Jonathan Patrick Moore

High‐altitude hypoxia elicits several profound physiological responses, including substantial increases in muscle sympathetic nerve activity (MSNA); however, the association of this heightened MSNA with cardiovascular and cerebrovascular haemodynamics remains unclear in lowlanders and indigenous highlander populations. We hypothesized that at high altitude resting MSNA would be associated with resting cardiovascular and cerebrovascular haemodynamics in lowlanders ( n = 26), and Sherpa ( n = 8) and Andean ( n = 23) indigenous highlanders. Data were retrospectively analysed from two separate high‐altitude expeditions to Nepal (2016; 5050 m) and Peru (2018; 4300 m). We assessed resting MSNA via radial or peroneal microneurography, and measured , heart rate, mean arterial pressure, brachial artery blood flow and endothelial function, and internal carotid and vertebral artery diameter, velocity, and blood flow. Resting MSNA demonstrated limited, population‐specific associations with vascular haemodynamics. Lowlanders showed the most consistent relationships, including positive associations between MSNA and heart rate, vertebral artery diameter and blood flow, and internal carotid artery velocity, while Sherpa and Andean highlanders showed few systemic or cerebrovascular associations with MSNA. No relationship was observed between MSNA and , brachial artery blood flow or endothelial function across populations. Sensitivity analysis confirmed that most directional relationships were robust to the removal of influential participants, although some associations, including the negative relationship between MSNA and brachial artery blood flow in Sherpa, were attenuated. These data highlight that single time‐point, resting MSNA may have limited predictive value for cardiovascular and cerebrovascular haemodynamics at high altitude within these specific populations; however, these data should be interpreted with caution, given the small cross‐sectional sample sizes.

This study provides insight into the mechanisms involved in the sympathetic control of blood pressure at rest and in response to autonomic stress in different populations at high altitude. We demonstrate that resting blood pressure regulation is mediated primarily through α-adrenergic mechanisms in both lowlanders and Indigenous Andean highlanders at high altitude. However, pressor responses to apneic stress appear to be regulated by an alternative mechanism, particularly in highlanders who require less sympathetic activation.

Sympathetic activation arising from both the peripheral chemoreflex in hypoxia and muscle metaboreflex during exercise mediate an increase in pulmonary artery systolic pressure (PASP). We tested the hypothesis that coactivation of the chemoreflex and metaboreflex would augment the PASP response, as has been shown previously for heart rate and ventilation. We conducted two experimental studies: (i) a laboratory study ( n = 15) in normoxia and acute isocapnic hypoxia (45 mmHg ) and (ii) a field study ( n = 14) at sea level (344 m) and after 4–6 days of acclimatisation to high altitude (3800 m). In both studies, participants performed 3 min of isometric handgrip at 30% of maximal voluntary contraction followed by 3 min of post‐exercise circulatory occlusion (PECO). PASP was assessed via transthoracic echocardiography. In Study 1, isocapnic hypoxia reduced (44.3 ± 5.3 mHg; P  < 0.001) but maintained (36.8 ± 2.3; P = 0.931) compared to normoxia. Both PECO (+5.3 ± 5.3 mmHg; P = 0.044) and hypoxia (+4.0 ± 2.0 mmHg; P = 0.016) elevated PASP from baseline, whereas combined hypoxic PECO further increased PASP (+8.4 ± 3.7 mmHg, P = 0.009). These responses were unaltered following acclimatisation to 3800 m in Study 2. Importantly, irrespective of the duration of hypoxic exposure and thus the degree of carotid body stimulation, the sum of the individual responses to hypoxia and PECO was not different compared to the combined hypoxic PECO stimulus in either acute ( P = 0.806) or chronic hypoxia ( P = 0.896). Therefore, although both chemoreflex activation with hypoxia and metaboreflex activation with PECO increase PASP, their coactivation results in an additive, not synergistic, response. image Key points: Activation of the peripheral chemoreflex (e.g. hypoxia) and muscle metaboreflex (e.g. exercise) both increase heart rate, arterial pressure, ventilation and pulmonary pressure. There is evidence of an augmented muscle metaboreflex response for heart rate and ventilation in acute hypoxia, but whether the same effect is seen in the pulmonary vasculature has not been explored. We completed two experimental studies where pulmonary artery systolic pressure (PASP) was assessed during post‐exercise circulatory occlusion (PECO) in response to acute isocapnic hypoxia and following acclimatisation to high altitude hypoxia (3800 m). Independent activation of the chemoreflex at rest and metaboreflex during PECO elevated PASP in both acute and chronic hypoxia. When combined, metaboreflex activation with PECO and chemoreflex activation with hypoxia have an additive but not interactive effect on PASP, irrespective of the duration of hypoxic exposure.

Hot‐water immersion (HWI) has been shown to reduce 24 h ambulatory systolic blood pressure in hypertensive adults and might represent a preventative strategy for maintaining cardiovascular health in normotensive adults. The purpose of this study was to determine the time course of post‐HWI hypotension and test the hypothesis that a single HWI reduces subsequent 24 h ambulatory blood pressure (ABP) in healthy adults. In a randomized, crossover design, 23 participants [7 female and 16 male; 26 (4) years of age] underwent blood pressure assessments before, during, immediately after and for 24 h following 60 min of immersion in 40.4°C hot water (HWI) and a thermoneutral (24.7°C) air control (CON). Thermal and cardiovascular variables were assessed during and for 60 min after the intervention, after which the participants were instrumented with an ABP monitor for 24 h. At min 60 of the interventions, body core temperature was higher [CON, 36.93 (0.28)°C; HWI, 38.83 (0.19)°C; P < 0.001] and diastolic ( P  < 0.001) and mean ( P  < 0.001) arterial blood pressure lower in HWI than CON. HWI increased the diastolic blood pressure nocturnal dip compared with CON [CON, 15.4 (7.2)%; HWI, 19.1 (7.4)%; P = 0.022]. No differences in ABP were observed for 24 h, daytime or nighttime systolic, diastolic or mean arterial blood pressures (all P  > 0.05). In conclusion, HWI transiently decreased mean arterial blood pressure and diastolic blood pressure for ≤20 min post‐heating and increased the subsequent nocturnal diastolic blood pressure dip in healthy adults.

Sympathetic nervous system activation is a hallmark of high‐altitude hypoxia, yet the afferent mechanisms remain incompletely defined. We examined the relative contributions of pulmonary arterial mechanoreceptors and carotid chemoreceptors – two excitatory pathways co‐activated by hypoxia – to sustained sympathoexcitation at altitude. Nine healthy lowlanders (27 ± 7 years, three female) were studied after 6–9 days at 3800 m under four conditions: (1) control, (2) inhaled nitric oxide (iNO, 40 ppm) to reduce pulmonary arterial pressure, (3) low‐dose dopamine infusion (2 µg kg ^{− 1} min ^{− 1} ) to suppress the carotid chemoreflex, and (4) combined iNO and dopamine. End‐tidal oxygen and carbon dioxide were kept constant throughout. We assessed muscle sympathetic nerve activity (MSNA), systemic haemodynamics, ventilation and pulmonary arterial systolic pressure. iNO reduced pulmonary arterial pressure and significantly decreased MSNA (condition 1: 25 ± 8 bursts min ⁻¹ vs. condition 2: 21 ± 7 bursts min ⁻¹ ; P = 0.0415), whereas dopamine infusion reduced ventilation ( P < 0.001) without a consistent effect on MSNA (condition 1: 25 ± 8 bursts min ⁻¹ vs. condition 3: 28 ± 13 bursts min ⁻¹ ; P = 0.112). Combined intervention produced a small reduction in sympathetic nerve activity (condition 3: 28 ± 13 bursts min ⁻¹ vs. condition 4: 26 ± 13 bursts min ⁻¹ ; P = 0.0643), likely due to baroreflex engagement. These findings confirm that unloading pulmonary arterial pressure attenuates MSNA, reinforcing the role of pulmonary mechanoreceptors in high altitude sympathoexcitation. Attempts to isolate a carotid chemoreflex contribution were likely confounded by dopamine's haemodynamic effect, which introduced variability and limited the specificity of this intervention. Thus, interpretation of this component remains exploratory, highlighting the integrative complexity of reflex control of high altitude sympathoexcitation in humans.

This study examined how sex influences blood flow during exercise at altitude and relative contributions of adrenergic mechanisms. Thirteen participants (8 M/5F) were tested at low and high altitude (days 3–11). Participants performed rhythmic handgrip for 3 min at 25% maximal voluntary contraction during local infusions of saline, propranolol (β‐adrenergic blockade), and phentolamine with propranolol (α‐β‐adrenergic blockade). Doppler ultrasound was used to examine brachial artery blood flow (FBF) and calculate forearm vascular conductance (FVC). Resting FBF and FVC were higher in males compared to females across all conditions ( p = 0.024; p = 0.025, respectively). Blockade condition significantly altered FBF and FVC ( p < 0.001 for both) but there was no effect of altitude ( p = 0.330; p = 0.718, respectively). During exercise, ΔFBF was influenced by condition ( p < 0.001), but not by sex ( p = 0.696) or altitude ( p = 0.813). Similarly, ΔFVC was different across conditions (control: 9.4 ± 2.3 mL/min/mmHg/FAV; β‐blockade: 11.4 ± 12.8 mL/min/mmHg/FAV; α‐β‐blockade: 3.9 ± 1.1 mL/min/mmHg/FAV; p < 0.001), with no effect of sex ( p = 0.646) or altitude ( p = 0.889). These results suggest males and females do not respond differently to exercise at altitude, and light‐intensity exercise hyperemia may be preserved during early acclimatization. α‐adrenergic receptors appear important for exercising blood flow, but β‐adrenergic receptors may not be critical in this response.

High‐altitude acclimatisation increases muscle sympathetic nerve activity (MSNA) via activation of the arterial chemoreflex, pulmonary arterial baroreceptors and resetting of the sympathetic vascular baroreflex. However attempting to silence these mechanisms only partially normalises MSNA, implicating other contributory mechanisms. Increased oxidant production may modulate central sympathetic outflow, while potentially modifying chemosensitivity and vasomotor signalling to the peripheral and pulmonary vasculature. Therefore we tested the hypothesis that blunting oxidative stress would reduce MSNA at high altitude. MSNA (microneurography of the peroneal nerve), continuous arterial pressure (photoplethysmography), vascular tone (duplex ultrasound of the brachial artery), pulmonary artery systolic pressure (PASP, echocardiography) and carotid body tonic activity (1‐min hyperoxia) were measured pre‐ and post‐ascorbic acid infusion (200 mg/min for 15‐min and then 40 mg/min) in healthy lowlanders ( n = 15) after 3–7 days of high‐altitude exposure (3800 m). Ascorbic acid infusion improved the redox environment, determined by an increase in whole cell nuclear factor erythroid 2‐related factor 2 activity ( P = 0.005). Post‐infusion MSNA burst frequency (−2 ± 2 bursts/min, P = 0.007) and incidence (−5 ± 4 bursts/100 heartbeats (HB), P = 0.006) decreased. However the infusion increased mean arterial (9 ± 4 mmHg, P ≤0.001), systolic (11 ± 8 mmHg, P  ≤ 0.004) and diastolic pressure (7 ± 4 mmHg, P  ≤ 0.001) and total peripheral resistance ( P = 0.013) concomitantly with a reduction in brachial diameter (−0.12 ± 0.14 mm, P = 0.002). Carotid body tonic activity ( P = 0.247) and PASP ( P = 0.365) remained unchanged by ascorbic acid infusion. In conclusion improving the antioxidant environment lowered MSNA at high altitude; however the small reduction is likely a consequence of the increased blood pressure secondary to the blunting of hypoxic vasodilation rather than a direct effect on sympathetic outflow. image Key points: High‐altitude acclimatisation increases muscle sympathetic nerve activity (MSNA) from sea level values. Pulmonary artery systolic pressure (PASP), peripheral arterial chemoreflex and high altitude‐induced hypovolaemia are involved in the increase in MSNA; however current evidence indicates additional contributory mechanisms. Hypoxia associated with high altitude results in an increase in the production of reactive oxygen species (ROS), which may be sympathoexcitatory. Therefore we tested the hypothesis that improving the redox environment using an ascorbic acid infusion would lower sympathetic nerve activity. After the infusion, sympathetic nerve activity was reduced alongside an increase in vascular tone and elevation in blood pressure. The reduction in MSNA occurred independently of changes in PASP and chemoreflex activity. Our findings demonstrate that ROS elevates sympathetic nerve activity at high altitude; however this reduction is likely a result of the elevated blood pressure after the blunting of hypoxic vasodilation.

To test the hypothesis that hot water immersion (HWI) improves cerebrovascular function via shear‐mediated mechanisms, this study determined cerebrovascular reactivity to carbon dioxide () before and after 60 min of 39°C HWI and a 21°C air control (CON) in 15 healthy participants. Thermal and haemodynamic variables were assessed throughout the trials, and was determined by a 4‐min inhalation of hypercapnic gas (6% CO₂, 21% O₂, N₂ balance) and the assessment of internal carotid artery (ICA) blood flow by duplex ultrasound before and 45 min after HWI and CON. At 60 min of the interventions, core body temperature (CON, 36.9 ± 0.3°C; HWI, 38.1 ± 0.3°C, P < 0.01), heart rate (P < 0.01) and ICA conductance (P < 0.01) were higher in HWI than CON, while, mean arterial blood pressure was lower (CON, 82 ± 9 mmHg; HWI 65 ± 8 mmHg, P < 0.01). No differences were observed for ICA diameter, ICA blood velocity, ICA shear rate and ICA blood flow between HWI and CON (all P > 0.05). ICA did not change after either CON (pre: 13.9 ± 9.2 to post: 11.3 ± 6.1 mL min⁻¹ mmHg⁻¹) or HWI (pre: 14.6 ± 7.9 to post: 10.9 ± 5.4 mL min⁻¹ mmHg⁻¹; Interaction P = 0.65). In conclusion, HWI reduced blood pressure and increased ICA conductance (i.e. autoregulation) to maintain blood flow to the brain; however, HWI did not influence subsequent cerebrovascular function, as assessed by .

Central command, muscle afferent feedback and arterial baroreceptors all contribute to sympathetic vasoconstrictor activity during moderate‐intensity dynamic exercise in humans; however, whether a causal link exists between pulmonary arterial mechanoreceptors and sympathetic outflow directed to inactive skeletal muscle (muscle sympathetic nerve activity, MSNA) remains to be explored. Twelve participants (28 ± 7 years, 2 females) performed two 6 min exercise bouts (heart rate ∼ 120∙beats∙min⁻¹) in hypoxia (FiO_2 = 12.5%) to elevate pulmonary artery pressure (PAP) above normal, whilst MSNA (microneurography), systemic blood pressure (photoplethysmography, BP), oxygen saturation (SpO₂) and minute ventilation (V_E) were measured continuously. Systolic PAP was estimated using Doppler echocardiography. In one trial nitric oxide was added to the inhaled air (iNO, 40 parts per million) to selectively dilate the pulmonary vasculature and reduce exercise PAP. MSNA burst frequency was supressed (30 ± 9 vs. 34 ± 9 bursts∙min⁻¹; p = 0.03) when exercise systolic PAP was lowered (36.8 vs. 42.9 ± 8 mmHg; p = 0.02). MSNA burst incidence (index of sympathetic baroreflex operating point) was reduced (25 ± 8 vs. 28 ± 9 bursts∙100 heartbeats⁻¹; p = 0.03) without any change in corresponding diastolic BP or spontaneous baroreflex gain. Mean BP, SpO₂ and V_E did not differ between trials. Together these data support a mechanistic link between pulmonary arterial mechanoreceptor activation and neurocirculatory control during hypoxic exercise. The effect of pulmonary arterial mechanoreceptor activity on exercise‐induced sympathetic activation and baroreflex resetting may have consequences for sympathetic vasomotor outflow (dys)regulation in health and disease where PAP is elevated. image Key points: Pulmonary arterial pressure increases proportionally to cardiac output during dynamic exercise; this pressure rise may contribute to excitation of sympathetic vasoconstrictor activity directed to skeletal muscle (muscle sympathetic nerve activity, MSNA) via stimulation of pulmonary arterial mechanoreceptors. In this study addition of nitric oxide to hypoxic inspired air (FiO₂ = 12.5%) reduced pulmonary arterial pressure during sub‐maximal cycling exercise; this coincided with reduced MSNA burst frequency (vasoconstrictor outflow) and burst incidence (operating point for baroreflex control of vasoconstrictor outflow). These findings demonstrate that a signal from pulmonary arterial mechanoreceptors is involved in sympathoexcitation during hypoxic exercise. Furthermore this mechanism could be relevant clinically in pulmonary and cardiac diseases associated with pulmonary hypertension and exaggerated sympathoexcitation during exercise.