16-16-dimethylprostaglandin-e2 and Necrosis

Cytoprotective effects of the prostaglandins 16,16-dimethyl PGE2 (dmPGE2) and PGF2 alpha tromethamine (PGF2 alpha) were evaluated in the rat model of acute hepatocellular necrosis induced by thioacetamide (TAA). dmPGE2 (100 micrograms/kg SC 8 hourly) did not induce a significant increase in survival when started after the onset of TAA-induced fulminant hepatic failure. However, priming with dmPGE2 (100 micrograms/kg SC 30 min before TAA) reduced TAA-induced elevations in serum ALT (684 +/- 68 (SEM) vs 274 +/- 135 IU/1, p less than 0.01). This phenomenon did not occur if dmPGE2 was administered after TAA or by the IP route. Modulation of TAA-induced centrizonal hepatocellular necrosis by dmPGE2 was associated with a striking increase in centrizonal ballooning of hepatocytes (p less than 0.01), and, as assessed by stereology, less hepatocellular necrosis and degenerative changes. PGF2 alpha, which in contrast to dmPGE2 does not act via cAMP, had no effect on TAA-induced changes in serum ALT or hepatic histology. These findings suggest that dmPGE2 decreases hepatocellular necrosis by activating surface membrane adenylate cyclase and consequently stimulating cAMP. Ballooning of hepatocytes could occur secondary to these membrane events and appears to be a marker of dmPGE2-induced cytoprotection in this model.

Topics: 16,16-Dimethylprostaglandin E2; Alanine Transaminase; Animals; Dinoprost; Hepatic Encephalopathy; Liver; Male; Necrosis; Rats; Rats, Sprague-Dawley; Thioacetamide

Pretreatment with prostaglandins at non-antisecretory doses protects the gastric mucosa, including the parietal cells, from deep necrosis produced by intragastric administration of necrotising agents such as absolute ethanol. Whether the parietal cells also retained their ability to secrete acid when rats were pretreated with a prostaglandin, in spite of exposure to ethanol, was investigated. Gastric acid secretion was abolished 4 hours after ethanol, and secretion returned to control values only after 5-6 days. Pretreatment with a single, non-antisecretory dose of 16, 16-dimethyl prostaglandin E2 (dm PGE2) maintained acid secretion, in spite of exposure to absolute ethanol. Absolute ethanol caused histological changes - extensive gastric mucosal necrosis (through the muscularis mucosae), oedema, haemorrhages, polymorphonuclear infiltration, and formation of granulation tissue - that were maximal 24-48 hours after ethanol and persisted for 2 to 4 weeks. None of these changes were present in animals treated with the prostaglandin. It is concluded that a single oral pretreatment with dmPGE2 protects the gastric mucosa against not only the morphological damage of absolute ethanol (preventing necrosis, haemorrhages, and polymorphonuclear infiltration) but also the functional damage (maintaining the acid secretory function of parietal cells).

Topics: 16,16-Dimethylprostaglandin E2; Administration, Oral; Animals; Ethanol; Female; Gastric Acid; Gastric Mucosa; Male; Necrosis; Rats; Rats, Inbred Strains

Topics: 16,16-Dimethylprostaglandin E2; Alprostadil; Animals; Dose-Response Relationship, Drug; Ethanol; Gastric Mucosa; Hydrochloric Acid; Necrosis; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains

Effects of acetaminophen against gastric mucosal lesions induced by three different necrotizing agents were studied. Acetaminophen (30, 100 mg/kg), given p.o. 0.5 hr before absolute ethanol, HCl . ethanol, or HCl . aspirin administration, afforded no cytoprotection against gastric mucosal lesions induced by the above agents in 24 hr fasted rats. However, 16,16-dimethyl prostaglandin E2 (3 micrograms/kg), given p.o. 0.5 hr before these necrotizing agents, completely prevented development of these lesions.

Topics: 16,16-Dimethylprostaglandin E2; Acetaminophen; Animals; Aspirin; Ethanol; Gastric Mucosa; Hydrochloric Acid; Male; Necrosis; Rats; Rats, Inbred Strains

Studies performed in the author's laboratory concerning the role of gastric mucosal blood flow in ethanol-induced gastric mucosal injury and prostaglandin cytoprotection are reviewed. Fluorescent in vivo microscopic and hydrogen gas clearance studies revealed total absence of blood flow in the gross ethanol-induced lesions. Prostaglandin pretreatment not only prevented gross lesion formation but flow was present throughout the mucosa. A cytoprotective dose of the prostaglandin analogue did not increase blood flow. Transmitted light in vivo microscopy revealed rapid cessation of blood flow through mucosal microvessels within 1 min of ethanol application. The microvessels remained filled with red blood cells, suggesting an intravascular coagulation phenomenon. Histologic studies revealed no necrotic lesion formation 1 min after ethanol, but increasing necrosis from 10 to 60 min. These findings suggest that the rapid ethanol-induced cessation of blood flow renders the gastric mucosa more susceptible to ethanol injury and prostaglandin acts by preventing this blood flow change.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Ethanol; Gastric Mucosa; Male; Necrosis; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains; Regional Blood Flow; Videotape Recording

Exogenous prostaglandins inhibit visible gastric mucosal lesions produced by both absolute ethanol and cold restraint in the rat. Pretreatment with "mild irritants" significantly reduces the magnitude of ethanol-induced lesions presumably by stimulating endogenous prostanoid production. The effect of mild irritant pretreatment on cold restraint-induced lesion formation has not been previously reported. This study was designed to compare the protective effect of pretreatment with two "mild irritants," 4% NaCl and 0.35 M HCl, and the synthetic prostanoid, 16,16 dimethyl PGE2(16,16-dm PGE2), on lesions produced by cold restraint or absolute ethanol. Pretreatment with both mild irritants produced complete visible protection against ethanol-induced injury but had variable effects against cold restraint-induced injury. Whereas 5 micrograms/kg 16,16-dmPGE2 provided complete visible protection against ethanol-induced injury, 20 micrograms/kg 16,16-dmPGE2 was required for complete visible protection against cold restraint-induced injury. We conclude that prostaglandin requirements for protection against cold restraint injury are greater than for protection against ethanol-induced gastric mucosal injury.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Cold Temperature; Ethanol; Gastric Mucosa; Hydrochloric Acid; Irritants; Male; Necrosis; Prostaglandins; Rats; Rats, Inbred Strains; Restraint, Physical; Saline Solution, Hypertonic

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

Damage to the rat gastric mucosa after oral administration of ethanol and the effect of pretreatment with a prostaglandin analogue has been evaluated using histologic and enzyme-marker techniques. Rat whole stomachs were incubated in vitro and the intraluminal release of the cytoplasmic enzyme lactate dehydrogenase and the lysosomal enzymes acid phosphatase and beta-glucuronidase was determined by spectrophotometric techniques. Ethanol irrigation in vivo for 10 min significantly elevated the subsequent intraluminal release of both cytoplasmic and lysosomal enzymes in vitro. Pretreatment with 16,16-dimethyl prostaglandin E2 (0.1-1.25 microgram/kg p.o.) in doses that substantially inhibited the formation of macroscopically apparent necrotic lesions failed to prevent enzyme release. However, higher doses of the prostaglandin analogue (2.5-20 micrograms/kg) did significantly reduce the intraluminal release of the cellular enzymes, with the lysosomal enzymes being more readily inhibited. Histologic studies confirmed that the lower doses of the prostanoid prevented deep tissue necrosis and vasocongestion, yet did not protect surface epithelial cells from ethanol-induced damage. However, with the highest dose of 16,16-dimethyl prostaglandin E2 (20 micrograms/kg) a significant reduction in the extent of damage to the superficial epithelial cells was observed, suggesting a correlation with the findings using enzyme markers of cell damage. The apparent protective mechanisms of this prostanoid under the present conditions may involve mucus and fluid effusion that could allow restitution of the surface epithelial layer.

Topics: 16,16-Dimethylprostaglandin E2; Acid Phosphatase; Animals; Cytoplasm; Ethanol; Gastric Mucosa; Glucuronidase; Indomethacin; L-Lactate Dehydrogenase; Lysosomes; Male; Necrosis; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains

Several prostaglandins are cytoprotective for the stomach; they prevent mucosal necrosis and hemorrhages produced by noxious agents, such as absolute ethanol. One possible mechanism of cytoprotection would be that the prostaglandin may prevent penetration of the necrotizing agent into the gastric mucosa. To test this hypothesis, 2 ml of 100% ethanol containing tracer amounts of 14C at carbon 1 was given orally to rats, after ligating the pylorus. [14C]Ethanol was measured in the gastric mucosa and in plasma from 2.5 to 60 min after ethanol administration. 16,16-Dimethyl prostaglandin E2 was given orally at a cytoprotective dose (10 micrograms/kg) 15 min before 100% ethanol. The level of [14C]ethanol (disintegrations per minute per gram of tissue) in the gastric mucosa of 16,16-dimethyl prostaglandin E2-treated animals were not different from those of control animals. The plasma levels were slightly lower during the first 10 min, but the area under the curve for the entire 60 min was the same in both groups. We conclude that (a) 16,16-dimethyl prostaglandin E2 does not prevent entry of ethanol into the gastric mucosa; (b) 16,16-dimethyl prostaglandin E2 protects the cells located deep in the gastric mucosa from necrosis, in spite of the fact that these cells are in contact with as much ethanol as cells of untreated animals; (c) gastric cytoprotection is probably due to a defense mechanism at the cellular level. These findings minimize the importance of luminal factors, such as an increase in mucus or bicarbonate, in the mechanism of cytoprotection.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Ethanol; Female; Gastric Mucosa; Muscle, Smooth; Necrosis; Prostaglandins E, Synthetic; Pyloric Antrum; Rats; Rats, Inbred Strains

Effects of 16-dimethyl prostaglandin E2 (16-dmPGE2) and necrotizing agents on gastric motility and gastric mucosa were studied in conscious rats. Gastric motility was determined using a miniature balloon positioned in the glandular part of the stomach, which was connected to a pressure transducer and polygraph. Necrotizing agents, such as absolute ethanol, 0.6 N HCl, 0.2 N NaOH, or 4 M NaCl, were instilled into the stomach through a small fistula prepared in the forestomach. One milliliter of these agents produced streak lesions in the glandular part of the stomach within 1 hr, which were preceded by violent gastric contraction in every case. An intragastric administration of 16-dmPGE2 (0.3-3 micrograms/kg) by itself increased a tonus of the gastric wall but dose-dependently lessened the number and the amplitude of contractions. In those rats treated with 16-dmPGE2 (3 micrograms/kg), necrotizing agents failed to enhance the motility or to induce streak lesions. Pretreatment with 1 M NaCl as a mild irritant also inhibited gastric motility and lesion formation, but those actions were significantly antagonized by indomethacin (5 mg/kg). These results indicate that necrotizing agents induce a violent gastric contraction, followed by development of lesions in the stomach, and that the inhibition of gastric hypercontraction may be involved in a cytoprotective action of a prostaglandin against those induced gastric lesions in rats.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Drug Interactions; Ethanol; Gastric Mucosa; Gastrointestinal Motility; Hydrochloric Acid; Indomethacin; Male; Muscle Contraction; Necrosis; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains; Sodium Chloride; Sodium Hydroxide; Transducers, Pressure

The effect of 16,16-dimethyl prostaglandin E2 (dmPGE2) on histologic and microcirculatory changes in alcohol-induced gastric mucosal injury was studied. A histologic study confirmed that dmPGE2 does not protect the surface mucous cells against ethanol injury but does protect against the deeper necrotic lesion. Both the gross injury and the necrotic lesion were as severe after 1 min of ethanol exposure as after 60 min. A study of benzidine-stained sections and hematoxylin and eosin-stained sections revealed marked engorgement of microvessels and hemorrhage in the superficial mucosa after ethanol injury. Pretreatment with dmPGE2 prevented these. An in vivo fluorescent microscopy study revealed that there was total stasis of blood flow in the injured area. After the intravascular injection of a fluorescein-albumin conjugate, the conjugate filled microvessels in grossly normal areas of mucosa but not in grossly injured areas. Pretreatment with dmPGE2 prevented this microcirculatory change. This alcohol-induced stasis of flow in injured areas may be of pathogenetic significance and prostaglandin protection might involve prevention of this microcirculatory change.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Eosine Yellowish-(YS); Ethanol; Gastric Mucosa; Hematoxylin; Hemoglobins; Hemorrhage; Male; Microcirculation; Microscopy, Fluorescence; Necrosis; Prostaglandins; Rats; Rats, Inbred Strains; Staining and Labeling

The effect of pretreatment with acetazolamide, a carbonic anhydrase inhibitor, was studied on the mucosal protection provided by and the gastric alkaline secretion stimulated by 16,16-dimethyl prostaglandin E2. Using a model employing a chamber of the rat whole stomach, 16,16-dimethyl prostaglandin E2 (1 microgram/ml) was found to significantly (p less than 0.05) increase the secretion of bicarbonate by 31.1 +/- 4.1 mu Eq/hr over basal values. This stimulated secretion was inhibited (to 18.0 +/- 2.2 mu Eq/hr) by pretreatment with acetazolamide (50 mg/kg body weight). In a separate series of experiments, the ability of this concentration of 16,16-dimethyl prostaglandin E2 to protect the rat stomach from necrosis caused by absolute ethanol was not impaired by prior exposure to the same dose of acetazolamide.

Topics: 16,16-Dimethylprostaglandin E2; Acetazolamide; Animals; Bicarbonates; Ethanol; Gastric Mucosa; Hydrogen-Ion Concentration; Male; Necrosis; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains; Stimulation, Chemical

It has been suggested that 16,16-dimethyl prostaglandin E2 may have a cytoprotective effect in the liver. To assess this hypothesis, we determined the effects of this prostaglandin on the metabolism and toxicity of bromobenzene in mice. Administration of 16,16-dimethyl prostaglandin E2 (50 micrograms/kg s.c., 30 min before, and every 6 hr after, the administration of bromobenzene) did not modify the disappearance curves of unchanged bromobenzene from plasma and liver, and did not modify the amount of bromobenzene metabolites covalently bound to hepatic proteins 1-24 hr after the administration of a toxic dose of bromobenzene (0.36 ml/kg i.p.). The prostaglandin, however, markedly reduced serum alanine aminotransferase activity, the extent of liver cell necrosis, the depletion of glutathione, and the disappearance of cytochrome P-450 after administration of this toxic dose of bromobenzene (0.36 ml/kg i.p.). It also markedly reduced mortality after administration of a lethal dose of bromobenzene (0.43 ml/kg i.p.). We conclude that 16,16-dimethyl prostaglandin E2 can prevent hepatic necrosis without decreasing the covalent binding of bromobenzene metabolites to hepatic proteins. The mechanism for this dissociation between covalent binding and toxicity remains unknown.

Topics: 16,16-Dimethylprostaglandin E2; Alanine Transaminase; Animals; Bromobenzenes; Cytochrome P-450 Enzyme System; Drug Interactions; Glutathione; Liver; Male; Mice; Necrosis; Prostaglandins E, Synthetic

These studies further evaluate the hepatocytoprotective properties of 16,16-dimethyl prostaglandin E2 (dmPGE2) by assessing its effect on survival, liver function, and hepatic regeneration in a model of in vivo isolated perfusion of the rat liver with high concentrations of cytotoxic drugs and regional hyperthermia. Isolated perfusion with 1.0 g/kg of 5-FU or hyperthermia of 41 degrees C X 10 min resulted in 90-100% mortality in control rats, with extensive, patchy necrosis and infarction on histologic examination, and markedly elevated levels of SGOT and SGPT at 24 hr after perfusion. Pretreatment with dmPGE2 (10 micrograms/kg sc) at 30 min before, and at 6 and 24 hr after hepatic perfusion significantly improved survival to 80% (P less than 0.01) following 5-FU perfusion and to 40% (P less than 0.05) following hyperthermic perfusion. Animals were followed for at least 21 days after perfusion and demonstrated normal liver histology, dmPGE2-treated rats demonstrated significantly lower SGOT and SGPT levels at 24 hr after perfusion. dmPGE2 (2 micrograms/kg sc) given as above improved the length of time of survival but eventual mortality was not significantly improved. Oral administration (50 micrograms/kg po at 30 min before, 6 and 24 hr after perfusion) and posttreatment (10 micrograms/kg sc at 1, 6, and 24 hr after perfusion) had no significant effect on survival. Hepatic regenerative capacity following partial hepatectomy was severely suppressed following isolated hyperthermochemotherapeutic hepatic perfusion. Pretreatment with dmPGE2 (10 micrograms/kg sc) restored the DNA synthetic response in perfused rats to that seen in normal control rats after partial hepatectomy (P less than 0.05 and P less than 0.01). The results from these studies further confirm the role of dmPGE2 as a hepatocytoprotective agent and suggest potential clinical application in situations where there has been deliberate, therapeutic insult to the liver.

Topics: 16,16-Dimethylprostaglandin E2; Alanine Transaminase; Animals; Aspartate Aminotransferases; Fluorouracil; Hot Temperature; Liver; Liver Regeneration; Male; Necrosis; Prostaglandins E, Synthetic; Rats; Rats, Inbred F344; Time Factors

We studied whether 16,16--dimethyl prostaglandin E2 (dmPGE2) may prevent acute liver damage induced by carbon tetrachloride (CCl4) in the rat. One hundred thirty male rats were divided into the following groups: (1) controls, (2) rats given CCl4 6670 mg/kg body wt subcutaneously, (3) rats pretreated with 5 micrograms/kg dmPGE2 given subcutaneously 30 min before, and 8 and 24 h after CCl4 administration, and (4) animals given dmPGE2 only as in group 3. Liver damage was assessed by biochemical studies (SGPT, serum alkaline phosphatase, and bilirubin) and by histology. In rats receiving CCl4 alone, SGPT activities were significantly elevated to 1024 +/- 82 U/L, 1270 +/- 120 U/L, 386 +/- 48 U/L and 208 +/- 20 U/L at 24, 48, 96, and 120 h after CCl4 respectively. In animals pretreated with dmPGE2 before CCl4, SGPT activities were 201 +/- 24 U/L, 55 +/- 4.6 U/L, 28 +/- 4 U/L, and 24 +/- 4 U/L at 24, 48, 96, and 120 h after CCl4, respectively (p less than 0.01, versus animals receiving CCl4 only). Histologically, livers of rats treated with CCl4 alone showed severe centrilobular necrosis at 24 and 48 h. Livers of animals pretreated with dmPGE2 before CCl4 did not show necrosis. It is concluded that dmPGE2 protects the liver against cell necrosis induced by CCl4 in the rat.

Topics: 16,16-Dimethylprostaglandin E2; Alanine Transaminase; Alkaline Phosphatase; Animals; Bilirubin; Carbon Tetrachloride; Liver; Male; Necrosis; Prostaglandins E, Synthetic; Rats