Assessing central and peripheral respiratory chemoreceptor interaction in humans

New Findings What is the central question of this study? We investigated the interaction between central and peripheral respiratory chemoreceptors in healthy, awake human participants by using a background of step increases in steady-state normoxic fraction of inspired carbon dioxide to alter central chemoreceptor activation and by using the transient hypoxia test to target the peripheral chemoreceptors. What is the main finding and its importance? Our data suggest that the interaction between central and peripheral respiratory chemoreceptors is additive in minute ventilation and respiratory rate, but hypo-additive in tidal volume. Our study adds important new data in reconciling chemoreceptor interaction in awake healthy humans and is consistent with previous reports of simple addition in intact rodents and humans. Arterial blood gas levels are maintained through respiratory chemoreflexes, mediated by central chemoreceptors in the CNS and peripheral chemoreceptors located in the carotid bodies. The interaction between central and peripheral chemoreceptors is controversial, and few studies have investigated this interaction in awake, healthy humans, owing, in part, to methodological challenges. We investigated the interaction between the central and peripheral chemoreceptors in healthy humans using a transient hypoxia test (three consecutive breaths of 100% N-2; TT-HVR), which targets the temporal domain and stimulus specificity of the peripheral chemoreceptors. The TT-HVRs were superimposed upon three randomized background levels of steady-state inspired fraction of normoxic CO2(FI,CO2${F}_{{\rm{I,C}}{{\rm{O}}}_{\rm{2}}}$; 0, 0.02 and 0.04). Chemostimuli [calculated oxygen saturation (ScO2${S}_{{\rm{cO}}_{\rm{2}}}$)] and respiratory variable responses [respiratory rate (R-R), inspired tidal volume (V-TI) and ventilation (V?I${{{\dot{V}}}_{\rm{I}}}$)] were averaged from all three TT-HVR trials at each FI,CO2${F}_{{\rm{I,C}}{{\rm{O}}}_{\rm{2}}}$ level. Responses were assessed as: (1) a change ( increment ) from baseline; and (2) indexed against Delta ScO2$\Delta {S}_{{\rm{cO}}_{\rm{2}}}$. Aside from a significantly lower increment V-TI response in 0.04 FI,CO2${F}_{{\rm{I,C}}{{\rm{O}}}_{\rm{2}}}$ (P = 0.01), the hypoxic rate responses ( increment R-R or increment R-R/Delta ScO2$\Delta {S}_{{\rm{cO}}_{\rm{2}}}$; P = 0.46 and P = 0.81), hypoxic tidal volume response (Delta VTI/Delta VTI Delta ScO2 Delta ScO2${{\Delta {V}_{{\rm{TI}}}} \mathord{/ {\vphantom {{\Delta {V}_{{\rm{TI}}}} {\Delta {S}_{{\rm{cO}}_{\rm{2}}}}}} \kern-\nulldelimiterspace} {\Delta {S}_{{\rm{cO}}_{\rm{2}}}}}$; P = 0.08) and the hypoxic ventilatory responses (Delta V?I${{\Delta {{\dot{V}}}_{\rm{I}}}}$ and Delta V?I/Delta V?I Delta ScO2 Delta ScO2${{\Delta {{\dot{V}}}_{\rm{I}}} \mathord{/ {\vphantom {{\Delta {{\dot{V}}}_{\rm{I}}} {\Delta {S}_{{\rm{cO}}_{\rm{2}}}}}} \kern-\nulldelimiterspace} {\Delta {S}_{{\rm{cO}}_{\rm{2}}}}}$; P = 0.09 and P = 0.31) were not significantly different across FI,CO2${F}_{{\rm{I,C}}{{\rm{O}}}_{\rm{2}}}$ trials. Our data suggest simple addition between central and peripheral chemoreceptors in V?I${{{\dot{V}}}_{\rm{I}}}$, which is mediated through simple addition in R-R responses, but hypo-addition in V-TI responses. Our study adds important new data in reconciling chemoreceptor interaction in awake, healthy humans and is consistent with previous reports of simple addition in intact rodents and humans.