Arterial CO2 partial pressure appears to modulate diving reflex-related active muscle hypoperfusion, as well as bradycardia, pressor response, and cerebral hyperemia in exercising adults, suggesting the diving reflex may serve to regulate CO2 homeostasis in addition to its traditional role as an oxygen-conservation response.
Key Findings
Results
Hypocapnic hyperventilation significantly increased apnea duration compared with normocapnic hyperventilation during exercise.
Apnea duration was 52 ± 16 s in the hypocapnic hyperventilation condition versus 31 ± 13 s in the normocapnic hyperventilation condition.
This difference was statistically significant (P < 0.001).
Hypocapnic hyperventilation reduced end-tidal CO2 partial pressure to approximately 20 mmHg prior to apnea.
Normocapnic hyperventilation maintained end-tidal CO2 at normocapnic levels via CO2 inhalation during hyperventilation.
Fourteen young adults (1 female) performed maximal-duration breath-holding during dynamic two-legged knee extension exercise at a heart rate of 100 beats·min-1.
Results
Leg blood flow during apnea was significantly higher in the hypocapnic hyperventilation condition than in the normocapnic hyperventilation condition at matched time points.
Leg blood flow was 2236 ± 583 mL·min-1 in the hypocapnic condition versus 1643 ± 576 mL·min-1 in the normocapnic condition at matched time points (P = 0.002).
This indicates that lower arterial CO2 levels (hypocapnia) attenuated apnea-induced muscle hypoperfusion.
The comparison was made at iso-time points between conditions to control for differences in apnea duration.
These findings suggest that elevated arterial CO2 during apnea contributes substantially to vasoconstriction in active muscles as part of the diving reflex.
Results
Hypocapnic hyperventilation attenuated apnea-induced bradycardia compared with normocapnic hyperventilation.
The attenuation of bradycardia in the hypocapnic condition was statistically significant compared to normocapnic condition (P < 0.001) at the iso-time point.
This indicates that arterial CO2 partial pressure modulates the cardiac component of the diving reflex, not just the vascular component.
The diving reflex characteristically includes bradycardia as a key component alongside peripheral vasoconstriction.
Results
Hypocapnic hyperventilation attenuated apnea-induced increases in mean arterial pressure compared with normocapnic hyperventilation.
The difference in mean arterial pressure response between conditions was statistically significant (P < 0.001) at the iso-time point.
This pressor response attenuation under hypocapnic conditions further implicates CO2 as a modulator of the full cardiovascular diving reflex response.
The pressor response is a recognized component of the diving reflex alongside bradycardia and peripheral vasoconstriction.
Results
Hypocapnic hyperventilation attenuated apnea-induced increases in middle cerebral artery mean blood velocity compared with normocapnic hyperventilation.
The difference in middle cerebral artery mean blood velocity between hypocapnic and normocapnic conditions was statistically significant (P < 0.001) at the iso-time point.
This indicates that CO2-mediated cerebral hyperemia during apnea is also modulated by pre-apnea arterial CO2 levels.
CO2 is a potent cerebral vasodilator, so higher CO2 during normocapnic apnea would be expected to increase cerebral blood flow more than during hypocapnic apnea.
Discussion
The diving reflex may serve to regulate CO2 homeostasis in addition to its traditionally recognized role as an oxygen-conservation response.
The authors propose that because CO2 elevation during apnea drives key components of the diving reflex (muscle vasoconstriction, bradycardia, pressor response, cerebral hyperemia), CO2 regulation may be a primary function of this reflex.
This challenges the traditional view that the diving reflex functions exclusively to preserve oxygen within the body.
The study used end-tidal CO2 measurements as a surrogate for arterial CO2 partial pressure.
The authors note this is described as a 'NEW & NOTEWORTHY' finding that CO2 is a major factor largely influencing apnea-induced responses during exercise.
Methods
The study used a within-subjects crossover design comparing hypocapnic hyperventilation and normocapnic hyperventilation (with CO2 inhalation) conditions prior to exercise apnea.
Fourteen young adults (1 female) participated in the study.
Participants performed maximal-duration breath-holding during dynamic two-legged knee extension exercise targeting a heart rate of 100 beats·min-1.
The 3-minute voluntary hyperventilation protocol preceded each apnea trial.
Normocapnia during hyperventilation was maintained by CO2 inhalation, allowing isolation of the CO2 variable.
Comparisons between conditions were made at matched (iso-time) time points to account for differences in apnea duration.
What This Means
This research suggests that carbon dioxide (CO2) levels in the blood play a major role in controlling how the body responds when someone holds their breath during exercise. When we hold our breath, the body activates what is called the 'diving reflex' — a set of physiological responses that includes reduced blood flow to working muscles, a slower heart rate, increased blood pressure, and increased blood flow to the brain. This study tested whether the CO2 that builds up during breath-holding is responsible for triggering these responses by comparing breath-holds after normal (normocapnic) versus low-CO2 (hypocapnic, achieved by hyperventilating) conditions in 14 young adults exercising on a knee extension machine.
The results showed that when participants started their breath-hold with low CO2 levels (after hyperventilating), their muscles received significantly more blood flow during the apnea (about 2236 vs. 1643 mL/min), their heart rate slowed less, their blood pressure rose less, and their brain received less extra blood flow compared to when they started with normal CO2 levels. Participants also held their breath longer when starting from a low-CO2 state (52 vs. 31 seconds on average). Together, these findings indicate that rising CO2 during breath-holding is a key driver of the cardiovascular changes associated with the diving reflex during exercise.
This research suggests that the diving reflex — long thought to be primarily about conserving oxygen — may also be an important mechanism for regulating CO2 levels in the body. This finding has potential implications for understanding breath-holding sports (such as freediving), the physiological limits of exercise under apneic conditions, and possibly for understanding conditions where CO2 regulation is impaired.
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Matsutake R, Ichinose M, Nishiyasu T, Fujimoto T, Dobashi K, Fujii N. (2026). Arterial CO2 partial pressure is a key modulator of active muscle hypoperfusion mediated by diving reflex in exercising young adults.. American journal of physiology. Regulatory, integrative and comparative physiology. https://doi.org/10.1152/ajpregu.00032.2026