Reflex sympathetic activation to inspiratory muscle loading is attenuated in females relative to males.

Intense inspiratory muscle work can evoke a metabolite-stimulated pressor reflex, commonly referred to as the respiratory muscle metaboreflex. When completing similar relative and absolute levels of inspiratory work, females have an attenuated blood pressure response. We sought to test the hypothesis that the lower blood pressure response to the respiratory muscle metaboreflex in females is associated with a reduced sympathetic response. Healthy young (26 ± 4 yr) males (n = 9) and females (n = 7) completed two experimental days. On day 1, participants completed pulmonary function testing and became familiarized with an inspiratory pressure-threshold loading (PTL) task. On the second day, balloon-tipped catheters were placed in the esophagus and stomach to measure pleural and gastric pressures, and transdiaphragmatic pressure was calculated. A microelectrode was inserted into the fibular nerve to quantify muscle sympathetic nerve activity (MSNA), and participants then completed isocapnic PTL to task failure. There was a significant sex-by-time interaction in the mean arterial pressure (MAP, P = 0.015) and burst frequency (P = 0.039) response to PTL. Males had a greater rise in MAP (Δ21 ± 9 mmHg) than females (Δ13 ± 5 mmHg, P = 0.026). Males also demonstrated a greater rise in MSNA burst frequency (Δ18 ± 7 bursts/min) than females (Δ10 ± 5 bursts/min, P = 0.015). The effect of sex was observed despite females and males completing the same magnitude of diaphragm work throughout the task (P = 0.755). Our findings provide novel evidence that the lower blood pressure response to similar relative and absolute inspiratory muscle work in females is associated with lower sympathetic activation.NEW & NOTEWORTHY The blood pressure response to high levels of inspiratory muscle work is lower in females and occurs alongside a reduced sympathetic response. The reduced blood pressure and sympathetic response occur despite males and females performing similar levels of absolute inspiratory work. Our findings provide evidence that sex differences in the respiratory muscle metaboreflex are, in part, sympathetically mediated.

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

NEW FINDINGS: 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. ABSTRACT: 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 ± 0.9 g·dL-1 ) and seven healthy highlanders ([Hb] 19.3 ± 0.8 g·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 ± 0.7 vs. 6.6 ± 0.7 cP; 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 ± 159 vs. 817 ± 50 ms; d = 1.4, P = 0.04) with a greater reflex gain (17.2 ± 6.8 vs. 8.8 ± 2.6 ms·mmHg-1 ; d = 1.8, P = 0.01) versus healthy highlanders. Basal sympathetic vasomotor activity was also lower compared to healthy highlanders (33 ± 11 vs. 45 ± 13 bursts·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.

Evidence for a physiological role of pulmonary arterial baroreceptors in sympathetic neural activation in healthy humans.

KEY POINTS: In an anaesthetised animal model, independent stimulation of baroreceptors in the pulmonary artery elicits reflex sympathoexcitation. In humans, pulmonary arterial pressure is positively related to basal muscle sympathetic nerve activity (MSNA) under conditions where elevated pulmonary pressure is evident (e.g. high altitude); however, a causal link is not established. Using a novel experimental approach, we demonstrate that reducing pulmonary arterial pressure lowers basal MSNA in healthy humans. This response is distinct from the negative feedback reflex mediated by aortic and carotid sinus baroreceptors when systemic arterial pressure is lowered. Afferent input from pulmonary arterial baroreceptors may contribute to sympathetic neural activation in healthy lowland natives exposed to high altitude. ABSTRACT: In animal models, distension of baroreceptors located in the pulmonary artery induces a reflex increase in sympathetic outflow; however, this has not been examined in humans. Therefore, we investigated whether reductions in pulmonary arterial pressure influenced sympathetic outflow and baroreflex control of muscle sympathetic nerve activity (MSNA). Healthy lowlanders (n = 13; 5 females) were studied 4-8 days following arrival at high altitude (4383 m; Cerro de Pasco, Peru), a setting that increases both pulmonary arterial pressure and sympathetic outflow. MSNA (microneurography) and blood pressure (BP; photoplethysmography) were measured continuously during ambient air breathing (Amb) and a 6 min inhalation of the vasodilator nitric oxide (iNO; 40 ppm in 21% O2 ), to selectively lower pulmonary arterial pressure. A modified Oxford test was performed under both conditions. Pulmonary artery systolic pressure (PASP) was determined using Doppler echocardiography. iNO reduced PASP (24 ± 3 vs. 32 ± 5 mmHg; P < 0.001) compared to Amb, with a similar reduction in MSNA total activity (1369 ± 576 to 994 ± 474 a.u min-1 ; P = 0.01). iNO also reduced the MSNA operating point (burst incidence; 39 ± 16 to 33 ± 17 bursts·100 Hb-1 ; P = 0.01) and diastolic operating pressure (82 ± 8 to 80 ± 8 mmHg; P < 0.001) compared to Amb, without changing heart rate (P = 0.6) or vascular-sympathetic baroreflex gain (P = 0.85). In conclusion, unloading of pulmonary arterial baroreceptors reduced basal sympathetic outflow to the skeletal muscle vasculature and reset vascular-sympathetic baroreflex control of MSNA downward and leftward in healthy humans at high altitude. These data suggest the existence of a lesser-known reflex input involved in sympathetic activation in humans.

Highs and lows of sympathetic neurocardiovascular transduction: influence of altitude acclimatization and adaptation.

High-altitude (>2,500 m) exposure results in increased muscle sympathetic nervous activity (MSNA) in acclimatizing lowlanders. However, little is known about how altitude affects MSNA in indigenous high-altitude populations. Additionally, the relationship between MSNA and blood pressure regulation (i.e., neurovascular transduction) at high-altitude is unclear. We sought to determine 1) how high-altitude effects neurocardiovascular transduction and 2) whether differences exist in neurocardiovascular transduction between low- and high-altitude populations. Measurements of MSNA (microneurography), mean arterial blood pressure (MAP; finger photoplethysmography), and heart rate (electrocardiogram) were collected in 1) lowlanders (n = 14) at low (344 m) and high altitude (5,050 m), 2) Sherpa highlanders (n = 8; 5,050 m), and 3) Andean (with and without excessive erythrocytosis) highlanders (n = 15; 4,300 m). Cardiovascular responses to MSNA burst sequences (i.e., singlet, couplet, triplet, and quadruplet) were quantified using custom software (coded in MATLAB, v.2015b). Slopes were generated for each individual based on peak responses and normalized total MSNA. High altitude reduced neurocardiovascular transduction in lowlanders (MAP slope: high altitude, 0.0075 ± 0.0060 vs. low altitude, 0.0134 ± 0.080; P = 0.03). Transduction was elevated in Sherpa (MAP slope, 0.012 ± 0.007) compared with Andeans (0.003 ± 0.002, P = 0.001). MAP transduction was not statistically different between acclimatizing lowlanders and Sherpa (MAP slope, P = 0.08) or Andeans (MAP slope, P = 0.07). When resting MSNA is accounted for (ANCOVA), transduction was inversely related to basal MSNA (bursts/minute) independent of population (RRI, r = 0.578 P < 0.001; MAP, r = -0.627, P < 0.0001). Our results demonstrate that transduction is blunted in individuals with higher basal MSNA, suggesting that blunted neurocardiovascular transduction is a physiological adaptation to elevated MSNA rather than an effect or adaptation specific to chronic hypoxic exposure.NEW & NOTEWORTHY This study has identified that sympathetically mediated blood pressure regulation is reduced following ascent to high-altitude. Additionally, we show that high altitude Andean natives have reduced blood pressure responsiveness to sympathetic nervous activity (SNA) compared with Nepalese Sherpa. However, basal sympathetic activity is inversely related to the magnitude of SNA-mediated fluctuations in blood pressure regardless of population or condition. These data set a foundation to explore more precise mechanisms of blood pressure control under conditions of persistent sympathetic activation and hypoxia.

Muscle sympathetic reactivity to apneic and exercise stress in high-altitude Sherpa.

Lowland-dwelling populations exhibit persistent sympathetic hyperactivity at altitude that alters vascular function. High-altitude populations, such as Sherpa, have previously exhibited greater peripheral blood flow in response to acute stress than Lowlanders, which may be explained through lower sympathetic activity. Our purpose was to determine whether Sherpa exhibit lower sympathetic reactivity to stress than Lowlanders. Muscle sympathetic nerve activity (MSNA; microneurography) was measured at rest in Lowlanders (n = 14; age = 27 ± 6 yr) at 344 m and between 1 and 10 days at 5,050 m. Sherpa (age = 32 ± 11 yr) were tested at 5,050 m (n = 8). Neurovascular reactivity (i.e., change in MSNA patterns) was measured during maximal end-expiratory apnea, isometric hand grip (IHG; 30% maximal voluntary contraction for 2-min), and postexercise circulatory occlusion (PECO; 3 min). Burst frequency (bursts/min) and incidence (bursts/100 heartbeats) and total normalized SNA (arbitrary units/min) were analyzed at rest, immediately before apnea breakpoint, and during the last minute of IHG and PECO. Vascular responses to apnea, IHG, and PECO were also measured. MSNA reactivity to apnea was smaller in Sherpa than Lowlanders at 5,050 m, although blood pressure responses were similar between groups. MSNA increases in Lowlanders during apnea at 5,050 m were significantly lower than at 344 m (P < 0.05), indicating that a possible sympathetic ceiling was reached in Lowlanders at 5,050 m. MSNA increased similarly during IHG and PECO in Lowlanders at both 334 m and 5,050 m and in Sherpa at 5,050 m, while vascular changes (mean brachial arterial pressure, contralateral brachial flow and resistance) were similar between groups. Sherpa demonstrate overall lower sympathetic reactivity that may be a result of heightened vascular responsiveness to potential apneic stress at altitude.

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

KEY POINTS: 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. ABSTRACT: 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; 344 m, Sherpa, Kathmandu; 1400 m) and following gradual ascent to 5050 m. 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 ± 16 vs. 22 ± 12 bursts 100 HB-1 , P = 0.001). Compared to Lowlanders at 5050 m, Sherpa had similar gain and operating pressure, although the operating point was lower (30 ± 13 bursts 100 HB-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.

Short-term hypoxia does not promote arrhythmia during voluntary apnea.

The presence of bradycardic arrhythmias during volitional apnea at altitude may be caused by chemoreflex activation/sensitization. We investigated whether bradyarrhythmic episodes became prevalent in apnea following short-term hypoxia exposure. Electrocardiograms (ECG; lead II) were collected from 22 low-altitude residents (F = 12; age=25 ± 5 years) at 671 m. Participants were exposed to normobaric hypoxia (SpO2 ~79 ± 3%) over a 5-h period. ECG rhythms were assessed during both free-breathing and maximal volitional end-expiratory and end-inspiratory apnea at baseline during normoxia and hypoxia exposure (20 min [AHX]; 5 h [HX5]). Free-breathing HR became elevated at AHX (78 ± 10 bpm; p < 0.0001) and HX5 (80 ± 12 bpm; p < 0.0001) compared to normoxia (68 ± 10 bpm), whereas apnea caused significant bradycardia at AHX (nadir end-expiratory -17 ± 14 bpm; p < 0.001) and HX5 (nadir end-expiratory -19 ± 15 bpm; p < 0.001), but not during normoxia (nadir end-expiratory -4 ± 13 bpm), with no difference in bradycardia responses between apneas at AHX and HX5. Conduction abnormalities were noted in five participants during normoxia (Premature Ventricular Contraction, Sinus Pause, Junctional Rhythm, Atrial Foci), which remained unchanged during apnea at AHX and HX5 (Premature Ventricular Contraction, Premature Atrial Contraction, Sinus Pause). End-inspiratory apneas were overall longer across conditions (normoxia p < 0.05; AHX p < 0.01; HX5 p < 0.001), with comparable HR responses to end-expiratory and fewer occurrences of arrhythmia. While short-term hypoxia is sufficient to elicit bradycardia during apnea, the occurrence of arrhythmias in response to apnea was not affected. These findings indicate that previously observed bradyarrhythmic events in untrained individuals at altitude only become prevalent following chronic hypoxia specificlly.

Sympathetic nervous system activity and reactivity in women with gestational diabetes mellitus.

INTRODUCTION: Gestational diabetes mellitus (GDM) is associated with vascular dysfunction. Sympathetic nervous system activity (SNA) is an important regulator of vascular function, and is influenced by glucose and insulin. The association between GDM and SNA (re)activity is unknown. We hypothesize that women with GDM would have increased SNA during baseline and during stress. METHODS: Eighteen women with GDM and 18 normoglycemic pregnant women (controls) were recruited. Muscle SNA (MSNA; peroneal microneurography) was assessed at rest, during a cold pressor test (CPT) and during peripheral chemoreflex deactivation (hyperoxia). Spontaneous sympathetic baroreflex gain was quantified versus diastolic pressure at rest and during hyperoxia. RESULTS: Age, gestational age (third trimester) and pre-pregnancy body mass index and baseline MSNA was not different among the groups. Women with GDM had a similar increase in MSNA, but a greater pressor response to CPT compared to controls (% change in MAP 17 ± 7% vs. 9 ± 9%; p = .004). These data are consistent with a greater neurovascular transduction in GDM (% change in total peripheral resistance/% change in burst frequency [BF]: 15.9 ± 30.2 vs. -5.2 ± 16.4, p = .03). Interestingly, women with GDM had a greater reduction in MSNA during hyperoxia (% change in BF -30 ± 19% vs. -6 ± 17%; p = .01). CONCLUSION: Women diagnosed with GDM have similar basal SNA versus normoglycemic pregnant women, but greater neurovascular transduction, meaning a greater influence of the sympathetic nerve activity in these women. We also document evidence of chemoreceptor hyperactivity, which may influence SNA in women with GDM but not in controls.

Physical Activity in Pregnancy Is Associated with Increased Flow-mediated Dilation.

PURPOSE: To determine the role of moderate-to-vigorous physical activity (MVPA) and sedentary behavior in flow-mediated dilation (FMD) and glucose metabolism during late pregnancy. METHODS: Seventy normotensive, euglycemic pregnant women (31.6 ± 2.9 yr) in their third trimester (28-39 wk) were recruited. After a fasted blood sample; FMD was measured (brachial artery Doppler ultrasonography, normalized for the shear stimulus [area under the curve]). Anterograde and retrograde shear rate were estimated. Physical activity (MVPA) and sedentary behavior were assessed via accelerometry for seven consecutive days (Actigraph wGT3X-BT). We categorized the women as active (>150 min·wk) or inactive (<150 min·wk) according to their accelerometry data. Data were corrected for age and gestational age. RESULTS: On average, women were sedentary 67.1% ± 8.2% of their waking hours. Active pregnant women (>150 min·wk MVPA, n = 32) engaged in 266.7 ± 99.3 min·wk MVPA, whereas inactive pregnant women (<150 min·wk MVPA, n = 38) engaged in 76.1 ± 42.5 min·wk MVPA. The FMD response (normalized to the magnitude of shear stress stimulus) was greater in active compared with inactive pregnant women (6.5 ± 4.4 a.u. vs 3.9 ± 3.5 a.u.; F = 4.619; P = 0.005). The MVPA in active pregnant women was inversely correlated with insulin concentrations (r = -0.556; P = 0.03). In inactive pregnant women, higher amounts of sedentary behavior were associated with lower amounts of retrograde shear rate (r = 0.504; P = 0.02), retrograde blood flow (r = 0.499; P = 0.02), and retrograde velocity (r = 0.508; P = 0.02) during baseline, but not correlated with the FMD response. CONCLUSIONS: Engaging in MVPA during pregnancy is associated with improved FMD and a lower insulin concentration. Sedentary behavior was not associated with FMD responses.

A review of acute responses, after-effects and chronic complications related to microneurography.

Microneurography, a technique used to detect postganglionic sympathetic nerve traffic in humans, is increasingly used to further the understanding of autonomic regulation in health and disease. The technique involves the transcutaneous insertion of a microelectrode into a peripheral nerve, following which, a variety of adverse acute responses; after-effect and chronic complications have been documented. Here, we comprehensively review the potential adverse outcomes of microneurography and provide updated quantifiable incidence rates of their occurrence within a general population. We also present recommendations for risk assessment and management of such outcomes, as well as recommendations to improve future reporting. This review aims to use objective evidence to improve the understanding of the rare, but present, adverse outcomes of microneurography.

Mechanisms of sympathetic regulation during Apnea.

Volitional Apnea produces a robust peak sympathetic response through several interacting mechanisms. However, the specific contribution of each mechanism has not been elucidated. Muscle sympathetic activity was collected in participants (n = 10; 24 ± 3 years) that performed four maximal volitional apneas aimed at isolating lung-stretch (mechanical) and chemoreflex drive: (Ainslie and Duffin ) end-expiratory breath-hold, (Ainslie et al. ) end-inspiratory breath-hold, (Alpher et al. ) prehyperventilation breath-hold, and (Andersson and Schagatay ) prehyperoxia breath-hold. A final repeated rebreathe breath-hold protocol was performed to measure the peak sympathetic response during successive breath-holds at increasing chemoreflex stress. Finally, the influence of dynamic ventilation was assessed through asphyxic rebreathe. Muscle sympathetic activity was calculated as the change in burst frequency (burst/min), burst incidence (burst/100 heart-beats), and amplitude (au) between baseline and prevolitional breakpoint. Rebreathe was analyzed at similar chemoreflex stress as inspiratory breath-hold. All maneuvers increased muscle sympathetic activity compared to baseline (P < 0.01). However, prehyperoxia exhibited a smaller increase (+22.18 ± 9.13 burst/min; +25.52 ± 11.7 burst/100 heart-beats) compared to inspiratory, expiratory, and prehyperventilation breath-holds. At similar chemoreflex strain, rebreathe sympathetic activity was blunted compared to inspiratory breath-hold (P < 0.01). Finally, muscle sympathetic activity was not different between the repeated rebreathe trials, despite elevated chemoreflex stress and lower breath-hold duration with each subsequent breath-hold. We have demonstrated an obligatory role of the peripheral, but not central, chemoreflex (prehyperventilation vs. prehyperoxia) in producing peak sympathetic responses. At similar chemoreflex stresses the act of dynamic ventilation, but not static lung stretch per se, blunts muscle sympathetic activity. Finally, similar peak sympathetic responses during successive repeated breath-holds suggest a sympathetic ceiling may exist.

Global REACH: Assessment of Brady-Arrhythmias in Andeans and Lowlanders During Apnea at 4330 m.

Background: Ascent to altitude increases the prevalence of arrhythmogenesis in low-altitude dwelling populations (Lowlanders). High altitude populations (i.e., Nepalese Sherpa) may have arrhythmias resistant adaptations that prevent arrhythmogenesis at altitude, though this has not been documented in other High altitude groups, including those diagnosed with chronic mountain sickness (CMS). We investigated whether healthy (CMS-) and CMS afflicted (CMS +) Andeans exhibit cardiac arrhythmias under acute apneic stress at altitude. Methods and Results: Electrocardiograms (lead II) were collected in CMS- (N = 9), CMS + (N = 8), and Lowlanders (N = 13) following several days at 4330 m (Cerro de Pasco, Peru). ECG rhythm and HR were assessed at both rest and during maximal volitional apnea. Both CMS- and CMS + had similar basal HR (69 ± 8 beats/min vs. 62 ± 11 beats/min), while basal HR was higher in Lowlanders (77 ± 18 beats/min; P < 0.05 versus CMS +). Apnea elicited significant bradycardia (nadir -32 ± 15 beats/min; P < 0.01) and the development of arrhythmias in 8/13 Lowlanders (junctional rhythm, 3° atrio-ventricular block, sinus pause). HR was preserved was prior to volitional breakpoint in both CMS- (nadir -6 ± 1 beat/min) and CMS + (1 ± 12 beats/min), with 2/17 Andeans developing arrhythmias (1 CMS+ and 1 CMS-; both Premature atrial contraction) prior to breakpoint. Conclusion: Andeans showed an absence of arrhythmias and preserved HR response to volitional apnea at altitude, demonstrating that potential cardio-resistant adaptations to arrhythmogenesis exist across permanent HA populations. Acclimatized Lowlanders have further demonstrated an increased prevalence of arrhythmias at altitude.

Peripheral chemoreceptor deactivation attenuates the sympathetic response to glucose ingestion.

Acute increases in blood glucose are associated with heightened muscle sympathetic nerve activity (MSNA). Animal studies have implicated a role for peripheral chemoreceptors in this response, but this has not been examined in humans. Heart rate, cardiac output (CO), mean arterial pressure, total peripheral conductance, and blood glucose concentrations were collected in 11 participants. MSNA was recorded in a subset of 5 participants via microneurography. Participants came to the lab on 2 separate days (i.e., 1 control and 1 experimental day). On both days, participants ingested 75 g of glucose following baseline measurements. On the experimental day, participants breathed 100% oxygen for 3 min at baseline and again at 20, 40, and 60 min after glucose ingestion to deactivate peripheral chemoreceptors. Supplemental oxygen was not given to participants on the control day. There was a main effect of time on blood glucose (P < 0.001), heart rate (P < 0.001), CO (P < 0.001), sympathetic burst frequency (P < 0.001), burst incidence (P = 0.01), and total MSNA (P = 0.001) for both days. Blood glucose concentrations and burst frequency were positively correlated on the control day (r = 0.42; P = 0.03) and experimental day (r = 0.62; P = 0.003). There was a time × condition interaction (i.e., normoxia vs. hyperoxia) on burst frequency, in which hyperoxia significantly blunted burst frequency at 20 and 60 min after glucose ingestion only. Given that hyperoxia blunted burst frequency only during hyperglycemia, our results suggest that the peripheral chemoreceptors are involved in activating MSNA after glucose ingestion.

Chemoreflex mediated arrhythmia during apnea at 5,050 m in low- but not high-altitude natives.

Peripheral chemoreflex mediated increases in both parasympathetic and sympathetic drive under chronic hypoxia may evoke bradyarrhythmias during apneic periods. We determined whether 1) voluntary apnea unmasks arrhythmia at low (344 m) and high (5,050 m) altitude, 2) high-altitude natives (Nepalese Sherpa) exhibit similar cardiovagal responses at altitude, and 3) bradyarrhythmias at altitude are partially chemoreflex mediated. Participants were grouped as Lowlanders ( n = 14; age = 27 ± 6 yr) and Nepalese Sherpa ( n = 8; age = 32 ± 11 yr). Lowlanders were assessed at 344 and 5,050 m, whereas Sherpa were assessed at 5,050 m. Heart rate (HR) and rhythm (lead II ECG) were recorded during rest and voluntary end-expiratory apnea. Peripheral chemoreflex contributions were assessed in Lowlanders ( n = 7) at altitude after 100% oxygen. Lowlanders had higher resting HR at altitude (70 ± 15 vs. 61 ± 15 beats/min; P < 0.01) that was similar to Sherpa (71 ± 5 beats/min; P = 0.94). High-altitude apnea caused arrhythmias in 11 of 14 Lowlanders [junctional rhythm ( n = 4), 3° atrioventricular block ( n = 3), sinus pause ( n = 4)] not present at low altitude and larger marked bradycardia (nadir -39 ± 18 beats/min; P < 0.001). Sherpa exhibited a reduced bradycardia response during apnea compared with Lowlanders ( P < 0.001) and did not develop arrhythmias. Hyperoxia blunted bradycardia (nadir -10 ± 14 beats/min; P < 0.001 compared with hypoxic state) and reduced arrhythmia incidence (3 of 7 Lowlanders). Degree of bradycardia was significantly related to hypoxic ventilatory response (HVR) at altitude and predictive of arrhythmias ( P < 0.05). Our data demonstrate apnea-induced bradyarrhythmias in Lowlanders at altitude but not in Sherpa (potentially through cardioprotective phenotypes). The chemoreflex is an important mechanism in genesis of bradyarrhythmias, and the HVR may be predictive for identifying individual susceptibility to events at altitude. NEW & NOTEWORTHY The peripheral chemoreflex increases both parasympathetic and sympathetic drive under chronic hypoxia. We found that this evoked bradyarrhythmias when combined with apneic periods in Lowlanders at altitude, which become relieved through supplemental oxygen. In contrast, high-altitude residents (Nepalese Sherpa) do not exhibit bradyarrhythmias during apnea at altitude through potential cardioprotective adaptations. The degree of bradycardia and bradyarrhythmias was related to the hypoxic ventilatory response, demonstrating that the chemoreflex plays an important role in these findings.