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In humans, AIH\u2010induced ventilatory LTF is dependent upon a sustained background of mild hypercapnia. It is not known whether changes in CO\n 2<\/jats:sub>\n chemoreflex sensitivity contribute to ventilatory LTF. We hypothesised that hypercapnic AIH increases the sensitivity of peripheral, but not central, chemoreflex responses to CO\n 2<\/jats:sub>\n . Twenty healthy adults (age\u00a0=\u00a025\u00a0\u00b1\u00a04 years) completed the study. On days 1 and 2, pulmonary function testing and three hyperoxic modified CO\n 2<\/jats:sub>\n rebreathing tests were performed to determine baseline central CO\n 2<\/jats:sub>\n 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\u2010matched control (CTRL). Two CO\n 2<\/jats:sub>\n rebreathing tests were performed approximately 45 and 75\u00a0min post\u2010trial. Transient CO\n 2<\/jats:sub>\n tests were used to quantify peripheral CO\n 2<\/jats:sub>\n chemoreflex sensitivity pre\u2010 and post\u2010trial. Twenty minutes after hypercapnic AIH, was increased 32\u00a0\u00b1\u00a022%\n versus<\/jats:italic>\n baseline, which was significantly greater than CTRL (\n P\u00a0<\u00a0<\/jats:italic>\n 0.001), demonstrating the presence of ventilatory LTF. Central CO\n 2<\/jats:sub>\n chemoreflex sensitivity (\n P\u00a0=\u00a0<\/jats:italic>\n 0.880) and the ventilatory recruitment threshold (\n P\u00a0=\u00a0<\/jats:italic>\n 0.425) were unchanged after all trials. Peripheral CO\n 2<\/jats:sub>\n chemoreflex sensitivity was increased 41\u00a0\u00b1\u00a046% after hypercapnic AIH, which was significantly greater than CTRL (\n P\u00a0<\u00a0<\/jats:italic>\n 0.001). We conclude that enhanced peripheral CO\n 2<\/jats:sub>\n chemoreflex sensitivity contributes to ventilatory LTF induced by hypercapnic AIH in awake humans.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n \n In awake humans, induction of ventilatory long\u2010term 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 CO\n 2<\/jats:sub>\n chemoreflex sensitivities.\n <\/jats:p>\n <\/jats:list-item>\n \n \n Central and peripheral CO\n 2<\/jats:sub>\n chemoreflex sensitivity were assessed by modified hyperoxic CO\n 2<\/jats:sub>\n rebreathing and transient CO\n 2<\/jats:sub>\n tests, respectively, before and after hypercapnic AIH, sustained hypercapnia, and a time\u2010matched control on separate days in 20 healthy young adults.\n <\/jats:p>\n <\/jats:list-item>\n \n \n Peripheral CO\n 2<\/jats:sub>\n chemoreflex sensitivity was increased 41\u00a0\u00b1\u00a046% after hypercapnic AIH but no statistically significant changes were found in central CO\n 2<\/jats:sub>\n chemoreflex sensitivity.\n <\/jats:p>\n <\/jats:list-item>\n \n \n These data indicate plasticity in the peripheral CO\n 2<\/jats:sub>\n chemoreflex after exposure to hypercapnic AIH that contributes to ventilatory LTF in a background of mild hypercapnia.\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp291647","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T19:00:02Z","timestamp":1788202802000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["CO\n 2<\/sub>\n chemoreflex contributions to ventilatory long\u2010term facilitation"],"prefix":"10.1113","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5434-8817","authenticated-orcid":false,"given":"Susan V.","family":"Cross","sequence":"first","affiliation":[{"name":"School of Sport, Exercise & Rehabilitation Sciences, College of Life & Environmental Sciences University of Birmingham Edgbaston Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4750-4923","authenticated-orcid":false,"given":"Elizabeth","family":"Keen","sequence":"additional","affiliation":[{"name":"School of Sport, Exercise & Rehabilitation Sciences, College of Life & Environmental Sciences University of Birmingham Edgbaston Birmingham UK"},{"name":"Birmingham Medical School, College of Medicine & Health University of Birmingham Edgbaston Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom E.","family":"Nightingale","sequence":"additional","affiliation":[{"name":"School of Sport, Exercise & Rehabilitation Sciences, College of Life & Environmental Sciences University of Birmingham Edgbaston Birmingham UK"},{"name":"International Collaboration on Repair Discoveries (ICORD), Faculty of Medicine University of British Columbia Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zubair","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Department of Inflammation & Ageing, School of Infection, Inflammation & Immunology, College of Medicine & Health University of Birmingham Edgbaston Birmingham UK"},{"name":"University Hospitals Birmingham NHS Foundation Trust Edgbaston Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8971-6691","authenticated-orcid":false,"given":"George M.","family":"Balanos","sequence":"additional","affiliation":[{"name":"School of Sport, Exercise & Rehabilitation Sciences, College of Life & Environmental Sciences University of Birmingham Edgbaston Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9285-7113","authenticated-orcid":false,"given":"Joseph F.","family":"Welch","sequence":"additional","affiliation":[{"name":"School of Sport, Exercise & Rehabilitation Sciences, College of Life & Environmental Sciences University of Birmingham Edgbaston Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00945.2016"},{"issue":"7","key":"e_1_2_5_3_1","first-page":"709","article-title":"Long\u2010term facilitation of ventilation in humans during NREM sleep","volume":"21","author":"Babcock M. 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