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 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.