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

Abstract

ABSTRACT-DS-4574 is a peptidoleukotriene antagonist with mast cell stabilizing activity. In the pres ent study, we studied the effects of this compound on gastric secretion and various acute gastric lesions in rats. Intraduodenal administration of DS-4574 at doses of 5 to 10 mg/kg significantly and dose dependently inhibited gastric acid secretion in pylorus-ligated rats, but a further increase in the dose up to 50 mg/kg did not cause any further inhibition. Shay ulceration in response to pylorus ligation was dose-dependently prevented by DS-4574 (10-25 mg/kg, i.d.). Water-immersion restraint stress and aspirin-induced gastric ulcers were also significantly prevented in a dose-related manner by oral pre treatment with DS-4574 (10-50 mg/kg). The lower doses of DS-4574 (1-10 mg/kg, p.o.) significantly and dose-dependently protected the gastric mucosa against the necrotizing action of either absolute ethanol or concentrated hydrochloric acid, indicating that this compound possesses a potent gastro protective activity. These antiulcer and gastric protective effects of DS-4574 were more potent than those of cimetidine used as a reference drug. These findings suggest that DS-4574 is useful for peptic ulcer therapy, as well as for the therapy of various allergic diseases, including asthma.

Antisecretory effect of DS-4574, a mast cell stabilizer with peptidoleukotriene antagonism, on gastric acid secretion in the pig

“…The mode of the antisecretory action of DS-4574 is thus apparently different from that of cimetidine. Recently, we found that DS-4574 inhibited both carbachol and pentagastrin-induced gastric acid hypersecretion, but did not affect the response to histamine in the rat [8], and that this compound had no effect on aminopyrine accumulation into rat parietal cells stimulated by carbachol, histamine or dibutyryl-cyclic AMP [8]. In addition, DS-4574 did not affect the K § ATPase activity in hog gastric vesicles.…”

“…This concept has been partly substantiated by the demonstration of histamine release in the isolated stomach in the rat [16], gastric glands in the rabbit [17], and isolated gastric enterochromaffin-like (ECL)cells in the rat [18,19] or the dog [20]. In addition, mast cell stabilizers such as disodium cromoglycate (DSCG), FPL 52694 and DS-4574 have been shown to inhibit gastric acid secretion occurring in response to pentagastrin in rats [8,21]. Moreover, gastrin-induced histidine decarboxytase [15,22] and histamine N-methyltransferase activities [15].…”

“…In anesthetized rats with acute gastric fistula, DS-4574 also inhibited both carbachol-and pentagastrin-induced hypersecretion of gastric acid, but did not affect histaminestimulated hypersecretion [8]. Furthermore, DS-4574 suppressed histamine leakage into the gastric juice in pylorus-ligated rats, which was induced by carbachol or pentagastrin, suggesting that the suppression of histamine release from histamine-containing cells is responsible, at least in part, for the antisecretory property of this compound [8]. In the present study, we evaluated the effect of DS-4574 on gastric acid hypersecretion stimulated by carbachol, tetragastrin or histamine in Goettingen miniature pigs.…”

“…Previously we found that DS-4574 prevented experimental gastric lesions in rats [6,7] and inhibited basal gastric acid secretion in pylorus-ligated rats [6]. In anesthetized rats with acute gastric fistula, DS-4574 also inhibited both carbachol-and pentagastrin-induced hypersecretion of gastric acid, but did not affect histaminestimulated hypersecretion [8].…”

“…Previously we found that DS-4574 prevented experimental gastric lesions in rats [6,7] and inhibited basal gastric acid secretion in pylorus-ligated rats [6]. In anesthetized rats with acute gastric fistula, DS-4574 also inhibited both carbachol-and pentagastrin-induced hypersecretion of gastric acid, but did not affect histaminestimulated hypersecretion [8]. Furthermore, DS-4574 suppressed histamine leakage into the gastric juice in pylorus-ligated rats, which was induced by carbachol or pentagastrin, suggesting that the suppression of histamine release from histamine-containing cells is responsible, at least in part, for the antisecretory property of this compound [8].…”