Acetic acid is an oxidative stressor in gastric cancer cells.

Acetic acid can cause cellular injury. We previously reported that acetic acid induces cancer cell-selective death in rat gastric cells. However, the mechanism is unclear. Generally, cancer cells are more sensitive to reactive oxygen species than normal cells. Accordingly, in this study, we investigated the involvement of oxidative stress in cancer cell-selective death by acetic acid using normal gastric mucosal cells and cancerous gastric mucosal cells. The cancer cell-selective death was induced at the concentration of 2-5 µM acetic acid. Cancerous gastric mucosal cells had increased expression of monocarboxylic transporter 1 and high uptake of acetic acid, compared to normal gastric mucosal cells. The exposure of cancerous gastric mucosal cells to acetic acid enhanced production of reactive oxygen species and expression of monocarboxylic transporter 1, and induced apoptosis. In contrast, acetic acid showed minor effects in normal gastric mucosal cells. These results indicate that acetic acid induced cancer cell-selective death in gastric cells through a mechanism involving oxidative stress.

Acetic acid induces cell death: an in vitro study using normal rat gastric mucosal cell line and rat and human gastric cancer and mesothelioma cell lines.

BACKGROUND AND AIM: We recently reported that topical application of acetic acid promptly caused tumor necrosis in a mouse model of gastric cancer. The aim of the present study was to examine whether acetic acid can directly induce cancer cell death. METHODS: Rat gastric epithelial cell line (RGM-1), rat gastric carcinoma cell line (RGK-1), human gastric cancer cell line (KATO III), and human mesothelioma cell lines (ACC-MESO1 and MSTO-211H) were used. Acetic acid was added into the cell culture at different concentrations for different time periods. Cell death was analyzed by MTT assay, flow cytometry, and trypan blue exclusion test. RESULTS: Acetic acid promptly induced the cell death of RGM-1, RGK-1 cells, and KATO III cells in a concentration-dependent manner from 0.01% to 0.5%. Acetic acid at 0.5% for 1 min induced the cell death by 80%. RGK-1 cells were more sensitive to acetic acid than RGM-l cells. KATO III cells were more sensitive to acetic acid than RGK-1 cells. Acetic acid at 0.5% for 10 min induced almost complete cell death of ACC-MESO1 and MSTO-211H. CONCLUSIONS: Acetic acid is a powerful anticancer agent. Topical application of acetic acid may be a feasible approach for the treatments of gastric cancer and possibly other malignancies.

Topical application of acetic acid in cytoreduction of gastric cancer. A technical report using mouse model.

BACKGROUND AND AIM: Application of acetic acid topically to the mucosal or serosal side of the stomach has been well used to create a chronic gastric ulcer model. The aim of the present study was to apply it as a new cytoreductive approach in a mouse model of gastric cancer. METHODS: A total of 43 genetically engineered mice, the so-called (INS-GAS) mice that develop spontaneously gastric cancer at 10-14 months of age, were included. Acetic acid-induced ulcer method was applied to mice under isofluran anesthesia. The ulcer at the cancer side was made by exposing either the anterior serosal or posterior mucosal side of gastric wall to 0.1 mL of 60% or 100% acetic acid for 30 or 60 s with a cylindrical metal mold (4 mm ID). Route to the serosal side was intra-abdominal and one to the mucosal side was through a small hole made in the forestomach. The opposite side of gastric wall (no treatment with acetic acid) was used as the corresponding control. After the mice were sacrificed, the stomachs were collected 1, 3, 6 h or 1, 3 and 7 days, postoperatively, and evaluated by visual inspection and histology. RESULTS: Gastric cancer was found in both the anterior and posterior walls of the corpus in all 43 mice. Intraluminal pH value was between 11 and 13. Severe necrosis in the cancer was observed in the side exposing to acetic acid, but not in the control side, shortly after the treatment (i.e. within 30 or 60 min). The muscularis mucosa and muscle layers were less damaged, regardless of the side of the treatment. Ulcer formation in the cancer took place 1, 3 or 7 days later. The ulcer depth was sometimes at the muscularis mucosa and muscle layers. At 3 and 7 days, regeneration of epithelial cells was clearly observed in the ulcer margin in the stomach of mice. CONCLUSIONS: Topical application of acetic acid either from mucosal or serosal surface promptly caused the necrosis of tumor, suggesting the potential approach of this simple and reliable method as a cytoreductive treatment of gastric cancer in patients through endoscopy or laparoscopy.

New method of inducing intestinal lesions in rats by intraduodenal administration of aspirin.

BACKGROUND AND AIMS: Enteroscopic observation has clearly demonstrated that non-steroidal anti-inflammatory drugs/low-dose aspirin (usually enteric-coated) induces hemorrhagic lesions, including ulcers and bleeding, in the small intestine of patients at a high incidence. Such intestinal lesions induced by NSAIDs have been confirmed in animal experiments. With aspirin, however, it has long been believed that it is difficult to induce any damage in the intestinal mucosa of laboratory animals. Therefore, we established a new method of inducing intestinal hemorrhagic lesions in rats by injecting aspirin into the proximal duodenum. METHODS: Under ether anesthesia, aspirin (50-200 mg/body), suspended in 2% methylcellulose (with or without 0.1 N HCl), was injected into the proximal duodenum of normally fed or 20-h non-fed rats (male Sprague-Dawley, 9 weeks old). At 1 h after treatment, the animals were killed with ether and the entire small intestine was removed for histological examination. In some experiments, 1% Evans blue was injected (i.v.) into the rats 1 h after aspirin treatment to visualize the lesions. An image analyzer determined the total area of the intestinal lesions. Oral proton pump inhibitors and histamine H(2)-receptor blockers were given 1 h before aspirin injection. 16,16-dimethyl prostaglandin E(2) (dmPGE(2)) was given s.c. 30 min before aspirin injection. RESULTS: Aspirin alone clearly induced severe lesions (including bleeding and ulcers) mainly in the jejunum at 100% incidence. Total score of lesions per rat obtained by histological examination was similar to the damaged area quantified with the dye method. Dose-related induction of lesions by aspirin was confirmed both by the histological and dye methods. The irritable effect of aspirin suspended in 0.1 N HCl solution was the same as that of aspirin alone; 0.1 N HCl alone induced only minor lesions in the intestine. Both proton pump inhibitors and histamine H(2)-receptor blockers, at doses that inhibit gastric acid secretion, had no or little effect on aspirin-induced intestinal lesions. Pretreatment with dmPGE(2) (3, 10, 30 microg/kg) showed significant prevention of both aspirin- and HCl/aspirin-induced intestinal lesions. CONCLUSION: This new aspirin lesion model will be useful for screening defensive drugs against aspirin-induced intestinal lesions and to elucidate the underlying mechanism.

Roles of calcitonin gene-related peptide in maintenance of gastric mucosal integrity and in enhancement of ulcer healing and angiogenesis.

BACKGROUND & AIMS: The gastrointestinal tract is known to be rich in neural systems, among which afferent neurons are reported to exhibit protective actions. We tested whether an endogenous neuropeptide, calcitonin gene-related peptide (CGRP), can prevent gastric mucosal injury elicited by ethanol and enhance healing of acetic acid-induced ulcer using CGRP knockout mice (CGRP(-/-)). METHODS: The stomach was perfused with 1.6 mmol/L capsaicin or 1 mol/L NaCl, and gastric mucosal injury elicited by 50% ethanol was estimated. Levels of CGRP in the perfusate were determined by enzyme immunoassay. Gastric ulcers were induced by serosal application of absolute acetic acid. RESULTS: Capsaicin inhibited injured area dose-dependently. Fifty percent ethanol containing capsaicin immediately increased intragastric levels of CGRP in wild-type (WT) mice, although 50% ethanol alone did not. The protective action of capsaicin against ethanol was completely abolished in CGRP(-/-). Preperfusion with 1 mol/L NaCl increased CGRP release and reduced mucosal damage during ethanol perfusion. However, 1 mol/L NaCl was not effective in CGRP(-/-). Healing of ulcer elicited by acetic acid in CGRP(-/-) mice was markedly delayed, compared with that in WT. In WT, granulation tissues were formed at the base of ulcers, and substantial neovascularization was induced, whereas those were poor in CGRP(-/-). Expression of vascular endothelial growth factor was more markedly reduced in CGRP(-/-) than in WT. CONCLUSIONS: CGRP has a preventive action on gastric mucosal injury and a proangiogenic activity to enhance ulcer healing. These results indicate that the CGRP-dependent pathway is a good target for regulating gastric mucosal protection and maintaining gastric mucosal integrity.

Neuroprotective effects of galanthamine and tacrine against glutamate neurotoxicity.

We examined the mechanisms of the neuroprotective effects of two central-type acetylcholinesterase inhibitors, galanthamine and tacrine, on nitric oxide-mediated glutamate neurotoxicity using primary cultures from the cerebral cortex of fetal rats. Galanthamine and tacrine showed prominent protective effects against glutamate neurotoxicity. Mecamylamine, a nicotinic acetylcholine receptor antagonist, but not scopolamine, a muscarinic acetylcholine receptor antagonist, inhibited the protective effects of these inhibitors on glutamate neurotoxicity. Furthermore, dihydro-beta-erythroidine, an alpha4-nicotinic receptor antagonist, and methyllycaconitine, an alpha7-nicotinic receptor antagonist, inhibited the neuroprotective effects of galanthamine but not tacrine. Next, we investigated the site of action where galanthamine and tacrine prevent glutamate neurotoxicity. Both these acetylcholinesterase inhibitors prevented glutamate- and ionomycin-induced neurotoxicity, but only tacrine prevented S-nitrosocysteine-induced neurotoxicity. These results suggest that galanthamine and tacrine protect cortical neurons from glutamate neurotoxicity via different mechanisms.

Differentiation of the gastric mucosa. I. Role of histamine in control of function and integrity of oxyntic mucosa: understanding gastric physiology through disruption of targeted genes.

Many physiological functions of the stomach depend on an intact mucosal integrity; function reflects structure and vice versa. Histamine in the stomach is synthesized by histidine decarboxylase (HDC), stored in enterochromaffin-like (ECL) cells, and released in response to gastrin, acting on CCK(2) receptors on the ECL cells. Mobilized ECL cell histamine stimulates histamine H(2) receptors on the parietal cells, resulting in acid secretion. The parietal cells express H(2), M(3), and CCK(2) receptors and somatostatin sst(2) receptors. This review discusses the consequences of disrupting genes that are important for ECL cell histamine release and synthesis (HDC, gastrin, and CCK(2) receptor genes) and genes that are important for "cross-talk" between H(2) receptors and other receptors on the parietal cell (CCK(2), M(3), and sst(2) receptors). Such analysis may provide insight into the functional significance of gastric histamine.

A novel gastric lesion model induced in rats by partial gastric vascular ligation.

Previous studies have suggested that histamine treatment after gastric vascular ligation induces mucosal damage in the rat stomach. Although ligation of left gastric artery and vein (L-AV) alone did not cause any damage in the stomach within 4 h, but provoked mild lesions due to ischaemia 24 h later. In the present study we demonstrated a new model of gastric lesions induced by L-AV ligation and examined the effects of various anti-ulcer drugs on this lesion model. The gastric lesions induced by L-AV ligation occurred at the corpus and antrum, especially at the corpus-antrum border, when examined 24 h later, and the severity of damage reached maximum 3 days after L-AV ligation. Repeated treatment with omeprazole or sucralfate for 3 days significantly prevented the development of gastric lesions induced by L-AV ligation, in whole mucosa, including the antrum. By contrast, famotidine given for 3 days showed a significant protection against total lesions in the whole mucosa, but had no effect on the antral lesions. Both omeprazole and famotidine dose-dependently decreased gastric acid output while sucralfate raised the intraluminal pH due to the acid-neutralizing action. These results suggest that the pathogenesis of gastric lesions induced by L-AV ligation differs depending on the region, the corpus and the antrum, and the lesions occurred in the latter area seem to be resistant to acid suppression. It is assumed that this new model of gastric lesions is useful for screening the drugs that affect gastric mucosal defense rather than acid secretion.

Histamine regulates growth of malignant melanoma implants via H2 receptors in mice.

The present study examined the effect of histamine H2-receptor antagonists and exogenous histamine on growth of malignant melanoma implant in mice. Drugs were administered to B16BL6 malignant-melanoma-implanted syngeneic mice, and the tumor volume was measured throughout the experiments. Cell proliferation was assessed by MTT assay and mRNA expression was determined by RT-PCR. Both roxatidine and cimetidine significantly suppressed growth of B16BL6 implant compared with vehicle. On the other hand, systemically administered histamine significantly stimulated growth of B16BL6 implants. In addition, the histamine-stimulated B16BL6 implant growth was markedly suppressed by co-administration of cimetidine in a dose-dependent manner. H2-receptor antagonists, however, failed to affect in vitro proliferation of B16BL6 cells. H2-receptor mRNA was detected in B16BL6 implants but not in the cell line. These results indicated that both endogenous and exogenous histamine have ability to stimulate growth of malignant melanoma implants via H2 receptors expressed in host cells.

An overview of acetic acid ulcer models--the history and state of the art of peptic ulcer research.

Four types of experimental chronic ulcer models, named acetic acid ulcer models, have been developed to examine the healing process of peptic ulcers, screen anti-ulcer drugs, and better evaluate the adverse effects of various anti-inflammatory drugs on the gastrointestinal mucosa. The model easily and reliably produces round, deep ulcers in the stomach and duodenum, allowing acetic acid ulcer production in mice, rats, Mongolian gerbils, guinea pigs, cats, dogs, miniature pigs, and monkeys. These ulcer models highly resemble human ulcers in terms of both pathological features and healing process. The models have been established over the past 35 years and are now used throughout the world by basic and clinical scientists. One of the characteristic features of acetic acid ulcers in rats is the spontaneous relapse of healed ulcers >100 d after ulceration, an endoscopically confirmed phenomenon. Indomethacin significantly delays the healing of acetic acid ulcers, probably by reducing endogenous prostaglandins and inhibiting angiogenesis in ulcerated tissue. Helicobacter pylori significantly delays healing of acetic acid ulcers and causes relapse of healed ulcers at a high incidence in Mongolian gerbils. Anti-secretory drugs (e.g. omeprazole), prostaglandin analogs, mucosal defense agents (e.g. sucralfate), and various growth factors all significantly enhance healing of acetic acid ulcers. Gene therapy with epidermal growth factor and vascular endothelial growth factor applied to the base of acetic acid ulcers in rats is effective in enhancing ulcer healing. Since an inhibitor of nitric oxide syntase prevents ulcer healing, nitric oxide might be involved in the mechanism underlying ulcer healing. We conclude that acetic acid ulcer models are quite useful for various studies related to peptic ulcers.

Cholinergically stimulated gastric acid secretion is mediated by M(3) and M(5) but not M(1) muscarinic acetylcholine receptors in mice.

Muscarinic acetylcholine receptors play an important role in the regulation of gastric acid secretion stimulated by acetylcholine; nonetheless, the precise role of each receptor subtype (M(1)-M(5)) remains unclear. This study examined the involvement of M(1), M(3), and M(5) receptors in cholinergic regulation of acid secretion using muscarinic receptor knockout (KO) mice. Gastric acid secretion was measured in both mice subjected to acute gastric fistula production under urethane anesthesia and conscious mice that had previously undergone pylorus ligation. M(3) KO mice exhibited impaired gastric acid secretion in response to carbachol. Unexpectedly, M(1) KO mice exhibited normal intragastric pH, serum gastrin and mucosal histamine levels, and gastric acid secretion stimulated by carbachol, histamine, and gastrin. Pirenzepine, known as an M(1)-receptor antagonist, inhibited carbachol-stimulated gastric acid secretion in a dose-dependent manner in M(1) KO mice as well as in wild-type (WT) mice, suggesting that the inhibitory effect of pirenzepine on gastric acid secretion is independent of M(1)-receptor antagonism. Notably, M(5) KO mice exhibited both significantly lower carbachol-stimulated gastric acid secretion and histamine-secretory responses to carbachol compared with WT mice. RT-PCR analysis revealed M(5)-mRNA expression in the stomach, but not in either the fundic or antral mucosa. Consequently, cholinergic stimulation of gastric acid secretion is clearly mediated by M(3) (on parietal cells) and M(5) receptors (conceivably in the submucosal plexus), but not M(1) receptors.

Exogenous histamine stimulates colorectal cancer implant growth via immunosuppression in mice.

Results from a limited number of studies suggest a potential role for endogenous histamine in regulating tumor growth in immunocompetent cells. The present study examined the effects of exogenous histamine on colorectal cancer growth and the immune response against tumor tissue in mice. Histamine was administered for 21 days to Colon 38 mouse colon adenocarcinoma-implanted syngeneic mice and tumor volume was measured throughout the experiment. Systemic administration of histamine for 21 days caused a significant increase in tumor implant growth compared with the vehicle. At the end of histamine administration, the interferon (IFN)-gamma / interleukin (IL)-4 ratio in peripheral lymphocytes, as well as histamine and cytokine levels in tumor implants were determined. Histamine levels in tumor implants remained unchanged after exogenous histamine delivery. Mice with tumor implants exhibited significantly elevated IFN-gamma / IL-4 ratios compared with mice lacking tumors. Nonetheless, the increased IFN-gamma / IL-4 ratios were markedly suppressed by histamine administration compared with vehicle. In addition, histamine delivery significantly decreased IFN-gamma and IL-12 mRNA expression, but increased IL-10 mRNA expression in tumor implants. It was concluded that exogenous histamine dysregulates the balance between T-helper 1 (Th1) and T-helper 2 (Th2) cells, attenuating anti-tumor cytokine expression in the tumor microenvironment, thus resulting in stimulated colorectal cancer growth.

[Acetic acid-induced gastro-duodenal ulcers in experimental animals--examples of serendipity and pseudoserendipity].

Our understanding of the function and etiology of various gastric diseases has exponentially expanded over the past 40 years. In particular, several animal models had been devised and used for screening of anti-ulcer drugs and elucidation of pathogenesis. This review describes how water-immersion stress ulcer model, Helicobacter pylori ulcer model, and acetic acid ulcer models were established in experimental animals. In recent years, genetically modified mice allowed rapid accumulation of very important findings. H(2)-receptor knockout mice revealed to exhibit Menetrier's disease-like gastric mucosal changes. Gastrin-transgenic mice infected with H. pylori revealed to develop gastric cancer. The hypothesis for the origin of parietal cells was provided.

Lack of histamine alters gastric mucosal morphology: comparison of histidine decarboxylase-deficient and mast cell-deficient mice.

Histamine plays an important role in the regulation of gastric acid secretion; however, its role in maintenance of gastric morphology remains unclear. To clarify the necessity of histamine for gastric mucosal development and maintenance, we evaluated two different kinds of mice that lacked either mast cells (one of the gastric histamine-producing cell types) or histidine decarboxylase (HDC; a histamine-synthesizing enzyme). Measurements of stomach weight, intragastric pH, mucosal histamine levels, as well as serum gastrin and albumin levels were performed in mice. Gastric mucosal appearance was examined by immunohistochemical techniques. Although gastric mucosal histamine levels in mast cell-deficient mice were half of those observed in the wild-type mice, intragastric pH, serum gastrin levels, and gastric morphology at 12 mo were unchanged compared with the wild-type mice. In contrast, HDC-deficient mice possessed no detectable gastric histamine, but did exhibit hypergastrinemia, as well as marked increases in intragastric pH and stomach weight compared with the wild-type mice. Histological analysis revealed that 9-mo-old HDC-deficient mice demonstrated hyperplasia in the oxyntic glandular base region, as well as increased numbers of parietal and enterochromaffin-like cells. These results indicate that enterochromaffin-like cell-derived histamine is potentially involved in gastric mucosal morphology regulation.

Gastric antisecretory and anti-ulcer effect of ME3407, a new benzimidazole derivative, in rats.

The effects of a new benzimidazole derivative, ME3407 (n-butyl-2-(thiazolo-[5,4-b]pyrid-2-yl) sulfinylacetate, CAS 133903-90-9), on gastric acid secretion and gastric and duodenal ulcers in rats were examined. ME3407, given orally, inhibited dose-dependently (0.3-30 mg/kg) the incidence of gastric lesions such as Shay ulcers, and water-immersion stress-, acetylsalicylic acid (ASA)- and histamine-induced erosions. In addition, ME3407 showed marked therapeutic effect on HCl- and ASA-induced lesions. In the lumen-perfused rats, oral administration of ME3407 inhibited dose-dependently (1-100 mg/kg) gastric acid secretion induced by histamine and tetragastrin with ED50 values of 3.02 and 3.37 mg/kg, respectively. Oral administration of ME3407 at a dose of 30 mg/kg also inhibited the elevation of serum gastrin level. The development of duodenal ulcers caused by mepirizole and systeamine was also potently inhibited by ME3407 at an oral dose of 0.1-30 mg/kg. However, when given at 30 mg/kg intraduodenally, subcutaneously or intravenously, ME3407 did not inhibit these acutely induced gastric elosion and acid output. ME3407 was not detected in the serum upon oral administration. These results indicated that ME3407 was active only by oral administration, and exerts direct action on the ulcers and acid secretion from the gastric membrane.

Roxatidine- and cimetidine-induced angiogenesis inhibition suppresses growth of colon cancer implants in syngeneic mice.

Cimetidine is known to suppress the growth of several tumors, including gastrointestinal cancer, in humans and animals. Nonetheless, whether other histamine H(2)-receptor antagonists exert such tumor suppressive effects remains unclear. The effect of roxatidine acetate hydrochloride (roxatidine), an H(2)-receptor antagonist, on the growth of colon cancer implanted in mice was examined and compared with that of cimetidine. Drugs were orally delivered for 26 - 29 days beginning before or after implantation of syngeneic colon cancer (Colon 38) in C57BL/6 mice. Tumor volume was determined throughout and histochemical analysis was also performed. Tumor tissue and serum vascular endothelial growth factor (VEGF) levels were measured. In vitro cell growth was assessed by the MTT assay. Both roxatidine and cimetidine significantly suppressed the growth of Colon 38 tumor implants. Histologic analysis revealed that such antagonists markedly increased necrotic areas and decreased the density of microvessels in tumor tissue. Both H(2)-receptor antagonists suppressed VEGF levels in tumor tissue and significantly decreased serum VEGF levels in Colon 38-bearing mice. Such drugs, however, failed to suppress in vitro growth of the cell line. In conclusion, both roxatidine and cimetidine were found to exert suppressive effects on the growth of colon cancer implants in mice by inhibiting angiogenesis via reducing VEGF expression.

Crucial role of histamine for regulation of gastric acid secretion ascertained by histidine decarboxylase-knockout mice.

Histidine decarboxylase (HDC) represents the sole enzyme that produces histamine in the body. The present work investigated the role of endogenous histamine in carbachol- and gastrin-induced gastric acid secretion with HDC-knockout (HDC-/-) mice. Acid secretion was measured in either mice subjected to acute fistula production under urethane anesthesia or conscious mice that had previously undergone pylorus ligation. In wild-type mice, carbachol and gastrin significantly stimulated acid secretion, increasing gastric mucosal histamine. In contrast, in HDC-/- mice, carbachol and gastrin had little impact when either delivered alone or together. Nonetheless, the two agents achieved a synergistic effect when delivered together with exogenous histamine, stimulating acid secretion in HDC-/- mice. Such synergism was abolished by the histamine H2-receptor antagonist famotidine. cAMP involvement in acid secretion was also examined with theophylline, a phosphodiesterase inhibitor, and forskolin, an adenylate cyclase activator. In wild-type mice, theophylline significantly increased acid secretion, enhancing carbachol- and gastrin-stimulated acid secretion. In contrast, in HDC-/- mice, theophylline failed to exert an effect on basal acid secretion, as well as carbachol- and gastrin-stimulated acid secretion. Although forskolin interacted with carbachol, allowing acid secretion in HDC-/- mice, similar results were not achieved with gastrin. Such results suggest that 1) histamine is essential for carbachol- and gastrin-stimulated gastric acid secretion in mice; and 2) histamine-induced cAMP production contributes to the in vivo response to carbachol or gastrin.

[An overview of acetic acid ulcer models and their utility for drug screening].

Since Takagi et al. reported an experimental chronic gastric ulcer model [acetic acid ulcers induced by submucosal injection of acetic acid (Type 1)], we further modified the methodology and subsequently devised three more models. The second model involves inducing ulcers by serosal application of an acetic acid solution (Type 2) and the third model achieves ulcer induction by intragastric application of an acetic acid solution (Type 3). The forth model was modification of the third model by giving the acetic acid solution and the same volume of air to make one ulcer in the stomach (Type 4). In general, animals accepted the procedures without problems and no undesirable effects were noticed. More importantly, this experimental animal model allows production of ulcers that highly resemble human ulcers in terms of both pathology and healing. Indeed, relapse is even endoscopically observed for 360 days after ulceration. The ulcers produced not only respond well to various anti-ulcer medications, such as antisecretory and mucosal protective drugs and growth factors, but also demonstrate appropriate responses to ulcerogenic agents such as NSAIDs. In addition, we have recently demonstrated that H. pylori infection resulted in delayed ulcer healing and recurrence of healed acetic acid ulcers induced in Mongolian gerbils. The present article gives a brief summary of the ulcer history before establishment of acetic acid ulcers and characteristic features of acetic acid ulcer, including both their merits and shortcomings.

On the mechanisms underlying histamine induction of gastric mucosal lesions in rats with partial gastric vascular occlusion.

Although it is well known that histamine induces gastric mucosal lesions in laboratory animals, the fundamental mechanisms remain unclear. In order to further analyze the vascular mechanisms underlying histamine-induced lesions, a new model was developed in the glandular stomach via administration of histamine (40 mg/kg, s.c.) twice to rats with partial gastric vascular occlusion (ligated left gastric artery and vein) also subjected to pylorus ligation. Both antagonists of histamine H(2)-receptors (roxatidine and famotidine) and H(1)-receptors (epinastine and tripelennamine) significantly inhibited lesion formation at doses that did not inhibit acid secretion. Combined treatment of tripelennamine and famotidine synergistically inhibited lesion formation. Nitro L-arginine methyl ester inhibited lesion development; inhibition was reversed by concomitantly administered L-arginine. Indomethacin, diclofenac, and SC-560 (a selective COX-1 inhibitor), but not rofecoxib (a selective COX-2 inhibitor), significantly inhibited lesion formation. In addition, sodium bicarbonate, pirenzepine, S-0509 (a gastrin/CCK(2) inhibitor), omeprazole, sucralfate, and a prostaglandin analog also significantly inhibited lesion formation. It was concluded that the mechanism by which histamine induces gastric lesions in rats with partial gastric vascular occlusion appears to involve extensive vasodilation resulting from histamine acting on microvasculature histamine H(1)- and H(2)-receptors, generation of endogenous nitric oxide and prostaglandins, with the presence of gastric acid.