title: Evaluation of early gastric mucosal permeability induced by central thyrotropin-releasing hormone administration.
abstract: Accumulating evidence suggests that central thyrotropin-releasing hormone (TRH) administration induces gastric erosion 4 h after administration through the vagal nerves. However, early changes in the gastric mucosa during these 4 h have not been described. To assess early changes in the gastric mucosa after intracisternal injection of a stable TRH analog, pGlu-His-(3,3'-dimethyl)-ProNH2 (RX-77368), we measured the blood-to-lumen 51Cr-labeled EDTA clearance and examined the effects of vagotomy, atropine, omeprazole, and hydrochloric acid (HCl) on RX-77368-induced mucosal permeability. A cytoprotective dose of RX-77368 (1.5 ng) did not increase mucosal permeability. However, higher doses significantly increased mucosal permeability. Permeability peaked within 20 min and gradually returned to control levels in response to a 15-ng dose (submaximal dose). Increased mucosal permeability was not recovered after a 150-ng dose (ulcerogenic dose). This increase in permeability was inhibited by vagotomy or atropine. Intragastric perfusion with HCl did not change the RX-77368 (15 ng)-induced increase in permeability, but completely inhibited the recovery of permeability after the peak. Pretreatment with omeprazole did not change the RX-77368 (15 ng)-induced increase in permeability, but quickened the recovery of permeability after the peak. These data indicate that the RX-77368-induced increase in permeability is mediated via the vagal-cholinergic pathway and is not a secondary change in RX-77368-induced acid secretion. Inhibited recovery of permeability on exposure to an ulcerogenic RX-77368 dose or on exposure to HCl plus a submaximal dose of RX-77368 may be crucial for the induction of gastric mucosal lesions by central RX-77368 administration.
authors.affiliation: Department of Internal Medicine and Bioregulation, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. tjoh@med.nagoya-cu.ac.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Joh
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Oshima
authors.forename: Nobuo
authors.initials: N
authors.lastname: Takahashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kaneko
authors.forename: Makoto
authors.initials: M
authors.lastname: Sasaki
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kataoka
authors.forename: Katsushi
authors.initials: K
authors.lastname: Watanabe
authors.forename: Masashi
authors.initials: M
authors.lastname: Sobue
authors.forename: Hideo
authors.initials: H
authors.lastname: Suzuki
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nomura
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Ohara
authors.forename: Makoto
authors.initials: M
authors.lastname: Itoh
mesh_terms: D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology; D001285:Atropine / Q000494:pharmacology; D001921:Brain / Q000187:drug effects*; D005753:Gastric Mucosa / Q000187:drug effects* / Q000502:physiology*; D006851:Hydrochloric Acid / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009853:Omeprazole / Q000494:pharmacology; D010539:Permeability / Q000187:drug effects; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000139:chemically induced; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014628:Vagotomy
chemical_list: D000897:Anti-Ulcer Agents; D018727:Muscarinic Antagonists; D013973:Thyrotropin-Releasing Hormone; C027979:L-pyroglutamyl-L-histidyl-3,3-dimethylprolinamide; D001285:Atropine; D009853:Omeprazole; D006851:Hydrochloric Acid; D011761:Pyrrolidonecarboxylic Acid