Cytoprotective Action of Mast Cell Stabilizers against Ethanol-Induced Gastric Les ons in Rats

Abstract

Abstract-We examined the effects of FPL-52694 and disodium cromoglycate (DSCG), mast cell stabilizers, on HCI ethanol-induced gastric lesions in rats and investigated the factors involved in their protection.Oral (p.o.) administration of 1 ml of HCI ethanol (60% in 150 mM HCI) induced linear hemor hagic lesions in the gastric mucosa within 1 hr. FPL-52694 (1-30 mg/kg), given both p.o. and intraperitoneally (i.p.), prevented these lesions in a dose-related manner. DSCG (3-30 mg/kg) also dose-dependently reduced the formation of these lesions when this agent was given i.p. The protective effects of these drugs on HCI-ethanol induced lesions were significantly attenuated by pretreatment with indomethacin (5 mg/kg, s.c.).Both gastric acid secretion and transmucosal potential difference were significantly reduced by topical application of FPL-52694 (>10 mg/kg), but were not affected by i.p. administration of FPL-52694 and DSCG. On the other hand, gastric motor activity measured as intraluminal pressure recordings was sig nificantly inhibited for 2 hr by both FPL-52694 (p.o. and i.p.) and DSCG (i.p.), and these effects were also significantly antagonized with prior administration of indomethacin.A significant relationship was found between the effects of these two drugs on the lesion index and the motility index (r: 0.9214, P<0.01), but not other factors.These results suggest that mast cell stabilizers such as FPL-52694 and DSCG protect the gastric mucosa against HCI-ethanol through a systemic action, probably mediated with endogenous prostaglandins. Although the mechanism of cytoprotection remains unknown, this property may be related to their inhibitory effects on gastric motor activity.

Gastric motility changes in capsaicin-induced cytoprotection in the rat stomach.

“…In addition, this effect was also impaired by either indomethacin pretreatment or desensitization of the capsaicin-sensitive afferent neurons, indicating that the motility effect of intragastric capsaicin is paralleled by a reduction in gross mucosal injury. These results support our previous observation that a variety of compounds showed cytoprotection at the doses that inhibit gastric motility (6)(7)(8). Inhibition of gastric motility may lead to flattening of the mucosal foldings and decreases the mucosal vulnerability to irritants, resulting in prevention of the fold-related band-like lesions (8,19).…”

“…Gastric motility was measured using a miniature balloon according to the previously published method (6). Briefly, under ether anesthesia, a balloon, the support catheter and another catheter for intragastric administration of drug were placed in the glandular stomach through an incision of the forestomach.…”

“…We have previously reported that a variety of compounds inhibited gastric motility at their cytoprotective doses and proposed motility inhibition as a possible mechanism of gastric cytoprotection (6)(7)(8). It is conceivable that relaxation of the stomach wall may lead to flattening of the foldings, resulting in a decrease of the mucosal vulnerability to irritants, and reduces the severity of mucosal damage.…”

Effects of TY-10957, a Stable PGI₂ Derivative, on Gastroduodenal Lesions and Secretory Responses in the Rat

“…Although a variety of hypotheses have been postulated concerning the mechanism of gastric cytoprotection -an increase of mucus/HCOj secretion and mucosal blood flow, inhibition of gastric motility, and dis solution of mucosal folds [15][16][17][18], none of them was without argument. The present study afforded a useful information about a relationship between the phenomena of cy toprotection and alkaline secretion.…”

Recent Advances in Gastrointestinal Pathophysiology: Role of Heat Shock Proteins in Mucosal Defense and Ulcer Healing.

“…26) It has been reported that an increase in gastric mucosal blood flow is observed after treatment with mild irritants 32) and that inhibition of the increase in mucosal blood flow by indomethacin, N G -nitro-L-arginine methyl ester (L-NAME), or sensory ablation, aggravates mucosal lesions resulting from strong irritants. [32][33][34] Based on such evidence, the mucosal microcirculation is believed to play an important role in mucosal protection by removing back-diffused acid in the mucosa and transporting humoral factors involved in cytoprotection into the epithelial cells. It has been suggested that gastric motility changes play a role in the development and prevention of gastric lesions following both stress and administration of nonsteroidal anti-inflammatory drugs.…”