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Cited by 115Sulfur Compounds in BiologyNitric Oxide and Endothelin EffectsRedox biology and oxidative stress

On the chemical biology of the nitrite/sulfide interaction

Open access
Cortese-Krott, Miriam M., Fernandez, Bernadette O., Kelm, Malte, Butler, Anthony R., Feelisch, Martin·2015·Nitric Oxide
DOI 10.1016/j.niox.2014.12.009
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Abstract

Sulfide (H2S/HS(-)) has been demonstrated to exert an astounding breadth of biological effects, some of which resemble those of nitric oxide (NO). While the chemistry, biochemistry and potential pathophysiology of the cross-talk between sulfide and NO have received considerable attention lately, a comparable assessment of the potential biological implications of an interaction between nitrite and sulfide is lacking. This is surprising inasmuch as nitrite is not only a known bioactive oxidation product of NO, but also efficiently converted to S-nitrosothiols in vivo; the latter have been shown to rapidly react with sulfide in vitro, leading to formation of S/N-hybrid species including thionitrite (SNO(-)) and nitrosopersulfide (SSNO(-)). Moreover, nitrite is used as a potent remedy against sulfide poisoning in the clinic. The chemistry of interaction between nitrite and sulfide or related bioactive metabolites including polysulfides and elemental sulfur has been extensively studied in the past, yet much of this information appears to have been forgotten. In this review, we focus on the potential chemical biology of the interaction between nitrite and sulfide or sulfane sulfur molecules, calling attention to the fundamental chemical properties and reactivities of either species and discuss their possible contribution to the biology, pharmacology and toxicology of both nitrite and sulfide.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that nitrite and sulfide do not react directly at biological pH, but can form reactive intermediates such as HSNO and the more stable SSNO⁻ after nitrite is converted to nitrosating species or via sulfur species in aprotic environments. It discusses the potential biological and pharmacological implications of these S/N-hybrid products and calls for experimental confirmation.

Key findings

  • At pH 7.4, the direct reaction of nitrite with HS⁻ is described as “encounter controlled and impossibly slow”; a calculation at pH 6 with 10⁻⁵ M nitrite and H₂S gives a rate of 1.6 × 10⁻¹⁵ M s⁻¹.
  • Under acidic conditions, nitrite forms nitrosating species ([H₂NO₂]⁺ at pH < 3; N₂O₃ at pH 3–7), which nitrosate HS⁻ to HSNO; HSNO can react with excess sulfide to form SSNO⁻, which is stable in millimolar reduced thiols and can release NO and polysulfides. Prior work cited by the review found SSNO⁻ releases NO and induces sGC-dependent cGMP production in cells.
  • In polar aprotic solvents, nitrite reacts efficiently with elemental sulfur (S₈) and polysulfides to form NO/N₂O and SSNO⁻ (λmax 448 nm), but this does not occur in water; aqueous nitrite/sulfide mixtures produced a trace photolabile NO-containing species detected by gas-phase chemiluminescence, whereas nitrite or sulfide alone produced no signal.
  • Preliminary rat data showed acute and chronic NaNO₂ reduced aortic total sulfide levels, with no changes in other tissues; chronic nitrite vs control p = 0.049, acute nitrite vs control p = 0.068 (non-significant), with group sizes control n = 4, acute n = 2, chronic n = 2.

Methods

  • Narrative review synthesizing older and recent literature on nitrite/sulfide chemistry and proposing a unified reaction scheme.
  • Includes unpublished experiments: equimolar nitrite/NaHS (50 mM each in Tris buffer pH 7.4 with DTPA) with gas-phase chemiluminescence after light or copper exposure; UV-visible spectrometry of nitrite with S₈/polysulfides in DMSO; and rat tissue sulfide measurement by methylene blue assay after acute or chronic NaNO₂.
  • Main analysis is chemical reasoning, rate calculations, product assignments, and comparison with cited studies; no systematic review methodology is stated.

Limitations

  • The paper states that the biological relevance of the nitrite/sulfide interaction is currently unclear, speculative, and needs experimental confirmation; detection of SSNO⁻ in cells/tissues has not yet been accomplished, and recent characterization of HSNO at physiological pH is described as surprising.
  • Evident from the text: the review is not systematic; several key observations are unpublished; in vivo groups are very small (n = 2 acute/chronic, n = 4 control); the photolabile NO-containing product was not further characterized; and no in vivo evidence for SSNO⁻ generation is presented.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.niox.2014.12.009

Cites

110 of 110 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 103 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    At pH 7.4, according to our calculations, the reaction of nitrite with HS- becomes encounter controlled and impossibly slow.

    “At pH 7.4 vanishingly low concentrations of [H2NO2] + are expected in nitrite-containing aqueous solutions and according to our calculations (see Appendix: Supplementary materials), the reaction of nitrite with HS -becomes encounter controlled and impossibly slow.”
    Quote in the paperSubstantial claim
  • Findingown data

    In our hands, mixtures of buffered aqueous solutions of sulfide and nitrite always contain small amounts of a photolabile NO-containing species.

    “Nevertheless, in our hands, mixtures of buffered aqueous solutions of sulfide/nitrite always contain small amounts of a photolabile NO-containing species (Fig. 1; unpublished data).”
    Quote in the paperSubstantial claim
  • Findingown data

    Using UV-visible spectrometry, we found that nitrite reacts with S8 (and under some conditions also with polysulfides) to form an NO-containing yellow compound with λmax 448 nm.

    “Using UV-visible spectrometry we found that nitrite reacts with S8 (and under some conditions also with polysulfides) to form an NO-containing yellow compound with λmax 448 nm (Fig. 1B-D; unpublished data).”
    Quote in the paperSubstantial claim
  • Findingreasoning

    At pH 6 with nitrite and H2S each at 10^-5 M, the concentration of HS- is 1.3 × 10^-6 M.

    “The concentration of HS -at this pH is 1.3 × 10 -6 M”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The pH is 6 in the calculation.
    • The authors state this as an assumption: The concentrations of both nitrite and H2S are 10^-5 M in the calculation.
  • Findingreasoning

    At pH 6 with nitrite and H2S each at 10^-5 M, the concentration of N2O3 is 3 × 10^-19 M.

    “while the concentration of N2O3 at this pH is only 3 × 10 -19 M”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The pH is 6 in the calculation.
    • The authors state this as an assumption: The concentrations of both nitrite and H2S are 10^-5 M in the calculation.
  • May combine two claims. 52
  • Classified as probably not a substantial claim. 23

  • May combine two claims.

    Findingown data

    Equimolar nitrite/sulfide mixtures exposed to high-intensity white light or copper produce a clear NO signal by gas phase chemiluminescence, whereas nitrite or sulfide alone produce no signal under these conditions.

    “When equimolar mixtures of nitrite and sulfide (50 mM each in Trisbuffer at pH 7.4 with diethylenetriaminepentaacetic acid (DTPA) at room temperature) are pre-incubated for more than a couple of minutes 1 , injected into the reaction chamber, and then exposed to high-intensity white light (Fig. 1) or copper (not shown) a clear NO signal can be detected by gas phase chemiluminescence, whereas nitri”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    SSNO- was able to release NO and induce sGC-dependent cGMP production in cells.

    “Indeed, we found that SSNO -was able to release NO and induce sGC-dependent cGMP production in cells [19], but its detection in cells/tissues necessitates development of specific and sufficiently sensitive analytical methods, a task that has not yet been accomplished.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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  • May combine two claims.

    Findingown data

    In preliminary experiments, both acute and chronic administration of sodium nitrite markedly reduced aortic sulfide levels, while no changes were seen in any other tissues.

    “In preliminary experiments, both acute and chronic administration of sodium nitrite markedly reduced aortic sulfide levels, while no changes whatsoever were seen in any other tissues (Fig. 1D; unpublished data).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Acute nitrite (5 min after i.p.) versus control in aorta shows p = 0.068, non significant.

    “§ p = 0.068 acute nitrite vs. control, non significant.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Nitrite is a weak nucleophile and, in aqueous conditions at biological pH, will not easily react with electrophiles.

    “Nitrite is a weak nucleophile [40], and in aqueous conditions and at biological pH, it will not easily react with electrophiles, also because of the solvation effects of water molecules.”
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  • May combine two claims.

    Premisecitation

    At physiological pH, H2S exists largely (75-80%) as the hydrosulfide anion HS-, with negligible S2- and very little dissolved uncharged gas.

    “Therefore, at physiological pH H2S exists largely (75-80%) in the form of the hydrosulfide anion (HS -), with negligible amounts of S 2- [8,9], and very little of it is in the form of the dissolved uncharged gas [9].”
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  • May combine two claims.

    Interpretationreasoning

    At higher pH, HNO2 is in equilibrium with N2O3, which nitrosates HS- and also leads to formation of HSNO.

    “At higher pH, HNO2 is in equilibrium with its anhydride N2O3 (Eq.4), which will nitrosate HS -as described for thiolates in Eq. 7, also leading to formation of HSNO.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    HSNO can undergo homolysis to give NO and the thiyl radical, followed by dimerization to disulfane (HSSH), which deprotonates to form hydrodisulfide or persulfide (HSS-).

    “Similarly to other nitrosothiols, HSNO can undergo homolysis to give NO and the thiyl radical (Eq.10), followed by dimerization leading to formation of disulfane (HSSH), which deprotonates to form hydrodisulfide or persulfide (HSS -).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Nitrite reacts very efficiently with elemental sulfur in polar aprotic solvents under deaerated conditions, and the reaction leads to formation of NO and N2O.

    “Indeed nitrite reacts very efficiently with elemental sulfur in polar aprotic solvents (albeit not in water [66][67][68]) under deaerated conditions [66,67], and according to Seel et al. [68], the reaction leads to formation of NO and N2O.”
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  • May combine two claims.

    Premisecitation

    All energy barriers to isomerization of HSNO isomers are small because of the mobile hydrogen, and all isomers appear to degrade thermally or rapidly polymerize.

    “Whatever the truth of the matter, all the energy barriers to isomerization are small because of the mobile hydrogen, and all isomers appear to degrade thermally to unknown products or rapidly polymerize [53,55].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    There are four isomers with the formula HNSO, HOSN, HSNO, HONS and their corresponding anions, and all have been characterized.

    “There are four isomers with the same formula (HNSO, HOSN, HSNO, HONS and their corresponding anions, respectively; Eq. 13) [56]), and all have been characterized.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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  • May combine two claims.

    Premisecitation

    The reaction of nitrite with polysulfide or sulfur in aqueous solution does not occur, although it is predicted to be thermodynamically favorable and highly exothermic.

    “The reaction of nitrite with polysulfide or sulfur in aqueous solution, although predicted to be thermodynamically favorable and highly exothermic [68], does not occur.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] source

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  • May combine two claims.

    Interpretationreasoning

    The reaction of HS- with HSNO is second order, so at higher hydrosulfide concentrations it dominates.

    “This is a second order reaction (rate = k[HSNO][HS -]) and so, while negligible at low concentrations of HS -, at higher hydrosulfide concentrations it dominates.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Nitrite may form NO via deoxyhemoglobin, deoxymyoglobin, xanthine oxidoreductase-mediated reduction, spontaneous disproportionation, or carbonic anhydrase-facilitated disproportionation.

    “Nitrite may form NO either via deoxyhemoglobin (deoxyHb, Fe II Hb) [80,81], deoxymyoglobin [82] or xanthine oxidoreductase (XOR)-mediated reduction [83], or via spontaneous [84] and carbonic anhydrase-facilitated disproportionation [85].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
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  • May combine two claims.

    Interpretationcitation

    Taken together, nitrite reacts with S8 and, seemingly less efficiently, with polysulfides in non-aqueous polar solvents to form products including SSNO-.

    “Taken together, nitrite reacts with S8 and, seemingly less efficiently, with polysulfides in non-aqueous polar solvents leading to the formation of similar products as observed previously in the reaction of NO with sulfide [69], and nitrosothiols with thiols [70], and with sulfide [19,71] including SSNO -.”
    Quote in the paperSubstantial claim0 of 4 sources checked
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  • May combine two claims.

    Premisenone given

    Most nitrite-to-NO processes show clear oxygen-dependence, and several are favored by low oxygen tension.

    “Most of these processes show a clear oxygen-dependence, and several are favored by low oxygen tension.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The nitrate-nitrite-NO cycle offers a conceptually attractive explanation for the blood pressure lowering and cardioprotective effects of diets rich in nitrate.

    “This nitrate-nitrite-NO cycle offers a conceptually attractive explanation for the blood pressure lowering and cardioprotective effects of diets rich in nitrate and may provide the molecular basis for past and future therapeutic uses of nitrite/nitrate [20,25], although definitive chemical evidence for the significance of this pathway under physiological conditions is still lacking.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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  • Classified as probably not a substantial claim.

    Premisecitation

    Earlier studies showed that nitrite can be reduced to NO following direct reaction with sulfide.

    “However, sulfide may facilitate nitrite reduction to NO via interaction with Fe 3+ protoporphyrin [30], while earlier studies showed that nitrite can be reduced to NO following direct reaction with sulfide [31,32].”
    Quote in the paperSubstantial claim0 of 2 sources checked
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  • May combine two claims.

    Premisecitation

    Nitrite can serve as an alternative source of NO and is a molecular entity with intrinsic signaling properties.

    “Alongside the discovery of sulfide as a physiological transmitter, the past decade has witnessed the recognition that nitrite (NO2 -) can serve as an alternative source of NO and is a molecular entity with intrinsic signaling properties [20,21].”
    Quote in the paperSubstantial claim0 of 2 sources checked
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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    H2S has been shown to exert a variety of beneficial biological effects, some of which resemble those of NO and may hold potential for therapeutic exploitation.

    “Hydrogen sulfide (H2S), previously recognized as a noxious, malodorous gas and potent inhibitor of mitochondrial respiration, has been shown to exert a dazzling variety of beneficial biological effects some of which resemble those of nitric oxide (NO) and may hold potential for therapeutic exploitation [1][2][3].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1][2][3]

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  • May combine two claims.

    Premisecitation

    Even nitrate can be reduced to nitrite by mammalian tissues, demonstrating that these anions are not mere end products of oxidative NO metabolism but are subject to partial recycling.

    “Even nitrate (NO3 -) can be reduced to nitrite by mammalian tissues [23,24] demonstrating that these anions are not mere end products of oxidative NO metabolism but subject to partial recycling.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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  • Classified as probably not a substantial claim.

    Premisecitation

    In simple aqueous solutions, nitrite does not appear to react directly with sulfide at any significant rate.

    “These observations appear to be at odds with the notion that in simple aqueous solutions nitrite does not appear to react directly with sulfide, at least not at any significant rate [30].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Nitrite is a known bioactive oxidation product of NO.

    “This is surprising inasmuch as nitrite is not only a known bioactive product of NO oxidation but also efficiently converted to S-nitrosothiols (and other NO metabolites) if administered in vivo [21].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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  • May combine two claims.

    Interpretationreasoning

    Thionitrate can decompose into polysulfide and NO2, which can act as a potent oxidant leading to formation of nitrate and NO and oxidized sulfur metabolites including sulfite, sulfate, thiosulfate and polythionate.

    “Alternatively, thionitrate can decompose into polysulfide and NO2, which can act as potent oxidant leading to the formation of nitrate and NO (from nitrite) and oxidized sulfur metabolites (from sulfide und disulfide) including sulfite, sulfate, thiosulfate and polythionate (from polysulfide).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisenone given

    It is thought that nitrite is the source of NO for vasodilation in hypoxic tissue, but the means whereby NO is released on demand is not known.

    “It is thought that nitrite is the source of NO for vasodilation in hypoxic tissue, but the means whereby NO is released on demand is not known.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Premisenone given

    The nature of the chemical interaction between different species belonging to either the sulfide or the NO stores is far from fully characterized at present.

    “The nature of the chemical interaction between different species belonging to either the sulfide or the NO stores is far from fully characterized at present.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationcitation

    The striking similarities between some effects of NO and sulfide, along with co-operative effects, raise the possibility of cross-talk between these species involving interaction with different proteins and direct chemical interaction.

    “The striking similarities between some of the effects of NO and sulfide, along with intriguing co-operative effects, raise the possibility of a cross-talk between these species [10][11][12][13][14][15][16], involving the interaction with different proteins belonging to the same pathway (e.g.activation of soluble guanylate cyclase by NO and inhibition of phosphodiesterase by sulfide [17]) together”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [10][11][12][13][14][15][16]

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Although polysulfides, and perhaps even S8, are likely to co-exist in certain cells, the significance of these reactions for the biological environment is unclear at present.

    “Although polysulfides, and perhaps even S8, are likely to co-exist in certain cells the significance of these reactions for the biological environment is unclear at present.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Premisenone given

    The chemistry of interaction between nitrite and sulfide or related bioactive metabolites including polysulfides and elemental sulfur has been extensively studied in the past, yet much of this information appears to have been forgotten.

    “The chemistry of interaction between nitrite and sulfide or related bioactive metabolites including polysulfides and elemental sulfur has been extensively studied in the past, yet much of this information appears to have been forgotten.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Several enzymatic and non-enzymatic sources contribute to the existing pool of sulfide in circulation and tissues, with a purportedly essential role in blood pressure regulation.

    “Several enzymatic and non-enzymatic sources have been identified to contribute to the existing pool of sulfide in circulation and tissues [1][2][3], with a purportedly essential role in blood pressure regulation [4].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    Premisecitation

    The existence of sulfide stores was proposed following critical revision and comparison of different concentrations of sulfide in blood, plasma and tissues obtained using different detection methods.

    “The existence of such stores was proposed some time ago following critical revision and comparison of the different concentrations of sulfide in blood, plasma and tissues obtained using different detection methods.”
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    • cites [72]

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  • May combine two claims.

    Interpretationnone given

    HSNO reacts with excess sulfide to form the more stable nitrosopersulfide SSNO-, various nitrogen oxide species including NO, HNO and N2O, and higher oxidized sulfur species including polysulfides, thiosulfate, polythionate and elemental sulfur.

    “HSNO reacts with excess sulfide to form the more stable nitrosopersulfide, (SSNO -), various nitrogen oxide species (including NO, HNO, N2O) and higher oxidized sulfur species (including polysulfides, thiosulfate, polythionate, and elemental sulfur).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    NO, CO and H2S differ in potency and appear to mediate their biological action via different signaling pathways, but their action spectrum shows remarkable overlap.

    “Although this recognition lacks universal agreement [6,7], and the three molecules differ in potency and appear to mediate their biological action via different signaling pathways, their action spectrum shows remarkable overlap.”
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  • May combine two claims.

    Premisecitation

    Sulfide concentrations in rodents are higher in tissues than in blood, and the highest concentrations are observed in the vasculature, rendering the aorta a relevant target for the interaction of nitrite with sulfide.

    “As with nitrite [78], sulfide concentrations in rodents are higher in tissues than in blood, and the highest concentrations are observed in the vasculature [79], rendering the aorta a relevant target for the interaction of nitrite with sulfide.”
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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    SSNO- was first characterized by Seel et al. in the 1980s by 15N-NMR, IR, ESR spectrometry, and X-ray crystallography.

    “SSNO -was first characterized by Seel et al. in the 1980s by 15 N-NMR, IR, ESR spectrometry, and X-ray crystallography.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Sulfur atoms with valence 0 or -1 are called sulfane sulfur and are present not only in S8 but also in polysulfide, polythionate and other sulfur compounds.

    “These sulfur atoms with valence 0 or -1 are called sulfane sulfur and are present not only in S8 but also in polysulfide, polythionate and other sulfur compounds [43,45].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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  • May combine two claims.

    Premisecitation

    SSNO- has pharmacological activity leading to sGC activation with concomitant cGMP formation in cells.

    “Evidence of pharmacological activity of SSNO -leading to sGC activation with concomitant cGMP formation in cells was presented by us recently [19].”
    Quote in the paperSubstantial claim0 of 1 sources checked
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  • May combine two claims.

    Interpretationcitation

    If sulfide is in excess over nitrosothiols (found in tissues typically at nM concentrations), SSNO- is likely to accumulate and may more easily transport and release NO than GSNO or S-nitrosoalbumin.

    “If sulfide is in excess over the nitrosothiol (which are found in tissues typically at nM concentrations), SSNO -is likely to accumulate and may more easily transport and release NO than GSNO or S-nitrosoalbumin [19].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] source

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  • May combine two claims.

    Interpretationreasoning

    A naturally occurring S-nitrosothiol on encountering tissue rich in HS- like the vasculature will immediately transnitrosate to form HSNO first and then the more stable SSNO-, restoring the thiol group to its reduced state.

    “It is possible that a naturally occurring S-nitrosothiol on encountering tissue rich in HS -like the vasculature will immediately transnitrosate to form HSNO first and then the more stable SSNO - (see Figs. 2 and 3), restoring the thiol group to its reduced state.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Both nitrite and sulfide can be converted with relative ease into metabolites with distinct chemical properties whose indirect chemical interaction gives rise to other bioactive metabolites, including SSNO-.

    “However, both can be converted with relative ease into metabolites with distinct chemical properties (e.g.molecules carrying respectively NO + or sulfane sulfur moieties such as N2O3 or DNIC, and polysulfides) the (indirect) chemical interaction of which gives rise to formation of other bioactive”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    SSNO- is a colored species containing a sulfane sulfur and a nitrosonium (NO+) moiety attached to opposite ends of a sulfur atom.

    “SSNO -is a colored species containing a sulfane sulfur and a nitrosonium (NO + ) moiety attached to opposite ends of a sulfur atom.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] source

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  • May combine two claims.

    Interpretationreasoning

    Nitrite and sulfide are both nucleophiles and anions, and as such do not chemically react with each other.

    “Nitrite and sulfide are both nucleophiles and anions, and as such do not chemically react with each other.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The reaction of transnitrosation between nitrosothiols and thiols is very fast, requiring stopped-flow techniques for kinetics.

    “They found the reaction to be very fast, requiring stopped-flow techniques for investigating the kinetics.”
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  • Classified as probably not a substantial claim.

    Interpretationnone given

    The presence of HS- may provide a route for NO release from S-nitrosothiols via transnitrosation to form HSNO.

    “However, the presence of HS -may provide a route for such release assuming formation of HSNO via transnitrosation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    Further products of the reaction might be nitroxyl and nitrous oxide (N2O).

    “As expected, by considering the chemistry of the reaction (Fig. 2), further products of this reaction might be nitroxyl as proposed previously [16,18,30], and nitrous oxide (N2O).”
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      Not checked in the free run.

    • cites [30] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    DNICs are formed in the vasculature from nitrosothiols and are in equilibrium with the nitrosothiol pool.

    “It was proposed that DNICs are formed in the vasculature from nitrosothiols and that they are in equilibrium with the nitrosothiol pool [103,104].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [103] source

      Not checked in the free run.

    • cites [104] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    An encounter of sulfide with nitrosothiols is plausible, making the vasculature a particularly interesting compartment for these interactions.

    “indicating that an encounter of sulfide with nitrosothiols is plausible making the vasculature a particularly interesting compartment for these interactions to occur.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Release of NO+ in its free form does not occur in biological environments; rather the [NO+] moiety is formally transferred from a bound form to another acceptor via a transnitrosation reaction.

    “Release of NO + in its “free” form does not occur in biological environments, rather the [NO + ] moiety is formally transferred from a bound form to another acceptor via a transnitrosation reaction.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Thomas et al. proposed that dinitrosyl-iron-complexes (DNICs) represent the most abundant NO-containing material in biological tissue.

    “Thomas et al. proposed these species to represent the most abundant NOcontaining material in biological tissue [102].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DNICs can be prepared from S-nitrosothiols, suggesting that NO+ transfer from RSNO to iron occurs readily.

    “That they can be prepared from S-nitrosothiols [105] suggests that NO + transfer from RSNO to iron occurs readily.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [105] source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    In non-aqueous polar aprotic solvents, nitrite reacts very efficiently already at room temperature with S8 and, in the presence of sulfide, also with polysulfides leading to accumulation of SSNO-, in turn releasing NO and polysulfides on decomposition.

    “However, in non-aqueous polar aprotic solvents, nitrite reacts very efficiently already at room temperature with S8 and, in the presence of sulfide, also with polysulfides leading to accumulation of SSNO -, in turn releasing NO and polysulfides on decomposition.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    N2O has been detected in exhaled breath of humans.

    “Yet, N2O has been detected in exhaled breath of humans [101].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [101] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    Hypoxic conditions are expected to lower the prevailing pH and increase the availability of H2S/HS- (due to reduced oxidative clearance) and that of nitrosothiols (due to enhanced nitrite reduction and/or metabolic conversion).

    “Hypoxic conditions are expected to lower the prevailing pH and increase the availability of H2S/HS -(due to reduced oxidative clearance) and that of nitrosothiols (due to enhanced nitrite reduction and/or metabolic conversion).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    The reductive and nucleophilic properties of H2S, and its presence in solution mainly in the form of HS-, are likely the most predominant aspects of sulfide chemistry in a biological environment.

    “On the other hand, the reductive and nucleophilic properties of H2S, and its presence in solution mainly in the form of HS -are likely the most predominant aspects of sulfide chemistry in a biological environment.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Nitrosothiols are found at nanomolar concentrations in most biological compartments.

    “Similarly to sulfide, nitrosothiols are found at nanomolar concentrations in most biological compartments;”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    In an aqueous environment the reactivity of nitrite is limited by its weak nucleophilicity and by solvation with water molecules.

    “In an aqueous environment the reactivity of nitrite is limited by its weak nucleophilicity and by solvation with water molecules.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    S-nitrosothiols appear to be more reactive toward sulfide compared to nitrite (and maybe to NO itself).

    “S-nitrosothiols appear to be more reactive toward sulfide compared to nitrite (and maybe to NO itself).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    SSNO- should be sufficiently stable in the reducing environment of the cell; at the same time, it is a better NO releaser than the parent nitrosothiol.

    “SSNO -should be sufficiently stable in the reducing environment of the cell; at the same time, it is a better NO releaser than the parent nitrosothiol [19].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    HSNO is known to readily undergo isomerization, homolysis or polymerization, and to further react with sulfide to form the more stable nitrosopersulfide, SSNO-, along with various nitrogen species (including NO, HNO, N2O) and oxidized sulfur species (including polysulfide, thiosulfate, polythionate, and elemental sulfur, S8).

    “This intermediate is known to readily undergo isomerization, homolysis or polymerization, and to further react with sulfide to form the more stable nitrosopersulfide, SSNO -along with various nitrogen species (including NO, HNO, N2O) and oxidized sulfur species (including polysulfide, thiosulfate, polythionate, and elemental sulfur, S8).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    SSNO- belongs to the class of perthionitrites; in contrast to polysulfides, it is stable in the presence of high concentration of reduced thiols, but can generate both NO and polysulfides at pH 7.4, thus serving as a dual-purpose signaling molecule carrying both sulfane sulfur and NO bioactivity.

    “This molecule belongs to the class of perthionitrites; in contrast to polysulfides, it is stable in the presence of high concentration of reduced thiols, but can generate both NO and polysulfides at pH 7.4, thus serving as a dual-purpose signaling molecules carrying both sulfane sulfur and NO bioactivity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Each of the intermediates and reaction products, including NO, HNO, H(S)S-, H(S)S•, SSNO-, can further react with one another, feeding the reaction forward and increasing the complexity of the reaction equilibria.

    “Each of the intermediates and reaction products, including NO, HNO, H(S)S -, H(S)S•, SSNO -, can further react with one another, all in all feeding the reaction forward and increasing the complexity of the reaction equilibria.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    A further level of interaction could be due to nitrite-derived nitrosothiol formation occasioned by an increase in sulfide levels (due to increased stability and decreased enzymatic breakdown) under hypoxic conditions.

    “A further level of interaction could be due to nitrite-derived nitrosothiol formation occasioned by an increase in sulfide levels (due to increased stability and decreased enzymatic breakdown) under hypoxic conditions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    At acidic pH, nitrite can be converted to the nitrosating species [H2NO2]+ (at pH < 3) and N2O3 (at pH 3-7), leading to nitrosation of HS- to form HSNO.

    “At acidic pH, nitrite can be converted to the nitrosating species [H2NO2] + (at pH < 3) and N2O3 (at pH 3-7), leading to nitrosation of HS -to form the reactive intermediate HSNO.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    HSNO is highly reactive and can isomerize to other similarly unstable species; in the presence of sulfide it can generate either nitroxyl (HNO), which dimerizes under water loss to nitrous oxide or is reduced by sulfide to hydroxylamine.

    “HSNO is highly reactive and can isomerize to other similarly unstable species; in the presence of sulfide it can generate either nitroxyl (HNO), which dimerizes under water loss to nitrous oxide or is reduced by sulfide to hydroxylamine.”
    Quote in the paperSubstantial claim
64 of 64

  • The authors state this as an assumption.

    Some reactions of nitrite with sulfur species occur in regions of the cell that are non-aqueous.

    “Nevertheless, it appears reasonable to assume that some reactions of nitrite with sulfur species occur in regions of the cell that are non-aqueous (Box 4).”

  • The authors state this as an assumption.

    Homolytic cleavage of ONSS- occurs, giving NO and the disulfide radical SS•- as the most likely initial product.

    “Assuming homolytic cleavage of ONSS -, the most likely initial product formed, in addition to NO, is the disulfide radical, SS •- (Eq.22).”

  • The authors state this as an assumption.

    The pH is 6 in the calculation.

    “If we assume that the pH is 6”

  • The authors state this as an assumption.

    The concentrations of both nitrite and H2S are 10^-5 M in the calculation.

    “the concentrations of both nitrite and H2S are 10 -5 M”

  • The authors state this as an assumption.

    N2O3 and HS- react on encounter in the calculation.

    “and that N2O3 and HS -react on encounter”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Aortic sulfide results are cited as the wrong panel

    Minor

    The text directs readers to Fig. 1D for the tissue sulfide results, but the figure caption identifies panel D as a nitrite-sulfur reaction and panel E as the tissue sulfide measurements.

  • Summary gives a different formula for the acidic nitrosating species

    Minor

    The summary calls the species [H2NO3]+, whereas the paper's figure description identifies it as [H2NO2]+. The formulas differ by one oxygen atom.

2 of 2

Cites

Flagged first, then by citations

2 of the 112 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Singh, 1996, The chemistry of the S-nitrosoglutathione/glutathione system, Proc. Natl. Acad. Sci. U.S.A., 93, 14428, 10.1073/pnas.93.25.14428 · DOI · Paper page

Cited by

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Related

Authors
Cortese-Krott, M. M., Fernandez, B. O., Kelm, M., Butler, A. R., & Feelisch, M.
Affiliations
  • Heinrich Heine University Düsseldorf (DE)
  • Southampton General Hospital (GB)
  • University of St Andrews (GB)
Corresponding author
Feelisch, Martin
ORCID
Venue
Nitric Oxide
Publisher
Elsevier BV
Published
2015-04
Volume
46
Pages
14-24
ISSN
1089-8603 (ISSN-L)
DOI
10.1016/j.niox.2014.12.009
OpenAlex
W2093742700
Semantic Scholar
001ace0d6e221e9278c01f77e2c7b8b6591f7082
Cited by
115
References
112
Citations by year
2026: 6 · 2025: 11 · 2024: 5 · 2023: 5 · 2022: 5 · 2021: 9 · 2020: 12 · 2019: 12 · 2018: 11 · 2017: 11 · 2016: 14 · 2015: 14
FWCI
1.11
Type
journal article
Language
en
Open access
Licence
Locations
  • Nitric Oxide (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • ePrints Soton (University of Southampton) (acceptedVersion)
  • St Andrews Research Repository (St Andrews Research Repository) (submittedVersion, cc-by-nc-nd)
Funders
  • Susanne-Bunnenberg-Stiftung
  • COST
  • University of Southampton
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords
nitrite, sulfide, S-nitrosothiols, thionitrites, sulfane sulfur, polysulfides, elemental sulfur, sulfide poisoning, chemical biology, toxicology
MeSH terms
Animals, Biochemistry, Humans, Nitric Oxide, Nitrites, Organ Specificity, Sulfides

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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