Healing Process of Duodenal Ulcers Induced by Indomethacin plus Histamine in Rats

Abstract

Healing of duodenal ulcers induced by indomethacin + histamine was investigated in rats. Animals were treated with indomethacin (5 mg/kg, s.c, once daily) and histamine (40 mg/kg, s.c, 3 times every 2.5 h after indomethacin treatment) for 2 days under fasting conditions, and they were fed normally thereafter. The duodenal ulcers so induced were confined to the proximal part of the duodenum and penetrated to the muscular mucosa with an incidence of over 80% when determined 32 h after the first injection of indomethacin (day 1). The ulcers became smaller and shallower within 7 days with granulation from the ulcer base, the mucosa grew in from the edges over the surface of granulation tissue, and they had healed almost completely after 15 days with epithelial regeneration from the edge of the ulcers. The healing of ulcers was significantly promoted by a 5-day treatment with an antacid (Al(OH)₃) as well as antisecretory agents (omeprazole, cimetidine, propantheline bromide) and 16,16-dimethyl prostaglandin E₂ at the dose which produced a potent inhibition of acid output and a marked increase in duodenal alkaline secretion. These results suggest that the duodenal ulcers induced in rats by indomethacin + histamine may provide a useful model for studying the healing process of duodenal ulcers and for the evaluation of the drugs with possible effects on ulcer healing.

Participation of prostaglandin E receptor EP4 subtype in duodenal bicarbonate secretion in rats

“…Endogenous PGE 2 indeed mediates the acid-induced HCO 3 Ϫ response, the process being very important in the mucosal defense against acid injury (4,18). The present study confirmed our previous findings that duodenal responses to PGE 2 as well as mucosal acidification are mediated through the activation of EP3 receptors (21,23) and further demonstrated the involvement of EP4 receptors in the stimulatory process.…”

“…Previous studies well demonstrated the importance of PGE 2 in the local regulation of duodenal HCO 3 Ϫ secretion (6,9,18,21). Endogenous PGE 2 indeed mediates the acid-induced HCO 3 Ϫ response, the process being very important in the mucosal defense against acid injury (4,18).…”

“…HCO 3 Ϫ secretion was determined in a duodenal loop or a chambered stomach, according to previously published methods (18,23). In brief, the abdomen was incised, and a duodenal loop (1.5 cm) was made between the pyloric ring and the area just above the outlet of the common bile duct to exclude the influences of bile and pancreatic juice.…”

“…The neuronal reflex pathway is not involved in stimulatory actions of these prostanoids. prostaglandin E2; EP receptor subtype; EP4 receptor SECRETION OF HCO 3 Ϫ FROM surface epithelial cells is one of the mucosal defensive mechanisms and plays an important role in protecting the duodenal mucosa against acid injury (6,4,18). Although the physiological regulation of this secretion involves several factors such as PGs, peptides, and neuronal factors (4,10,19,20), endogenous PGs are particularly important in the local control of the process.…”

Stimulation by nizatidine, a histamine H2-receptor antagonist, of duodenal HCO3-secretion in rats: relation to anti-cholinesterase activity

“…Small amounts of HCO 3 -protect the mucosa against large amounts of acid by neutralizing H + ions that diffuse back into the mucus layer [13] . A number of studies demonstrated a close relationship between the mucosal ulcerogenic response and the duodenal HCO 3 -disorder [12,13,29] . Indeed, it is reported that patients with inactive duodenal ulcers have decreased production of HCO 3 -in the proximal duodenum during exposure to acid [30] , though the exact mechanism involved remains unknown.…”