In vivo determination of the stress-strain relation of the human myometrium

Effects of L-glutamine on gastric lesion models in rats and guinea pigs were studied. Shay ulceration in rats was not inhibited by oral L-glutamine. Although stress-induced gastric lesions in intact rats were not inhibited by L-glutamine, a strong antagonism of gastric lesions was induced in pylorus-ligated rats under the same stress by the amino acid. Histamine-induced gastric lesions in intact rats and guinea pigs were also markedly inhibited by L-glutamine. L-Glutamine inhibited the gastric lesions in rats induced by compound 48/80 but not significantly. Reserpine- or serotonin-induced gastric lesions in rats were not affected by L-glutamine. The mechanism of L-glutamine protection was discussed.     

Effects of various amino acids on gastric lesions induced by acetylsalicylic acid (ASA) and gastric secretion in pylorus-ligated rats

The simultaneous oral administration of various amino acids such as L-lysine, L-arginine, L-histidine, L-serine and others at 750, 250 or 83.3 mg/kg in pylorus-ligated rats produced a marked prevention of the gastric mucosal damages caused by oral acetylsalicylic acid (ASA) at 100 mg/kg. In regard with L-lysine and L-arginine, it was assumed that these amino acids might inhibit the ASA-induced gastric lesions through neutralization of acid because of the high alkalinity of these amino acids. In addition, the lesser effect of the hydrochoride salts of these amino acids as compared with the free form on ASA-induced gastric lesions was observed. The other effective amino acids markedly prevented the back diffusion of acid in response to ASA, suggesting as one of the possible mechanisms of lesion formation. However, L-cysteine, which exerted insignificant effect on ASA-induced gastric lesions, also prevented the back diffusion of acid even though the Na+ concentration had not returned to the control level.     

Effects of cyclooxygenase-2 selective and nitric oxide-releasing nonsteroidal antiinflammatory drugs on mucosal ulcerogenic and healing responses of the stomach

Effects of selective cyclooxygenase-2 (COX-2) inhibitors (NS-398) and nitric oxide (NO) -releasing aspirin (NO-ASA) on gastric ulcerogenic and healing responses were examined in comparison with nonselective COX inhibitors such as indomethacin and aspirin (ASA). Hypothermic stress (28-30 degrees C, 4 hr) induced gastric lesions in anesthetized rats with an increase of acid secretion. The lesions induced by hypothermic stress were markedly worsened by subcutaneous administration of both indomethacin and ASA but were not affected by either NS-398 or NO-ASA, although the increased acid secretion during hypothermia was not affected by any of the drugs. On the other hand, the healing of gastric ulcers induced in mice by thermal cauterization (70 degrees C, 15 sec) was significantly delayed by daily subcutaneous administration of indomethacin and ASA as well as NS-398, but not by NO-ASA. COX-2 mRNA was not detected in the intact mucosa but was positively expressed in the ulcerated mucosa, most potently on day 3 after ulceration. Prostaglandin contents in the intact mouse stomach were reduced by indomethacin, ASA, and NO-ASA, while the increased prostaglandin generation in the ulcerated mucosa was inhibited by all drugs including NS-398. After subcutaneous administration of NO-ASA to pylorus-ligated rats and mice, high amounts of NOx were detected in both the gastric contents and serum. In addition, both NS-398 and NO-ASA showed an equipotent antiinflammatory effect against carrageenan-induced paw edema in rats as compared with indomethacin and ASA. These results suggest that both indomethacin and ASA not only increased the mucosal ulcerogenic response to stress but impaired the healing response of gastric ulcers as well. The former action was due to inhibition of COX-1, while the latter effect was accounted for by inhibition of COX-2 and was mimicked by the COX-2-selective inhibitor NS-398. NO-ASA, although it inhibited both COX-1 and COX-2 activity, had no deleterious effects on gastric ulcerogenic and healing responses.     

Disruption of local retinoid-mediated gene expression accompanies abnormal development in the mammalian olfactory pathway

Glycine, a neutral amino acid has been studied for its ability to inhibit gastric secretion and to protect the gastric mucosa against chemically and stress-induced ulcers. Acid secretion studies were undertaken in pylorus-ligated rats with and without glycine treatment. Experimental gastric lesions were induced by hypothermic-restraint stress, indomethacin and necrotizing agents including 80% ethanol, 0.2 M sodium hydroxide and 0.6 M hydrochloric acid in rats. The level of nonprotein sulfhydryl compounds and gastric wall mucus were also measured in the glandular stomach of the rats following ethanol-induced gastric lesions. The results of this study demonstrate that glycine dose dependently reduced the gastric secretions in rats. Pretreatment with glycine significantly protected animals against stress-, indomethacin- and necrotizing agents induced gastric lesions. The antiulcer activity of glycine was associated with significant inhibition of ethanol-induced depletion of nonprotein sulfhydryls and gastric wall mucus. In conclusion, this study demonstrates that glycine possesses significant antiulcer and cytoprotective activity. However, further detailed studies are warranted to establish the mechanism(s) of action, and to determine its role in the prophylaxis and treatment of gastric ulcer disease.     

The dynamics of pAL2-1 homologous linear plasmids in Podospora anserina

We have investigated the properties of the newly synthesized proton-pump inhibitor, 3-butyryl-8-methoxy-4-[(2-thiophenyl)amino]quinoline (YJA20379-6), on gastric mucosal proton-pump (H+/K+-ATPase) activity, gastric acid secretion and gastroduodenal lesions in experimental rats. YJA20379-6 markedly inhibited H+/K+-ATPase activity in rabbit isolated gastric mucosal microsomes, confirming its classification as a proton-pump inhibitor. The inhibitory efficacy of YJA20379-6 on the proton pump was approximately 14-times higher than that of omeprazole at pH 7.4. YJA20379-6 given intraduodenally had a potent inhibitory effect on gastric secretion in pylorus-ligated rats (ED50 22.9 mg kg(-1)) but was less active than omeprazole. Pretreatment of rats with YJA20379-6 dose-dependently protected the gastric mucosa from damage induced by water-immersion stress, indomethacin and absolute ethanol, and the duodenal mucosa from damage induced by mepirizole. Repeated administration of YJA20379-6 also dose-dependently accelerated the spontaneous healing of acetic acid-induced gastric ulcers. These results suggest that YJA20379-6 has potent anti-secretory and anti-ulcer effects which are exerted by suppression of H+/K+-ATPase activity in gastric parietal cells. YJA20379-6 might be useful for the clinical treatment of peptic ulcer diseases.     

Influence of age on natural and delayed healing of experimentally-induced gastric ulcers in rats

This study aimed to investigate the effect of age on natural ulcer healing and delayed ulcer healing induced by nonsteroidal antiinflammatory drugs, using a rat model. Gastric ulcers were induced in young, adult, and aged rats using serosal or mucosal (kissing ulcers) application of acetic acid. Rats were treated with indomethacin 1 mg/kg/day subcutaneously or vehicle for two weeks. Ulcers were assessed by macroscopic and histological measurements of ulcer size. Ulcer induction was affected by age. Aged rats developed significantly smaller ulcers when induced by serosal application of acetic acid and significantly larger ulcers from mucosal application of acetic acid. However, measurements of ulcer size from both models showed no age-related differences in natural ulcer healing. Similarly, indomethacin-induced delayed gastric ulcer healing was not effected by age. We conclude that there are age-related differences in the development of gastric ulcers but there are no age-related differences in natural or delayed ulcer healing in rats.     

Effects of intravenous lansoprazole on acute gastric mucosal lesions and acid secretion

The effects of lansoprazole given intravenously on gastric mucosal lesions, gastric bleeding and acid secretion were investigated in rats in comparison with those of omeprazole, famotidine and ranitidine. Lansoprazole inhibited the formation of gastric mucosal lesions in rats induced by water-immersion stress or aspirin with ID50 values of 0.26 and 0.99 mg/kg, respectively, and also inhibited gastric bleeding induced by hemorrhagic shock or water-immersion stress with ID50 values of 0.46 and 1.22 mg/kg, respectively. Lansoprazole was more potent than omeprazole, famotidine and ranitidine in inhibiting gastric mucosal lesions and hemorrhagic shock- or stress-induced bleeding. Famotidine and ranitidine showed negligible inhibition of water-immersion stress-induced gastric bleeding. Lansoprazole strongly inhibited water-immersion stress-stimulated acid secretion in rats, whereas famotidine and ranitidine did not show a potent inhibitory effect. These results indicate that lansoprazole exerts prominent inhibitory actions against the formation of gastric mucosal lesions and gastric bleeding by inhibiting acid secretion, and they show that it is superior to histamine H2-receptor antagonists in inhibiting stress-induced gastric bleeding.     

Antithrombotic effects of 3-([1:1',2':1"]-3'-terphenyl)propanol in animals

3-([1:1',2':1"]-3'-Terphenyl)propanol (CAS 186835-06-3, F050) and acetylsalicylic acid (ASA) inhibited platelet aggregation induced by CaCl2, arachidonic acid, collagen, adenosine diphosphate (ADP) and thrombin in guinea pigs, rabbits and rats in vitro. However, F050 had a wider spectrum of actions than ASA. Orally administered F050 inhibited platelet aggregation ex vivo. F050 significantly reduced the thrombus formation in the extracorporeal circulation thrombosis model in guinea pigs. It inhibited erythrocyte hemolysis induced by hypotonic NaCl, while ASA did not. F050, but not ASA, inhibited increases in platelet [CA2+]i caused by thrombin in guinea pigs. F050 is a parent compound that will facilitate the development of an orally active drug for the treatment of thrombotic diseases.     

Increase of satellite tobacco ringspot virus RNA initiated by inoculating circular RNA

The present studies examined the actions of a series of novel arylpiperazine 5-hydroxytryptamine1A (5-HT1A) agonists, developed originally for anxiolytic efficacy, in several models of gastric secretion and experimental gastric mucosal injury. These models included conscious gastric acid secretion, pylorus ligation (gastric acid and pepsin secretion), stress-induced gastric mucosal injury, ethanol-induced gastric mucosal damage and gastric adherent mucus levels. 2-(4-[4-(4-Nitropyrazol-1- yl)butyl]-1-piperazinyl)pyrimidine (E4414) and 2-(4-[4-(4-chloropyrazol-1-yl)butyl]-1-piperazinyl)pyrimidine dihydrochloride (E4424) significantly inhibited gastric acid secretion in conscious as well as in pylorus-ligated rats. Both compounds also significantly reduced pepsin secretion in pylorus-ligated animals. E4414 and E4424 significantly reduced both stress-induced and ethanol-induced gastric mucosal injury, and both compounds significantly maintained gastric adherent mucus levels in rats subjected to stress. The antisecretory and gastroprotective actions of E4414 and E4424 were of significantly greater magnitude than those of the reference 5-HT1A agonists, buspirone and 8-hydroxy-2-(di-n- propylamino)tetralin. These results suggest that some novel 5-HT1A agonists exert gastroprotection not only through reduction of aggressive elements in the gut (acid and pepsin secretion) but also through enhancement of defensive gastrointestinal factors such as adherent mucus.     

Chronic nicotine intake causes vascular dysregulation in the rat gastric mucosa

Chronic cigarette smoking has adverse effects on peptic ulcer disease because the healing of ulcers is delayed and the incidence of relapses is enhanced. Short term intake of nicotine induces vascular damage in the rat gastric mucosa, but the pathophysiological mechanisms of nicotine's action in the stomach are largely unknown. In this study rats were treated with nicotine, added to their drinking water, for 50 days. They were then anaesthetised and their stomachs perfused with acidified acetylsalicylic acid (ASA). Chronic nicotine treatment failed to change the effects of acidified ASA to induce gastric mucosal acid back diffusion, haemorrhagic damage and bleeding. Basal blood flow in the gastric mucosa was also unchanged by chronic nicotine intake, whereas the mucosal hyperaemia evoked by ASA induced acid back diffusion was averted. The concentrations of sulfidoleukotrienes were significantly augmented in the gastric wall of nicotine treated rats. These data show that chronic nicotine intake causes dysregulation of the gastric microcirculation, an effect that is associated with biochemical changes in the stomach. This study thus substantiates the adverse effects of smoking on gastric mucosal pathophysiology. These data suggest that inappropriate regulation of gastric mucosal blood flow inhibits recovery from gastric mucosal injury in smokers.     

Induction of gastric lesions and hypoglycemic response by food deprivation in streptozotocin-diabetic rats

Overnight fasting causes hemorrhagic lesions in the stomach of streptozotocin (STZ)-induced diabetic rats, but the pathogenetic mechanism remains unknown. The present study was performed to investigate the pathogenesis of such lesions developed in STZ-diabetic rats after starvation, mainly in relation to blood glucose changes. A single injection of STZ (70 mg/kg, intraperitoneally) induced hyperglycemic conditions one week after the administration, and high blood glucose levels (BGL: > 350 mg%) remained up to three weeks later. The STZ-diabetic rats developed gastric lesions with the marked reduction of BGL after 18 hr of fasting, depending upon the duration of diabetes; the lesion score and delta BGL reduction in the 3-week-old STZ rats were 32.0 +/- 7.8 mm and > 250 mg/100 ml, respectively. Acid secretion in the pylorus-ligated rats was not significantly changed in the STZ-induced diabetic conditions for the initial two weeks but slightly decreased at three weeks when compared with normal rats. Fasting of normal rats for 18 hr did not cause either BGL reduction or any lesion in the stomach. In the 3-week-old STZ animals, the severity of gastric lesions increased with the duration of fasting (4-18 hr) and was again closely associated with the degree of delta BGL reduction. These lesions induced by 18 hr of starvation in 3-week-old STZ rats were significantly inhibited by pretreatment with insulin (4 units/rat/day) for the last one week to maintain BGL within normal ranges or by intravenous infusion of 25% glucose during fasting period. Both of these treatments significantly prevented BGL reduction in response to fasting.(ABSTRACT TRUNCATED AT 250 WORDS)     

Platelet-derived growth factor reverses the effects induced by NSAIDs on ulcer healing

BACKGROUND: It is known that non-steroidal anti-inflammatory drug (NSAID) use delays the healing of peptic ulcers and that growth factors play an important role in the ulcer healing process. AIM: To evaluate the effect of platelet-derived growth factor (PDGF) in healing chronic gastric ulcers in rats treated with NSAIDs. METHODS: Chronic gastric ulcers were induced with acetic acid in male Wistar rats and then treated with either aspirin (100 mg/kg/day), indomethacin (2 mg/kg/day), PDGF-BB (0.1 nM/kg/day) or combinations. Gastric secretion and ulcer size, wound contraction, mucosal regeneration and cell proliferation were assessed in histological specimens. RESULTS: Both aspirin and indomethacin delayed the healing rate of gastric ulcers and reduced ulcer contraction, mucosal regeneration and cell proliferation. All these effects were completely reversed by oral treatment with PDGF-BB without affecting gastric acid secretion. CONCLUSION: Oral administration of PDGF accelerates ulcer healing and reverses the effects induced by NSAIDs on ulcer healing without affecting gastric secretion.     

Synthesis and antiulcer activity of N-2-(2-hydroxy-2-phenyl)ethyl-N"-(methanesulfonyl)guanidine analogue of ranitidine. Development of a new antiulcer agent T-593

A series of the aryl-substituted N'-2-(2-hydroxy-2-phenyl)ethyl derivatives of N"-methanesulfonyl-N-2-((5-dimethylaminomethyl or 5-methylaminomethyl) furfurylthio)ethylguanidine have been synthesized as potential antisecretory and mucosal protective antiulcer agents. The synthetic routes involves, at the last stage, the reaction of 2-hydroxy-2-phenylethylamines with N-2-(furfurylthio)-ethyl-N'-methanesulfonyl-S-methylisothiourea or its O-phenylisourea counterpart. The primary screening test to assess the inhibitory activity of the synthetic compounds on histamine-induced gastric acid secretion was carried out in anesthetized rats by the lumen-perfusion technique of Ghosh and Schild and also by the pylorus-ligated preparation method. The best profile of histamine H2-antagonist activity was much better than that of the prototype ranitidine, and obtained with N'-(2-(2-hydroxy-2-(4-hydroxyphenyl)) ethyl-N"-methanesulfonyl-N-2-(5-(methylaminomethyl)furfurylthio)et hylguanidine (12f), which was also characterized by enhancing the gastric mucosal blood flow in rabbits as observed by the thermoelectric method. This compound 12f, designated as T-593, significantly inhibited the formation of the indomethacin-induced gastric lesions in rats; 3.5-fold more potent than ranitidine, but 4-fold less active than famotidine. On the other hand, T-593 and famotidine displayed comparable activities in healing the acetic acid-induced gastric ulcer with and without the dosing of indomethacin. Additional notable features of T-593, as determined in rats, are that its protective effect on the hemorrhagic shock-induced lesion under the prior dosing of histamine is ca. 10- and 2-fold greater than ranitidine and famotidine, respectively, and that a decrease in the gastric mucosal blood flow caused by a partial blood-withdrawal is more strongly recovered with T-593 than with famotidine. These experimental results suggest that the antiulcer efficacy of T-593 can be explained by its dual activities: antisecretion of gastric acid and, more importantly, protection of gastric mucous membrane.     

Protective effect of "wei tong ling" on gastric mucosa and influence on quality of gastric ulcer healing

The acute gastric ulcer rat models were induced by dehydrated alcohol, 0.6 N hydrochloric acid and 0.6 N sodium hydroxide, and the chronic gastric ulcer rat models were established by means of acetic acid, the protective effect of Chinese medicine "Wei Tong Ling" (WTL) on gastric mucous membrane was studied. Using histochemical mucin stain, AgNOR stain and immunohistochemical technique the regenerated mucosa of healed gastric ulcer induced by acetic acid in rats was observed quantitatively. They were compared with that of WTL. The results showed that the regenerated mucosa of healed gastric ulcer might be the morphological basis for the recurrence of gastric ulcer and be associated with canceration. WTL could not only accelerate the healing of ulcer but also raise the quality of gastric ulcerous healing which was beneficial for the prevention of ulcer recurrence and canceration. The protective effect of WTL on gastric mucosa was confirmed by various assays.     

Fibrinolytic components in nasal mucosa and nasal secretion

Effects of a newly synthesized antiulcer agent, YJA20379-4, on gastric proton pump (H+/K+-ATPase) activity, Helicobacter pylori (H. pylori) growth, gastric acid secretion, and gastro-duodenal lesions, were examined in comparison with those of omeprazole. YJA20379-4 markedly inhibited the H+/K+-ATPase activity in a concentration-dependent manner and the inhibitory effect was increased under a weak acidic condition; the IC50 values were 32 and 81 microM at pH 6.4 and 7.4, respectively. The inhibition was completely antagonized by 0.5 mM dithiothreitol (DTT). In addition, YJA20379-4 showed a significant anti-H. pylori activity determined by the agar dilution method. The value of minimum inhibitory concentration (MIC, 3.9-11.7 microg/ml) was at least 3 times more potent than that of omeprazole. In pylorus ligated rats, YJA20379-4 inhibited basal gastric acid secretion when administered by the intraduodenal route (ED50: 23.6 mg/kg). In experimental ulcer models, YJA20379-4 administered by the oral route dose-dependently prevented the development of gastro-duodenal lesions in rats. Moreover, repeated administration of YJA20379-4 promoted the healing of gastric ulcers induced by acetic acid. On the basis of the data obtained, it is suggested that YJA20379-4 has a wide spectrum of antiulcer activities, and its mode of antiulcer actions is dependent on the inhibition of H+/K+-ATPase activity and H. pylori growth and the enhancement of a mucosal defense. Thus, YJA20379-4 might prove to be a beneficial therapy for gastritis and peptic ulcer diseases.     

Pharmacological studies on the new quinoline derivative 1-(2-methylphenyl)-4-[(3-hydroxypropyl) amino]-6-trifluoromethoxy-2,3-dihydropyrrolo[3,2-c] quinoline with potent anti-ulcer effect

The effects of the novel acylquinoline derivative, 1-(2-methylphenyl)-4-[(3-hydroxypropyl)amino]-6-trifluoromethoxy-2,3- dihydropyrrolo[3,2-c]quinoline (AU-006) on experimental ulcer models and on gastric secretion were examined. AU-006 prevented dose dependently gastric lesions induced by 95% ethanol when given orally (30-300 mg/kg). Similarly, gastric lesions caused by 0.3 N NaOH were inhibited by oral pretreatment with AU-006. To investigate the anti-ulcer mechanism of AU-006, the effect of AU-006 on gastric acid secretion was tested. Intraduodenal administration of AU-006 reduced in vivo gastric acid secretion. The protective effect of AU-006 against gastric lesions induced by ethanol was not affected by a nitric oxide synthase inhibitor, NG-nitro-L-arginine-methyl ester (l-NAME). In addition, the ethanol-induced mucus reduction was not recovered upon AU-006 administration. These results suggest that AU-006 is effective in the treatment of gastric ulcers by inhibiting gastric acid secretion, and that its activity is not related to either nitric oxide production or mucus secretion.     

The efficacy of using enzymes in treating toxic-allergic reactions after cataract extraction with intraocular lens implantation

In experimental study of antiulcerative activity of dibunol on various models of gastric ulcers in rats the drug caused a marked antiulcerative effect in all of them, reduced the incidence of ulcer formation, and shortened the time of ulcer healing. In a model of "acetic" ulcer dibunol oil solution led to quick normalization of lipid peroxidation in the gastric mucosa, which was evidence of high antioxidant activity in cases of ulcer lesions.     

Subcutaneous loperamide prevents gastric lesions induced by necrotizing agents in rats

The effects of subcutaneous loperamide on gastric lesions induced by necrotizing agents were investigated in the rat. Loperamide produced a dose-dependent increase of gastric fluid volume and inhibition of gastric lesions caused by 0.6 N HCl or absolute ethanol. Pretreatment with naloxone almost completely blocked both fluid pooling effect and mucosal protective effect of loperamide. Omeprazole reduced the acidity of the gastric fluid in rats treated with loperamide without significantly decreasing the fluid volume. Various volumes of acid, given orally immediately before 0.6 N HCl, volume-dependently prevented gastric lesions. We conclude that subcutaneous loperamide protects the gastric mucosa against necrotizing agents through luminal dilution of irritants, which is mediated by naloxone-sensitive opiate receptors.     

Structural features of Glycera dibranchiata monomer hemoglobins. Primary sequences of monomer hemoglobin components II and III

Glucocorticoids promote the development of many organs including intestine. At the cellular level, the activity of glucocorticoids is regulated by 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) which converts active glucocorticoids to inactive metabolites. As 11 beta HSD is also expressed in the intestine, this enzyme may be an important regulator of intestinal maturation. To investigate this, we have performed the systematic study of the development of intestinal 11 beta HSD activity and its cofactor preference as well as of the effect of 11 beta HSD inhibition by carbenoxolone on postnatal development of sucrase, alkaline phosphatase and Na,K-ATPase in the intestine. The activity of 11 beta HSD was low in ileum of suckling rats and significantly increased during the weaning period. In colon, the activity was already high in suckling rats and gradually rose during the postnatal development. 11 beta HSD activity was undetectable in jejunum both in young and adult rats. At 14.5 nM corticosterone, colonic 11 beta HSD utilized predominantly NAD as a cofactor, but displayed significant sensitivity also to NADP. Ileal 11 beta HSD had similar sensitivity to both cofactors. With NAD as a cofactor, ileal 11 beta HSD had a Km (59 +/- 10 nM) compatible with the colonic enzyme (81 +/- 14 nM). Carbenoxolone administration to suckling and weanling rats in vivo did not result in any changes of sucrase activity in jejunum and ileum, alkaline phosphatase activity in ileum and distal colon or Na,K-ATPase activity in ileum. However, carbenoxolone significantly increased Na,K-ATPase activity in distal colon. Our results indicate that the high-affinity type of 11 beta HSD is expressed not only in colon but also in ileum and that 11 beta HSD is an important factor in the regulation of tissue levels of active glucocorticoids in developing colon but not in the small intestine.