title: Esophagoprotection mediated by exogenous and endogenous melatonin in an experimental model of reflux esophagitis.
abstract: Reflux esophagitis is a common clinical entity in western countries with approximately 30% of the population experiencing the symptoms at least once every month. The imbalance between the protective and aggressive factors leads to inflammation and damage of the esophageal mucosa. We compared the effect of exogenous melatonin and melatonin derived endogenously from L-tryptophan with that of pantoprazole or ranitidine in acid reflux esophagitis due to ligation of the rat pylorus and the limiting ridge between the forestomach and the corpus. Four hours after the induction of gastric reflux, an increase in mucosal lesions associated with edema of the submucosa and with the infiltration of numerous neutrophils and the fall in esophageal blood flow (EBF) were observed. Both melatonin and L-tryptophan or pantoprazole significantly reduced the lesion index (LI) and raised the EBF. Pinealectomy that significantly decreased plasma melatonin levels aggravated LI and these effects were reduced by melatonin and L-tryptophan. Luzindole, the MT2 receptor antagonist, abolished the melatonin-induced reduction in LI and the rise in EBF. L-NNA and capsaicin that augmented LI and decreased EBF, also significantly reduced melatonin-induced protection and hyperemia; both were restored with L-arginine and calcitonin gene-related peptide (CGRP) added to melatonin. Upregulation of IL-1β and TNF-α mRNAs and plasma IL-1β and TNF-α levels were significantly attenuated by melatonin and L-tryptophan. We conclude that melatonin protects against acid reflux-induced damage via activation of MT2 receptors mediated by NO and CGRP released from sensory nerves and the suppression of expression and release of TNF-α and IL-1β.
authors.affiliation: Department of Internal Medicine, Thuringia-Clinic Saalfeld, Teaching Hospital of the University Jena, Saalfeld, Germany.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Konturek
authors.forename: Iwona
authors.initials: I
authors.lastname: Brzozowska
authors.forename: Aneta
authors.initials: A
authors.lastname: Targosz
authors.forename: Michal
authors.initials: M
authors.lastname: Pawlik
authors.forename: Joanna
authors.initials: J
authors.lastname: Kania
authors.forename: Thomas
authors.initials: T
authors.lastname: Hess
authors.forename: Slawomir
authors.initials: S
authors.lastname: Kwiecien
authors.forename: Stanislaw J
authors.initials: SJ
authors.lastname: Konturek
authors.forename: Russel J
authors.initials: RJ
authors.lastname: Reiter
authors.forename: Tomasz
authors.initials: T
authors.lastname: Brzozowski
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D013505:Digestive System Surgical Procedures; D004195:Disease Models, Animal; D004942:Esophagitis, Peptic / Q000473:pathology*; D004947:Esophagus / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D008297:Male; D008550:Melatonin / Q000378:metabolism / Q000494:pharmacology*; D009092:Mucous Membrane / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D010870:Pineal Gland / Q000601:surgery; D020011:Protective Agents / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014364:Tryptophan / Q000494:pharmacology
chemical_list: D020011:Protective Agents; D009569:Nitric Oxide; D014364:Tryptophan; D001120:Arginine; D008550:Melatonin; D002211:Capsaicin
keywords: L‐tryptophan; capsaicin‐sensitive afferent nerves; melatonin; nitric oxide; pineal gland; proinflammatory cytokines; reflux esophagitis; stress‐induced gastric lesions