Effect of prostaglandin synthesis inhibitors on neurotensin and sodium salicylate-induced gastric cytoprotection in rats

Sodium salicylate (SA) has been reported to inhibit the formation of gastric ulcerations induced by aspirin, indomethacin, and absolute ethanol. In this study, SA dose-dependently inhibited gastric ulcers induced by three hours of cold-restraint stress (CRS); SA-induced cytoprotection was prevented by both acetylsalicylic acid (aspirin) and indomethacin pretreatment. Neurotensin (NT), which has previously been demonstrated to prevent the development of CRS-induced gastric ulcerations after intracisternal administration, was found to be ineffective in animals pre-treated with aspirin, and with indomethacin, as previously described. These data suggest that in the CRS model both NT- and SA-induced gastric cytoprotection require a functionally intact gastrointestinal prostaglandin synthetic pathway.     

The interrelationships between the development of ethanol-, HCl, NaOH and NaCl-induced gastric mucosal damage and the gastric mucosal superoxide dismutase activity in the rats

Gastric mucosal damage was produced by intragastric administration of 96% ethanol, 0.6 M HCl, 0.2 M NaOH or 25% NaCl. The animals were killed 1 hr later, when the number and severity of gastric lesions (ulcers) was recorded. At the time of the sacrifice of the animals gastric mucosal superoxide dismutase (SOD) activity was measured. It was found that (1) the gastric mucosal damage could be induced by the administration of any of the necrotizing agents in all animals, (2) superoxide dismutase (SOD) activity increased significantly in the damaged gastric mucosa following 96% ethanol, while its activity decreased significantly during the development of gastric mucosal damage produced by the intragastric administration of 0.6 M HCl, 0.2 M NaOH or 25% NaCl. It has been concluded that: (1) the enzyme systems necessary to generate the superoxide free radical anions can be stimulated by ethanol, and they can be inhibited by the application of 0.6 M HCl, 0.2 M NaOH and 25% NaCl: (2) the observed stimulation or inhibition of the enzyme systems to generate the superoxide free radical anions may be of pathological significance in the development of gastric mucosal damage produced by the intragastric administration of 96% ethanol, 0.6 M HCl, 0.2 M. NaOH or 25% NaCl.     

Failure of prostacyclin, beta-carotene, atropine and cimetidine to produce gastric cyto- and general mucosal protection in surgically vagotomized rats

Different chemicals (such as ethanol, HCl, drugs) produce gastric mucosal injury. A special type of gastric mucosal defense, which differed from the inhibition of gastric acid secretion, was discovered in response to small doses of prostaglandins. This phenomenon was termed "gastric cytoprotection". Later, the existence of gastric cytoprotection was proved using different compounds, such as vitamin A and other carotenoids, prostacyclin, small doses of anticholinergic and H2-blocking agents. These compounds produce cyto-protection by different mechanisms. In this study we tested the role of vagus nerve on the development of these different types of gastric cytoprotection. These compounds prevent ethanol-induced gastric mucosal injury in rats with intact vagus nerve, but their cyto- and mucosal protective effects disappear in surgically vagotomized rats. These results indicate that the intact vagus nerve is basically necessary for the overproduction of HCl and pepsin secretion, and for the development of gastric cytoprotection, produced by different compounds (e.g. prostacyclin, beta-carotene, small doses of atropine and cimetidine) acting without the presence of inhibition of gastric acid secretion.     

Adaptive cytoprotection by 0.25 M HCl is truly "cytoprotective" and may not depend upon elevated levels of prostaglandin synthesis

The ability of a mild irritant to reduce ethanol-induced damage to the rat gastric mucosa was investigated using an ex vivo gastric chamber preparation. Exposure to 0.25 M hydrochloric acid (HCl) did not cause significant damage to the surface epithelium, but did reduce both the lesion area and the extent of superficial epithelial damage caused by subsequent exposure to 40% ethanol (EtOH). "Adaptive cytoprotection" was also demonstrated by the reduction of ethanol-induced changes in transmural potential difference and net K+ efflux, and by rapid recovery of these physiological parameters following the removal of ethanol from the chamber. Pretreatment of rats with indomethacin at a dose that has been shown to significantly inhibit gastric cyclooxygenase activity did not significantly affect the ability of 0.25 M HCl to reduce the effects of ethanol on lesion area, epithelial damage, potential difference, and net K+ efflux.     

胃粘膜血流量对大鼠胃粘膜适应性细胞保护作用的影响

采用氢气清除法测定胃粘膜血流量,观察大鼠胃内灌洗低浓度盐酸酒精后灌注高浓度盐酸酒精（０．６ｍｏｌ／ＬＨＣｌ＋１５％ＥｔＯＨ）对ＧＭＢＦ和胃粘膜损害的影响。以及ＧＭＢＦ在适应性细胞保护中的作用。结果如下：（１）先用低浓度盐酸酒精作为弱刺激灌注随之以高浓度盐酸酒精作为强刺激灌注,引起胃粘膜适应性保护现象,它表现为：大体操作和损伤深度分别比单独泊组减少４７．０９％和４４．５７％应性现象,它表现为：大体损     

Endogenous mediators in adaptive cytoprotection against ethanol-induced gastric gland damage in rabbits

The present study determined the participation of different endogenous mediators in adaptive cytoprotection against gastric gland damage caused by ethanol in rabbits. Using the isolated gland preparation, pretreatment with 10⁻⁵M of either indomethacin, N^w-nitro-L-arginine methyl ester (L-NAME) or N-ethylmaleimide (NEM), but not of substance P antagonist, intensified the 10% (v/v) ethanol-induced gastric gland damage and lessened the degree of cytoprotection evoked by 2% (v/v) ethanol to a significant level. Co-administration with 10⁻⁴M of prostaglandin E₂, L-arginine or glutathione to the respective groups completely reversed the above adverse effects. These results demonstrate the involvement of endogenous prostaglandins, nitric oxide and glutathione in gastric adaptive cytoprotection against the damaging action of ethanol in the rabbit gastric glands.     

Interrelationships between the membrane-bound ATP-dependent energy systems of the gastric mucosa and the gastric cytoprotective effect of beta-carotene on the development of gastric mucosal damage produced by 0.6 M HCl in rats

The effects of different doses (0.01-0.1-1.0-10.0/mg/kg-1) of beta-carotene were studied on gastric secretory responses of 4 hr pylorus-ligated rats: development of gastric mucosal damage (as assessed by number and severity of lesions) produced by intragastric administration of 0.6 M HCl; tissue level of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), adenylate pool (ATP + ADP + AMP), ratio of ATP X ADP-1, "energy charge" (ATP + 0.5 ADP X X (ATP + ADP + AMP)-1) (during the development of gastric mucosal damage by 0.6 M HCl and of gastric cytoprotection by beta-carotene. It was found that beta-carotene did not decrease the gastric secretory responses of 4 hr pylorus-ligated rats; The development of gastric mucosal damage could be decreased dose-dependently by the administration of beta-carotene; the ATP transformation could be decreased by beta-carotene; the tissue levels of cAMP and AMP could be increased significantly and dose-dependently by beta-carotene; the ratio of ATP X ADP-1 could be increased significantly and dose-dependently by beta-carotene; the values of adenylate pool and "energy charge" remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

Contributions of physical and chemical properties of mild irritants to gastric cytoprotection in rats

The present study demonstrated the cytoprotective abilities of low concentrations of ethanol, NaCl and HCl, against the gastric mucosal damage caused by 100% ethanol, and the contributions of the physical and chemical properties of these mild irritants to their protective actions. The results have shown the differential protective effects of ethanol (10–40%), NaCl (2.5–12.5%) and HCl (0.15–0.45M), with the optimal cytoprotective concentrations being 20% ethanol, 5% NaCl and 0.3M HCl, respectively. Solutions of KCl and NaCl with similar osmolarity, and H₂SO₄ and HCl of similar acidity and osmolarity, all showed similar protective potentials as compared to the osmotic agent mannitol, which possessed a concentration- and tonicity-dependent protective action against 100% ethanol-induced mucosal damage. Same concentration of methanol, propan-2-ol and ethanol, having similar osmolarity with deionized water, exerted indifferent protective effects. It is therefore concluded that adaptive cytoprotection induced by low concentrations of NaCl and HCl could depend on their physical properties, while that of ethanol could act through its unique chemical property.     

The key-role of vagal nerve and adrenals in the cytoprotection and general gastric mucosal integrity.

BACKGROUND: Our laboratory group observed earlier that the gastric mucosal cytoprotective effect of prostacyclin (PGI(2)) disappeared after surgical vagotomy in rats. Similarly to this, the beta-carotene induced gastric cytoprotection disappeared in adrenalectomized rats too. AIMS: In these studies we aimed to investigate the possible role of vagal nerve and adrenals in the development of gastric mucosal lesions induced by exogenously administered chemicals (ethanol, HCl, NaOH, NaCl and indomethacin), and on the effects of cytoprotective and antisecretory drugs (atropine, cimetidine), and scavengers (vitamin A and beta-carotene). METHODS: The observations were carried out in fasted CFY strain rats. The gastric mucosal lesions were produced by intragastric (i.g.) administration of narcotising agents (96% ethanol; 0.6 M HCl; 0.2 M NaOH; 25% NaCl) or subcutaneously (s.c.) administered indomethacin (20 mg/kg) in intact, surgically bilaterally vagatomized, and adrenalectomized rats without or with glucocorticoid supplementation (Oradexon, 0.6 mg/kg given i.m. for 1 week). The gastric mucosal protective effect of antisecretory doses of atropine (0.1-0.5-1.0 mg/kg i.g.) and cimetidine (10-25-50 mg/kg i.g.), and vitamin A and beta-carotene (0.01-0.1-1.0-10 mg/kg i.g.) was studied. The number and severity of mucosal gastric lesions was numerically or semiquantitatively measured. In other series of observations the gastric acid secretion and mucosal damage were studied in 24 h pylorus-ligated rats without and with acute bilateral surgical vagotomy. RESULTS: It was found that: (1) the chemical-induced gastric mucosal damage was enhanced in vagotomized and adrenalectomized rats, meanwhile the endogenous secretion of gastric acid, and the development of mucosal damage can be prevented by surgical vagotomy; (2) the gastric cyto- and general protection produced by the drugs and scavengers disappeared in vagotomized and adrenalectomized rats; (3) the gastric mucosal protective effects of drugs and of scavengers returned after sufficient glucocorticoid supplementation of the rats. CONCLUSION: It has been concluded that the intact vagal nerve and adrenals have a key role in the gastric mucosal integrity, and in drugs- and scavengers-induced gastric cyto- and general mucosal protection.     

Interrelationships between the gastric cytoprotective effects of vitamin A and beta-carotene and the gastric mucosal superoxide dismutase activity in rats

Gastric mucosal damage was produced in rats by the intragastric administration of 96% ethanol or 0.6 M HCl, according to the method of Robert et al. Vitamin A or beta-carotene, in doses of 10 mg/kg, given intragastrically 30 min before the administration of the necrotizing agents. The animals were killed 1 hr after the administration of the necrotizing agents. The following experimental parameters were studied, without and with application of vitamin A and beta-carotene; number of gastric lesions (ulcers); severity of gastric mucosal lesions (ulcers); gastric mucosal superoxide dismutase (SOD) activity. It was found that; vitamin A and beta-carotene, in doses of 10 mg/kg, are able to prevent significantly both the number and severity of gastric mucosal lesions (ulcers) produced by the application of 96% ethanol or 0.6 M HCl; the significant increase of ethanol-induced gastric mucosal SOD activity can be inhibited by the application of vitamin A and beta-carotene; vitamin A and beta-carotene are capable of preventing the development of gastric mucosal lesions (ulcers) produced by the intragastric administration of 0.6 M HCl, while these agents fail to compensate for the HCl-induced decrease of gastric mucosal SOD activity. It has been suggested that; vitamin A and beta-carotene are gastric cytoprotective agents; the ulcer preventive effects of vitamin A and beta-carotene are partly dependent on their scavanger behaviour.     

Effect of atropine, PGF2 alpha and cimetidine on the beta-carotene induced cytoprotection in ethanol-treated rats

The aim of the study was to evaluate the influence of atropine, PGF2 alpha and cimetidine on the gastric cytoprotective effect of beta-carotene. Mucosal damage was produced by intragastric (i.g.) addition of 96% ethanol in CFY-strain rats of both sexes weighing 180-220 g. Gastric cytoprotection caused by i. g. pretreatment with 1.0 mg/kg beta-carotene 30 minutes before ethanol administration, was observed after 1 hour. Atropine (0.5 mg/kg), cimetidine (50 mg/kg) and PGF2 alpha (200 micrograms/kg) were given intraperitoneally (i.p.) 30 minutes before ethanol administration with and without beta-carotene and the changes in the number and severity of the gastric ulcers were detected. PGF2 alpha did not influence the gastric cytoprotective effect of beta-carotene meanwhile it was inhibited by atropine and markedly by cimetidine. Deleterious effect of cimetidine on the beta-carotene-induced cytoprotection may be explained perhaps by the adverse effect of the two compounds on ATP-cAMP transformation hereby counteracting one another, but more data are needed to the better understanding of drug interactions relating to mucosal cytoprotection.     

Endothelin induces vascular and mucosal lesions, enhances the injury by HCl/ethanol, and the antibody exerts gastroprotection.

Vascular factors play an important role in the pathogenesis and prevention of acute gastric mucosal lesions. Endothelin-3 (ET-3), a potent vasoactive peptide, was infused intra-arterially to induce gastric microvascular and hemorrhagic mucosal lesions, and to enhance the damaging effects of dilute HCl and ethanol. ET-3 antibody was injected intravenously to decrease hemorrhagic mucosal lesions induced by ethanol. Locally infused ET (0.01, 0.1, and 1.0 nmol.100 g-1.min-1 for up to 15 min) was followed in some cases by intragastric dilute ethanol or HCl, which alone caused no or only mild vascular and mucosal lesions. Monastral blue was used to visualize and quantify vascular injury. ET-3 produced dose-dependent vascular lesions that affected the walls of mucosal capillaries and venules and induced mucosal congestion and focal endothelial labeling in vessels of the gastric muscular layers. The highest dose of ET induced hemorrhagic gastric mucosal lesions, mortality, and periods of hyper- and hypotension in the rat. Medium and low doses of ET-3 caused vascular injury, and dose-dependently potentiated the vascular and hemorrhagic mucosal lesions caused by dilute HCl and ethanol. Indomethacin slightly enhanced damage induced by ET and 50% ethanol, suggesting a limited mediatory role of prostaglandins in the ET-induced mucosal lesions. Anti-ET-3 serum dose-dependently decreased but did not abolish the hemorrhagic gastric mucosal lesions induced by 75% ethanol. Thus, ET-3 causes endothelial damage in capillaries and venules of rat stomach and predisposes to mucosal damage even after exposure to dilute ethanol or HCl. ET is more potent than leukotrienes and histamine and thus may play an important role in the mechanisms of acute gastric mucosal injury and protection where the vascular network appears to be a major target.     

Molecular mechanism of adaptive cytoprotection induced by ethanol in human gastric cells

Adaptive cytoprotection is the process by which the pretreatment of cells with low concentrations of a noxious agent prevents the damage caused by a subsequent exposure of those cells to higher concentrations of that same agent. In this study, a human gastric carcinoma cell line was used to examine the molecular mechanism of adaptive cytoprotection induced by ethanol. Pretreatment of cells with 1%-4% ethanol made cells resistant to a subsequent exposure to 8% ethanol. This adaptive cytoprotection was accompanied by an increase in prostaglandin E2 synthesis and was partially inhibited by inhibitors of cyclooxygenase-2, but not by an inhibitor of cyclooxygenase-1. Furthermore, the adaptive cytoprotection was not dependent on newly synthesized proteins and was inhibited by a protein tyrosine kinase inhibitor. Based on these results, it is proposed that the stimulation of cyclooxygenase-2-dependent prostaglandin E2 synthesis, which is regulated post-translationally by protein tyrosine phosphorylation, plays an important role in adaptive cytoprotection induced by ethanol in gastric cells.     

A pharmacological approach to cellular mechanisms of PGI2-induced gastric cytoprotection on ethanol-induced gastric mucosal damage in rats

The aims of this study were as follows: 1. to analyse the effects of drugs with different subcellular mechanisms on the PGI2-induced gastric cytoprotection in a non acid dependent (ethanol-induced) gastric ulcer model; 2. to identify the affinity and intrinsic activity curves on the PGI2-induced gastric cytoprotection; 3. to evaluate the main cellular mechanisms of PGI2-induced gastric mucosal defence. The observations were carried out on both sexes of CFY-strain rats, weighing 180 to 210 g. The gastric mucosal damage was produced by intragastric administration of 96% ethanol. The animals were killed at 1 hr after administration of ethanol, and the number and severity of gastric mucosal lesions (ulcers) was noted. Atropine, actinomycin D, cimetidine, mannomustine, dinitrophenol, epinephrine, pentagastrin, histamine, ouabain, tetracycline were given intraperitoneally (in different doses) at 30 min before administration of ethanol. The effects of these drugs were tested on the PGI2-induced (5 micrograms/kg was given intragastrically) gastric cytoprotection. It has been found that: 1. atropine, actinomycin D, cimetidine, epinephrine, ouabain, tetracycline and mannomustine inhibited the PGI2-induced gastric cytoprotection; 2. histamine, pentagastrin and 2,4-dinitrophenol enhanced the PGI2-induced gastric cytoprotection; 3. the molar concentrations of these drugs modifying the PGI2-induced gastric cytoprotection differed significantly. It has been concluded that: 1. the drugs stimulating or inhibiting the cell functions are capable to modify the extent of PGI2-induced gastric cytoprotection; 2. different subcellular mechanisms (oxidative phosphorylation, increased synthesis of proteins, ribonucleic and deoxyribonucleic acids, modifications of membrane-bound ATP-dependent energy systems) are involved in the development of PGI2-induced gastric cytoprotection.     

Interrelationships between the development of the gastric cytoprotective effects of prostacyclin, atropine, cimetidine and the gastric mucosal superoxide dismutase activity in rats

Gastric mucosal damage was produced by the intragastric administration of 96% ethanol or 0.6 M HCl. The cytoprotective doses of prostacyclin (PGI2) (5 micrograms/kg), atropine (0.025 mg/kg) or cimetidine (2.5 mg/kg) were given intraperitoneally 30 min before the administration of the necrotizing agents. The animals were killed 1 hr later. The number and severity of gastric mucosal lesions (ulcer) were recorded. At the time of the sacrifice of the animals, superoxide dismutase (SOD) was prepared from the gastric fundic mucosa and its activity was measured. It was found that PGI2 (5 micrograms/kg), atropine (0.025 mg/kg) and cimetidine (2.5 mg/kg) significantly decreased the number and severity of gastric mucosal lesions (ulcers) produced by the intragastric administration of 96% ethanol a 0.6 M HCl, PGI2, atropine, cimetidine, given in cytoprotective doses, significantly mounted the ethanol-induced increase of gastric mucosal SOD activity; PGI2, atropine, cimetidine, given them in cytoprotective doses significantly shunted the HCl-induced decrease of gastric mucosal SOD activity. It has been concluded that; chemically different cytoprotective agents (PGI2, atropine, cimetidine) give rise to similar tendencies in the changes of gastric mucosal SOD activity; both the significant decrease (in the ethanol-model) and the significant increase (in the HCl-model) of this enzyme seem to be involved in the development of gastric mucosal protection by PGI2, atropine and cimetidine.     

Mechanisms of action of retinoids in gastrointestinal mucosal protection in animals, human healthy subjects and patients.

Retinoids prevent chemically induced gastric mucosal damage without inhibiting gastric acid secretion ("nutritional gastric cytoprotection"). The gastroprotective effects of retinoids do not depend on 1) vitamin A activity; 2) number of unsaturated double bonds; 3) the presence of a characteristic chemical structure of their terminal components; however, they depend on 1) intact vagal nerve and 2) adrenals in experimental animals. The gastric cytoprotective effect of retinoids produces a dose-dependent inhibition of ATP-transformation into ADP. It also increases the transformation of ATP into cAMP. Other features of these gastric cytoprotective effects of retinoids include: 1) The retinoid-induced gastric mucosal protection differs from that of PGs; 2) The cAMP is an intracellular signal in the development of gastric mucosal damage produced by chemicals (e.g., ethanol, HCl, indomethacin) and in the protection of gastric mucosa induced by retinoids (but not by PGs); 3) The gastric mucosal protection induced by retinoids and gastric mucosal permeability can be separated in time. The existence of gastric mucosal protection can be demonstrated in healthy persons (against indomethacin treatment), in patients with gastric ulcer (GU) and duodenal ulcer (DU) without any inhibition of gastric acid secretion. The serum levels of vitamin A and zeaxanthin were significantly decreased in patients with chronic gastrointestinal (GI) inflammatory diseases (e.g., terminal ileitis, ulcerative colitis), colorectal polyposis, and different (e.g., esophageal, gastric, pancreatic, hepatocellular and colorectal) malignant diseases. The serum levels of vitamin A provitamins were unchanged and their GI mucosal protective effects do not depend on vitamin A activity. Conclusions: 1) Abundant experimental and human observations clearly proved the defensive role of retinoids in the GI tract; 2) There is a correlation between the a) scavenger properties of retinoids vs. intact vagal nerve; b) scavenging properties vs. intact adrenals. 3) The GI mucosal protective effect of retinoids is correlated with biochemical changes in the GI mucosa.     

Interleukin-1 is cytoprotective, antisecretory, stimulates PGE2 synthesis by the stomach, and retards gastric emptying

Human recombinant interleukin 1 beta (IL-1) administered intraperitoneally to rats produced the following gastric effects: 1. It was cytoprotective, preventing gastric mucosal necrosis produced by oral administration of one ml of absolute ethanol to fasted animals. The ED50 was 1200 units/kg (110 ng per animal). IL-1 was 125 times more potent than prostaglandin E2 (on a weight basis), and 6,000 times more potent (on a molar basis). 2. The cytoprotective effect of IL-1 was blocked by indomethacin (inhibitor of prostaglandin synthesis) and by IRAP (a specific interleukin-1 receptor antagonist protein). IRAP did not inhibit cytoprotection induced by PGE2. 3. IL-1 prevented the formation of gastric erosions induced by aspirin. 4. IL-1 inhibited gastric secretion (volume, acid concentration and output), in the pylorus-ligated rat, with an ED50 of 300 units/kg (3.2 ng per animal). 5. Indomethacin and IRAP blocked the antisecretory effect of IL-1. 6. IL-1 retarded gastric emptying, an effect blocked by IRAP, but not by indomethacin. 7. IL-1 increased synthesis of prostaglandin E2 by the gastric mucosa by 111%. IL-1 is the most potent of known agents that are gastric cytoprotective, antiulcer, antisecretory, and delay gastric emptying. It appears to act mostly by stimulating the synthesis of prostaglandins by the stomach. These studies suggest that the stomach possesses IL-1 receptors. These are probably located on parietal cells (that produce acid), on prostaglandin-producing cells, on smooth muscle cells (responsible for gastric emptying), and on as yet unidentified cells involved in gastric cytoprotection. Both IL-1 and IRAP, being natural substances, may play a physiological role in the maintenance of gastric mucosal integrity, and in the regulation of acid secretion and gastric motility.     

Lack of gastric toxicity of nitric oxide-releasing aspirin, NCX-4016, in the stomach of diabetic rats

We compared the gastric toxic effect of aspirin (ASA) in both normal and diabetic rats, with that of NCX-4016, a derivative of ASA with nitric oxide (NO) releasing moiety. Animals were injected with streptozotocin and used after 5 weeks of diabetes with blood glucose levels of >350 mg/dl in the presence of omeprazole. Oral administration of ASA (with 150 mM HCl) did not produce damage at 30 mg/kg in the conscious rat but caused hemorrhagic gastric lesions in STZ-diabetic rats. By contrast, NCX-4016 even at 190 mg/kg (a dose equimolar to 100 mg/kg of ASA) did not cause damage in both normal and STZ-diabetic rat stomachs. Plasma salicylic acid levels were not different between normal and diabetic rats after administration of ASA or NCX-4016, though the latter gave significantly lower levels as compared to ASA. Intragastric application of ASA (80 mM in 50 mM HCl) for 30 min caused a reduction of transmucosal PD and increase of luminal H+ loss with a minimal effect on mucosal blood flow (GMBF) in both normal and diabetic rats, yet resulting in much severe damage in the stomach of the latter group. Mucosal application of NCX-4016, however, did not cause PD reduction and luminal H+ loss, but produced a marked hyperemia, resulting in no damage in the stomach of both normal and STZ-diabetic rats. The increased gastric toxicity of ASA in STZ-diabetic rats was significantly mitigated by co-application of a NO donor FK-409 together with ASA, with an increase of GMBF, despite similar degrees of PD reduction and luminal H+ loss being observed. We conclude that NCX-4016 does not have a toxic effect in either normal or diabetic rat stomachs, although the diabetic rat stomach is more vulnerable to ASA-induced damage. NCX-4016, though absorbed more slowly than ASA, counteracts the injurious effect of aspirin on the gastric mucosa, probably by increasing GMBF mediated by NO.     

Effect of sialoadenectomy on stomach lesions induced by indomethacin and ethanol in relation to gastric vascular permeability, the gastrin level and HCl secretion in rats.

Stomach lesions induced by indomethacin (20 mg.kg-1 i.p.) and ethanol (1 ml 95% intragastrically) were studied after a 24 hour fast in rats which had undergone sialoadenectomy. The size of the lesions was correlated with gastric HCl secretion, with gastric vascular permeability (determined from the Evans blue concentration in the stomach tissue after its i.v. administration) and with the serum gastrin level. These parameters were also studied in sialoadenectomized rats and in animals given epidermal growth factor (EGF) (50 lg.kg-1). It was found that sialoadenectomy significantly (p < 0.01) raised the incidence of stomach lesions after the administration of indomethacin and also after ethanol (p < 0.05). A significant increase in both basal and stimulated HCl secretion was found after sialoadenectomy. Both indomethacin and ethanol also increased gastric vascular permeability in rats not subjected to sialoadenectomy, but sialoadenectomy raised it significantly compared with the non-sialoadenectomized group. The serum gastrin levels fell after sialoadenectomy and the decrease was significant after the subsequent administration of indomethacin or ethanol. The administration of EGF to sialoadenectomized rats lowered the incidence of stomach lesions, inhibited HCl secretion and reduced vascular permeability. The lowered susceptibility of the gastric mucosa to the formation of lesions in sialoadenectomized rats given indomethacin or ethanol can be regarded as the outcome of the uptake of EGF.     

Prophylactic and healing properties of a new anti-ulcer compound from Enantia chlorantha in rats.

Decoctions prepared from Enantia chlorantha are used in the traditional treatment of some forms of ulcers. We have tested the anti-ulcer actions of a novel protoberberine-type alkaloid (7,8,-dihydro-8-hydroxypalmatine (1)) obtained from the bark of E. chlorantha using the HCl/ethanol, absolute ethanol and pylorus ligation techniques. The healing effect on chronic acetic acid-induced gastric ulcer was also tested. 1 (50 and 100 mg/kg) dose-dependently inhibited the formation of gastric ulcers induced by HCl/ethanol (35-52% inhibition), absolute ethanol (46-53% inhibition) and pylorus ligation (38-62% inhibition). The prophylactic actions were associated with significant increases in gastric mucus production compared with the controls. The significant inhibition of pylorus-ligated ulcers occurred at gastric acid concentrations (83 mEq/l) previously known to induce severe gastric ulceration in rats. The ulcer-healing test showed significant macromorphological and histological acceleration of healing following 10-day treatment with 1 (40 - 80 mg/kg). The results show that 1 has no anti-secretory effects. The prophylactic anti-ulcer effects are associated with enhanced mucus production, which is an important factor in the mechanism of the local healing process of chronic gastric ulcers.