V̇co2: the essential underpinning to homeostatic control of breathing.

This essay addresses the fundamental mechanism underlying the precise regulation of [Formula: see text] during steady states of air-breathing eupnea and hyperpnea. First, an argument is made for CO2/H+ chemoreception as an important compensatory feedback regulator of breathing and breathing stability, especially during nonrapid eye movement (NREM) sleep. Tonic contributions to respiratory drive occur from the carotid chemoreceptors and retrotrapezoid nucleus (RTN). A case against chemoreception of Pco2 as the primary homeostatic [Formula: see text] regulator is made based on conditions where precise [Formula: see text] control during air-breathing exists even when ventilatory responsiveness to raised Pco2 is markedly subnormal or when a measurable [Formula: see text] error signal is nonexistent. Alternatively, a case is made that homeostatic ventilatory control incorporates information critically dependent on pulmonary CO2 exchange, as revealed when: 1) V̇co2, per se, is altered at rest or exercise; 2) Vd/VT is raised or lowered; and 3) the resting [Formula: see text] set point is changed, thereby changing respiratory system plant gains. In each of these common conditions, substantial ventilatory adjustments occur to achieve near-proportional V̇a:V̇co2 linkages at rest and/or exercise with no coincidence changes in CO2 chemoreception. We view this V̇co2-mediated mechanism as a dedicated tracking system for alveolar ventilation that provides an essential underpinning in a traditional hybrid model of homeostatic ventilatory control. Although some potential mediators of these V̇co2 effects have been suggested, such as an integrative role for the RTN, they remain inadequately explored. It is time to restart enquiry, using modern neuroscience approaches, into the mediation of V̇co2 as the critical underpinning to [Formula: see text] homeostasis.