Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 392, Issue 12, pp 1561–1568 | Cite as

Effects of fast versus slow-releasing hydrogen sulfide donors in hypertension in pregnancy and fetoplacental growth restriction

  • Gabriela Palma Zochio
  • Jose Sergio Possomato-Vieira
  • Jessica Sabbatine Chimini
  • Maria Luiza Santos da Silva
  • Carlos Alan Dias-JuniorEmail author
Original Article


Hydrogen sulfide (H2S) is a vasorelaxant gas with therapeutic potential in several diseases. However, effects of H2S donors in hypertensive pregnancy complicated by feto-placental growth restriction are unclear. Therefore, we aimed to examine and compare the effects of fast-releasing H2S donor (sodium hydrosulfide—NaHS) and slow-releasing H2S donor (GYY4137) in hypertension-in-pregnancy. Pregnant rats were distributed into four groups: normal pregnancy (Norm-Preg), hypertensive pregnancy (HTN-Preg), hypertensive pregnancy + NaHS (HTN-Preg + NaHS), and hypertensive pregnancy + GYY4137 (HTN-Preg + GYY). Systolic blood pressure, plasma H2S levels, fetal and placental weights, number of viable fetuses, litter size, and endothelium-dependent vasodilation were examined. Also, oxidative stress was assessed in placenta. We found that GYY4137 attenuated hypertension on gestational days 16 and 18, while NaHS presented antihypertensive effect only on gestational day 18. GYY4137, but not NaHS, increased plasma H2S levels. Greater fetal and placental weights were found with GYY4137 than NaHS treatment. Also, HTN-Preg + NaHS presented further reductions in placental weights when compared to HTN-Preg group. Number of viable fetuses and litter size presented no significant changes. GYY4137 reduced placental oxidative stress caused by hypertension, while greater increases in oxidative stress were found in HTN-Preg + NaHS than HTN-Preg group. Hypertensive pregnancy caused impaired endothelium-dependent vasodilation, while GYY4137 and NaHS treatments blunted endothelial dysfunction. Endothelium-dependent vasodilation was completely blocked by the nitric oxide synthase inhibitor. We conclude that slow-releasing H2S donor GYY4137 is advantageous compared with fast-releasing H2S-donor NaHS to attenuate hypertension-in-pregnancy and to protect against feto-placental growth restriction and oxidative stress.


Hypertensive pregnancy Hydrogen sulfide donors Vasodilation Rats 


Author’s contribution

GPZT designed and performed experiments, analyzed data, interpreted results of experiments, and drafted manuscript; JSPV, JSC, and MLSS helped to analyze and interpret results of experiments; CADJ edited and revised manuscript; all authors approved final version of manuscript.

Funding information

This study was supported by Fundacao de Amparo a Pesquisa do Estado de Sao Paulo, Brazil (FAPESP–Finance Code: 2016/18.782-3) and National Council for Scientific and Technological Development, Brazil (CNPq).

Compliance with ethical standards

All procedures for animal experimentation were approved by the Ethics Committee, Biosciences Institute of Botucatu, Sao Paulo State University (protocol no 619/2014) which is complied with international guidelines of the European Community for the use of experimental animals.

Conflict of interest

The authors declare that they have no conflicts of interest.


  1. Ahamed M, Mehrotra PK, Kumar P, Siddiqui MK (2009) Placental lead-induced oxidative stress and preterm delivery. Environ Toxicol Pharmacol 27:70–74PubMedGoogle Scholar
  2. Ahmed A (2014) Molecular mechanisms and therapeutic implications of the carbon monoxide/hmox1 and the hydrogen sulfide/CSE pathways in the prevention of pre-eclampsia and fetal growth restriction. Pregnancy Hypertens 4(3):243–244PubMedGoogle Scholar
  3. Ali MY, Ping CY, Mok YY, Ling L, Whiteman M, Bhatia M, Moore PK (2006) Regulation of vascular nitric oxide in vitro and in vivo; a new role for endogenous hydrogen sulphide? Br J Pharmacol 149:625–634PubMedPubMedCentralGoogle Scholar
  4. Baskar R, Li L, Moore PK (2007) Hydrogen sulfide-induces DNA damage and changes in apoptotic gene expression in human lung fibroblast cells. FASEB J 21:247–255PubMedGoogle Scholar
  5. Bucci M, Papapetropoulos A, Vellecco V, Zhou Z, Zaid A, Giannogonas P, Cantalupo A, Dhayade S, Karalis KP, Wang R, Feil R, Cirino G (2012) cGMP-dependent protein kinase contributes to hydrogen sulfide-stimulated vasorelaxation. PLoS One 7:e53319PubMedPubMedCentralGoogle Scholar
  6. Calvert JW, Jha S, Gundewar S, Elrod JW, Ramachandran A, Pattillo CB, Kevil CG, Lefer DJ (2009) Hydrogen sulfide mediates cardioprotection through Nrf2 signaling. Circ Res 105:365–374PubMedPubMedCentralGoogle Scholar
  7. Goncalves-Rizzi VH, Possomato-Vieira JS, Sales Graca TU, Nascimento RA, Dias-Junior CA (2016) Sodium nitrite attenuates hypertension-in-pregnancy and blunts increases in soluble fms-like tyrosine kinase-1 and in vascular endothelial growth factor. Nitric Oxide Biol Chem 57:71–78Google Scholar
  8. Holwerda KM, Burke SD, Faas MM, Zsengeller Z, Stillman IE, Kang PM, van Goor H, McCurley A, Jaffe IZ, Karumanchi SA, Lely AT (2014) Hydrogen sulfide attenuates sFlt1-induced hypertension and renal damage by upregulating vascular endothelial growth factor. J Am Soc Nephrol 25:717–725PubMedGoogle Scholar
  9. Hosoki R, Matsuki N, Kimura H (1997) The possible role of hydrogen sulfide as an endogenous smooth muscle relaxant in synergy with nitric oxide. Biochem Biophys Res Commun 237:527–531PubMedGoogle Scholar
  10. Hua W, Jiang J, Rong X, Wu R, Qiu H, Zhang Y, Chen Q (2009) The dual role of the cystathionine gamma-lyase/hydrogen sulfide pathway in CVB3-induced myocarditis in mice. Biochem Biophys Res Commun 388:595–600PubMedGoogle Scholar
  11. Huang B, Chen CT, Chen CS, Wang YM, Hsieh HJ, Wang DL (2015) Laminar shear flow increases hydrogen sulfide and activates a nitric oxide producing signaling cascade in endothelial cells. Biochem Biophys Res Commun 464(4):1254–1259PubMedGoogle Scholar
  12. Ianosi-Irimie M, Vu HV, Whitbred JM, Pridjian CA, Nadig JD, Williams MY, Wrenn DC, Pridjian G, Puschett JB (2005) A rat model of preeclampsia. Clin Exp Hypertens 27:605–617PubMedGoogle Scholar
  13. Li L, Whiteman M, Guan YY, Neo KL, Cheng Y, Lee SW, Zhao Y, Baskar R, Tan CH, Moore PK (2008) Characterization of a novel, water-soluble hydrogen sulfide-releasing molecule (GYY4137): new insights into the biology of hydrogen sulfide. Circulation 117:2351–2360PubMedGoogle Scholar
  14. Liang YF, Zhang DD, Yu XJ, Gao HL, Liu KL, Qi J, Li HB, Yi QY, Chen WS, Cui W, Zhu GQ, Kang YM (2017) Hydrogen sulfide in paraventricular nucleus attenuates blood pressure by regulating oxidative stress and inflammatory cytokines in high salt-induced hypertension. Toxicol Lett 270:62–71PubMedGoogle Scholar
  15. Ma RQ, Sun MN, Yang Z (2010) Effects of preeclampsia-like symptoms at early gestational stage on feto-placental outcomes in a mouse model. Chin Med J 123:707–712PubMedGoogle Scholar
  16. Mao Z, Huang Y, Zhang Z, Yang X, Zhang X, Huang Y, Sawada N, Mitsui T, Takeda M, Yao J (2019) Pharmacological levels of hydrogen sulfide inhibit oxidative cell injury through regulating the redox state of thioredoxin. Free Radic Biol Med 134:190–199PubMedGoogle Scholar
  17. Mathai JC, Missner A, Kugler P, Saparov SM, Zeidel ML, Lee JK, Pohl P (2009) No facilitator required for membrane transport of hydrogen sulfide. Proc Natl Acad Sci U S A 106:16633–16638PubMedPubMedCentralGoogle Scholar
  18. McCarthy FP, Kingdom JC, Kenny LC, Walsh SK (2011) Animal models of preeclampsia; uses and limitations. Placenta 32(6):413–419PubMedGoogle Scholar
  19. Milosevic-Stevanovic J, Krstic M, Radovic-Janosevic D, Stefanovic M, Antic V, Djordjevic I (2016) Preeclampsia with and without intrauterine growth restriction-two pathogenetically different entities? Hypertens Pregnancy 35(4):573–582PubMedGoogle Scholar
  20. Mitchell BM, Cook LG, Danchuk S, Puschett JB (2007) Uncoupled endothelial nitric oxide synthase and oxidative stress in a rat model of pregnancy-induced hypertension. Am J Hypertens 20:1297–1304PubMedGoogle Scholar
  21. Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358PubMedGoogle Scholar
  22. Olson KR, DeLeon ER, Liu F (2014) Controversies and conundrums in hydrogen sulfide biology. Nitric Oxide 41:11–26PubMedGoogle Scholar
  23. Pan LL, Liu XH, Gong QH, Wu D, Zhu YZ (2011) Hydrogen sulfide attenuated tumor necrosis factor-alpha-induced inflammatory signaling and dysfunction in vascular endothelial cells. PLoS One 6:e19766PubMedPubMedCentralGoogle Scholar
  24. Possomato-Vieira JS, Goncalves-Rizzi VH, Graca TU, Nascimento RA, Dias-Junior CA (2016) Sodium hydrosulfide prevents hypertension and increases in vascular endothelial growth factor and soluble fms-like tyrosine kinase-1 in hypertensive pregnant rats. Naunyn Schmiedeberg's Arch Pharmacol 389:1325–1332Google Scholar
  25. Possomato-Vieira JS, Chimini JS, da Silva MLS, Dias-Junior CA (2018) Increases in placental nitric oxide, but not nitric oxide-mediated relaxation, underlie the improvement in placental efficiency and antihypertensive effects of hydrogen sulphide donor in hypertensive pregnancy. Clin Exp Pharmacol Physiol 45:1118–1127PubMedGoogle Scholar
  26. Powell CR, Dillon KM, Matson JB (2018) A review of hydrogen sulfide (H2S) donors: chemistry and potential therapeutic applications. Biochem Pharmacol 149:110–123PubMedGoogle Scholar
  27. Riahi S, Rowley CN (2014) Why can hydrogen sulfide permeate cell membranes? J Am Chem Soc 136:15111–15113PubMedGoogle Scholar
  28. Roberts JM, Bell MJ (2013) If we know so much about preeclampsia, why haven't we cured the disease? J Reprod Immunol 99(1–2):1–9PubMedPubMedCentralGoogle Scholar
  29. Roberts JM, Hubel CA (2009) The two stage model of preeclampsia: variations on the theme. Placenta 30(Suppl a):S32–S37PubMedGoogle Scholar
  30. Rose P, Dymock BW, Moore PK (2015) GYY4137, a novel water-soluble, H2S-releasing molecule. Methods Enzymol 554:143–167PubMedGoogle Scholar
  31. Shefa U, Kim MS, Jeong NY, Jung J (2018) Antioxidant and cell-signaling functions of hydrogen sulfide in the central nervous system. Oxidative Med Cell Longev 2018:1873962Google Scholar
  32. Sikora M, Drapala A, Ufnal M (2014) Exogenous hydrogen sulfide causes different hemodynamic effects in normotensive and hypertensive rats via neurogenic mechanisms. Pharmacol Rep 66:751–758PubMedGoogle Scholar
  33. Sun X, Wang W, Dai J, Jin S, Huang J, Guo C, Wang C, Pang L, Wang Y (2017) A long-term and slow-releasing hydrogen sulfide donor protects against myocardial ischemia/reperfusion injury. Sci Rep 7(1):3541PubMedPubMedCentralGoogle Scholar
  34. Szabo C (2018) A timeline of hydrogen sulfide (H2S) research: from environmental toxin to biological mediator. Biochem Pharmacol 149:5–19PubMedGoogle Scholar
  35. Truong DH, Eghbal MA, Hindmarsh W, Roth SH, O'Brien PJ (2006) Molecular mechanisms of hydrogen sulfide toxicity. Drug Metab Rev 38:733–744PubMedGoogle Scholar
  36. Wang R (2012) Shared signaling pathways among gasotransmitters. Proc Natl Acad Sci U S A 109:8801–8802PubMedPubMedCentralGoogle Scholar
  37. Wang K, Ahmad S, Cai M, Rennie J, Fujisawa T, Crispi F, Baily J, Miller MR, Cudmore M, Hadoke PW, Wang R, Gratacos E, Buhimschi IA, Buhimschi CS, Ahmed A (2013) Dysregulation of hydrogen sulfide producing enzyme cystathionine gamma-lyase contributes to maternal hypertension and placental abnormalities in preeclampsia. Circulation 127:2514–2522PubMedGoogle Scholar
  38. Wedmann R, Bertlein S, Macinkovic I, Boltz S, Miljkovic J, Munoz LE, Herrmann M, Filipovic MR (2014) Working with "H2S": facts and apparent artifacts. Nitric Oxide Biol Chem 41:85–96Google Scholar
  39. Wen YD, Wang H, Zhu YZ (2018) The drug developments of hydrogen sulfide on cardiovascular disease. Oxidative Med Cell Longev 2018:4010395Google Scholar
  40. Whiteman M, Li L, Rose P, Tan CH, Parkinson DB, Moore PK (2010) The effect of hydrogen sulfide donors on lipopolysaccharide-induced formation of inflammatory mediators in macrophages. Antioxid Redox Signal 12(10):1147–1154PubMedPubMedCentralGoogle Scholar
  41. Xiao Q, Ying J, Xiang L, Zhang C (2018) The biologic effect of hydrogen sulfide and its function in various diseases. Medicine (Baltimore) 97:e13065Google Scholar
  42. Xie ZZ, Liu Y, Bian JS (2016) Hydrogen Sulfide and Cellular Redox Homeostasis. Oxidative Med Cell Longev 2016:6043038Google Scholar
  43. Yang G, Sun X, Wang R (2004) Hydrogen sulfide-induced apoptosis of human aorta smooth muscle cells via the activation of mitogen-activated protein kinases and caspase-3. FASEB J 18:1782–1784PubMedGoogle Scholar
  44. Yang G, Wu L, Jiang B, Yang W, Qi J, Cao K, Meng Q, Mustafa AK, Mu W, Zhang S, Snyder SH, Wang R (2008) H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase. Science 322:587–590PubMedPubMedCentralGoogle Scholar
  45. Zhang L, Wang Y, Li Y, Li L, Xu S, Feng X, Liu S (2018) Hydrogen sulfide (H2S)-releasing compounds: therapeutic potential in cardiovascular diseases. Front Pharmacol 9:1066PubMedPubMedCentralGoogle Scholar
  46. Zhao W, Wang R (2002) H(2)S-induced vasorelaxation and underlying cellular and molecular mechanisms. Am J Physiol Heart Circ Physiol 283:H474–H480PubMedGoogle Scholar
  47. Zhao W, Zhang J, Lu Y, Wang R (2001) The vasorelaxant effect of H(2) S as a novel endogenous gaseous K (ATP) channel opener. EMBO J 20:6008–6016PubMedPubMedCentralGoogle Scholar
  48. Zhuo Y, Chen PF, Zhang AZ, Zhong H, Chen CQ, Zhu YZ (2009) Cardioprotective effect of hydrogen sulfide in ischemic reperfusion experimental rats and its influence on expression of survivin gene. Biol Pharm Bull 32:1406–1410PubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmacology, Biosciences Institute of BotucatuSao Paulo State University–UNESPBotucatuBrazil

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