Exercise hyperpnoea: Unravelling layers of regulation

How ventilation ( ${\dot{V}}_E$ ) matches gas exchange ( ${\dot{V}}_{C{O}_2}$ ) while maintaining isocapnia during exercise remains unresolved. We measured ${\dot{V}}_E$ , ${\dot{V}}_{C{O}_2}$ , arterialized-venous $P_{C{O}_2}$ (PāCO₂) and hypercapnic ventilatory responsiveness (HCVR = ∆ ${\dot{V}}_E$ /∆ $P_{C{O}_2}$ ) during four steady-state exercise intensities below the respiratory compensation point (RCP) and used a mathematical model to characterize feedforward contributions to exercise hyperpnoea and test the hypothesis that CO₂ chemofeedback is inhibitory. Model assumptions were that the ventilatory response to exercise-intensity changes (G_SYS = ∆ ${\dot{V}}_E$ /∆ ${\dot{V}}_{C{O}_2}$ ) equals the sum of a feedforward exercise stimulus proportional to ${\dot{V}}_{C{O}_2}$ (G_EX) modified by the CO₂ chemoreflex (HCVR). Using experimental data G_SYS was quantified as ∆ ${\dot{V}}_E$ /∆ ${\dot{V}}_{C{O}_2}$ between exercise steps and G_EX equalled G_SYS minus chemoreflex feedback (i.e. HCVRx∆PāCO₂/∆ ${\dot{V}}_{C{O}_2}$ ). Twenty healthy young participants completed a maximal cycling test and three submaximal step-incremental protocols of two 8 min stages below the estimated lactate threshold (θ_LT; MOD₁ and MOD₂) and two 12 min stages between θ_LT and RCP (HVY₁ and HVY₂). During visits 2 and 3, three rebreathing tests performed at each intensity provided HCVR (average ${\dot{V}}_E$ -end-tidal $P_{C{O}_2}$ slope). During visit 4, heated hand vein blood provided PāCO₂ at each intensity, and ${\dot{V}}_{C{O}_2}$ and ${\dot{V}}_E$ were measured by metabolic cart. With higher steady-state ${\dot{V}}_{C{O}_2}$ , one-way repeated-measures ANOVA showed that HCVR rose from 2.4 ± 0.9 at MOD₁ to 2.8 ± 0.8, 3.2 ± 0.8 and 3.6 ± 1.0 L · min^-1 · mmHg^-1 at MOD₂, HVY₁ and HVY₂, respectively; ∆PāCO₂/∆ ${\dot{V}}_{C{O}_2}$ decreased (P < 0.001) from 0.2 ± 4.3 at MOD₁ to -1.9 ± 5.0, -5.5 ± 4.5 and -8.0 ± 4.6 mmHg · L · min^-1; and G_EX increased (P < 0.001) from 26.9 ± 15.1 at MOD₁ to 34.5 ± 20.3, 53.9 ± 19.1 and 73.4 ± 27.5 L · min^-1. Exercise hyperpnoea may reflect the balance of intensity-dependent feedforward and inhibitory CO₂ chemofeedback drive. KEY POINTS: We aimed to quantify exercise intensity-dependent changes in CO₂ chemoreflexes and interpret their role in exercise hyperpnoea. Ventilatory, gas exchange, arterialized-venous $P_{C{O}_2}$ (PāCO₂) and hypercapnic ventilatory responses (HCVR) were measured during successive work-to-work cycling exercise transitions from low-to-moderate to heavy-intensity work rates. The measured HCVR at each intensity and ∆ ${\dot{V}}_E$ /∆ ${\dot{V}}_{C{O}_2}$ and ∆PāCO₂/∆ ${\dot{V}}_{C{O}_2}$ from one work rate to the next were included in a mathematical model to characterize feedforward contributions to exercise hyperpnoea at four intensities. With increasing steady-state ${\dot{V}}_{C{O}_2}$ , ∆ ${\dot{V}}_E$ /∆ ${\dot{V}}_{C{O}_2}$ and HCVR progressively increased, whereas ∆PāCO₂/∆ ${\dot{V}}_{C{O}_2}$ progressively became more negative. Assuming ∆ ${\dot{V}}_E$ is the sum of a feedforward gain plus linear CO₂ chemofeedback gain responding to changes in ${\dot{V}}_{C{O}_2}$ and $P_{\mathrm{aC}{O}_2}$ from rest to exercise, respectively, we estimated that feedforward gain rises with increasing exercise intensities, attaining a drive that exceeds requirements for $P_{C{O}_2}$ regulation at its resting level. Exercise hyperpnoea, therefore, requires a feedforward exercise stimulus constrained by inhibitory chemofeedback from rest to exercise to minimize hypocapnia .