Russian Journal of PhysiologyRussian Journal of PhysiologyРоссийский физиологический журнал им. И.М. Сеченова0869-81392658-655XThe Russian Academy of Sciences69825510.7868/S2658655X25110073EXPERIMENTAL ARTICLESЭКСПЕРИМЕНТАЛЬНЫЕ СТАТЬИResearch ArticleEffects of Hydrogen Sulfide and Nitric Oxide on Rat Jejunum Contractions in a Model of Irritable Bowel SyndromeВЛИЯНИЕ СЕРОВОДОРОДА И ОКСИДА АЗОТА НА СОКРАЩЕНИЯ ТОЩЕЙ КИШКИ КРЫСЫ В МОДЕЛИ СИНДРОМА РАЗДРАЖЕННОГО КИШЕЧНИКАSorokinaD. MСорокинаД. Мdinagabita@mail.ruShaidullovI. FШайдулловИ. ФKhaertdinovN. NХаертдиновН. НLifanovaA. SЛифановаА. СSitdikovF. GСитдиковФ. ГSitdikovaG. FСитдиковаГ. ФKazan Federal UniversityКазанский федеральный университет1511202511111VOL 111, NO11 (2025)ТОМ 111, №11 (2025)1797181309122025Copyright ©; 2025, Russian Academy of SciencesCopyright ©; 2025, Российская академия наук2025Russian Academy of SciencesРоссийская академия наукhttps://journals.eco-vector.com/0869-8139/article/view/698255

Irritable bowel syndrome (IBS) is a functional, multifactorial gastrointestinal disorder that is characterized by impaired intestinal motility and visceral hypersensitivity. The aim of the study was to analyze the effect of H2S and NO on spontaneous contractions of the jejunum in a rat model of IBS. The IBS was induced by neonatal maternal deprivation and verified by assessing visceral hypersensitivity. Spontaneous contractions of an isolated rat jejunum were recorded under isometric conditions. In a rat model of IBS, the amplitude of spontaneous contractions and the tonus were lower than in the control group, without changing the frequency of spontaneous contractions. The H2S donor, sodium hydrosulfide (NaHS), had an inhibitory effect on jejunum contractions in the control, but this effects of NaHS were not manifested in the IBS group. The NO donor, sodium nitroprusside (SNP), caused inhibition of the amplitude in both groups, reduced the inhibitory effects of NaHS in the control group, while in the IBS group the effects of NaHS were not observed. The nitric oxide synthase (NOS) inhibitor, L-NAME, increased the amplitude of spontaneous contractions in both groups, with more pronounced effects in the IBS group. Under conditions of NOS inhibition, the inhibitory effect of NaHS on the amplitude of spontaneous contractions was restored in the IBS group. In the IBS group, the expression of cystathionine-β-synthase (CBS), the level of sulfides and the activity of H2S-synthesizing enzymes in the rat jejunum tissues were lower, while the expression of nNOS and the concentration of NO metabolites were increased compared to the control. It has been suggested that in IBS, due to excessive NO synthesis, changes occur in the signaling pathways and/or targets through which H2S acts, which leads to changes in jejunal motility in IBS and causes symptoms of increased peristalsis in IBS with diarrhea (IBS-D).

Синдром раздраженного кишечника (СРК) – функциональное, многофакторное расстройство желудочно-кишечного тракта, характеризующееся нарушением моторики кишечника и внецеральной гиперчувствительностью. Целью исследования явился анализ влияния H2S и NO на спонтанные сокращения тощей кишки крыс с моделью СРК. СРК вызывался неонатальной материнской депривацией и верифицировался оценкой внецеральной гиперчувствительности. Спонтанные сокращения изолированного препарата тощей кишки крысы регистрировались в изометрических условиях. У крыс с СРК амплитуда спонтанных сокращений и тонус препарата были ниже, чем в группе контроля, без изменения частоты спонтанных сокращений. Донор H2S – гидросульфид натрия (NaHS) оказывал ингибирующее действие на сокращения тощей кишки в контроле, тогда как в группе СРК угнетающие эффекты NaHS не проявлялись. Донор NO – нитропруссид натрия (SNP) вызывал угнетение амплитуды в обеих группах и уменьшал угнетающие эффекты NaHS в контрольной группе. Ингибитор синтазы оксида азота (NOS) – L-NAME приводил к повышению амплитуды спонтанных сокращений в обеих группах с более выраженными эффектами в группе СРК. В условиях блокирования NOS наблюдали восстановление ингибирующего действия NaHS на амплитуду спонтанных сокращений в группе СРК. В группе СРК экспрессия цистатионин-β-синтазы (CBS), уровень сульфидов и активность ферментов синтеза H2S в тканях тощей кишки крысы были ниже, тогда как экспрессия нейрональной NOS и концентрация метаболитов NO были повышены по сравнению с контролем. Предположено, что при СРК вследствие избыточного синтеза NO происходят изменения активности CBS, сигнальных путей и/или мишеней, через которые действует H2S, что приводит к нарушению моторики тощей кишки и обуславливает симптомы усиления перистальтики при СРК диарейного типа (СРК-Д).

hydrogen sulfidenitric oxidecontractile activityirritable bowel syndromejejunumсероводородоксид азотасократительная активностьсиндром раздраженного кишечникатощая кишкаРабота выполнена в рамках Программы стратегического академического лидерства Казанского (Приволжского) федерального университета ("ПРИОРИТЕТ-2030")Spiller R, Garsed K (2009) Infection, inflammation, and the irritable bowel syndrome. Dig Liver Dis 41: 844–849. https://doi.org/10.1016/j.dld.2009.07.007Farzaei MH, Bahramsoltani R, Abdollahi M, Rahimi R (2016) The role of visceral hypersensitivity in irritable bowel syndrome: Pharmacological targets and novel treatments. J Neurogastroenterol Motil 22: 558–574. https://doi.org/10.5056/jnm16001Luo M, Zhuang X, Tian Z, Xiong L (2021) Alterations in short-chain fatty acids and serotonin in irritable bowel syndrome: a systematic review and meta-analysis. BMC Gastroenterol 21: 14. https://doi.org/10.1186/s12876-020-01577-5Zhuang X, Tian Z, Li L, Zeng Z, Chen M, Xiong L (2018) Fecal microbiota alterations associated with diarrhea-predominant irritable bowel syndrome. Front Microbiol 9: 1600. https://doi.org/10.3389/fmicb.2018.01600Zhao Y, Zou DW (2023) Gut microbiota and irritable bowel syndrome. J Dig Dis 24: 312–320. https://doi.org/10.1111/1751-2980.13204Chuah KH, Hian WX, Lim SZ, Beh KH, Mahadeva S (2023) Impact of small intestinal bacterial overgrowth on symptoms and quality of life in irritable bowel syndrome. J Dig Dis 24: 194–202. https://doi.org/10.1111/1751-2980.13189Aggeletopoulou I, Triantos C (2024) Microbiome Shifts and Their Impact on Gut Physiology in Irritable Bowel Syndrome. Int J Mol Sci 25. (22): 12395. https://doi.org/10.3390/ijms252212395Wang C, Fang X (2021) Inflammation and overlap of irritable bowel syndrome and functional dyspepsia. J Neurogastroenterol Motil 27: 153–164. https://doi.org/10.5056/JNM20175Emmanuel A, Raeburn A (2011) Small intestine and colon motility. Medicine (Baltimore) 39: 218-223. https://doi.org/10.1016/j.mpmed.2011.01.002Pimentel M, Saad RJ, Long MD, Rao SSC (2020) ACG Clinical Guideline: Small Intestinal Bacterial Overgrowth. Am J Gastroenterol 115: 165-178. https://doi.org/10.14309/ajg.00000000000000501Pyleris E, Tzivras D, Barbatzas C, Giamarellos-Bourboulis EJ, Koussoulas V, Pimentel M (2012) The prevalence of overgrowth by aerobic bacteria in the small intestine by small bowel culture: Relationship with irritable bowel syndrome. Dig Dis Sci 57: 1321-1329. https://doi.org/10.1007/s10620-012-2033-7Takakura W, Pimentel M (2020) Small Intestinal Bacterial Overgrowth and Irritable Bowel Syndrome - An Update. Front Psychiatry 11: 664. https://doi.org/10.3389/fpsyt.2020.00664Shaidullov I, Bouchareb D, Sorokina D, Sitdikova G (2025) Nitric oxide in the mechanisms of inhibitory effects of sodium butyrate on colon contractions in a mouse model of irritable bowel syndrome. Naunyn Schmiedebergs Arch Pharmacol 398: 1905-1914. https://doi.org/10.1007/s00210-024-03403-1Shaidullov IF, Shafigullin MU, Gabitova LM, Sitdikov FG, Zefirov AL, Sitdikova GF (2018) Role of Potassium Channels in the Effects of Hydrogen Sulfide on Contractility of Gastric Smooth Muscle Cells in Rats. J Evol Biochem Physiol 54: 400-407. https://doi.org/10.1134/s0022093018050083Sorokina DM, Shaidullov IF, Gizzatullin AR, Sitdikov FG, Sitdikova GF (2023) The Roles of Nitric Oxide and Calcium Ions in the Effects of Hydrogen Sulfide on the Contractile Activity of the Rat Jejunum. Biophysisics 68: 836-843. https://doi.org/10.1134/S0006350923050287Li YR, Li Y, Jin Y, Xu M, Fan HW, Zhang Q, Tan GH, Chen J, Li YQ (2022) Involvement of nitrergic neurons in colonic motility in a rat model of ulcerative colitis. World J Gastroenterol 28: 3854-3868. https://doi.org/10.3748/wjg.v28.i29.3854Singer-Englar T, Rezaie A, Gupta K, Pichetshote N, Sedighi R, Lin E, Chua KS, Pimentel M (2018) 1089 - A Novel 4-Gas Device for Breath Testing Shows Exhaled H2S is Associated with Diarrhea and Abdominal Pain in a Large Scale Prospective Trial. Gastroenterology 154: S-213. https://doi.org/10.1016/s0016-5085(18)31104-1Gabitova DM, Shaidullov IF, Sabirullina GI, Shafigullin MU, Sitdikov FG, Sitdikova GF (2017) Role of Cyclic Nucleotides in the Effect of Hydrogen Sulfide on Contractions of Rat Jejunum. Bull Exp Biol Med 163: 14-17. https://doi.org/10.1007/s10517-017-3726-xMeng XM, Huang X, Zhang CM, Liu DH, Lu HL, Kim YC, Xu WX (2015) Hydrogen sulfide-induced enhancement of gastric fundus smooth muscle tone is mediated by voltage-dependent potassium and calcium channels in mice. World J Gastroenterol 21: 4840-4851. https://doi.org/10.3748/wjg.v21.i16.4840Liu Y, Luo H, Liang C, Xia H, Xu W, Chen J, Chen M (2013) Actions of Hydrogen Sulfide and ATP-Sensitive Potassium Channels on Colonic Hypermotility in a Rat Model of Chronic Stress. PLoS One 8: e55853. https://doi.org/10.1371/journal.pone.0055853Xiao A, Liu C, Li J (2021) The Role of H2S in the Gastrointestinal Tract and Microbiota. Adv Exp Med Biol 1315: 67-98. https://doi.org/10.1007/978-981-16-0991-6_4Yao CK, Sarbagili-Shabat C (2023) Gaseous metabolites as therapeutic targets in ulcerative colitis. World J Gastroenterol 29: 682-691. https://doi.org/10.3748/wjg.v29.i4.682Szabo C (2007) Hydrogen sulphide and its therapeutic potential. Nat Rev Drug Discov 6: 917-935. https://doi.org/10.1038/nrd2425Jimenez M, Gil V, Martinez-Cutillas M, Mañé N, Gallego D (2017) Hydrogen sulphide as a signalling molecule regulating physiopathological processes in gastrointestinal motility. Br J Pharmacol 174: 2805-2817. https://doi.org/10.1111/bph.13918Linden DR, Levitt MD, Farrugia G, Szurszewski JH (2010) Endogenous production of H2S in the gastrointestinal tract: Still in search of a physiologic function. Antioxidants Redox Signal 12: 1135–1146. https://doi.org/10.1089/ars.2009.2885Birg A, Lin HC (2025) The Role of Bacteria-Derived Hydrogen Sulfide in Multiple Axes of Disease. Int J Mol Sci 26(7): 3340. https://doi.org/10.3390/ijms26073340Lu Y, Huang J, Zhang Y, Huang Z, Yan W, Zhou T, Wang Z, Liao L, Cao H, Tan B (2021) Therapeutic Effects of Berberine Hydrochloride on Stress-Induced Diarrhea-Predominant Irritable Bowel Syndrome Rats by Inhibiting Neurotransmission in Colonic Smooth Muscle. Front Pharmacol 12: 2498. https://doi.org/10.3389/fphar.2021.596686Wallace JL, Ianaro A, de Nucci G (2017) Gaseous Mediators in Gastrointestinal Mucosal Defense and Injury. Dig Dis Sci 62: 2223–2230. https://doi.org/10.1007/s10620-017-4681-0Paragomi P, Rahimian R, Kazemi MH, Gharedaghi MH, Khalifeh-Soltani A, Azary S, Javidan AN, Moradi K, Sakuma S, Delpour AR (2014) Antinociceptive and antidiarrheal effects of pioglitazone in a rat model of diarrhoea-predominant irritable bowel syndrome: Role of nitric oxide. Clin Exp Pharmacol Physiol 41: 118–126. https://doi.org/10.1111/1440-1681.12188Masliukov PM, Moiseev K, Budnik AF, Nozdrachev AD, Timmermans JP (2017) Development of Calbindin- and Calretinin-Immunopositive Neurons in the Enteric Ganglia of Rats. Cell Mol Neurobiol 37: 1257–1267. https://doi.org/10.1007/s10571-016-0457-xMasliukov PM, Budnik AF, Nozdrachev AD (2017) Neurochemical Features of Metasympathetic System Ganglia in the Course of Ontogenesis. Adv Gerontol 7: 281–289. https://doi.org/10.1134/S2079057017040087Brüne B (2003) Nitric oxide: NO apoptosis or turning it ON? Cell Death Differ 10: 864–869. https://doi.org/10.1038/sj.cdd.4401261Barrachina M, Panes J, Esplugues J (2005) Role of Nitric Oxide in Gastrointestinal Inflammatory and Ulcerative Diseases: Perspective for Drugs Development. Curr Pharm Des 7: 31–48. https://doi.org/10.2174/1381612013398491Sen N, Hara MR, Kornberg MD, Cascio MB, Bae B II, Shahani N, Thomas B, Dawson TM, Dawson VL, Snyder SH, Sawa A (2008) Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis. Nat Cell Biol 10: 866–873. https://doi.org/10.1038/ncb1747Ramachandran A, Madesh M, Balasubramanian KA (2000) Apoptosis in the intestinal epithelium: Its relevance in normal and pathophysiological conditions. J Gastroenterol Hepatol 15: 109–120. https://doi.org/10.1046/j.1440-1746.2000.02059.xUpperman JS, Potoka D, Grishin A, Hackam D, Zamora R, Ford HR (2005) Mechanisms of nitric oxide-mediated intestinal barrier failure in necrotizing enterocolitis. Semin Pediatr Surg 14: 159–166. https://doi.org/10.1053/j.sempedsurg.2005.05.004Vicente JB, Colaco HG, Mendes MIS, Sarti P, Leandro P, Giuffrè A (2014) NO• binds human cystathionine β-synthase quickly and tightly. J Biol Chem 289: 8579–8587. https://doi.org/10.1074/jbc.M113.507533Giuffrè A, Vicente JB (2018) Hydrogen Sulfide Biochemistry and Interplay with Other Gaseous Mediators in Mammalian Physiology. Oxid Med Cell Longev 2018: 6290931. https://doi.org/10.1155/2018/6290931Shaidullov IF, Sorokina DM, Sitdikov FG, Hermann A, Abdulkhakov SR, Sitdikova GF (2021) Short chain fatty acids and colon motility in a mouse model of irritable bowel syndrome. BMC Gastroenterol 21: 37. https://doi.org/10.1186/s12876-021-01613-ySorokina DM, Shaidullov IF, Buchareb D, Sitdikov FG, Sitdikova GF (2023) Effect of Hydrogen Sulphide on Spontaneous Contractions of the Rat Jejunum. Role of KV-, KCa-, and Kir-Channels. Biol Membr 40: 432–442. https://doi.org/10.31857/S0233475523060099Nalli AD, Rajagopal S, Mahavadi S, Grider JR, Murthy KS (2015) Inhibition of rhoa-dependent pathway and contraction by endogenous hydrogen sulfide in rabbit gastric smooth muscle cells. Am J Physiol Cell Physiol 308: 485–495. https://doi.org/10.1152/ajpcell.00280.2014Murthy KS, Zhou H, Grider JR, Makhlouf GM (2003) Inhibition of sustained smooth muscle contraction by PKA and PKG preferentially mediated by phosphorylation of RhoA. Am J Physiol – Gastrointest Liver Physiol 284(6): G1006–G1016. https://doi.org/10.1152/ajpgi.00465.2002Temiz TK, Demir O, Simsek F, Kaplan YC, Bahceci S, Karadas B, Celik A, Koyluoglu G (2016) Effect of nitrergic system on colonic motility in a rat model of irritable bowel syndrome. Indian J Pharmacol 48: 424–429. https://doi.org/10.4103/0253-7613.186189Huang C, Hu Y, Sun S, Li H, Zhuang Z, Lv B (2023) Effects of nNOS inhibition on the Escherichia coli and butyrate-producing bacteria in IBS rats with visceral hypersensitivity. Res Square V1: Preprint. https://doi.org/10.21203/RS.3.RS-2964008/V1Holtmann GJ, Ford AC, Talley NJ (2016) Pathophysiology of irritable bowel syndrome. Lancet Gastroenterol. Hepatology 1: 133–146.Enck P, Aziz Q, Barbara G, Farmer AD, Fukudo S, Mayer EA, Niesler B, Quigley EMM, Rajilić-Stojanović M, Schemann M, Schwille-Kiuntke J, Simren M, Zipfel S, Spiller RC (2016) Irritable bowel syndrome. Nat Rev Dis Prim 2: 16014. https://doi.org/10.1038/nrdp.2016.14Low EXS, Al Mandhari MNK, Herndon CC, Loo EXL, Tham EH, Siah KTH (2020) Parental, perinatal, and childhood risk factors for development of irritable bowel syndrome: A systematic review. J Neurogastroenterol Motil 26: 437–446. https://doi.org/10.5056/jnm20109Ren TH, Wu J, Yew D, Ziea E, Lao L, Leung WK, Berman B, Hu PJ, Sung JJY (2007) Effects of neonatal maternal separation on neurochemical and sensory response to colonic distension in a rat model of irritable bowel syndrome. Am J Physiol – Gastrointest Liver Physiol 292(3): G849–G856. https://doi.org/10.1152/ajpgi.00400.2006Zheng Z, Tang J, Hu Y, Zhang W (2022) Role of gut microbiota-derived signals in the regulation of gastrointestinal motility. Front Med 9: 961703. https://doi.org/10.3389/fmed.2022.961703Singh SY, Ganguly R, Jaiswal K, Yadav AK, Kumar R, Pandey AK (2023) Molecular signalling during cross talk between gut brain axis regulation and progression of irritable bowel syndrome: A comprehensive review. World J Clin Cases 11: 4458–4476. https://doi.org/10.12998/wjcc.v11.i19.4458Singh R, Zogg H, Wei L, Bartlett A, Ghoshal UC, Rajender S, Ro S (2021) Gut microbial dysbiosis in the pathogenesis of gastrointestinal dysmotility and metabolic disorders. J Neurogastroenterol Motil 27: 19–34. https://doi.org/10.5056/JNM20149Lin M, Hu G, Yu B (2023) Dysregulated cystathionine-β-synthase/hydrogen sulfide signaling promotes chronic stress-induced colonic hypermotility in rats. Neurogastroenterol Motil 35: e14488. https://doi.org/10.1111/NMO.14488Chen S, Zuo S, Zhu J, Yue T, Bu D, Wang X, Wang P, Pan Y, Liu Y (2019) Decreased Expression of Cystathionine β-Synthase Exacerbates Intestinal Barrier Injury in Ulcerative Colitis. J Crohn’s Colitis 13: 1067–1080.Taniguchi E, Matsunami M, Kimura T, Yonezawa D, Ishiki T, Sekiguchi F, Nishikawa H, Maeda Y, Ishikura H, Kawabata A (2009) Rhodanese, but not cystathionine-γ-lyase, is associated with dextran sulfate sodium-evoked colitis in mice: A sign of impaired colonic sulfide detoxification? Toxicology 264: 96–103. https://doi.org/10.1016/j.tox.2009.07.018Wallace JL, Vong L, McKnight W, Dicay M, Martin GR (2009) Endogenous and Exogenous Hydrogen Sulfide Promotes Resolution of Colitis in Rats. Gastroenterology 137(2): 569–578. https://doi.org/10.1053/j.gastro.2009.04.012De Cicco P, Sanders T, Cirino G, Maloy KJ, Ianaro A (2018) Hydrogen sulfide reduces myeloid-derived suppressor cell-mediated inflammatory response in a model of Helicobacter hepaticus-induced colitis. Front Immunol 9: 351402. https://doi.org/10.3389/fimmu.2018.00499Oh GS, Pae HO, Lee BS, Kim BN, Kim JM, Kim HR, Jeon SB, Jeon WK, Chae HJ, Chung HT (2006) Hydrogen sulfide inhibits nitric oxide production and nuclear factor-κB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Free Radic Biol Med 41: 106-119. https://doi.org/10.1016/j.freeradbiomed.2006.03.021Stummer N, Weghuber D, Feichtinger RG, Huber S, Mayr JA, Kofler B, Neureiter D, Klieser E, Hochmann S, Lauth W, Schneider AM (2022) Hydrogen Sulfide Metabolizing Enzymes in the Intestinal Mucosa in Pediatric and Adult Inflammatory Bowel Disease. Antioxidants 11(11): 2235. https://doi.org/10.3390/antiox11112235Wallace JL, Dicay M, McKnight W, Martin GR (2007) Hydrogen sulfide enhances ulcer healing in rats. FASEB J 21: 4070-4076. https://doi.org/10.1096/fj.07-8669comMinamishima S, Bougaki M, Sips PY, De Yu J, Minamishima YA, Elrod JW, Lefer DJ, Bloch KD, Ichinose F (2009) Hydrogen sulfide improves survival after cardiac arrest and cardiopulmonary resuscitation via a nitric oxide synthase 3-dependent mechanism in mice. Circulation 120: 888-896. https://doi.org/10.1161/CIRCULATIONAHA.108.833491Nalli AD, Bhattacharya S, Wang H, Kendig DM, Grider JR, Murthy KS (2017) Augmentation of cGMP/PKG pathway and colonic motility by hydrogen sulfide. Am J Physiol – Gastrointest Liver Physiol 313: G330-G341. https://doi.org/10.1152/ajpgi.00161.2017Martinez-Cutillas M, Gil V, Mañé N, Clave P, Gallego D, Martin MT, Jimenez M (2015) Potential role of the gaseous mediator hydrogen sulphide (H2S) in inhibition of human colonic contractility. Pharmacol Res 93: 52-63. https://doi.org/10.1016/j.phrs.2015.01.002Jang DE, Bae JH, Chang YJ, Lee YH, Nam KT, Kim IY, Seong JK, Lee YC, Yeom SC (2018) Neuronal Nitric Oxide Synthase Is a Novel Biomarker for the Interstitial Cells of Cajal in Stress-Induced Diarrhea-Dominant Irritable Bowel Syndrome. Dig Dis Sci 63: 619-627. https://doi.org/10.1007/s10620-018-4933-7Tjong YW, Ip SP, Lao L, Wu J, Fong HHJ, Sung JJY, Berman B, Che CT (2011) Role of neuronal nitric oxide synthase in colonic distension-induced hyperalgesia in distal colon of neonatal maternal separated male rats. Neurogastroenterol Motil 23(7): 666-e278. https://doi.org/10.1111/j.1365-2982.2011.01697.xHan JP, Lee JH, Lee GS, Koo OJ, Yeom SC (2021) Positive correlation between nnos and stress-activated bowel motility is confirmed by in vivo hibit system. Cells 10(5): 1028. https://doi.org/10.3390/cells10051028Reinders CI, Herulf M, Ljung T, Hollenberg J, Weitzberg E, Lundberg JO, Hellström PM (2005) Rectal mucosal nitric oxide in differentiation of inflammatory bowel disease and irritable bowel syndrome. Clin Gastroenterol Hepatol 3: 777-783. https://doi.org/10.1016/S1542-3565(05)00182-5Yazar A, Buyukafsar K, Polat G, Pata C, Kanyik A, Tiftik EN, Baddatodlu O (2005) The urinary 5-hydroxyindole acetic acid and plasma nitric oxide levels in irritable bowel syndrome: A preliminary study. Scott Med J 50: 27-29. https://doi.org/10.1177/003693300505000111Wang J, Li J, Yu M, Wang Y, Ma Y (2019) An enhanced expression of hypothalamic neuronal nitric oxide synthase in a rat model of stimulated transport stress. BMC Vet Res 15: 323. https://doi.org/10.1186/S12917-019-2071-XZhu LJ, Liu MY, Li H, Liu X, Chen C, Han Z, Wu HY, Jing X, Zhou HH, Suh H, Zhu DY, Zhou QG (2014) The different roles of glucocorticoids in the hippocampus and hypothalamus in chronic stress-induced HPA axis hyperactivity. PLoS One 9: e97689. https://doi.org/10.1371/journal.pone.0097689Kasparek MS, Linden DR, Farrugia G, Sarr MG (2012) Hydrogen sulfide modulates contractile function in rat jejunum. J Surg Res 175: 234-242. https://doi.org/10.1016/j.jss.2011.03.069Wang Y, Qu R, Hu S, Xiao Y, Jiang X, Xu GY (2012) Urregulation of Cystathionine β-Synthetase Expression Contributes to Visceral Hyperalgesia Induced by Heterotypic Intermittent Stress in Rats. PLoS One 7: e53165. https://doi.org/10.1371/journal.pone.0053165Savidge TC (2014) Importance of NO and its related compounds in enteric nervous system regulation of gut homeostasis and disease susceptibility. Curr Opin Pharmacol 19: 54–60. https://doi.org/10.1016/j.coph.2014.07.009Fung C, Vanden Berghe P (2020) Functional circuits and signal processing in the enteric nervous system. Cell Mol Life Sci 77: 4505–4522. https://doi.org/10.1007/s00018-020-03543-6Miranda MR, Vestuto V, Moltedo O, Manfra M, Campiglia P, Pepe G (2023) The Ion Channels Involved in Oxidative Stress-Related Gastrointestinal Diseases. Oxygen 3: 336–365. https://doi.org/10.3390/oxygen3030022