Vagus-mediated activation of mucosal mast cells in the stomach: Effect of ketotifen on gastric mucosal lesion formation and acid secretion induced bya high dose of intracisternal TRH analogue

TRH analogue, RX 77368, injected intracisternally (i.c.) at high dose (3 mu g/rat) produces gastric mucosal lesion formation through vagal-dependent p athway. The gastric mucosal hyperemia induced by i.c. RX 77368 was shown to be mediated by muscarinic vagal efferent fibres and mast cells. Furthermor e, electrical vagal stimulation was observed to induce gastric mucosal mast cell degranulation. The aim of the study was to assess the influence of ke totifen, a mast cell stabilizer, on RX 77368-induced gastric lesion formati on and gastric acid secretion. RX 77368 (3 mu g, i.c.) or vehicle (10 mu L, i.c.) was delivered 240 min prior to the sacrifice of the animals. Ketotif en or vehicle (0.9% NaCl, 0.5 mt) was injected intraperitoneally (i.p.) at a dose of 10 mg.kg(-1) 30 min before RX 77368 injection. The extent of muco sal damage was planimetrically measured by a video image analyzer (ASK Ltd. , Budapest) device. In the gastric acid secretion studies, the rats were pr etreated with ketotifen (10 mg.kg(-1), i.p.) or vehicle (0.9% NaCl, 0.5 mt, i.p.), 30 min later pylorus-ligation was performed and RX 77368 (3 mu g, i .c.) or vehicle (0.9% NaCl, 10 mu L, i.c.) was injected. The rats were kill ed 240 min after i.c. injection, and the gastric acid secretion was measure d through the titration of gastric contents with 0.1 N NaOH to pH 7.0. RX 7 7368 (3 mu g, i.c.) resulted in a gastric mucosal lesion formation involvin g 8.2% of the corpus mucosa (n = 7). Ketotifen elicited an 85% inhibition o n the development of mucosal lesions (n = 7, P < 0.001) whereas ketotifen a lone had no effect on the lesion formation in the mucosa (n = 7). The RX 77 368 induced increase of gastric acid secretion was not influenced by ketoti fen pretreatment in 4-h pylorus-ligated animals. Central vagal activation i nduced mucosal lesion formation is mediated by the activation of mucosal ma st cells in the stomach. Mast cell inhibition by ketotifen does not influen ce gastric acid secretion induced by i.c. TRH analogue in 4-h pylorus-ligat ed rats. (C) 2000 Elsevier Science Ltd. Published by Editions scientifiques et medicales Elsevier SAS.