Rethinking O2, CO2 and breathing during wakefulness and sleep

We have examined the importance of three long‐standing questions concerning chemoreceptor influences on cardiorespiratory function which are currently experiencing a resurgence of study among physiologists and clinical investigators. 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‐CB hypoxaemia also provides dose‐dependent ventilatory stimulation sufficient to account for 40–50% of the total ventilatory response to steady‐state hypoxaemia. Extra‐CB hyperoxia also provides a dose‐ and time‐dependent hyperventilation. Extra‐CB sites of O2‐driven 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 CO2 sensitivity, so that tonic CB activity accounts for as much as 35–40% of the normal, air‐breathing eupnoeic drive to breathe. Thirdly, we argue for a key role for CO2 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 CO2 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. figure legend The carotid body (CB) is the primary contributor to the hypoxic ventilatory response. However, experimental unanaesthetized animal models that anatomically isolate and maintain normal CB tonic activity retain a ventilatory response to extra‐CB systemic hypoxia that amounts to 40–50% of the intact model (left panel). O2‐sensitive sites in: (1) Pre‐Bötzinger astrocytes, (2) renal medulla, and (3) thoracic spinal cord, may contribute to the extra‐CB ventilatory response to whole‐body hypoxia. The CB also contributes to CO2 sensing at the retrotrapezoid nucleus (RTN) in the medulla (middle and right panels). Isolated CB inhibition with extra‐corporeal hyperoxic/hypocapnic perfusate, or CB resection, bo