Hemoglobin Effects on Nitric Oxide Mediated Hypoxic Vasodilation

  • Zimei RongEmail author
  • Chris E. Cooper
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 876)


The brain responds to hypoxia with an increase in cerebral blood flow (CBF). However, such an increase is generally believed to start only after the oxygen tension decreases to a certain threshold level. Although many mechanisms (different vasodilator and different generation and metabolism mechanisms of the vasodilator) have been proposed at the molecular level, none of them has gained universal acceptance. Nitric oxide (NO) has been proposed to play a central role in the regulation of oxygen supply since it is a vasodilator whose production and metabolism are both oxygen dependent. We have used a computational model that simulates blood flow and oxygen metabolism in the brain (BRAINSIGNALS) to test mechanism by which NO may elucidate hypoxic vasodilation. The first model proposed that NO was produced by the enzyme nitric oxide synthase (NOS) and metabolized by the mitochondrial enzyme cytochrome c oxidase (CCO). NO production declined with decreasing oxygen concentration given that oxygen is a substrate for nitric oxide synthase (NOS). However, this was balanced by NO metabolism by CCO, which also declined with decreasing oxygen concentration. However, the NOS effect was dominant; the resulting model profiles of hypoxic vasodilation only approximated the experimental curves when an unfeasibly low Km for oxygen for NOS was input into the model. We therefore modified the model such that NO generation was via the nitrite reductase activity of deoxyhemoglobin instead of NOS, whilst keeping the metabolism of NO by CCO the same. NO production increased with decreasing oxygen concentration, leading to an improved reproduction of the experimental CBF versus PaO2 curve. However, the threshold phenomenon was not perfectly reproduced. In this present work, we incorporated a wider variety of oxygen dependent and independent NO production and removal mechanisms. We found that the addition of NO removal via oxidation to nitrate mediated by oxyhemoglobin resulted in the optimum fit of the threshold phenomenon by the model. Our revised model suggests, but does not prove, that changes in NO concentration can be the primary cause of the relationship between pO2 and cerebral blood flow.


Hemoglobin Nitric oxide Hypoxic vasodilation Nitrite Nitrite reductase activity 



This work is financially supported by the Leverhulme Trust.


  1. 1.
    Brown M, Wade J, Marshall J (1985) Fundamental importance of arterial oxygen content in the regulation of cerebral blood flow in man. Brain 108:81–93CrossRefPubMedGoogle Scholar
  2. 2.
    Rong Z, Banaji M, Moroz T, Cooper CE (2013) Can mitochondrial cytochrome oxidase mediate hypoxic vasodilation via nitric oxide metabolism? Adv Exp Med Biol 765:231–238CrossRefPubMedGoogle Scholar
  3. 3.
    Gladwin MT, Kim-Shapiro DB (2008) The functional nitrite reductase activity of the heme-globins. Blood 112:2636–2647CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    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 U S A 104:18508–18513CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Rong Z, Cooper CE (2013) Modeling hemoglobin nitrite reductgase activity as a mechanism of hypoxic vasodilation? Adv Exp Med Biol 789:361–368CrossRefPubMedGoogle Scholar
  6. 6.
    Antunes F, Boveris A, Cadenas E (2007) On the biological role of the reaction of NO with oxidized cytochrome c oxidase. Antioxid Redox Signal 9:1569–1579CrossRefPubMedGoogle Scholar
  7. 7.
    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
  8. 8.
    Monod J, Wyman J, Changeux J (1965) On the nature of allosteric transitions: a plausible model. J Mol Biol 12:88–118CrossRefPubMedGoogle Scholar
  9. 9.
    Patel RP, Hogg N, Kim-Shapiro DB (2011) The potential role of the red blood cell in nitrite-dependent regulation of blood flow. Cardiovasc Res 89:507–515CrossRefPubMedGoogle Scholar
  10. 10.
    Rong Z, Wilson MT, Cooper CE (2013) A model for the nitric oxide producing nitrite reductase activity of hemoglobin as a function of oxygen saturation. Nitric Oxide 33:74–80CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, New York 2016

Authors and Affiliations

  1. 1.Centre for English Language EducationUniversity of Nottingham Ningbo ChinaNingboChina
  2. 2.School of Biological SciencesUniversity of EssexColchesterUK

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