Altitude-induced plasticity of respiratory central-peripheral chemoreflex interaction

Stable breathing depends on the integrated action of central and peripheral chemoreceptors, but the nature of this interaction in humans and its physiological importance remain controversial. Previous studies reported additive, hypo-additive and hyper-additive responses across species, preparations and protocols. Here, we used a novel method to quantify peripheral chemoreflex sensitivity across graded levels of central chemoreceptor activation to test whether central-peripheral chemoreceptor interaction in awake humans is fixed or state dependent. At low altitude, the form of interaction varied across individuals, with most showing additive responses (12/17) and a substantial subset showing hypo-additivity (5/17). After 7-10 days of acclimatization to 3500 m, all five hypo-additive individuals became additive, and four additive participants became hyper-additive. This shift in interaction towards hyper-additivity provides the first evidence that central-peripheral chemoreceptor integration is plastic. Plasticity during wakefulness was not associated with individual differences in central sleep apnoea severity at high altitude. Thus, our findings confirm that central-peripheral chemoreceptor interaction differs among individuals and suggest that the form of interaction can be reshaped by hypobaric hypoxic stress. KEY POINTS: How central and peripheral chemoreceptor drives to breathe interact in humans and whether this process is plastic remains uncertain. We quantified peripheral chemoreflex sensitivity to hypoxia (PChS) across graded levels of central chemoreceptor activation at low altitude and after 7-10 days of high-altitude exposure (3500 m). Seventeen participants performed repeated modified rebreathing tests with end-tidal $P_{O_2}$ fixed at 150 (hyperoxia), 60 and 45 mmHg (hypoxia). PChS was computed at 1 mmHg intervals of end-tidal $P_{C{O}_2}$ ( $P_{\mathrm{ETC}{O}_2}$ ) from linear regression of the difference in ventilation between hypoxic and hyperoxic conditions vs. calculated arterial oxygen saturation (ScO₂) (L·min^-1·mmHg^-1·%ScO₂ ^-1). At low altitude, PChS increased with $P_{\mathrm{ETC}{O}_2}$ in all individuals; the relationship was linear (no interaction) in 12 participants, and 5 showed hypo-additivity. After acclimatization, central and peripheral chemoreflex sensitivities increased. All hypo-additive individuals became additive; four additive individuals became hyper-additive. Central-peripheral chemoreceptor interaction is plastic in humans and can shift towards hyper-additivity with sustained hypobaric hypoxia.