The role of nitrite in nitric oxide homeostasis: A comparative perspective

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Nitrite is endogenously produced as an oxidative metabolite of nitric oxide, but it also functions as a NO

donor that can be activated by a number of cellular proteins under hypoxic conditions. This article discusses

the physiological role of nitrite and nitrite-derived NO in blood flow regulation and cytoprotection from a

comparative viewpoint, with focus on mammals and fish. Constitutive nitric oxide synthase activity results in

similar plasma nitrite levels in mammals and fish, but nitrite can also be taken up across the gills in

freshwater fish, which has implications for nitrite/NO levels and nitrite utilization in hypoxia. The nitrite

reductase activity of deoxyhemoglobin is a major mechanism of NO generation from nitrite and may be

involved in hypoxic vasodilation. Nitrite is readily transported across the erythrocyte membrane, and the

transport is enhanced at low O2 saturation in some species. Also, nitrite preferentially reacts with

deoxyhemoglobin rather than oxyhemoglobin at intermediate O2 saturations. The hemoglobin nitrite

reductase activity depends on heme O2 affinity and redox potential and shows species differences within

mammals and fish. The NO forming capacity is elevated in hypoxia-tolerant species. Nitrite-induced

vasodilation is well documented, and many studies support a role of erythrocyte/hemoglobin-derived NO.

Vasodilation can, however, also originate from nitrite reduction within the vessel wall, and at present there is

no consensus regarding the relative importance of competing mechanisms. Nitrite reduction to NO provides

cytoprotection in tissues during ischemia-reperfusion events by inhibiting mitochondrial respiration and

limiting reactive oxygen species. It is argued that the study of hypoxia-tolerant lower vertebrates and diving

mammals may help evaluate mechanisms and a full understanding of the physiological role of nitrite.

TidsskriftBiochimica et Biophysica Acta - Bioenergetics
Sider (fra-til)841-848
StatusUdgivet - 2009