Hypoxic cerebrovascular oxidative–nitrosative stress: Take my breath away

Blood flow to the brain is highly regulated to maintain a continuous supply of oxygen and nutrients and ensure removal of metabolic waste products. Accordingly, excursions in arterial carbon dioxide or oxygen tension will activate swift cerebrovascular responses aiming to keep the microenvironment stable. One of the first steps in our understanding of these responses and the underlying mechanisms was taken by Kety and Schmidt (1948), who became the first to measure global cerebral blood flow in humans using inhaled nitrous oxide as the tracer, and reported a marked increase following a reduction in inspired oxygen fraction or during inhalation of air mixed with carbon dioxide. Several studies followed that took advantage of various applications of the Kety–Schmidt technique and the Fick principle to consolidate the findings of hypoxia- and hypercapnia-induced cerebral blood flow changes in human volunteers under different contexts, such as at high altitude or during the inhalation of gas mixtures. In the late 1970s, pial arteriolar dilatation to hypoxia and hypercapnia was observed directly using a cranial window in anaesthetized cats. Subsequent breakthroughs involved the discovery of hypoxia-inducible factors as ubiquitous intracellular oxygen sensors and initiators of compensatory pathways, of hypercapnia as an activator of hypoxia-inducible factor degradation and thus a suppressor of hypoxia-inducible factor pathways, and of nitric oxide as one of several important vasodilating agents released after activation of these pathways. Thus, astrocytes were recently reported to reduce nitrite to release nitric oxide during hypoxia (Christie et al., 2023). Moreover, hypercapnia induces relaxation of pericytes with ensuing arteriolar and capillary dilatation (Hartmann et al., 2021); however, although nitric oxide is involved in pericyte relaxation (Hall et al., Nature 2014), nitric oxide signalling has not been formally demonstrated during carbon dioxide-induced relaxation in pericytes. In this issue of The Journal of Physiology, Bailey et al. (2024) address the interplay between hypoxia/hypercapnia, cerebral haemodynamics and oxidative–nitrosative stress. It profits from the capacity of elite apneists (free-divers) for prolonged breath-holding. In a cross-over design, 10 elite apneists exposed themselves to two maximal breath-holding sessions, of which the first was preceded by normoxic normoventilation, whereas the second was preceded by hyperoxic hyperventilation. Using duplex ultrasound as well as blood sampling from arterial, in addition to jugular bulb catheters, the investigators compared cerebral blood flow, oxidative metabolism, and cerebrovascular uptake/output of markers of oxidative and nitrosative stress during hypoxaemic hypercapnia and hyperoxaemic hypercapnia. Compared to hyperoxaemic hypercapnia, the net cerebrovascular release of ascorbate radical and lipid hydroperoxides, important markers of oxidative stress, was increased during hypoxaemic hypercapnia. Conversely, the net uptake of nitrite, a 'precursor' for nitric oxide, increased during hypercapnia but to a lesser extent, indicating less nitric oxide consumption, during hypoxaemic compared to hyperoxaemic hypercapnia. Cerebral blood flow increased during both hyperoxaemic and hypoxaemic hypercapnia, but was lower during hypoxaemic compared to hyperoxaemic hypercapnia. The results suggest a role for oxidative–nitrosative stress in the comparatively impaired cerebral blood flow response during hypoxaemic hypercapnia, and indicates the reduction of nitrite to nitrogen oxide as an important mediator of cerebrovascular vasodilatation during hypoxia and hypercapnia. As noted by Bailey et al. (2024), there are several caveats and reservations regarding the non-randomized design, the different durations and severity of apnoea, the non-steady-state at end-apnoea, and the inevitable presence of involuntary muscular activity. Nonetheless, the results of this rigorously conducted study contribute to our understanding of the physiology and pathophysiology of cerebral haemodynamic regulation. First, the present results appear to be in line with previous observations of nitric oxide as a central mediator of cerebrovascular function. Second, the cerebral pathophysiology of healthy humans exposed to, as well as the diseases associated with, severe hypoxia and hypercapnia is elucidated. The study is obviously directly relevant for healthy freedivers, who expose themselves to hyperoxaemic and (whether voluntarily or accidentally) hypoxaemic hypercapnia. Furthermore, obstructive sleep apnoea, which is characterized by repeated episodes during sleep of partial or complete upper airway obstruction, leading to hypercapnia, hypoxaemia and disrupted sleep, is notably associated with an increased risk of stroke. Although increased sympathetic activity and hypertension may also be involved, future studies could address whether the cerebrovascular response to hypoxaemia and hypercapnia, with ensuing oxidative–nitrosative stress, may lead to ischaemia, infarction and clinical brain injury in these patients. Finally, combined hypoxaemia and hypercapnia commonly occurs during severe respiratory failure; here, hypoxaemia should probably be perceived as potentially more dangerous to the brain, at least in terms of oxidative–nitrosative stress, than hyperoxaemia applied for resuscitative purposes. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. No competing interests declared. K.M. was responsible for the conception or design of the work, drafting the work or revising it critically for important intellectual content and final approval of the version submitted for publication. K.M. agrees to be accountable for all aspects of the work. Kirsten Møller has received funding from Novo Nordisk Fonden (ref. NNF20OC0065750), the Danish Victims' Foundation (ref. 20-610-00103) and Rigshospitalet's Board of Research (ref. NA).