Microneurography on the mountain: Evaluating the role of ROS in mediating sympathoexcitation at altitude

High-altitude (>2500 m) acclimatization in humans is characterized by pronounced sympathoexcitation, as evidenced by microneurographic assessments of resting multiunit postganglionic sympathetic discharge, commonly known as muscle sympathetic nerve activity (MSNA) (Sander, 2016). In the early phase of altitude acclimatization, the increase in MSNA is driven primarily by changes in MSNA burst frequency (therefore linked with the increase in heart rate) and is considered a compensatory response designed to counter the vasodilatory effects of hypoxaemia and to increase oxygen delivery; however, the precise mechanisms responsible for this elevation remain incompletely understood (Simpson et al., 2024). While tempting to attribute the rise in sympathetic activity to elevated peripheral chemoreceptor tonic activity caused by the high-altitude–mediated fall in arterial oxygen levels, past work has shown that hyperoxic breathing produces only modest reductions in MSNA after 10–20 days at 5050 m (Simpson et al., 2019). Additional work has established supporting roles for pulmonary baroreceptor activation secondary to hypoxic pulmonary vasoconstriction and hypovolemia-induced unloading of arterial baroreceptors (Simpson et al. 2024). Consideration of these independent mechanisms only accounts for partial normalization of elevated MSNA, highlighting a key knowledge gap. Hypoxia increases the production of reactive oxygen species (ROS), which can directly or indirectly increase central sympathetic outflow (Simpson et al., 2024). Elevated oxidative stress is involved in mediating elevations in resting MSNA in patients with untreated essential hypertension (Bruno et al., 2012). However, whether elevated ROS is involved in increasing MSNA at high altitude has not been studied. In this issue of The Journal of Physiology, Corr & colleagues (2025) sought to determine whether blunting ROS through the administration of high-dose intravenous infusion of ascorbic acid (200 mg/min for 15 min, then 40 mg/min maintenance) would reduce MSNA during a high-altitude sojourn. They studied 15 healthy lowlanders after 3–7 days of acclimatization at 3800 m and hypothesized that ROS contribute to high-altitude sympathoexcitation. Importantly the study also measured changes in pulmonary arterial systolic pressure, peripheral chemoreceptor tonic activity and peripheral vascular tone to enable an integrated examination of potential sympathoexcitatory mechanisms before and after ascorbic acid infusion. The results of the study showed that ascorbic acid led to an increase in anti-oxidant capacity, as demonstrated by rising levels of nuclear factor E2-related factor 2 (Nrf2), the master regulator of redox homeostasis. At the same time MSNA burst frequency and incidence decreased, accompanied by increases in peripheral vascular resistance and arterial pressure, and decreases in brachial artery diameter. Notably the reduction in MSNA occurred independently of changes in pulmonary arterial systolic pressure, assessed using echocardiography, or peripheral chemoreflex tonic activity, determined using a series of transient hyperoxic (100% oxygen) tests. Despite the reduction in MSNA the authors concluded that the attenuated sympathetic outflow is likely not a primary consequence of diminished ROS but instead occurs secondary to a baroreflex-mediated response to increases in arterial pressure. This interpretation supports a model where ROS function as signalling molecules to promote hypoxic vasodilation. When this vasodilatory signal is attenuated by systemic ascorbic acid infusion, peripheral vascular tone and arterial pressure increase, activating the arterial baroreflex to suppress MSNA. The study is strengthened by several thoughtful methodological choices. Notably, the authors used brief (∼1 min) hyperoxic trials rather than prolonged hyperoxia or dopamine infusion. Prolonged hyperoxia elevates oxidative stress and can stimulate increases in MSNA (Prasad et al., 2020). By using multiple brief (4-5 bouts) hyperoxic trials to quantify the mean ventilatory nadir, the authors obtained a robust index of tonic peripheral chemoreflex activity while minimizing additional ROS generation. This approach also circumvents the haemodynamic changes associated with dopamine infusion, which induces vasodilation and baroreflex-mediated sympathoexcitation independent of chemoreceptor inhibition, which could complicate the interpretation of sympathetic outcomes (Simpson et al., 2024). Several considerations also warrant acknowledgement and may influence the generalizability of results. All measurements were collected during the relatively early and heterogeneous acclimatization window (3–7 days). It remains unclear whether the contribution of ROS to vascular tone and sympathetic regulation is similar during early acclimatization and late acclimatization (>10 days), when increases in MSNA peak and plateau (Simpson et al., 2024). Persistent elevations in MSNA are also observed up to 5 days following return to sea-level after high-altitude exposure (Sander, 2016). The assessment of Nrf2 provides insight into the capacity of ascorbic acid to modulate systemic redox status; however it is not specific to understanding whether oxidative stress is altered in brainstem regions involved in regulating sympathetic outflow. This distinction is important to resolve how ROS mediates sympathoexcitation in chronic disease states (Bruno et al., 2012), but not at high altitude in healthy adults. Examining the time-course of changes in ROS may help better understand its role in regulating vascular tone. Finally only 4 of the 15 participants were female, limiting robust evaluation of potential sex-specific differences in the mechanisms underlying hypoxic sympathoexcitation and the regulation of vascular tone. In summary the study by Corr and colleagues highlights the importance of conducting field-based research to help address fundamental questions in human physiology. The results provide another clue towards understanding whether oxidative stress contributes to sympathoexcitation during altitude-mediated hypoxic exposure. Their findings support that ROS act predominantly as mediators of hypoxic vasodilation, influencing MSNA indirectly through their effects on vascular tone and arterial baroreflex loading, rather than a central sympathoexcitatory agent. This novel view of redox biology during high-altitude sojourn will stimulate new directions for research into the complex interaction between ROS, vascular regulation and autonomic control in both physiological and pathological contexts. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. The authors declared no competing interests. J.S.T., N.I.M. and P.J.M. were responsible for the conception or design of the work, drafting the work or revising it critically for important intellectual content, and approving the final version of the manuscript submitted for publication. All authors agree to be accountable for all aspects of the work. J.S.T. was supported by a Natural Sciences and Engineering Research Council of Canada (NSERC) Canadian Graduate Student Master's award. N.I.M. was supported by an Ontario Graduate Scholarship. P.J.M. was supported a NSERC Discovery grant.