How important is the CO₂ chemoreflex for the control of breathing? Environmental and evolutionary considerations

Haldane and Priestley (1905) discovered that the ventilatory control system is highly sensitive to CO₂. This "CO₂ chemoreflex" has been interpreted to dominate control of resting arterial PCO₂/pH (P_aCO₂/pH_a) by monitoring P_aCO₂/pH_a and altering ventilation through negative feedback. However, P_aCO₂/pH_a varies little in mammals as ventilation tightly couples to metabolic demands, which may minimize chemoreflex control of P_aCO₂. The purpose of this synthesis is to (1) interpret data from experimental models with meager CO₂ chemoreflexes to infer their role in ventilatory control of steady-state P_aCO₂, and (2) identify physiological causes of respiratory acidosis occurring normally across vertebrate classes. Interestingly, multiple rodent and amphibian models with minimal/absent CO₂ chemoreflexes exhibit normal ventilation, gas exchange, and P_aCO₂/pH_a. The chemoreflex, therefore, plays at most a minor role in ventilatory control at rest; however, the chemoreflex may be critical for recovering P_aCO₂ following acute respiratory acidosis induced by breath-holding and activity in many ectothermic vertebrates. An apparently small role for CO₂ feedback in the genesis of normal breathing contradicts the prevailing view that central CO₂/pH chemoreceptors increased in importance throughout vertebrate evolution. Since the CO₂ chemoreflex contributes minimally to resting ventilation, these CO₂ chemoreceptors may have instead decreased importance throughout tetrapod evolution, particularly with the onset and refinement of neural innovations that improved the matching of ventilation to tissue metabolic demands. This distinct and elusive "metabolic ventilatory drive" likely underlies steady-state P_aCO₂ in air-breathers. Uncovering the mechanisms and evolution of the metabolic ventilatory drive presents a challenge to clinically-oriented and comparative respiratory physiologists alike.