title: Impaired ghrelin signaling is associated with gastrointestinal dysmotility in rats with gastroesophageal reflux disease.
abstract: Gastroesophageal reflux disease (GERD) is often associated with decreased upper gastrointestinal motility, and ghrelin is an appetite-stimulating hormone known to increase gastrointestinal motility. We investigated whether ghrelin signaling is impaired in rats with GERD and studied its involvement in upper gastrointestinal motility. GERD was induced surgically in Wistar rats. Rats were injected intravenously with ghrelin (3 nmol/rat), after which gastric emptying, food intake, gastroduodenal motility, and growth hormone (GH) release were investigated. Furthermore, plasma ghrelin levels and the expression of ghrelin-related genes in the stomach and hypothalamus were examined. In addition, we administered ghrelin to GERD rats treated with rikkunshito, a Kampo medicine, and examined its effects on gastroduodenal motility. GERD rats showed a considerable decrease in gastric emptying, food intake, and antral motility. Ghrelin administration significantly increased gastric emptying, food intake, and antral and duodenal motility in sham-operated rats, but not in GERD rats. The effect of ghrelin on GH release was also attenuated in GERD rats, which had significantly increased plasma ghrelin levels and expression of orexigenic neuropeptide Y/agouti-related peptide mRNA in the hypothalamus. The number of ghrelin-positive cells in the gastric body decreased in GERD rats, but the expression of gastric preproghrelin and GH secretagogue receptor mRNA was not affected. However, when ghrelin was exogenously administered to GERD rats treated with rikkunshito, a significant increase in antral motility was observed. These results suggest that gastrointestinal dysmotility is associated with impaired ghrelin signaling in GERD rats and that rikkunshito restores gastrointestinal motility by improving the ghrelin response.
authors.affiliation: Dept. of Pathophysiology and Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo, Hokkaido, Japan. h_takeda@pharm.hokudai.ac.jp
authors.forename: Miwa
authors.initials: M
authors.lastname: Nahata
authors.forename: Shuichi
authors.initials: S
authors.lastname: Muto
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Oridate
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Ohnishi
authors.forename: Koji
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Chiharu
authors.initials: C
authors.lastname: Sadakane
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Saegusa
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Hattori
authors.forename: Masahiro
authors.initials: M
authors.lastname: Asaka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takeda
mesh_terms: D054369:Agouti-Related Protein / Q000378:metabolism; D000818:Animals; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D004386:Duodenum / Q000187:drug effects / Q000502:physiology; D004435:Eating / Q000187:drug effects; D005746:Gastric Emptying / Q000187:drug effects; D005764:Gastroesophageal Reflux / Q000503:physiopathology*; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology*; D054439:Ghrelin / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D013006:Growth Hormone / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D009478:Neuropeptide Y / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013270:Stomach / Q000187:drug effects / Q000502:physiology
chemical_list: D054369:Agouti-Related Protein; D004365:Drugs, Chinese Herbal; D054439:Ghrelin; D009478:Neuropeptide Y; D010936:Plant Extracts; C084136:liu-jun-zi-tang; D012313:RNA; D013006:Growth Hormone