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Firstly, while carotid chemoreceptors (CB) are required for hypoxic stimulation of breathing, use of an isolated, extracorporeally perfused CB preparation in unanaesthetized animals with maintained tonic input from the CB, reveals that extra\u2010CB hypoxaemia also provides dose\u2010dependent ventilatory stimulation sufficient to account for 40\u201350% of the total ventilatory response to steady\u2010state hypoxaemia. Extra\u2010CB hyperoxia also provides a dose\u2010 and time\u2010dependent hyperventilation. Extra\u2010CB sites of O<jats:sub>2<\/jats:sub>\u2010driven ventilatory stimulation identified to date include the medulla, kidney and spinal cord. Secondly, using the isolated or denervated CB preparation in awake animals and humans has demonstrated a hyperadditive effect of CB sensory input on central CO<jats:sub>2<\/jats:sub> sensitivity, so that tonic CB activity accounts for as much as 35\u201340% of the normal, air\u2010breathing eupnoeic drive to breathe. Thirdly, we argue for a key role for CO<jats:sub>2<\/jats:sub> chemoreception and the neural drive to breathe in the pathogenesis of upper airway obstruction during sleep (OSA), based on the following evidence: (1) removal of the wakefulness drive to breathe enhances the effects of transient CO<jats:sub>2<\/jats:sub> changes on breathing instability; (2) oscillations in respiratory motor output precipitate pharyngeal obstruction in sleeping subjects with compliant, collapsible airways; and (3) in the majority of patients in a large OSA cohort, a reduced neural drive to breathe accompanied reductions in both airflow and pharyngeal airway muscle dilator activity, precipitating airway obstruction.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp15751-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1113\/jp284551","type":"journal-article","created":{"date-parts":[[2023,9,26]],"date-time":"2023-09-26T08:30:08Z","timestamp":1695717008000},"page":"5571-5585","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Rethinking O<sub>2<\/sub>, CO<sub>2<\/sub> and breathing during wakefulness and sleep"],"prefix":"10.1113","volume":"602","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5979-6427","authenticated-orcid":false,"given":"Jerome A.","family":"Dempsey","sequence":"first","affiliation":[{"name":"University of Wisconsin\u2010Madison  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Travis D.","family":"Gibbons","sequence":"additional","affiliation":[{"name":"University of British Columbia\u2010Okanagan  Kelowna British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,9,26]]},"reference":[{"key":"e_1_2_2_2_1","doi-asserted-by":"publisher","DOI":"10.1042\/CS20130343"},{"key":"e_1_2_2_3_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1995.78.5.1806"},{"key":"e_1_2_2_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abm1444"},{"key":"e_1_2_2_5_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1996.81.4.1683"},{"issue":"6","key":"e_1_2_2_6_1","first-page":"964","article-title":"Recovery of peripheral chemoreceptor function after denervation in ponies","volume":"49","author":"Bisgard G. 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