Chronic Gastric Ulcers In Rats Research Articles

Teprenone promotes the healing of acetic acid-induced chronic gastric ulcers in rats by inhibiting neutrophil infiltration and lipid peroxidation in ulcerated gastric tissues

Teprenone, an anti-ulcer drug, has been reported to promote the healing of acetic acid-induced chronic gastric ulcers in rats by stimulating gastric mucus synthesis and secretion. Recently, it has been implicated that neutrophil infiltration and lipid peroxidation in ulcerated gastric tissues have an inhibitory effect on the healing of acetic acid-induced chronic gastric ulcers in rats. Therefore, we attempted to clarify whether teprenone exerts a healing-promoting effect on acetic acid-induced chronic gastric ulcers through its inhibitory effect on neutrophil infiltration and lipid peroxidation in ulcerated gastric tissues. In rats with chronic gastric ulcers made by applying acetic acid to the stomach, gastric ulcer healing started later than 3 days after the acetic acid application. Gastric mucosal myeloperoxidase (MPO) activity, an index of tissue neutrophil infiltration, and lipid peroxide content were higher in the ulcerated region than in the intact region on the 8th, 15th, and 22nd day after the acetic acid application. Gastric mucosal non-protein SH content was lower in the ulcerated region than in the intact region on the 8th, 15th, and 22nd day after the acetic acid application, and gastric mucosal adherent mucus content was lower in the ulcerated region than in the intact region on the 8th and 15th day. Daily oral administration of teprenone (100 mg kg−1× 2) for 7 or 14 days, starting on the 8th day after the application of acetic acid to the stomach, enhanced the reduction of the ulcer area with attenuation of all these biochemical changes found in the ulcerated region. The teprenone administration caused a decrease in MPO activity and an increase in adherent mucus content in the gastric mucosa of the intact region. These results suggest that the healing-promoting effect of teprenone on acetic acid-induced chronic gastric ulcers in rats could be due not only to stimulation of gastric mucus secretion but also to inhibition of neutrophil infiltration and enhanced lipid peroxidation in the ulcerated gastric tissue.

Recent advances in gastrointestinal pathophysiology: role of heat shock proteins in mucosal defense and ulcer healing.

The defense mechanism of the gastrointestinal mucosa against aggressive factors, such as hydrochloric acid, bile acid and non-steroidal anti-inflammatory drugs, mainly consists of functional, humoral and neuronal factors. Mucus-alkaline secretion, mucosal microcirculation, and motility act as functional factors, while prostaglandins and nitric oxide act as humoral factors, and capsaicin sensitive sensory neurons act as neuronal factors. All the above factors are known to contribute to mucosal protection. In recent years, heat shock proteins (HSPs), to include HSP70, have been implicated to be an additional factor utilized for the defense mechanisms of the gastrointestinal mucosa at the intracellular level. The expression of HSP70 and HSP47 markedly changes during the development and healing of chronic gastric ulcers in rats. It was revealed that HSC70 (a constitutive form of HSP70) is coprecipitated with cyclooxygenase-1 and the neuronal form of nitric oxide synthase after treatment with a mild irritant (20% ethanol). A positive relationship between enhanced interaction of HSC70 with either cyclooxygenase-1 or nitric oxide synthase and mucosal protection against a strong irritant (100% ethanol) was observed. It was concluded that HSPs might contribute to mucosal defense mechanisms and ulcer healing, most probably through protecting key enzymes related to cytoprotection.

The effects of water extracts of CagA positive or negative Helicobacter pylori on proliferation, apoptosis and connexin formation in acetic acid-induced gastric ulcer of rats.

To investigate the influence of water extracts of CagA-positive or -negative Helicobacter pylori on healing of chronic gastric ulcers and on connexin formation, proliferation and apoptosis, in acetic acid-induced chronic gastric ulcers in rats. Acetic acid was used to induce chronic gastric ulcers in rats, and a water extract of H. pylori was given by mouth every day. Connexin 32 formation was assessed using Western blotting as previously described. The frequencies of proliferating cell nuclear antigen staining and of TdT-mediated dUTP-biotin nick end labelling were examined. In untreated rats, acetic acid-induced gastric ulcers healed after 14 days and the electrophoretic band corresponding to connexin 32 appeared 4 days after ulcer induction. Treatment with a water extract of H. pylori delayed ulcer healing, with the ulcers remaining unhealed even on the 14th day; healing was delayed more when treatment was with an extract of CagA-positive rather than CagA-negative H. pylori. Connexin 32 appeared earlier when treatment was with a CagA-negative rather than a CagA-positive extract, but in both cases later than in the untreated control group. Proliferating cell nuclear antigen labelling on the fourth day was seen in 14.5% +/- 1.6% of mucosal cells of control group, but in 35.9% +/- 1.4% and 36.5% +/- 1.4% of mucosal cells treated with either VacA(+)CagA(-) and VacA(+)CagA(+) H. pylori extract, respectively. Furthermore, extracts of both H. pylori strains, especially VacA(+)Cag(+) H. pylori promoted apoptosis. A water extract of H. pylori increased both proliferation and apoptosis, which are related to exacerbation and healing of ulcer as well as appearance of connexin 32.

Biochemical and pharmacological characteristics of a newly synthesized H+-K+ATPase inhibitor, YJA20379-1, 2-amino-4,5-dihydro-8-phenylimidazole [2,1-b]thiazolo[5,4-g]benzothiazole

The biochemical and pharmacological characteristics of a newly synthesized H+-K+ ATPase inhibitor, 2-amino-4,5-dihydro-8-phenylimidazole[2,1-b]thiazolo[5,4-g]benzothiazole (YJA20379-1), were investigated. In the pig gastric microsomes, YJA20379-1 inhibited the gastric H+-K+ ATPase regardless of pH condition, IC50 values being 21 and 24 microM at pH 6.4 and 7.4, respectively. The inhibitory activity of YJA20379-1 was antagonized by dithiothreitol treatment but could not be reversed by dilution and washing of the enzyme preparation. In Sprague-Dawley rats, YJA20379-1, administered i.d., p.o, i.v., or s.c., significantly inhibited basal gastric acid secretion, with ED50 values of 4.7, 20.2, 6.3, and 13.4 mg/kg, respectively. The antisecretory action of YJA20379-1 was short lasting (less than 7 h at an oral dosing of 30 mg/kg). Oral administration of YJA20379-1 also prevented the formation of ethanol, indomethacin, and water immersion stress induced gastric lesions and mepirizole-induced duodenal ulcers in rats. Furthermore, YJA20379-1 accelerated the healing of acetic acid induced chronic gastric ulcers in rats. In conclusion, these results suggest that YJA20379-1 has a potent inhibitory activity on the gastric H+-K+ ATPase but much shorter duration of antisecretory action than omeprazole, thereby exerting its anti-ulcer effects partly with cytoprotective activity.

Water Extracts of Helicobacter pylori Delay Healing of Chronic Gastric Ulcers in Rats: Role of Cytokines and Gastrin-Somatostatin Link

Background: Helicobacter pylori (Hp) is considered as a major risk factor of peptic ulcer, but the pathogenic mechanism of its action has not been fully explained. Aims: This study was designed: (1) to compare the ulcer healing effects of water extract (WE) obtained from type-I cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA) expressing Hp and from type-II CagA- and VacA-negative Hp strain with those of vehicle (saline), and (2) to determine the alterations in gastric secretion, gastric blood flow (GBF) and expression of Hp-related cytokines during the ulcer healing in rats treated with toxigenic (type-I) and non-toxigenic (type-II) Hp-derived WE. Methods: Gastric ulcers were produced by serosal application of acetic acid in rats with or without gastric fistula treated with vehicle (saline) or WE originating from type-I or type-II Hp administered intragastrically on days 1, 3, 5 and 7 upon ulcer induction. On days 3, 9 and 15, animals were lightly anesthetized with ether, the abdomen was opened and the GBF was measured by the H₂-gas clearance technique in the ulcer area and non-ulcerated mucosa. Venous blood was withdrawn for the measurement of plasma cytokine (IL-1β and TNFα) levels and plasma and gastric contents were also collected for gastrin and somatostatin determination by specific radioimmunoassay. Results: Gastric ulcers healed gradually in vehicle-treated controls and the ulcer area on days 3, 9 and 15 was reduced by 12, 43 and 92%, respectively. In rats treated with WE of type-I Hp, ulcer healing was significantly delayed, and gastritis and infiltration of ulcerated gastric mucosa with inflammatory cells were observed histologically. The prolongation of ulcer healing by WE of both Hp strains was accompanied by a marked fall in the GBF at the ulcer margin and transient hyposecretion especially in rats given WE of type-I Hp strain. On day 15 of ulcer healing, the plasma concentration of IL-1β and TNFα was negligible in vehicle control rats, but it was significantly elevated particularly in rats treated with WE of type-I Hp. RT-PCR analysis revealed that mucosal expression of IL-1β and TNFα mRNA was significantly upregulated in the gastric mucosa of rats treated with either toxigenic or non-toxigenic Hp WE. The plasma gastrin level was significantly higher and the luminal concentration of somatostatin was significantly lower in rats treated with Hp-WE than in vehicle-treated controls and these alterations were more pronounced in rats treated with WE type-I than type-II Hp. Conclusions: WE of toxigenic Hp strain delays ulcer healing due to the reduction in the gastric microcirculation at the ulcer margin, the overexpression of inflammatory cytokines and the impairment of the gastrin-somatostatin link.

Involvement of bradykinin in the healing of chronic gastric ulcer in rats

Involvement of bradykinin in the healing of chronic gastric ulcer in rats

Role of pancreatic secretory trypsin inhibitor (PSTI) in healing of chronic gastric ulcers in rats

Role of pancreatic secretory trypsin inhibitor (PSTI) in healing of chronic gastric ulcers in rats

Short term effect of Salvia miltiorrhiza in treating rat acetic acid chronic gastric ulcer and long term effect in preventing recurrence.

AIM:To study the short-term effect of Danshen (Salvia miltiorrhiza) on acetic acid induced chronic gastric ulcer in rats and its long-term effect in preventing recurrence.METHODS:Rats with acetic acid-induced gastric ulcer were treated with Danshen and cimetidine for 30 days.Traditional gastric mucosal auto-radiography and (3)H-TdR incorporation into gastric mucosa in vitro were employed to study the effects of Danshen in rat acetic acid-induced chronic gastric ulcer, including ulcer index (UI), ulcer inhibitory rate (IR) and label rate (LR).RESULTS:On the day 5, 30 and 126 of ulcer-making, the UI in the Danshen group was obviously lower than that in the cimetidine group and the control group (42.3 ± 3.9, 3.6 ± 1.2, 4.4 ± 2.3; 49.1 ± 3.6, 5.9 ± 1.4, 9.2 ± 1.3; 61.0 ± 3.8, 8.9 ± 2.5, 12.4 ± 2.4, respectively, P < 0.01), the IR (%) in the Danshen group was obviously higher than that in the cimetidine group (31, 59, 64.8; 19, 33, 26, respectively), and the LR in the Danshen group was obviously higher than that in the cimetidine group and the control group (10.0 ± 0.5,16.2 ± 0.8, 15.0 ± 0.6; 9.0 ± 0.5, 13.9 ± 0.6, 10.8 ± 0.7; 6.5 ± 0.7, 10.1 ± 0.5, 8.0 ± 0.7, respectively, P < 0.01). There was no obvious difference in UI in the Danshen group on day 30 as compared with that on day 126.CONCLUSION:Danshen is effective in promoting ulcer healing and preventing recurrence. The mechanism of action is to strengthen the gastric mucosal barrier and to promote the gastric mucosal cell proliferation along the edge of the ulcer.

P-645 - Effects of T-593, a novel anti-ulcer agent, on healing process of chronic gastric ulcers in rats

P-645 - Effects of T-593, a novel anti-ulcer agent, on healing process of chronic gastric ulcers in rats

O-323 - Effect of S-0509, a New Potent and Selective Gastrin/Cholecystokinin-B Receptor Antagonist, on Acid Secretion and Healing of Chronic Gastric Ulcers in Rats

O-323 - Effect of S-0509, a New Potent and Selective Gastrin/Cholecystokinin-B Receptor Antagonist, on Acid Secretion and Healing of Chronic Gastric Ulcers in Rats

Role of basic fibroblast growth factor (bFGF) and sucralfate (SUC) in healing of chronic gastric ulcers in rats: [formula omitted], S.J. Konturek, D. Drozdowicz, B.L. Slomiany, J. Piotrowski & A. Slomiany. Inst. Physiol., Univ. Sch. Med., Krakow, Poland & UMDNJ, Newark, NJ, USA

Role of basic fibroblast growth factor (bFGF) and sucralfate (SUC) in healing of chronic gastric ulcers in rats: [formula omitted], S.J. Konturek, D. Drozdowicz, B.L. Slomiany, J. Piotrowski & A. Slomiany. Inst. Physiol., Univ. Sch. Med., Krakow, Poland & UMDNJ, Newark, NJ, USA

Influence of aging on the healing of chronic gastric ulcers in rats: [formula omitted], S. Okabe. Department of Applied Pharmacology, Kyoto Pharmaceutical University, Kyoto, Japan

Influence of aging on the healing of chronic gastric ulcers in rats: [formula omitted], S. Okabe. Department of Applied Pharmacology, Kyoto Pharmaceutical University, Kyoto, Japan

Omentum and basic fibroblast growth factor in healing of chronic gastric ulcerations in rats.

Omentum was shown to exhibit angiogenic activity, but its role in healing of chronic gastric ulcers is unknown. This study was designed to compare the effects of omentum and basic fibroblast growth factor (bFGF), a potent angiogenic factor, on healing of chronic gastric ulcers in rats. Several series of rats with gastric ulcers were used: series A with intact omentum (control), series B with omentum resected, and series C with omentum placed on the serosal side of the ulcer. Series A-C were divided into four groups treated with vehicle (I); indomethacin (II), an inhibitor of prostaglandin formation, difluoromethylornithine (DFMO) (III); an inhibitor of polyamine biosynthesis or bFGF (IV). Seven days after ulcer induction, the animals were anesthetized, the gastric blood flow (GBF) was determined by laser Doppler flowmetry (LDF), and the ulcer area was measured by planimetry. Biopsy samples of the ulcer margin were taken for determination of the number of capillaries and myofibroblasts in the granulation tissue. Attachment of omentum significantly accelerated ulcer healing, whereas omentectomy delayed this process. LDF revealed the decrease in the GBF at the ulcer margin to 45% and at the ulcer bed to 18% of the value recorded in the intact adjacent mucosa. Attachment of the omentum significantly increased the blood flow at the ulcer margin and increased the number of capillaries and myofibroblasts in the granulation tissue. Indomethacin (1 mg/kg/day) that inhibited mucosal PGE2 by about 85% delayed significantly ulcer healing without affecting the blood flow in the ulcer area.(ABSTRACT TRUNCATED AT 250 WORDS)

Functional ablation of capsaicin sensitive afferent nerves impairs healing of chronic gastric ulcers in rats

Functional ablation of capsaicin sensitive afferent nerves impairs healing of chronic gastric ulcers in rats

Influence of capsaicin-sensitive afferent fibers on acetic acid-induced chronic gastric ulcers in rats.

Accumulating evidence indicates that capsaicin-sensitive afferent fibers play a pivotal role in acute gastroprotection. However, whether they also influence healing of chronic gastric ulcers is still unknown. The effects of ablation of sensory neurons on acetic acid-induced chronic gastric ulcers in rats were investigated at morphologic and biochemical levels by computerized imaging analysis of the ulcerated area, histologic examination, and neuropeptide determination. Afferent nerve ablation, as a result of treating rats with a neurotoxic dose of capsaicin (50 + 50 mg/kg subcutaneously over 2 days), produced a significant increase in the ulcer area at 1 and 2 weeks after acetic acid injection. The delay in ulcer healing was associated with a marked and persistent decrease in tissue calcitonin gene-related peptide-like immunoreactivity, whereas gastric vasoactive intestinal polypeptide was unaffected by capsaicin pretreatment. Histologically, as compared with control rats, capsaicin-desensitized animals only differed in a slight increase in the inflammatory infiltrate during the early phase of ulcer formation. These findings suggest that capsaicin-sensitive afferent fibers may play a role in the healing of chronic experimental gastric ulcers in rats, but the underlying mechanisms remain to be elucidated and deserve further investigation.

Gastroprotective capability of exogenous phosphatidylcholine in experimentally induced chronic gastric ulcers in rats.

Phosphatidylcholine (PC) is a main component of the hydrophobic gastric mucosal barrier. Exogenously administered, it prevents acute lesions. We evaluated the gastroprotective capacity of exogenous PC in both acute (ethanol- and indomethacin-induced) and chronic (indomethacin-induced) lesions in rats. Polyunsaturated (PPC) or hydrogenated PC in different concentrations were given intragastrically, before or after the injury factor, in single or repeated doses. Mucosal lesions were significantly reduced by a single dose of PPC, given before or after the injury factor, in both acute models. In the chronic model a single dose of PPC or hydrogenated PC significantly reduced lesions evaluated 6 h after ulcer induction, whereas after 72 h no protective effect was noticed. Repeated doses of PC were ineffective. In conclusion, in acute models exogenous PC reduces lesions in a dose-dependent manner and contributes to the mucosal defense. In chronic models an incomplete and temporary protection might be due to complex pathogenesis that requires activation of all levels in the mucosal defense. Strengthening of only one level was insufficient to restrict injury.

Effects of naringenin and quercetin on experimental chronic gastric ulcer in rat. Studies on the histological findings

AbstractThe effects of chronic intragastric administration of the flavonoid derivatives naringenin and quercetin (100 mg/kg body weight) on mucosal lesion induced by acetic acid were studied in the rat. The evolution of the healing process of the ulcer by histological measurement was also investigated. Ranitidine was used as a positive reference drug. Compounds were consecutively administered to different groups of rats for 8, 21 and 50 days. The values for the histological mucosa regeneration index as well as the morphological results, indicated that the naringenin cure potential in prolonged treatments was higher than that of the other drugs.

Effects of a New Histamine H2-Receptor Antagonist, Z-300, on Gastric Secretion and Gastro-Duodenal Lesions in Rats: Comparison with Roxatidine.

We examined the effects of a new compound, N-[3-[3-(piperidinomethyl)phenoxy]-propyl]-2-(2-hydroxyethyl-1- thio)acetamido.2-(4-hydroxy benzoyl)benzoate (Z-300), on the histamine H2-receptor, gastric secretion in rats and dogs, and acute gastro-duodenal lesions or chronic gastric ulcers in rats. Roxatidine acetate hydrochloride (roxatidine), a known histamine H2-receptor antagonist, was used as a reference compound. The pA2 values for Z-300 and roxatidine for the isolated guinea pig atrium were 6.8 and 7.0, respectively. These agents at less than 10(-5) M did not affect the contraction of guinea pig ileum in response to carbachol. Z-300, administered either orally or parenterally, significantly inhibited the basal and histamine-stimulated gastric acid secretion in rats. Gastric acid secretion stimulated by histamine, pentagastrin or carbachol in Heidenhain pouch dogs was also significantly inhibited by the compound. The effect persisted for greater than 7 hr in the case of histamine-stimulation. Oral Z-300 significantly protected the gastric mucosa from water-immersion stress-, indomethacin-, aspirin- and HCl.ethanol-induced lesions and protected the duodenal mucosa against mepirizole- and cysteamine-induced ulcers. These effects on gastric secretion and lesion formation were, as a whole, stronger than those observed with roxatidine. Z-300, but not roxatidine, significantly accelerated the spontaneous healing of acetic acid ulcers induced in rats and prevented the delay in ulcer healing caused by indomethacin. The mechanism of action of Z-300 on acute lesions and chronic ulcers appears to be mostly related to its potent antisecretory and mucosal-protective activities.

Effects of a New Histamine H2-Receptor Antagonist, Z-300, on Gastric Secretion and Gastro-Duodenal Lesions in Rats: Comparison with Roxatidine

We examined the effects of a new compound, N-[3-[3-(piperidinomethyl)phenoxy]-propyl]-2-(2-hydroxyethyl-1-thio)acetamido-2-(4-hydroxy benzoyl)benzoate (Z-300), on the histamine H2-receptor, gastric secretion in rats and dogs, and acute gastro-duodenal lesions or chronic gastric ulcers in rats. Roxatidine acetate hydrochloride (roxatidine), a known histamine H2-receptor antagonist, was used as a reference compound. The pA2 values for Z-300 and roxatidine for the isolated guinea pig atrium were 6.8 and 7.0, respectively. These agents at <10−5 M did not affect the contraction of guinea pig ileum in response to carbachol. Z-300, administered either orally or parenterally, significantly inhibited the basal and histamine-stimulated gastric acid secretion in rats. Gastric acid secretion stimulated by histamine, pentagastrin or carbachol in Heidenhain pouch dogs was also significantly inhibited by the compound. The effect persisted for >7 hr in the case of histamine-stimulation. Oral Z-300 significantly protected the gastric mucosa from water-immersion stress-, indomethacin-, aspirin- and HCl* ethanol-induced lesions and protected the duodenal mucosa against mepirizole- and cysteamine-induced ulcers. These effects on gastric secretion and lesion formation were, as a whole, stronger than those observed with roxatidine. Z-300, but not roxatidine, significantly accelerated the spontaneous healing of acetic acid ulcers induced in rats and prevented the delay in ulcer healing caused by indomethacin. The mechanism of action of Z-300 on acute lesions and chronic ulcers appears to be mostly related to its potent antisecretory and mucosal-protective activities.

Effects of Prostaglandins on Hydrocortisone-Induced Delayed Healing of Chronic Gastric Ulcers in the Rat

We have previously shown that chronic steroid administration delays the healing of experimental gastric ulcers in rats. This study was designed to test the beneficial effects of 16,16-dimethylprostaglandin E2 or TRY-200, a stable prostaglandin I2 analogue, on the delayed healing by hydrocortisone (HC) of chronic gastric ulcers in rats. Chronic gastric ulcers were produced in male Wistar rats, weighing 180 g, by serosal application of 100% acetic acid. The rats were randomly divided into six groups: (1) saline, (2) saline, HC-treated, (3) 10 micrograms/kg of 16,16-dimethylprostaglandin E2, (4) TRY-200, a stable prostaglandin I2 analogue, at 5 micrograms/kg, or (5) 10 micrograms/kg, or (6) 30 micrograms/kg. All rats, except for control, were given daily intraperitoneal injection of 2.5 mg/kg of HC sodium phosphate. Tested drugs were administered intragastrically twice a day for 2 weeks. Rats were killed 14 days later and ulcer size was measured. Chronic administration of HC sodium phosphate resulted in a significant delay of ulcer healing induced by acetic acid. Treatment with TRY-200 at 10 or 30 micrograms/kg abolished the deleterious effect of steroids, whereas 16,16-dimethylprostaglandin E2 had no effect. These results indicate that prostaglandin I2 is more effective than prostaglandin E2 in reversing the delayed healing by steroids of chronic gastric ulcers in the rat.