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Hemoglobin Effects on Nitric Oxide Mediated Hypoxic Vasodilation

Rong, Zimei and Cooper, Chris E (2016) 'Hemoglobin Effects on Nitric Oxide Mediated Hypoxic Vasodilation.' Advances in Experimental Medicine and Biology, 876. pp. 121-127. ISSN 0065-2598

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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.

Item Type: Article
Uncontrolled Keywords: Hemoglobin; Nitric oxide; Hypoxic vasodilation; Nitrite; Nitrite reductase activity
Subjects: Q Science > QP Physiology
Divisions: Faculty of Science and Health
Faculty of Science and Health > Life Sciences, School of
SWORD Depositor: Elements
Depositing User: Elements
Date Deposited: 18 Apr 2016 09:57
Last Modified: 15 Jan 2022 00:21

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