Influence of a new antiulcer agent, ammonium 7-oxobicyclo (2, 2, 1) hept-5-ene-3-carbamoyl-2-carboxylate (KF-392) on gastric lesions and gastric mucosal barrier in rats.
Antiulcer effects of KF-392 were studied in several experimental gastric ulcer models in rats. It was found that KF-392 given orally at 1.0 to 5.0 mg/kg had a marked suppression on the developments of Shay ulcer as well as the aspirin-, stress-, and reserpine-induced gastric lesions. The influence of KF-392 on gastric mucosal barrier was also studied. A back diffusion of H+ into the gastric mucosa and a fall of transmucosal potential difference were induced with KF-392 given orally at the above mentioned doses. KF-392 given s.c. at 5.0 mg/kg showed no inhibition of Shay ulcer and no induction of back diffusion of H+ into the gastric mucosa. (+info)
Anti-ulcer effects of 4'-(2-carboxyetyl) phenyl trans-4-aminomethyl cyclohexanecarboxylate hydrochloride (cetraxate) on various experimental gastric ulcers in rats.
Anti-ulcer effects of cetraxate, a new compound possessing anti-plasmin, anti-casein and anti-trypsin actions were investigated by using experimental gastric ulcer models in rats. Cetraxate, 300 mg/kg p.o. showed significant inhibitory effects of 65.3%, 70.0%, 30.2%, and 67.1% against aucte types of ulcers producing by aspirin, phenylbutazone, indomethacin, and pyloric ligature (Shay's ulcer), respectively. These effects were greater than those obtained by gefarnate and aluminum sucrose sulfate may be mainly attributed to the protecting action of this drug on gastric mucosa. Ctraxate further revealed remarkable inhibitory effects on chronic types of ulcers produced by acetic acid, clamping, and clamping-cortisone. In acetic acid ulcer in particular, cetraxate was found to have a dose-dependent inhibitory effect at doses over 50 mg/kg. Of test drugs including L-glutamine and methylmethionine sulfonium chloride, cetraxate showed the most remarkable inhibitory effect on beta-glucuronidase activity in ulcer tissue of these three types of ulcers. These findings suggest that cetraxate may prevent the connective tissue in the ulcer location from decomposition due to lysosomal enzymes such as beta-glucuronidase, thereby accelerating the recovery from ulcer. (+info)
Anti-inflammatory and ulcerogenic effects of 3-(N,N-diethylamino) propylindometacin HCl.
AIM: To study anti-inflammatory effects of a novel indometacin ester, 3-(N,N-diethylamino) propyl-indometacin HCl (prodrug) and its ulcerogenicity in fats. METHODS: Carrageenin (Car)-induced paw edema and ulcer index were examined. RESULTS: Car-induced paw edema was inhibited by 36.6% (P < 0.01) at 3 h and 34.6% (P < 0.01) at 5 h after a single i.p. injection of the prodrug 7.09 mg.kg-1. On the same molar basis, indometacin (Ind) 5 mg.kg-1 i.p. inhibited edema by 45.6% at 3 h and 39.2% at 5 h, however, there was no statistical significant difference (P > 0.05) between the edema-inhibitory effect of the prodrug and that of Ind. The dose 10 micrograms/paw exhibited 64% inhibition of the swelling, the prodrug > 10 micrograms/paw showed no additional inhibition of swelling; the acute gastric lesion properties of the prodrug were much lower than those of Ind 6 h after p.o. CONCLUSION: The prodrug is a potent anti-inflammatory agent with lower ulcerogenicity in the stomach. (+info)
Role of apoptosis induced by Helicobacter pylori infection in the development of duodenal ulcer.
BACKGROUND: Helicobacter pylori affects gastric epithelium integrity by acceleration of apoptosis. However, it remains unclear what product of the bacteria causes apoptosis, or whether or not the apoptosis is involved in the development of ulcers. AIMS: To elucidate the factor from H pylori that causes acceleration of apoptosis and the role of apoptosis in the development of duodenal ulcer in H pylori infection. PATIENTS: Five H pylori negative healthy volunteers, 47 H pylori positive patients with duodenal ulcer, and 35 H pylori positive patients with gastric ulcer. METHODS: An endoscopic examination was carried out to diagnose ulcers and determine their clinical stage. To analyse apoptosis, a cell cycle analysis was performed using biopsy specimens. RESULTS: There was a significant correlation between the urease activity of the H pylori strain and the level of apoptosis induced by this bacterial strain. Moreover, in duodenal ulcer patients infected with H pylori, the patients with an active ulcer exhibited a significantly higher level of apoptosis than those with ulcers at both the healing and scarring stages. CONCLUSION: These findings suggest that acceleration of apoptosis in the antral mucosa caused by the urease of H pylori plays a crucial role in the development of ulcers in the duodenum. (+info)
Helicobacter pylori-induced chronic active gastritis, intestinal metaplasia, and gastric ulcer in Mongolian gerbils.
The establishment of persisting Helicobacter pylori infection in laboratory animals has been difficult, but in 1996 Hirayama reported the development of a successful Mongolian gerbil model. The present study was undertaken with two aims: to better characterize the normal histological structure and histochemical properties of the gastric mucosa of the Mongolian gerbil; and to evaluate the progression of the histopathological features of H. pylori-induced gastritis in this animal model for one year after the experimental infection. Seventy-five Mongolian gerbils were used. Mongolian gerbils were sacrificed at 2, 4, 8, 12, 26, 38, and 52 weeks after H. pylori inoculation. Sections prepared from stomachs immediately fixed in Carnoy's solution were stained with hematoxylin and eosin and Alcian blue at pH 2.5/periodic acid-Schiff, a dual staining consisting of the galactose oxidase-cold thionin Schiff reaction and paradoxical Concanavalin A staining, and with immunostaining for H. pylori and BrdU. H. pylori infection induced in the Mongolian gerbil a chronic active gastritis, in which a marked mucosal infiltration of neutrophils on a background of chronic inflammation became detectable 4 weeks after inoculation and continued up to 52 weeks. Intestinal metaplasia and gastric ulcers appeared after 26 weeks in some of the animals, whereas others developed multiple hyperplastic polyps. The Mongolian gerbil represents a novel and useful model for the study of H. pylori-induced chronic active gastritis and may lend itself to the investigation of the epithelial alterations that lead to intestinal metaplasia and gastric neoplasia. (+info)
Effects of nicorandil on experimentally induced gastric ulcers in rats: a possible role of K(ATP) channels.
The anti-ulcer effects of nicorandil [N-(2-hydroxyethyl)nicotinamide nitrate ester] were examined on water-immersion plus restraint stress-induced and aspirin-induced gastric ulcers in rats, compared with those of cimetidine. Nicorandil (3 and 10 mg/kg) given orally to rats dose-dependently inhibited the development of acid-related damage (water-immersion- and aspirin-induced gastric lesions) in the models. Cimetidine (50 mg/kg, p.o.) also had anti-ulcer effects in the same models. However, in the presence of glibenclamide (20 mg/kg, i.v.), an antagonist of K(ATP) channels, nicorandil did not inhibit the formation of gastric lesions. Nicorandil (10 mg/kg) given intraduodenally (i.d.), like cimetidine (50 mg/kg), significantly reduced the volume of the gastric content, total acidity and total acid output in the pylorus ligation model. Glibenclamide reversed the changes caused by i.d. nicorandil. I.v. infusion of nicorandil (20 microg/kg per min) significantly increased gastric mucosal blood flow, without affecting blood pressure and heart rate, but the increase in the blood flow was not observed after i.v. treatment with glibenclamide (20 mg/kg). These results indicate that nicorandil administered orally to rats produces the anti-ulcer effect by reducing the aggressive factors and by enhancing the defensive process in the mucosa through its K(ATP)-channel-opening property. (+info)
Role of thromboxane A2 in healing of gastric ulcers in rats.
We investigated the role of thromboxane (TX) A2 in gastric ulcer healing in rats. Acetic acid ulcers were produced in male Donryu rats. TXA2 synthesis in the stomachs with ulcers was significantly elevated in ulcerated tissue, but not in intact tissue, compared with that in the gastric mucosa of normal rats. Indomethacin inhibited both TXA2 and prostaglandin E2 (PGE2) synthesis in ulcerated tissue, while NS-398 (selective cyclooxygenase-2 inhibitor) reduced only PGE2 synthesis. OKY-046 (TXA2 synthase inhibitor) dose-relatedly inhibited only TXA2 synthesis. The maximal effect of OKY-046 (80% inhibition) was found at more than 30 mg/kg. When OKY-046 was administered for 14 days, the drug at more than 30 mg/kg significantly accelerated ulcer healing without affecting acid secretion. The maximal reduction of ulcerated area by OKY-046 was about 30%, compared with the area in the control. Histological studies revealed that regeneration of the mucosa was significantly promoted by OKY-046, but neither maturation of the ulcer base nor angiogenesis in the base were affected. OKY-046 and TXB2 had no effect on proliferation of cultured rat gastric epithelial cells, but U-46619 (TXA2 mimetic) dose-relatedly prevented the proliferation without reducing cell viability. These results indicate that the increased TXA2, probably derived from cyclooxygenase-1 in ulcerated tissue, exerts a weak inhibitory effect on ulcer healing in rats. The effect of TXA2 might be due partly to prevention of gastric epithelial cell proliferation at the ulcer margin. (+info)
Lateralized effects of medial prefrontal cortex lesions on neuroendocrine and autonomic stress responses in rats.
The medial prefrontal cortex (mPFC) is highly activated by stress and modulates neuroendocrine and autonomic function. Dopaminergic inputs to mPFC facilitate coping ability and demonstrate considerable hemispheric functional lateralization. The present study investigated the potentially lateralized regulation of stress responses at the level of mPFC output neurons, using ibotenic acid lesions. Neuroendocrine function was assessed by plasma corticosterone increases in response to acute or repeated 20 min restraint stress. The primary index of autonomic activation was gastric ulcer development during a separate cold restraint stress. Restraint-induced defecation was also monitored. Plasma corticosterone levels were markedly lower in response to repeated versus acute restraint stress. In acutely restrained animals, right or bilateral, but not left mPFC lesions, decreased prestress corticosterone levels, whereas in repeatedly restrained rats, the same lesions significantly reduced the peak stress-induced corticosterone response. Stress ulcer development (after a single cold restraint stress) was greatly reduced by either right or bilateral mPFC lesions but was unaffected by left lesions. Restraint-induced defecation was elevated in animals with left mPFC lesions. Finally, a left-biased asymmetry in adrenal gland weights was observed across animals, which was unaffected by mPFC lesions. The results suggest that mPFC output neurons demonstrate an intrinsic right brain specialization in both neuroendocrine and autonomic activation. Such findings may be particularly relevant to clinical depression which is associated with both disturbances in stress regulatory systems and hemispheric imbalances in prefrontal function. (+info)