Respiratory control at high altitude: The chemoreceptor as a paragon of plasticity

The mechanisms underlying time-dependent hyperventilation at high altitude (acclimatization-VAH) and its continuation upon return to sea level (deacclimatization-DAH) have fascinated physiologists throughout the last 100+ years. The sojourner to high altitude depends critically on VAH as a first line of defence against environmental hypoxaemia, but also must tolerate the associated increased work of breathing and perceptions of excessive respiratory effort during exercise. In the late 1970s, Ralph Kellogg (Kellogg, 1977) evaluated how history repeated itself in the testing of hypotheses proposed by J. S. Haldane in 1919 and by John Severinghaus and Robert Mitchell in the 1960s. These insightful and then widely accepted hypotheses focused on progressive ventilatory stimulation at high altitudes via adaptive, time-dependent restoration of [H+] – first in the arterial plasma (Haldane) and later in the CSF (Severinghaus) – combined with constant sensory input from the hypoxic carotid chemoreceptors as contributors to VAH, followed by acidification of central chemoreceptors exposed to CSF to drive continued hyperventilation (DAH) upon return to normoxia. Eventually, evidence accumulated to show that both concepts failed to explain either phenomenon (VAH or DAH) (Dempsey et al., 2014; Kellogg, 1977). To the contrary, studies in humans and other species throughout the 1970s demonstrated that alkalinity persisted and to equal extents in both arterial plasma and CSF throughout altitude sojourn – and thus the level of chemoreceptor stimuli appeared to be more a consequence, rather than a mediator, of VAH and DAH (Dempsey et al., 2014; Kellogg, 1977). Then, beginning in the 1980s, a series of animal studies using carotid body (CB) denervation, carotid sinus nerve (CSN) recordings, CB morphology and especially the use of prolonged extracorporeal perfusion of the isolated CB in the unanaesthetized goat – the last by Gerald Bisgard – revealed: (1) that exposure of the CB to hypoxaemia elicited time-dependent increases in tonic carotid sinus nerve sensory activity, glomus cell number, upregulation of CB neuromodulators and VAH; (2) following acclimatization, returning to normoxia resulted in elevated tonic CSN activity – relative to chronic normoxia – and hyperventilation persisted; and (3) time-dependent VAH and DAH required prolonged CB stimulation specific to hypoxaemia and did not occur if only extra-CB hypoxic sensitive areas (i.e. in the CNS and elsewhere) were exposed to chronic hypoxia (summarized in Dempsey et al., 2014; He et al., 2006). Up to the present, the question remained whether these findings in animal models pointing to a major role for enhanced CB tonic activity in both VAH and DAH also pertained to the human sojourner? Now, Getu and his western Canadian colleagues (Getu et al., 2025) have shed considerable new light on these contributions from upregulation of tonic CB activity by quantifying transient ventilatory responses to <1 min duration of hyperoxia in healthy humans. They showed significant augmentation in the transient reductions in ventilation (relative to those in chronic normoxia) at rest and during moderate-intensity exercise after 13 days at 3800 m and also 3 days following removal of the hypoxic stimulus during return to normoxia. Importantly, these augmented effects of acute hyperoxia occurred despite accompanying reductions in eupnoeic P aC O 2 P_aCO₂ and H+ – both of which by themselves would constrain tonic CSN activity. In addition to the novelty of their findings in humans there is much to like about the Getu et al. study design, including the choice of transient rather than longer hyperoxic exposures which are commonly employed but are known to elicit increased reactive oxygen species (ROS) production and ventilatory stimulation rather than serve only to reduce tonic CB activity, their use of multiple acute hyperoxia trials to capture more reliable mean values to quantify transient ventilatory decline, and their care to compare responses during exercise between chronic normoxia and hypoxia using both absolute and relative work intensities. On the limitations side, we note that including additional measurements of CB tonicity throughout the sojourn at 3800 m – rather than only at 13 days – would have revealed the contribution of CB tonicity to the time-dependent acclimatization process. Further, measurements of arterial blood gases and V ̇ C O 2 V_CO₂ during and following sojourn at 3800 m would have improved the capability for identifying periods of hypo- and hyperventilation. The common practice of comparing absolute VE values alone – as used here – does not accomplish this goal. In summary, Getu et al. have revealed a significant contribution to VAH and DAH at rest and exercise in humans from increased tonic CB activity resulting from sustained hypoxic exposure. We wonder if this same increase in CB tonicity contributes significantly to enhanced sympathetic nerve activity reported during and following chronic hypoxic exposure in sojourning humans and, on the other hand, if a relatively suppressed CB tonicity explains the constrained ventilatory response to exercise in hypoxia in the long-term resident of high altitude compared to the sojourner (Dempsey et al., 2014). Further, additional significant contributions to both VAH and DAH also appear to be due to a translation of increasing carotid chemoreceptor activity to elevate the gain of central respiratory motor output mechanisms, as demonstrated in rodents and humans via the enhanced ventilatory response to pharmacological or electrical CB stimulation during chronic hypoxia. This enhanced CNS response to CB sensory input via chronic hypoxaemia was associated with neuronal hyperactivity at the levels of the paraventricular nucleus and rostral ventrolateral medulla (Dempsey et al., 2014). Finally, we point out that the increased tonic CB activity as currently revealed in healthy human sojourners has also recently been reported to be highly prevalent in such chronic disease states as congestive heart failure, chronic obstructive pulmonary disease, hypertension and sleep apnoea, providing significant contributions to elevated sympathetic vasoconstrictor activity, sleep disordered breathing and exercise hyperventilation in many of these patients (Kamra et al., 2025). We congratulate Getu and his collaborators for providing a much-needed solution to an important, long-standing mystery of human bioadaptability and for their insight in recognizing the critical importance of assessing commonly neglected eupnoeic (and hyperpnoeic) tonic drives to breathe. 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 declare no conflict of interest. J.D. conceived or designed the work; drafted the work or revised it critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. None.