Expression of NADPH-d in the vagal nuclei of the chronic esophagitis model in rats

Ümit Süleyman ŞEHİRLİ, Halil TUĞTEPE, Ural VERİMLİ, Özlem KİRAZLI, Mazhar ÖZKAN, Emrullah Tolga DAĞLI
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To evaluate the changes in the number of NADPH diaphorase (NADPH-d) stained neurons in the vagal nuclei in a chronic esophagitis model. Materials and methods: There were 3 groups of rats examined: 1) a chronic gastroesophageal reflux rat group, which was created by a partial gastric outlet obstruction; 2) a sham group; and 3) a ranitidine treated group. Serial sections of brainstems of all groups were cut and NADPH-d staining, which selectively stains the nitric acid synthase-containing neurons, was done. Results: Histopathological changes due to chronic reflux esophagitis was observed in the reflux group. The ranitidine treatment and sham control groups showed no changes related to esophagitis. The staining in the dorsal motor nucleus of the vagus and nucleus tractus solitarius showed statistically significant differences compared to the control group (P < 0.0001). Conclusion: The increased nitric oxide expressions in the dorsal vagal nucleus and nucleus tractus solitarius are most probably due to adaptive changes to disturbed esophageal motility and mucosal damage.


Key words: Esophagitis, lower esophageal sphincter, nitric oxide, dorsal motor nucleus, nucleus tractus solitarius

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Wolfe M, Michael M. An overview of gastroesophageal reflux disease. Am J Manag Care 2000; 6: 461 –6.

Goyal RK, Chaudhury A. Physiology of normal esophageal motility. J Clin Gastroenterol 2008; 42: 610–9.

Tugtepe H, Tugay M, Bozkurt S, Yildiz F, Utkan T, Yegen B, Dagli TE. Esophageal smooth muscle reactivity is impaired in chronic reflux esophagitis by both receptor- and nonreceptormediated mechanisms. J Pediatr Surg 2007; 42: 641–6.

Neuhuber WL, Raab M, Berthoud HR, Wörl J. Innervation of the mammalian esophagus. Adv Anat Embryol Cell Biol 2006; 185: 1–73.

Shuai XW, Xie PY. Expression and localization of c-Fos and NOS in the central nerve system following esophageal acid stimulation in rats. World J Gastroenterol 2004; 10: 2287–91.

Zhang XY, Ai HB, Cui XY. Effects of nucleus ambiguus and dorsal motor nuclei of vagus on gastric H(+) and HCO(3)(-) secretion in rats. World J Gastroenterol 2006; 12: 3271–4.

Guix FX, Uribesalgo I, Coma M, Muñoz FJ. The physiology and pathophysiology of nitric oxide in the brain. Prog Neurobiol 2005; 76: 126–52.

Bredt DS, Hwang PM, Snyder SH. Localization of nitric oxide synthase indicating a neural role for nitric oxide. Nature 1995; 347: 768–70.

Dawson TM, Bredt DS, Fotuhi M, Hwang PM, Snyder SH. Nitric oxide synthase and neuronal NADPH diaphorase are identical in brain and peripheral tissues. Proc Natl Acad Sci USA 1991; 88: 7797–801.

Forster ER, Southam E. The intrinsic and vagal extrinsic innervation of the rat stomach contains nitric oxide synthase. Neuroreport 1993 Mar; 4: 275–8.

Berthoud HR. Anatomical demonstration of vagal input to nicotinamide acetamide dinucleotide phosphate diaphorasepositive (nitrergic) neurons in rat fundic stomach. J Comp Neurol 1995; 31; 358: 428–39.

Toda N, Herman AG. Gastrointestinal function regulation by nitrergic efferent nerves. Pharmacol Rev 2005; 57: 315–38.

Omura N, Kashiwagi H, Chen G, Suzuki Y, Yano F, Aoki T. Establishment of surgically induced chronic acid reflux esophagitis in rats. Scand J Gastroenterol 1999; 34: 948–53.

Özer M, Duman M, Taş Ş, Demirci Y, Aydın MF, Reyhan E, Atıcı AE, Bostancı EB, Akoğlu M, Genç E. In vitro effects of famotidine and ranitidine on lower esophageal sphincter tone in rats. Turk J Gastroenterol 2012; 23: 438–43.

Yamato S, Saha JK, Goyal RK. Role of nitric oxide in lower esophageal sphincter relaxation to swallowing. Life Sci 1992; 50: 1263–72.

Saito Y, Kawashima Y, Kondo A, Chikumaru Y, Matsui A, Nagata I, Ohno K. Dysphagia-gastroesophageal reflux complex: complications due to dysfunction of solitary tract nucleus-mediated vago-vagal reflex. Neuropediatrics 2006; 37: 115–20.

Thumshirn M. Gastrointestinal motility disorders relevant to general practice. Praxis (Bern 1994) 2002; 91: 1741–7.

Ghia JE, Blennerhassett P, El-Sharkawy RT, Collins SM. The protective effect of the vagus nerve in a murine model of chronic relapsing colitis. Am J Physiol Gastrointest Liver Physiol 2007; 293: G711–8.

Andrews PL, Sanger GJ. Abdominal vagal afferent neurons: an important target for the treatment of gastrointestinal dysfunction. Curr Opin Pharmacol 2002; 2: 650–6.

Hornby PJ, Abrahams TP. Central control of lower esophageal sphincter relaxation. Am J Med 2000; 108 Suppl: 90–8

Faris PL, Hofbauer RD, Daughters R, Vandenlangenberg E, Iversen L, Goodale RL, Maxwell R, Eckert ED, Hartman BK. De-stabilization of the positive vago-vagal reflex in bulimia nervosa. Physiol Behav 2008; 94: 136–53.

Chang HY, Mashimo H, Goyal RK. Musings on the wanderer: what’s new in our understanding of vago-vagal reflex? IV. Current concepts of vagal efferent projections to the gut. Am J Physiol Gastrointest Liver Physiol 2003; 284: G357–66.

Hyland NP, Abrahams TP, Fuchs K, Burmeister MA, Hornby PJ. Organization and neurochemistry of vagal preganglionic neurons innervating the lower esophageal sphincter in ferrets. J Comp Neurol 2001; 430: 222–34.

Rossiter CD, Norman WP, Jain M, Hornby PJ, Benjamin S, Gillis RA. Control of lower esophageal sphincter pressure by two sites in dorsal motor nucleus of the vagus. Am J Physiol 1990; 259: G899–906.

Bieger D, Triggle C. Pharmacological properties of mechanical responses of the rat oesophageal muscularis mucosae to vagal and field stimulation. Br J Pharmacol 1985; 84: 93–106.

Storr M, Geisler F, Neuhuber WL, Schusdziarra V, Allescher HD. Characterization of vagal input to the rat esophageal muscle. Auton Neurosci 2001; 91: 1–9.

Watson N, Reddy H, Eglen RM. Characterization of muscarinic receptor and beta-adrenoceptor interactions in guinea-pig oesophageal muscularis mucosae. Eur J Pharmacol 1995; 294: 779–85.

Mittal RK, Holloway R, Dent J. Effect of atropine on the frequency of reflux and transient lower esophageal sphincter relaxation in normal subjects. Gastroenterology 1995; 109: 1547–54.

Sifrim D, Holloway R. Transient lower esophageal sphincter relaxations: how many or how harmful? Am J Gastroenterol 2001; 96: 2529–32.

Tİttrup A, Knudsen MA, Gregersen H. The role of the L-arginine-nitric oxide pathway in relaxation of the opossum lower oesophageal sphincter. Br J Pharmacol 1991; 104: 113–6. Yamato S, Spechler SJ, Goyal RK. Role of nitric oxide in esophageal peristalsis in the opossum. Gastroenterology 1992; 103: 197–204.

Zheng ZL, Rogers RC, Travagli RA. Selective gastric projections of nitric oxide synthase-containing vagal brainstem neurons. Neuroscience 1999; 90: 685–94.

Murray J, Du C, Ledlow A, Bates JN, Conklin JL. Nitric oxide: mediator of nonadrenergic noncholinergic responses opossum esophageal muscle. Am J Physiol 1991; 261: G401–6.