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To the Editor: In their study of cocoa intake and blood pressure, Dr Taubert and colleagues¹ concluded that the reduction of diastolic and systolic blood pressure caused by dark chocolate intake was due to increased formation of S-nitrosoglutathione. Many biochemical markers were measured in the study using commercially available assays or reported methods. However, we are not aware of reports of the analytical performance of the liquid chromatography tandem mass spectrometry method used for the measurement of plasma S-nitrosoglutathione. This is potentially an important problem for research involving S-nitrosothiols, for which the reported concentrations in biological fluids has a 3–order magnitude range.²

We are also unaware of previous reports of achieving measurement (with a lower limit of detection of 0.1 nmol/L) of such low plasma baseline levels of S-nitrosoglutathione (0.33 nmol/L) by liquid chromatography tandem mass spectrometry.^2-3 Such methods require full validation to avoid analytical errors; this is particularly true regarding research on the physiological roles of S-nitrosothiols, as well as the relative importance of individual S-nitrosothiols such as S-nitrosoglutathione.

We believe that accurate liquid chromatography tandem mass spectrometry analysis of S-nitrosothiols is best performed by use of stable-isotope labeled analogues as internal standards. Use at high molar excess of a chemically unrelated compound like thiamazole (which carries a sulfhydryl group) as in the study by Taubert et al would be expected to lead to a reaction with S-nitrosoglutathione, thus diminishing its concentration.

Finally, S-nitrosoglutathione in humans is a selective inhibitor of platelet aggregation.⁴ Clinical studies involving S-nitrosoglutathione preferably include measurement of platelet aggregation. Since S-nitrosoglutathione infusion in humans has not resulted in reduction of blood pressure,^4-5 it is unlikely that the blood pressure decrease observed in the study by Taubert et al is attributable to S-nitrosoglutathione, at least at the measured S-nitrosoglutathione concentrations.

Financial Disclosures: None reported.

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

Ranieri Rossi, PhD
Department of Evolutionary Biology
Laboratory of Pharmacology and Toxicology
University of Siena
Siena, Italy

1. Taubert D, Roesen R, Lehmann C, Jung N, Schömig E. Effects of low habitual cocoa intake on blood pressure and bioactive nitric oxide. JAMA. 2007;298(1):49-60. FREE FULL TEXT 2. Giustarini D, Milzani A, Dalle-Donne I, Rossi R. Detection of S-nitrosothiols in biological fluids: a comparison among the most widely applied methodologies. J Chromatogr B Analyt Technol Biomed Life Sci. 2007;851(1-2):124-139. FULL TEXT | ISI | PUBMED 3. Rellán-Álvarez R, Hernández LE, Abadía J, Álvarez-Fernández A. Direct and simultaneous determination of reduced and oxidized glutathione and homoglutathione by liquid chromatography-electrospray/mass spectrometry in plant tissue extracts. Anal Biochem. 2006;356(2):254-264. FULL TEXT | ISI | PUBMED 4. de Belder AJ, MacAllister R, Radomski MW, Moncada S, Vallance PJ. Effects of S-nitroso-glutathione in the human forearm circulation: evidence for selective inhibition of platelet activation. Cardiovasc Res. 1994;28(5):691-694. ISI | PUBMED 5. Ramsay B, Radomski M, de Belder A, Martin JF, Lopez-Jaramillo P. Systemic effects of S-nitroso-glutathione in the human following intravenous infusion. Br J Clin Pharmacol. 1995;40(1):101-102. ISI | PUBMED

Letters Section Editor: Robert M. Golub, MD, Senior Editor.

JAMA. 2007;298:1862-1863.

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Cocoa Intake and Blood Pressure—Reply
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Effects of Low Habitual Cocoa Intake on Blood Pressure and Bioactive Nitric Oxide: A Randomized Controlled Trial
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