Human brain blood flow and metabolism during isocapnic hyperoxia: the role of reactive oxygen species

Abstract

Key points It is unknown whether excessive reactive oxygen species (ROS) production drives the isocapnic hyperoxia (IH)‐induced decline in human cerebral blood flow (CBF) via reduced nitric oxide (NO) bioavailability and leads to disruption of the blood–brain barrier (BBB) or neural‐parenchymal damage. Cerebral metabolic rate for oxygen (CMRnormalO2) and transcerebral exchanges of NO end‐products, oxidants, antioxidants and neural‐parenchymal damage markers were simultaneously quantified under IH with intravenous saline and ascorbic acid infusion. CBF and CMR normalO2 were reduced during IH, responses that were followed by increased oxidative stress and reduced NO bioavailability when saline was infused. No indication of neural‐parenchymal damage or disruption of the BBB was observed during IH. Antioxidant defences were increased during ascorbic acid infusion, while CBF, CMR normalO2, oxidant and NO bioavailability markers remained unchanged. ROS play a role in the regulation of CBF and metabolism during IH without evidence of BBB disruption or neural‐parenchymal damage. Abstract To test the hypothesis that isocapnic hyperoxia (IH) affects cerebral blood flow (CBF) and metabolism through exaggerated reactive oxygen species (ROS) production, reduced nitric oxide (NO) bioavailability, disturbances in the blood–brain barrier (BBB) and neural‐parenchymal homeostasis, 10 men (24 ± 1 years) were exposed to a 10 min IH trial (100% O2) while receiving intravenous saline and ascorbic acid (AA, 3 g) infusion. Internal carotid artery blood flow (ICABF), vertebral artery blood flow (VABF) and total CBF (tCBF, Doppler ultrasound) were determined. Arterial and right internal jugular venous blood was sampled to quantify the cerebral metabolic rate of oxygen (CMRnormalO2), transcerebral exchanges (TCE) of NO end‐products (plasma nitrite), antioxidants (AA and AA plus dehydroascorbic acid (AA+DA)) and oxidant biomarkers (thiobarbituric acid‐reactive substances (TBARS) and 8‐isoprostane), and an index of BBB disruption and neuronal‐parenchymal damage (neuron‐specific enolase; NSE). IH reduced ICABF, tCBF and CMR normalO2, while VABF remained unchanged. Arterial 8‐isoprostane and nitrite TCE increased, indicating that CBF decline was related to ROS production and reduced NO bioavailability. AA, AA+DA and NSE TCE did not change during IH. AA infusion did not change the resting haemodynamic and metabolic parameters but raised antioxidant defences, as indicated by increased AA/AA+DA concentrations. Negative AA+DA TCE, unchanged nitrite, reductions in arterial and venous 8‐isoprostane, and TBARS TCE indicated that AA infusion effectively inhibited ROS production and preserved NO bioavailability. Similarly, AA infusion prevented IH‐induced decline in regional and total CBF and re‐established CMR normalO2. These findings indicate that ROS play a role in CBF regulation and metabolism during IH without evidence of BBB disruption or neural‐parenchymal damage.

Brain BOLD MRI O2and CO2stress testing: Implications for perioperative neurocognitive disorder following surgery

“…Other human studies have indicated that hyperoxia induces cerebral vasoconstriction as a consequence of altered regional nitric oxide potentially contributing to the stress diathesis under anaesthesia. 44 Also of note are findings of altered CVR with increasing age 45 and with signs of dementia in the elderly 46 or in patients with biomarkers such as APO4ε related to early onset Alzheimer's disease. 47 The identification of regional 'intracranial steal' or 'blue brain' on the BOLD images with a CO2 ramp protocol is increasingly being used to establish the need for and measure results from revascularization with superficial temporal artery to middle cerebral artery (STA-MCA) anastomoses in patients with severe intracranial vascular compromise.…”

Oxygen is rocket fuel for the human brain; a radical perspective!

“…Given that the brain's O 2 supply is so delicate, walking the tightrope between too much or too little of this rocket fuel, it would seem intuitive for evolution to favour feedback mechanisms capable of sensing subtle changes in blood O 2 concentration and transmitting signals to the cerebrovasculature coupling local cerebral O 2 delivery to tissue metabolic demand. The new information presented by Mattos et al (2019) adds to an emerging, albeit limited, body of human evidence, indicating that free radicals may well fulfil such a role in preserving cellular O 2 homeostasis.…”

“…The new information presented by Mattos et al . () adds to an emerging, albeit limited, body of human evidence, indicating that free radicals may well fulfil such a role in preserving cellular O 2 homeostasis.…”

“…The findings published in this issue of The Journal of Physiology by Mattos et al . () speak to these potentially neuroprotective mechanisms providing much‐needed human insight into the redox‐regulation of ‘cerebral O 2 ‐sensing’. By combining paired sampling of arterial and jugular venous blood to assess trans‐cerebral metabolic exchange with regional assessment of CBF, the authors demonstrated that acute isocapnic hyperoxia decreased CBF and cerebral metabolic rate of O 2 (CMRO 2 ) subsequent to increased systemic and cerebral oxidative‐nitrosative stress confirmed by a free radical‐mediated reduction in nitric oxide (NO) bioavailability.…”

“…However, emerging evidence suggests that over billions of years of evolution, life has changed from simply eliminating free radicals and associated reactive oxygen species (ROS) to utilising them for selective advantage; indeed rather than being simply labelled as toxic, mutagenic 'accidents' of in vivo chemistry constrained to cellular oxidative damage and pathophysiology, it is becoming increasingly clear that at physiological, albeit undefined, concentrations, free radicals and ROS can equally serve as important signal transductants regulating gene expression and vasomotor tone that collectively serve to defend cerebral O 2 homeostasis (Bailey, 2019). The findings published in this issue of The Journal of Physiology by Mattos et al (2019) speak to these potentially neuroprotective mechanisms providing much-needed human insight into the redox-regulation of 'cerebral O 2 -sensing' . By combining paired sampling of arterial and jugular venous blood to assess trans-cerebral metabolic exchange with regional assessment of CBF, the authors demonstrated that acute isocapnic hyperoxia decreased CBF and cerebral metabolic rate of O 2 (CMRO 2 ) subsequent to increased systemic and cerebral oxidative-nitrosative stress confirmed by a free radical-mediated reduction in nitric oxide (NO) bioavailability.…”