: P=0.08-0.94). Altogether, age-related changes in neuro-cardiovascular reactivity exist in males but not females during fatiguing exercise and seem to be related to testosterone. This sex-specific impact of age underscores the importance of considering biological sex when assessing age-related changes in neuro-cardiovascular control during exercise. KEY POINTS: Older males have the largest increase in blood pressure despite having the smallest increases in sympathetic vasomotor outflow during rhythmic handgrip exercise. Young males demonstrate greater increases in sympathetic action potential (AP) discharge compared with young females during rhythmic handgrip exercise. Older adults (regardless of sex) demonstrate smaller increases in muscle sympathetic nerve activity (MSNA) burst amplitude and total AP clusters compared with young adults during exercise, as well as smaller increases in integrated MSNA burst frequency, incidence and total MSNA activity during post-exercise circulatory occlusion (i.e. independent effect of age). Males, but not females (regardless of age), reflexively modify AP conduction velocity during exercise. Our results indicate that age and sex independently and interactively impact the neural and cardiovascular homeostatic adjustments to fatiguing small muscle mass exercise.

PS-BPB04-5: SELECTIVE ACTIVATION OF GLUTAMATERGIC NEURONS WITHIN THE SFO EVOKES A PRESSOR RESPONSE THAT IS DEPENDENT ON THE PVN

Objective: An overactive glutamatergic projection from the subfornical organ (SFO) to the paraventricular nucleus (PVN) is associated with the development of hypertension. Despite this, the functional relationship of this pathway under normotensive conditions remains poorly defined within the literature. Without this knowledge, it remains unknown if a dysfunction of this pathway is the underlying cause of hypertension or rather simply a consequence of the underlying hypertensive disease pathology. As such, the aim of this study is to identify the short-term function of the SFO and PVN pathway under normotensive conditions. Design and Methods: An optogenetic viral vector (pAAV-CaMKIIa-hChR2 (H134R)-EYFP) was microinjected into the SFO of Lewis rats (n = 5). Three weeks later, rats were anaesthetised and instrumented to record blood pressure and sympathetic nerve activity, administer intravenous drugs and to photo-stimulate glutamatergic SFO neurons. Results: Photostimulation of glutamatergic SFO neurons produced a pressor response that was abolished by inhibition of neuronal transmission within the PVN (9 ± 1mmHg vs 3 ± 1mmHg peak change from baseline, baseline vs PVN inhibition, n = 2 rats, 3 replicates per rat). In a separate cohort (n = 3 rats, 5 replicates per rat), we determined if the pressor response elicited was dependant on the sympathetic nervous system and/or the release of the vasoactive hormone vasopressin. Blockade of sympathetic vasomotor outflow attenuated the pressor response by 76%, whereas combined inhibition of sympathetic outflow and vasopressin 1a receptors attenuated the pressor response by 88%. Finally, photostimulation of glutamatergic SFO neurons led to a peak increase in sympathetic nerve activity (n = 2) that was abolished by phenylephrine administration, suggesting that the neuronal circuitry underpinning this response is barosensitive. Conclusions: This study demonstrates that the pressor response elicited by glutamatergic SFO neurons is dependent on the PVN and is largely mediated by the sympathetic nervous system via barosensitive neuronal circuitry. Chronic activation of this pathway will be undertaken to determine if an overactivation of this neuronal pathway induces hypertension in normotensive animals.

Sympathetic vasomotor outflow during low-intensity leg cycling in healthy older males.

What is the central question of this study? Sympathetic vasomotor outflow is reduced during low-intensity dynamic leg exercise in younger individuals: does ageing influence the sympathoinhibitory effect during low-intensity leg cycling? What is the main finding and its importance? Muscle sympathetic nerve activity during low-intensity cycling decreased in older males, as seen in young males. It is possible that cardiopulmonary baroreflex-mediated inhibition of sympathetic vasomotor outflow during dynamic leg exercise is preserved in healthy older males. Muscle sympathetic nerve activity (MSNA) is reduced during low-intensity dynamic leg exercise in young males. It is suggested that this inhibition is mediated by loading of the cardiopulmonary baroreceptors. The purpose of this study was to clarify the impact of age on MSNA during dynamic leg exercise. Nine younger males (YM, mean±SD, 20±1years) and nine older males (OM, 72±3years) completed the study. The subjects performed two 4-min cycling exercises at 10% of their heart rate reserve using a cycle ergometer in a semirecumbent position (MSNA and estimated central venous pressure (eCVP) trials). MSNA was recorded via microneurography of the left radial nerve. The CVP was estimated based on peripheral venous pressure, which was monitored using a cannula in the right large antecubital vein. The magnitude of the increase in mean arterial blood pressure during leg cycling was larger in OM (+9.3±5.5mmHg) compared with YM (+2.8±4.7mmHg). MSNA burst frequency was decreased during cycling in both YM (-8.1±3.8bursts/min) and OM (-10.6±3.3bursts/min), but no significant difference was found between the two groups. The eCVP increased during exercise in both groups, and there was no difference in the changes in eCVP between YM (+1.1±0.4mmHg) and OM (+1.2±0.7mmHg). These data indicate that inhibition of sympathetic vasomotor outflow during low-intensity cycling appears in OM as seen in YM. It is possible that the muscle pump-induced loading of the cardiopulmonary baroreflex is preserved during cycling in healthy older males.

Aortic haemodynamics: the effects of habitual endurance exercise, age and muscle sympathetic vasomotor outflow in healthy men

PurposeWe determined the effect of habitual endurance exercise and age on aortic pulse wave velocity (aPWV), augmentation pressure (AP) and systolic blood pressure (aSBP), with statistical adjustments of aPWV and AP for heart rate and aortic mean arterial pressure, when appropriate. Furthermore, we assessed whether muscle sympathetic nerve activity (MSNA) correlates with AP in young and middle-aged men.MethodsAortic PWV, AP, aortic blood pressure (applanation tonometry; SphygmoCor) and MSNA (peroneal microneurography) were recorded in 46 normotensive men who were either young or middle-aged and endurance-trained runners or recreationally active nonrunners (10 nonrunners and 13 runners within each age-group). Between-group differences and relationships between variables were assessed via ANOVA/ANCOVA and Pearson product-moment correlation coefficients, respectively.ResultsAdjusted aPWV and adjusted AP were similar between runners and nonrunners in both age groups (all, P > 0.05), but higher with age (all, P < 0.001), with a greater effect size for the age-related difference in AP in runners (Hedges’ g, 3.6 vs 2.6). aSBP was lower in young (P = 0.009; g = 2.6), but not middle-aged (P = 0.341; g = 1.1), runners compared to nonrunners. MSNA burst frequency did not correlate with AP in either age group (young: r = 0.00, P = 0.994; middle-aged: r = − 0.11, P = 0.604).ConclusionThere is an age-dependent effect of habitual exercise on aortic haemodynamics, with lower aSBP in young runners compared to nonrunners only. Statistical adjustment of aPWV and AP markedly influenced the outcomes of this study, highlighting the importance of performing these analyses. Further, peripheral sympathetic vasomotor outflow and AP were not correlated in young or middle-aged normotensive men.

Respiratory modulation of sympathetic vasomotor outflow during graded leg cycling.

Respiratory modulation of sympathetic vasomotor outflow to skeletal muscles (muscle sympathetic nerve activity; MSNA) occurs in resting humans. Specifically, MSNA is highest at end-expiration and lowest at end-inspiration during quiet, resting breathing. We tested the hypothesis that within-breath modulation of MSNA would be amplified during graded leg cycling. Thirteen (n = 3 females) healthy young (age: 25.2 ± 4.7 yr) individuals completed all testing. MSNA (right median nerve) was measured at rest (baseline) and during semirecumbent cycle exercise at 40%, 60%, and 80% of maximal workload (Wmax). MSNA burst frequency (BF) was 20.0 ± 4.0 bursts/min at baseline and was not different during exercise at 40%Wmax (21.3 ± 3.7 bursts/min; P = 0.292). Thereafter, MSNA BF increased significantly compared with baseline (60%Wmax: 31.6 ± 5.8 bursts/min; P < 0.001, 80%Wmax: 44.7 ± 5.3 bursts/min; P < 0.001). At baseline and all exercise intensities, MSNA BF was lowest at end-inspiration and greatest at mid-to-end expiration. The within-breath change in MSNA BF (ΔMSNA BF; end-expiration minus end-inspiration) gradually increased from baseline to 60%Wmax leg cycling, but no further increase appeared at 80%Wmax exercise. Our results indicate that within-breath modulation of MSNA is amplified from baseline to moderate intensity during dynamic exercise in young healthy individuals, and that no further potentiation occurs at higher exercise intensities. Our findings provide an important extension of our understanding of respiratory influences on sympathetic vasomotor control.NEW & NOTEWORTHY Within-breath modulation of sympathetic vasomotor outflow to skeletal muscle (muscle sympathetic nerve activity; MSNA) occurs in spontaneously breathing humans at rest. It is unknown if respiratory modulation persists during dynamic whole body exercise. We found that MSNA burst frequency was lowest at end-inspiration and highest at mid-to-end expiration during rest and graded leg cycling. Respiratory modulation of sympathetic vasomotor outflow remains intact and is amplified during dynamic whole body exercise.

Blunted sympathetic neurovascular transduction is associated to the severity of obstructive sleep apnea.

Obstructive sleep apnea (OSA) is a common disorder (~ 4%) that augments sympathetic nerve activity (SNA) and elevates blood pressure. The relationship between sympathetic vasomotor outflow and vascular responsiveness, termed sympathetic neurovascular transduction (sNVT), has been sparsely characterized in patients with OSA. Therefore, we sought to quantify spontaneous sympathetic bursts and related changes in diastolic pressure. Twelve participants with variable severities of OSA were recruited. We collected muscle sympathetic nerve activity (MSNA) (microneurography) and beat-by-beat diastolic pressure (finger photoplethysmography) during normoxia (FiO2 = 0.21) and hyperoxia (FiO2 = 1.0) to decrease MSNA burst frequency. MSNA burst sequences (i.e. singlets, doublets, triplets and quadruplets) were identified and coupled to changes in diastolic pressure over 15 cardiac cycles as an index of sNVT. sNVT slope for each individual was calculated from the slope of the relationship between peak responses in outcome plotted against normalized burst amplitude. sNVT slope was unchanged during hyperoxia compared to normoxia (normoxia 0.0024 ± 0.0011 Δ mmHg total activity [a.u.]-1 vs. hyperoxia 0.0029 ± 0.00098 Δ mmHg total activity [a.u.]-1; p = 0.14). sNVT slope was inversely associated with burst frequency during hyperoxia (r = -0.58; p = 0.04), but not normoxia (r = -0.11; p = 0.71). sNVT slope was inversely associated with the apnea-hypopnea index (AHI) (r = -0.62; p = 0.030), but not after age was considered. We have demonstrated that the prevailing MSNA frequency is unmatched to the level of sNVT, and this can be altered by acute hyperoxia.

Global REACH 2018: Andean highlanders, chronic mountain sickness and the integrative regulation of resting blood pressure.

What is the central question of this study? Does chronic mountain sickness (CMS) alter sympathetic neural control and arterial baroreflex regulation of blood pressure in Andean (Quechua) highlanders? What is the main finding and its importance? Compared to healthy Andean highlanders, basal sympathetic vasomotor outflow is lower, baroreflex control of muscle sympathetic nerve activity is similar, supine heart rate is lower and cardiovagal baroreflex gain is greater in mild CMS. Taken together, these findings reflect flexibility in integrative regulation of blood pressure that may be important when blood viscosity and blood volume are elevated in CMS. The high-altitude maladaptation syndrome chronic mountain sickness (CMS) is characterized by excessive erythrocytosis and frequently accompanied by accentuated arterial hypoxaemia. Whether altered autonomic cardiovascular regulation is apparent in CMS is unclear. Therefore, during the 2018 Global REACH expedition to Cerro de Pasco, Peru (4383 m), we assessed integrative control of blood pressure (BP) and determined basal sympathetic vasomotor outflow and arterial baroreflex function in eight Andean natives with CMS ([Hb] 22.6±0.9g·dL-1 ) and seven healthy highlanders ([Hb] 19.3±0.8g·dL-1 ). R-R interval (RRI, electrocardiogram), beat-by-beat BP (photoplethysmography) and muscle sympathetic nerve activity (MSNA; microneurography) were recorded at rest and during pharmacologically induced changes in BP (modified Oxford test). Although [Hb] and blood viscosity (7.8±0.7vs. 6.6±0.7cP; d=1.7, P=0.01) were elevated in CMS compared to healthy highlanders, cardiac output, total peripheral resistance and mean BP were similar between groups. The vascular sympathetic baroreflex MSNA set-point (i.e. MSNA burst incidence) and reflex gain (i.e. responsiveness) were also similar between groups (MSNA set-point, d=0.75, P=0.16; gain, d=0.2, P=0.69). In contrast, in CMS the cardiovagal baroreflex operated around a longer RRI (960±159vs. 817±50ms; d=1.4, P=0.04) with a greater reflex gain (17.2±6.8vs. 8.8±2.6ms·mmHg-1 ; d=1.8, P=0.01) versus healthy highlanders. Basal sympathetic vasomotor activity was also lower compared to healthy highlanders (33±11vs. 45±13bursts·min-1 ; d=1.0, P=0.08). In conclusion, our findings indicate adaptive differences in basal sympathetic vasomotor activity and heart rate compensate for the haemodynamic consequences of excessive erythrocyte volume and contribute to integrative blood pressure regulation in Andean highlanders with mild CMS.

Muscle pump-induced inhibition of sympathetic vasomotor outflow during low-intensity leg cycling is attenuated by muscle metaboreflex activation.

Muscle sympathetic nerve activity (MSNA) decreases during leg cycling at low intensity because of muscle pump-induced increases in venous return and loading of the cardiopulmonary baroreceptors. However, MSNA increases during leg cycling when exercise is above moderate intensity or for a long duration, suggesting that the sympathoinhibitory effect of the cardiopulmonary baroreflex can be overridden by a powerful sympathoexcitatory drive, such as the skeletal muscle metaboreflex. Therefore, we tested the hypothesis that high-intensity muscle metaboreflex activation attenuates muscle pump-induced inhibition of MSNA during leg cycling. MSNA (left radial nerve) was recorded during graded isolation of the muscle metaboreflex in the forearm with postexercise ischemia (PEI) after low (PEI-L)- and high (PEI-H)-intensity isometric handgrip exercise (20% and 40% maximum voluntary contraction, respectively). Leg cycling (15-20 W) was performed alone and during each PEI trial (PEI-L+Cycling, PEI-H+Cycling). Cycling alone induced a significant decrease in MSNA burst frequency (BF) and total activity (TA). MSNA BF and TA also decreased when cycling was performed during PEI-L. However, the magnitude of decrease in MSNA during PEI-L+Cycling [∆BF: -19 ± 2% (P < 0.001), ∆TA: -25 ± 4% (P < 0.001); mean ± SE] was less than that during cycling alone [∆BF: -39 ± 5% (P = 0.003), ∆TA: -45 ± 5% (P = 0.002)]. More importantly, MSNA did not decrease during cycling with PEI-H [∆BF: -1 ± 2% (P = 0.845), ∆TA: +2 ± 3% (P = 0.959)]. These results suggest that muscle pump-induced inhibition of sympathetic vasomotor outflow during low-intensity leg cycling is attenuated by muscle metaboreflex activation in an intensity-dependent manner.NEW & NOTEWORTHY There are no available data concerning the interaction between the sympathoinhibitory effect of muscle pump-induced cardiopulmonary baroreflex loading during leg cycling and the sympathoexcitatory influence of the muscle metaboreflex. In this study, muscle metaboreflex activation attenuated the inhibition of muscle sympathetic nerve activity (MSNA) during leg cycling. This may explain, in part, the response of MSNA to graded-intensity dynamic exercise in which low-intensity leg cycling inhibits MSNA whereas high-intensity exercise elicits graded sympathoexcitation.

GABAA receptors modulate sympathetic vasomotor outflow and the pressor response to skeletal muscle metaboreflex activation in humans.

The activation of the group III/IV skeletal muscle afferents is one of the principal mediators of cardiovascular responses to exercise; however, the neuronal circuitry mechanisms that are involved during the activation of group III/IV muscle afferents in humans remain unknown. Recently, we showed that GABAergic mechanisms are involved in the cardiac vagal withdrawal during the activation of mechanically sensitive (predominantly mediated by group III fibres) skeletal muscle afferents in humans. In the present study, we found that increases in muscle sympathetic nerve activity and mean blood pressure during isometric handgrip exercise and postexercise ischaemia were significantly greater after the oral administration of diazepam, a benzodiazepine that increases GABAA activity, but not after placebo administration in young healthy subjects. These findings indicate for the first time that GABAA receptors modulate sympathetic vasomotor outflow and the pressor responses to activation of metabolically sensitive (predominantly mediated by group IV fibres) skeletal muscle afferents in humans. Animal studies have indicated that GABAA receptors are involved in the neuronal circuitry of the group III/IV skeletal muscle afferent activation-induced neurocardiovascular responses to exercise. In the present study, we aimed to determine whether GABAA receptors modulate the neurocardiovascular responses to activation of metabolically sensitive (predominantly mediated by group IV fibres) skeletal muscle afferents in humans. In a randomized, double-blinded, placebo-controlled and cross-over design, 17 healthy subjects (eight women) performed 2min of ischaemic isometric handgrip exercise at 30% of the maximal voluntary contraction followed by 2min of postexercise ischaemia (PEI). Muscle sympathetic nerve activity (MSNA), blood pressure (BP) and heart rate (HR) were continuously measured and trials were conducted before and 60min after the oral administration of either placebo or diazepam (10mg), a benzodiazepine that enhances GABAA activity. At rest, MSNA was reduced, whereas HR and BP did not change after diazepam administration. During ischaemic isometric handgrip, greater MSNA (pre: ∆13±9burstsmin-1 vs. post: ∆29±15burstsmin-1 , P<0.001), HR (pre: ∆23±11beatsmin-1 vs. post: ∆31±17beatsmin-1 , P<0.01) and mean BP (pre: ∆33±12mmHg vs. post: ∆37±12mmHg, P<0.01) responses were observed after diazepam. During PEI, MSNA and mean BP remained elevated from baseline before diazepam (∆10±8burstsmin-1 and ∆25±14mmHg, respectively) and these elevations were increased after diazepam (∆17±12burstsmin-1 and ∆28±13mmHg, respectively) (P≤0.05). Importantly, placebo pill had no effect on neural, cardiac and pressor responses. These findings demonstrate for the first time that GABAA receptors modulate MSNA and the pressor responses to skeletal muscle metaboreflex activation in humans.

Muscle sympathetic nerve activity during exercise.

Appropriate cardiovascular adjustment is necessary to meet the metabolic demands of working skeletal muscle during exercise. The sympathetic nervous system plays a crucial role in the regulation of arterial blood pressure and blood flow during exercise, and several important neural mechanisms are responsible for changes in sympathetic vasomotor outflow. Changes in sympathetic vasomotor outflow (i.e., muscle sympathetic nerve activity: MSNA) in inactive muscles during exercise differ depending on the exercise mode (static or dynamic), intensity, duration, and various environmental conditions (e.g., hot and cold environments or hypoxic). In 1991, Seals and Victor [6] reviewed MSNA responses to static and dynamic exercise with small muscle mass. This review provides an updated comprehensive overview on the MSNA response to exercise including large-muscle, dynamic leg exercise, e.g., two-legged cycling, and its regulatory mechanisms in healthy humans.

Influence of Sex, Menstrual Cycle, and Menopause Status on the Exercise Pressor Reflex.

In this review, we highlight the underlying mechanisms responsible for the sex differences in the exercise pressor reflex (EPR), and, importantly, the impact of sex hormones and menopausal status. The EPR is attenuated in premenopausal women compared with age-matched men. Specifically, activation of the metaboreflex (a component of the EPR) results in attenuated increases in blood pressure and sympathetic vasomotor outflow compared with age-matched men. In addition, premenopausal women exhibit less transduction of sympathetic outflow to the peripheral vasculature than men. In stark contrast, postmenopausal women exhibit an augmented EPR arising from exaggerated metaboreflex-induced autonomic and cardiovascular reflexes. We propose that metaboreflex-induced autonomic and cardiovascular changes associated with menopause majorly contribute to the elevated blood pressure response during dynamic exercise in postmenopausal women. In addition, we discuss the potential mechanisms by which sex hormones in premenopausal women may impact the EPR as well as metaboreflex.

Baroreflex control of sympathetic vasomotor activity and resting arterial pressure at high altitude: insight from Lowlanders and Sherpa

Hypoxia, a potent activator of the sympathetic nervous system, is known to increase muscle sympathetic nerve activity (MSNA) to the peripheral vasculature of native Lowlanders during sustained high altitude (HA) exposure. We show that the arterial baroreflex control of MSNA functions normally in healthy Lowlanders at HA, and that upward baroreflex resetting permits chronic activation of basal sympathetic vasomotor activity under this condition. The baroreflex MSNA operating point and resting sympathetic vasomotor outflow both are lower for highland Sherpa compared to acclimatizing Lowlanders; these lower levels may represent beneficial hypoxic adaptation in Sherpa. Acute hyperoxia at HA had minimal effect on baroreflex control of MSNA in Lowlanders and Sherpa, raising the possibility that mechanisms other than peripheral chemoreflex activation contribute to vascular sympathetic baroreflex resetting and sympathoexcitation. These findings provide a better understanding of sympathetic nervous system activation and the control of blood pressure during the physiological stress of sustained HA hypoxia. Exposure to high altitude (HA) is characterized by heightened muscle sympathetic neural activity (MSNA); however, the effect on arterial baroreflex control of MSNA is unknown. Furthermore, arterial baroreflex control at HA may be influenced by genotypic and phenotypic differences between lowland and highland natives. Fourteen Lowlanders (12 male) and nine male Sherpa underwent haemodynamic and sympathetic neural assessment at low altitude (Lowlanders, low altitude; 344m, Sherpa, Kathmandu; 1400m) and following gradual ascent to 5050m. Beat-by-beat haemodynamics (photoplethysmography) and MSNA (microneurography) were recorded lying supine. Indices of vascular sympathetic baroreflex function were determined from the relationship of diastolic blood pressure (DBP) and corresponding MSNA at rest (i.e. DBP 'operating pressure' and MSNA 'operating point'), as well as during a modified Oxford baroreflex test (i.e. 'gain'). Operating pressure and gain were unchanged for Lowlanders during HA exposure; however, the operating point was reset upwards (48±16vs. 22±12 bursts 100HB-1 ,P=0.001). Compared to Lowlanders at 5050m, Sherpa had similar gain and operating pressure, although the operating point was lower (30±13 bursts 100HB-1 , P=0.02); MSNA burst frequency was lower for Sherpa (22±11 vs. 30±9 bursts min-1 P=0.03). Breathing 100% oxygen did not alter vascular sympathetic baroreflex function for either group at HA. For Lowlanders, upward baroreflex resetting promotes heightened sympathetic vasoconstrictor activity and maintains blood pressure stability, at least during early HA exposure; mechanisms other than peripheral chemoreflex activation could be involved. Sherpa adaptation appears to favour a lower sympathetic vasoconstrictor activity compared to Lowlanders for blood pressure homeostasis.

Muscle pump‐induced inhibition of sympathetic vasomotor outflow during leg cycling is blunted by high‐intensity muscle metaboreflex activation

Muscle sympathetic nerve activity (MSNA) decreases during leg cycling at light or mild intensity (below 40%VO2max), and this is attributed to loading of the cardiopulmonary baroreceptors via muscle pump‐induced increases in venous return. In contrast, MSNA increases during leg cycling above moderate intensity, suggesting that the sympathoinhibitory effect of the cardiopulmonary baroreflex could be overridden by a powerful sympathoexcitatory drive. Skeletal muscle metaboreflex is known to elicit robust sympathoexcitation. Therefore, we tested the hypothesis that high‐intensity muscle metaboreflex activation attenuates muscle pumpinduced cardiopulmonary baroreflex‐mediated inhibition of MSNA during leg cycling. In five healthy young men (25 ± 2 yrs, mean ± SE), MSNA (radial nerve) and thoracic impedance were recorded. Subjects performed cycling at 30 watts with and without muscle metaboreflex activation. Graded isolation of the muscle metaboreflex was achieved by post‐exercise ischemia (PEI) following low and high intensity isometric handgrip at 20% (PEI‐L) and 40% (PEI‐H) maximum voluntary contraction, before the onset of leg cycling. Resting MSNA burst frequency was 23.4 ± 0.4 burst·min−1 and MSNA total activity was 1503 ± 20 AU·min−1. As expected, leg cycling alone significantly decreased MSNA burst frequency and total activity (Δtotal activity: −43.0 ± 4.9%, P &lt; 0.05). When leg cycling was performed during muscle metaboreflex activation with PEI, MSNA burst frequency and total activity decreased significantly during PEI‐L (Δtotal activity: −32.8 ± 7.1%, P &lt; 0.05), but not during PEI‐H (Δtotal activity: +1.6 ± 7.1%, P = 0.89). Thoracic admittance, which was calculated from thoracic impedance as an index of central blood volume, was not changed during handgrip or PEI, whereas leg cycling evoked similar increases in thoracic admittance during all conditions (ΔLeg cycling alone: +3.5 ± 1.0, ΔPEI‐L: +3.6 ± 1.0, ΔPEI‐H: +3.6 ± 0.8 S·10−4, one‐way repeated measures ANOVA: F = 0.02, P = 0.98). These preliminary findings suggest that high intensity muscle metaboreflex activation attenuates muscle pump‐induced cardiopulmonary baroreflex inhibition of sympathetic vasomotor outflow during dynamic leg cycling.Support or Funding InformationJSPS KAKENHI Grant Number JP16KK0201, UTA College of Nursing and Health InnovationThis 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 diaphragmatic fatigue: the cardiovascular response to inspiratory resistance.

Diaphragmatic fatigue (DF) elicits a sympathetically mediated metaboreflex resulting in increased heart rate, blood pressure and limb vascular resistance. Women may be more resistant to DF compared to men, and therefore it was hypothesised that women would experience an attenuated inspiratory muscle metaboreflex during inspiratory pressure-threshold loading (PTL) performed to task failure. At the time of PTL task failure, the severity of DF was not different between sexes; however, inspiratory muscle endurance time was significantly longer in women than in men. For a given cumulative diaphragmatic force output, the severity of DF was less in women than in men. Women exhibited a blunted cardiovascular response to inspiratory resistance (i.e. metaboreflex) that may have implications for exercise tolerance. Diaphragmatic fatigue (DF) elicits reflexive increases in sympathetic vasomotor outflow (i.e. metaboreflex). There is some evidence suggesting women may be more resistant to DF compared to men, and therefore may experience an attenuated inspiratory muscle metaboreflex. To this end, we sought to examine the cardiovascular response to inspiratory resistance in healthy young men (n=9, age=24±3years) and women (n=9, age=24±3years). Subjects performed isocapnic inspiratory pressure-threshold loading (PTL, 60% maximal inspiratory mouth pressure) to task failure. Diaphragmatic fatigue was assessed by measuring transdiaphragmatic twitch pressure (Pdi,tw ) using cervical magnetic stimulation. Heart rate (HR) and mean arterial pressure (MAP) were measured beat-by-beat throughout PTL via photoplethysmography, and low-frequency systolic pressure (LFSBP ; a surrogate for sympathetic vasomotor tone) calculated from arterial waveforms using power spectrum analysis. At PTL task failure, the degree of DF was similar between sexes (∼23% reduction in Pdi,tw ; P=0.33). However, time to task failure was significantly longer in women than in men (27±11vs. 16±11min, respectively; P=0.02). Women exhibited less of an increase in HR (13±8vs. 19±12bpm; P=0.02) and MAP (10±8vs. 14±9mmHg; P=0.01), and significantly lower LFSBP (23±11vs. 34±8mmHg2 ; P=0.04) during PTL compared to men. An attenuation of the inspiratory muscle metaboreflex may influence limb and respiratory muscle haemodynamics with implications for exercise performance.

Blunted Sympathetic Vasomotor Outflow To Inspiratory Resistive Breathing During Exercise In Women Compared to Men

It has been reported that in young men high inspiratory muscle work at rest and during exercise reflexively increases muscle sympathetic nerve activity (MSNA), with corresponding increases in arterial blood pressure (ABP). This sympathoexcitation occurs through an inspiratory muscle-induced metaboreflex. Young women have attenuated inspiratory muscle metaboreflex-induced increases in ABP compared to age-matched men. One potential mechanism is less sympathetic vasomotor output in women compared to men. PURPOSE: We compared changes in MSNA and cardiovascular variables during leg cycle exercise with increased inspiratory muscle resistance in men and women. METHODS: Eight young women (19.5±0.2) and seven men (20.3±0.3) completed the study. The subjects performed two 10-min submaximal cycle ergometer exercises in a semirecumbent position. The first 5-min was spontaneous breathing, and latter 5-min half was voluntary hyperventilation with or without inspiratory resistive breathing. Mean arterial blood pressure (MAP) was measured using finger photoplethysmography and MSNA was recorded via microneurography of the arm at the elbow. RESULTS: During exercise with inspiratory resistive breathing, MSNA burst frequency was significantly increased accompanied by an increase (p<0.05) in MAP in both men and women. Women had significantly less of an increase in MSNA (Women: +9.6±1.0 vs. Men: +14.6±2.4 bursts/min) and MAP (Women: +22.8±5.7 vs. Men: +32.2±2.0 mmHg) as compared to men. CONCLUSION: These results suggest that lesser sympathetic vasomotor outflow partially contributes the attenuated inspiratory muscle-induced metaboreflex during exercise in young women. Supported by JSPS KAKENHI Grant Number 15H3079.

High-intensity muscle metaboreflex activation attenuates cardiopulmonary baroreflex-mediated inhibition of muscle sympathetic nerve activity.

Previous studies have shown that muscle sympathetic nerve activity (MSNA) is reduced during low- and mild-intensity dynamic leg exercise. It has been suggested that such inhibition is mediated by loading of the cardiopulmonary baroreceptors and that this effect is overridden by muscle metaboreflex activation with higher-intensity exercise. However, limited data are available regarding the interaction between the cardiopulmonary baroreflex and the muscle metaboreflex. Therefore, we tested the hypothesis that cardiopulmonary baroreflex-mediated inhibition of MSNA is attenuated during high-intensity muscle metaboreflex activation. In nine young men, MSNA (right peroneal nerve), mean arterial pressure (MAP), and thoracic impedance were recorded. Graded isolation of muscle metaboreflex activation was achieved via postexercise ischemia (PEI) following low (PEI-L)-, moderate (PEI-M)-, and high (PEI-H)-intensity isometric handgrip performed at 20, 30, and 40% maximum voluntary contraction, respectively. Lower-body positive pressure (LBPP, +10 Torr) was applied at rest and during PEI, to load the cardiopulmonary baroreceptors. Handgrip exercise elicited intensity-dependent increases in MSNA and MAP that were maintained during PEI, indicating a graded muscle metaboreflex activation. LBPP at rest significantly decreased MSNA burst frequency (BF: -36.7 ± 4.7%, mean ± SE, P < 0.05), whereas MAP was unchanged. When LBPP was applied during PEI, MSNA BF decreased significantly at PEI-L (-40.0 ± 9.2%, P < 0.05) and PEI-M (-27.0 ± 6.3%, P < 0.05), but not at PEI-H (+1.9 ± 7.1%, P > 0.05). These results suggest that low- and moderate-intensity muscle metaboreflex activation does not modulate the inhibition of MSNA by cardiopulmonary baroreceptor loading, whereas high-intensity metaboreflex activation can override cardiopulmonary baroreflex-mediated inhibition of sympathetic vasomotor outflow. NEW & NOTEWORTHY The interaction between the sympathoinhibitory influence of cardiopulmonary baroreflex and sympathoexcitatory effect of skeletal muscle metaboreflex is not completely understood. In the current study, light- to moderate-intensity muscle metaboreflex activation did not modulate the suppression of muscle sympathetic nerve activity by cardiopulmonary baroreceptor loading, whereas high-intensity muscle metaboreflex activation attenuated the cardiopulmonary baroreflex-mediated inhibition of muscle sympathetic nerve activity. These results provide important information concerning the neural reflex mechanisms regulating sympathetic vasomotor outflow during exercise.

High Intensity Muscle Metaboreflex Activation Blunts Cardiopulmonary Baroreflex Control of Sympathetic Vasomotor Outflow

Muscle sympathetic nerve activity (MSNA) is reduced during low intensity dynamic leg exercise. This reduction in MSNA has been attributed to loading of the cardiopulmonary baroreflex with increased venous return and it has been suggested that such inhibition is overridden with higher intensity exercise due to muscle metaboreflex activation. However, limited data are available regarding the interaction between the cardiopulmonary baroreflex and the muscle metaboreflex. Herein, we tested the hypothesis that cardiopulmonary baroreflex control of MSNA is attenuated when the muscle metaboreflex is strongly activated. In eight healthy young men, MSNA (right peroneal nerve), mean arterial blood pressure (MAP, Finometer), heart rate (ECG), and thoracic impedance were recorded. Graded isolation of the muscle metaboreflex was achieved by post‐exercise ischemia (PEI) following low‐ (PEI‐L), moderate‐ (PEI‐M) and high‐ (PEI‐H) intensity isometric handgrip performed at 20%, 30% and 40% maximum voluntary contraction, respectively. Lower‐body positive pressure (LBPP, +10 mmHg), to load the cardiopulmonary baroreflex, was applied at rest and during PEI. Handgrip exercise elicited intensity‐dependent increases in MSNA and MAP that were maintained during PEI indicating a graded muscle metaboreflex activation. LBPP at rest significantly decreased MSNA burst frequency and total activity (total activity: −39.5 ± 5.7%, mean ± SE, P &lt; 0.05), while MAP was unchanged. When LBPP was applied during PEI, MSNA burst frequency and total activity decreased significantly at PEI‐L (total activity: −41.8 ± 10.6%, P &lt; 0.05) and PEI‐M (total activity: −34.7 ± 8.6%, P &lt; 0.05), but not at PEI‐H (total activity: −11.8 ± 8.6%, n.s., one‐way repeated measures ANOVA: F = 5.07, P &lt; 0.05). Thoracic admittance, which was calculated from thoracic impedance as an index of central blood volume, was not changed during handgrip or PEI alone, whereas LBPP evoked similar increases in thoracic admittance during all conditions (rest: +5.4±0.8, PEI‐L: +5.8±0.5, +PEI‐M: +5.4±0.5, PEI‐H: +5.8±0.5 S·10−4, one‐way repeated measures ANOVA: F = 0.38, n.s.). These preliminary findings suggest that high intensity muscle metaboreflex activation attenuates cardiopulmonary baroreflex control of sympathetic vasomotor outflow.Support or Funding InformationNIH R01 HL127071 JSPS KAKENHI Grant Number JP16KK0201This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Elevated sympathetic vasomotor outflow in response to increased inspiratory muscle activity during exercise is less in young women compared with men.

What is the central question of this study? Premenopausal women have an attenuated inspiratory muscle metaboreflex-induced increase in arterial blood pressure compared with men. It is unclear whether sympathetic vasomotor outflow during dynamic exercise with increased inspiratory muscle activation is less in young women than in men. What is the main finding and its importance? The magnitude of increased sympathetic vasomotor outflow during leg cycling with inspiratory resistance was smaller in women than in men. Less sympathetic vasomotor outflow with inspiratory muscle metaboreflex activation could be one of the mechanisms for the attenuated inspiratory muscle-induced metaboreflex during exercise in young women. We compared changes in muscle sympathetic nerve activity (MSNA) and cardiovascular variables during leg cycle exercise with increased inspiratory muscle resistance in men and women. We hypothesized that sympathetic vasomotor outflow during exercise with increased inspiratory resistance would be attenuated in young women compared with age-matched men. Eight women and seven men completed the study. The subjects performed two 10min exercise bouts at 40% peak oxygen uptake using a cycle ergometer in a semirecumbent position [spontaneous breathing for 5min and voluntary hyperventilation with or without inspiratory resistive breathing for 5min (breathing frequency 50breathsmin-1 with a 50% duty cycle; inspiratory resistance 30% of maximal inspiratory pressure)]. Mean arterial blood pressure (MAP) was acquired using finger photoplethysmography. The MSNA was recorded via microneurography of the right median nerve at the cubital fossa. During leg cycle exercise with inspiratory resistive breathing, MSNA burst frequency was increased, accompanied by an increase in MAP in both men and women. Women, compared with men, had less of an increase in MAP (women +22.8±12.3mmHg versus men +32.2±5.4mmHg; P<0.05) and MSNA burst frequency (women +9.6±2.9burstsmin-1 versus men +14.6±6.4burstsmin-1 ; P<0.05). These results suggest that the attenuated inspiratory muscle-induced metaboreflex during exercise in young women is attributable, in part, to a lesser sympathetic vasomotor outflow compared with men.