Reactive oxygen species play a modulatory role in the hyperventilatory response to poikilocapnic hyperoxia in humans

Abstract

Key points The proposed mechanism for the increased ventilation in response to hyperoxia includes a reduced brain CO2–[H+] washout‐induced central chemoreceptor stimulation that results from a decrease in cerebral perfusion and the weakening of the CO2 affinity for haemoglobin. Nonetheless, hyperoxia also results in excessive brain reactive oxygen species (ROS) formation/accumulation, which hypothetically increases central respiratory drive and causes hyperventilation. We then quantified ventilation, cerebral perfusion/metabolism, arterial/internal jugular vein blood gases and oxidant/antioxidant biomarkers in response to hyperoxia during intravenous infusion of saline or ascorbic acid to determine whether excessive ROS production/accumulation contributes to the hyperoxia‐induced hyperventilation in humans. Ascorbic acid infusion augmented the antioxidant defence levels, blunted ROS production/accumulation and minimized both the reduction in cerebral perfusion and the increase in ventilation observed during saline infusion. Hyperoxic hyperventilation seems to be mediated by central chemoreceptor stimulation provoked by the interaction between an excessive ROS production/accumulation and reduced brain CO2–[H+] washout. Abstract The hypothetical mechanism for the increase in ventilation (normalV̇E) in response to hyperoxia (HX) includes central chemoreceptor stimulation via reduced CO2–[H+] washout. Nonetheless, hyperoxia disturbs redox homeostasis and raises the hypothesis that excessive brain reactive oxygen species (ROS) production/accumulation may increase the sensitivity to CO2 or even solely activate the central chemoreceptors, resulting in hyperventilation. To determine the mechanism behind the HX‐evoked increase in normalV̇E, 10 healthy men (24 ± 4 years) underwent 10 min trials of HX under saline and ascorbic acid infusion. normalV̇E, arterial and right internal right jugular vein (ijv) partial pressure for oxygen (PO2) and CO2 (PCO2), pH, oxidant (8‐isoprostane) and antioxidant (ascorbic acid) markers, as well as cerebral blood flow (CBF) (Duplex ultrasonography), were quantified at each hyperoxic trial. HX evoked an increase in arterial partial pressure for oxygen, followed by a hyperventilatory response, a reduction in CBF, an increase in arterial 8‐isoprostane, and unchanged PijvCO2 and ijv pH. Intravenous ascorbic acid infusion augmented the arterial antioxidant marker, blunted the increase in arterial 8‐isoprostane and attenuated both the reduction in CBF and the HX‐induced hyperventilation. Although ascorbic acid infusion resulted in a slight increase in PijvCO2 and a substantial decrease in ijv pH, when compared with the saline bout, HX evoked a similar reduction and a paired increase in the trans‐cerebral exchanges for PCO2 and pH, respectively. These findings indicate that the poikilocapnic hyperoxic hyperventilation is likely mediated via the interaction of the acidic brain interstitial fluid and an increase in central chemoreceptor sensitivity to CO2, which, in turn, seems to be evoked by the...

Oxygen toxicity: cellular mechanisms in normobaric hyperoxia

“…Non-mitochondria-targeted antioxidants can also reduce the extent of hyperoxia injury. Ascorbic acid is effective in reducing the levels of the oxidative damage biomarker 8-isoprostane in young men breathing 100% O 2 (Fernandes et al 2021 ). The antioxidant N-aceylcysteine reduces lung injury in rats exposed to 90% O 2 (Qiao et al 2019 ).…”

Revisiting the assumption of a rebreathing‐induced arterial–brain CO2 equilibrium half a century later

“…Thus, if these findings in the rodent apply to the human, during rebreathing the observed rise in jugular venous $${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$$ in parallel with $${P_{{\mathrm{aC}}{{\mathrm{O}}_{\mathrm{2}}}}}$$ might not be reflected accurately in a similar change in the medullary chemosensitive area. The several minutes of marked hyperventilation and cerebral tissue alkalosis imposed before initiating rebreathing are likely to incur increased lactic acid production, which would be reflected to varying degrees in brain intracellular and interstitial fluids, including in chemosensitive areas, but not in arterial or jugular venous blood. Even a few minutes of hyperoxia (as used in the rebreathing test) provide a significant stimulus to ventilation, which might occur independently of the measured change in $${P_{{\mathrm{aC}}{{\mathrm{O}}_{\mathrm{2}}}}}$$ (or jugular venous $${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$$) during rebreathing. One source of this ventilatory stimulation might be found in increased production of reactive oxygen species, as demonstrated in humans by the reduced hyperoxic‐induced hyperventilation achieved via blockade of reactive oxygen species (Fernandes et al., 2021). The assumption that the ventilatory response to hyperoxic hypercapnia is solely a function of central chemoreception is inconsistent with the significant inhibitory effects of denervation or acute inhibition of carotid chemoreceptors on hyperoxic CO 2 chemosensitivity, as shown in several studies of unanaesthetized mammals, including in humans (for references, see Dempsey and Gibbons (2023).…”

“…r Even a few minutes of hyperoxia (as used in the rebreathing test) provide a significant stimulus to ventilation, which might occur independently of the measured change in P aCO 2 (or jugular venous P CO 2 ) during rebreathing. One source of this ventilatory stimulation might Perspective J Physiol 601.19 be found in increased production of reactive oxygen species, as demonstrated in humans by the reduced hyperoxic-induced hyperventilation achieved via blockade of reactive oxygen species (Fernandes et al, 2021).…”