thromboxane-a2 and Stomach-Ulcer

Aspirin causes peptic ulcers predominately by reducing gastric mucosal cyclooxygenase (COX) activity and prostaglandin synthesis. Because aspirin circulates for only a few hours, we hypothesized that aspirin's inhibitory effect on gastric COX activity must be prolonged. We performed a placebo-controlled experiment in healthy humans to determine the duration of inhibition of aspirin on gastric mucosal COX activity (PGE(2) and PGF(2alpha) synthesis rates). Recovery of gastric COX activity after stopping aspirin was slow and linear. Seventy-two hours after 325-mg aspirin, gastric COX activity was still reduced by 57% (P < 0.001). Duration of inhibition of gastric COX activity was estimated to be 7-8 days after 325-mg aspirin and 5 days after 81-mg aspirin. Recovery of gastric prostaglandin synthesis after 325-mg but not after 81-mg aspirin occurred at slower rates in subjects with Helicobacter pylori-associated gastritis than in those with normal histology. In conclusion, aspirin inhibits gastric COX activity for much longer than predicted from its pharmacokinetic profile, explaining why aspirin at widely spaced intervals is ulcerogenic.

Topics: Adolescent; Adult; Aspirin; Blood Platelets; Cyclooxygenase Inhibitors; Dinoprost; Dinoprostone; Female; Gastric Mucosa; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Prostaglandin-Endoperoxide Synthases; Regression Analysis; Stomach Ulcer; Thromboxane A2; Time Factors

Arachidonic acid (AA), when cleaved from phospholipids by cytosolic phospholipase A2 alpha (cPLA2a), generates eicosanoids, with pro-hemostatic, pro-inflammatory, vasoactive and gastro-protective functions. We describe a patient (27-year-old man) and his twin-sister with early-onset bleeding diathesis and recurrent gastro-intestinal (GI) ulcers. Platelet aggregation/δ-granules secretion by collagen was impaired, but normal by AA; serum levels of thromboxane (Tx) B2 and 12-hydroxyeicosatetraenoic acid, and urinary levels of 11-dehydro-TxB2 were extremely low. Patients were homozygous for 1723G>C transition in PLA2G4A gene, which changed the codon for Asp575 to His. GI ulcers affected 5/14 heterozygous (< 40 years) and 1/16 wild-type homozygous (> 60 years) family members; none had bleeding diathesis. The proband, his sister and mother also had mildly reduced factor XI levels. Platelet messenger RNA expression did not differ among subjects with different PLA2G4A genotypes. Conversely, platelet cPLA2a was undetectable by Western Blotting in the proband and his sister, and decreased in 1723G>C heterozygous subjects, suggesting that the variant is transcribed, but not translated or translated into an unstable protein. We described a syndromic form of deficiency of cPLA2a , characterised by recurrent GI ulcers and bleeding diathesis, associated with mild inherited deficiency of factor XI. Unlike other reported patients with cPLA2a deficiency, these patients had extremely low levels of platelet TxA2 biosynthesis.

Topics: Adult; Blood Coagulation Disorders, Inherited; Blood Platelets; DNA Mutational Analysis; Duodenal Ulcer; Factor XI; Female; Genetic Predisposition to Disease; Group IV Phospholipases A2; Hemostasis; Heredity; Heterozygote; Homozygote; Humans; Male; Middle Aged; Pedigree; Phenotype; Platelet Aggregation; Platelet Function Tests; Recurrence; Stomach Ulcer; Thromboxane A2; Twins

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

The use of aspirin as an anti-platelet drug is limited by its propensity to induce gastric injury and by its adverse effect on vascular prostacyclin formation. Two phenolic non-steroidal anti-inflammatory drugs (salicylic acid and diflunisal) were modified by esterification with a series of O-acyl moieties. The short-term ulcerogenic in vitro and in vivo anti-platelet properties, pharmacodynamic profiles, and extent of hepatic extraction of these phenolic esters were compared with aspirin (acetylsalicylic acid). The more lipophilic esters (longer carbon chain length in O-acyl group) show significantly less gastrotoxicity in stressed rats than does aspirin after a single oral dose. The in vitro and in vivo anti-platelet studies show that these phenolic esters inhibited (1) arachidonate-triggered human platelet aggregation and (2) thrombin-stimulated rat serum thromboxane A2 production by platelets in the clotting process almost as effectively as aspirin. The hepatic extractions of these O-acyl derivatives are significantly higher than those of aspirin. The pharmacodynamic studies show that these O-acyl derivatives of salicylic acid and diflunisal probably bind to, or combine with, the same site on the platelet cyclooxygenase as aspirin. Replacing the O-acetyl group with longer chain O-acyl moiety in this series of phenolic esters markedly reduced the potential of these agents to induce short-term gastric injury but did not lessen their activity as inhibitors of platelet aggregation. These non-acetyl salicylates may therefore represent a novel class of anti-platelet drugs with less ulcerogenic potential.

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Aspirin; Blood Platelets; Diflunisal; Dose-Response Relationship, Drug; Female; Fibrinolytic Agents; Gastric Mucosa; In Vitro Techniques; Inactivation, Metabolic; Liver; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats; Rats, Wistar; Steroids; Stomach Ulcer; Thromboxane A2

The study examines the anti-ulcer activity of Cu(I)-(nicotinic acid)2Cl [CuCl(HNA)2]. A dose of 8 mg (23 mumol) of complex/kg body mass was suspended in 0.25% Tween-80 in saline solution and administered intragastrically to male Wistar albino rats which had developed gastric ulcers as a result of pyloric ligation (Shay-rat model). Another group of animals received 5 mg (25 mumol)/kg body mass of the copper-glycinate complex Cu(II)(glycinate)2 [Cu(II)(Gly)2]. Both protected as shown by reduction in the ulcer index, inhibition of gastric perforation and death. Significant increases in gastric juice volume and superoxide dismutase (SOD) activity in the gastric mucosa and blood plasma were found with both copper complexes, while the gastric juice prostaglandin E2 (PGE2) content was significantly decreased in the Cu(II)(Gly)2-treated group, it was significantly increased in the gastric mucosa of the CuCl(HNA)2-treated group. The copper complex-treated animals, especially those which received Cu(II)(Gly)2 had a marked fall in thromboxane A2 (TXA2) levels. These results suggest that intragastric administration of either CuCl(HNA)2 or Cu(II)(Gly)2 produced anti-ulcerogenic activity, with different modes of action.

Topics: Animals; Anti-Ulcer Agents; Copper; Dinoprostone; Gastric Acidity Determination; Gastric Fundus; Gastric Mucosa; Glycine; Male; Nicotinic Acids; Organometallic Compounds; Rats; Rats, Wistar; Stomach Ulcer; Superoxide Dismutase; Thromboxane A2

The pathogenesis of non-steroidal anti-inflammatory drugs (NSAIDs)-induced ulceration is still not completely understood, but it is possible that these effects are associated with a cytoprotective prostaglandin deficiency. Visible marks of gastric mucosa erosions induced by 25 mg/kg indomethacin in rats were determined parallel with the changes of PGE2, PGI2, TxA2 and leukotrienes content in gastric mucosa at various intervals. Beside the decreased level of the so-called cytoprotective prostaglandins caused by the inhibition of cyclooxygenase enzyme an overproduction of 5-lipoxygenase products (leukotrienes) was also found. To investigate the hypothesis that the gastric damage caused by NSAIDs is due not only to the decreased level of cyclooxygenase products but to the increased level of lipoxygenase products as well, different lipoxygenase inhibitors and leukotriene antagonists were tested. A lipoxygenase inhibitor and the structurally similar phenidone inhibited the ulcerogenic effect of indomethacin at the same high dose range. The selective lipoxygenase inhibitor nordihydroquaiaretic acid and dual inhibitors can reduce the severity of ulcer formation in lower concentrations as well. The first specific antagonist of SRS-A and a potent and selective antagonist of LTD4 produced a significant gastroprotective effect at i.p. treatment only at high doses. All of these results suggest that an overproduction of leukotrienes and other lipoxygenase products, following cyclooxygenase blockade induced by NSAIDs, may play a role in the development of gastric mucosal damage.

Topics: Animals; Dinoprostone; Eicosanoids; Epoprostenol; Gastric Mucosa; Indomethacin; Leukotriene Antagonists; Leukotrienes; Lipoxygenase Inhibitors; Male; Rats; Rats, Wistar; Stomach Ulcer; Thromboxane A2

5-Alkyl-2-aryl-4-pyridylimidazoles were synthesized and tested in rat ex vivo platelet aggregation studies. Among these compounds, 2-(2-fluorophenyl)-5-methyl-4-(3-pyridyl)imidazole (25) was most potent, and showed 98% inhibition at a dose of 10 mg/kg (p.o.). 25 had inhibitory activity on cyclooxygenase, thromboxane A2 (TXA2) synthetase, and phosphodiesterase, and also showed inhibited KCl-induced contraction of rat aorta. All compounds have little acute toxicity and appear to be free of adverse effects on the stomach.

Topics: Animals; Cyclooxygenase Inhibitors; Humans; Imidazoles; Male; Muscle, Smooth; Phosphodiesterase Inhibitors; Platelet Aggregation Inhibitors; Rabbits; Rats; Rats, Sprague-Dawley; Stomach Ulcer; Structure-Activity Relationship; Thromboxane A2

The recent discovery of potent, specific, long-acting thromboxane receptor antagonists, like SQ 33,961, mandated that studies be conducted to follow up an earlier study, which showed potential antiulcer activity of the short-acting thromboxane antagonist, SQ 28,668, in the taurocholic acid gastric erosion model in rats. In experiments conducted with the same taurocholic acid protocol, SQ 33,961 caused a dose-related reduction in taurocholate-induced gastric erosions, with an ID50 value of 12 micrograms/kg, i.p. In additional studies, aspirin and indomethacin were shown to produce gastric erosions in rats, and SQ 33,961 also inhibited gastric erosion in response to these anti-inflammatory drugs. The ID50 values were 0.24 and 0.26 mg/kg i.p. vs. aspirin (200 mg/kg, p.o.) and indomethacin (200 mg/kg, s.c.), respectively. The inhibition of aspirin-induced gastric injury by SQ 33,961 was confirmed histologically. This gastroprotective activity was not peculiar to SQ 33,961, because the structurally unrelated thromboxane receptor antagonist, BM 13,505, also significantly inhibited the development of aspirin-induced gastric lesions. In a more severe model, SQ 33,961 (10 mg/kg, i.p.) reduced gastric erosions by only 32% (not significant) 1 hr after ethanol ingestion (1 ml, p.o.) in rats. SQ 33,961 did not inhibit the antiphlogistic activity (carrageenan paw edema assay) of indomethacin, nor did it inhibit the analgesic activity (phenylquinone writhing assay) of aspirin. A dose of SQ 33,961 producing > or = 95% inhibition of nonsteroidal anti-inflammatory drug-induced gastric erosion (10 mg/kg, i.p.) produced a 37% reduction in the volume of gastric secretion without changing the titratable acidity of gastric contents.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzoquinones; Gastric Mucosa; Male; Mice; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane; Stomach Ulcer; Taurocholic Acid; Thromboxane A2

Topics: Animals; Arachidonic Acids; Dinoprostone; Epoprostenol; Gastric Mucosa; Indomethacin; Rats; Stomach Ulcer; Thromboxane A2

This study was undertaken to evaluate the efficacy of iloprost and UK 38485 in the prevention of gastric lesions due to restraint-cold stress, ethanol or indomethacin. Prior injection of iloprost to the rats significantly prevented the increase in ulcer index by restraint- cold stress or indomethacin but nonsignificantly reduced the ulcer index induced by ethanol. UK 38 485 at lower doses caused a highly significant decrease in the ulcer index induced by all noxious stimuli used in this study. UK 38 485 also reduced the increased 3H back diffusion due to restraint-cold stress. Higher doses of the compound, however, failed to decrease the mucosal damage due to restraint-cold stress. Combination of iloprost and UK 38 485 produced a further significant decrease in the ulcer index induced by all noxious stimuli and increased 3H back diffusion induced by restraint-cold stress. In relation to these results the importance of PGI2/TXA2 ratio in the production of gastric mucosal lesions is discussed.

Topics: Animals; Epoprostenol; Ethanol; Female; Gastric Mucosa; Iloprost; Imidazoles; Indomethacin; Male; Rats; Stomach Ulcer; Stress, Physiological; Thromboxane A2; Thromboxane-A Synthase

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 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

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

Topics: Animals; Gastric Acid; Gastric Mucosa; Humans; Imidazoles; Immersion; Indomethacin; Ischemia; Male; Rats; Regional Blood Flow; Stomach Ulcer; Stress, Psychological; Thromboxane A2; Thromboxanes

Human gastric mucosa synthesizes significant amounts of thromboxane, which has recently been found to be highly ulcerogenic, in addition to protective prostaglandins. The ratio of the various mucosal arachidonic acid metabolites formed may, therefore, exert a modifying influence on the resistance of the mucosa against noxious agents. This hypothesis is supported by the finding that carbenoxolone, a drug accelerating peptic ulcer healing by a mechanism which does not involve inhibition of acid secretion, stimulates gastric mucosal prostaglandin formation and, in parallel, inhibits mucosal thromboxane synthesis. Ulcerogenic non-steroidal anti-inflammatory drugs, on the other hand, usually reduce gastric prostaglandin formation. The inhibitory activity of the various compounds is dependent on their affinity to the gastric mucosal cyclooxygenase, as well as on pharmacokinetic properties. Since gastrointestinal side-effects frequently occur during anti-inflammatory-analgesic therapy, the elucidation of the underlying mechanisms seems of considerable clinical relevance.

Topics: Anti-Inflammatory Agents; Carbenoxolone; Dinoprostone; Gastric Mucosa; Humans; Prostaglandins; Prostaglandins E; Species Specificity; Stomach Ulcer; Thromboxane A2; Thromboxanes

There is accumulating evidence that the presence of the imidazole ring is essential for the inhibition of the thromboxane synthetase activity of several compounds synthetized so far. Inhibition of arachidonic acid (AA) induced platelet aggregation was observed by us with a series of tripeptides in which the imidazole ring belongs to histidine, included in a proper aminoacid sequence. Among these compounds the N-acetyl-L-phenylalanyl-L-phenylalanyl-L-histidine methylester (ZAMI-420) was the most effective. The bioassay of the supernatant of an AA-added platelet-rich plasma (PRP) preparation, preincubated with increasing concentrations of ZAMI-420, showed a dose-related reduction in thromboxane-A2 (TXA2)-like activity, an increase of PG-like response and disappearance of the TXB2 peak in the radiochromatogram; RIA experiments led to the same results. ZAMI-420 does not influence cyclooxygenase activity as the AA-induced increase in O2-consumption by the microsomal fraction of bovine seminal vesicles was unaltered by this compound. Administered orally to the rat, ZAMI-420 was able to prevent gastric damage provoked by a variety of pharmacological agents, including ASA, 5HT and alcohol. The protective effect on experimentally-induced gastric damage is not mediated through the antisecretory properties of this compound but is more likely to be due to a cytoprotective mechanism based on blockade of TXA2 synthesis.

Topics: Animals; Arachidonic Acids; Biological Assay; Carbenoxolone; Chromatography, Thin Layer; Cimetidine; Ethanol; Female; Guinea Pigs; Imidazoles; Oligopeptides; Platelet Aggregation; Prostaglandin-Endoperoxide Synthases; Rabbits; Radioimmunoassay; Rats; Rats, Inbred Strains; Serotonin; Stomach; Stomach Ulcer; Thromboxane A2; Thromboxanes; Vasoconstriction

Topics: Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Central Nervous System; Death, Sudden; Imidazoles; In Vitro Techniques; Kinetics; Male; Mice; Platelet Aggregation; Rabbits; Rats; Rats, Inbred Strains; Salicylates; Salicylic Acid; Stomach Ulcer; Thromboxane A2; Thromboxanes

To assess how endogenous prostaglandin (PG) in gastric mucosa acts against ulcer formation, we determined the mucosal prostacyclin (PGI2), PGE2, PGF2 alpha, and thromboxane A2(TXA2) concentrations before and after polypectomy in 6 patients in whom gastric ulcers were produced by electric burning resection of gastric polyps. These artificially induced ulcers all healed within short periods (25.7 +/- 7.4 days, mean +/- SE). Of the PGs assayed, the level of PGI2 was highest. The pG levels were increased at 4 and 7 days post-polypectomy; the most remarkable increase took place in the mucosa along the ulcer margin rather than the mucosa far from the ulcer site. We suggest that the observed increase in endogenous PGs represents a physiological response against polypectomy-induced ulcer formation.

Topics: Alprostadil; Dinoprost; Dinoprostone; Electrocoagulation; Epoprostenol; Female; Gastric Mucosa; Gastroscopy; Humans; Intestinal Polyps; Male; Middle Aged; Prostaglandins; Prostaglandins E; Prostaglandins F; Stomach Neoplasms; Stomach Ulcer; Thromboxane A2

Topics: Animals; Dogs; Imidazoles; Platelet Aggregation; Regional Blood Flow; Stomach; Stomach Ulcer; Thromboxane A2; Thromboxane-A Synthase; Thromboxanes; Vasoconstriction