Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Hydrogen sulphide and its therapeutic potential

Key Points

  • Hydrogen sulphide (H2S), together with nitric oxide and carbon monoxide, belongs to a family of labile biological mediators called gasotransmitters.

  • H2S has long been known as a toxic gas emanating from sewers and as a by-product of industrial processes; however, the biological processes of sulphide and its metabolism and fate in biological systems is now beginning to be understood.

  • H2S is synthesized endogenously in numerous mammalian tissues by two enzymes responsible for metabolizing L-cysteine — cystathionine β-synthase (CBS) and cystathionine γ-lyase (CGS). CBS is the predominant H2S-generating enzyme in the brain and nervous system. CSE is mainly expressed in the liver and in the vascular and non-vascular smooth muscle. Other sources of H2S include enterobacterial flora and inorganic sources.

  • H2S exerts numerous biological effects on various biological targets, leading to responses that range from cytotoxic effects (due to free radical and oxidant generation) to cytoprotective (antinecrotic or anti-apoptotic) actions. In particular, H2S has been specifically shown to exert a pharmacological effect on potassium-opened ATP (KATP) channels.

  • These opposing effects have been demonstrated in various animal models. Inhibition of sulphide in animal models of haemorrhagic shock has been demonstrated to accelerate the recovery of mean arterial pressure. H2S can also induce a suspended-animated-like state in mice — whether this can be achieved in larger animals remains to be seen. Protection from lethal hypoxic insult, myocardial injury and inflammation has also been shown.

  • The options that could be explored to utilize this knowledge for therapeutic purposes are discussed. Two main pathways are considered viable: the development of inhibitors of CBS or CSE, and the development of H2S or H2S-releasing compounds. In this rapidly emerging field, there are still many unknowns — including the relationship of H2S with the other two gasotransmitters — however, further studies are likely to yield a number of therapeutic possibilities, and early stage drug candidates are already in development.

Abstract

Hydrogen sulphide (H2S) is increasingly being recognized as an important signalling molecule in the cardiovascular and nervous systems. The production of H2S from L-cysteine is catalysed primarily by two enzymes, cystathionine γ-lyase and cystathionine β-synthase. Evidence is accumulating to demonstrate that inhibitors of H2S production or therapeutic H2S donor compounds exert significant effects in various animal models of inflammation, reperfusion injury and circulatory shock. H2S can also induce a reversible state of hypothermia and suspended-animation-like state in rodents. This article overviews the physiology and biochemistry of H2S, summarizes the effects of H2S inhibitors or H2S donors in animal models of disease and outlines the potential options for the therapeutic exploitation of H2S.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Enzymatic pathways of H2S production in mammalian cells.
Figure 2: Some biological effects of H2S in mammalian cells.
Figure 3: Structures of PAG and BCA.
Figure 4: Induction of a suspended animation-like state in mice by H2S inhalation.
Figure 5: Protective effects of sulphide donors in disease models.
Figure 6: Potential mechanisms of protective effects of H2S.

References

  1. 1

    Wang, R. Two's company, three's a crowd: can H2S be the third endogenous gaseous transmitter? FASEB J. 16, 1792–1798 (2002).

    CAS  PubMed  Google Scholar 

  2. 2

    Fiorucci, S., Distrutti, E., Cirino, G. & Wallace, J. L. The emerging roles of hydrogen sulfide in the gastrointestinal tract and liver. Gastroenterology 131, 259–271 (2006).

    CAS  PubMed  Google Scholar 

  3. 3

    Kamoun, P. Endogenous production of hydrogen sulfide in mammals. Amino Acids 26, 243–254 (2004).

    CAS  PubMed  Google Scholar 

  4. 4

    Doeller, J. E. et al. Polarographic measurement of hydrogen sulfide production and consumption by mammalian tissues. Anal. Biochem. 341, 40–51 (2005).

    CAS  PubMed  Google Scholar 

  5. 5

    Puranik, M. et al. Dynamics of carbon monoxide binding to cystathionine β-synthase. J. Biol. Chem. 281, 13433–13438 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Eto, K. & Kimura, H. A novel enhancing mechanism for hydrogen sulfide-producing activity of cystathionine β-synthase. J. Biol. Chem. 277, 42680–42685 (2002).

    CAS  PubMed  Google Scholar 

  7. 7

    Miles, E. W. & Kraus, J. P. Cystathionine β-synthase: structure, function, regulation, and location of homocystinuria-causing mutations. J. Biol. Chem. 279, 29871–29874 (2004).

    CAS  PubMed  Google Scholar 

  8. 8

    Ishii. I. et al. Murine cystathionine γ-lyase: complete cDNA and genomic sequences, promoter activity, tissue distribution and developmental expression. Biochem. J. 381, 113–123 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Furne, J., Springfield, J., Koenig, T., DeMaster, E. & Levitt, M. D. Oxidation of hydrogen sulfide and methanethiol to thiosulfate by rat tissues: a specialized function of the colonic mucosa. Biochem. Pharmacol. 62, 255–259 (2001).

    CAS  PubMed  Google Scholar 

  10. 10

    Searcy, D. G. & Lee, S. H. Sulfur reduction by human erythrocytes. J. Exp. Zool. 282, 310–322 (1998).

    CAS  PubMed  Google Scholar 

  11. 11

    Parcell, S. Sulfur in human nutrition and applications in medicine. Altern. Med. Rev. 7, 22–44 (2002).

    PubMed  Google Scholar 

  12. 12

    Komarnisky, L. A., Christopherson, R. J. & Basu, T. K. Sulfur: its clinical and toxicologic aspects. Nutrition 19, 54–61 (2003).

    CAS  PubMed  Google Scholar 

  13. 13

    Iciek, M. & Wlodek, L. Biosynthesis and biological properties of compounds containing highly reactive, reduced sulfane sulfur. Pol. J. Pharmacol. 53, 215–225 (2001).

    CAS  PubMed  Google Scholar 

  14. 14

    Mueller, E. G. Trafficking in persulfides: delivering sulfur in biosynthetic pathways. Nature Chem. Biol. 2, 185–194 (2006).

    CAS  Google Scholar 

  15. 15

    Fontecave, M. Iron-sulfur clusters: ever-expanding roles. Nature Chem. Biol. 2, 171–174 (2006).

    CAS  Google Scholar 

  16. 16

    Ubuka, T. Assay methods and biological roles of labile sulfur in animal tissues. J. Chromatogr. B. Analyt. Technol. Biomed. Life Sci. 781, 227–249 (2002).

    CAS  PubMed  Google Scholar 

  17. 17

    Lowicka, E. & Beltowski, J. Hydrogen sulfide (H2S) — the third gas of interest for pharmacologists. Pharmacol. Rep. 59, 4–24 (2007).

    CAS  PubMed  Google Scholar 

  18. 18

    Nagai, Y., Tsugane, M., Oka, J. & Kimura, H. Hydrogen sulfide induces calcium waves in astrocytes. FASEB J. 18, 557–559 (2004).

    CAS  PubMed  Google Scholar 

  19. 19

    Yang, G., Wu, L. & Wang, R. Pro-apoptotic effect of endogenous H2S on human aorta smooth muscle cells. FASEB J. 20, 553–555 (2006).

    CAS  PubMed  Google Scholar 

  20. 20

    Deplancke, B. & Gaskins, H. R. Hydrogen sulfide induces serum-independent cell cycle entry in nontransformed rat intestinal epithelial cells. FASEB J. 17, 1310–1312 (2003).

    CAS  PubMed  Google Scholar 

  21. 21

    Yang, G., Cao, K., Wu, L., & Wang, R. Cystathionine γ-lyase overexpression inhibits cell proliferation via a H2S-dependent modulation of ERK1/2 phosphorylation and p21Cip/WAK-1. J. Biol. Chem. 279, 49199–49205 (2004).

    CAS  PubMed  Google Scholar 

  22. 22

    Oh, G. S. et al. Hydrogen sulfide inhibits nitric oxide production and nuclear factor-κB via heme oxygenase-1 expression in RAW2647. macrophages stimulated with lipopolysaccharide. Free Radic. Biol. Med. 41, 106–119 (2006).

    CAS  PubMed  Google Scholar 

  23. 23

    Rose, P. et al. Hydrogen sulfide protects colon cancer cells from chemopreventative agent β-phenylethyl isothiocyanate induced apoptosis. World J. Gastroenterol. 11, 3990–3997 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Kimura, Y. & Kimura, H. Hydrogen sulfide protects neurons from oxidative stress. FASEB J. 18, 1165–1167 (2004).

    CAS  PubMed  Google Scholar 

  25. 25

    Kimura, Y., Dargusch, R., Schubert, D. & Kimura, H. Hydrogen sulfide protects HT22 neuronal cells from oxidative stress. Antioxid. Redox. Signal. 8, 661–670 (2006).

    CAS  PubMed  Google Scholar 

  26. 26

    Whiteman, M. et al. The novel neuromodulator hydrogen sulfide: an endogenous peroxynitrite 'scavenger'? J. Neurochem. 90, 765–768 (2004). Original report identifying H 2 S as an antioxidant agent.

    CAS  PubMed  Google Scholar 

  27. 27

    Whiteman, M. et al. Hydrogen sulphide: a novel inhibitor of hypochlorous acid-mediated oxidative damage in the brain? Biochem. Biophys. Res. Commun. 326, 794–798 (2005).

    CAS  PubMed  Google Scholar 

  28. 28

    Yan, S. K. et al. Effects of hydrogen sulfide on homocysteine-induced oxidative stress in vascular smooth muscle cells. Biochem. Biophys. Res. Commun. 361, 485–491 (2006).

    Google Scholar 

  29. 29

    Rinaldi, L. et al. Hydrogen sulfide prevents apoptosis of human PMN via inhibition of p38 and caspase 3. Lab. Invest. 86, 391–397 (2006).

    CAS  PubMed  Google Scholar 

  30. 30

    Baskar, R., Li, L. & Moore, P. K. Hydrogen sulfide-induces DNA damage and changes in apoptotic gene expression in human lung fibroblast cells. FASEB J. 21, 247–255 (2007).

    CAS  PubMed  Google Scholar 

  31. 31

    Truong, D.H., Eghbal, M.A., Hindmarsh, W., Roth, S. H. & O'Brien, P. J. Molecular mechanisms of hydrogen sulfide toxicity. Drug Metab. Rev. 38, 733–744 (2006).

    CAS  PubMed  Google Scholar 

  32. 32

    Szabó, C., Kiss, L. & Pankotai, E. Cytoprotective and anti-inflammatory effects of hydrogen sulfide in macrophages and in mice. Crit. Care 11 (Suppl. 2), P2 (2007).

    PubMed Central  Google Scholar 

  33. 33

    Geng, B. et al. Endogenous hydrogen sulfide regulation of myocardial injury induced by isoproterenol. Biochem. Biophys. Res. Commun. 318, 756–763 (2004).

    CAS  PubMed  Google Scholar 

  34. 34

    Qingyou, Z. et al. Impact of hydrogen sulfide on carbon monoxide/heme oxygenase pathway in the pathogenesis of hypoxic pulmonary hypertension. Biochem. Biophys. Res. Commun. 317, 30–37 (2004).

    PubMed  Google Scholar 

  35. 35

    Ryter, S. W., Alam, J. & Choi. A. M. Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol. Rev. 86, 583–650 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Jeong, S. O. et al. Hydrogen sulfide potentiates interleukin-1β-induced nitric oxide production via enhancement of extracellular signal-regulated kinase activation in rat vascular smooth muscle cells. Biochem. Biophys. Res. Commun. 345, 938–944 (2006).

    CAS  PubMed  Google Scholar 

  37. 37

    Zhao, W., Zhang, J., Lu, Y. & Wang, R. The vasorelaxant effect of H2S as a novel endogenous gaseous KATP channel opener. EMBO J. 20, 6008–6016 (2001). The first report to implicate K ATP -channel activation in the vascular effects of H 2 S.

    CAS  Article  Google Scholar 

  38. 38

    Yang, W., Yang, G., Jia, X., Wu, L. & Wang, R. Activation of KATP channels by H2S in rat insulin-secreting cells and the underlying mechanisms. J. Physiol. 569, 519–531 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Kaneko, Y., Kimura, Y., Kimura, H. & Niki, I. L-cysteine inhibits insulin release from the pancreatic β-cell: possible involvement of metabolic production of hydrogen sulfide, a novel gasotransmitter. Diabetes 55, 1391–1397 (2006).

    CAS  PubMed  Google Scholar 

  40. 40

    Kubo, S., Doe, I., Kurokawa, Y., Nishikawa, H. & Kawabata, A. Direct inhibition of endothelial nitric oxide synthase by hydrogen sulfide: contribution to dual modulation of vascular tension. Toxicology 232, 138–146 (2007).

    CAS  PubMed  Google Scholar 

  41. 41

    Koenitzer, J. R. et al. Hydrogen sulfide mediates vasoactivity in an oxygen dependent manner. Am. J. Physiol. Heart Circ. Physiol. 292, H1953–H1960 (2007). Studies on the mechanism and oxygen dependence of sulphide-induced vascular relaxations.

    CAS  PubMed  Google Scholar 

  42. 42

    Dombkowski, R. A., Doellman, M. M., Head, S. K. & Olson, K. R. Hydrogen sulfide mediates hypoxia-induced relaxation of trout urinary bladder smooth muscle. J. Exp. Biol. 209, 3234–3240 (2006).

    PubMed  Google Scholar 

  43. 43

    Rees, D. D., Palmer, R. M., & Moncada, S. Role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc. Natl Acad. Sci. USA 86, 3375–3378 (1989).

    CAS  PubMed  Google Scholar 

  44. 44

    Kovach, A. G. et al. Effects of NG-nitro-L-arginine and L-arginine on regional cerebral blood flow in the cat. J. Physiol. 449, 183–196 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Ali, M. Y. et al. Regulation of vascular nitric oxide in vitro and in vivo; a new role for endogenous hydrogen sulphide? Br. J. Pharmacol. 149, 625–634 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Coleman, J. E. Mechanism of action of carbonic anhydrase. Subtrate, sulfonamide, and anion binding. J. Biol. Chem. 242, 5212–5219 (1967).

    CAS  PubMed  Google Scholar 

  47. 47

    Klentz, R. D. & Fedde, M. R. Hydrogen sulfide: effects on avian respiratory control and intrapulmonary CO2 receptors. Respir. Physiol. 32, 355–367 (1978).

    CAS  PubMed  Google Scholar 

  48. 48

    Hill, B. C. et al. Interactions of sulphide and other ligands with cytochrome c oxidase. An electron-paramagnetic-resonance study. Biochem. J. 224, 591–600 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Mason, M. G., Nicholls, P., Wilson, M. T. & Cooper, C. E. Nitric oxide inhibition of respiration involves both competitive (heme) and noncompetitive (copper) binding to cytochrome c oxidase. Proc. Natl Acad. Sci. USA 103, 708–713 (2006).

    CAS  PubMed  Google Scholar 

  50. 50

    Lane, N. Cell biology: power games. Nature 443, 901–903 (2006).

    CAS  PubMed  Google Scholar 

  51. 51

    Leschelle, X. et al. Adaptative metabolic response of human colonic epithelial cells to the adverse effects of the luminal compound sulfide. Biochim. Biophys. Acta 1725, 201–212 (2005).

    CAS  PubMed  Google Scholar 

  52. 52

    Blackstone, E., Morrison, M., & Roth, M. B. H2S induces a suspended animation-like state in mice. Science 308, 518 (2005). A demonstration of the ability of H 2 S to induce a state akin to suspended animation in mice.

    CAS  PubMed  Google Scholar 

  53. 53

    Khan, A. A. et al. Effects of hydrogen sulfide exposure on lung mitochondrial respiratory chain enzymes in rats. Toxicol. Appl. Pharmacol. 103, 482–490 (1990).

    CAS  PubMed  Google Scholar 

  54. 54

    Nicholson, R. A. et al. Inhibition of respiratory and bioenergetic mechanisms by hydrogen sulfide in mammalian brain. J. Toxicol. Environ. Health A 54, 491–507 (1998).

    CAS  PubMed  Google Scholar 

  55. 55

    Jiang, H. L., Wu, H. C., Li, Z. L., Geng, B. & Tang, C. S. Changes of the new gaseous transmitter H2S in patients with coronary heart disease. Di Yi Jun Yi Da Xue Xue Bao 25, 951–954 (2005) (in Chinese).

    CAS  PubMed  Google Scholar 

  56. 56

    Du, J., Yan, H., & Tang, C. Endogenous H2S is involved in the development of spontaneous hypertension. Beijing Da Xue Xue Bao 35,102 (2003) (in Chinese).

  57. 57

    Bhatia, M., Sidhapuriwala, J., Moochhala, S. M. & Moore, P. K. Hydrogen sulphide is a mediator of carrageenan-induced hindpaw oedema in the rat. Br. J. Pharmacol. 145, 141–144 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Bhatia, M. et al. Role of hydrogen sulfide in acute pancreatitis and associated lung injury. FASEB J. 19, 623–625 (2005).

    CAS  PubMed  Google Scholar 

  59. 59

    Mok, Y. Y. et al. Role of hydrogen sulphide in haemorrhagic shock in the rat: protective effect of inhibitors of hydrogen sulphide biosynthesis. Br. J. Pharmacol. 143, 881–889 (2004). A study on the protective effect of inhibitors of H 2 S biosynthesis in circulatory shock.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Collin, M. et al. Inhibition of endogenous hydrogen sulfide formation reduces the organ injury caused by endotoxemia. Br. J. Pharmacol. 146, 498–505 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Li, L. et al. Hydrogen sulfide is a novel mediator of lipopolysaccharide-induced inflammation in the mouse. FASEB J. 19, 1196–1198 (2005).

    CAS  PubMed  Google Scholar 

  62. 62

    Zhang, H., Zhi, L., Moore, P. K. & Bhatia, M. Role of hydrogen sulfide in cecal ligation and puncture-induced sepsis in the mouse. Am. J. Physiol. Lung Cell. Mol. Physiol. 290, L1193–L1201 (2006).

    CAS  PubMed  Google Scholar 

  63. 63

    Yusuf, M. et al. Streptozotocin-induced diabetes in the rat is associated with enhanced tissue hydrogen sulfide biosynthesis. Biochem. Biophys. Res. Commun. 333, 1146–1152 (2005).

    CAS  PubMed  Google Scholar 

  64. 64

    Hannestad, U., Margheri, S. & Sorbo, B. A sensitive gas chromatographic method for determination of protein-associated sulfur. Anal. Biochem. 178, 394–398 (1989).

    CAS  PubMed  Google Scholar 

  65. 65

    Togawa, T. et al. High performance liquid chromatographic determination of bound sulfide and sulfite and thiosulfate at their low levels in human serum by pre-column fluorescence derivatization with monobromobimane. Chem. Pharm. Bull. 40, 3000–3004 (1992).

    CAS  PubMed  Google Scholar 

  66. 66

    Ogasawara, Y., Ishii, K., Togawa, T. & Tanabe, S. Determination of bound sulfur in serum by gas dialysis/high-performance liquid chromatography. Anal. Biochem. 215, 73–81 (1993).

    CAS  PubMed  Google Scholar 

  67. 67

    Marcotte, P. & Walsh, C. Active site-directed inactivation of cystathionine γ-synthetase and glutamic pyruvic transaminase by propargylglycine. Biochem. Biophys. Res. Commun. 62, 677–682 (1975).

    CAS  PubMed  Google Scholar 

  68. 68

    Teague, B., Asiedu, S. & Moore, P. K. The smooth muscle relaxant effect of hydrogen sulphide in vitro: evidence for a physiological role to control intestinal contractility. Br. J. Pharmacol. 137, 139–145 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Marcotte, P. & Walsh, C. Vinylglycine and proparglyglycine: complementary suicide substrates for L-amino acid oxidase and D-amino acid oxidase. Biochemistry 15, 3070–3076 (1976).

    CAS  PubMed  Google Scholar 

  70. 70

    Burnett, G., Marcotte, P. & Walsh, C. Mechanism-based inactivation of pig heart L-alanine transaminase by L-propargylglycine. Half-site reactivity. J. Biol. Chem. 255, 3487–3491 (1980).

    CAS  PubMed  Google Scholar 

  71. 71

    Szabó, C. & Salzman, A. L. Inhibition of ATP-activated potassium channels exerts pressor effects and improves survival in a rat model of severe hemorrhagic shock. Shock 5, 391–394 (1996).

    PubMed  Google Scholar 

  72. 72

    Sivarajah, A., McDonald, M. C. & Thiemermann, C. The production of hydrogen sulfide limits myocardial ischemia and reperfusion injury and contributes to the cardioprotective effects of preconditioning with endotoxin, but not ischemia in the rat. Shock 26, 154–161 (2006).

    CAS  PubMed  Google Scholar 

  73. 73

    Zhu, Y. Z. et al. Hydrogen sulfide and its cardioprotective effects in myocardial ischemia in experimental rats. J. Appl. Physiol. 102, 261–268 (2007).

    CAS  PubMed  Google Scholar 

  74. 74

    Pan, T. T., Feng, Z. N., Lee, S. W., Moore, P. K. & Bian, J. S. Endogenous hydrogen sulfide contributes to the cardioprotection by metabolic inhibition preconditioning in the rat ventricular myocytes. J. Mol. Cell. Cardiol. 40, 119–130 (2006).

    CAS  PubMed  Google Scholar 

  75. 75

    Fiorucci, S. et al. Inhibition of hydrogen sulfide generation contributes to gastric injury caused by anti-inflammatory nonsteroidal drugs. Gastroenterology 129, 1210–1224 (2005).

    CAS  PubMed  Google Scholar 

  76. 76

    Zanardo, R. C. et al. Hydrogen sulfide is an endogenous modulator of leukocyte-mediated inflammation. FASEB J. 20, 2118–2120 (2006). A demonstration of the ability of sulphide to inhibit neutrophil adhesion/activation.

    CAS  PubMed  Google Scholar 

  77. 77

    Bian, J. S. et al. Role of hydrogen sulfide in the cardioprotection caused by ischemic preconditioning in the rat heart and cardiac myocytes. J. Pharmacol. Exp. Ther. 316, 670–678 (2006).

    CAS  PubMed  Google Scholar 

  78. 78

    Johansen, D., Ytrehus, K. & Baxter, G. F. Exogenous hydrogen sulfide (H2S) protects against regional myocardial ischemia-reperfusion injury — evidence for a role of KATP channels. Basic Res. Cardiol. 101, 53–60 (2006). A demonstration of the cardioprotective effect of H 2 S in vitro.

    CAS  PubMed  Google Scholar 

  79. 79

    Elrod, J. W., Calvert, J.W., Duranski, M.R. & Lefer, D. J. Hydrogen sulfide donor protects against acute myocardial ischemia-reperfusion injury. American Heart Association web site [online], (2006).

  80. 80

    Sodha, N. et al. Exogenous sulfide reduces myocardial apoptosis in response to ischemia-reperfusion injury. Interact. Cardiovasc. Thorac. Surg. 6 (Suppl. 3), S275 (2007).

    Google Scholar 

  81. 81

    Distrutti, E. et al. Evidence that hydrogen sulfide exerts antinociceptive effects in the gastrointestinal tract by activating KATP channels. J. Pharmacol. Exp. Ther. 316, 325–335 (2006).

    CAS  PubMed  Google Scholar 

  82. 82

    Distrutti, E. et al. 5-Amino-2-hydroxybenzoic acid 4-(5-thioxo-5H-[1,2]dithiol-3yl)-phenyl ester (ATB-429), a hydrogen sulfide-releasing derivative of mesalamine, exerts antinociceptive effects in a model of postinflammatory hypersensitivity. J. Pharmacol. Exp. Ther. 319, 447–458 (2006). H 2 S-releasing modified anti-inflammatory compounds exert superior therapeutic effects and improved safety profile in rodent models of inflammation.

    CAS  PubMed  Google Scholar 

  83. 83

    Qu, K., Chen, C. P., Halliwell, B., Moore, P. K. & Wong, P. T. Hydrogen sulfide is a mediator of cerebral ischemic damage. Stroke 37, 889–893 (2006).

    CAS  PubMed  Google Scholar 

  84. 84

    Li, L. et al. Anti-inflammatory and gastrointestinal effects of a novel diclofenac derivative. Free Radic. Biol. Med. 42, 706–719 (2007).

    PubMed  Google Scholar 

  85. 85

    Padilla, P. A. & Roth, M. B. Oxygen deprivation causes suspended animation in the zebrafish embryo. Proc. Natl. Acad. Sci. USA 98, 7331–7335 (2001).

    CAS  PubMed  Google Scholar 

  86. 86

    Padilla, P. A., Nystul, T. G., Zager, R. A., Johnson, A. C. & Roth, M. B. Dephosphorylation of cell cycle-regulated proteins correlates with anoxia-induced suspended animation in Caenorhabditis elegans. Mol. Biol. Cell 13, 1473–1483 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Nystul, T. G., Goldmark, J. P., Padilla, P. A., & Roth, M. B. Suspended animation in C. elegans requires the spindle checkpoint. Science 302, 1038–1041 (2003).

    CAS  PubMed  Google Scholar 

  88. 88

    Nystul, T. G. & Roth, M. B. Carbon monoxide-induced suspended animation protects against hypoxic damage in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 101, 9133–9136 (2004).

    CAS  PubMed  Google Scholar 

  89. 89

    Roth, M. B. & Nystul, T. Buying time in suspended animation. Sci. Am. 292, 48–55 (2005).

    PubMed  Google Scholar 

  90. 90

    Volpato, G. P. et al. Cardiovascular response to breating hydrogen sulfide in a murine model: separating the effects of body temperature. APS Intersociety Meeting web site [online], (2006).

  91. 91

    Lindell, S. L. et al. Natural resistance to liver cold ischemia-reperfusion injury associated with the hibernation phenotype. Am. J. Physiol. Gastrointest. Liver Physiol. 288, G473–G480 (2005).

    CAS  PubMed  Google Scholar 

  92. 92

    Nakao, A. et al. Ex vivo application of carbon monoxide in University of Wisconsin solution to prevent intestinal cold ischemia/reperfusion injury. Am. J. Transplant. 6, 2243–2255 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Martins, P. N. et al. Induction of carbon monoxide in donor animals prior to organ procurement reduces graft immunogenicity and inhibits chronic allograft dysfunction. Transplantation 82, 938–944 (2006).

    PubMed  Google Scholar 

  94. 94

    Timmons, J. A. Reflections on the purpose of oxygen consumption. Science Magazine [online], (2005).

  95. 95

    Blackstone, E. & Roth, M. B. Suspended animation-like state protects mice from lethal hypoxia. Shock 27, 370–372 (2006).

    Google Scholar 

  96. 96

    Minard, F. N. & Grant, D. S. Hypothermia as a mechanism for drug-induced resistance to hypoxia. Biochem. Pharmacol. 31, 1197–1203 (1982).

    CAS  PubMed  Google Scholar 

  97. 97

    Szabó, C., Veres, G., Radovits, T. Karck, M. & Szabó, G. Infusion of sodium sulfide improves myocardial and endothelial function in a canine model of cardiopulmonary bypass. Crit. Care 11 (Suppl. 2), P1 (2007).

    PubMed Central  Google Scholar 

  98. 98

    Meng, Q. H. et al. Protective effect of hydrogen sulfide on balloon injury-induced neointima hyperplasia in rat carotid arteries. Am. J. Pathol. 170, 1406–1414 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Miura, T. & Miki, T. ATP-sensitive K+ channel openers: old drugs with new clinical benefits for the heart. Curr. Vasc. Pharmacol. 1, 251–258 (2003).

    CAS  PubMed  Google Scholar 

  100. 100

    Auchampach, J. A., Maruyama, M., Cavero, I. & Gross, G. J. Pharmacological evidence for a role of ATP-dependent potassium channels in myocardial stunning. Circulation 86, 311–319 (1992).

    CAS  PubMed  Google Scholar 

  101. 101

    Toombs, C. F., Moore, T. L. & Shebuski, R. J. Limitation of infarct size in the rabbit by ischaemic preconditioning is reversible with glibenclamide. Cardiovasc. Res. 27, 617–622 (1993).

    CAS  PubMed  Google Scholar 

  102. 102

    Bianchi, C. et al. A novel peroxynitrite decomposer catalyst (FP-15) reduces myocardial infarct size in an in vivo peroxynitrite decomposer and acute ischemia-reperfusion in pigs. Ann. Thorac. Surg. 74, 1201–1207 (2002).

    PubMed  Google Scholar 

  103. 103

    Jiang, H. L., Wu, H. C., Li, Z.L., Geng, B. & Tang, C. S. Changes of the new gaseous transmitter H2S in patients with coronary heart disease. Di Yi Jun Yi Da Xue Xue Bao 25, 951–954 (2005) (in Chinese).

    CAS  PubMed  Google Scholar 

  104. 104

    Davies, N. M. et al. NO-naproxen vs. naproxen: ulcerogenic, analgesic and anti-inflammatory effects. Aliment. Pharmacol. Ther. 11, 69–79 (1997).

    CAS  PubMed  Google Scholar 

  105. 105

    Wallace, J. L., Del Soldato P., Cirino, G. & Muscara, M. N. Nitric oxide-releasing NSAIDs: GI-safe antithrombotics. IDrugs 2, 321–326 (1999).

    CAS  PubMed  Google Scholar 

  106. 106

    Joshi, G. P. NCX-701. NicOx. Curr. Opin. Investig. Drugs 5, 755–759 (2004).

    CAS  PubMed  Google Scholar 

  107. 107

    Zagli, G. et al. Hydrogen sulfide inhibits human platelet aggregation. Eur. J. Pharmacol. 559, 65–68 (2007).

    CAS  PubMed  Google Scholar 

  108. 108

    Handy, R. L. & Moore, P. K. A comparison of the effects of L-NAME, 7-NI and L-NIL on carrageenan-induced hindpaw oedema and NOS activity. Br. J. Pharmacol. 123, 1119–1126 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Fernandes, D., Da Silva-Santos, J. E. & Assreuy, J. Nitric oxide-induced inhibition of mouse paw edema: involvement of soluble guanylate cyclase and potassium channels. Inflamm. Res. 51, 377–384 (2002).

    CAS  PubMed  Google Scholar 

  110. 110

    Miles, E. W. & Kraus, J. P. Cystathionine β-synthase: structure, function, regulation, and location of homocystinuria-causing mutations. J. Biol. Chem. 279, 29871–29874 (2004).

    CAS  PubMed  Google Scholar 

  111. 111

    Hamelet, J., Demuth, K., Paul, J. L., Delabar, J. M. & Janel, N. Hyperhomocysteinemia due to cystathionine β synthase deficiency induces dysregulation of genes involved in hepatic lipid homeostasis in mice. J. Hepatol. 46, 151–159 (2007).

    CAS  PubMed  Google Scholar 

  112. 112

    Booke, M. & Westphal, M. Treatment of sepsis and septic shock: is there a light at the end of the tunnel? Curr. Opin. Anaesthesiol. 16, 101–104 (2003).

    PubMed  Google Scholar 

  113. 113

    Kinsella, J. P. & Abman, S. H. Inhaled nitric oxide therapy in children. Paediatr. Respir. Rev. 6, 190–198 (2005).

    PubMed  Google Scholar 

  114. 114

    Hillier, S. C. Recent advances in the treatment of pulmonary hypertension. Curr. Opin. Anaesthesiol. 16, 331–336 (2003).

    PubMed  Google Scholar 

  115. 115

    Beauchamp, R. O. Jr., Bus, J. S., Popp, J. A., Boreiko, C. J. & Andjelkovich, D. A. A critical review of the literature on hydrogen sulfide toxicity. Crit. Rev. Toxicol. 13, 25–97 (1984). A key review on the toxicology and metabolism of sulphide, from the environmental toxicology viewpoint.

    CAS  PubMed  Google Scholar 

  116. 116

    U.S. Environmental Protection Agency (EPA). Toxicological review of hydrogen sulfide (CASRN 7783-06-04). EPA web site [online], (2003).

  117. 117

    Woodall, G. M., Smith, R. L. & Granville, G. C. Proceedings of the hydrogen sulfide health research and risk assessment symposium October 31–November 2, 2000. Inhal. Toxicol. 17, 593–639 (2005).

    CAS  PubMed  Google Scholar 

  118. 118

    Reiffenstein, R. J., Hulbert, W. C. & Roth, S. H. Toxicology of hydrogen sulfide. Annu. Rev. Pharmacol. Toxicol. 32, 109–134 (1992).

    CAS  PubMed  Google Scholar 

  119. 119

    Lloyd, D. Hydrogen sulfide: clandestine microbial messenger? Trends Microbiol. 14, 456–462 (2006).

    CAS  PubMed  Google Scholar 

  120. 120

    Lopez, A., Prior, M. G., Reiffenstein, R. J. & Goodwin, L. R. Peracute toxic effects of inhaled hydrogen sulfide and injected sodium hydrosulfide on the lungs of rats. Fundam. Appl. Toxicol. 12, 367–373 (1989).

    CAS  PubMed  Google Scholar 

  121. 121

    Almeida, A. F. & Guidotti, T. L. Differential sensitivity of lung and brain to sulfide exposure: a peripheral mechanism for apnea. Toxicol. Sci. 50, 287–293 (1999).

    CAS  PubMed  Google Scholar 

  122. 122

    Dorman, D. C., Struve, M. F., Gross, E. A. & Brenneman, K. A. Respiratory tract toxicity of inhaled hydrogen sulfide in Fischer-344 rats, Sprague-Dawley rats, and B6C3F1 mice following subchronic (90-day) exposure. Toxicol. Appl. Pharmacol. 198, 29–39 (2004).

    CAS  PubMed  Google Scholar 

  123. 123

    Brenneman, K. A. et al. Olfactory mucosal necrosis in male CD rats following acute inhalation exposure to hydrogen sulfide: reversibility and the possible role of regional metabolism. Toxicol. Pathol. 30, 200–208 (2002).

    CAS  PubMed  Google Scholar 

  124. 124

    Bhambhani, Y. & Singh, M. Physiological effects of hydrogen sulfide inhalation during exercise in healthy men. J. Appl. Physiol. 71, 1872–1877 (1991).

    CAS  PubMed  Google Scholar 

  125. 125

    Bhambhani, Y., Burnham, R., Snydmiller, G., MacLean, I. & Martin, T. Effects of 5 ppm hydrogen sulfide inhalation on biochemical properties of skeletal muscle in exercising men and women. Am. Ind. Hyg. Assoc. J. 57, 464–468 (1996).

    CAS  PubMed  Google Scholar 

  126. 126

    Kilburn, K. H. & Warshaw, R. H. Hydrogen sulfide and reduced-sulfur gases adversely affect neurophysiological functions. Toxicol. Ind. Health 11, 185–197 (1995).

    CAS  PubMed  Google Scholar 

  127. 127

    Kage, S., Ito, S., Kishida, T., Kudo, K. & Ikeda, N. A fatal case of hydrogen sulfide poisoning in a geothermal power plant. J. Forensic Sci. 43, 908–910 (1998).

    CAS  PubMed  Google Scholar 

  128. 128

    Kage, S., Kashimura, S., Ikeda, H., Kudo, K. & Ikeda, N. Fatal and nonfatal poisoning by hydrogen sulfide at an industrial waste site. J. Forensic Sci. 47, 652–655 (2002).

    PubMed  Google Scholar 

  129. 129

    Warenycia, M. W., Smith, K. A., Blashko, C. S., Kombian, S. B. & Reiffenstein, R. J. Monoamine oxidase inhibition as a sequel of hydrogen sulfide intoxication: increases in brain catecholamine and 5-hydroxytryptamine levels. Arch. Toxicol. 63, 131–136 (1989).

    CAS  PubMed  Google Scholar 

  130. 130

    Bhatia, M., Zhi, L., Zhang, H., Ng, S. W. & Moore, P. K. Role of substance P in hydrogen sulfide-induced pulmonary inflammation in mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 291, L896–L904 (2006).

    CAS  PubMed  Google Scholar 

  131. 131

    Trevisani, M. et al. Hydrogen sulfide causes vanilloid receptor 1-mediated neurogenic inflammation in the airways. Br. J. Pharmacol. 145, 1123–1131 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Dorman, D. C. et al. Cytochrome oxidase inhibition induced by acute hydrogen sulfide inhalation: correlation with tissue sulfide concentrations in the rat brain, liver, lung, and nasal epithelium. Toxicol. Sci. 65, 18–25 (2002).

    CAS  PubMed  Google Scholar 

  133. 133

    Dorman, D. C. et al. Fertility and developmental neurotoxicity effects of inhaled hydrogen sulfide in Sprague-Dawley rats. Neurotoxicol. Teratol. 22, 71–84 (2000).

    CAS  PubMed  Google Scholar 

  134. 134

    Attene-Ramos, M. S., Wagner, E. D., Plewa, M. J. & Gaskins, H. R. Evidence that hydrogen sulfide is a genotoxic agent. Mol. Cancer Res. 4, 9–14 (2006).

    CAS  PubMed  Google Scholar 

  135. 135

    Kage, S., Takekawa, K., Kurosaki, K., Imamura, T. & Kudo, K. The usefulness of thiosulfate as an indicator of hydrogen sulfide poisoning: three cases. Int. J. Legal Med. 110, 220–222 (1997).

    CAS  PubMed  Google Scholar 

  136. 136

    Dziewiatkowski, D. D. Conversion of sulfide sulfur to cystine sulfur in the rat, with use of radioactive sulfur. J. Biol. Chem. 164, 165–171 (1946).

    CAS  PubMed  Google Scholar 

  137. 137

    Furne, J., Springfield, J., Koenig, T., DeMaster, E. & Levitt, M. D. Oxidation of hydrogen sulfide and methanethiol to thiosulfate by rat tissues: a specialized function of the colonic mucosa. Biochem. Pharmacol. 62, 255–259 (2001).

    CAS  PubMed  Google Scholar 

  138. 138

    Warenycia, M. W. et al. Acute hydrogen sulfide poisoning. Demonstration of selective uptake of sulfide by the brainstem by measurement of brain sulfide levels. Biochem. Pharmacol. 38, 973–981 (1989).

    CAS  PubMed  Google Scholar 

  139. 139

    Warenycia, M. W. et al. Dithiothreitol liberates non-acid labile sulfide from brain tissue of H2S-poisoned animals. Arch. Toxicol. 64, 650–655 (1990).

    CAS  PubMed  Google Scholar 

  140. 140

    Varenne, O. et al. Local adenovirus-mediated transfer of human endothelial nitric oxide synthase reduces luminal narrowing after coronary angioplasty in pigs. Circulation 98, 919–926 (1998).

    CAS  PubMed  Google Scholar 

  141. 141

    Janssens, S. P. et al. Adenoviral-mediated transfer of the human endothelial nitric oxide synthase gene reduces acute hypoxic pulmonary vasoconstriction in rats. J. Clin. Invest. 98, 317–324 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Tzeng, E. et al. Vascular gene transfer of the human inducible nitric oxide synthase: characterization of activity and effects on myointimal hyperplasia. Mol. Med. 2, 211–225 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143

    Volkel, S. & Berenbrink, M. Sulphaemoglobin formation in fish: a comparison between the haemoglobin of the sulphide-sensitive rainbow trout (Oncorhynchus mykiss) and of the sulphide-tolerant common carp (Cyprinus carpio). J. Exp. Biol. 203, 1047–1058 (2000).

    CAS  PubMed  Google Scholar 

  144. 144

    Noor, M. & Beutler, E. Acquired sulfhemoglobinemia. An underreported diagnosis? West J. Med. 169, 386–389 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    Lyons, J. et al. Cysteine metabolism and whole blood glutathione synthesis in septic pediatric patients. Crit. Care. Med. 29, 870–877 (2001).

    CAS  PubMed  Google Scholar 

  146. 146

    Ensabella, F. et al. Measurement of sulfhemoglobin (S-Hb) blood levels to determine individual hydrogen sulfide exposure in thermal baths in Italy. Ig. Sanita Pubbl. 60, 201–217 (2004).

    PubMed  Google Scholar 

  147. 147

    Park, C. M. & Nagel, R. L. Sulfhemoglobinemia. Clinical and molecular aspects. N. Engl. J. Med. 310, 1579–1584 (1984).

    CAS  PubMed  Google Scholar 

  148. 148

    Tatsuno, Y. et al. Four cases of fatal poisoning by hydrogen sulfide. A study of greenish discoloration of the skin and formation of sulfhemoglobin. Nihon Hoigaku Zasshi 40, 308–315 (1986) (in Japanese).

    CAS  PubMed  Google Scholar 

  149. 149

    Wilson, K., Mudra, M., Furne, J. & Levitt, M. Differentiation of the roles of sulfide oxidase and rhodanese in the detoxification of sulfide by the colonic mucosa. Dig. Dis. Sci. 6 June 2007 (doi:10.1007/s10620-007-9854-9).

    PubMed  Google Scholar 

  150. 150

    Eghbal, M. A., Pennefather, P. S. & O'Brien, P. J. H2S cytotoxicity mechanism involves reactive oxygen species formation and mitochondrial depolarization. Toxicology 203, 69–76 (2004).

    CAS  PubMed  Google Scholar 

  151. 151

    Stadler, J. et al. Effect of endogenous nitric oxide on mitochondrial respiration of rat hepatocytes in vitro and in vivo. Arch. Surg. 126, 186–191 (1991).

    CAS  PubMed  Google Scholar 

  152. 152

    Shen, W., Hintze, T. H. & Wolin, M. S. Nitric oxide. An important signaling mechanism between vascular endothelium and parenchymal cells in the regulation of oxygen consumption. Circulation 92, 3505–3512 (1995).

    CAS  PubMed  Google Scholar 

  153. 153

    Goubern, M., Andriamihaja, M., Nubel, T., Blachier, F. & Bouillaud, F. Sulfide, the first inorganic substrate for human cells. FASEB J. 21, 1699–1706 (2007).

    CAS  PubMed  Google Scholar 

  154. 154

    Mitsuhashi, H. et al. Oxidative stress-dependent conversion of hydrogen sulfide to sulfite by activated neutrophils. Shock 24, 529–534 (2005).

    CAS  PubMed  Google Scholar 

  155. 155

    Shigehara, T. et al. Sulfite induces adherence of polymorphonuclear neutrophils to immobilized fibrinogen through activation of Mac-1 β2-integrin (CD11b/CD18). Life Sci. 70, 2225–2232 (2002).

    CAS  PubMed  Google Scholar 

  156. 156

    Ratthe, C., Pelletier, M., Roberge, C. J. & Girard, D. Activation of human neutrophils by the pollutant sodium sulfite: effect on cytokine production, chemotaxis, and cell surface expression of cell adhesion molecules. Clin. Immunol. 105, 169–175 (2002).

    CAS  PubMed  Google Scholar 

  157. 157

    Pelletier, M., Lavastre, V. & Girard, D. Activation of human epithelial lung A549 cells by the pollutant sodium sulfite: enhancement of neutrophil adhesion. Toxicol. Sci. 69, 210–216 (2002).

    CAS  PubMed  Google Scholar 

  158. 158

    Vincent, A. S. et al. Sulfite-mediated oxidative stress in kidney cells. Kidney Int. 65, 393–402 (2004).

    CAS  PubMed  Google Scholar 

  159. 159

    Reed, G. A. & Jones, B. C. Enhancement of benzo[a]pyrene diol epoxide mutagenicity by sulfite in a mammalian test system. Carcinogenesis 17, 1063–1068 (1996).

    CAS  PubMed  Google Scholar 

  160. 160

    De Giovanni-Donnelly, R. The mutagenicity of sodium bisulfite on base-substitution strains of Salmonella typhimurium. Teratog. Carcinog. Mutagen. 5, 195–203 (1985).

    CAS  PubMed  Google Scholar 

  161. 161

    Whiteman, M. et al. Evidence for the formation of a novel nitrosothiol from the gaseous mediators nitric oxide and hydrogen sulphide. Biochem. Biophys. Res. Commun. 343, 303–310 (2006). The first description of a novel nitrosothiol formed from the reaction of NO and sulphide.

    CAS  PubMed  Google Scholar 

  162. 162

    Han, Y., Qin, J., Chang, X., Yang, Z. & Du, J. Hydrogen sulfide and carbon monoxide are in synergy with each other in the pathogenesis of recurrent febrile seizures. Cell. Mol. Neurobiol. 26, 101–107 (2006).

    PubMed  Google Scholar 

  163. 163

    Yanfei, W., Lin, S., Junbao, D. & Chaoshu, T. Impact of L-arginine on hydrogen sulfide/cystathionine-γ-lyase pathway in rats with high blood flow-induced pulmonary hypertension. Biochem. Biophys. Res. Commun. 345, 851–857 (2006).

    PubMed  Google Scholar 

  164. 164

    Geng, B. et al. Hydrogen sulfide downregulates the aortic L-arginine/nitric oxide pathway in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 18 July 2007 (doi:10.1152/ajpregu.00207.2006).

    CAS  PubMed  Google Scholar 

  165. 165

    Kubo, S., Doe, I., Kurokawa, Y., Nishikawa, H. & Kawabata, A. Direct inhibition of endothelial nitric oxide synthase by hydrogen sulfide: contribution to dual modulation of vascular tension. Toxicology 232, 138–146 (2007).

    CAS  PubMed  Google Scholar 

  166. 166

    Ramasamy, S., Singh, S., Taniere, P., Langman, M. J. & Eggo, M. C. Sulfide-detoxifying enzymes in the human colon are decreased in cancer and upregulated in differentiation. Am. J. Physiol. Gastrointest. Liver Physiol. 291, G288–G296 (2006).

    CAS  PubMed  Google Scholar 

  167. 167

    Levine, J., Ellis, C. J., Furne, J. K., Springfield, J. & Levitt, M. D. Fecal hydrogen sulfide production in ulcerative colitis. Am. J. Gastroenterol. 93, 83–87 (1998).

    CAS  PubMed  Google Scholar 

  168. 168

    Suarez, F., Furne, J., Springfield, J. & Levitt, M. Production and elimination of sulfur-containing gases in the rat colon. Am. J. Physiol. 274, G727–G733 (1998).

    CAS  PubMed  Google Scholar 

  169. 169

    Suarez, F. L., Furne, J. K., Springfield, J. & Levitt, M. D. Bismuth subsalicylate markedly decreases hydrogen sulfide release in the human colon. Gastroenterology 114, 923–929 (1998).

    CAS  PubMed  Google Scholar 

  170. 170

    Furne, J. K., Suarez, F. L., Ewing, S. L., Springfield, J. & Levitt, M. D. Binding of hydrogen sulfide by bismuth does not prevent dextran sulfate-induced colitis in rats. Dig. Dis. Sci. 45, 1439–1443 (2000).

    CAS  PubMed  Google Scholar 

  171. 171

    Lee, S. W., Cheng, Y., Moore, P. K. & Bian, J. S. Hydrogen sulphide regulates intracellular pH in vascular smooth muscle cells. Biochem. Biophys. Res. Commun. 358, 1142–1147 (2007).

    CAS  PubMed  Google Scholar 

  172. 172

    Elrod, J. W. et al. Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury by preservation of mitochondrial function. Proc. Natl Acad. Sci. USA. 104, 15560–15565 (2007). Describes cardioprotective effects of sulphide in vivo , including functional and biochemical evidence, and links to metabolic modulation and neutrophil adhesion.

    CAS  PubMed  Google Scholar 

  173. 173

    Shi, Y. X. et al. Chronic sodium hydrosulfide treatment decreases medial thickening of intramyocardial coronary arterioles, interstitial fibrosis and ROS production in SHR. Am. J. Physiol. Heart. Circ. Physiol. 13 July 2007 (doi:10.1152/ajpheart.00088.2007).

    CAS  PubMed  Google Scholar 

  174. 174

    Morrison, M. et al. Surviving blood loss using hydrogen sulfide. J. Trauma (in the press).

  175. 175

    Hu, Y. et al. Cardioprotection induced by hydrogen sulfide preconditioning involves activation of ERK and PI3K/Akt pathways. Pflugers Arch. 1 Aug 2007 (doi:10.1007/s00424-007-0321-4).

    PubMed  Google Scholar 

  176. 176

    Pyriochou, A., Szabó, C. & Papapetropoulos, A. IK-1001, a hydrogen sulfide donor stimulates angiogenesis. Free Radicals in Montevideo Meeting, Montevideo Sept 2–6 Book of Abstracts. 49 (2007).

  177. 177

    Cai, W. J. et al. The novel proangiogenic effect of hydrogen sulfide is dependent on Akt phosphorylation. Cardiovasc. Res. 76, 29–40 (2007).

    CAS  PubMed  Google Scholar 

  178. 178

    Wallace, J. L., Dicay, M., McKnight, W. & Martin, G. R. Hydrogen sulfide enhances ulcer healing in rats. FASEB J. 18 July 2007 (doi:10.1096/fj.07-8669com).

    CAS  PubMed  Google Scholar 

  179. 179

    Yonezawa, D. et al. A protective role of hydrogen sulfide against oxidative stress in rat gastric mucosal epithelium. Toxicology 6 Aug 2007 (doi:10.1016/j.tox.2007.07.020).

    CAS  PubMed  Google Scholar 

  180. 180

    Chuah, S. C., Moore, P. K. & Zhu, Y. Z. S-allylcysteine mediates cardioprotection in an acute myocardial infarction rat model via a hydrogen sulphide mediated pathway. Am. J. Physiol. Heart Circ. Physiol. 31 Aug 2007 (doi:10.1152/ajpheart.00853.2007).

    CAS  PubMed  Google Scholar 

  181. 181

    Benavides, G. A. et al. Hydrogen sulfide mediates the vasoactivity of garlic. Proc. Natl Acad. Sci. USA (in the press).

Download references

Acknowledgements

The author thanks K. Tomaselli, T. Deckwerth, C. Toombs, E. Wintner and M. Roth for helpful discussions. Also, the author is grateful for T. Deckwerth and E. Wintner for preparing figures 1 and 2, respectively, and F. Su and C. Toombs for providing the data for figure 5b.

Author information

Affiliations

Authors

Ethics declarations

Competing interests

C.S. is an employee and stock holder to Ikaria, a for-profit organization involved in the development of H2S-related technologies.

Supplementary information

Supplementary information S1 (table)

Some pharmacological and toxicological effects of H2S in animals. (PDF 119 kb)

Supplementary information S2 (table)

Some pharmacological or toxicological effects of H2S in humans (PDF 126 kb)

Related links

Related links

DATABASES

SwissProt ENZYME

Amine oxidase

carbonate dehydratase

cystathionine β-synthase

cystathionine γ-lyase

cystathionine γ-synthase

cytochrome c oxidase

glutamate cysteine ligase

thiosulphate sulphurtransferase

FURTHER INFORMATION

Ikaria Inc.

Glossary

Sulphide

In this article, the term sulphide is used to collectively describe all biologically active sulphide-related species, including HS. When referring to the chemical compounds, the chemical terms H2S, Na2S or NaHS are used.

Endotoxin

A toxin produced by Gram-negative bacteria and released from the bacterial cell.

Long-term potentiation

The prolonged strengthening of synaptic communication, which is induced by patterned input and is thought to be involved in learning and memory formation.

Haem proteins

Haem proteins contain an iron complex of porphyrin, usually protoporphyrin IX, and function as catalysts in many biological processes.

Cytochrome c oxidase

A component of the oxidative phosphorylation machinery within the cell that normally binds oxygen.

Suspended animation

A state of temporary and reversible slowing down or cessation of life functions by external means.

Cecal ligation and puncture

An experimental model of polymicrobial sepsis that is generally considered more relevant to the human disease than rodents injected with bacterial lipopolysaccharide (endotoxin).

Hibernation

It is well known that various organisms can reversibly arrest their essential life processes, in some cases for several years at a time. This phenomenon is known as quiescence, torpor or hibernation. An important aspect of this process is a significant reduction in both energy production and energy consumption. Organisms in this state are resistant to environmental stresses including temperature extremes and oxygen deprivation.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Szabó, C. Hydrogen sulphide and its therapeutic potential. Nat Rev Drug Discov 6, 917–935 (2007). https://doi.org/10.1038/nrd2425

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing