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Circulation Research. 2004;94:e106

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(Circulation Research. 2004;94:e106.)
© 2004 American Heart Association, Inc.

Letters to the Editor

S-Nitrosoalbumin and Other S-Nitrosothiols in the Blood: Is Their Quantity of No Relevance?

Dimitrios Tsikas

Hannover Medical School, Institute of Clinical Pharmacology, Hannover, Germany, tsikas.dimitros{at}mh-hannover.de

To the Editor:

Similarity of results is the most appropriate criterion to assess agreement between methods and clinical measurements.1 Reference intervals of a biochemical parameter are of particular importance for the definition of pathological conditions and the judgment of therapy success by pharmacological, nutritional, or physical measures. In this context, mass spectrometry is generally accepted as the gold standard.2 Recent advances in the methods of analysis make it possible to suggest reference intervals for many members of the L-arginine/nitric oxide family, including asymmetric dimethylargine3 and 3-nitrotyrosine.4 Circulating S-nitrosothiols have evaded the definition of reference intervals to date. Stamler et al first reported on the presence of S-nitrosothiols in plasma of healthy humans of the order of 7000 nmol/L, with S-nitrosoalbumin suggested as the most abundant circulating S-nitrosothiol.5 At present, reported basal levels of circulating S-nitrosothiols range between 10 and 10 000 nmol/L.6–12 The single reported mass spectrometric method revealed S-nitrosoalbumin mean basal plasma levels of 181 nmol/L.7

The physiological roles and the levels of S-nitrosothiols in the blood are the subject of active discussion.13–17 In an editorial recently published in Circulation Research, Stamler17 commented on this issue and the recent studies by Ng et al10 and Massy et al,11 but he did not consider critical contributions by other groups.7,13,15,16 Stamler expressed the opinion that the quantitative aspect of the results is not very meaningful. I would agree with Stamler’s opinion, when the basal S-nitrosothiol levels are on the same order of magnitude. However, this is not the case. The range is exceptionally wide, as it covers more than three orders of magnitude. Chemical lability of S-nitrosothiols is a crucial and important factor. However, there are numerous other well-known analytical problems, especially the interference by nitrite, which has not been adequately addressed by many investigators. For example,10,16 ammonium sulfamate cannot eliminate nitrite at plasma pH, but it absolutely requires acidic conditions. It is, therefore, likely16 that Marzinzig et al,6 Wlodek et al,9 and Massy et al11 have measured nitrite plus S-nitrosothiols in plasma, with nitrite representing by far the major fraction.

The most urgent and important future prospect in this research area is, in my opinion, the establishment of reference intervals for circulating S-nitrosoproteins, namely S-nitrosoalbumin and S-nitrosohemoglobin—the most abundant and most stable S-nitrosothiols in the blood. Not considering circulating intervals will give free rein to consider any value to be valid. We should pay more attention to the methods of analysis of S-nitrosothiols, both from the analytical and the review point of view. Thus, newly developed and validated analytical methods should be published in peer reviewed journals prior to use in clinical studies, and, in addition, clinical journals should nominate one (bio)chemist analyst as a referee who would serve as an expert in the analysis of S-nitrosothiols.

References

  1. Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet. 1986; 1: 307–310.[CrossRef][Medline] [Order article via Infotrieve]
  2. Lawson AM, Gaskell SJ, Hjelm M. Methodological aspects on quantitative mass spectrometry used for accuracy control in clinical chemistry. J Clin Chem Clin Biochem. 1985; 23: 433–441.[Medline] [Order article via Infotrieve]
  3. Martens-Lobenhoffer J, Bode-Böger SM. Simultaneous detection of arginine, asymmetric dimethylarginine, symmetric dimethylarginine and citrulline in human plasma and urine applying liquid chromatography-mass spectrometry with very straightforward sample preparation. J Chromatogr B. 2003; 798: 231–239.[CrossRef]
  4. Söderling AS, Ryberg H, Gabrielsson A, Lärstad M, Torén K, Niari S, Caidahl K. A derivatization assay using gas chromatography/negative chemical ionization tandem mass spectrometry to quantify 3-nitrotyrosine in human plasma. J Mass Spectrom. 2003; 38: 1187–1196.[CrossRef][Medline] [Order article via Infotrieve]
  5. Stamler JS, Jaraki O, Osborne J, Simon DI, Keaney J, Vita J, Singel D, Valeri CR, Loscalzo J. Nitric oxide circulates in mammalian plasma primarily as an S-nitroso adduct of serum albumin. Proc Natl Acad Sci U S A. 1992; 89: 7674–7677.[Abstract/Free Full Text]
  6. Marzinzig M, Nussler AK, Stadler J, Marzinzig E, Barthlen W, Nussler NC, Beger HG, Morris SM, Brückner UB. Improved methods to measure end products of nitric oxide in biological fluids: nitrite, nitrate, and S-nitrosothiols. Nitric Oxide. 1997; 1: 177–189.[CrossRef][Medline] [Order article via Infotrieve]
  7. Tsikas D, Sandmann J, Gutzki FM, Stichtenoth DO, Frölich JC. Measurement of S-nitrosoalbumin by gas chromatography-mass spectrometry. II. Quantitative determination of S-nitrosoalbumin in human plasma using S-[15N]nitrosoalbumin as internal standard. J Chromatogr B. 1999; 726: 13–24.
  8. Tyurin VA, Liu SX, Tyurina Y, Sussman NB, Hubel, CA, Roberts JM, Taylor RN, Kagan VE. Elevated levels of S-nitrosoalbumin in preeclampsia plasma. Circ Res. 2001; 88: 1210–1215.[Abstract/Free Full Text]
  9. Wlodek PJ, Kucharsczyk J, Sokolovska MM, Milkowski A, Markiewiecz A, Smolenski OB, Wlodek LB. Alteration in plasma levels of nonprotein sulfhydryl compounds and S-nitrosothiols in chronic renal failure patients. Clin Chim Acta. 2003; 327: 87–94.[CrossRef][Medline] [Order article via Infotrieve]
  10. Ng ESM, Jourd’heuil D, McCord JM, Hermandez D, Yasui M, Knight D, Kubes P. Enhanced S-nitroso-albumin formation from inhaled NO during ischemia/reperfusion. Circ Res. 2004; 94: 559–565.[Abstract/Free Full Text]
  11. Massy ZA, Fumeron C, Borderie D, Tuppin P, Nguyen-Khoa T, Benoit MO, Jacquot C, Buisson C, Drüeke TB, Ekindjian OG, Lacour B, Iliou MC. Increased plasma S-nitrosothiol concentrations predict cardiovascular outcomes among patients with end-stage renal disease: a prospective study. J Am Soc Nephrol. 2004; 15: 470–476.[Abstract/Free Full Text]
  12. Cannon OR, Schechter AN, Panza JA, Ognibene FP, Pease-Fye ME, Waclawiw MA, Shelhamer JH, Gladwin MT. Effects of inhaled nitric oxide on regional blood flow are consistent with intravascular nitric oxide delivery. J Clin Invest. 2001; 108: 279–287.[CrossRef][Medline] [Order article via Infotrieve]
  13. Rossi R, Giustarini D, Milzani A, Colombo R, Dalle-Donne I, Di Simplicio P. Physiological levels of S-nitrosothiols in human plasma. Circ Res. 2001; 89: e47.[Medline] [Order article via Infotrieve]
  14. Tsikas D, Frölich JC. S-Nitrosoalbumin plasma levels in health and disease: facts or artifacts? Value of analytical chemistry in nitric oxide clinical research. Circ Res. 2002; 90: e39.[Medline] [Order article via Infotrieve]
  15. Tsikas D, Frölich JC. Are plasma S-nitrosothiol levels elevated in chronic renal failure? Nephrol Dial Transplant. 2003; 918: 2199–2201.
  16. Tsikas D. Measurement of physiological S-nitrosothiols: a problem child and a challenge. Nitric Oxide. 2003; 9: 53–55.[CrossRef][Medline] [Order article via Infotrieve]
  17. Stamler JS. S-Nitrosothiols in the blood. Roles, amounts, and methods of analysis. Circ Res. 2004; 94: 414–417.[Free Full Text]



This article has been cited by other articles:


Home page
 Proc. Natl. Acad. Sci. USAHome page
A. Hausladen, R. Rafikov, M. Angelo, D. J. Singel, E. Nudler, and J. S. Stamler
Assessment of nitric oxide signals by triiodide chemiluminescence
PNAS, February 13, 2007; 104(7): 2157 - 2162.
[Abstract] [Full Text] [PDF]

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