Effects of FPL-52694, a new mast cell stabilizer, on gastric secretion and various acute gastric lesions in rats

Abstract

Oral FPL-52694 [5-(2-hydroxypropoxy)-8-propyl-4-oxo-4H-1-benzopyran-2-carboxylic acid Na], a new mast cell stabilizer, dose-dependently inhibited gastric acid secretion but increased the volume and pepsin output in pylorus-ligated rats. Intraduodenal FPL-52694 significantly inhibited all of the volume, acidity, acid output and pepsin output. Concerning the acidity, oral administration of the agent showed much more potent inhibition than intraduodenal administration. Oral FPL-52694 markedly inhibited the development of pylorus-ligated ulcers, water-immersion stress- and aspirin-induced gastric erosions and moderately inhibited the formation of reserpine-induced gastric erosions in rats. Intraduodenal FPL-52694 also inhibited pylorus-ligated ulcers whereas it had no effect on aspirin-induced gastric erosions. Histamine-induced gastric erosions were not affected by oral FPL-52694. These effects of FPL-52694 were almost the same as those of cimetidine, except that cimetidine tended to inhibit histamine-induced gastric erosions. Although the precise mechanism of action of FPL-52694 remains unknown, oral FPL-52694 appears to be a promising agent for the treatment of peptic ulcers.

Mechanisms of Antisecretory Action of Intragastric FPL-52694: A Mast Cell Stabilizer in Anesthetized Rats

“…Since histamine plays an important role in the physiological regulation of gastric acid secre tion, the effect of FPL-52694 has been sug gested to occur as the result of its influence on the role of histamine in the body. However, the antisecretory effect of FPL-52694 in py lorus-ligated rats or fistula dogs was in marked contrast with different routes of ad ministration; the inhibition being much greater by the intragastric administration than by the intraduodenal or intravenous one [2,6,7], In the current study, we investigated the effects of FPL-52694 on basal and stimu lated acid secretion, transmucosal potential difference (PD), and ionic flux across the mucosa in anesthetized rats, in attempts to search for the local mechanisms involved in the antisecretory action of intragastric FPL-52694.…”

“…The inhibitory effect of this agent on gastric acid secretion was dem onstrated in rats, dogs and humans [2,[4][5][6], but the mechanism remains unknown. Since histamine plays an important role in the physiological regulation of gastric acid secre tion, the effect of FPL-52694 has been sug gested to occur as the result of its influence on the role of histamine in the body.…”

“…[5-(2-hydroxypropoxyl)-4-oxo-8-propyl-4H-l-benzopyran-2-carboxylic acid Na] effectively inhibited histamine re lease from the isolated peritoneal mast cells as induced by compound 48/80 or antigenantibody reaction, and exerted an antiulcer activity on experimentally induced gastric le sions in rats [1][2][3]. The inhibitory effect of this agent on gastric acid secretion was dem onstrated in rats, dogs and humans [2,[4][5][6], but the mechanism remains unknown.…”

Effect of DS-4574, a Novel Peptidoleukotriene Antagonist with Mast Cell Stabilizing Action, on Acute Gastric Lesions and Gastric Secretion in Rats

“…Further more, a representative peptidoleukotriene antagonist (FPL-55712) has been reported to lack an inhibitory effect on gastric acid secretion in rats (9). It is, there fore, conceivable that the suppressed gastric secretion after DS-4574 treatment is mediated by the inhibition of endogenous histamine release from histamine-storing cells such as mast cells and enterochromaffin-like (ECL) cells in the stomach, as has been proposed for other mast cell stabilizers such as disodium cromogly cate and FPL-52694 (10,11).…”

“…Several mast cell stabilizing agents effective ly prevented stress-induced gastric ulceration (11,15). An ulcerogenic dose of aspirin induced mucosal mast cell degranulation with a concomitant reduction in gas tric mucosal content of histamine (16).…”