Export file:


  • RIS(for EndNote,Reference Manager,ProCite)
  • BibTex
  • Text


  • Citation Only
  • Citation and Abstract

Interaction between hydrogen sulfide, nitric oxide, and carbon monoxide pathways in the bovine isolated retina

1 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 77004, USA
2 Department of Pharmacy Sciences, School of Pharmacy and Health Professions, Creighton University, Omaha, NE 68178, USA

Special Issues: Special Issue on Neuronal Nitric Oxide

Purpose: Nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) are physiologically relevant gaseous neurotransmitters that are endogenously produced in mammalian tissues. In the present study, we investigated the possibility that NO and CO can regulate the endogenous levels of H2S in bovine isolated neural retina. Methods: Isolated bovine neural retina were homogenized and tissue homogenates were treated with a NO synthase inhibitor, NO donor, heme oxygenase-1 inhibitor, and/donor. H2S concentrations in bovine retinal homogenates were measured using a well-established colorimetric assay. Results: L-NAME (300 nM–500 μM) caused a concentration-dependent decrease in basal endogenous levels of H2S by 86.2%. On the other hand, SNP (10–300 μM) elicited a concentration-related increase in H2S levels from 18.3 nM/mg of protein to 65.7 nM/mg of protein. ZnPP-IX (300 nM–10 μM) caused a concentration-dependent increase in the endogenous production of H2S whereas hemin (300 nM–20 μM) attenuated the basal levels of H2S. Conclusion: We conclude that changes in the biosynthesis and availability of both NO and CO can interfere with the pathway/s involved in the production of H2S in the retina. The demonstrated ability of NO, CO and H2S to interact in the mammalian retina affirms a physiological/pharmacological role for these gaseous mediators in the eye.
  Article Metrics

Keywords gasotransmitters; retina; endogenous production; hydrogen sulfide; carbon monoxide; nitric oxide

Citation: Madhura Kulkarni-Chitnis, Leah Mitchell-Bush, Remmington Belford, Jenaye Robinson, Catherine A. Opere, Sunny E. Ohia, Ya Fatou N. Mbye. Interaction between hydrogen sulfide, nitric oxide, and carbon monoxide pathways in the bovine isolated retina. AIMS Neuroscience, 2019, 6(3): 104-115. doi: 10.3934/Neuroscience.2019.3.104


  • 1.Wang R (2010) Hydrogen sulfide: the third gasotransmitter in biology and medicine. Antioxid Redox Sign 12: 1061–1064.    
  • 2.Ritter JM (2010) Human pharmacology of hydrogen sulfide, putative gaseous mediator. Br J Clin Pharmacol 69: 573–575.    
  • 3.Li L, Moore PK (2007) An overview of the biological significance of endogenous gases: new roles for old molecules. Biochem Soc Trans 35: 1138–1141.    
  • 4.Szabo C (2016) Gasotransmitters in cancer: from pathophysiology to experimental therapy. Nat Rev Drug Discov 15: 185–203.    
  • 5.van den Born JC, Hammes HP, Greffrath W, et al. (2016) Gasotransmitters in vascular complications of diabetes. Diabetes 65: 331–345.    
  • 6.Lowicka E, Beltowski J (2007) Hydrogen sulfide (H2S)-the third gas of interest for pharmacologists. Pharmacol Rep 59: 4–24.
  • 7.Kolluru GK, Shen X, Bir SC, et al. (2013) Hydrogen sulfide chemical biology: pathophysiological roles and detection. Nitric Oxide 35: 5–20.    
  • 8.Kram L, Grambow E, Mueller-Graf F, et al. (2013) The anti-thrombotic effect of hydrogen sulfide is partly mediated by an upregulation of nitric oxide synthases. Thromb Res 132: e112–117.    
  • 9.Wang R (2003) The gasotransmitter role of hydrogen sulfide. Antioxid Redox Signal 5: 493–501.    
  • 10.Pong WW, Stouracova R, Frank N, et al. (2007) Comparative localization of cystathionine beta-synthase and cystathionine gamma-lyase in retina: differences between amphibians and mammals. J Comp Neurol 505: 158–165.    
  • 11.Kimura H, Shibuya N, Kimura Y (2012) Hydrogen sulfide is a signaling molecule and a cytoprotectant. Antioxid Redox Signal 17: 45–57.    
  • 12.Kimura H, Nagai Y, Umemura K, et al. (2005) Physiological roles of hydrogen sulfide: synaptic modulation, neuroprotection, and smooth muscle relaxation. Antioxid Redox Signal 7: 795–803.    
  • 13.Kimura H (2002) Hydrogen sulfide as a neuromodulator. Mol Neurobiol 26: 13–19.    
  • 14.Kimura H (2011) Hydrogen sulfide: its production, release and functions. Amino Acids 41: 113–121.    
  • 15.Persa C, Osmotherly K, Chen KC-W, et al. (2006) The distribution of cystathionine beta-synthase (CBS) in the eye: implication of the presence of a trans-sulfuration pathway for oxidative stress defense. Exp Eye Res 83: 817–823.    
  • 16.Shibuya N , Kimura H (2013) Production of hydrogen sulfide from d-cysteine and its therapeutic potential. Front Endocrinol (Lausanne) 4: 87.
  • 17.Shibuya N, Koike S, Tanaka M, et al. (2013) A novel pathway for the production of hydrogen sulfide from D-cysteine in mammalian cells. Nat Commun 4: 1366.    
  • 18.Shibuya N, Mikami Y, Kimura Y, et al. (2009) Vascular endothelium expresses 3-mercaptopyruvate sulfurtransferase and produces hydrogen sulfide. J Biochem 146: 623–626.    
  • 19.Shibuya N, Tanaka M, Yoshida M, et al. (2009) 3-Mercaptopyruvate sulfurtransferase produces hydrogen sulfide and bound sulfane sulfur in the brain. Antioxid Redox Signal 11: 703–714.    
  • 20.Tanizawa K (2011) Production of H2S by 3-mercaptopyruvate sulphurtransferase. J Biochem 149: 357–359.    
  • 21.Ali MY, Ping CY, Mok YY, et al. (2006) Regulation of vascular nitric oxide in vitro and in vivo; a new role for endogenous hydrogen sulphide? Br J Pharmacol 149: 625–634.    
  • 22.Li L, Salto-Tellez M, Tan CH, et al. (2009) GYY4137, a novel hydrogen sulfide-releasing molecule, protects against endotoxic shock in the rat. Free Radic Biol Med 47: 103–113.    
  • 23.Wang R (2002) Two's company, three's a crowd: can H2S be the third endogenous gaseous transmitter? FASEB J 16: 1792–1798.    
  • 24.Whiteman M, Le Trionnaire S, Chopra M, et al. (2011) Emerging role of hydrogen sulfide in health and disease: critical appraisal of biomarkers and pharmacological tools. Clin Sci (Lond) 121: 459–488.    
  • 25.Huang X, Meng XM, Liu DH, et al. (2013) Different regulatory effects of hydrogen sulfide and nitric oxide on gastric motility in mice. Eur J Pharmacol 720: 276–285.    
  • 26.Yong QC, Cheong JL, Hua F, et al. (2011) Regulation of heart function by endogenous gaseous mediators-crosstalk between nitric oxide and hydrogen sulfide. Antioxid Redox Signal 14: 2081–2091.    
  • 27.Whiteman M, Li L, Kostetski I, et al. (2006) Evidence for the formation of a novel nitrosothiol from the gaseous mediators nitric oxide and hydrogen sulphide. Biochem Biophys Res Commun 343: 303–310.    
  • 28.Zhang QY, Du JB, Zhou WJ, et al. (2004) Impact of hydrogen sulfide on carbon monoxide/heme oxygenase pathway in the pathogenesis of hypoxic pulmonary hypertension. Biochem Biophys Res Commun 317: 30–37.    
  • 29.Jin HF, Du JB, Li XH, et al. (2006) Interaction between hydrogen sulfide/cystathionine gamma-lyase and carbon monoxide/heme oxygenase pathways in aortic smooth muscle cells. Acta Pharmacol Sin 27: 1561–1566.    
  • 30.Kulkarni Chitnis M, Belford R, Robinson J, et al. (2014) Interaction between hydrogen sulfide and nitric oxide in isolated bovine retina (1060.2). FASEB J 28, 1 Supplement: 1060–1062.
  • 31.Yetik-Anacak G, Dereli MV, Sevin G, et al. (2015) Resveratrol stimulates hydrogen sulfide (H2S) formation to relax murine corpus cavernosum. J Sex Med 12: 2004–2012.    
  • 32.Dufton N, Natividad J, Verdu EF, et al. (2012) Hydrogen sulfide and resolution of acute inflammation: A comparative study utilizing a novel fluorescent probe. Sci Rep 2: 499.    
  • 33.Fitzgerald R, DeSantiago B, Lee DY, et al. (2014) H2S relaxes isolated human airway smooth muscle cells via the sarcolemmal K(ATP) channel. Biochem Biophys Res Commun 446: 393–398.    
  • 34.Zheng Y, Liao F, Du JB, et al. (2012) Modified methylene blue method for measurement of hydrogen sulfide level in plasma. Sheng Li Xue Bao: [Acta Physiologica Sinica] 64: 681–686.
  • 35.Whiteman M, Moore PK (2009) Hydrogen sulfide and the vasculature: a novel vasculoprotective entity and regulator of nitric oxide bioavailability? J Cell Mol Med 13: 488–507.    
  • 36.Xia M, Chen L, Muh RW, et al. (2009) Production and actions of hydrogen sulfide, a novel gaseous bioactive substance, in the kidneys. J Pharmacol Exp Ther 329: 1056–1062.    
  • 37.Kulkarni M, Njie-Mbye YF, Okpobiri I, et al. (2011) Endogenous production of hydrogen sulfide in isolated bovine eye. Neurochem Res 36: 1540–1545.    
  • 38.Wu D, Hu Q, Zhu Y (2016) Therapeutic application of hydrogen sulfide donors: the potential and challenges. Front Med 10: 18–27.    
  • 39.Kolesnikov SI, Vlasov BY, Kolesnikova LI (2015) Hydrogen sulfide as a third essential gas molecule in living tissues. Vestn Ross Akad Med Nauk 2: 237–241.
  • 40.van Goor H, van den Born JC, Hillebrands JL, et al. (2016) Hydrogen sulfide in hypertension. Curr Opin Nephrol Hypertens 25: 107–113.    
  • 41.Ahmad A, Sattar MA, Rathore HA, et al. (2015) A critical review of pharmacological significance of hydrogen sulfide in hypertension. Indian J Pharmacol 47: 243–247.    
  • 42.Kida K, Ichinose F (2015) Hydrogen sulfide and neuroinflammation. Handb Exp Pharmacol 230: 181–189.    
  • 43.Cui Y, Duan X, Li H, et al. (2015) Hydrogen sulfide ameliorates early brain injury following subarachnoid hemorrhage in rats. Mol Neurobiol 53: 3646–3657.
  • 44.Wang YF, Mainali P, Tang CS, et al. (2008) Effects of nitric oxide and hydrogen sulfide on the relaxation of pulmonary arteries in rats. Chinese Med J 121: 420–423.    
  • 45.Altaany Z, Yang G, Wang R (2013) Crosstalk between hydrogen sulfide and nitric oxide in endothelial cells. J Cell Mol Med 17: 879–888.    
  • 46.Pong WW, Eldred WD (2009) Interactions of the gaseous neuromodulators nitric oxide, carbon monoxide, and hydrogen sulfide in the salamander retina. J Neurosci Res 87: 2356–2364.    
  • 47.Salomone S, Foresti R, Villari A, et al. (2014) Regulation of vascular tone in rabbit ophthalmic artery: cross talk of endogenous and exogenous gas mediators. Biochem Pharmacol 92: 4661–4668.
  • 48.Zhao W, Wang R (2002) H(2)S-induced vasorelaxation and underlying cellular and molecular mechanisms. Am J Physiol-Heart C 283: H474–480.    
  • 49.Zhao W, Zhang J, Lu Y, et al. (2001) The vasorelaxant effect of H(2)S as a novel endogenous gaseous K(ATP) channel opener. EMBO J 20: 6008–6016.    
  • 50.Zhao W, Ndisang JF, Wang R (2003) Modulation of endogenous production of H2S in rat tissues. Can J Physiol Pharmacol 81: 848–853.    
  • 51.Guo W, Kan JT, Cheng ZY, et al. (2012) Hydrogen sulfide as an endogenous modulator in mitochondria and mitochondria dysfunction. Oxid Med Cell Longev 2012.
  • 52.Yanfei W, Lin S, Junbao D, et al. (2006) Impact of L-arginine on hydrogen sulfide/cystathionine-gamma-lyase pathway in rats with high blood flow-induced pulmonary hypertension. Biochem Biophys Res Commun 345: 851–857.    
  • 53.Brancaleone V, Roviezzo F, Vellecco V, et al. (2008) Biosynthesis of H2S is impaired in non-obese diabetic (NOD) mice. Br J Pharmacol 155: 673–680.
  • 54.Dyson RM, Palliser HK, Latter JL, et al. (2015) Interactions of the gasotransmitters contribute to microvascular tone (dys)regulation in the preterm neonate. PLoS One 10: e0121621.    
  • 55.Holwerda KM, Faas MM, van Goor H, et al. (2013) Gasotransmitters: a solution for the therapeutic dilemma in preeclampsia? Hypertension 62: 653–659.    
  • 56.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: 527–531.    
  • 57.Privitera MG, Potenza M, Bucolo C, et al. (2007) Hemin, an inducer of heme oxygenase-1, lowers intraocular pressure in rabbits. J Ocul Pharmacol Ther 23: 232–239.    
  • 58.Stagni E, Bucolo C, Motterlini R, et al. (2010) Morphine-induced ocular hypotension is modulated by nitric oxide and carbon monoxide: role of μ3 receptors. J Ocul Pharmacol Ther 26: 31–36.    
  • 59.Peng YJ, Nanduri J, Raghuraman G, et al. (2010) H2S mediates O2 sensing in the carotid body. Proc Natl Acad Sci USA 107: 10719–10724.    
  • 60.Shintani T, Iwabuchi T, Soga T, et al. (2009) Cystathionine beta-synthase as a carbon monoxide-sensitive regulator of bile excretion. Hepatology 49: 141–150.    
  • 61.Morikawa T, Kajimura M, Nakamura T, et al. (2012) Hypoxic regulation of the cerebral microcirculation is mediated by a carbon monoxide-sensitive hydrogen sulfide pathway. Proc Natl Acad Sci USA 109: 1293–1298.    
  • 62.Monjok EM, Kulkarni KH, Kouamou G, et al (2008) Inhibitory action of hydrogen sulfide on muscarinic receptor-induced contraction of isolated porcine irides. Exp Eye Res 87: 612–616.    
  • 63.Kulkarni-Chitnis M, Njie-Mbye YF, Mitchell L, et al. (2015) Inhibitory action of novel hydrogen sulfide donors on bovine isolated posterior ciliary arteries. Exp Eye Res 134: 73–79.    
  • 64.Chitnis MK, Njie-Mbye YF, Opere CA, et al. (2013) Pharmacological actions of the slow release hydrogen sulfide donor GYY4137 on phenylephrine-induced tone in isolated bovine ciliary artery. Exp Eye Res 116: 350–354.    


Reader Comments

your name: *   your email: *  

© 2019 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution Licese (http://creativecommons.org/licenses/by/4.0)

Download full text in PDF

Export Citation

Copyright © AIMS Press All Rights Reserved