title: Modeling hemoglobin nitrite reductase activity as a mechanism of hypoxic vasodilation?
abstract: The brain's response to hypoxia is to increase cerebral blood flow (CBF). However, the molecular mechanism underpinning this phenomenon is controversial. We have developed a model to simulate brain blood flow and oxygen metabolism called BRAINSIGNALS. This model is primarily designed to assist in the interpretation of multimodal noninvasive clinical measurements. However, we have recently used this model to test the feasibility of a range of molecular mechanisms proposed to explain hypoxic vasodilation. An increase in the concentration of the vasodilator nitric oxide (NO) at low pO2 is a feature of many such mechanisms. One model suggests that mitochondrial cytochrome c oxidase (CCO) catalyzes the metabolism of NO. This metabolism declines at low pO2, resulting in an increase in the steady-state levels of NO and a consequent increase in CBF. Using BRAINSIGNALS we were able to model this effect. However, the increases in NO and CBF occurred at far lower pO2 values than predicted from physiological data (Rong et al. 2013 Adv Exp Med Biol. 765, 231-238). The aim of the present study was to test an alternative mechanism, one that actively generates NO as pO2 drops, namely, the reduction of nitrite to NO by deoxyhemoglobin. In this mechanism, NO synthesis has a maximum of NO production near the hemoglobin p50. The addition of this mechanism resulted in a significantly better fit to the experimental data of the CBF(PaO2) curve.
authors.affiliation: School of Biological Sciences, University of Essex, Colchester, CO4 3SQ, UK. zimeirong@hotmail.com.
authors.forename: Zimei
authors.initials: Z
authors.lastname: Rong
authors.affiliation: School of Biological Sciences, University of Essex, Colchester, CO4 3SQ, UK.
authors.forename: Chris E
authors.initials: CE
authors.lastname: Cooper
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000201:enzymology / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000502:physiology; D004285:Dogs; D006454:Hemoglobins / Q000378:metabolism*; D000860:Hypoxia / Q000201:enzymology / Q000378:metabolism*; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism; D009572:Nitrite Reductases / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D014664:Vasodilation
chemical_list: D006454:Hemoglobins; D009569:Nitric Oxide; C100003:deoxyhemoglobin; D009572:Nitrite Reductases; D010100:Oxygen