Bronchodilatory Effect of Hydrogen Sulfide in Rat

Document Type : Original Article


1 Physiology Research Centre and Department of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

2 School of Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran


The aims of present study were to elucidate the effect of NaHS as a H2S donor on precontracted rat trachea smooth muscle, role of epithelium and nitric oxide in this action.
Materials and Methods
Tracheal rings from male adult Wistar rats were isolated and mounted in an organ bath containing Krebs–Henseleit solution under 1.5 g resting tension and contractions were recorded isometrically. After equilibrium period (60  min), cumulative concentrations of NaHS (0.2-1.2 mM) were applied on the tracheal basal tone or on the plateau of contractions induced by KCl (60 mM) or carbachol (CCh, 0.55 μM) in the absence and presence of certain antagonists and inhibitors. 
The tracheal basal tone was unaffected by NaHS but tracheal contractions induced by KCl and CCh were attenuated by NaHS in a concentration-dependent manner (P< 0.001). Removing the tracheal epithelial did not attenuate the NaHS spasmolytic effect in the tissue precontracted by KCl and CCh. The bronchodilatory effect was unaffected by tissue incubation (30 min, 1 μM) with, glibenclamide, propranolol, indomethacin, methylene blue (10 μM), and L-NAME (300 μM).
It seems that bronchodilatory effect of H2S was not mediated by KATP channels, β-adrenoceptors, epithelium and production of nitric oxide, cGMP and prostaglandins. Since CCh and KCl activate Ca2+ influx and CCh promotes Ca2+ from intracellular pool as well, therefore, we may conclude that the relaxant effect of NaHS was mediated by the Ca2+ influx blockade and cholinergic receptors inactivation. This preliminary study shows the possible therapeutical property of H2S in obstructive pulmonary diseases.


1. Wagner F, Asfar P, Calzia E, Radermacher P, Szabo C. Bench-to-bedside review: Hydrogen sulfide-the third gaseous transmitter: applications for critical care. Crit Care 2009; 13:213-221.
2. Trevisani M, Patacchini R, Nicoletti P, Gatti R, Gazzieri D, Lissi N, et al. Hydrogen sulfide causes vanilloid receptor 1-mediated neurogenic inflammation in the airways. Br J Pharmacol 2005; 145:1123-1131.
3. Jin HF, Du JB, Tang CS. Waste gas is not waste: Advance in the research of hydrogen sulfide. Sheng Li Xue Bao 2010; 62:495-504.
4. Marquet P, Duncan SH, Chassard C, Bernalier-Donadille A, Flint HJ. Lactate has the potential to promote hydrogen sulphide formation in the human colon. FEMS Microbiol Lett 2009; 299:128-134.
5. Wagner CA. Hydrogen sulfide, a new gaseous signal molecule and blood pressure regulator. J Nephrol 2009; 22:173-176.
6. Rowan FE, Docherty NG, Coffey JC, O'Connell PR. Sulphate-reducing bacteria and hydrogen sulfide in the a etiology of ulcerative colitis. Br J Surg 2009; 96:151-158.
7. Li X, Jin H, Bin G, Wang L, Tang C, Du J. Endogenous hydrogen sulfide regulates pulmonary artery collagen remodeling in rats with high pulmonary blood flow. Exp Biol Med 2009; 234:504-512.
8. Laggner H, Hermann M, Esterbauer H, Muellner MK, Exner M, Gmeiner BM, et al. The novel gaseous vasorelaxant hydrogen sulfide inhibits angiotensin-converting enzyme activity of endothelial cells. J Hypertens 2007; 25:2100-2104.
9. Chen YH, Yao WZ, Geng B, Ding YL, Lu M, Zhao MW, et al. Endogenous hydrogen sulfide in patients with COPD. Chest 2005; 128:3205-3211.
10. Wang R. Is H2S a stinky remedy for atherosclerosis? Arterioscler Thromb Vasc Biol 2009; 29:156-157.
11. Shibuya N, Mikami Y, Kimura Y, Nagahara N, Kimura H. Vascular endothelium expresses 3-mercaptopyruvat sulfutransferase and produces hydrogen sulfide. J Biochem 2009; 146:623-626.
12. Dhaese I, Lefebvre RA. Myosin light chain phosphatase activation is involved in the hydrogen sulfide-induced relaxation in mouse gastric fundus. Eur J Pharmacol 2009; 606: 180-186.
13. Webb GD, Lim LH, Oh VMS, Yeo SB, Cheong YP, Ali MY, et al. Contractile and vasorelaxant effects of hydrogen sulfide and its biosynthesis in the human internal mammary artery. J Pharmacol Exp Ther 2008; 324:876-882.
14. Zhao P,  Huang X, Wang ZY, Qiu ZX, Han YF, Lu HL, et al. Dual effect of exogenous hydrogen sulfide on the spontaneous contraction of gastric smooth muscle in guinea-pig. Eur J Pharmacol 2009; 616:223-228.
15. Shibata M, Saito M, Yoshimura M, Yamaguchi M, Nishioka K, Makita T, et al. Anticholinesterase drugs stimulate smooth muscle contraction of the rat trachea through the Rho-kinase pathway. Anesth Analg 2006; 102:1121–1126.
16. Saito M, Shibata O, Matsunaga S, Tsuda A, Makita T, Sumikawa K. Hyperosmolarity attenuates the contraction of rat trachea through the inhibition of phosphatidylinositol response. Acta Med Nagasaki 2008; 52:107-110.
17. Saito M, Shibata O, Yamaguchi M, YoshimuraM, Makita T, Harada N,  et al. Metoclopramide causes airway smooth muscle relaxation through inhibition of muscarinic M3 receptor in the rat trachea. Anesth Analg 2004; 98:1325-1329.
18. Gilani AH, Mandukhail SUR, Iqbal J, Yasinzai M, Aziz N, Khan A, et al. Antispasmodic and vasodilator activities of Morinda citrifolia root extract are mediated through blockade of voltage dependent calcium channels. BMC Complement Altern Med  2010; 10:2-10.
19. Srilatha B, Hu L, Adaikan PG, Moore PK. Initial characterization of hydrogen sulfide effects in female sexual function. J Sex Med 2009; 6:1875-1884.
20. Zhao W, Wang R. H2S-induced vasorelaxation and underlying cellular and molecular mechanisms. Am J Physiol Heart Circ Physiol 2002; 283: H474-H480.
21. Small RC, Good DM, Dixon JS, Kennedy I. The effects of epithelium removal on the actions of cholinomimetic drugs in opened segments and perfused tubular preparations of guinea-pig trachea. Br J Pharmacol 1990; 100:516-522.
22. Collins LC, Roberts AM, Robinson TW, Joshua IG. Direct effects of meconium on rat tracheal smooth muscle tension in vito. Pediatr Res 1996; 40:587-591.
23. Long JW, Yang XD, Cao L, Lu SM, Cao YX. Alteration of airway responsiveness mediated by receptors in ovalbumin-induced asthmatic E3 rats. Acta Pharmacol Sin 2009; 30:965-972.
24. Tilley SL, Hartney JM, Erikson CJ, Jania C, Nguyen M, Stock J, et al. Receptors and pathways mediating the effect of prostaglandin E2 on airway tone. Am J Physiol Lung Cell Mol Physiol 2003; 284:L599-L606.
25. Perez-Zoghbi JF, Bai Y, Sanderson MJ. Nitric oxide induces airway smooth muscle cell relaxation by decreasing the frequency of agonist-induced Ca2+ oscillations. J Gen Physiol 2010; 135:247-259.
26. Jeong SO, Pae HO, Oh GS, Jeong GS, Lee BS, Lee S, 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 2006; 345:938-944.
27. Li YH, Yan CD, Bian JS. Hydrogen sulfide: a novel signaling molecule in the vascular system. J Cardiovasc Pharmacol In press 2011.
28.  Zhao W, Zhang J, Lu Y, Wang R. The vasorelaxant effect of H2S as a novel endogenous gaseous KATP channel opener. EMBO J 2001; 20:6008-6016.
29. d’Emmanuele di Villa Bianca R, Sorrentino R, Maffia P, Mirone V, Imbimbo C, Fusco F, et al. Hydrogen sulfide as a mediator of human corpus cavernosum smooth-muscle relaxation. Proc Natl Acad Sci USA 2009; 106:4513-4518.
30. Dorman DC, Moulin FJM, McManus BE, Mahle KC, James RA Struve MF. 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 2002; 65:18-25.