Can Mitochondrial Cytochrome Oxidase Mediate Hypoxic Vasodilation Via Nitric Oxide Metabolism?

  • Zimei Rong
  • Murad Banaji
  • Tracy Moroz
  • Chris E. Cooper
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 765)


The brain responds to hypoxia with an increase in cerebral blood flow (CBF). Many mechanisms have been proposed for this hypoxic vasodilation, but none has gained universal acceptance. Although there is some disagreement about the shape of the relationship between arterial oxygen partial pressure (PaO2) and CBF, it is generally agreed that CBF does not increase until the PaO2 reaches a threshold value. We used a previously published computational model of brain oxygen transport and metabolism (BRAINSIGNALS) to test possible molecular mechanisms for such a threshold phenomenon. One suggestion has been that a decrease in the metabolism of nitric oxide by mitochondrial cytochrome c oxidase (CCO) at low PaO2 could be responsible for raising NO levels and the consequent triggering of the hypoxic blood flow increase. We tested the plausibility of this mechanism using the known rate constants for NO interactions with CCO. We showed that the shape of the CBF–PaO2 curve could indeed by reproduced, but only if NO production by the enzyme nitric oxide synthase had a very low Michaelis constant Km for oxygen. Even then, in the current version of BRAINSIGNALS the NO-induced CBF rise occurs at much lower PaO2 than is consistent with the in vivo data.


Cytochrome oxidase Hypoxic vasodilation Nitric oxide 



This work is financially supported by the Leverhulme Trust.


  1. 1.
    Shimojyo S, Scheinberg P, Kogure K et al (1968) The effect of graded hypoxia upon transient cerebral blood flow and oxygen consumption. Neurology 18:127–133CrossRefGoogle Scholar
  2. 2.
    Gjedde A (2002) Cerebral blood flow change in arterial hypoxemia is consistent with negligible oxygen tension in brain mitochondria. NeuroImage 17:1876–1881CrossRefGoogle Scholar
  3. 3.
    Grubb B, Colacino JM, Schmidt-Nielsen K (1978) Cerebral blood flow in birds: effect of hypoxia. Am J Physiol 234 (Heart Circ Physiol 3(3)):H230–H234CrossRefGoogle Scholar
  4. 4.
    Grubb B, Jones JH, Schmidt-Nielsen K (1979) Avian cerebral blood flow: influence of the Bohr effect on oxygen supply. Am J Physiol 234 (Heart Circ Physiol 5(5)):H744–H749CrossRefGoogle Scholar
  5. 5.
    Palacios-Callender M, Hollis V, Mitchison M et al (2007) Cytochrome c oxidase regulates endogenous nitric oxide availability in respiring cells: a possible explanation for hypoxic vasodilation. Proc Natl Acad Sci USA 104:18508–18513CrossRefGoogle Scholar
  6. 6.
    Brown MM, Wade JPH, Marshall J (1985) Fundamental importance of arterial oxygen content in the regulation of cerebral blood flow in man. Brain 108:81–93CrossRefGoogle Scholar
  7. 7.
    Kogure K, Scheinberg P, Reinmuth OM et al (1970) Mechanisms of cerebral vasodilatation in hypoxia. J Appl Physiol 29:223–229CrossRefGoogle Scholar
  8. 8.
    McDowall DG (1966) Interrelationship between blood oxygen tensions and cerebral blood flow. In: Payne JP, Hill DW (eds) Oxygen measurements in blood and tissue and their significance. Churchill, London, pp 205–219Google Scholar
  9. 9.
    Gupta AK, Menon DK, Czosnyka M et al (1997) Threshold for hypoxic cerebral vasodilation in volunteers. Anesth Analg 85:817–820CrossRefGoogle Scholar
  10. 10.
    Ellingsen I, Hauge A, Nicolaysen G et al (1987) Changes in human cerebral blood flow due to step changes in PAO2 and PACO2. Acta Physiol Scand 129:157–163CrossRefGoogle Scholar
  11. 11.
    Banaji M, Mallet A, Elwell CE et al (2008) A model of brain circulation and metabolism: NIRS signal changes during physiological challenges. PLoS Comput Biol 4(11):e1000212. doi: 10.1371/journal.pcbi.1000212 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    BRAINCIRC: an open source modelling environment. Brain signal model:
  13. 13.
    Cooper CE (2002) Nitric oxide and cytochrome oxidase: substrate, inhibitor or effector? Trend Biochem Sci 27:33–39CrossRefGoogle Scholar
  14. 14.
    Antunes F, Boveris A, Cadenas E (2007) On the biological role of the reaction of NO with oxidized cytochrome c oxidase. Antioxid Redox Signal 9:1569–1579CrossRefGoogle Scholar
  15. 15.
    Golanov EV, Christenson JRC, Reis DJ (2001) Neurons of a limited subthalamic area mediate elevations in cortical cerebral blood flow evoked by hypoxia and excitation of neurons of the rostral ventrolateral medulla. J Neurosci 21:4032–4041CrossRefGoogle Scholar
  16. 16.
    Crawford JH, Isbell TS, Huang Z et al (2006) Hypoxia, red blood cells, and nitrite regulate NO-dependent hypoxic vasodilation. Blood 107:566–574CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Zimei Rong
    • 1
    • 2
    • 3
  • Murad Banaji
    • 1
    • 2
  • Tracy Moroz
    • 1
    • 2
  • Chris E. Cooper
    • 1
    • 2
  1. 1.Department of Biological SciencesUniversity of EssexColchesterUK
  2. 2.Department of Medical Physics and BioengineeringUniversity College LondonLondonUK
  3. 3.University of EssexIlford, EssexUK

Personalised recommendations