rozdowicz D

Role of Leukotrienes in Acute Gastric Lesions Induced by Ethanol, Taurocholate, Aspirin, Platelet-Activating Factor and Stress in Rats

This study was designed to determine the role of leukotriene C4 (LTC4) in the formation of acute gastric lesions induced by 100% ethanol, acidified taurocholate (TC), acidified aspirin (ASA), platelet-activating factor (PAF), and water-immersion and restraint stress. Exogenous LTC4 alone administered in gradually increasing doses (5–20μg/kg/hr) caused only mild hemorrhagic lesions in the gastric mucosa but when combined with 100% ethanol, acidified TC, acidified ASA, or stress, it increased significantly the mean lesion area and lesion number as compared to those produced by these ulcerogens alone. FPL 55712, a LTC4 antagonist, given orally (2.5–10 mg/kg) reduced dose-dependently the extent of gastric lesions in all experimental models used and completely prevented the deleterious effects of exogenous LTC4 on gastric mucosa. PAF augmented the mucosal lesions induced by 100% ethanol, and this was also reduced by the pretreatment with FPL 55712. FPL 55712-induced gastroprotection against various ulcerogens was reversed, in part, by indomethacin, indicating that it could be attributed not only to the LTC4 antagonism but also to increased biosynthesis of PGs. This study provides evidence that LTC4 is involved in the formation of acute gastric damage and the antagonism of LTC4 may protect the mucosa against various ulcerogens.

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.

Cytoprotective and Ulcer Healing Properties of Prostaglandin E2, Colloidal Bismuth and Sucralfate in Rats

This study describes the model of chronic gastric and duodenal ulcerations induced by the application of acetic acid on a strictly defined area of the serosal surface of the stomach and duodenum for 10 and 20 s, respectively. Acetic acid applied for longer (20-60 s) or on a larger area (28-64 mm2) resulted in the formation of severe ulcerations which penetrated into the surrounding organs and had very prolonged healing time. Ulcers induced by the application of acetic acid for 10-20 s on a smaller area (7-13.8 mm2) healed spontaneously within 2-3 weeks, thus constituting a model suitable for evaluation of drugs affecting the process of ulcer healing. Our preliminary results of 7- to 14-day treatment with certain drugs indicate that sucralfate and De-Nol, at the dose which does not affect gastric acid secretion, accelerated the healing rate of both gastric and duodenal ulcers so that the observed ulcer healing effect could be attributed to their ulcer healing property. In contrast, 16, 16-dimethyl PGE2 (dmPGE2) in cytoprotective dose was completely ineffective in enhancing ulcer healing. Higher, gastric inhibitory dose of dmPGE2 accelerated the healing of duodenal but not gastric ulcerations, indicating that the inhibition of gastric secretion rather that cytoprotective activity is responsible for ulcer healing effect of this prostaglandin.

Epidermal Growth Factor in the Gastroprotective and Ulcer-Healing Actions of Sucralfate in Rats

Sucralfate exhibits gastroprotective properties in laboratory animals and enhances the healing of chronic gastroduodenal ulcers, but the mechanisms of these actions have not been entirely elucidated. The present study was designed to determine whether or not epidermal growth factor (EGF), which also has gastroprotective and ulcer-healing properties, contributes to the action of sucralfate in rat stomach. It was confirmed that sucralfate, like 16,16-dimethyl prostaglandin E2, protects the gastric mucosa against ethanol damage and increases mucosal generation of prostaglandins. Removal of the endogenous source of EGF (sialoadenectomy) did not abolish the protective and prostaglandin-stimulating effects of sucralfate. Exogenous EGF and 16,16-dimethyl prostaglandin E2 were also protective in rats with intact and removed salivary glands. Sucralfate, like EGF, enhanced the healing of chronic gastric and duodenal ulcerations induced by serosal application of acetic acid. Sucralfate was found to bind EGF in a pH-dependent manner and to accumulate it in ulcer areas. Thus, the peptide is available locally in high concentrations to accelerate tissue repair and the healing process in ulcerated mucosa. The ulcer-healing effects of sucralfate were reduced with sialoadenectomy and partially restored with oral administration of EGF. It was concluded that EGF is not essential for the gastroprotection induced by sucralfate, but seems to play an important role in the ulcer-healing action of this drug.

Epidermal growth factor, polyamines, and prostaglandins in healing of stress-induced gastric lesions in rats

Previous studies demonstrated that epidermal growth factor (EGF) and polyamines (PA) are capable of protecting gastric mucosa against topical irritants. This study was designed to examine whether EGF, PA, and PG affect the healing of acute gastric lesions induced by water immersion and restraint stress. It was found that the healing process of stress lesions in sham-operated rats was significant after 6 hr after stress, and after 24 hr the number of stress lesions was reduced by about 75%. In sham-operated rats, the healing of ulcerations observed at 6, 12, and 24 hr after the stress was accompanied by gradual restoration of DNA synthesis, and both these processes were significantly reduced by administration of DFMO (an inhibitor of ornithine decarboxylase activity) or indomethacin (an inhibitor of cyclooxygenase). In salivectomized rats, the healing was significantly delayed and the DNA was lowered at all time intervals after the stress. Administration of EGF, spermine, aminoguanidine (an inhibitor of degradation of PA), or 16,16-dmPGE2 after stress promoted significantly the healing and DNA synthesis, but pretreatment with DFMO abolished the effect of EGF but not that of spermine. We conclude that EGF, PA, and PG are implicated in healing of stress lesions and that EGF acts, at least in part, by the stimulation of PA formation in the gastric mucosa.

Advances in the understanding of the mechanism of cytoprotective action by colloidal bismuth subcitrate.

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.

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.

Nocloprost, a unique prostaglandin E2 analog with local gastroprotective and ulcer-healing activity

Nocloprost (9 beta-chloro-16,16-dimethyl prostaglandin E2 (PGE2)) was examined for gastroprotective and ulcer-healing activity and compared to 16,16-dimethyl PGE2 (dmPGE) in rats. Nocloprost given intragastrically (i.g.) at various doses (0.01-10 micrograms/kg) 30 min before 100% ethanol, acidified aspirin (ASA), acidified taurocholate, water immersion, or restraint stress dose dependently prevented the formation of gastric lesions, the ID50 values being 0.25, 0.58, 0.06 and 0.12 micrograms/kg, respectively. The gastroprotection provided by nocloprost given i.g. was somewhat enhanced by the presence of acid in the stomach and was reduced by inhibition of gastric acid secretion. Nocloprost given s.c. also showed protective activity against ethanol damage but was ineffective when applied intraduodenally. The protective effect of nocloprost lasted about 8 h whereas that induced by dmPGE lasted 6 h. Nocloprost (0.01-100 micrograms/kg) given i.g. failed to affect gastric acid secretion or intestinal secretion (enteropooling) but prevented the increased gastroduodenal alkaline secretion. Nocloprost alone caused only a transient increase in the mucosal blood flow but prevented the fall in blood flow caused by 100% ethanol. [3H]Nocloprost was absorbed from the small intestine but was then taken up and metabolized by the liver and excreted into the bile so that very little reached the systemic circulation in an unchanged form. Nocloprost, unlike dmPGE, accelerated the healing of chronic gastric ulcerations and enhanced mucosal growth. We conclude that nocloprost is a locally active PGE2 analog with high cytoprotective and ulcer-healing efficacy.

Role of leukotrienes and platelet activating factor in acute gastric mucosal lesions in rats

Leukotriene C4 (LTC4) and platelet activating-factor (PAF) were found to affect gastric microcirculation and mucosal integrity but their role in acute gastric damage has not been established. The present study with rats confirms that exogenous LTC4 (10 micrograms/kg.h s.c.) or PAF (10 micrograms/kg i.p.) alone caused only mild gastric mucosal injury but greatly augmented mucosal lesions produced by other irritants such as absolute ethanol, taurocholate, aspirin or stress. These acute lesions were accompanied by a significant increase in mucosal generation of LTC4, and the addition of PAF further increased it. Pretreatment with BN 52021, a PAF receptor antagonist, abolished PAF-induced gastric lesions and reduced LTC4 generation in tests with PAF plus ethanol. Nordihydroguaiaretic acid, an inhibitor of the lipoxygenase pathway, and FPL 55712, an LTC receptor-antagonist, reduced dose dependently the extent of gastric damage in various models of gastric lesions. Again, these protective effects were accompanied by a reduction in mucosal LTC4 formation. In addition, the protection induced by nordihydroguaiaretic acid was reversed in part by the pretreatment with indomethacin, suggesting that it could be attributed to increased biosynthesis of protective PG. The results indicated that LTC4 biosynthesis is increased in various forms of gastric damage and that LTC4 may be involved in the pathogenesis of this damage.

Healing of chronic gastroduodenal ulcerations by antacids: Role of prostaglandins and epidermal growth factor

Antacids show gastroprotective action against various irritants in experimental animals and enhance the healing of chronic gastroduodenal ulcers in humans but the mechanisms of these effects are unknown. The present study was designed to determine whether prostaglandin (PG) and epidermal growth factor (EGF), which also have protective and antiulcer properties, contribute to the action of antacids on rats stomach. It was found that Maalox 70 and its active component, Al(OH)3, enhance significantly the healing of chronic gastric and duodenal ulcers observed during 7 and 14 days after their induction. Pretreatment with indomethacin caused a significant prolongation of ulcer healing, and this was accompanied by a significant reduction in PG and EGF formation, suggesting that both factors may be involved in ulcer healing. Maalox and Al(OH)3 failed to prevent the suppression of PG by indomethacin but were equally effective in ulcer healing in rats without and with indomethacin administration, suggesting that endogenous PG may not play any important role in the healing process by these drugs. Removal of salivary glands, the major source of EGF, also prolonged ulcer healing but, again, Maalox was as effective in ulcer healing as in rats with intact salivary glands. Our findings that Maalox at pH above 3.0 binds significant amounts of EGF, enhances the binding of EGF to the ulcer area, and stimulates mucosal growth, suggest that EGF may be involved in ulcer healing; however, because antacids are also effective after sialoadenectomy, EGF does not seem to be the major factor in ulcer healing by these drugs.