Assessing central and peripheral respiratory chemoreceptor interaction in humans

Abstract

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 CO 2 (F I,CO 2 ; 0, 0.02 and 0.04). Chemostimuli [calculated oxygen saturation (S cO 2 )] and respiratory variable responses [respiratory rate (R R ), inspired tidal volume (V TI ) and ventilation ( VI )] were averaged from all three TT-HVR trials at each F I,CO 2 level. Responses were assessed as: (1) a change (∆) from baseline; and (2) indexed against ΔS cO 2 . Aside from a significantly lower ∆V TI response in 0.04 F I,CO 2 (P = 0.01), the hypoxic rate responses (∆R R or ∆R R /ΔS cO 2 ; P = 0.46 and P = 0.81), hypoxic tidal volume response (ΔV TI ∕ΔS cO 2 ; P = 0.08) and the hypoxic ventilatory responses (Δ VI and Δ VI ∕ΔS cO 2 ; P = 0.09 and P = 0.31) were not significantly different across F I,CO 2 trials. Our data suggest simple addition between central and peripheral chemoreceptors in VI , 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.

A test of the interaction between central and peripheral respiratory chemoreflexes in humans

“…Although the majority of participants exhibited an additive central-peripheral interaction, 25% of the group did not. This heterogeneity is consistent with other human-based experiments (Clement et al, 1992;Cui et al, 2012;Milloy et al, 2022;St Croix et al, 1996), indicating that different phenotypes may exist amongst humans. The consequence of such differences is unknown.…”

“…1. Although it has been proposed that additive central–peripheral interactions of $$\dot{V}$$ E , necessitate, from a mathematical perspective, linear and hypo‐additive relationships of V T and fB (or vice versa) (Milloy et al., 2022; Wilson & Teppema, 2016), it is our opinion that this may be an oversimplification. Our data support that either more complex, higher‐order models and/or strategies to limit variability of these variables are required (e.g.…”

“…Applying a different approach to test whether central chemoreceptor activation affects peripheral respiratory chemoreflex sensitivity, Milloy et al. (2022) performed transient HVR tests immediately after an 8 min period of breathing inspired CO 2 fractions of 0%, 2% and 4%. Importantly, sufficient time was provided to allow central chemoreceptors to establish a steady‐state of local $${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$$ and $$\dot{V}$$ E , and the HVR stimulus was initiated in all three conditions from a common $${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$$ (and presumably $${P_{{\mathrm{aC}}{{\mathrm{O}}_{\mathrm{2}}}}}$$).…”

Steady‐state chemoreflex drive captures ventilatory acclimatization during incremental ascent to high altitude: Effect of acetazolamide

“…Rebreathing or steady‐state hypoxic tests involve exposing a participant to various fractions of inspired oxygen using chambers, small rebreathing bags or large Douglas bags pre‐filled with mixed gasses, or dynamic end‐tidal forcing systems, over several minutes (Teppema & Dahan, 2010 ). Alternatively, transient hypoxic tests expose participants to short bouts of hypoxia (i.e., one or more breaths) via administration of 100% N 2 (e.g., Milloy et al, 2022 ; Pfoh et al, 2016 ; Teppema & Dahan, 2010 ). In both cases, the HVR is often quantified by the initial peak in ventilation following the acute hypoxic stimulus.…”

Strategies to improve respiratory chemoreflex characterization by Duffin's rebreathing

“…The ventilatory recruitment threshold (VRT) gives the $${P_{{\rm{ET,C}}{{\rm{O}}_{\rm{2}}}}}$$ at which $$\dot {\rm V}$$ E begins to rise from a prior period of stability, and the slope above VRT ($$\dot {\rm V}$$ E S) gives the chemoreflex sensitivity to $${P_{{\rm{C}}{{\rm{O}}_{\rm{2}}}}}$$ (Duffin et al., 2000). Assuming that the peripheral respiratory chemoreflex is nearly eliminated by hyperoxia (Lloyd & Cunningham, 1963; Mohan & Duffin, 1997) and that central and peripheral chemoreflexes do not interact in humans (Clement et al., 1992; Cui et al., 2012; Duffin & Mateika, 2013; Milloy et al., 2022; St. Croix et al., 1996), the hyperoxic test provides the central respiratory chemoreflex sensitivity, and the difference in $$\dot {\rm V}$$ E S between the hypoxic and hyperoxic tests gives an estimate of the peripheral respiratory chemoreflex sensitivity.…”