Development Of Gastric Mucosal Damage Research Articles

Toxicokinetic Study of a Gastroprotective Dose of Capsaicin by HPLC-FLD Method.

Background: A low dose of capsaicin and its natural homologs and analogs (capsaicinoids) have shown to prevent development of gastric mucosal damage of alcohol and non-steroid anti-inflammatory drugs. Based on this experimental observation, a drug development program has been initiated to develop per os applicable capsaicin containing drugs to eliminate gastrointestinal damage caused by non-steroid anti-inflammatory drugs. Methods: As a part of this program, a sensitive and selective reverse-phase high-performance liquid chromatography-based method with fluorescence detection has been developed for quantification of capsaicin and dihydrocapsaicin in experimental dog’s plasma. Results: The method was evaluated for a number of validation characteristics (selectivity, repeatability, and intermediate precision, LOD, LOQ, and calibration range). The limit of detection (LOD) was 2 ng/mL and the limit of quantification (LOQ) was 10 ng/mL for both capsaicin and dihydrocapsaicin. The method was used for analysis of capsaicin and dihydrocapsaicin in the plasma samples obtained after per os administration of low doses (0.1, 0.3, and 0.9 mg/kg bw) of Capsaicin Natural (USP 29) to the experimental animals. Conclusions: The obtained results indicated that the administered capsaicinoids did not reach the general circulation.

A Novel Combination of Wheat Peptides and Fucoidan Attenuates Ethanol-Induced Gastric Mucosal Damage through Anti-Oxidant, Anti-Inflammatory, and Pro-Survival Mechanisms.

Gastritis or peptic ulcer is believed to affect about half of people worldwide. Traditional medications can lead to adverse effects, therefore, alternative nutritional strategies are needed to prevent the development of gastric mucosal damage. A novel combination of two food-grade ingredients, wheat peptides and fucoidan (WPF), was prepared to treat male Sprague Dawley rats for 30 days before gastric mucosal damage was induced by oral administration of ethanol. The serum levels of biomarkers were determined by enzyme-linked immunosorbent assay. Biomarkers in stomach tissue were analyzed using immunohistochemistry. In addition, human gastric epithelial cell line (GES-1) was used to investigate protein expression by Western blot. WPF could attenuate ethanol-induced gastric mucosal damage in an inverse dose-dependent manner, with both ulcer index and pathological index improved. WPF increased superoxide dismutase level and decreased malondialdehyde level. WPF also decreased the levels of interleukin-8, platelet-activating factor, and Caspase 3, while increasing the levels of prostaglandin E-2, epidermal growth factor (EGF), and EGF receptor (EGFR). Furthermore, phosphorylation of EGFR and extracellular signal–regulated kinases was induced by WPF in GES-1 cells. In conclusion, the novel combination of wheat peptides and fucoidan attenuated ethanol-induced gastric mucosal damage in rats through anti-oxidant, anti-inflammatory, and pro-survival mechanisms.

Cellular Energetical Actions of "Chemical" and "Surgical" Vagotomy in Gastrointestinal Mucosal Damage and Protection: Similarities, Differences and Significance for Brain-Gut Function.

BackgroundThe authors, as internists, registered significant difference in the long lasting actions of surgical and chemical (atropine treatment) vagotomy in patients with peptic ulcer during second half of the last century (efficency, gastric acid secretion, gastrointestinal side effects, briefly benefical and harmful actions were examined).Aims1. Since the authors participated in the establishing of human clinical pharmacology in this field, they wanted to know more and more facts of the acute and chronic effects of surgical and chemical (atropine treatment) on the gastrointestinal mucosal biochemisms and their actions altered by bioactive compounds and scavengers regarding the development of gastric mucosal damage and protection.MethodsThe observations were carried out in animals under various experimental conditions (in intact, pylorus-ligated rats, in different experimental ulcer models, together with application of various mucosal protecting compounds) without and with surgical vagotomy and chemical vagotomy produced by atropine treatment.Results1. No changes were obtained in the cellular energy systems (ATP, ADP, AMP, cAMP, “adenylate pool”, “energy charge“ [(ATP+ 0.5 ADP)/ (ATP+ADP+AMP)] of stomach (glandular part, forestomach) in pylorus ligated rats after surgical vagotomy in contrast to those produced by only chemical vagotomy; 2. The effects of the gastric mucosal protective compounds [atropine, cimetidine, prostaglandins, scavengers (like vitamin A, β-carotene), capsaicin] disappeared after surgical vagotomy; 3. The extents of different chemical agents induced mucosal damaging effects were enhanced by surgical vagotomy and was not altered by chemical vagotomy; 4. The existence of feedback mechanisms of pharmacological (cellular and intracellular) regulatory mechanisms between the membrane-bound ATP-dependent energy systems exists in the gastric mucosa of intact animals, and after chemical vagotomy, but not after surgical vagotomy.Conclusions1. Increased vagal nerve activity takes place in the gastric mucosal damage; 2 both surgical and chemical vagotomy result mucosal protective affect on the gastric mucosal in different damaging experimental models; 3. The capsaicin-induced gastric mucosal damage depends on the applied doses, presence of anatomically intact vagal nerve (but independent from the chemical vagotomy), 4. The central and pheripheral neural regulations differ during gastric mucosal damage and protection induced by drugs, bioactive compounds, scavengers.

Effect of Cannabis sativa extract on gastric acid secretion, oxidative stress and gastric mucosal integrity in rats

Studies were conducted in pylorus-ligated rats to investigate the effect of Cannabis sativa extract on gastric acid secretion, experimental gastric ulcer and on oxidative stress and inflammatory markers in the gastric mucosa. C. sativa (5, 10 and 20 mg/kg, expressed as Δ9-tetrahydrocannabinol) was administered subcutaneously daily for 4 weeks prior to pylorus ligation and different treatments. Under basal conditions, pretreatment with cannabis extract at doses of 5 and 10 mg/kg increased gastric acid secretion and induced minimally visible gastric mucosal lesions in the 4 h pylorus-ligated rat. Malondialdehyde and nitric acid concentration increased, while reduced glutathione decreased by cannabis at doses of 5 and 10 mg/kg in gastric mucosa. TNF-α increased by cannabis extract at doses of 5 and 10 mg/kg but decreased following the high dose of 20 mg/kg. On the other hand, the gastric acid secretory responses stimulated by pentagastrin or carbachol (but not histamine) were inhibited in rats pretreated with cannabis extract. Under these conditions, cannabis decreased pepsin content after pentagastrin and carbachol but not histamine stimulation. Cannabis also decreased lipid peroxidation and nitric oxide content, and increased both reduced glutathione and catalase activity in mucosa. Moreover, cannabis decreased mucosal inflammation (level of TNF-α) and the development of gastric mucosal lesions. Cannabis administered for 1 month prior to pylorus-ligation and either acidified aspirin or ethanol (96 %) decreased the development of gastric mucosal damage in a dose-dependent manner, along with reduction in gastric acid output, gastric mucosal oxidative stress and inflammation (TNF-α). Sections of gastric mucosa stained with periodic acid Schiff showed increased mucus secretion by cannabis in basal conditions and after treatment with aspirin or ethanol. Results indicate that: (1) the effect of cannabis differs in basal conditions and after exposure of the gastric mucosa to high acid concentrations or other chemical noxious agents; (2) cannabis administered systemically exerts gastric mucosal protective effects against mucosal damage evoked by stimulation of gastric acid secretion, acidified aspirin or ethanol. These effects of cannabis are likely to involve inhibition of gastric acid and pepsin secretion, increased mucus, decreased oxidative stress and inflammation in gastric mucosa.

Intracisternal injection of orexin-A prevents ethanol-induced gastric mucosal damage in rats

Accumulating evidence indicates that orexin-A in the brain stimulates vagal flow projecting to the stomach. Since the vagal system plays an important role in gastric mucosal integrity, we hypothesized that orexin-A in the brain might have a gastroprotective action. We examined the effect of centrally administered orexin-A on the development of gastric mucosal damage evoked by ethanol and its possible mechanism of action in rats. Intracisternal but not intraperitoneal injection of orexin-A significantly inhibited the severity of gastric mucosal damage by 70% ethanol in a dose-dependent manner, suggesting that orexin-A acts in the brain to prevent ethanol-induced gastric mucosal damage. The antiulcer action was observed in rats administered with orexin-A centrally but not orexin-B, indicating that the action is mediated through orexin 1 receptors. The gastroprotective action of centrally administered orexin-A was blocked by pretreatment with atropine, Nomega-nitro-L-arginine methylester, or indomethacin. These results suggest that orexin-A acts on orexin 1 receptors in the brain to exert a gastroprotective action against ethanol. The vagal muscarinic system, nitric oxide, and prostaglandins may mediate the cytoprotective action of centrally administered orexin-A.

The inhibition of gastric mucosal lesion, oxidative stress and neutrophil-infiltration in rats by the lichen constituent diffractaic acid

The antiulcerogenic effect of diffractaic acid (DA) isolated from Usnea longissima, a lichen species, on indomethacin (IND)-induced gastric lesions was investigated in rats. Administration of 25, 50, 100 and 200 mg/kg doses of DA and ranitidine (RAN) (50 mg/kg dose) reduced the gastric lesions by 43.5%, 52.9%, 91.4%, 96.7% and 72.7%, respectively. It is known that oxidative stress leads to tissue injury in organisms. Thus, in all treated groups of rats, the in vivo activities of the antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and the levels of reduced glutathione (GSH) and lipid peroxidation (LPO) were evaluated. IND caused oxidative stress, which resulted in LPO in tissues, by decreasing the levels of GPx, SOD and GSH as compared to healthy rats. In contrast to IND, the administration of DA and RAN showed a significant decrease in LPO level and an increase in tissue SOD, GPx and GSH levels. However, while CAT activity was significantly increased by the administration of IND, the administration of DA and RAN decreased CAT activity. The administration of IND also increased the myeloperoxidase (MPx) activity, which shows neutrophil infiltration into the gastric mucosal tissues. In contrast to IND, the administration of DA and RAN decreased MPx activity. The changes in activities of gastric mucosal nitric oxide synthases (NOS) throughout the development of gastric mucosal damage induced by IND were also studied. A decrease in constitutive NOS (cNOS) activity and an increase in inducible NOS (iNOS) activity were determined in gastric damaged tissues induced by IND. The administration of DA (100 mg/kg dose) and RAN reversed the activities of iNOS and cNOS. These results suggest that the gastroprotective effect of DA can be attributed to its enhancing effects on antioxidant defense systems as well as reducing effects of neutrophil infiltration.

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.

The role of the interaction between endogenous opioids and nitric oxide in the pathophysiology of ethanol-induced gastric damage in cholestatic rats.

Interaction between endogenous opioids and nitric oxide (NO) has been shown in different biological models and pharmacological evidence suggest that opioids can induce NO release in endothelium as well as in neural cells. Cholestasis is associated with NO overproduction. The reason for increased NO synthesis is not clearly known but it can potentiate development of gastric mucosal damage in cholestatic subjects. Based on increased plasma levels of endogenous opioids and existence of NO overproduction in cholestasis, the present experiments were performed to investigate the role of interaction between endogenous opioids and NO in generation of ethanol-induced gastric damage in cholestatic rats. Cholestasis was induced by surgical ligation of bile duct and sham-operated rats served as controls. The animals received either 20 mg/kg of naltrexone or saline for 6 days and then were fasted and received L-arginine (200 mg/kg), NG-nitro-L-arginine methylester (L-NAME; 2, 5 and 10 mg/kg) or saline. The ethanol-induced gastric mucosal damage was significantly more severe in cholestatic rats than in sham-operated animals (115 +/- 12 mm2 vs. 72 +/- 11 mm2, P < 0.05). L-NAME significantly enhanced the development of gastric mucosal lesions in sham-operated rats. But in cholestatic animals, L-NAME decreased and L-arginine enhanced the severity of gastric damage. Pretreatment of animals with naltrexone decreased severity of gastric mucosal damage in cholestatic rats. Concurrent administration of naltrexone with L-arginine was protective against ethanol-induced gastric damage in both normal and cholestatic groups. Administration of naltrexone with L-NAME had the same effect in cholestatic and control rats and increased severity of gastric damage. Plasma levels of NO2- + NO3- were significantly higher in cholestatic rats than control animals (72 +/- 6 microM vs. 39 +/- 3 microM, P < 0.05). Pretreatment of animals with naltrexone significantly reduced plasma levels of NO2- + NO3- in cholestatic animals, but not in control rats (33 +/- 6 microM vs. 32 +/- 4 microM). The protective effect of L-NAME against gastric damage in cholestatic rats can be explained by inhibition of NO overproduction and it seems that interaction between opioids and NO may have an important role in generation of NO overproduction and gastric complications in cholestatic rats.

Effects of chronic administration of Helicobacter pylori extracts on rat gastric mucosal microcirculation in vivo.

The mechanisms by which Helicobacter pylori contributes to gastroduodenal injury are unclear. We have previously described platelet aggregation within rat gastric mucosal microcirculation following acute administration of H. pylori extracts. However, leukocyte activation was not observed. This study aimed to determine whether chronic administration of H. pylori could induce leukocyte activation. Rats were gavaged with either H. pylori or E. coli extracts or with distilled water three times daily at three-day intervals. Acridine red was used to quantitate gastric mucosal leukocyte/platelet activity using fluorescent in vivo microscopy. Further animals received additional acute H. pylori after 1 hr and recordings were made for a further 1 hr. Significant numbers of "flyers," "rollers," and adherent leukocytes were observed throughout the study in H. pylori animals. Only adherent leukocytes were observed following E. coli. Acute H. pylori induced a further significant increase in adherent leukocytes. Significant platelet thrombi were also present in H. pylori-treated animals. In conclusion, earlier studies demonstrated platelet aggregation but no leukocyte activation, which is in contrast to the current chronic studies. Platelet activation may be the initial response to H. pylori and involved in recruitment of leukocytes. These activated cells may contribute to the development of gastric mucosal damage.

Protective effect of vitamin E on gastric mucosal injury in rats with biliary obstruction.

Patients with liver disease display increased susceptibility to gastric mucosal damage. A role of free radicals has been suggested in the development of gastric mucosal damage in normal subjects. The effects of antioxidant vitamin E treatment on the liver and stomach in cirrhotic rats were examined. Fifty rats were divided into three groups. Cirrhosis was induced by bile duct ligation in 40 of 50 rats. Controls underwent a sham operation. Gastric mucosal lesions were produced by intragastric administration of 1 mL of 95% ethanol in all three groups. Twenty bile duct-ligated rats were injected intramuscularly with vitamin E (100 mg/kg/day). Liver and stomach histology, and stomach malondialdehyde and glutathione levels were determined. Portal hypertension was measured. Macroscopic and microscopic gastric mucosal injury were significantly greater in the control and common bile duct-ligated groups than in the vitamin E-pretreated group (P<0.05). The tissue malondialdehyde and glutathione levels were significantly decreased in the vitamin E-administrated group compared with the common bile duct-ligated group (P<0.001). Vitamin E administration may be cytoprotective for both the liver and gastric mucosa in bile duct-ligated rats.

Intracisternal injection of basic fibroblast growth factor reduces the severity of gastric mucosal lesions evoked by ethanol in rats.

This study was conducted to examine the hypothesis that basic fibroblast growth factor (bFGF) may have an anti-ulcer action through an acid-independent mechanism. The intracisternal injection of bFGF (1 microgram/10 microliters) significantly attenuated the development of gastric mucosal damage evoked by either subcutaneous indomethacin or intragastric absolute ethanol. On the other hand, intraperitoneally injected bFGF (1 microgram) failed to inhibit the formation of gastric mucosal injury by indomethacin or ethanol. These results suggest that bFGF acts in the brain to exert a gastroprotective action. Since ethanol-induced gastric lesion formation does not depend upon luminal acid, we speculate that an acid-independent mechanism may mediate the anti-ulcer action of central bFGF.

Susceptibility to the Development of Gastric Mucosal Damage in OLETF Rat Not Expressing the CCK-A Receptor

Otsuka Long-Evans Tokushima Fatty (OLETF) rats are a new model of a congenital defect of the CCK-A receptor gene and should be useful for determining CCK-A receptor function. Since the CCK-A receptor plays an important role in gastrointestinal function, in the present study we examined, using OLETF rats, the hypothesis that a defect of the CCK-A receptor may influence gastric mucosal integrity. The gastric mucosal integrity was evaluated by the severity of gastric mucosal damage induced by ulcerogenic manipulations. The severity of gastric mucosal lesions seen after administration of intracisternal thyrotropin-releasing hormone analogue, subcutaneous indomethacin, intragastric HCl, or intragastric ethanol was evaluated in OLETF and control LETO rats. Administration of thyrotropin-releasing hormone analogue, indomethacin, HCl, or ethanol significantly increased the severity of gastric mucosal lesions in OLETF rats compared with control LETO rats. These results suggest for the first time that gastric mucosal integrity may be impaired in OLETF rats. It is furthermore speculated that individuals that lack of CCK-A receptors are highly susceptible to gastric ulceration.

Apolipoprotein A-IV acts centrally in the brain to reduce the severity of gastric ulceration in the rat

We have recently reportd that apolipoprotein A-IV (apo A-IV), a protein associated with lipoproteins, acts in the brain to inhibit gastric acid secretion. In the present study, we determined whether or not apo A-IV has an anti-ulcer action via the central nervous system using Sprague-Dawley rats. Intracisternal injection of apo A-IV dose-dependently (2.0–4.0 μg/rat) reduced the severity of gastric mucosal lesions induced by intravenous injection of 2-deoxy- d-glucose or subcutaneous administration of indomethacine. A higher dose (15 μg) of apo A-IV injected intraperitoneally failed to inhibit the development of gastric mucosal damage evoked by these ulcerogenic agents. These results suggest for the first time that apo A-IV has an anti-ulcer action through a central mechanism.

Role of endothelin 1 in hemorrhagic shock-induced gastric mucosal injury in rats

Background/Aims: Gastric microcirculatory disturbances are involved in the pathogenesis of stress ulcers; however, vasomodulators regulating this process are not fully understood. This study was conducted to investigate the role of endothelin 1 (ET-1) in hemorrhagic shock-induced gastric mucosal damage in rats. Methods: ET-1 contents in plasma and gastric mucosa were measured and gastric mucosal damage was evaluated during a control period, 60 minutes of ischemia, 15 minutes of reperfusion, and 30 minutes of postreperfusion. Next, effects of BQ-123, an endothelina receptor antagonist, on the gastric mucosal damage and hemodynamics were studied. Results: Both plasma and mucosal ET-1 significantly increased after ischemia and reperfusion compared with the control values, but only mucosal ET-1 continued to increase after reperfusion, leading to the development of gastric mucosal damage. BQ-123, administered just before reperfusion, reduced mucosal damage in the postreperfusion period dose-dependently and improved mean gastric mucosal blood flow and mucosal hemoglobin oxygen saturation during the 30-minute postreperfusion period. Conclusions: These results suggest that endogenous ET-1 plays an important role in the pathogenesis of hemorrhagic shock-induced gastric mucosal damage through impairment of mucosal microcirculation. Further, endothelina antagonists may have therapeutic benefits for shock-induced gastric mucosal damage.

Vagal stimulation-induced gastric damage in rats

The role of the vagus nerve in the development of gastric mucosal damage was examined in urethan-anesthetized male Sprague-Dawley rats. Electrical stimulation was applied to the vagus nerves for a period of 60 min, after which macroscopic gastric damage was scored and samples of the stomach were fixed for later histological assessment. Damage scores were assigned blindly based on a 0 (normal) to 3 (severe) scale. Stimulation of vagal afferents or efferents in isolation did not result in significant damage to the gastric mucosa (P greater than 0.1). In contrast, stimulation of both intact vagus nerves resulted in significant gastric mucosal damage (mean damage score, 2.0 +/- 0.33, P less than 0.01). A second series of experiments demonstrated this gastric damage to be induced within 30-60 min; extending the stimulation period to 120 min did not worsen the gastric damage scores significantly (P greater than 0.1). In a third study, stimulation of both intact vagus nerves after paraventricular nucleus (PVN) lesion resulted in damage scores (0.33 +/- 0.17) that were significantly reduced compared with intact PVN and non-PVN-lesioned animals (P less than 0.01). These results indicate that the development of vagal stimulation-induced gastric damage requires the activation of both afferent and efferent vagal components and suggest further that such damage is dependent upon an intact PVN.

Classical absorption theory and the development of gastric mucosal damage associated with the non-steroidal anti-inflammatory drugs.

Evidence has accumulated during the last decade to support the view that the pharmacokinetic behaviour of non-steroidal anti-inflammatory drugs (NSAIDs) contributes not only decisively to their therapeutic effects but also to the type and incidence of their side effects. It has been shown that NSAIDs reach particularly high concentrations in those compartments in which they cause effects and side effects. Specifically, the data reviewed herein indicate that the accumulation of NSAID within gastric mucosal cells a priori is a principal factor associated with the intervention of intracellular biochemical events and resultant gastric mucosal damage. To a large extent this behaviour is according to the precepts of classical absorption theory; in this respect the limitations of such theory are examined. Our survey further indicates that the failure of certain NSAIDs to significantly reduce gastric mucosal levels of prostaglandins (PG) in vivo may reflect pharmacokinetic differences between NSAIDs rather than tissue-specific differences in their potency as inhibitors of cyclo-oxygenase.

Interrelationships between membrane-bound ATP-dependent energy systems,gastric mucosal damage produced by NaOH,hypertonic NaCl, HC1, and alcohol, and prostacyclin-induced gastric cytoprotection in rats

Rat gastric mucosal lesions (ulcers) were produced by topical application of 0.2 M NaOH, 25% NaCl, 0.6 M HC1 and 96% ethanol. The animals were sacrificed 1 hr after administration of the different necrotizing agents.The number of gastric lesions (ulcers) was noted and their severities scored.Different doses ( 5 and 50 ug.kg-1) of prostacyclin (PGI2) were given intraperitoneally at 30 minutes before administration of necrotizing agents, and their effects were studied on the number and severity of gastric lesions (ulcers).At the time of killing of animals, the rat gastric fundic mucosa was removed for biochemical examinations. Tissue levels of adenosine triphosphate (ATP),adenosine diphosphate (ADP),adenosine monophosphate (AMP) and lactate were determined enzymatically, while the tissue content of cyclic adenosine monophosphate (cAMP) was measured by radioimmunoassay. The values of the adenylate pool (ATP+ADP+ AMP), the ratio of ATP.ADP-1 and the energy charge (ATP+0.5 ADP. ATP+ADP+AMP-1) were calculated. All biochemical results were calculated in relation to one mg mucosal protein. It was found that;l. the tissue levels of ATP,cAMP,AMP decreased significantly,while the tissue level of ADP increased ( without statistical significance) in all models, during the development of gastric mucosal damage; 2. the tissue level of lactate increased only in the model produced by 0.6 M HC1, while its level was unchanged in the other models during the development of gastric mucosal damage; 3. PGI2 decreased dose-dependently the number and severity of gastric lesions (ulcers); 4. the tissue level of ATP, ratio of ATP.ADP-1 and energy charge were decreased significantly, while the tissue level of ADP was increased significantly by PGI2 in all models; 5. the tissue level of lactate and the adenylate pool remained unchanged during the PGI2 effects. It was concluded that: 1, the development of gastric mucosal damage, produced by topical application of 0,2 M Na0H,25% NaCl, 0.6 M HC1 and 96% ethanol, is associated with an active metabolic adaptation of the gastric fundic mucosa; 2, the metabolic adaptation of the rat gastric fundic mucosa is further increased by PGI2,without resulting in hypoxaemic damage of the gastric mucosa; 3.the feed-back mechanism system - between the membrane-bound ATP-dependent energy systems - is broken during the development of gastric mucosal damage produced by different necrotizing agents, which is modified further by PGI2 at the time of gastric cytoprotection; 4,the biochemical results indicate that the possible roles of ATP - membrane ATPase - ADP and of ATP - adenylate cyclase - cAMP(membrane-bound ATP-dependent energy) systems and changes in their neural,hormonal and pharmacological regulations differ significantly from the control group during development of gastric mucosal damage and of gastric cytoprotection by PGI2.

Cellular mechanisms of the development of gastric mucosal damage and of gastrocytoprotection induced by prostacyclin in rats. A pharmacological study

The rat gastric mucosal damage (lesion) can be produced by the topical application of 96% ethanol and its development can be prevented by the administration of prostacyclin (PGI2) in doses which have no inhibitory effect on gastric acid secretion. The bases for this phenomenon are unknown. In this study the following observations were carried out: 1. The effects of different drugs (actinomycin D, atropine, cimetidine, Degranol,2,4-dinitro-phenol, histamine, epinephrine, pentagastrin, prostacyclin, tetracycline) and of bilateral surgical vagotomy were studied on the development of ethanol-induced rat gastric mucosal damage (ulcer); 2. The effect of PGI2 (applied in a dose of 5 μg/kg) was studied on the ulcer preventive effects of different drugs and of surgical vagotomy; 3. The effects of different drugs and of surgical vagotomy were estimated on the development of gastrocytoprotection produced by PGI2. The drugs and surgical vagotomy were applied alone or in a parallel administration with the PGI2 cytoprotective dose of μg/kg, at 30 minutes before giving the ethanol. The animals were killed 1 hr after ethanol administration. The number of gastric lesions (ulcers) were noted and their severities scored. The single application of atropine, cimetidine, Degranol, epinephrine, histamine, pentagastrin and PGI2 decreased significantly the number and severity of ulcers; the other drugs (tetracycline, actinomycin D,2,4-dinitrophenol) diminished the lesions but without statistical significance. The PGI2 ( in a dose of 5 μg/kg) decreased significantly the ulcer preventive effect of Degranol, tetracycline, cimetidine, atropine, epinephrine and of surgical vagotomy; while the effects of actinomycin D, pentagastrin and 2,4-dinitrophenol were significantly increased by PGI2 administration. The cytoprotective effect of PGI2 was decreased significantly when it was given together with Degranol, tetracycline, actinomycin D, cimetidine, atropine, epinephrine and surgical vagotomy. The parallel administration of PGI2 with pentagastrin and 2,4-dinitrophenol increased significantly the extent of PGI2-induced gastrocytoprotection. These data suggest that very complex cellular mechanisms (energy liberations, d e n o v o synthesis of DNA,RNA,protein, oxydative phosphorylation) may be involved in the development of gastric mucosal damage by topical application of ethanol and of gastrocytoprotection produced by PGI2.

Aspirin, Prostaglandins and mucopolysaccharide/glycoprotein secretion.

The object of the present study was to investigate the possibility that the ulcer-protective action of prostaglandins (PGs) in eliciting mucus discharge in the stomach could be due to their effect in enhancing the biosynthesis of mucus. Intraperitoneal injection of 2,5 mg/kg PGE2, or the same dose of PGE2 plus 200 mg/kg aspirin (p.o.), both failed to cause any statistically significant changes in the incorporation of radioactive sulphate into gastric mucus glycoproteins in vivo compared with controls. Aspirin, under these conditions, inhibits mucus synthesis in this effect may be related to the development of gastric mucosal damage by this drug. In contrast, PGE2 administration reverses the gastric mucosal damage induced by aspirin so that the ulcer-protective effect of PGE2 appears to be unrelated to mucus synthesis. PGE2 (0.125 - 1.25 microgram/ml) inhibited oxygen consumption and 14CO2 output from 1-14C, and 6-14C glucose in rat gastric mucosal slices in vitro. Thus the absence of effect of PGE2 on mucus biosynthesis may be due to an effect of this PG in reducing the capacity of the mucosa to yield energy (ATP) from the metabolism of glucose.

The role of aspirin in gastric ulceration . Some factors involved in the development of gastric mucosal damage induced by aspirin in rats exposed to various stress conditions.

The gastric irritant effects of aspirin were studied in rats treated with a variety of physical and "disease" (inflammatory) stress conditions (which may mimic responses to some stress states encountered clinically) with the object of establishing whether these stress states increase the susceptibility of the gastric mucosa to the potentially ulcerogenic actions of aspirin. While exposure to physical (eg, cold) stress conditions markedly increased the sensitivity of the gastric mucosa to aspirin, exposure to various disease stressors (eg, adjuvant arthritis, acute pain, or paw inflammation) did not appreciably affect the mucosal sensitivity to this drug. Attempts were made to determine the mechanisms of the physical stress plus aspirin interaction by use of pharmacological agents. The results suggest a major involvement of the parasympathetic-vagal, sympathetic, and histamine-producing systems, but not the adrenocortical axis, in this model of gastric ulcerogenesis. No differences were observed in the mucosal uptake of [14C]aspirin, showing that accelerated uptake of the drug is not a factor in the development of gastric ulceration.