Healing of chronic gastroduodenal ulcerations by antacids

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 rat's 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.     

Gastroprotective and ulcer-healing activities of a new H2-receptor antagonist: ebrotidine.

Ebrotidine is a novel H2-receptor antagonist that exhibits both gastroprotective and ulcer-healing properties. Gastroprotection afforded by ebrotidine against ethanol damage was observed only after intragastric, but not parenteral administration, and it was accompanied by an increase in the mucosal blood flow. Ranitidine given at the same dose (100 mg/kg i.g. or s.c.) did not show any protective activity. When administered twice daily at various doses (1-100 mg/kg) for 10 days, ebrotidine reduced dose dependently the area of chronic gastric ulcers, and it was accompanied by significantly higher contents of epidermal growth factor (EGF) in the ulcer bed than in the intact mucosa. Administration of ranitidine resulted in a similar rate of ulcer healing and in a similar accumulation of EGF in the ulcer area to that observed after ebrotidine, but the increments in plasma gastrin levels in rats treated with ranitidine were observed at lower doses than in tests with ebrotidine. Concurrent administration of indomethacin delayed ulcer healing and reduced the accumulation of EGF in the ulcer area, but did not affect the ulcer healing by ebrotidine or ranitidine. We conclude that ebrotidine but not ranitidine shows gastroprotective activity, but it enhances the healing of chronic ulcerations in a similar manner to ranitidine.     

Role of growth factors in gastroduodenal protection and healing of peptic ulcers

Proliferation and growth of gastroduodenal mucosal cells represent important elements of mucosal defense and any alterations in the balance between cell proliferation and cell loss may lead to trophic changes in mucosa. Acute mucosal lesions induced by local irritants such as bile salts, ethanol, aspirin, or stress are accompanied by widespread damage of surface epithelium followed by almost immediate repair due to mucosal cell restitution, which is unrelated to cell proliferation but does depend on the intrinsic property of mucosal cells to cover superficial defects. Cytoprotection involves the protection of the regeneration zone and the maintenance of blood flow to the mucosa. Various factors that exhibit mucosal growth-promoting action include EGF, gastrin, growth hormone, and GH-releasing factor. These factors protect the mucosa against acute injury but the mechanism of this effect is not clear. These trophic agents, especially EGF, accelerate the healing of chronic gastroduodenal ulceration and may contribute to the healing effects of sucralfate or De-Nol. These effects of trophic substances are related to their stimulation of cell proliferation and DNA, RNA, and protein synthesis and can be reversed by the suppression of mucosal growth. Prostaglandins, especially their stable methylated analogs, display trophic effects on the gastric mucosa but neither gastroprotective nor ulcer healing actions of PG can be attributed to their trophic effect. With increasing attention being paid to mucosal growth and repair as components of mucosal defense, the emphasis of drug therapy of acute or chronic gastroduodenal lesions is likely to move toward strengthening mucosal defense rather than the inhibition of aggressive factors.     

Gastrocytoprotection by colloidal bismuth subcitrate (De-Nol) and sucralfate. Role of endogenous prostaglandins.

This study compares the gastroprotective effects of colloidal bismuth subcitrate (De-Nol) with those of sucralfate and a methylated analogue of prostaglandin E2 (PGE2) against acute gastric lesions induced by acidified aspirin and absolute ethanol in rats. Both De-Nol and sucralfate given orally prevented dose dependently the formation of gastric lesions by these ulcerogens, De-Nol being, respectively, twice and seven times more potent, on a weight basis, than sucralfate. As the gastroprotective activities of both De-Nol and sucralfate on ethanol lesions can be reversed by pretreatment with indomethacin and as De-Nol and sucralfate increase the mucosal generation and luminal release of PGE2, we postulate that mucosal prostaglandins may be involved in the mechanism of action of these drugs on the gastric mucosa.     

Delayed gastric ulcer healing after extirpation of submandibular glands is sex-dependent

This study examines the effect of excision of the submandibular salivary glands, the main source of epidermal growth factor (EGF), and the role of gender on the healing of acetic acid-induced gastric ulcers in rats. In male rats excision of the submandibular glands delayed ulcer healing. At 15 and 25 days the unhealed ulcer areas were significantly larger in the sialoadenectomy group than in control animals, and fewer completely healed ulcers were seen in this group at 25 days. Ulcer healing in female rats was slower. At day 25 ulcers were healed in 12% of female rats with intact salivary glands, compared with 68% in males. Female rats also showed larger unhealed ulcer areas after sialoadenectomy than controls. We conclude that removal of the main source of EGF in the gastrointestinal tract is associated with a delay in healing of gastric ulcers. The significant difference in healing observed between female and male rats may be influenced by the known androgenic regulation of EGF production in the salivary glands.     

Fibroblast growth factor in gastroprotection and ulcer healing: interaction with sucralfate.

The study was designed to determine the gastroprotective and ulcer healing efficacy of basic transforming growth factor (bFGF) and to assess whether this peptide contributes to the action of sucralfate on the rat stomach. Application of human recombinant bFGF (1-100 micrograms/kg/hour subcutaneously) failed to affect the formation of acute gastric lesions induced by 100% ethanol and acidified aspirin but reduced the stress induced by gastric lesions. Sucralfate (100-200 mg/kg given orally) protected gastric mucosa against the ethanol, aspirin, and stress induced acute gastric lesions but the addition of bFGF (100 micrograms/kg subcutaneously or intragastrically) failed to affect sucralfate induced protection against ethanol or aspirin but increased that against stress. Administration of bFGF (3-300 micrograms/kg/day) by an intragastric or an intraperitoneal route or sucralfate (400 mg/kg/day) orally to rats with acetic acid induced gastric ulcers, enhanced the healing rate of these ulcers during seven day treatment in a dose dependent manner. This was accompanied by a pronounced increase in the number of capillaries and myofibroblasts and in DNA synthesis and DNA and RNA concentrations in the granulation tissue in the ulcer area. [125I]bFGF (1 microCi) applied subcutaneously or intragastrically accumulated in two to threefold higher amounts in the ulcer area than in the intact mucosa, particularly in rats treated with sucralfate. Concurrent treatment with indomethacin (2 mg/kg intraperitoneally) delayed ulcer healing and reduced the binding of labelled bFGF to the ulcer area, angiogenesis, and DNA synthesis by sucralfate. Addition of [125I]bFGF to sucralfate at various pHs resulted in the coprecipitation of bFGF by sucralfate in a pH dependent manner from about 10% at pH 7.0 to 90% at pH 1.5. Thus bFGF shows little protective activity and is not essential for gastroprotection afforded by sucralfate but plays an important part in healing of gastric ulcers possibly due to its growth promoting and angiogenic actions.     

Role of epidermal growth factor in healing of chronic gastroduodenal ulcers in rats

The healing of acetic acid-induced gastric and duodenal ulcers was examined together with biochemical indices of growth in gastric and duodenal mucosa in rats with intact or removed salivary glands after treatment with epidermal growth factor (EGF) or somatostatin, or both. After the extirpation of salivary glands, the healing rate of gastric and duodenal ulcerations was delayed and gastric content of immunoreactive EGF was reduced. This was accompanied by a significant decrease in the contents of deoxyribonucleic acid and ribonucleic acid in the gastric and duodenal mucosa. Repeated administration of EGF either subcutaneously or orally accelerated the healing of gastroduodenal ulcers in rats with intact salivary glands and completely reversed the delay in ulcer healing in sialoadenectomized animals. These effects were also accompanied by a significant increase in the growth parameters of gastric and duodenal mucosa. Administration of somatostatin, which prevented the growth-promoting action of subcutaneous EGF, resulted in a significant decrease in the EGF-stimulated healing of gastric and duodenal ulcerations in both intact and sialoadenectomized rats. Our findings suggest that cell proliferation is an important factor in healing of gastric and duodenal ulcerations and that EGF plays an important role in ulcer healing due to its mitogenic action.     

Epidermal Growth Factor in Gastric Ulcer Healing by Nocloprost,a Stable Prostaglandin E2 Derivative

Background: The gastroprotective and ulcer-healing properties of prostaglandins, especially in gastric ulcers induced by non-steroidal anti-inflammatory drugs, are well established. Ulcer healing is an active process of filling the mucosal defect with migrating and proliferating epithelial cells combined with angiogenesis in granulation tissue at the ulcer bed. Growth factors, especially epidermal growth factor (EGF) and transforming growth factor alpha (TGFa) are crucial in the regulation of the reconstruction of damaged mucosal structures. Methods: In this double-blind, randomized, prospective study 40 patients with gastric ulcer were treated with nocloprost, a stable prostaglandin E₂ derivative, or with ranitidine. All subjects underwent endoscopy before and after 4 and 8 weeks of anti-ulcer therapy. During endoscopy mucosal biopsies were performed for determination of EGF content in gastric mucosa at the ulcer margin and in the intact mucosa. Additionally, EGF output in saliva and its plasma concentrations were determined in all subjects before and during the treatment. Results: The gastric ulcer healing rate after 4 weeks was significantly higher in patients treated with nocloprost than in those treated with ranitidine (63% versus 39%, respectively). At initial examination the EGF content in the gastric mucosa obtained from the ulcer edge was significantly higher than that in the intact mucosa. There was a significant increase in the EGF content in both the ulcer margin and the intact mucosa in subjects treated with nocloprost but not in patients under treatment with ranitidine. Similarly, patients treated with nocloprost had significantly higher EGF output in saliva and higher EGF concentration in plasma throughout the anti-ulcer therapy. Conclusion: Nocloprost is superior to ranitidine in the treatment of chronic gastric ulcers, and these effects could be due, at least in part, to higher expression and mucosal content of EGF in the ulcer area.     

Gastroprotective and ulcer healing effects of nitric oxide-releasing non-steroidal anti-inflammatory drugs

BACKGROUND & AIM: New class of nitric oxide-releasing non-steroidal anti-inflammatory drugs was shown to inhibit cyclooxygenase and prostaglandin generation without causing mucosal damage but whether these agents are capable of affecting gastric mucosal damage induced by strong irritants and healing of chronic gastric ulcers remains to be studied. In this investigation, effects of nitric oxide-releasing aspirin and nitric oxide-releasing naproxen were compared with those of native agents on gastric lesions provoked by 100% ethanol and on healing of chronic acetic acid ulcers. RESULTS: Both, nitric oxide-releasing aspirin and naproxen dose-dependently attenuated ethanol-induced damage and produced a significant rise in gastric blood flow but did not delay healing of gastric ulcers while native aspirin and naproxen had no influence on ethanol-induced gastric damage but significantly prolonged ulcer healing, reduced gastric blood flow and suppressed mucosal generation of prostaglandin E2. The gastroprotective and hyperaemic effects of both nitric oxide-non-steroidal anti-inflammatory drugs were completely abolished by ODQ, an inhibitor of guanylyl cyclase-cGMP system but not influenced by suppression of nitric oxide-synthase with L-NNA. The damaging effects of native acetyl salicylate acid or naproxen were aggravated by acidification of these non-steroidal anti-inflammatory drugs but the exogenous acid added to nitric oxide-acetyl salicylate acid or nitric oxide-naproxen failed to influence their effect. Despite inhibiting of PGE2 generation, both nitric oxide-releasing derivatives and native aspirin and naproxen failed to affect expression of cyclooxygenase-1 mRNA but upregulated the cyclooxygenase-2 mRNA. Concurrent inhibition of cyclooxygenase-2 by selective inhibitor NS-398 which by itself delayed ulcer healing and attenuated the gastric blood flow at ulcer margin, significantly worsened the effects of these nitric oxide-non-steroidal anti-inflammatory drugs and their parent drugs on ulcer healing and the gastric blood flow at the ulcer margin. CONCLUSIONS: 1) Coupling of nitric oxide to aspirin or naproxen attenuates ethanol-induced damage, possibly due to an increase in gastric microcirculation mediated by excessive release and action of nitric oxide that probably compensates for PG deficiency induced by non-steroidal anti-inflammatory drugs; and 2) nitric oxide-non-steroidal anti-inflammatory drug, unlike classic non-steroidal anti-inflammatory drugs, does not affect intact gastric mucosa and fails to delay the healing of pre-existing ulcers.     

Healing of duodenal ulcers is not impaired by indomethacin or rofecoxib,the selective COX-2 inhibitor,in rats

BACKGROUND/AIM: Studies have demonstrated an important role for endogenous PG and NO in the healing of chronic gastric ulcers. We investigated the effects of COX and NOS inhibitors on the healing of duodenal ulcers, in comparison with gastric ulcers, in rats. METHODS: Gastric and duodenal ulcers were induced by serosal application of acetic acid (0.1 ml of 100% acetic acid) for 60 and 20 s, respectively. Indomethacin (a nonselective COX inhibitor) or rofecoxib (a selective COX-2 inhibitor) was given p.o. once daily for 14 days from 3 days after ulcer induction, while N(G)-nitro-L-arginine methyl ester (L-NAME: a nonselective NOS inhibitor) or aminoguanidine (a relatively selective iNOS inhibitor) was given s.c. twice daily during this period. RESULTS: Both gastric and duodenal ulcers induced by acetic acid healed spontaneously within 17 days to a minimal size. Daily administration of indomethacin or rofecoxib significantly delayed the healing of gastric but not duodenal ulcers. In contrast, the healing of both gastric and duodenal ulcers was delayed by repeated administration of either L-NAME or aminoguanidine. Ulceration markedly increased the PGE(2) content of the ulcerated mucosa in both the stomach and duodenum, and the increased PG biosynthetic response was inhibited by either indomethacin or rofecoxib in both tissues. The expression of both COX-2 and iNOS mRNAs was upregulated in the ulcerated mucosa of the stomach and duodenum. CONCLUSION: These results suggest that COX-2/PG is actively involved in the healing of gastric but not duodenal ulcers, although the mRNA for COX-2 is expressed in the duodenal mucosa after ulceration, as potently as in the gastric mucosa. In contrast, NO produced by both cNOS and iNOS plays a role in the healing of both gastric and duodenal ulcers.     

Transforming Growth Factor Alpha and Epidermal Growth Factor in Protection and Healing of Gastric Mucosal Injury

Transforming growth factor alpha (TGF) and epidermal growth factor (EGF) present in the gastric mucosa are polypeptides with similar biologic activity. This study compares the activity of TGF and EGF in the protection against injury by 100% ethanol and stress and in healing of acute gastric ulcerations. TGF and EGF (12.5-100 μg/kg-h) infused subcutaneously 30 min before and during ethanol or stress decreased mucosal lesions dose-dependently. The ID₅₀ for ethanol- and stress-induced lesions after TGF were 40 and 70 μg/kg-h and after EGF 60 and 100 ug/kg-h. TGF and EGF infused subcutaneously into intact rats inhibited gastric acid secretion but did not affect the gastric blood flow or mucosal generation of prostaglandin E₂ (PGE₂). Both TGF and EGF also significantly enhanced the healing of stress-induced lesions and the restoration of DNA synthesis. Ethanol and stress reduced blood flow in the oxyntic mucosa by 68% and 51%, respectively, and this effect was partially reversed by EGF and TGF. Pretreatment with indomethacin (5 mg/kg intraperitoneally), which reduced mucosal generation of PGE₂ by 85%, decreased in part the protection by TGF and EGF against ethanol-induced damage and virtually abolished the protective action of these peptides against stress-induced injury. We conclude therefore that 1) TGF and EGF show similar and comparable gastroprotective activity against ethanol- and stress-induced damage; 2) the protection by TGF and EGF is accompanied by an increase in gastric blood flow which appears to be an essential factor in gastroprotection; 3) mucosal PG is necessary for manifestation of the protective activity of TGF and EGF against acute gastric damage; and 4) TGF and EGF enhance the healing of gastric lesions, possibly via stimulation of DNA synthesis and cell proliferation.     

Gastroprotective and ulcer healing effects of solon, a synthetic flavonoid derivative of sophoradin

Solon, a synthetic isoprenyl flavonoid derived from sophoradin isolated from the root of an ancient Chinese plant, administered orally to rats, prevented, dose-dependently, the formation of acute gastric lesions produced by absolute ethanol given orally. Solon also enhanced the healing of chronic gastric and duodenal ulcerations induced by the serosal application of acetic acid. The gastroprotective action of Solon was probably mediated by increased mucosal content of prostaglandins (PG) due mainly to the inhibition of 15-OH-prostaglandin dehydrogenase. The ulcer-healing action of Solon was probably related to the stimulation of mucus-alkaline secretion, increased mucosal blood flow and the formation of a protective barrier on the ulcer base.     

Acid, pepsin, and mucus secretion in patients with gastric and duodenal ulcer before and after colloidal bismuth subcitrate (De-Nol).

Basal and pentagastrin stimulated gastric secretion was measured in seven patients with duodenal, and six with gastric ulcers before and after four weeks' treatment with colloidal bismuth subcitrate (as De-Nol), one tablet four times a day. Each duodenal and all but one of the gastric ulcers healed. After De-Nol there were no significant changes in basal, or pentagastrin stimulated volume, acid output, or primary parietal component. There were marked decreases in basal (duodenal ulcer -25%; gastric ulcer -16%) and pentagastrin stimulated total pepsin outputs, (duodenal ulcer -42%, gastric ulcer -36%). There were insignificant decreases in basal output of mucus, but postpentagastrin stimulated mucus output was significantly inhibited (p less than 0.05) in patients with duodenal (-16%) and with gastric ulcer (-27%). The drop in gastric proteolysis after De-Nol is unlikely to be because of the healing of the ulcers and is more likely to be because of the drug. The ulcer healing efficacy of De-Nol may be related to this decline in the proteolytic action of gastric juice, but is unlikely to be because of a quantitative change in mucus, or in acid secretion.     

Interaction of growth hormone-releasing factor and somatostatin on ulcer healing and mucosal growth in rats: role of gastrin and epidermal growth factor

Growth hormone-releasing factor (GRF) was reported to possess the growth-promoting action on the gastroduodenal mucosa that can be augmented by removal of endogenous somatostatin. Since mucosal proliferation was considered to contribute to healing of chronic gastroduodenal ulcerations, we designed the study to determine the interaction of GRF and somatostatin on the healing rate of acetic acid-induced chronic gastric and duodenal ulcers and on the growth of gastroduodenal mucosa in rats. GRF injected subcutaneously twice daily at 100 micrograms/kg/day for 7 days resulted in a significant enhancement of healing rate of both gastric and duodenal ulcerations and this was accompanied by a significant increase in the weight of the mucosa and the contents of RNA and DNA. GRF also significantly increased serum gastrin levels and the tissue contents of epidermal growth factor (EGF) in salivary glands, duodenum and pancreas, suggesting that both gastrin and EGF could contribute to mucosal trophic and ulcer healing effects of GRF. Somatostatin (100 micrograms/kg/day for 7 days) abolished almost completely the ulcer healing and mucosal growth-promoting effects of GRF and this was accompanied by the reduction in serum gastrin level and the tissue contents of EGF suggesting that the suppression of gastrin and EGF release could contribute to the observed effects of somatostatin. We conclude that GRF has both the ulcer healing and the mucosal trophic actions which can be antagonized by somatostatin and that gastrin and EGF may be implicated in these actions.     

Effect of capsaicin and chilli on ethanol induced gastric mucosal injury in the rat.

Capsaicin, the pungent ingredient of chilli, is gastroprotective against experimental gastric injury when given intragastrically. Epidemiological and clinical data suggest that chilli ingestion may have a beneficial effect on human peptic ulcer disease. This study showed a gastroprotective effect of intragastric capsaicin, in doses of 2 and 5 mg, on ethanol induced gastric mucosal injury using macroscopic, histological, scanning electron microscopic, and biochemical indices. Subcutaneous administration of 2 mg of capsaicin had the same gastroprotective effect as intragastric administration. Acute intragastric administration and chronic ingestion of chilli powder in doses comparable with that consumed in humans (up to 200 mg in single doses or 200 mg daily for four weeks) likewise protected the gastric mucosa. Both the mucosa and gastric juice had higher mucus contents when capsaicin or chilli rather than saline or solvent was used before ethanol challenge. In control animals capsaicin also increased gastric juice mucus content although the mucosal content was unaffected. Increased gastric mucus production may therefore be one mechanism by which capsaicin and chilli exert their gastroprotective effect although an alternative explanation is that the reduction in mucosal mucus depletion is secondary to the protective effect of capsaicin and chilli.     

Effect of sialoadenectomy on gastric mucosal integrity and growth in the rat

The effect of removal of the submandibular-sublingual salivary gland (sialoadenectomy) has been examined in terms of the effects on the susceptibility of the gastric mucosa to the inflammatory and damaging actions of ethanol. In addition, the effects of sialoadenectomy on cell turnover in the gastric mucosa has been examined. Animals were examined at one to five weeks after removal of the submandibular-sublingual salivary gland complex. In response to 100% w/v ethanol, sialoadenectomized rat displayed greater hemorrhagic damage to the gastric mucosa than sham-operated control rats. The difference between sialoadenectomized and sham control rats was significant at two to five weeks after surgery. The rate of [³H]thymidine incorporation into gastric mucosa was significantly reduced in sialoadenectomized rats at one and two weeks. Mucosal DNA concentration was significantly reduced in sialoadenectomized rats at four and five weeks after surgery. Mucosal myeloperoxidase activity was greater in sialoadenectomized rats treated with ethanol compared to control animals, but this difference was only significant at two weeks after surgery. Sialoadenectomy was also associated with a reduction in duodenal and gastric mucosal levels of immunoreactive epidermal growth factor (EGF). Differences between sialoadenectomized and control rats were not significant until three to four weeks after surgery. These data indicate that sialoadenectomy was associated with an increase in the susceptibility of rat gastric mucosa to ethanol-mediated damage. Sialoadenectomy also resulted in a reduction in gastric mucosal growth and gastroduodenal mucosal levels of EGF. However, the influence of sialoadenectomy on the susceptibility of the rat gastric mucosa to ethanol-mediated damage occurred prior to any significant effect on mucosal DNA concentration or EGF levels.This work was supported by a grant from the Medical Research Council of Canada, Grant No. MT6426.     

Oral administration of synthetic human urogastrone promotes healing of chronic duodenal ulcers in rats

The effect of oral administration of synthetic human epidermal growth factor/urogastrone (EGF/URO) on healing of chronic duodenal ulcers induced by cysteamine in rats was investigated and compared with that of cimetidine, a H2-receptor antagonist. After 25 and 50 days of treatment, synthetic human EGF/URO significantly increased healing of chronic duodenal ulcers to the same extent as cimetidine. Combined treatment with synthetic human EGF/URO and cimetidine for 25 days was more effective than synthetic human EGF/URO given alone, whereas combined treatment for 50 days was significantly more effective than cimetidine alone. These results show that a combination of an agent inhibiting gastric acid secretion and the cytoprotective and growth-stimulating peptide EGF/URO seems to be more effective with regard to duodenal ulcer healing than individual administration of the two substances. Synthetic human EGF/URO is a potent inhibitor of gastric acid secretion when administered intravenously, but had no effect on acid secretion when given intraduodenally, which suggests that the effect of synthetic human EGF/URO is a direct action on the duodenal mucosa. In conclusion, this study showed that oral synthetic human EGF/URO has a significant effect on healing of duodenal ulcers in rats. The amount of synthetic human EGF/URO administered is comparable to that found in saliva during stimulation of the salivary glands. Our results, therefore, suggest that EGF/URO is one of the endogenous factors participating in healing of duodenal ulcers.     

Impairment of Gastric Ulcer Healing by Alendronate,a Nitrogen-Containing Bisphosphonate,in Rats

Bisphosphonates such as alendronate have been developed as antiresorptive agents capable of treating diseases related to bone remodeling. In the present study, we examined the effect of alendronate on the healing of acetic acid-induced gastric ulcers in rats and investigated the mechanism involved in this action both in vivo and in vitro using the rat gastric epithelial cell line (RGM1). Acetic acid-induced gastric ulcers healed spontaneously, with up-regulation of COX-2/prostaglandin E₂ production as well as expression of vascular endothelium-derived growth factor (VEGF) and basic fibroblast growth factor (bFGF) in ulcerated mucosa. The healing of ulcers was impaired by indomethacin (2 mg/kg, s.c.) or alendronate (60 mg/kg, p.o.) given once daily for 7 days, starting 3 days after acid application. Indomethacin, but not alendronate, inhibited mucosal prostaglandin E₂ production. Alendronate as well as indomethacin decreased the protein expression of both VEGF and bFGF in ulcerated mucosa, resulting in a reduction of angiogenesis in the ulcer base. Supplementation of recombinant bFGF significantly reverted the delay in ulcer healing caused by alendronate. On the other hand, the size of cell-free areas in RGM1 cells in vitro decreased with time after wound induction, and this process was promoted by epidermal growth factor (EGF; 10 ng/ml). Co-incubation with alendronate (1 mM) did not affect the spontaneous healing but significantly suppressed the accelerated wound healing caused by EGF. These results suggest that alendronate impairs the healing of gastric ulcers in rats, and this effect may be related to down-regulation of VEGF and bFGF, the important growth factors for vascularization/granulation, as well as suppression of the stimulatory action of EGF on epithelial proliferation/migration.     

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.