15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Stomach-Ulcer

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.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Cell Division; Cell Line; Cell Survival; Enzyme Inhibitors; Epithelial Cells; Gastric Mucosa; Male; Methacrylates; Rats; Rats, Inbred Strains; Stomach; Stomach Ulcer; Thromboxane A2; Thromboxane-A Synthase; Transforming Growth Factor alpha; Vasoconstrictor Agents

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 16,16-Dimethylprostaglandin E2; Animals; Eicosanoids; Gastric Mucosa; Hydrogen Peroxide; Male; Prostaglandin Endoperoxides, Synthetic; Rats; Stomach; Stomach Ulcer; Sulfonamides

The pro-ulcerogenic actions of the thromboxane mimetic, U-46619 on the rat gastric mucosa have been investigated, utilizing a novel technique which allows administration directly into the left gastric artery. Local intra-arterial infusion of U-46619 (100-500 ng/kg/min for 10 min) induced dose-dependent macroscopic damage in both the corpus and antral regions, characterized as vasocongestion, disruption and haemorrhage, with deep penetrating ulcers in the antral mucosa. Vascular congestion, epithelial cell and glandular disruption was observed histologically in both corpus and antral regions. Local intra-arterial infusion of lower doses of U-46619 (25-100 ng/kg/min) significantly disrupted the mucosa in the presence of 10% ethanol in a concentration which itself did not induce macroscopic damage. The damaging actions of U-46619 were substantially reduced by pretreatment with the thromboxane-receptor antagonist, BM 13,177 (5mg/kg i.v.) or 16,16-dimethyl PGE2 (5 micrograms/kg s.c.). These findings support the role of endogenous thromboxane A2 as a local mediator of gastric injury.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 16,16-Dimethylprostaglandin E2; Animals; Arteries; Drug Synergism; Ethanol; Gastric Mucosa; Infusions, Intra-Arterial; Male; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Inbred Strains; Receptors, Prostaglandin; Receptors, Thromboxane; Stomach; Stomach Ulcer; Sulfonamides

The effects of the thromboxane A2-mimetic, U46619, and the thromboxane receptor antagonist, AH23848, on ethanol-induced gastric mucosal damage and gastric non-parietal secretion have been examined in the rat. Oral dosing with U46619 or AH23848 produced a dose-related inhibition of ethanol-induced gastric mucosal damage in the conscious rat, and these effects were partially blocked by indomethacin treatment. Intragastric application of U46619 or AH23848 to the stomach of the anaesthetized rat stimulated the gastric secretion of a juice which consisted principally of Na+ and Cl- ions. These secretagogue effects of both compounds were blocked by indomethacin treatment. These results show that U46619 and AH23848 induce secretory and protective effects in the stomach of the rat, although these responses probably do not involve thromboxane receptors and are mediated, at least in part, by endogenous prostaglandins. The results are discussed in relation to the role of endogenous thromboxane A2 in gastric mucosal protection, and of the possible protective function of non-parietal secretion in the stomach.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Anti-Ulcer Agents; Biphenyl Compounds; Ethanol; Female; Gastric Mucosa; Indomethacin; Prostaglandin Endoperoxides, Synthetic; Rats; Stomach Ulcer; Thromboxane A2; Thromboxanes

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Dogs; Gastric Mucosa; Indomethacin; Prostaglandin Endoperoxides; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Stomach Ulcer; Vasoconstriction