Exercise hyperpnoea: Unravelling layers of regulation.

How ventilation ( V ̇ E ) matches gas exchange ( V ̇ C O 2 ) while maintaining isocapnia during exercise remains unresolved. We measured V ̇ E , V ̇ C O 2 , arterialized-venous P C O 2 (PāCO2) and hypercapnic ventilatory responsiveness (HCVR = ∆ 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 (GSYS = ∆ V ̇ E /∆ V ̇ C O 2 ) equals the sum of a feedforward exercise stimulus proportional to V ̇ C O 2 (GEX) modified by the CO2 chemoreflex (HCVR). Using experimental data GSYS was quantified as ∆ V ̇ E /∆ V ̇ C O 2 between exercise steps and GEX equalled GSYS minus chemoreflex feedback (i.e. HCVRx∆PāCO2/∆ 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 (θLT; MOD1 and MOD2) and two 12 min stages between θLT and RCP (HVY1 and HVY2). During visits 2 and 3, three rebreathing tests performed at each intensity provided HCVR (average V ̇ E -end-tidal P C O 2 slope). During visit 4, heated hand vein blood provided PāCO2 at each intensity, and V ̇ C O 2 and V ̇ E were measured by metabolic cart. With higher steady-state 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/∆ 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 GEX 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 ∆ V ̇ E /∆ V ̇ C O 2 and ∆PāCO2/∆ 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 V ̇ C O 2 , ∆ V ̇ E /∆ V ̇ C O 2 and HCVR progressively increased, whereas ∆PāCO2/∆ V ̇ C O 2 progressively became more negative. Assuming ∆ V ̇ E is the sum of a feedforward gain plus linear CO2 chemofeedback gain responding to changes in V ̇ C O 2 and P 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 .