Correspondence Article Type Letter by Tsikas and Cooper Regarding Article, “Dysregulation of Hydrogen Sulfide (H2S) Producing Enzyme Cystathionine γ-lyase (CSE) Contributes to Maternal Hypertension and Placental Abnormalities in Preeclampsia” To the Editor: We read with great interest the article by Wang et al,1 who reported that the synthesis of the gasotransmitter H2S is impaired in preeclampsia and concluded that H2S may contribute to the pathogenesis of preeclampsia. H2S is only 1 of several contributors to the highly redox-sensitive labile sulfur pool comprising free H2S, acid-labile sulfide, and protein-associated labile sulfur (sulfane sulfur).2,3 The plasma H2S concentrations measured by Wang et al1 both in control and in preeclampsia patients deserve closer attention and discussion in the light of the current literature. Interference-free analytical methods, unified nomenclature, and explicit declaration of the measured labile sulfur species are of key importance in elucidating the physiology of endogenous H2S and the pharmacology of increasingly utilized H2S donors. Careful analysis of sulfur pools revealed actual human plasma concentrations of H2S in the lower nmol/L range, whereas higher plasma H2S concentrations are considered toxic.2,3 In the assay used by Wang et al,1 N,Ndimethyl-p-phenylenediamine (DPD) and FeCl3 serve as reactants for the colorimetric estimation of H2S. DPD is a highly sensitive redoxactive compound (pH range, 1–10).4 Under the acidic conditions used to measure H2S by the DPD/FeCl3 method, numerous reaction products may be formed from DPD in addition to methylene blue.4 H2S-unrelated, DPD-derived species likely contribute to H2S, thus yielding overestimated H2S concentrations. Implicit in the work of Wang et al1 is the notion that cystathionine γ-lyase is a major contributor to the labile sulfur pool. However, Shen et al3 showed that in cystathionine γ-lyase–knockout mice there is no decrease in plasma acid-labile bound sulfane sulfur, a marked decrease in free H2S and a small decrease in acid-labile sulfide. Overall, however, the decrease in total reactive sulfur is modest, a finding inconsistent with the H2S/cystathionine γ-lyase role in preeclampsia envisaged by Wang et al.1

In conclusion, H2S is an important gasotransmitter with multiple biological functions and H2S-releasing drugs are currently of particular pharmacological interest. H2S occurs in several forms in biological fluids, is derived from different pathways, and its actions are a matter of concentration and dose. Use of unified nomenclature and reliable analytic approaches for the measurement of H2S and its other forms will facilitate the elucidation of the biochemical fate and pharmacology of H2S and its relatives.

Disclosures None. Dimitrios Tsikas, PhD Institute of Clinical Pharmacology Hannover Medical School Hannover, Germany Arthur J.L. Cooper, PhD, DSc Department of Biochemistry and Molecular Biology New York Medical College Valhalla, New York

References 1. Wang K, Ahmad S, Cai M, Rennie J, Fujisawa T, Crispi F, Baily J, Miller MR, Cudmore M, Hadoke PW, Wang R, Gratacós E, Buhimschi IA, Buhimschi CS, Ahmed A. Dysregulation of hydrogen sulfide producing enzyme cystathionine γ-lyase contributes to maternal hypertension and placental abnormalities in preeclampsia. Circulation. 2013;127:2514–2522. 2. Tangerman A. Measurement and biological significance of the volatile sulfur compounds hydrogen sulfide, methanethiol and dimethyl sulfide in various biological matrices. J Chromatogr B. 2009;877:3366–3377. 3. Shen X, Peter EA, Bir S, Wang R, Kevil CG. Analytical measurement of discrete hydrogen sulfide pools in biological specimens. Free Radic Biol Med. 2012;52:2276–2283. 4. Modestov AD, Gun J, Savotine I, Lev O. Online electrochemical-mass spectrometry study of the mechanism of oxidation of N,N-dimethylp-phenylenediamine in aqueous electrolytes. J Electroanal Chem. 2004;565:7–19.

(Circulation. 2014;129:e516.) © 2014 American Heart Association, Inc. Circulation is available at http://circ.ahajournals.org

DOI: 10.1161/CIRCULATIONAHA.113.004320

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Letter by Tsikas and Cooper Regarding Article, ''Dysregulation of Hydrogen Sulfide (H2 S) Producing Enzyme Cystathionine γ-lyase (CSE) Contributes to Maternal Hypertension and Placental Abnormalities in Preeclampsia'' Dimitrios Tsikas and Arthur J.L. Cooper Circulation. 2014;129:e516 doi: 10.1161/CIRCULATIONAHA.113.004320 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539

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