Ireneusz Piastucki

Role of locally generated prostaglandins in adaptive gastric cytoprotection

This study was designed to determine the role of mucosal generation of prostaglandins (PGs) in the ability of mild irritants (20% ethanol or 5% NaCl) to protect against the formation of mucosal lesions caused by necrotizing agents (100% ethanol or 25% NaCl) or acidified aspirin (ASA). Mild irritants protected against damage from necrotizing agents but not from ASA. This protection was accompanied by increased mucosal generation of PGE2 and PGI2-like substances. Exogenous PGE2 and PGI2 applied topically to the gastric mucosa in a nonantisecretory dose greatly inhibited the formation of lesions induced by either necrotizing agents or ASA. Pretreatment with indomethacin, which suppressed the generation of mucosal PGs augmented formation of lesions by necrotizing agents and partly counteracted the protective effect of mild irritants. We conclude that mild irritants, and exogenous PGs inhibit the formation of gastric lesions by necrotizing agents, at least in part, by mucosal generation of PGs.

Antiulcer and gastroprotective effects of solon, a synthetic flavonoid derivative of sophoradin. Role of endogenous prostaglandins

Abstract Solon is a synthetic isoprenyl flavonoid derived from sophoradin which is isolated from the root of an ancient Chinese plant. Solon was administered orally or intraperitoneally to rats. It inhibited dose dependently gastric ulcers produced by acidified aspirin, water immersion and restraint stress. Solon was also gastroprotective for the stomach as it reduced dose dependently the gastric necrotic lesions induced by absolute ethanol given orally. The degree of gastroprotection decreased with time, the optimal effects occurring 60–90 min after oral administration. Pretreatment with indomethacin partly prevented the gastroprotective effects of Solon. When given alone to fasted rats, Solon increased dose dependently the mucosal content of prostaglandins (PG), suggesting that the protective effects of this drug may be mediated at least in part by endogenous PG.

Role of prostaglandin and thromboxane biosynthesis in gastric necrosis produced by taurocholate and ethanol

The effects of a new selective inhibitor of thromboxane biosynthesis, OKY-1581, and a potent inhibitor of cyclooxygenase, indomethacin, on gastric mucosal lesions induced by turocholate or ethanol and mucosal generation of prostaglandins have been studied in rats. OKY-1581 prevented, dose dependently, the formation of taurocholate- but not ethanol-induced gastric necrosis, and this effect was accompanied by an increase in gastric mucosal generation of prostaglandin E2 and I2-like activity and a reduction in the thromboxane generation during platelet aggregation. OKY-1581 enhanced the cytoprotective action of “mild” irritants such as 5 mM taurocholate against gastric damage by 100 mM taurocholate, whereas indomethacin produced opposite effects. This study indicates: (1) the inhibition of thromboxane biosynthesis results in increased generation of prostaglandins which seems to contribute to the gastric mucosal integrity and, (2) thromboxanes may be involved in the pathogenesis of taurocholate-induced gastric mucosal lesions.

Studies on the gastroprotective and ulcer-healing effects of colloidal bismuth subcitrate.

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.

Aspirin-induced gastric ulcers in cats. Prevention by prostacyclin.

Gastric ulcers were produced in conscious cats in 3 hr by simultaneous intravenous or intragastric administration of acetylsalicylic acid (ASA), plus intravenous infusion of histamine (80 μg/kg/hr), pentagastrin (8 μg/kg/hr), or intragastric instillation of HCl. The formation of these ulcers was accompanied by almost complete inhibition of prostaglandin (PG) biosynthesis, suggesting that the withdrawal of normal protection of gastric mucosa by PGs may be major factor in pathogenesis of ASA-induced gastric lesions. Prostacyclin (PGI2), infused at a dose producing about 50% inhibition of histamine or pentagastrin-induced acid secretion, significantly reduced the formation of gastric ulcers produced by ASA + histamine or pentagastrin. Inhibition of gastric acid secretion by about 50% using ranitidine, a new H2-receptor antagonist, also decreased the formation of gastric ulcers induced by ASA + gastric secretagogue, but the degree of this reduction was significantly smaller than after PGI2. In addition, PGI2 decreased significantly the severity of gastric ulcers produced by a combination of ASA plus gastric perfusion of HCl, the antiulcer effect being more pronounced when PGI2 infusion was started prior to, rather than during, ASA administration. This study confirms that the administration of ASA plus gastric secretagogue or gastric instillation of HCl is a reliable model of gastric ulcerations probably resulting from withdrawal of biosynthesis of mucosal PGs and shows that PGI2 is capable of preventing the formation of these ulcers by means other than its effect on gastric acid secretion.

Gastric cytoprotection by acetazolamide: role of endogenous prostaglandins

This study was designed to determine the influence of acetazolamide, a potent inhibitor of carbonic anhydrase, on the formation of gastric mucosal lesions induced by acidified aspirin (ASA) or absolute ethanol and on gastric cytoprotection induced by prostaglandin E2 (PGE2). Acetazolamide prevented dose-dependently ethanol-induced gastric lesions and this effect was accompanied by an increased biosynthesis of mucosal PGs, indicating that endogenous PGs may be involved in cytoprotection by acetazolamide. This is supported by the finding that acetazolamide failed to affect gastric ulcerations produced by acidified ASA when mucosal PG biosynthesis was almost completely suppressed. Pretreatment with acetazolamide did not influence the protective action of PGE2 on ethanol-induced mucosal lesions and only slightly inhibited the protective effect of PGE2 on ASA-induced gastric ulcerations. This study indicates that: (1) acetazolamide prevents ethanol- but not ASA-induced gastric mucosal lesions probably via stimulation of PG biosynthesis and (2) gastric alkaline secretion, mediated by carbonic anhydrase, is probably not an essential mechanism responsible for this cytoprotection induced by PGE2.

Gastric Mucosal Protection by Agents Altering Gastric Mucosal Sulfhydryls

Intragastric administration of sulfhydryl-containing cysteamine or sulfhydryl-oxidizing diethylmaleate caused a dose-dependent reduction in the mean area of gastric lesions induced by absolute ethanol. The protective effects of these agents are abolished by the sulfhydryl blocker N-ethylmaleimide, while indomethacin, a potent inhibitor of cyclooxygenase, caused only about 50% reduction in this protection. This study indicates that mucosal generation of prostaglandins contributes to the gastric cytoprotection by these agents administered intragastrically, but endogenous sulfhydryls are also involved in the gastric mucosal protection by sulfhydryl-containing or sulfhydryl-oxidizing compounds.

Prostaglandin E2 in gastric mucosa and its role in the prevention of ulcers induced by acetyl salicylic acid in cats.

Gastric mucosa of the cat generates PGE2 activity at a significantly higher concentration in the antral 59.25 +/- 7.42 ng/g) than in the oxyntic (28.06 +/- 4.50 ng/ml) gland area. Intravenous (i.v.) infusion of histamine 80 micrograms/kg/h) or intragastric (i.g.) instillation of 0.1 N HCl (4 mEq/h) for 3 h significantly decreased the generation of PGE2 in antral and fundic mucosa, but did not result in the formation of gastric lesions. Aspirin (ASA) given i.v. or i.g. for 3 h caused a further fall in the generation of PGE2 in the mucosa and when combined with i.v. histamine or i.g. HCl, it caused almost complete disappearance of PGE2 activity and the formation of antral ulcers in all tested cats. Exogenous PGE2, given i.v. in a dose (30 micrograms/kg/h) reducing histamine-stimulated (80 micrograms/kg/h) acid secretion by about 50%, prevented almost completely the formation of gastric ulcers induced by a combination of ASA plus i.v. histamine or i.g. HCl. This study indicates that the gastric mucosa generates PGE2 which is capable of preventing gastric ulcers induced by ASA combined with histamine or mucosal acidification.