Reactive oxygen species and cyclooxygenase products explain the majority of hypoxic cerebral vasodilation in healthy humans

Abstract

Aim:The role of reactive oxygen species (ROS) in human cerebral blood flow (CBF) during hypoxia is largely unknown. Additionally, it is unknown whether ROS interact with cyclooxygenase-derived signals during hypoxia to increase CBF. We hypothesized ROS inhibition would reduce hypoxic CBF, and combined inhibition of cyclooxygenase (COX) and ROS would decrease hypoxic CBF more than ROS suppression alone. Methods: We measured middle cerebral artery velocity with transcranial Doppler ultrasound in 12 healthy adults during normoxia and 2 isocapnic hypoxia trials.Intravenous ascorbic acid infusion during the first hypoxia trial suppressed ROS.Oral indomethacin inhibited COX between hypoxia trials. The second bout of hypoxia tested the combined effects of ROS and COX inhibition. Middle cerebral artery velocity was normalized for blood pressure as cerebrovascular conductance index. Results: Hypoxia increased cerebrovascular conductance index in both trials (P < 0.05). Ascorbic acid infusion did not alter cerebrovascular conductance index during hypoxia. Combined ascorbic acid and indomethacin significantly reduced hypoxia-mediated increases in cerebrovascular conductance index from 17 ± 2 to 4 ± 1 cm s −1 100 mm Hg −1 (P < 0.05). Conclusion: ROS are not obligatory for hypoxic cerebral vasodilation. Current data indicate ROS and COX together may account for the majority of the increase in CBF through the middle cerebral artery during hypoxia. These data are the first to demonstrate compensatory hypoxic vasodilatory signalling in human cerebral circulation. K E Y W O R D S cerebral blood flow, cyclooxygenase, hypoxia, reactive oxygen species PAQ (kcal wk −1 ) 2281 ± 546 Note: Values are mean ± SE. Abbreviations: BMI, body mass index; BP, blood pressure; HbA 1C , glycated hemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoproteins; PAQ, physical activity questionnaire.

Environment and exposure

“…15 While, in general, altitude acclimatization can be considered a rather rare form of environmental exposure reaction, altitude physiology helps us understand other mechanistically related pathophysiological phenomena such as hypoxic cerebral vasodilation. 16 Zhang et al recently showed how keratins may counteract pulmonary artery remodelling, a major pathophysiological event in the development of pulmonary artery hypertension, which, in turn, leads to progressively increased pulmonary vascular resistance and right heart dysfunction, 17 with potential implications for novel therapeutic approaches. 18 In a similar line, Strielkov et al described how epoxygenase-derived epoxyeicosatrienoic acids are involved in the regulation of pulmonary vascular tone, and may thus be utilized therapeutically for treatment of hypoxic pulmonary vasoconstriction and related diseases.…”

Scratching the surface of hypoxic cerebral vascular control: a potentially polarizing view of mechanistic research in humans

“…2016), albeit prostaglandins appear to interact with reactive oxygen species to regulate CBF in hypoxia (Harrell et al . 2019). Unfortunately, no study has utilized volumetric measures of CBF to investigate the influence of nitric oxide on hypoxic cerebral vasodilatation.…”

“…To this effect, while ‘scratching the surface’ has not yet provided clear insights into the regulation of cerebral hypoxic vasodilatation, there remains utility in interrogating the specific pathways to precisely discern the independent and interacting roles of these pathways in the control of hypoxic cerebral vasodilatation (Harrell et al . 2019).…”

“…For instance, we have demonstrated, through theophylline administration, that adenosine is presumably not required to induce hypoxic cerebral vasodilatation (Hoiland et al 2017). Similarly, prostaglandin signalling has not been implicated as obligatory for hypoxic cerebral vasodilatation (Hoiland et al 2016), albeit prostaglandins appear to interact with reactive oxygen species to regulate CBF in hypoxia (Harrell et al 2019). Unfortunately, no study has utilized volumetric measures of CBF to investigate the influence of nitric oxide on hypoxic cerebral vasodilatation.…”

Recent advances in blood pressure research

“…Investigating the mechanisms of blood pressure regulation was again a focus of a number of articles published in Acta physiologica in the recent year. The research on basic physiological questions and mechanism in model organisms is complemented with studies that include clinical patient data …”