Home Complementary mechanisms of modulation of spontaneous phasic contractions by the gaseous signalling molecules NO, H2S, HNO and the polysulfide Na2S3 in the rat colon
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Complementary mechanisms of modulation of spontaneous phasic contractions by the gaseous signalling molecules NO, H2S, HNO and the polysulfide Na2S3 in the rat colon

  • Ervice Pouokam ORCID logo , Adriana Vallejo , Emma Martínez , Sara Traserra and Marcel Jimenez EMAIL logo
Published/Copyright: October 8, 2021

Abstract

Objectives

Reactive oxygen and nitrogen species may be produced during inflammation leading to the formation of NO, H2S or HNO. Enzymes such as iNOS, CSE and CBS might also be responsible for polysulfide production. Since these signalling molecules might have an impact on colonic motility, the aim of this study was to compare their effect on rat colonic slow phasic contractions (SPC).

Methods

Organ bath measurements with strips obtained from rat proximal colon were performed using the polysulfide Na2S3, sodium nitroprusside (NaNP), sodium hydrogen sulfide (NaHS), Angeli’s salt as NO, H2S, and HNO donors, respectively. TTX (1 µM) was used to block neuronal activity.

Results

All four molecules, concentration-dependently, inhibited the amplitude and frequency of SPC both in the circular and longitudinal muscle layer. The relative potency was NaNP>Angeli’s salt>NaHS>Na2S3. The inhibitory response induced by NaNP (1 µM) and Angeli’s salt (50 µM) was reversed by ODQ (10 µM) whereas the inhibitory effect of NaHS (1 mM) was reversed by apamin (1 µM) and glibenclamide (10 µM). Na2S3 (1 mM) response was partially reversed by apamin (1 µM) and glibenclamide (10 µM). High concentrations of Na2S3 caused an increase in tone. Low concentrations of NaHS or Na2S3 did not potentiate NaNP responses.

Conclusions

All signalling molecules inhibit SPC in both muscle layers. The effect is independent of neural activity and involves guanylyl cyclase (NO and HNO) and SKCa and KATP channels (NaHS or Na2S3). Other pathways might also be involved in Na2S3 responses. Accordingly, complementary mechanisms of inhibition might be attributable to these signalling molecules.


Corresponding author: Marcel Jimenez, Ph.D, Department of Cell Biology, Physiology and Immunology and Neurosciences Institute, Universitat Autònoma de Barcelona, Barcelona, Spain, Phone: 34 935811566, E-mail:

Funding source: German Research Foundation

Award Identifier / Grant number: PO 2143/1-1

  1. Research funding: This study was supported by a research fund from the German Research Foundation (PO 2143/1-1).

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission. All five authors performed the experiments and analyzed the data; Ervice Pouokam and Marcel Jimenez designed the experiments and wrote the paper.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Not applicable.

  5. Ethical approval: Not applicable.

References

1. Dickens, EJ, Hirst, GD, Tomita, T. Identification of rhythmically active cells in Guinea-pig stomach. J Physiol 1999;514:515–31. https://doi.org/10.1111/j.1469-7793.1999.515ae.x.Search in Google Scholar PubMed PubMed Central

2. Huizinga, JD, Robinson, TL, Thomsen, L. The search for the origin of rhythmicity in intestinal contraction; from tissue to single cells. Neuro Gastroenterol Motil 2000;12:3–9. https://doi.org/10.1046/j.1365-2982.2000.00177.x.Search in Google Scholar PubMed

3. Sanders, KM, Ward, SM, Koh, SD. Interstitial cells: regulators of smooth muscle function. Physiol Rev 2014;94:859–907. https://doi.org/10.1152/physrev.00037.2013.Search in Google Scholar PubMed PubMed Central

4. Mañé, N, Gil, V, Martínez-Cutillas, M, Martín, MT, Gallego, D, Jiménez, M. Dynamics of inhibitory co-transmission, membrane potential and pacemaker activity determine neuromyogenic function in the rat colon. Pflueg Arch Eur J Physiol 2014;466:2305–21. https://doi.org/10.1007/s00424-014-1500-8.Search in Google Scholar PubMed

5. Yoneda, S, Fukui, H, Takaki, M. Pacemaker activity from submucosal interstitial cells of Cajal drives high-frequency and low-amplitude circular muscle contractions in the mouse proximal colon. Neuro Gastroenterol Motil 2004;16:621–7. https://doi.org/10.1111/j.1365-2982.2004.00546.x.Search in Google Scholar PubMed

6. Corsetti, M, Costa, M, Bassotti, G, Bharucha, AE, Borrelli, O, Dinning, P, et al.. First translational consensus on terminology and definitions of colonic motility in animals and humans studied by manometric and other techniques. Nat Rev Gastroenterol Hepatol 2019;16:559–79. https://doi.org/10.1038/s41575-019-0167-1.Search in Google Scholar PubMed PubMed Central

7. Plujà, L, Albertí, E, Fernández, E, Mikkelsen, HB, Thuneberg, L, Jiménez, M. Evidence supporting presence of two pacemakers in rat colon. Am J Physiol Gastrointest Liver Physiol 2001;281:G255–G266. https://doi.org/10.1152/ajpgi.2001.281.1.g255.Search in Google Scholar PubMed

8. Yoneda, S, Takano, H, Takaki, M, Suzuki, H. Properties of spontaneously active cells distributed in the submucosal layer of mouse proximal colon. J Physiol 2002;542:887–97. https://doi.org/10.1113/jphysiol.2002.018705.Search in Google Scholar PubMed PubMed Central

9. Huizinga, JD, Martz, S, Gil, V, Wang, X-Y, Jimenez, M, Parsons, S. Two independent networks of interstitial cells of cajal work cooperatively with the enteric nervous system to create colonic motor patterns. Front Neurosci 2011;5:93. https://doi.org/10.3389/fnins.2011.00093.Search in Google Scholar PubMed PubMed Central

10. Gallego, D, Malagelada, C, Accarino, A, De Giorgio, R, Malagelada, JR, Azpiroz, F, et al.. Nitrergic and purinergic mechanisms evoke inhibitory neuromuscular transmission in the human small intestine. Neuro Gastroenterol Motil 2014;26:419–29. https://doi.org/10.1111/nmo.12293.Search in Google Scholar PubMed

11. Jiménez, M, Clavé, P, Accarino, A, Gallego, D. Purinergic neuromuscular transmission in the gastrointestinal tract; functional basis for future clinical and pharmacological studies. Br J Pharmacol 2014;171:4360–75. https://doi.org/10.1111/bph.12802.Search in Google Scholar PubMed PubMed Central

12. Schemann, M. Control of gastrointestinal motility by the “gut brain”--the enteric nervous system. J Pediatr Gastroenterol Nutr 2005;41:S4–6. https://doi.org/10.1097/01.scs.0000180285.51365.55.Search in Google Scholar PubMed

13. Wood, JD. Enteric nervous system: reflexes, pattern generators and motility. Curr Opin Gastroenterol 2008;24:149–58. https://doi.org/10.1097/mog.0b013e3282f56125.Search in Google Scholar PubMed

14. Smith, TK, McCarron, SL. Nitric oxide modulates cholinergic reflex pathways to the longitudinal and circular muscle in the isolated Guinea-pig distal colon. J Physiol 1998;512:893–906. https://doi.org/10.1111/j.1469-7793.1998.893bd.x.Search in Google Scholar PubMed PubMed Central

15. Beck, K, Voussen, B, Reigl, A, Vincent, AD, Parsons, SP, Huizinga, JD, et al.. Cell-specific effects of nitric oxide on the efficiency and frequency of long distance contractions in murine colon. Neuro Gastroenterol Motil 2019;31: e13589. https://doi.org/10.1111/nmo.13589.Search in Google Scholar PubMed

16. Groneberg, D, Lies, B, König, P, Jäger, R, Seidler, B, Klein, S, et al.. Cell-specific deletion of nitric oxide-sensitive guanylyl cyclase reveals a dual pathway for nitrergic neuromuscular transmission in the murine fundus. Gastroenterology 2013;145:188–96. https://doi.org/10.1053/j.gastro.2013.03.042.Search in Google Scholar PubMed

17. Mañé, N, Gil, V, Martínez-Cutillas, M, Clavé, P, Gallego, D, Jiménez, M. Differential functional role of purinergic and nitrergic inhibitory cotransmitters in human colonic relaxation. Acta Physiol 2014;212:293–305. https://doi.org/10.1111/apha.12408.Search in Google Scholar PubMed

18. Lundberg, S, Holst, M, Hellström, PM. Expression of iNOS mRNA associated with suppression of colonic contraction in rat colitis. Acta Physiol 2006;187:489–94. https://doi.org/10.1111/j.1748-1716.2006.01576.x.Search in Google Scholar PubMed

19. Jimenez, M, Gil, V, Martinez-Cutillas, M, Mañé, N, Gallego, D. Hydrogen sulphide as a signalling molecule regulating physiopathological processes in gastrointestinal motility. Br J Pharmacol 2017;174:2805–17. https://doi.org/10.1111/bph.13918.Search in Google Scholar PubMed PubMed Central

20. Gallego, D, Clavé, P, Donovan, J, Rahmati, R, Grundy, D, Jiménez, M, et al.. The gaseous mediator, hydrogen sulphide, inhibits in vitro motor patterns in the human, rat and mouse colon and jejunum. Neuro Gastroenterol Motil 2008;20:1306–16. https://doi.org/10.1111/j.1365-2982.2008.01201.x.Search in Google Scholar PubMed

21. Kimura, H. Hydrogen sulfide and polysulfide signaling. Antioxidants Redox Signal 2017;27:619–21. https://doi.org/10.1089/ars.2017.7076.Search in Google Scholar PubMed

22. Kimura, Y, Toyofuku, Y, Koike, S, Shibuya, N, Nagahara, N, Lefer, D, et al.. Identification of H2S3 and H2S produced by 3-mercaptopyruvate sulfurtransferase in the brain. Sci Rep 2015;5:14774. https://doi.org/10.1038/srep14774.Search in Google Scholar PubMed PubMed Central

23. Miyamoto, R, Koike, S, Takano, Y, Shibuya, N, Kimura, Y, Hanaoka, K, et al.. Polysulfides (H2Sn) produced from the interaction of hydrogen sulfide (H2S) and nitric oxide (NO) activate TRPA1 channels. Sci Rep 2017;7:45995. https://doi.org/10.1038/srep45995.Search in Google Scholar PubMed PubMed Central

24. Eberhardt, M, Dux, M, Namer, B, Miljkovic, J, Cordasic, N, Will, C, et al.. H2S and NO cooperatively regulate vascular tone by activating a neuroendocrine HNO–TRPA1–CGRP signalling pathway. Nat Commun 2014;5:4381. https://doi.org/10.1038/ncomms5381.Search in Google Scholar PubMed PubMed Central

25. An, W, Ryan, LS, Reeves, AG, Bruemmer, KJ, Mouhaffel, L, Gerberich, JL, et al.. A chemiluminescent probe for HNO quantification and real-time monitoring in living cells. Angew Chem Int Ed 2019;58:1361–5. https://doi.org/10.1002/anie.201811257.Search in Google Scholar PubMed PubMed Central

26. Zhou, Y, Zhang, X, Yang, S, Li, Y, Qing, Z, Zheng, J, et al.. Ratiometric visualization of NO/H2S cross-talk in living cells and tissues using a nitroxyl-responsive two-photon fluorescence probe. Anal Chem 2017;89:4587–94. https://doi.org/10.1021/acs.analchem.7b00073.Search in Google Scholar PubMed

27. Gastreich-Seelig, M, Jimenez, M, Pouokam, E. Mechanisms associated to nitroxyl (HNO)-Induced relaxation in the intestinal smooth muscle. Front Physiol 2020;11:1–18. https://doi.org/10.3389/fphys.2020.00438.Search in Google Scholar PubMed PubMed Central

28. Traserra, S, Villarte, S, Traini, C, Palacin, S, Vergara, P, Vannucchi, MG, et al.. The asymmetric innervation of the circular and longitudinal muscle of the mouse colon differently modulates myogenic slow phasic contractions. Neuro Gastroenterol Motil 2020;32: e13778. https://doi.org/10.1111/nmo.13778.Search in Google Scholar PubMed

29. Dieter, G, Barbara, V, Andreas, F. Integrative control of gastrointestinal motility by nitric oxide. Curr Med Chem 2016;23:2715–35.10.2174/0929867323666160812150907Search in Google Scholar

30. Voussen, B, Beck, K, Mauro, N, Keppler, J, Friebe, A. Comparison of nitrergic signaling in circular and longitudinal smooth muscle of murine ileum. Neuro Gastroenterol Motil 2018;30:e13175. https://doi.org/10.1111/nmo.13175.Search in Google Scholar PubMed

31. Baker, SA, Hennig, GW, Ward, SM, Sanders, KM. Temporal sequence of activation of cells involved in purinergic neurotransmission in the colon. J Physiol 2015;593:1945–63. https://doi.org/10.1113/jphysiol.2014.287599.Search in Google Scholar PubMed PubMed Central

32. Kurahashi, M, Mutafova-Yambolieva, V, Koh, SD, Sanders, KM. Platelet-derived growth factor receptor-α-positive cells and not smooth muscle cells mediate purinergic hyperpolarization in murine colonic muscles. Am J Physiol Cell Physiol 2014;307:C561–70. https://doi.org/10.1152/ajpcell.00080.2014.Search in Google Scholar PubMed PubMed Central

33. Kurahashi, M, Kito, Y, Baker, SA, Jennings, LK, Dowers, JGR, Koh, SD, et al.. A novel postsynaptic signal pathway of sympathetic neural regulation of murine colonic motility. Faseb J 2020;34:5563–77. https://doi.org/10.1096/fj.201903134r.Search in Google Scholar PubMed PubMed Central

34. Gallego, D, Gil, V, Aleu, J, Aulí, M, Clavé, P, Jiménez, M. Purinergic and nitrergic junction potential in the human colon. Am J Physiol Gastrointest Liver Physiol 2008;295:G522–33. https://doi.org/10.1152/ajpgi.00510.2007.Search in Google Scholar PubMed

35. Mustafa, AK, Gadalla, MM, Sen, N, Kim, S, Mu, W, Gazi, SK, et al.. H2S signals through protein S-sulfhydration. Sci Signal 2009;2:ra72. https://doi.org/10.1126/scisignal.2000464.Search in Google Scholar PubMed PubMed Central

36. Jarosz, AP, Wei, W, Gauld, JW, Auld, J, Özcan, F, Aslan, M, et al.. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is inactivated by S-sulfuration in vitro. Free Radic Biol Med 2015;89:512–21. https://doi.org/10.1016/j.freeradbiomed.2015.09.007.Search in Google Scholar PubMed

37. Kimura, H. Hydrogen sulfide signalling in the CNS – comparison with NO. Br J Pharmacol 2020;177:5031–45. https://doi.org/10.1111/bph.15246.Search in Google Scholar PubMed PubMed Central

38. Takata, T, Araki, S, Tsuchiya, Y, Watanabe, Y. Persulfide signaling in stress-initiated calmodulin kinase response. Antioxidants Redox Signal 2020;33:1308–19. https://doi.org/10.1089/ars.2020.8138.Search in Google Scholar PubMed

39. Takata, T, Tsukuda, A, Tsuchiya, Y, Akaike, T, Watanabe, Y. The active-site cysteine residue of Ca2+/calmodulin-dependent protein kinase I is protected from irreversible modification via generation of polysulfidation. Nitric Oxide 2019;86:68–75. https://doi.org/10.1016/j.niox.2019.02.008.Search in Google Scholar PubMed

40. Hosoki, R, Matsuki, N, Kimura, H. The possible role of hydrogen sulfide as an endogenous smooth muscle relaxant in synergy with nitric oxide. Biochem Biophys Res Commun 1997;237:527–31. https://doi.org/10.1006/bbrc.1997.6878.Search in Google Scholar PubMed

41. Albertí, E, Mikkelsen, HB, Larsen, JO, Jimenez, M. Motility patterns and distribution of interstitial cells of Cajal and nitrergic neurons in the proximal, mid- and distal-colon of the rat. Neuro Gastroenterol Motil 2005;17:133–47. https://doi.org/10.1111/j.1365-2982.2004.00603.x.Search in Google Scholar PubMed

42. Gil, V, Gallego, D, Grasa, L, Martín, MT, Jiménez, M. Purinergic and nitrergic neuromuscular transmission mediates spontaneous neuronal activity in the rat colon. Am J Physiol Gastrointest Liver Physiol 2010;299:G158–69. https://doi.org/10.1152/ajpgi.00448.2009.Search in Google Scholar PubMed

43. Chen, JH, Zhang, Q, Yu, Y, Li, K, Liao, H, Jiang, L, et al.. Neurogenic and myogenic properties of pan-colonic motor patterns and their spatiotemporal organization in rats. PloS One 2013;8: e60474. https://doi.org/10.1371/journal.pone.0060474.Search in Google Scholar PubMed PubMed Central

44. Tan, W, Lee, G, Chen, J-H, Huizinga, JD. Relationships between distention-, butyrate- and pellet-induced stimulation of peristalsis in the mouse colon. Front Physiol 2020;11:109. https://doi.org/10.3389/fphys.2020.00109.Search in Google Scholar PubMed PubMed Central

45. Gil, V, Parsons, S, Gallego, D, Huizinga, J, Jimenez, M. Effects of hydrogen sulphide on motility patterns in the rat colon. Br J Pharmacol 2013;169:34–50. https://doi.org/10.1111/bph.12100.Search in Google Scholar PubMed PubMed Central

Received: 2021-06-16
Revised: 2021-09-24
Accepted: 2021-09-26
Published Online: 2021-10-08

© 2021 Walter de Gruyter GmbH, Berlin/Boston

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