Nitrite protects against morbidity and mortality associated with TNF- or LPS-induced shock in a soluble guanylate cyclase–dependent manner

Abstract

Nitrite (NO2−), 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) α1 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.

Gaseous Mediators in Temperature Regulation

“…Although it is not a study investigating specifically the peripheral role of NO, it has been shown that the LPS-induced anapyrexia is potentiated in terms of magnitude and duration in mice deficient in iNOS (294), indicating that the absence of NO seems to impair the recovery of mechanisms of thermogenesis necessary to restore T b to basal levels as LPS is being eliminated from the circulation or neutralized (see Table 4). In support to this speculation, it has been shown that peripheral administration of nitrite-which serves as a hypoxic/acidic NO donor in appropriate hypoxic/acidic organs-reduces magnitude and duration of the LPS-induced anapyrexia in mice (60). Exciting is the possibility of using nitrite to regulate shock, which might be considered by translating the results from mouse models to the clinic (59).…”

Surviving a Massive Sodium Azide Poisoning with Toxic Cardiomyopathy

“…Buys et al reported in mice a protective effect of nitric oxide against cardiac dysfunction caused by inflammatory shock, known to interfere with mitochondrial respiration, mediated by soluble guanylate cyclase producing cyclic guanosin monophosphate 7 . Cauwels et al found that nitrite had a protective effect on mitochondrial respiration and improved cellular energetics against TNFmediated inhibition of complexes I and IV of the mitochondrial respiratory chain 8 . We can hypothesize that the nitrates improved the metabolic tolerance of the sodium azide toxicity on the mitochondrial chain.…”

Oral Nitrate Increases Microvascular Reactivity and the Number of Visible Perfused Microvessels in Healthy Volunteers

“…However, most of these data have come from in vitro studies exposing mitochondria to very high NO concentrations. Several other studies have pointed toward protective roles for the mitochondria under hypoxic conditions by increasing the ATP production-to-VO 2 ratio [36], by inducing a state of “short-term hibernation” [52] and even improving the mitochondrial tolerance under hypoxic conditions in animal models of sepsis [53]. Finally, one should also consider the potential risks associated with an increase in peroxynitrites, especially if hypoxia persists [54], and of methemoglobinemia, although this would only be a concern if much higher doses were administered [20,55].…”