J Physiol. 2026 Aug 31. doi: 10.1113/JP291647. Online ahead of print.
ABSTRACT
Ventilatory long-term facilitation (LTF) is a persistent increase in minute ventilation ( V ̇ I ) elicited by acute intermittent hypoxia (AIH) that outlasts the stimulus duration. In humans, AIH-induced ventilatory LTF is dependent upon a sustained background of mild hypercapnia. It is not known whether changes in CO2 chemoreflex sensitivity contribute to ventilatory LTF. We hypothesised that hypercapnic AIH increases the sensitivity of peripheral, but not central, chemoreflex responses to CO2. Twenty healthy adults (age = 25 ± 4 years) completed the study. On days 1 and 2, pulmonary function testing and three hyperoxic modified CO2 rebreathing tests were performed to determine baseline central CO2 chemoreflex sensitivity. On days 3 and 4, participants were randomly assigned to hypercapnic AIH or mild hypercapnia alone. On day 5, 16 participants returned to the laboratory to complete a time-matched control (CTRL). Two CO2 rebreathing tests were performed approximately 45 and 75 min post-trial. Transient CO2 tests were used to quantify peripheral CO2 chemoreflex sensitivity pre- and post-trial. Twenty minutes after hypercapnic AIH, V ̇ I was increased 32 ± 22% versus baseline, which was significantly greater than CTRL (P < 0.001), demonstrating the presence of ventilatory LTF. Central CO2 chemoreflex sensitivity (P = 0.880) and the ventilatory recruitment threshold (P = 0.425) were unchanged after all trials. Peripheral CO2 chemoreflex sensitivity was increased 41 ± 46% after hypercapnic AIH, which was significantly greater than CTRL (P < 0.001). We conclude that enhanced peripheral CO2 chemoreflex sensitivity contributes to ventilatory LTF induced by hypercapnic AIH in awake humans. KEY POINTS: In awake humans, induction of ventilatory long-term facilitation (LTF) by acute intermittent hypoxia (AIH) requires a continuous background of mild hypercapnia; thus, ventilatory LTF may arise from increases in central and/or peripheral CO2 chemoreflex sensitivities. Central and peripheral CO2 chemoreflex sensitivity were assessed by modified hyperoxic CO2 rebreathing and transient CO2 tests, respectively, before and after hypercapnic AIH, sustained hypercapnia, and a time-matched control on separate days in 20 healthy young adults. Peripheral CO2 chemoreflex sensitivity was increased 41 ± 46% after hypercapnic AIH but no statistically significant changes were found in central CO2 chemoreflex sensitivity. These data indicate plasticity in the peripheral CO2 chemoreflex after exposure to hypercapnic AIH that contributes to ventilatory LTF in a background of mild hypercapnia.
PMID:42673352 | DOI:10.1113/JP291647
