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Exercise hyperpnoea: Unravelling layers of regulation
Nasimi A Guluzade1, Gordon S Mitchell2,3,4, Daniel A Keir1,5,6
1School of Kinesiology, The University of Western Ontario, London, Ontario, Canada.
The Journal of Physiology
|July 28, 2026
Summary
Exercise ventilation matches gas exchange by balancing feedforward drive with inhibitory CO2 feedback. This study quantifies these responses during cycling, revealing that feedforward gain increases with intensity, necessitating feedback to maintain stable CO2 levels.
Area of Science:
- Exercise Physiology
- Respiratory Control
- Cardiovascular Regulation
Background:
- The precise mechanisms by which ventilation (V̇E) matches gas exchange (V̇CO2) to maintain isocapnia during exercise are not fully understood.
- Understanding the interplay between feedforward exercise stimuli and CO2 feedback is crucial for explaining exercise hyperpnoea.
Purpose of the Study:
- To quantify exercise intensity-dependent changes in CO2 chemoreflexes during cycling exercise.
- To interpret the role of these chemoreflexes in exercise hyperpnoea using a mathematical model.
- To test the hypothesis that CO2 chemofeedback is inhibitory during exercise.
Main Methods:
- Measured ventilation (V̇E), CO2 production (V̇CO2), arterialized-venous PCO2 (PaCO2), and hypercapnic ventilatory responsiveness (HCVR) across four incremental exercise intensities below the respiratory compensation point (RCP).
- Utilized a mathematical model incorporating experimental data (HCVR, V̇E/V̇CO2, PaCO2/V̇CO2) to estimate feedforward contributions (GEX) to exercise hyperpnoea.
- Participants (n=20) underwent maximal and submaximal cycling tests with rebreathing maneuvers and blood gas sampling.
Main Results:
- Hypercapnic ventilatory responsiveness (HCVR) increased significantly with rising exercise intensity (from 2.4 to 3.6 L·min⁻¹·mmHg⁻¹).
- The change in PaCO2 relative to V̇CO2 (ΔPaCO2/ΔV̇CO2) became progressively more negative with increasing exercise intensity (from 0.2 to -8.0 mmHg·L·min⁻¹).
- Estimated feedforward gain (GEX) increased substantially with exercise intensity (from 26.9 to 73.4 L·min⁻¹), suggesting a drive exceeding resting CO2 regulation.
Conclusions:
- Exercise hyperpnoea appears to be regulated by a balance between intensity-dependent feedforward stimulation and inhibitory CO2 chemofeedback.
- The increasing feedforward drive during exercise necessitates inhibitory feedback to prevent excessive decreases in PaCO2 (hypocapnia).
- The findings support the hypothesis that CO2 chemofeedback plays an inhibitory role in modulating ventilation during exercise.
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