Evaluation of early gastric mucosal permeability induced by central thyrotropin-releasing hormone administration.
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.
Joh
Takashi
T
Department of Internal Medicine and Bioregulation, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. tjoh@med.nagoya-cu.ac.jp
Oshima
Tadayuki
T
Takahashi
Nobuo
N
Kaneko
Hiroshi
H
Sasaki
Makoto
M
Kataoka
Hiromi
H
Watanabe
Katsushi
K
Sobue
Masashi
M
Suzuki
Hideo
H
Nomura
Tomoyuki
T
Ohara
Hirotaka
H
Itoh
Makoto
M
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
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