Skip to main content
SpringerLink
Log in

Propargylglycine aggravates liver damage in LPS-treated rats: Possible relation of nitrosative stress with the inhibition of H2S formation

  • Original research article
  • Published:
Pharmacological Reports Aims and scope Submit manuscript

    We’re sorry, something doesn't seem to be working properly.

    Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Abstract

Background: Hydrogen sulfide (H2S) is a naturally occurring gaseous transmitter, which may play important roles in normal physiology and disease. Here, we investigated the effect of endogenously formed H2S in the endotoxemic organ injury.

Methods: Male Wistar rats were subjected to acute endotoxemia [Escherichia coli lipopolysaccharide (LPS) 20 mg kg−1, intraperitoneally (ip)]. A group of animals was injected d,l-propargylglycine (PAG, 50 mg kg−1,ip), an inhibitor of the H2S-synthesizing enzyme cystathionine-γ-lyase (CSE), 60 min before LPS administration. Six hours after the LPS treatment, animals were sacrificed. Myeloperoxidase (MPO), dimethylarginine dimethylaminohydrolase (DDAH) activities and levels of nitrotyrosine and GSH were measured in the liver. Asymmetric dimethylarginine (ADMA) and arginine levels in both liver and plasma were determined using HPLC.

Results: LPS injections caused liver injury, as evidenced by the activities of serum aspartate aminotransferase and arginase. After LPS injections, increased arginine content and arginine/ADMA ratio were observed in the liver, together with significant decrements in both DDAH activity and GSH levels. Despite the accumulation of ADMA in the plasma, its level remained unchanged in the liver. PAG pretreatment aggravated the LPS-induced increase in the activities of MPO and serum enzymes. The most profound effect of PAG pretreatment was observed in nitrotyrosine levels in the liver, which were increased significantly as compared with the control and LPS-injected groups.

Conclusion: These findings support the view that the suppression of nitrosative stress by endogenous H2S is one of the mechanisms to protect liver against endotoxemic injury.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Łowicka E, Bełtowski J. Hydrogen sulfide (H2S) – the third gas of interest for pharmacologists. Pharmacol Rep 2007;59:4–24.

    PubMed  Google Scholar 

  2. Wagner F, Asfar P, Calzia E, Radermacher P, Szabó C. Bench-to-bedside review: hydrogen sulfide—the third gaseous transmitter: applications for critical care. Crit Care 2009;13:213.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Whiteman M, Winyard PG. Hydrogen sulfide and inflammation: the good, the bad, the ugly and the promising. Expert Rev Clin Pharmacol 2011;4:13–32.

    Article  CAS  PubMed  Google Scholar 

  4. Chai W, Wang Y, Lin JY, Sun XD, Yao LN, Yang YH, et al. Exogenous hydrogen sulfide protects against traumatic hemorrhagic shock via attenuation of oxidative stress. Surg Res 2012;176:210–9.

    Article  CAS  Google Scholar 

  5. Bracht H, Scheuerle A, Grö ger M, Hauser B, Matallo J, McCook O, et al. Effects of intravenous sulfide during resuscitated porcine hemorrhagic shock. Crit Care Med 2012;40:2157–67.

    Article  CAS  PubMed  Google Scholar 

  6. Dudek M, Bilska-Wilkosz A, Knutelska J, Mogilski S, Bednarski M, Zygmunt M, et al. Are anti-inflammatory properties of lipoic acid associated with the formation of hydrogen sulfide? Pharmacol Rep 2013;65:1018–24.

    Article  CAS  PubMed  Google Scholar 

  7. Ang SF, Moochhala SM, MacAry PA, Bhatia M. Hydrogen sulfide and neurogenic inflammation in polymicrobial sepsis: involvement of substance P and ERK-NF-ĸB signaling. PLoS ONE 2011;6:e24535.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Yan Y, Chen C, Zhou H, Gao H, Chen L, Chen L, et al. Endogenous hydrogen sulfide formation mediates the liver damage in endotoxemic rats. Res Vet Sci 2013;94:590–5.

    Article  CAS  PubMed  Google Scholar 

  9. Mok YY, Moore PK. Hydrogen sulphide is pro-inflammatory in haemorrhagic shock. Inflamm Res 2008;57:512–8.

    Article  CAS  PubMed  Google Scholar 

  10. Mayer B, Hemmens B. Biosynthesis and action of nitric oxide in mammalian cells. Trends Biochem Sci 1997;22:477–81.

    Article  CAS  PubMed  Google Scholar 

  11. Rawlingson A. Nitric oxide, inflammation and acute burn injury. Burns 2003;29:631–40.

    Article  PubMed  Google Scholar 

  12. Mashimo H, Goyal RK. Lessons from genetically engineered animal models. IV: Nitric oxide synthase gene knockout mice. Am J Physiol 1999;277:G745–50.

    CAS  PubMed  Google Scholar 

  13. Hierholzer C, Billiar TR. Molecular mechanisms in the early phase of hemorrhagic shock. Langenbecks Arch Surg 2001;386:302–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mori M, Gotoh T. Regulation of nitric oxide production by arginine metabolic enzymes. Biochem Biophys Res Commun 2000;275:715–9.

    Article  CAS  PubMed  Google Scholar 

  15. Mosser DM. The many faces of macrophage activation. J Leukoc Biol 2003;73:209–12.

    Article  CAS  PubMed  Google Scholar 

  16. Corraliza IM, Campo ML, Soler G, Modolell M. Determination of arginase activity in macrophages: a micromethod. J Immunol Methods 1994;174:231–5.

    Article  CAS  PubMed  Google Scholar 

  17. MacAllister RJ, Parry H, Kimoto M, Ogawa T, Russell RJ, Hodson H, et al. Regulation of nitric oxide synthesis by dimethylarginine dimethylaminohydrolase. Br J Pharmacol 1996;119:1533–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Leiper J, Murray-Rust J, McDonald N, Vallance P. S-nitrosylation of dimethylarginine dimethylaminohydrolase regulates enzyme activity: further interactions between nitric oxide synthase and dimethylarginine dimethylaminohydrolase. Proc Natl Acad Sci U S A 2002;99:13527–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Beutler E, Duron O, Kelly BM. Improved method for the determination of blood glutathione. J Lab Clin Med 1963;61:882–8.

    CAS  PubMed  Google Scholar 

  20. Rachmilewitz D, Stamler JS, Karmeli F, Mullins ME, Singel DJ, Loscalzo J, et al. Peroxynitrite-induced rat colitis—a new model of colonic inflammation. Gastroenterology 1993;105:1681–8.

    Article  CAS  PubMed  Google Scholar 

  21. Teerlink T. Determination of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine in biological samples by HPLC. Methods Mol Med 2005;108:263–74.

    CAS  PubMed  Google Scholar 

  22. Tain YL, Baylis C. Determination of dimethylarginine dimethylaminohydrolase activity in the kidney. Kidney Int 2007;72:886–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bronte V, Zanovello P. Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol 2005;5:641–54.

    Article  CAS  PubMed  Google Scholar 

  24. Venketaraman V, Talaue MT, Dayaram YK, Peteroy-Kelly MA, Bu W, Connell ND. Nitric oxide regulation of L-arginine uptake in murine and human macrophages. Tuberculosis (Edinb) 2003;83:311–8.

    Article  Google Scholar 

  25. Szabó C, Mó dis K. Pathophysiological roles of peroxynitrite in circulatory shock. Shock 2010;4–14.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Hausladen A, Fridovich I. Superoxide and peroxynitrite inactivate aconitases, but nitric oxide does not. J Biol Chem 1994;269:29405–08.

    CAS  PubMed  Google Scholar 

  27. Brunelli L, Crow JP, Beckman JS. The comparative toxicity of nitric oxide and peroxynitrite toEscherichia coli. Arch Biochem Biophys 1995;316:327–34.

    Article  CAS  PubMed  Google Scholar 

  28. Szabó C, Salzman AL. Endogenous peroxynitrite is involved in the inhibition of mitochondrial respiration in immuno-stimulated J774.2 macrophages. Biochem Biophys Res Commun 1995;209:739–43.

    Article  PubMed  Google Scholar 

  29. Virág L, Szabó E, Gergely P, Szabó C. Peroxynitrite-induced cytotoxicity: mechanism and opportunities for intervention. Toxicol Lett 2003;140-141:113–24.

    Article  PubMed  Google Scholar 

  30. Szabó C. Mechanisms of cell necrosis. Crit Care Med 2005;33:S530–4.

    Article  PubMed  Google Scholar 

  31. Halliwell B. What nitrates tyrosine? Is nitrotyrosine specific as a biomarker of peroxynitrite formation in vivo? FEBS Lett 1997;411:157–60.

    CAS  PubMed  Google Scholar 

  32. Tan G, Pan S, Li J, Dong X, Kang K, Zhao M, et al. Hydrogen sulfide attenuates carbon tetrachloride-induced hepatotoxicity, liver cirrhosis and portal hypertension in rats. PLoS ONE 2011;6:e25943.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang K, Ahmad S, Cai M, Rennie J, Fujisawa T, Crispi F, et al. Dysregulation of hydrogen sulfide producing enzyme cystathionine-γ-lyase contributes to maternal hypertension and placental abnormalities in preeclampsia. Circulation 2013;127:2514–22.

    Article  CAS  PubMed  Google Scholar 

  34. Norris EJ, Feilen N, Nguyen NH, Culberson CR, Shin MC, Fish M, et al. Hydrogen sulfide modulates sinusoidal constriction and contributes to hepatic microcirculatory dysfunction during endotoxemia. Am J Physiol Gastrointest Liver Physiol 2013;304:G1070–78.

    Article  CAS  PubMed  Google Scholar 

  35. Hua W, Zhou SL, Gong FQ. Biphasic regulation of hydrogen sulfide in inflammation. Chin Med J (Engl) 2013;126:1360–3.

    Google Scholar 

  36. Wallace JL. Hydrogen sulfide-releasing anti-inflammatory drugs. Trends Pharmacol Sci 2007;28:501–5.

    Article  CAS  PubMed  Google Scholar 

  37. Whiteman M, Armstrong JS, Chu SH, Jia-Ling S, Wong BS, Cheung NS, et al. The novel neuromodulator hydrogen sulfide: an endogenous peroxynitrite ‘scavenger’. J Neurochem 2004;90:765–8.

    Article  CAS  PubMed  Google Scholar 

  38. Whiteman M, Li L, Kostetski I, Chu SH, Siau JL, Bhatia M, et al. Evidence for the formation of a novel nitrosothiol from the gaseous mediators, nitric oxide and hydrogen sulphide. Biochem Biophys Res Commun 2006;343:303–10.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey

    Seldag Bekpinar, Yesim Unlucerci, Mujdat Uysal & Figen Gurdol

Authors
  1. Seldag Bekpinar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yesim Unlucerci
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mujdat Uysal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Figen Gurdol
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Figen Gurdol.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bekpinar, S., Unlucerci, Y., Uysal, M. et al. Propargylglycine aggravates liver damage in LPS-treated rats: Possible relation of nitrosative stress with the inhibition of H2S formation. Pharmacol. Rep 66, 897–901 (2014). https://doi.org/10.1016/j.pharep.2014.05.014

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1016/j.pharep.2014.05.014

Keywords

Search

Navigation