ozagrel 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

Effects of OKY-046, a thromboxane synthetase inhibitor; BM 13.177, a thromboxane A2-receptor antagonist and FPL 55712, a leukotriene antagonist have been studied on gastric lesions induced by necrotizing agents (80% ethanol, 0.6 M HCl, 0.2 M NaOH, 25% NaCl and 100 mM sodium taurocholate), aspirin, indomethacin, reserpine and hypothermic restraint stress in rats. Ro 22-6923, a synthetic trimethyl prostanoid has been used for comparison. OKY-046, FPL 55712 and Ro 22-6923 produced dose dependent inhibition of gastric lesions induced by necrotizing agents and reduced the severity of aspirin, indomethacin, reserpine and hypothermic restraint stress induced lesions. BM 13.177 was not found effective against any of the models used in this study. These observations indicate towards the role of thromboxane A2 and leukotriene C4 in the genesis of gastric lesions induced by different methods. FPL 55712 required considerably lower doses than those of OKY-046 to display its protective effects in these models. Further studies on the levels of thromboxane A2 and leukotriene C4 in the gastric mucosa, are suggested to substantiate these observations.

Topics: Animals; Anti-Ulcer Agents; Chromones; Female; Fibrinolytic Agents; Male; Methacrylates; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains; SRS-A; Stomach Ulcer; Sulfonamides; Thromboxane A2

The involvement of a thromboxane (TX) A2-like substance in the decrease of mucosal blood flow (MBF) and occurrence of gastric erosions in rats under water-immersion stress was examined. MBF was estimated by aminopyrine clearance. Stress increased acid output without a parallel increase in MBF and caused erosions. OKY-046, an inhibitor of TXA2 synthesis, and ONO-11120, an antagonist of TXA2 receptors, increased MBF during stress in parallel with an increase in acid output, and erosions did not form. In another experiment, the effects of a TXA2-like substance on MBF during vagal stimulation were examined. Although vagal stimulation alone increased acid output, there were no erosions in the stomach, probably because MBF was increased in parallel with acid output. Intra-arterial administration of a TXA2-like substance formed by the metabolism of arachidonic acid in the blood reduced MBF during vagal stimulation. Intra-arterial administration of ONO-11113, an agonist of TXA2 receptors, also reduced MBF during vagal stimulation. Neither agent affected the elevated level of acid output during vagal stimulation, and erosions formed in the glandular part of the stomach. These results suggested that the gastric mucosal erosions induced by water-immersion stress in rats were due to mucosal ischemia produced by the presumed formation of a TXA2-like substance and to the increased secretion of acid.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Gastric Juice; Gastric Mucosa; Ischemia; Male; Methacrylates; Rats; Receptors, Prostaglandin; Receptors, Thromboxane; Regional Blood Flow; Stomach Ulcer; Stress, Psychological; Thromboxane A2; Vagus Nerve