16-16-dimethylprostaglandin-e2 and Gastrointestinal-Hemorrhage

We studied whether pretreatment with prostaglandin (16,16-dimethyl (dm) prostaglandin E2) may protect the human gastric mucosa against alcohol-induced injury. Healthy volunteers received (via an endoscope) intragastric pretreatment with either: A) placebo or B) 16,16 dm prostaglandin E2, 1 microgram/kg, and 15 min later 40 ml 60% alcohol was sprayed directly on gastric mucosa.. endoscopic appearance of the gastric mucosa was evaluated and scored (scale 0-5) by two investigators, gastric mucosal potential difference (PD) was continuously recorded, and mucosal biopsies were obtained at 30 min after alcohol for histologic examination. Alcohol instillation in subjects pretreated with placebo (group A) produced within 30 min prominent endoscopic hemorrhagic lesions (grade 4.8 +/- 0.2). Histologic examination showed exfoliation of the surface epithelium, extensive edema of lamina propria, and deep hemorrhagic necrotic lesions in 86% +/- 10 of specimens. These morphologic changes coincided with a sudden drop in gastric PD of 42 mV. Prostaglandin pretreatment (group B) significantly reduced alcohol-induced endoscopically visible lesions (grade 3.1 +/- 0.2, P less than 0.01 vs group A). Histologically, prostaglandins reduced deep hemorrhagic erosions (4.5-fold reduction) and subepithelial hemorrhages, but did not prevent exfoliation of the surface epithelium and gastric PD drop. Thus, prostaglandin administration to human volunteers effectively reduced alcohol injury to the gastric mucosa.

Topics: 16,16-Dimethylprostaglandin E2; Adult; Ethanol; Gastric Mucosa; Gastrointestinal Hemorrhage; Gastroscopy; Humans; Male; Membrane Potentials; Prostaglandins E, Synthetic

The gastroduodenal mucus layer is progressively eroded at its luminal surface as a consequence of pepsin mucolysis. Diosmectite binds to gastric mucus and modifies its rheological properties. Prostaglandins are well-known mucus secretagogues. The aim of this study is to describe interactions of diosmectite and 16,16 dimethyl prostaglandin E2 on adherent gastroduodenal mucus and pepsin mucolysis in the rat.. Instillation of pepsin (1 or 2 mg.mL-1 at pH1 or pH2) into the pylorus ligated stomach of anaesthetised rats resulted in progressive disruption of the adherent mucus layer and a large, significant, increase in soluble degraded mucin compared to that following instillation of HCl pH1 or pH2. Pepsin (2 mg.mL-1), instillation over 2 hours, but not HCl alone, consistently resulted in small focal, haemorrhagic mucosal lesions, significant bleeding into the lumen and histologically, localised punctate ulcers in an otherwise intact epithelium. Diosmectite (500 mg.kg-1) and 16,16 dimethyl prostaglandin E2 were given by oro-gastric intubation.. Diosmectite, given 30 minutes beforehand, inhibited breakdown of the adherent gastric mucus barrier by pepsin in vivo. When administered up to 16 hours prior to the experiment, diosmectite prevented pepsin induced gastric mucosal haemorrhage and histological epithelial damage. Substantial amounts of diosmectite (39.6 micrograms/mm2, equivalent in volume to layer 93 microns thick) were bound to the gastric mucosa 30 minutes after administration. Diosmectite (100:1 by weight to enzyme) completely inhibited pepsin hydrolysis of protein in vitro. Topical 16,16 dimethyl prostaglandin E2, 5 micrograms.kg-1 increased the thickness of the adherent mucus layer by two-fold. Both doses of the prostaglandin prevented pepsin induced gastric mucosal haemorrhage and histological epithelial damage.. These results show that both diosmectite and prostaglandin increase the effectiveness of the mucus barrier against mucosal damage by pepsin in vivo.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Depression, Chemical; Gastric Mucins; Gastric Mucosa; Gastrointestinal Agents; Gastrointestinal Hemorrhage; Iron; Male; Pepsin A; Rats; Rats, Wistar; Silicates

The gastric mucosa of newborn rats is sensitive to the damaging effects of acid and ethanol. We measured gastric mucus gel thickness in newborn, suckling, and weaned rats by inversion microscopic observation. The thickness in newborn rats was 52.2 +/- 6.7 microns and increased with age, reaching 96.8 +/- 5.6 microns in 8-wk-old rats (p less than 0.001). Oral administration of 16,16-dimethyl prostaglandin E2 at concentrations of 10 and 100 micrograms/kg body weight increased mucus thickness in 8-wk-old rats but had no effect in 1-wk-old rats. We also assessed the effect of 16,16-dimethyl prostaglandin E2 on the prevention of gastric mucosal damage induced by ethanol. Oral 16,16-dimethyl prostaglandin E2 reduced damage in 8-wk-old rats, but there was no effect in 1-wk-old rats. These data suggest that the susceptibility of newborn rats to gastric mucosal injury may be related to the relative thinness of the gastric mucus gel layer and the failure of prostaglandins to increase the mucus gel layer thickness.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Animals, Newborn; Ethanol; Gastric Mucosa; Gastrointestinal Hemorrhage; Mucus; Rats; Rats, Inbred Strains

We studied the conversion of acute edematous pancreatitis (AEP) to acute hemorrhagic pancreatitis (AHP) in an experimental model in cats. In the model, 16,16 dimethyl PgE2 effects this conversion by increasing microvascular permeability. First, we induced AEP in cats and then gave PgE2 at increasing intervals after the induction of AEP to see how long an interval would still allow conversion. In 6 groups of cats, PgE2 was administered for 2 h, starting at 2, 4, 6, 8, 10, or 12 h after the creation of AEP. Twelve h later, the cats were sacrificed and the pancreases were graded for inflammation and hemorrhage. Significant pancreatic hemorrhage did not occur when the PgE2 was administered at 12 h compared to 2 h. Next, we determined that PgE2 still retained its ability to increase pancreatic vascular permeability when administered 12 h after the creation of AEP. This was done by perfusing a marker molecule through the MPD (fluorescein isothiocyanate labeled dextran: FITC-D, mol wt 20,000) and then finding it in portal venous blood (PVB). The presence of FITC-D in PVB signified increased vascular permeability, since normally none was present. We concluded that conversion of AEP to AHP was possible during the first 12 h after induction of AEP. Lack of conversion at 12 h was not caused by a lack of vascular reactivity at that time.

Topics: 16,16-Dimethylprostaglandin E2; Acute Disease; Animals; Capillary Permeability; Cats; Disease Models, Animal; Edema; Gastrointestinal Hemorrhage; Pancreatic Juice; Pancreatitis; Time Factors

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

Protection of the gastric mucosa may be the result of either increased cellular resistance to injury (cytoprotection) or, alternatively, decreased exposure of mucosal cells to the damaging agent. To determine whether decreased exposure of mucosal cells to damaging agents plays a role in mucosal protection by 16,16-dm PGE2 or sodium thiosulfate, we estimated the intramucosal concentration of 22NaCl and measured its absorption from the gastric lumen into the systemic circulation 1 and 5 min after intragastric administration of hypertonic (25% w/v) 22NaCl. In an attempt to explain the differences observed, we also measured the net transmucosal water flux in control animals and rats pretreated with the protective agents. Administration of hypertonic NaCl rapidly (within 1 min) induced extensive hemorrhagic mucosal lesions that were significantly reduced by pretreatment with 16,16-dm PGE2 or sodium thiosulfate. Ultra-low temperature autoradiography indicated that luminal hypertonic 22NaCl penetrates the upper layers of the mucosa in relatively high concentrations (12.5% w/v) within 1 min but its concentration decreases rapidly and reached low levels (3.12% w/v) by 5 min. Absorption of NaCl from the gastric lumen into the systemic circulation 1 and 5 min after hypertonic NaCl was lower in both pretreatment groups than in the control. Net gastric transmucosal water flux (from serosa to mucosa) increased (P less than 0.05) from 100 +/- 2 in controls, to 1470 +/- 8 and 715 +/- 9 microliters in rats pretreated with 16,16-dm PGE2 and sodium thiosulfate, respectively. We conclude that 16,16-dm PGE2 and sodium thiosulfate protect the gastric mucosa against hypertonic NaCl, diminish mucosal penetration of NaCl, decrease mucosal absorption of NaCl, and significantly increase serosal to mucosal transmucosal water flux.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 16,16-Dimethylprostaglandin E2; Animals; Antioxidants; Female; Gastric Mucosa; Gastrointestinal Hemorrhage; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains; Saline Solution, Hypertonic; Sodium Radioisotopes; Thiosulfates; Time Factors

Gastric bleeding caused by cyclooxygenase inhibitors has been assessed by a novel method. Rats are adapted to a strict light-dark cycle with limited access to food to reduce the stress associated with starvation. Such animals are then labeled with 51Cr-red blood cells from donor animals and dosed with the compound under evaluation. After 24 hr. animals are sacrificed and the amount of blood that has accumulated in the lumen of the cecum is quantitated. The potency of cyclooxygenase inhibitors in this assay to cause gastric bleeding is as follows: indomethacin greater than piroxicam greater than naproxen greater than ibuprofen greater than diflunisal which is similar to their antiinflammatory potency in the rat. In addition, the protective activity of PGE2 on indomethacin-induced gastric bleeding is clearly shown by this method.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Cyclooxygenase Inhibitors; Gastrointestinal Hemorrhage; Indomethacin; Male; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains

While the incidence of duodenal ulcer disease has been documented to be greater in men than in women, this observation has not been previously noted in animal studies of the upper gastrointestinal tract. In this study, we questioned whether the cytoprotective properties of 16, 16-dimethyl PGE2 were sex-related by comparing the degree of ethanol-induced hemorrhagic gastritis in male and female rats pretreated with 16,16-dimethyl PGE2 or lithium chloride. Animals receiving 16,16-dimethyl PGE2 or lithium chloride had significantly less ethanol-induced hemorrhagic gastritis (1.17 +/- 0.15 and 1.24 +/- 0.13, respectively, p less than 0.001) when compared with controls (2.69 +/- 0.10). Female rats treated with 16,16-dimethyl PGE2 had 59% less hemorrhagic gastritis than male rats treated similarly (0.76 +/- 0.14 vs 1.86 +/- 0.19 respectively, p less than 0.001). This sex-related difference in hemorrhagic gastritis was not noted in male and female rats receiving lithium chloride (1.24 +/- 0.15 vs 1.23 +/- 0.27, respectively). However, female rats treated with 16, 16-dimethyl PGE2 had significantly less hemorrhagic gastritis when compared with female rats receiving lithium chloride (0.76 +/- 0.14 vs 1.24 +/- 0.15 respectively, p less than 0.05).

Topics: 16,16-Dimethylprostaglandin E2; Animals; Chlorides; Ethanol; Female; Gastric Mucosa; Gastritis; Gastrointestinal Hemorrhage; Lithium; Lithium Chloride; Male; Peptic Ulcer; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains; Sex Factors

The ability of prostaglandin E2 (PGE2) and its analogue, 16,16-dimethyl PGE2 (dmPGE2) to protect the rat gastric mucosa from damage has been investigated using the release of enzyme markers as an index of surface cell disruption. These studies have been extended to investigate whether prostanoids can also enhance the rapid repair process which re-establishes epithelial continuity. With low oral doses of PGE2 (100 micrograms kg-1) and dmPGE2 (2.5 micrograms kg-1), the deep necrotic damage induced by intragastric instillation of ethanol was inhibited, yet the mucosal enzyme release (acid phosphatase and lactate dehydrogenase) determined in vitro was unaltered. At higher doses, both prostanoids reduced enzyme release, suggesting some preservation or rapid re-establishment of epithelial cell continuity under these conditions. Studies utilizing the gastric chamber indicated that high doses of dmPGE2 (20-40 micrograms kg-1) reduced the changes in potential difference and potassium efflux following challenge with 50% ethanol, and accelerated the rate of recovery of these parameters. Furthermore, a reduced level of epithelial cell discontinuity was determined by histological techniques. Thus, prostanoids not only protect deeper mucosal cells from necrotic damage by local irritants, but may protect the surface cells at higher doses under some conditions, and may enhance the process of epithelial restitution.

Topics: 16,16-Dimethylprostaglandin E2; Acid Phosphatase; Animals; Dinoprostone; Ethanol; Gastric Mucosa; Gastrointestinal Hemorrhage; In Vitro Techniques; L-Lactate Dehydrogenase; Male; Prostaglandins E; Prostaglandins E, Synthetic; Rats

The purpose of the present study was to determine whether the gastric cytoprotective effect of a prostaglandin such as 16,16-dimethyl prostaglandin (dmPGE2) is mediated by an increase in mucosal blood flow. Gastric mucosal blood flow was measured in urethane-anesthetized rats by the hydrogen gas clearance technique. In control rats given no ethanol, intragastric administration of dmPGE2 (10 micrograms/kg body wt) produced a significant reduction (15.3%) in gastric mucosal blood flow 30 min after treatment. This dose of dmPGE2 significantly reduced the formation of the gross gastric lesions produced by absolute ethanol in anesthetized rats. In vehicle-pretreated animals, blood flow was invariably absent in the ethanol-induced mucosal lesion areas. In the nonlesion areas, gastric mucosal blood flow was the same in prostaglandin-pretreated and vehicle-pretreated animals as in control (no ethanol) rats. Thus, although dmPGE2 pretreatment protected against ethanol-induced gastric mucosal injury and prevented the accompanying blood flow stasis, it did not do this by an increase in gastric mucosal blood flow. The protection also is not due to a decrease in flow because, in separate groups of anesthetized rats, a 15% reduction in gastric mucosal blood flow induced by either hemorrhage or intravenous vasopressin did not protect the gastric mucosa against absolute ethanol-induced injury. Whether the maintenance of gastric mucosal blood flow is a primary or secondary effect of prostaglandin cytoprotection remains to be determined.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Ethanol; Gastric Mucosa; Gastrointestinal Hemorrhage; Male; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains; Regional Blood Flow; Stomach Diseases; Vasopressins

The effects of pretreatment with 16,16-dimethyl prostaglandin E2 (DmPGE2) on the recovery of gastric mucosal 'barrier' parameters after ethanol-induced damage were studied using an ex vivo chamber preparation in the rat. DmPGE2 (4-40 micrograms kg-1) significantly reduced the extent of haemorrhagic damage to the gastric mucosa induced by the topical application of 50% ethanol followed by 0.05 M hydrochloric acid. The lowest dose of DmPGE2 tested (4 micrograms kg-1) had no effect on the ethanol-induced changes in transmucosal potential difference (PD) or K+ efflux. However, DmPGE2 at doses at 20 or 40 micrograms kg-1 significantly reduced the changes in these indices of epithelial integrity. The recovery of PD and K+ efflux to control levels after ethanol-injury was accelerated by DmPGE2. With the two higher doses of DmPGE2 (20 and 40 micrograms kg-1) there was a significantly (P less than 0.001) lower level of epithelial discontinuity, measured histologically, in samples taken at the end of the experiment. These results suggest that at the higher doses, DmPGE2 confers some protection to the gastric epithelium as well as accelerating the recovery of epithelial integrity after damage induced by ethanol.

Topics: 16,16-Dimethylprostaglandin E2; Administration, Topical; Animals; Ethanol; Gastric Mucosa; Gastrointestinal Hemorrhage; Male; Membrane Potentials; Necrosis; Potassium; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains

The gastric mucosa of animals and man can be damaged by noxious agents and protected by prostaglandins. We developed a Heidenhain pouch dog model which allows the study of multiple doses of the protective or noxious agent. Mucosal damage in the pouch caused by instillation of 160 mM aspirin suspended in 150 mM HCl for two 15-min periods was determined by measuring hemoglobin concentration in isotonic mannitol washes. Hemoglobin levels 24 h after the administration of the acid-aspirin suspension were significantly higher than basal levels. Pretreatment with oral doses of 0.3-3 micrograms/kg 16,16-dimethyl PGE2 at 24 and 18 h and 30 min before the acid-aspirin suspension decreased hemoglobin concentrations in the washes (p less than 0.001).

Topics: 16,16-Dimethylprostaglandin E2; Animals; Aspirin; Disease Models, Animal; Dogs; Female; Gastric Mucosa; Gastrointestinal Hemorrhage; Male; Prostaglandins E, Synthetic; Stomach; Stomach Diseases