Can Mitochondrial Cytochrome Oxidase Mediate Hypoxic Vasodilation Via Nitric Oxide Metabolism?
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.
KeywordsCytochrome oxidase Hypoxic vasodilation Nitric oxide
This work is financially supported by the Leverhulme Trust.
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