Nitrite (NO(2)(-)), previously viewed as a physiologically inert metabolite and
biomarker of the endogenous
vasodilator NO, was recently identified as an important
biological NO reservoir in vasculature and tissues, where it contributes to hypoxic signaling, vasodilation, and cytoprotection after
ischemia-reperfusion injury. Reduction of
nitrite to NO may occur enzymatically at low pH and
oxygen tension by
deoxyhemoglobin,
deoxymyoglobin,
xanthine oxidase, mitochondrial complexes, or
NO synthase (NOS). We show that
nitrite treatment, in sharp contrast with the worsening effect of NOS inhibition, significantly attenuates
hypothermia, mitochondrial damage, oxidative stress and dysfunction, tissue
infarction, and mortality in a mouse
shock model induced by a lethal
tumor necrosis factor challenge. Mechanistically,
nitrite-dependent protection was not associated with inhibition of mitochondrial complex I activity, as previously demonstrated for
ischemia-reperfusion, but was largely abolished in mice deficient for the
soluble guanylate cyclase (sGC) alpha1 subunit, one of the principal intracellular NO receptors and signal transducers in the cardiovasculature.
Nitrite could also provide protection against toxicity induced by Gram-negative
lipopolysaccharide, although higher doses were required. In conclusion, we show that
nitrite can protect against toxicity in
shock via sGC-dependent signaling, which may include hypoxic vasodilation necessary to maintain microcirculation and organ function, and cardioprotection.