CO₂ chemoreflex contributions to ventilatory long-term facilitation

Ventilatory long-term facilitation (LTF) is a persistent increase in minute ventilation ( ${\dot{V}}_I$ ) 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, ${\dot{V}}_I$ 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.