16-16-dimethylprostaglandin-e2 and Stomach-Ulcer

This study compares the involvement of ATP-sensitive potassium (K(ATP)) channels and prostaglandins in various forms of gastroprotection in the rat. Instillation of 1 ml of 70% ethanol induced severe gastric mucosal damage (lesion index 39 +/- 0.8), which was substantially but not maximally reduced by oral pretreatment with 16,16-dimethyl-prostaglandin (PG) E(2) (75 ng/kg), 20% ethanol (1 ml), sodium salicylate (15 mg/kg), the metal salt lithium chloride (7 mg/kg), the sulfhydryl-blocking agent diethylmaleate (5 mg/kg), and the thiol dimercaprol (10 mg/kg). Administration of indomethacin (20 mg/kg) increased gastric mucosal damage induced by 70% ethanol (lesion index 45 +/- 0.8) and significantly reduced the protective effect of 20% ethanol, sodium salicylate, lithium chloride, diethylmaleate, and dimercaprol. The blocker of K(ATP) channels glibenclamide (5-10 mg/kg) significantly antagonized the protective effect of 16,16-dimethyl-PGE(2), 20% ethanol, sodium salicylate, lithium chloride, diethylmaleate, and dimercaprol. The inhibition of protection induced by glibenclamide was reversed by pretreatment with the K(ATP) channel activator cromakalim (0.3-0.5 mg/kg). In conclusion, our results indicate a role of K(ATP) channels in the gastroprotective effect of 16,16-dimethyl-PGE(2) and of the other agents tested. Since the protection afforded by these agents is additionally indomethacin-sensitive, it is suggested that under these conditions endogenous prostaglandins act as activators of K(ATP) channels, and this mechanism, at least in part, mediates gastroprotection.

Topics: 16,16-Dimethylprostaglandin E2; Adaptation, Physiological; Adenosine Triphosphate; Administration, Oral; Animals; ATP-Binding Cassette Transporters; Dimercaprol; Dose-Response Relationship, Drug; Ethanol; Gastric Mucosa; Glyburide; KATP Channels; Lithium Chloride; Male; Maleates; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Inwardly Rectifying; Prostaglandins; Rats; Rats, Wistar; Sodium Salicylate; Stomach Ulcer

Prostaglandin (PG) and nitric oxide (NO) have been known to inhibit the lesion formation induced by necrotic agents. However, no clear correlation between PG and NO has been shown in the gastroprotective action against necrotic agent-induced gastric mucosal lesions in rats. Thus, the present study was performed to clarify this correlation. Gastric mucosal lesions were induced by the oral administration of 0.6 M HCl in rats. 16,16-Dimethyl PGE2 (0.3-3 microg/kg, p.o.; dim-PGE2), sodium nitrite (0.3 and 1 mg/kg, s.c.) and sodium nitroprusside (30 and 100 microg/kg, i.v.; SNP) dose-dependently inhibited the lesion formation. Orally administered sodium nitrite or SNP (3 mg/kg) also significantly inhibited the lesion formation. The gastroprotective action by dim-PGE2 was not affected by the pre-treatment with N(G)-nitro-L-arginine methylester (10 mg/kg, i.v.). The gastroprotective effect by sodium nitrite or SNP was markedly attenuated by the pre-treatment with indomethacin (10 mg/kg, s.c.). These findings suggest that NO donating compounds inhibit the HCl-induced mucosal lesions mainly through prostaglandin, but dim-PGE2 directly inhibits the lesions without involvement of NO in rats.

Topics: 16,16-Dimethylprostaglandin E2; Administration, Oral; Animals; Gastric Mucosa; Hydrochloric Acid; Indomethacin; Male; Nitric Oxide Donors; Nitroprusside; Rats; Rats, Sprague-Dawley; Sodium Nitrite; Stomach Ulcer

Lafutidine (CAS 118288-08-7, FRG-8813) is a novel histamine H2-receptor antagonist with gastroprotective activity. The aim of this study was to investigate the property of the gastro-protective activity of lafutidine by examining the effect on ammonia-induced change in transmucosal potential difference (PD), basal gastric mucosal blood flow (GMBF) and noxious agent-induced cell damage. Intragastrical application of lafutidine accelerated the recovery of the PD reduction after exposure of the mucosa to 0.25% ammonia solution and the accelerating effect was abolished by chemical deafferentation, but not with indometacin, a cyclooxygenase inhibitor. The application of capsaicin, as a reference compound, significantly promoted the recovery of the ammonia-induced PD reduction and this effect was not altered with indometacin. Lafutidine given intragastrically caused a sustained increase in GMBF in a dose-dependent fashion, which was also completely inhibited in the deafferentated rats. In vitro studies revealed that, in contrast to 16,16-dimethyl prostaglandin E2, lafutidine did not protect isolated gastric superficial epithelial cells from ethanol- or ammonia-induced damage. In conclusion, the gastroprotection of lafutidine is induced by promoting the restitution of the damaged mucosa after a noxious agent, not by directly protecting the epithelial cells and this effect may be caused through the mechanism of capsaicin-sensitive afferent nerves.

Topics: 16,16-Dimethylprostaglandin E2; Acetamides; Ammonia; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Capsaicin; Central Nervous System Depressants; Ethanol; Gastric Mucosa; Histamine H2 Antagonists; Indomethacin; Male; Membrane Potentials; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Stomach Ulcer

Lafutidine is a new type antiulcer agent with antisecretory and gastroprotective activities. We investigated the effect of lafutidine on indomethacin-induced antral ulcer in refed rats. Subcutaneous indomethacin injection resulted in the formation of gastric antral ulcer. Lafutidine (1-10 mg/kg, p.o.) reduced the area of ulcer in a dose-dependent manner when administered immediately after the indomethacin injection. Capsaicin at 3 mg/kg, p.o. and 16,16-dimethyl prostaglandin E2 at 3 microg/kg, p.o. also reduced the ulcer area. Chemical deafferentation of capsaicin-sensitive neurons or N(G)-nitro-L-arginine treatment aggravated the ulcer formation and abolished the preventive effect of lafutidine and capsaicin. After the induction of gastric ulcer, lafutidine given twice daily for 2.5 days reduced the area of ulcer in a dose-dependent manner with a significant effect at 10 mg/kg, p.o., as compared with that of the control group. In chemically-deafferentated rats, lafutidine did not show any healing effect. Cimetidine (30 mg/kg, p.o.) and famotidine (1 mg/kg, p.o.) had no significant effect on indomethacin-induced antral ulcer. These results may suggest that lafutidine, unlike cimetidine and famotidine, can prevent the indomethacin-induced antral ulcer formation and accelerate the healing of the ulcer in refed rats through mechanisms involving the capsaicin-sensitive afferent neurons and nitric oxide.

Topics: 16,16-Dimethylprostaglandin E2; Acetamides; Administration, Oral; Animals; Anti-Ulcer Agents; Capsaicin; Cimetidine; Denervation; Dose-Response Relationship, Drug; Enzyme Inhibitors; Famotidine; Food; Indomethacin; Male; Nitroarginine; Piperidines; Pyloric Antrum; Pyridines; Rats; Rats, Sprague-Dawley; Stomach Ulcer; Wound Healing

Effects of a novel zinc compound polaprezinc [N-(3-aminopropionyl)-L-histidinatozinc] and sucralfate on the mucosal ulcerogenic responses induced by monochloramine (NH2Cl) were examined in rat stomachs. Oral administration of NH2Cl (>60 mM) produced severe lesions in unanesthetized rat stomachs, with concomitant increase of lipid peroxidation. These lesions were aggravated by sensory deafferentation but not affected by pretreatment with indomethacin or L-NAME. The mucosal ulcerogenic response to NH2Cl was significantly inhibited by oral pretreatment with either dmPGE2 (10 microg/kg), capsaicin (30 mg/kg), or NOR-3 (3 mg/kg), the NO donor. Gastric lesions induced by NH2Cl were also inhibited by prior oral administration of polaprezinc (3-30 mg/kg) as well as sucralfate (30 and 100 mg/kg). The protective effect of polaprezinc was not affected by any pretreatments such as indomethacin, L-NAME, or sensory deafferentation, while that of sucralfate was significantly mitigated in the presence of either indomethacin or L-NAME. On the other hand, mucosal exposure to NH4OH (60 mM) caused a marked PD reduction in ex vivo stomachs made ischemic by bleeding from the carotid artery, followed by severe gastric lesions. These ulcerogenic and PD responses caused by NH4OH plus ischemia were also attenuated by prior application of polaprezinc, while dmPGE2 and sucralfate prevented such lesions without affecting the reduced PD response. These results suggest that: (1) NH2Cl generated either exogenously or endogenously damages the gastric mucosa, (2) both polaprezinc and sucralfate protect the stomach against injury caused by NH2Cl, and (3) the mechanisms underlying the protective action of sucralfate may be partly mediated by both endogenous PGs and NO but may be different from those of polaprezinc.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Anti-Ulcer Agents; Carnosine; Chloramines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Interactions; Gastric Mucosa; Male; Organometallic Compounds; Rats; Rats, Sprague-Dawley; Stomach Ulcer; Sucralfate; Zinc; Zinc Compounds

Lansoprazole, a proton pump inhibitor, has been reported to inhibit ethanol-induced injury in rats. However, the mechanism of the protective effect is not known. This study was carried out to investigate the role of prostaglandin (PG) in the protective effect of lansoprazole. Male Wistar rats were given either 30 mg/kg of lansoprazole or vehicle alone intragastrically 30 min before administration of ethanol. They were killed to measure the gross mucosal lesions in the stomach as the ulcer index. In another experiment, 5 mg/kg of indomethacin was injected 30 min before administration of lansoprazole. The effects of 16,16-dimethyl PGE2 (dmPGE2) on ethanol-induced injury over time were compared with lansoprazole. PGE2 synthesis in gastric mucosa after administration of lansoprazole was measured by radioimmunoassay. Lansoprazole reduced gastric mucosal injury by lansoprazole. DmPGE2 significantly reduced gastric mucosal injury from 5 min after exposure to ethanol. Lansoprazole did not affect PGE2 synthesis in the gastric mucosa. These results suggest that PG may not be involved in the protective effect of lansoprazole.

Topics: 16,16-Dimethylprostaglandin E2; 2-Pyridinylmethylsulfinylbenzimidazoles; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Ethanol; Gastric Mucosa; Indomethacin; Lansoprazole; Male; Omeprazole; Prostaglandins; Proton Pump Inhibitors; Rats; Rats, Wistar; Stomach Ulcer

We examined the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on mucosal ulceration in isolated bullfrog stomachs and investigated the roles of endogenous prostaglandins (PGs) and nutrient HCO3- in the mucosal protection in vitro. Gastric sacs were prepared by separation from the muscle layer and incubation for 1-8 h in HCO3--Ringer's solution gassed with 95% 02/5% CO2 or PO3(-)4-Ringer's solution gassed with 100% 02 in the presence of histamine (1 x 10(-4) M). Under these conditions, multiple ulcers developed in the mucosa only when the gastric sacs were incubated in HCO3--free nutrient solution; both the number and severity of ulcers increased with time and reached a maximum after 6 h of incubation. Luminal pH was decreased because of stimulation of acid secretion by histamine, irrespective of whether the mucosa was bathed in Ringer's solution with or without HCO3-, while gastric potential difference was reduced only in the mucosa bathed in HCO3--free nutrient solution. 16,16-Dimethyl PGE2 added to the nutrient side significantly reduced the number of ulcers developed in the mucosa bathed in HCO3--free nutrient solution. In contrast, indomethacin and aspirin, but not salicylate, caused ulceration even in the mucosa bathed in HCO3--nutrient solution. Histamine-induced acid secretion was reduced by 16,16-dimethyl PGE2 but not affected by these NSAIDs. In conclusion, ulceration of the isolated gastric mucosa in the presence of acid depends upon either a deficiency of endogenous PGs or a lack of nutrient HCO3-/CO2.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Anti-Ulcer Agents; Bicarbonates; Gastric Acid; Gastric Mucosa; Hydrogen-Ion Concentration; In Vitro Techniques; Prostaglandins; Rana catesbeiana; Stomach Ulcer

Hung, C.R., T.S. Wu and T.Y. Chang. The comparison between the effects of ethanol-extracted saikosaponin (SS) and 16, 16-dimethyl prostaglandin E2 (dmPGE2) on gastric acid back diffusion and mucosal damage induced by 100 mg/kg of acidified tannic acid (tannic acid dissolved in 100 mm HCl + 54 mM NaCl solution) was studied in the vagotomized rat. Crude saikosaponin (500 mg/kg) given by intragastric irrigation (I.G.) produced a significant inhibition (p < 0.05), while dmPGE2 (100 micrograms/kg) provoked a significant increase (p < 0.05) in acid back diffusion induced by acid solution. When graded doses of SS (100-1000 mg/kg) were added to acidified tannic acid solution and instilled to the stomach, a dose-dependent inhibition in acidified tannic acid-induced mucosal ulceration and acid back diffusion was achieved. The decrease in the H+ concentration and the increase in the Na+ concentration in the final samples induced by acidified tannic acid were also significantly (p < 0.05) inhibited by the same doses of SS. However, neither intraduodenal (I.D.) nor intravenous (i.v.) administration of SS was effective in inhibiting these ulcerogenic parameters. When dmPGE2 (3-100 micrograms/kg) was given concomitantly with acidified tannic acid solution, the acid back diffusion as well as mucosal ulceration provoked by acidified tannic acid were not significantly improved. The volume of luminal contents but not electrolyte concentrations in the final sample was considerably increased by adding dmPGE2 to the acidified tannic acid solution. The failure of I.D. or i.v. of dmPGE2 in inhibiting tannic acid-induced acid back diffusion and mucosal ulceration was also observed in other series of experiments.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 16,16-Dimethylprostaglandin E2; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Diffusion; Electrolytes; Gastric Acid; Gastric Mucosa; Hydrolyzable Tannins; Male; Oleanolic Acid; Permeability; Rats; Rats, Sprague-Dawley; Sapogenins; Saponins; Stomach Ulcer; Vagotomy

The relationship of gastric hypermotility to mucosal hemodynamics, lipid peroxidation and vascular permeability changes was investigated in the pathogenesis of indomethacin-induced gastric lesions in rats. Subcutaneous administration of indomethacin (25 mg/kg) produced an increase in both the amplitude and frequency of stomach contraction from 30 min after treatment, resulting in hemorrhagic damage 2 h later. Gastric mucosal blood flow measured by a Laser flowmetry showed oscillatory fluctuations under hypercontractile states: a decrease during contraction followed by an increase during relaxation. Mucosal lipid peroxidation and vascular permeability were significantly increased with time after indomethacin treatment, and these changes preceded the appearance of hemorrhagic damage. All these events were prevented when gastric hypermotility was inhibited by atropine or 16,16-dimethyl prostaglandin E2. Pretreatment of the animals with allopurinol and hydroxyurea or continuous infusion of superoxide dismutase and dimethyl sulfoxide during a test period also attenuated these functional changes and mucosal lesions induced by indomethacin, without affecting the motility response. We conclude that oxygen free radicals may play a role in the development of mucosal lesions associated with gastric hypermotility in indomethacin-treated rats.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Atropine; Capillary Permeability; Free Radicals; Gastric Mucosa; Gastrointestinal Motility; Indomethacin; Lipid Peroxidation; Male; Rats; Rats, Inbred Strains; Regional Blood Flow; Stomach Ulcer

We have previously shown that chronic steroid administration delays the healing of experimental gastric ulcers in rats. This study was designed to test the beneficial effects of 16,16-dimethylprostaglandin E2 or TRY-200, a stable prostaglandin I2 analogue, on the delayed healing by hydrocortisone (HC) of chronic gastric ulcers in rats. Chronic gastric ulcers were produced in male Wistar rats, weighing 180 g, by serosal application of 100% acetic acid. The rats were randomly divided into six groups: (1) saline, (2) saline, HC-treated, (3) 10 micrograms/kg of 16,16-dimethylprostaglandin E2, (4) TRY-200, a stable prostaglandin I2 analogue, at 5 micrograms/kg, or (5) 10 micrograms/kg, or (6) 30 micrograms/kg. All rats, except for control, were given daily intraperitoneal injection of 2.5 mg/kg of HC sodium phosphate. Tested drugs were administered intragastrically twice a day for 2 weeks. Rats were killed 14 days later and ulcer size was measured. Chronic administration of HC sodium phosphate resulted in a significant delay of ulcer healing induced by acetic acid. Treatment with TRY-200 at 10 or 30 micrograms/kg abolished the deleterious effect of steroids, whereas 16,16-dimethylprostaglandin E2 had no effect. These results indicate that prostaglandin I2 is more effective than prostaglandin E2 in reversing the delayed healing by steroids of chronic gastric ulcers in the rat.

Topics: 16,16-Dimethylprostaglandin E2; Acetates; Acetic Acid; Animals; Epoprostenol; Gastric Mucosa; Hydrocortisone; Male; Rats; Rats, Inbred Strains; Stomach Ulcer; Wound Healing

We have observed that removal of the salivary glands is associated with an increase in the susceptibility to gastric mucosal damage in the rat. In the present study, we have examined the effect of sialoadenectomy on ethanol-induced mucosal hemorrhagic damage and myeloperoxidase (MPO) activity. Hemorrhagic damage and MPO activity in response to intragastric 50% w/v ethanol were greater in sialoadenectomized rats when compared with sham-operated animals. Pretreatment with 16,16-dimethylprostaglandin E2 (0.3 micrograms/kg s.c.) reduced damage and MPO activity in both sialoadenectomized and sham control rats receiving 50% ethanol. The reduction in these parameters was greater in control than in sialoadenectomized rats. Pretreatment with epidermal growth factor (5 micrograms/kg s.c.) significantly reduced MPO activity but did not significantly affect the extent of damage. These data suggest that sialoadenectomy is associated with an increase in mucosal inflammation in animals given ethanol. However, in some situations tissue inflammation (as indicated by MPO activity) was reduced, while the proportion of gastric mucosa exhibiting hemorrhagic damage was not changed.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Dinoprostone; Epidermal Growth Factor; Ethanol; Gastrointestinal Hemorrhage; Male; Neutrophils; Peroxidase; Rats; Rats, Inbred Strains; Salivary Glands; Stomach Ulcer

Epidermal growth factor promotes the growth of and protects gastric mucosa against various ulcerogens, including stress, but little is known about its role in the pathogenesis of stress ulcerations. In this study, Wistar rats with intact and resected salivary glands were exposed to water-immersion and restraint stress. During 2-14 hours of water-immersion restraint stress, the formation of gastric ulcerations increased progressively and the duration of stress was accompanied by a decrease in DNA synthesis in the gastric mucosa. Following sialoadenectomy, a significant increase in the number of stress ulcerations and further reduction in DNA synthesis were observed. Exogenous epidermal growth factor and dimethyl prostaglandin E2 significantly reduced the ulcerations in the stressed rats with intact salivary glands, but this reduction was significantly less pronounced after sialoadenectomy. Water-immersion restraint stress also resulted in about 50% reduction in mucosal prostaglandin E2 generation, and the pretreatment with indomethacin, which suppressed prostaglandin E2 by about 90%, almost doubled the number of stress ulcerations and abolished the gastro-protective effect of exogenous epidermal growth factor (but not dimethyl prostaglandin E2) against the stress lesions. An inhibition of ornithine decarboxylase activity by difluoromethyl ornithine also augmented stress-induced ulcerogenesis and abolished the protective action of epidermal growth factor while the administration of spermine almost completely prevented stress ulcerations in rats both without and with pretreatment with difluoromethylornithine. Water-immersion restraint stress also significantly reduced mucosal content of glutathione. Cysteamine increased tissue glutathione and reduced stress ulcerations but N-ethylmaleimide, an sulfhydryl blocker, decreased mucosal content of glutathione without affecting the stress ulcerations. This study indicates that the stress ulcers are accompanied by the reduction in mucosal synthesis of DNA, prostaglandin, and glutathione and that the presence of salivary glands attenuates the stress ulcerogenesis probably by releasing epidermal growth factor which acts, in part, by enhancing ornithine decarboxylase activity, mucosal growth, and prostaglandin and glutathione formation.

Topics: 16,16-Dimethylprostaglandin E2; Animals; DNA; Eflornithine; Epidermal Growth Factor; Ethylmaleimide; Gastric Mucosa; Glutathione; Male; Ornithine Decarboxylase; Prostaglandins; Rats; Rats, Inbred Strains; Salivary Glands; Stomach Ulcer; Stress, Physiological; Sulfhydryl Compounds; Thymidine

The mechanism of cytoprotection by prostaglandins (PGs) is still unknown, although many hypotheses have been proposed. We postulated a hypothesis that increased gastric content and thickened mucus gel layer by PGs may protect the gastric mucosa against damage from necrotizing agents. Two series of experiments were performed on Wistar male rats, weighing 250-300 g. (1) 16,16-dimethyl prostaglandin E2 (dmPGE2) in doses of 20 micrograms/kg was given orogastrically. Fifteen minutes later, the stomachs were emptied and/or the mucus gel layer removed, and several concentration of ethanol applied. After ten minutes, the stomachs were removed and lesions of the gastric mucosae were evaluated macroscopically and histologically. (2) Volume and pH of the gastric content and mucus thickness were measured 15 minutes after dmPGE2 administration. DmPGE2 did not protect the gastric mucosa against 40% ethanol in the emptied stomach. This agent had no cytoprotective action on the emptied and mucus gel-removed stomach in 30% ethanol application. These results had no significant difference with control group (saline 1 ml p.o.) about the extent of erosion. In histological study of the erosive region by scanning and light microscopy, we also found no differences in the depth of erosion between dmPGE2 group and control. In addition, dmPGE2 increased the gastric volume and mucus thickness significantly. These data suggest that following two effects by PGs play major role in cytoprotection of the gastric mucosa; (1) dilution of necrotizing agents by increased gastric content, and (2) thickening of the mucus gel layer.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Ethanol; Gastric Juice; Gastric Mucosa; Male; Mucus; Rats; Stomach Ulcer

The effects of zinc L-carnosine on ethanol-induced damage and the correlation of these effects with endogenous prostaglandin E2 were evaluated in rat gastric mucosa in vivo and in vitro. When given either intragastrically or intraperitoneally, zinc L-carnosine (10 or 30 mg/kg) prevented gross visible damage to gastric mucosa caused by ethanol without affecting the mucosal prostaglandin E2 level. This protective effect of zinc L-carnosine was not inhibited by indomethacin. Histological assessment showed that zinc L-carnosine inhibited deep mucosal necrosis, as did 16,16-dimethyl prostaglandin E2. Zinc L-carnosine (10(-6) or 10(-5) M) inhibited the damage caused by ethanol to gastric cells isolated from rat gastric mucosa in vitro; this effect was not inhibited by indomethacin. The results suggested that zinc L-carnosine protects the gastric mucosa and enhances cellular resistance to ethanol without the mediation of endogenous prostaglandins.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Anti-Ulcer Agents; Carnosine; Dinoprostone; Dipeptides; Ethanol; Gastric Mucosa; Indomethacin; Rats; Rats, Inbred Strains; Stomach Ulcer; Zinc

Pathogenesis of indomethacin-induced gastric lesions was investigated in the rat by measuring lesions, gastric motility, and terminal blood glucose levels and correlating them with each other. Subcutaneously administered indomethacin (3-25 mg/kg) dose-dependently produced lesions in the stomach with concomitant gastric hypermotility and reduction of blood glucose levels. When the lesion score and the motility were plotted against terminal glucose levels, a highly significant relationship was found among these three factors (P less than 0.01). Gastric lesions and hypermotility induced by indomethacin (25 mg/kg) were suppressed significantly by 16,16-dmPGE2 (10 micrograms/kg) with no effect on the glucose levels, while intravenous infusion of glucose (25% w/w, 1.4 ml/hr) prevented these responses and restored the reduced glucose levels above the basal values. In addition, both 16,16-dmPGE2 and glucose infusion afforded a significant protection against gastric lesions induced by indomethacin even in the acid-perfused stomach (150 mM HCl). These results confirmed gastric hypermotility as a key element in the pathogenesis of indomethacin-induced lesions and further suggested that indomethacin may sensitive gastric contractility through glycoprivic receptors by inducing hypoglycemia and PG deficiency.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Blood Glucose; Dose-Response Relationship, Drug; Drug Interactions; Gastric Acid; Gastric Mucosa; Gastrointestinal Motility; Glucose; Indomethacin; Male; Rats; Rats, Inbred Strains; Stomach Ulcer

The present study investigated the preventive and curative effects of prostaglandins (PGs) on gastric ulcer in rats induced by physical or psychological stresses; some rats were electrically shocked, while others were exposed to affective stimuli arising from the shocked animals. The synthetic PGs dimethyl-PGE2 and rioprostil were administered orally, and their preventive effect on gastric ulceration was evaluated by determining the incidence and the ulcer index of lesions. The curative effect of drugs on ulcer healing was evaluated by determining a time-dependent change in the mucosal surface of the stomach with an endoscopic technique. Oral administration of dimethyl-PGE2 or rioprostil (25 and 50 micrograms/kg) prevented gastric ulceration significantly. Oral administration of these drugs (50 micrograms/kg, twice per day) significantly promoted the healing process of lesions 24 and 36 hr after termination of stress loading. The present results give direct evidence of the curative effect of PGs on stress ulcers and suggest that application of the endoscopic technique to the pathology of the rat's stomach may be a substantial aid in the preclinical evaluation of antiulcer drugs.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Anti-Ulcer Agents; Electroshock; Gastric Mucosa; Gastroscopy; Male; Prostaglandins E; Prostaglandins E, Synthetic; Rats; Rioprostil; Stomach Ulcer; Stress, Physiological; Stress, Psychological

This study was designed to determine the gastroprotective actions of an antacid (Maalox 70) and its components, Al(OH)3 and Mg(OH)2, against acute gastric lesions induced by absolute ethanol, acidified aspirin (ASA), and water immersion and restraint stress in rats. Given orally, the antacid prevented dose-dependently the formation of gastric lesions by all three ulcerogens, and these effects were similar to those obtained with a methylated prostaglandin E2 (PGE2) analog. Active Al(OH)3 gel was equipotent with Maalox, whereas Mg(OH)2 was significantly less effective in gastroprotection than Maalox 70. Chemically inactive Al(OH)3 wet gel showed only small and insignificant protective properties. Since the gastroprotective activities of Maalox 70 against ethanol lesions cannot be reversed by pretreatment with indomethacin, and since neither Maalox 70 nor its active components affected the mucosal generation of PGE2 and leukotriene C4, we postulate that mucosal prostanoids are not the primary mediators in the mechanism of their protective action on the gastric mucosa.

Topics: 16,16-Dimethylprostaglandin E2; Aluminum Hydroxide; Animals; Dose-Response Relationship, Drug; Gastric Acid; Gastric Mucosa; Magnesium; Magnesium Hydroxide; Prostaglandins E; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains; SRS-A; Stomach Ulcer

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

The present study investigates whether prostaglandins "cytoprotect" the gastric mucosa against hemorrhage-induced stress ulceration by assessing the influence of 16,16-dimethyl prostaglandin E2 (16,16-dm PGE2) on gross and microscopic lesion formation, intramucosal tissue pH, H+ back-diffusion, and mucosal blood flow in rat gastric mucosa exposed to luminal acid (100 mM HCl) during hemorrhagic shock (13 ml/kg for 20 min). Intramucosal tissue pH was measured using pH-sensitive antimony microelectrodes, and mucosal blood flow was measured by the radiolabeled microsphere technique. 16,16-dm PGE2 (5 micrograms/ml topically) significantly protected the gastric mucosa against gross (lesion index 2.25 +/- 0.34 vs 0.87 +/- 0.21) and microscopic (lesion index 2.12 +/- 0.20 vs 0.87 +/- 0.09) damage during the shock. This protection was associated with a significantly lesser acidification of the mucosa during the shock (intramural tissue pH 6.67 +/- 0.08 vs 6.03 +/- 0.17). In order to elucidate whether the lesser intramucosal acidification was due to diminished entry of H+ (H+ back diffusion) into or better disposal of H+ from the mucosa, the influences of 16,16-dm PGE2 on transmucosal H+ fluxes and mucosal blood flow were determined. It appeared that 16,16-dm PGE2 had no influence on the rate of H+ back-diffusion, but it significantly enhanced mucosal blood flow both in the corpus (0.23 +/- 0.04 vs 0.14 +/- 0.03 ml/min/g) and in the antrum (0.24 +/- 0.03 vs. 0.14 +/- 0.03 ml/min/g) during the shock.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 16,16-Dimethylprostaglandin E2; Animals; Disease Models, Animal; Hydrogen-Ion Concentration; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains; Shock, Hemorrhagic; Stomach Ulcer; Stress, Physiological

Gastric mucosal damage produced by topical application of necrotizing agents is diminished by topical or systemic pretreatment with a variety of E and F prostaglandins. The rat restraint model of gastric mucosal injury is more analogous to clinical stress ulceration than are models using intragastric application of toxic solutions; however, previous use of prostaglandin E1 in the restraint model resulted in a prohibitive incidence of GI morbidity. The current study used the restraint model of stress ulceration to compare the effects of a more potent prostaglandin analogue, 16,16-dimethyl prostaglandin E2, with hyperosmolar glucose and antacids. All three agents afforded significant protection from grossly apparent mucosal lesions, alone and in combination. Although other physiologic effects of each agent differed, the only effect which correlated with prevention of mucosal lesions was suppression of gastric acidity. Since effective doses of cytoprotective prostaglandins did not produce notable morbidity in comparison with other agents, they may prove to be a useful adjunct to stress ulcer prophylaxis in clinical settings.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Antacids; Drug Evaluation, Preclinical; Gastric Mucosa; Glucose; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains; Stomach Ulcer; Stress, Physiological

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

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

Different doses of the new chemically stable PGE2 analogue, FCE 20700, (150, 300, 450, 900, 1200 and 1800 micrograms kg-1) and of 16,16-dimethyl PGE2, DMPGE2, (1, 3, 10, 30 and 100 micrograms kg-1) were administered by gavage to pylorus-ligated rats. The dose-response relationship in preventing gastric mucosal damage and in inhibiting gastric acid and pepsin secretion was investigated. In the same animals, a simultaneous evaluation of barrier and luminal mucus was also performed. Both compounds were markedly active in preventing the macroscopic damage of the gastric mucosa and, at higher doses, in inhibiting gastric acid secretion. FCE 20700 was approximately 100-150 times less potent than DMPGE2. Mucosal protection appeared to be exerted by the two prostaglandins independently of any action on mucus. Furthermore, as the antisecretory doses were approached, a decline in protective activity became evident, suggesting that the dosage of prostaglandins is critical, making it possible to orient their activity either towards mucosal protection or towards acid inhibition.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Dinoprostone; Dose-Response Relationship, Drug; Female; Gastric Acid; Gastric Mucosa; Mucus; Pepsin A; Prostaglandins E, Synthetic; Pylorus; Rats; Rats, Inbred Strains; Reference Values; Stomach Ulcer

Effects of atropine, cimetidine, and 16,16-dimethyl prostaglandin E2 (16,16-dmPGE2) on indomethacin-induced gastric lesions were investigated in rats by correlating their effects on gastric acid and HCO3- secretion and motility. Subcutaneously administered indomethacin (25 mg/kg) produced gastric mucosal lesions within 4 hr. In parallel studies, an equivalent dose of indomethacin inhibited gastric HCO3- secretion, and stimulated gastric motor activity measured as intraluminal pressure recordings, whereas acid secretion was unaffected. The lesions induced by indomethacin were significantly prevented by three agents: cimetidine (100 mg/kg), which reduced acid secretion; atropine (1 mg/kg), which reduced acid secretion and gastric motility; and 16,16-dmPGE2 (10 micrograms/kg), which reduced acid secretion and motility and increased gastric HCO3- secretion. If acid (150 mM HCl) was infused into the stomach (1.2 ml/hr) during indomethacin treatment, only the latter two agents significantly prevented the formation of gastric lesions in response to indomethacin. Since only the effect on gastric motility was common to these two agents (atropine and 16,16-dmPGE2), the increased gastric motility may be an important pathogenetic factor in indomethacin-induced gastric lesions. The presence of acid as well as a deficiency of endogenous PGs may be prerequisite for later extension of the lesions but cannot account for the induction of mucosal lesions in rats following administration of indomethacin.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Atropine; Bicarbonates; Cimetidine; Gastric Acid; Gastric Mucosa; Indomethacin; Injections, Subcutaneous; Male; Peristalsis; Premedication; Rats; Rats, Inbred Strains; Stomach; Stomach Ulcer

We investigated whether the trophic actions of prostaglandins, omeprazole, and indomethacin on gastric mucosa lead to accelerated healing of gastric ulcers in the rat. Cryoulcers were produced in the corpus area and treated with 16,16-dimethyl prostaglandin E2 (5 or 100 micrograms/kg b.i.d., intragastrically), omeprazole (40 mumol/kg once daily, subcutaneously), indomethacin (2 mg/kg b.i.d., subcutaneously), or placebo. At the end of the treatment, plasma gastrin, cell labeling index (autoradiography with [3H]thymidine), and the size and depth of mucosal defects were measured. Compared with placebo, omeprazole accelerated ulcer healing as indicated by a smaller ulcer area [1.1 +/- 0.2 vs. 4.8 +/- 1.2 mm2 (mean +/- SEM)] and smaller ulcer depth (383 +/- 31 vs. 488 +/- 41 microns) after 10 days of treatment. Prostaglandins did not affect ulcer healing despite thickening of gastric corpus mucosa. Indomethacin delayed ulcer healing and reduced the labeling index. Omeprazole induced a marked hypergastrinemia (208 +/- 12 vs. 66 +/- 12 pmol/L on day 5, and 469 +/- 23 vs. 58 +/- 16 pmol/L on day 10). The results indicate that abolishment of acid secretion by omeprazole accelerates healing. Trophic actions and "cytoprotective" effects by prostaglandins are not relevant for ulcer healing in this model.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Autoradiography; Body Weight; Gastric Mucosa; Gastrins; Indomethacin; Male; Omeprazole; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains; Stomach Ulcer

Intravenous and orally administered prostaglandin E2 (PGE2) and 16,16-dimethyl PGE2 (dmPGE2) protect the rat gastric mucosa from injury induced by oral administration of acidified 40% ethanol. The effects of pretreatment with these prostaglandins on platelet activating factor (Paf)-induced gastric damage has now been investigated in the rat. A 10 min infusion of Paf (50 or 100 ng kg-1 min-1, i.v.) resulted in dose-related vasocongestion of the gastric mucosa. Intravenous pretreatment with dmPGE2 (20 micrograms kg-1) failed to prevent the gastric damage induced by the higher dose of Paf. Pretreatment with PGE2 (10-100 micrograms kg-1) or dmPGE2 (1-20 micrograms kg-1), either orally or intravenously, also failed to prevent the gastric vasocongestion induced by the lower dose of Paf. On the contrary, significant augmentation of Paf-induced damage was observed with several of the doses of PGE2 and dmPGE2. These studies demonstrate that the protective properties of PGE2 and dmPGE2 in the gastric mucosa do not extend to damage induced by Paf.

Topics: 16,16-Dimethylprostaglandin E2; Administration, Oral; Animals; Blood Pressure; Capillary Permeability; Dinoprostone; Ethanol; Injections, Intravenous; Male; Platelet Activating Factor; Prostaglandins E; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains; Stomach Ulcer

The purpose of these studies was to determine the role played by endogenous prostaglandins in the development of gastric ulcers produced by indomethacin, and of duodenal ulcers produced by mepirizole in rats. Indomethacin (10 mg/kg subcutaneously) produced gastric ulcers, whereas mepirizole (100 mg/kg subcutaneously) produced exclusively duodenal ulcers. Both drugs, given at ulcerogenic doses, reduced the gastric and duodenal generation of PGE2, PGF2 alpha, 6-keto-PGF1 alpha, and thromboxane B2. In this regard, the extent of reduction was more pronounced after indomethacin than after mepirizole. Despite this greater inhibition of prostaglandin synthesis by indomethacin, this drug did not produce duodenal ulcers, whereas mepirizole was duodenoulcerogenic. In addition, mepirizole increased gastric acid secretion by 74%, whereas indomethacin had no effect on acid secretion. Oral administration of 16,16-dimethyl PGE2, given at nonantisecretory doses (0.5-5 micrograms/kg), prevented formation of indomethacin-induced gastric ulcers, whereas antisecretory doses were required to prevent formation of mepirizole-induced duodenal ulcers. We conclude that a reduction of prostaglandin formation in the duodenal mucosa is not by itself sufficient to induce duodenal ulcers. We hypothesize that three changes, produced by mepirizole, must be present for duodenal ulcers to develop: increased gastric acid secretion, decreased duodenal bicarbonate secretion (as demonstrated earlier), and decreased duodenal content of prostaglandins. The decreased prostaglandin formation, although not causing duodenal ulcers, may lower the resistance of duodenal mucosa to the hyperacidity induced by mepirizole. On the other hand, in the case of gastric ulcers following administration of indomethacin, a decrease in gastric mucosal levels of prostaglandins may play a more important role than changes in gastric acidity.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Dose-Response Relationship, Drug; Drug Interactions; Duodenal Ulcer; Duodenum; Epirizole; Female; Gastric Mucosa; Indomethacin; Intestinal Mucosa; Prostaglandins; Pyrazoles; Rats; Rats, Inbred Strains; Stomach Ulcer; Time Factors

We investigated the gastroprotective effects of colloidal bismuth subcitrate (CBS, De-Nol) in comparison with agents such as sucralfate and methylated PGE2. Both CBS and sucralfate given orally prevented dose dependently the formation of gastric lesions by acidified aspirin, ethanol and restraint stress, CBS being more potent on a weight-to-weight basis than sucralfate. CBS and sucralfate were also equally effective in enhancing the healing rate of chronic gastric and duodenal ulcer induced by serosal application of acetic acid, while methylated PGE2 was completely ineffective in this model. Non-colloidal bismuth subnitrate, in contrast to CBS, was ineffective against stress-induced lesions. CBS stimulated mucosal generation and luminal release of PGE2 dose dependently.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Anti-Ulcer Agents; Aspirin; Immersion; Organometallic Compounds; Rats; Rats, Inbred Strains; Stomach Ulcer; Stress, Physiological; Sucralfate

This study was designed to compare the gastroprotective effects of colloidal bismuth subcitrate (CBS) with those of sucralfate and methylated analog of prostaglandin E2 (PGE2) against acute gastric lesions induced by absolute ethanol, acidified aspirin (ASA), and water immersion and restraint stress in rats. When given orally, both CBS and sucralfate prevented in a dose-dependent way the formation of gastric lesions induced by all three ulcerogens, CBS being about 7, 2, and 20 times more potent, respectively on a weight-to-weight basis than sucralfate. Methylated PGE2 was also highly effective against these ulcerogens. Bismuth subnitrate was ineffective against acute gastric lesions induced by stress conditions. The protection of both CBS and sucralfate was reversible when the animals were pretreated with indomethacin to suppress the generation of endogenous prostaglandins. Since CBS and sucralfate increased the production of PGE2 in the gastric mucosa, we postulate that their gastric protective action may be mediated, at least partly, by mucosal prostaglandins.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Bismuth; Dinoprostone; Gastric Mucosa; Organometallic Compounds; Prostaglandins E; Rats; Rats, Inbred Strains; Stomach Ulcer; Sucralfate

Flavonoids reportedly inhibit histidine decarboxylase and reduce gastric mucosal histamine content. We studied the effects of acute and chronic intragastric administration to rats of meciadanol, a new synthetic flavonoid (Zyma S.A., Nyon, Switzerland). The action of meciadanol was compared to that of 16,16-dimethyl PGE2. Meciadanol did not affect acid or pepsin output at any dose used. High doses of 16,16-dimethyl PGE2 reduced both acid and pepsin output. Meciadanol partially prevented aspirin-induced lesions but the prevention required chronic administration of meciadanol. In contrast, a single dose of meciadanol completely prevented ethanol-induced lesions. Chronic administration of meciadanol also completely prevented ethanol-induced lesions. 16,16-Dimethyl PGE2 prevented both aspirin-induced and ethanol-induced lesions in doses that did not affect acid or pepsin output. Meciadanol did not influence the effect that either aspirin or ethanol had on endogenous mucosal PGI2. Thus, the dose range of meciadanol that protected against ulcerogens did not affect either gastric acid secretion or pepsin output. Therefore, we conclude that meciadanol's action represents true cytoprotection, which was previously attributed only to prostaglandins.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Anti-Ulcer Agents; Aspirin; Benzopyrans; Carboxy-Lyases; Catechin; Epoprostenol; Ethanol; Female; Gastric Acid; Gastric Mucosa; Histidine Decarboxylase; Male; Rats; Rats, Inbred Strains; Stomach Ulcer; Time Factors

We studied the effects of elcatonin (eel calcitonin), on various gastric and duodenal lesions, gastric acid and duodenal alkaline secretion, and gastric motility in rats. Elcatonin at 1-30 unit/kg, given subcutaneously, dose-dependently inhibited the development of HCl-aspirin-, HCl-ethanol-, water-immersion stress- and indomethacin-induced gastric lesions. This agent also significantly prevented the formation of duodenal lesions induced by indomethacin plus histamine at 30 unit/kg, although it showed only a tendency of inhibition against mepirizole-induced duodenal lesions. 16, 16-Dimethyl prostaglandin E2 (3-30 micrograms/kg), given orally as a reference drug, showed a potent inhibition against all types of lesions tested herein at the dose of 3 micrograms/kg or greater. Elcatonin dose-dependently inhibited gastric secretion (volume, acid and pepsin output) in pylorus-ligated rats and gastric motility in conscious rats, but had no effect on duodenal alkaline secretion in anesthetized rats. On the other hand, 16, 16-dimethyl prostaglandin E2 at 10 micrograms/kg, given intraduodenally, significantly inhibited gastric secretion and motility, but stimulated duodenal alkaline secretion. We conclude that elcatonin markedly protects the gastrointestinal mucosa from injury induced by stress or various irritants. These effects might be in part accounted for by the antisecretory and antimotility activities of this peptide, although some other unknown mechanisms may be involved in the mucosal protection afforded by elcatonin.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Anti-Ulcer Agents; Calcitonin; Duodenal Ulcer; Gastric Mucosa; Gastrointestinal Motility; Intestinal Mucosa; Male; Rats; Rats, Inbred Strains; Stomach Ulcer; Stress, Physiological

Topics: 16,16-Dimethylprostaglandin E2; Animals; Cimetidine; Hepatectomy; Liver Regeneration; Male; Postoperative Complications; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains; Stomach Ulcer; Stress, Psychological; Vagotomy; Vagus Nerve

Topics: 16,16-Dimethylprostaglandin E2; Ammonia; Animals; Male; Rats; Stomach Ulcer

Mefenamic acid, given orally to rats at a single dose of 1200 mg/kg, produced renal papillary necrosis (RPN) in 63% of animals. The incidence was reduced to 27% by 16,16-dimethyl PGE2 (dmPGE2), given at an oral dose of 0.75 mg/kg t.i.d. RPN is likely to be caused by the renal prostaglandin depletion elicited by mefenamic acid, an inhibitor of prostaglandin cyclooxygenase. Substitution with dmPGE2 reduces RPN presumably by preventing the prostaglandin depletion. We conclude that the prostaglandin used is cytoprotective for the kidney. Mefenamic acid, like most nonsteroidal anti-inflammatory compounds (NOSAC), produced ulcerations of the small intestine (jejunum and ileum). These were prevented by dmPGE2 (intestinal cytoprotection). Unlike most other NOSAC, however, mefenamic acid produced duodenal ulcers in nearly all animals (80%). Of these ulcers, 88% were perforated. Twenty-five of the twenty-six animals that died had a perforated ulcer. These duodenal ulcers were also prevented by dmPGE2. Mefenamic acid-induced ulcers could be used as an experimental model for testing agents with a potential for preventing or healing duodenal ulcers.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Duodenal Ulcer; Female; Intestinal Diseases; Kidney Papillary Necrosis; Mefenamic Acid; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains; Stomach Ulcer

Stress ulcer is a common phenomenon after hepatectomy for cirrhotic liver. We examined experimentally the influence of cimetidine and 16,16-dm PGE2 dosaged as counter-measures against stress ulcer on liver regeneration after partial hepatectomy for cirrhotic liver. Using cimetidine and 16,16-dm PGE2, there was a noticeable suppression of the onset of water immersion stress ulcer, and both a decline in the blood flow in the wall of the stomach and a drop in PH in the stomach were inhibited after partial hepatectomy for cirrhotic liver. The group given 16,16-dm PGE2 after partial hepatectomy had a higher rate of DNA synthesis as compared with the group which had only partial hepatectomy. No difference was seen between the group given cimetidine and the only partial hepatectomy groups. The group given indomethacin before partial hepatectomy for cirrhotic liver had a noticeable decrease in mitotic index 30 hours after partial hepatectomy. However, the group given both indomethacin and 16,16-dm pGE2, showed some recovery of the mitotic index.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Cimetidine; Gastric Mucosa; Hepatectomy; Liver Cirrhosis, Experimental; Liver Regeneration; Male; Postoperative Complications; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains; Regional Blood Flow; Stomach Ulcer; Stress, Physiological

About 50% of patients receiving intrahepatic infusion of 5-fluorouracil deoxyriboside (5-FUDR) for colorectal cancer with hepatic metastasis develop significant gastroduodenal lesions. This paper reviews two studies on the effect of 16,16 dimethyl prostaglandin E2 (DMPGE2) on 5-fluorouracil-induced mucosal lesions in dogs. DMPGE2 at high doses (2 micrograms X kg-1 X h-1), which reduced histamine-stimulated gastric acid secretion by 65%, reduced gastric mucosal injury. Interestingly, DMPGE2 at much lower doses (0.02 micrograms X kg-1 X h-1), which had no effect on histamine-stimulated gastric acid secretion, was also effective in lowering gastric mucosal injury. These animal studies, if supported by the results of a larger patient study, would provide a rational basis for the use of prostaglandins in the prophylaxis and treatment of chemotherapy-induced ulcers.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Cimetidine; Dogs; Dose-Response Relationship, Drug; Floxuridine; Gastric Mucosa; Gastroscopy; Prostaglandins E, Synthetic; Stomach Ulcer

Acetazolamide, a carbonic anhydrase inhibitor, was administered orally and subcutaneously to rats. Acetazolamide increased the gastric ulcerogenicity of indomethacin, but inhibited gastric ulcers produced by acidified aspirin. When administered alone to fasted rats, it did not produce gastric ulcers. Acetazolamide was also cytoprotective for the stomach (it reduced dose dependently the number of gastric necrotic lesions caused by absolute ethanol given orally) and for the small intestine (it prevented dose dependently intestinal lesions produced by administration of a high dose of indomethacin). Acetazolamide did not prevent the antiulcer effect of PGE2 (against aspirin-induced ulcers) nor the cytoprotective effect of 16,16-dimethyl PGE2 (against ethanol-induced gastric lesions). The degree of gastric cytoprotection increased with time after a single administration of acetazolamide; the optimal effect occurred 60 and 90 min after oral and subcutaneous administration, respectively. Pretreatment with indomethacin completely prevented the cytoprotective effect of acetazolamide; this suggests that the cytoprotective effect may be mediated by endogenous release of prostaglandins by the stomach. All the effects of acetazolamide reported here were observed after either oral or subcutaneous administration. The mechanism by which acetazolamide influences ulcer formation and is cytoprotective is unknown.

Topics: 16,16-Dimethylprostaglandin E2; Acetazolamide; Animals; Aspirin; Dinoprostone; Ethanol; Female; Gastric Mucosa; Indomethacin; Prostaglandins E; Rats; Rats, Inbred Strains; Stomach Ulcer; Time Factors

The 'gastric mucosal barrier' is a descriptive term for the ability of the gastric epithelium to hold a large (10(5)) H+ concentration gradient from lumen to mucosa under physiological conditions. Compounds which classically have been used to describe the functional integrity of the 'barrier', in addition to very low H+ diffusion from lumen to mucosa, include low diffusion of Na+ and K+ from mucosa to lumen and maintenance of a lumen-negative transmucosal potential difference (PD). Na+ appearance in the luminal fluid is a function of active transport and diffusion. Fixed charges within diffusion channels with pK values greater than or equal to 9, may contribute to maintenance of H+ gradients. Luminal application of aspirin, bile salts, and ethanol increases net cationic flux and reduces PD. When acidified, these luminal agents produce histological and visible damage, yet damage can be produced by parenteral agents without concomitant change in these components. Although no anatomical 'barrier' has been described, it has been suggested that the gel mucus and epithelial phospholipids are constituents. Exogenous administration of a variety of prostanoids attenuate the change in cationic flux and PD produced by those agents in both animals and humans. The role of endogenous prostaglandins in barrier integrity has been questioned since it has been shown that salicylic acid produces permeability changes which are equal to aspirin, yet the former does not inhibit cyclooxygenase while the latter does. The gastric mucosal barrier is physiologically important because, by whatever mechanism, H+ back-diffusion is kept to a minimum under physiological conditions.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Diffusion; Gastric Mucosa; Humans; Hydrogen-Ion Concentration; Membrane Lipids; Membrane Potentials; Potassium; Prostaglandins; Sodium; Stomach Ulcer

The effects of cimetidine and ranitidine, alone or combined with sulglycotide or carbenoxolone, and those of 16,16-dimethyl prostaglandin E2 were investigated on mucosal lesions induced in pylorus-ligated rats. The drugs were administered orally after pylorus ligation; 3 hr later the animals were killed, the stomachs removed and examined for the presence of mucosal lesions. Volume, pH, total acidity, pepsin, free and barrier mucus were determined. H2-antagonists both at nonantisecretory and antisecretory doses failed to prevent gastric mucosal lesions or to affect significantly mucus and pepsin. Sulglycotide and carbenoxolone inhibited pepsin secretion, the latter enhanced barrier mucus and both reduced lesion severity. A nearly complete prevention of mucosal damage was observed after anti-secretory doses of cimetidine plus sulglycotide or carbenoxolone. Data obtained compared with those of 16,16-dimethyl prostaglandin E2 suggest that mucus and pepsin might have a partial role in ulcer prevention.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Anti-Ulcer Agents; Drug Therapy, Combination; Gastric Acidity Determination; Gastric Mucosa; Histamine H2 Antagonists; Male; Mucus; Pepsin A; Rats; Rats, Inbred Strains; Stomach Ulcer

The effects of prostacyclin (PGI2) and its stable thia-thimo-analogue (Hoe 892) on gastric and intestinal secretions and gastric mucosal lesions have been determined in conscious rats. Both PGI2 and Hoe 892 given subcutaneously (s.c.) reduced dose-dependent gastric acid secretion, the ID50 (dose producing 50% inhibition) being about 48.6 and 11.8 micrograms/kg, respectively. In contrast, intragastric (i.g.) PGI2 and Hoe 892 did not cause any change in gastric acid secretion at doses ranging from 1 to 100 micrograms/kg. Both PGI2 and Hoe 892 reduced significantly intestinal fluid secretion (antienteropooling activity). PGI2 and Hoe 892 given i.g. or s.c. reduced dose-dependent gastric ulcer formation induced by acidified aspirin (ASA), Hoe 892 being somewhat less potent than PGI2. Both PGI2 and Hoe 892 were equally effective against gastric mucosal necrosis induced by absolute ethanol and this effect was observed both after i.g. and s.c. administration of these agents. We conclude that stable thia-imino-PGI2 analogue, Hoe 892, has similar gastric and intestinal antisecretory and protective activity as PGI2 and may be useful in the prevention of gastric damage by various noxious agents.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Aspirin; Epoprostenol; Gastric Acid; Gastric Mucosa; Intestinal Mucosa; Male; Rats; Rats, Inbred Strains; Stomach Ulcer

M&B 28,767 [(+/-)11-deoxy-16-phenoxy-omega-tetranor PGE1] and 16, 16'-dimethyl PGE2 methylester (DMPG) were compared for their effects on gastric acid secretion (GAS) and gastric ulceration (GU), employing various laboratory models. In anaesthetised rats, GAS was stimulated by a continuous i.v. infusion of pentagastrin (30 micrograms/kg/h), and PG analogues were perfused through the stomach for 1 h. M&B 28,767 (3-15 micrograms/kg/h) and DMPG (3-60 micrograms/kg/h) reduced GAS in a dose-related manner, the ED50 values being 4 and 15 micrograms/kg/h respectively. In conscious rats possessing indwelling gastric cannulae, oral doses of M&B 28,767 (0.025-0.1 microgram/kg) and DMPG (0.50-1.0 microgram/kg) caused a prolonged inhibition of pentagastrin-stimulated GAS. M&B 28,767 was 17 times more potent than DMPG; the respective ED50 values were 0.036 and 0.6 microgram/kg. Indomethacin-induced ulceration in rats, was reduced by both M&B 28,767 and DMPG; the respective ED50 values being 3.0 and 0.8 micrograms/kg. Both compounds given orally increased gastrointestinal motility in mice; M&B 28,767 (1-3 mg/kg) and DMPG (0.1-0.3 mg/kg) caused diarrhoea, the former being about 0.1 times as potent as the latter. In another test, M&B 28,767 (0.5-5.0 mg/kg) and DMPG (10-40 micrograms/kg) overcame morphine-induced constipation in a dose-related manner, the respective ED50s being 0.9-1.4 mg/kg and 20-40 micrograms/kg. Thus, M&B 28,767 had a better profile of activity than DMPG as an antisecretory and antiulcer agent.

Topics: 16,16-Dimethylprostaglandin E2; Alprostadil; Animals; Constipation; Diarrhea; Gastric Acid; Gastrointestinal Motility; Indomethacin; Male; Mice; Morphine; Pentagastrin; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains; Stomach Ulcer

Several prostaglandins inhibit gastric acid secretion and prevent ulcer formation in animals by mechanisms that are independent from each other. Little is known about these properties in humans. The effects of 16,16-dimethyl-prostaglandin E2 and the thiaprostaglandin E2 EMD 33 290 were tested on basal acid secretion as well as on the aspirin- and bile salt-induced fall of gastric transmucosal potential difference in man. 16,16-dm PGE2 and EMD 33 290 prevented the drop in gastric potential difference caused by 1000 mg aspirin or 50 ml of 4 mmol/l Na-taurocholate. The protective doses against aspirin were 0.1 microgram and 50 micrograms for 16,16-dm PGE, and EMD 33 290 respectively. Against Na-taurocholate, doses of 1.0 microgram and 250 micrograms were effective. By contrast, 20-100 times higher doses of both prostaglandin analogues were necessary to inhibit gastric acid secretion. Half maximal inhibition of basal acid output was achieved by 0.1 microgram/kg b.w. of 16,16-dm PGE2 and by 28 micrograms/kg b.w. EMD 33 290. In analogy to animal findings, antisecretory prostaglandins protect the human stomach against aspirin and bile salts in doses which are much smaller than the threshold antisecretory ones.

Topics: 16,16-Dimethylprostaglandin E2; Adult; Aspirin; Bile Acids and Salts; Dose-Response Relationship, Drug; Gastric Acid; Gastric Mucosa; Humans; Male; Membrane Potentials; Prostaglandins, Synthetic; Stomach Ulcer

Gastric ulcerations were produced in rats by oral administration of aspirin (ASA) suspended in a vehicle consisting of either water or increasing concentrations of HCl (0.005 M to 0.35 M). The lesions were prevented by antisecretory doses of a histamine H2 blocker (cimetidine) and by an anticholinergic agent (pro-banthine), but only when the acidity of the vehicle was low (0.05 M to 0.15 M), not at higher (0.35 M). On the other hand, 16,16-dimethyl PGE2 prevented ulcer formation even when ASA was suspended in all HCl concentrations, including 0.35 M HCl. In other studies, gastric mucosal necrosis was produced by oral administration of absolute ethanol. These lesions were not affected by cimetidine or two anticholinergic agents, pro-banthine and methscopolamine bromide, nor by alkalinization of the gastric lumen with NaHCO3 or pH 7 buffer; however, these ethanol-induced lesions were completely prevented by 16,16-dimethyl PGE2. We conclude that antisecretory agents, by blocking endogenous formation of acid, are antiulcer as long as no acid or only small amounts of acid (1 ml of 0.15 M or less) are given together with ASA. When higher concentrations are used (e.g. 0.35 M HCl), the antisecretory effect of the inhibitors is overcome by the exogenous acid, and ulcers still form. Under these conditions, only "true" cytoprotective agents, such as 16,16-dimethyl PGE2, prevent ASA-induced ulcers, even in the presence of high acidity. Although cimetidine and pro-banthine were shown earlier to reduce ASA-induced ulcers at nonantisecretory doses, these agents may still decrease acid formation within the gastric glands.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 16,16-Dimethylprostaglandin E2; Animals; Anti-Ulcer Agents; Aspirin; Cimetidine; Ethanol; Female; Gastric Acid; N-Methylscopolamine; Propantheline; Rats; Rats, Inbred Strains; Scopolamine Derivatives; Secretory Rate; Stomach Ulcer

Focal ischemia is postulated to contribute to gastric mucosal stress ulceration. This study evaluated directly whether or not mucosal ulceration during hemorrhagic shock is preceded by focal gastric mucosal blood flow changes, and whether or not topical Dm-PGE2 (16,16-dimethyl prostaglandin E2) affects focal gastric mucosal blood flow during hemorrhagic shock. Twelve anesthetized miniature swine had pyloric ligation and intragastric infusion of 5 ml/kg autogenous bile in 140 mM HCl. Gastric mucosal blood flow was documented by radiolabeled microspheres during normotension, initial hemorrhagic shock (50 mm Hg), and hemorrhagic shock + 50 micrograms topical Dm-PGE2. Stable shock was then maintained for 3 hr. During this time ulceration developed, shedding radiolabeled microsphere-bearing mucosa into the lumen. Intact gastric mucosa and luminal contents were collected, weighed, and gamma counted. Blood flow to intact mucosa was calculated by standard techniques. The weight of shed tissue, as well as the blood flow to shed tissue, was calculated from luminal microspheres.. gastric mucosal blood flow was decreased 35% with hemorrhagic shock (28.8 +/- 4.0 vs 18.7 +/- 2.7 ml/100 g/min, P less than 0.05). Blood flow to tissue which was subsequently shed averaged 6.4 +/- 3.1 ml/100 g/min at the same time period (P less than 0.05 vs surrounding tissue). Addition of Dm-PGE2 increased blood flow to shed tissue from 29 +/- 8% to 48 +/- 10% of blood flow to intact tissue (P less than 0.05).. (1) gastric mucosal ulceration is preceded by focal decreases in gastric mucosal blood flow, and (2) topical Dm-PGE2 reverses focal mucosal ischemia during hemorrhagic shock. Dm-PGE2's ability to reverse focal ischemia suggests a mechanism for prostaglandin-mediated cytoprotection.

Topics: 16,16-Dimethylprostaglandin E2; Administration, Topical; Animals; Gastric Mucosa; Ischemia; Prostaglandins E, Synthetic; Regional Blood Flow; Shock, Hemorrhagic; Stomach Ulcer; Stress, Physiological; Swine; Swine, Miniature; Time Factors

Most research on the beneficial effects of pharmacologic agents on stress-induced acute gastric erosions in animals is directed at prevention. It is only the rare study that has been concerned with treatment of established erosions. A treatment model has been created using cervical cord-injured male Sprague-Dawley rats which consistently developed extensive linear erosions of the glandular portions of the stomach within 12 hr. A group of spinal rats was sacrificed after 12 hr to serve as a base of pretreatment ulcer severity. Treatment of established erosions with cimetidine 25 mg/kg every 2 hr in one group and 16,16-dimethyl prostaglandin E2 (16,16-dmPGE2) 5 micrograms/kg every 2 hr in a second group was compared to saline-treated controls. All drugs were administered by intraperitoneal route. Treatment began 12 hr after the cord transection and continued for another 12 hr at which time the rats were sacrificed. Both cimetidine and 16,16-dmPGE2 significantly inhibited the degree of erosion progression after 12 hr compared to saline controls (P less than 0.05). Acid output studies were carried out on a second set of rats subjected to the same experimental conditions with the addition of pyloric ligation 6 hr prior to sacrifice. A significant decrease in acid output (P less than 0.05) occurred only in the cimetidine group compared to control. It is concluded that both cimetidine and 16,16-dmPGE2 can arrest the progression of erosive changes in the stomach after cervical cord injury in rats. This is likely related to acid reduction by cimetidine and cytoprotection by prostaglandin.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Cimetidine; Gastric Acid; Guanidines; Male; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains; Spinal Cord Injuries; Stomach Ulcer

Fasted rats were given either 16,16-dimethyl-PGE2 (dmPGE2) (1 microgram/kg) or normal saline subcutaneously followed by the oral administration of 1 ml of 100% ethanol or saline 30 min later. At 1, 3, 6, and 24 hr later, animals were sacrificed, their stomachs examined for necrotic ulcerations, and the incorporation of [3H]thymidine into DNA as well as tissue levels of DNA, RNA, and protein content of glandular mucosa determined. Compared with control animals, severe ulcerations of 70-80% of the glandular mucosa were observed in rats given 100% ethanol at all time periods. Accompanying these ulcerations were marked depressions in tissue levels of DNA and RNA at 1, 3, 6, and 24 hr after exposure to ethanol, and protein at 1, 3, and 6 hr following ethanol. In rats pretreated with dmPGE2 before ethanol administration, these alterations in tissue levels of DNA, RNA, and protein were prevented as were ulcerations of the glandular stomach at each time period. Synthesis of mucosal DNA was not significantly different from control rats in any of the groups studied. It is concluded that (1) gastric mucosal damage by alcohol is associated with a decrease in tissue levels of DNA, RNA, and protein; (2) dmPGE2 maintains normal tissue levels of DNA, RNA, and protein by preventing the shedding of mucosal cells by alcohol; and (3) the ability of dmPGE2 to prevent gastric damage by alcohol is not mediated through stimulation of DNA synthesis.

Topics: 16,16-Dimethylprostaglandin E2; Animals; DNA; Ethanol; Gastric Mucosa; Male; Prostaglandins E, Synthetic; Proteins; Rats; Rats, Inbred Strains; RNA; Stomach Ulcer

In order to investigate the cytoprotective action of 16-16-dimethyl-prostaglandin E2 (16-16D), we studied its effect on sacs of isolated amphibian gastric mucosa known to ulcerate with high frequency in the absence of nutrient HCO3-. The actions of 16-16D, 2.85 X 10(-6) M, were also studied in an in vitro chamber. The incidence of ulceration in HCO3- -free nutrient media containing 10(-4) M histamine was significantly reduced by 16-16D. When artificial gastric juice (AGJ) was instilled into the lumen of the sac, protection occurred only after a pretreatment period of 60 min. Cytoprotection was not observed when active secretion of H+ was inhibited with 10(-3) M metiamide, and AGJ was placed in the lumen of the sac. In open sheets of fundus stimulated with 10(-4) M histamine, 16-16D did not influence H+ secretion. Isc was significantly higher than in control tissues. We conclude that 16-16D is cytoprotective in amphibian gastric mucosa by an action independent of changes in acid secretion or in blood flow. In addition, our studies suggest that 16-16D may increase the availability to the surface cells of nutrient HCO3- produced by actively secreting oxyntic cells.

Topics: 16,16-Dimethylprostaglandin E2; Acid-Base Equilibrium; Animals; Anura; Buffers; Gastric Mucosa; Histamine; In Vitro Techniques; Male; Metiamide; Prostaglandins E, Synthetic; Rana catesbeiana; Stomach Ulcer; Time Factors

The prostaglandins E2 and 16,16-dimethyl-PGE2 methyl ester were compared with the H2-receptor antagonists burimamide and metiamide for their effects on gastric acid secretion (GAS) and gastric mucosal blood flow (MBF) in rats and dogs, and on ulcer formation in rats. Orally, both 16,16-dimethyl-PGE2 methyl ester (20 microgram/kg) and metiamide (6 mg/kg) were markedly effective inhibitors of GAS stimulated by histamine acid phosphate or pentagastrin in Heidenhain pouch dogs, producing a reduction both in volume of gastric juice and in the concentration of titratable acid. In anaesthetised rats, however, the H2-receptor antagonists, when perfused into the gastric lumen, did not consistently inhibit the increased GAS caused by various secretagogues. In contrast, the prostaglandins, under the same conditions, caused marked inhibition of GAS provoked by all secretagogues. Intravenously, both burimamide and metiamide were effective in inhibiting GAS in rats but were less potent than the prostaglandins. The order of potency was: 16,16-dimethyl-PGE2 methyl ester greater than PGE2 greater than metiamide greater than burimamide. By the oral route, the H2-receptor antagonists were found to be very weak inhibitors of indometacin-induced gastric ulcer in rats, as compared to the prostaglandins. MBF studies in rats and in Heidenhain dogs showed that i.v. or p.o. administration inhibited both GAS and MBF in most cases. The ratio r = [MBF (ml/min)/GAS (mumol H+/min)] was generally increased by both types of compounds, suggesting a preferential effect on GAS.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Constipation; Dogs; Female; Gastric Mucosa; Gastrointestinal Motility; Histamine H2 Antagonists; Indomethacin; Male; Mice; Morphine; Prostaglandins E; Prostaglandins E, Synthetic; Rats; Regional Blood Flow; Stomach Ulcer

Topics: 16,16-Dimethylprostaglandin E2; Animals; Aspirin; Dogs; Gastric Acid; Gastric Mucosa; Prostaglandins E, Synthetic; Stomach Ulcer