Gastric Defense Research Articles

Antisecretory and gastroprotective activities of compounds endowed with H 2 antagonistic and nitric oxide (NO) donor properties

In spite of the well recognized gastric antisecretory activity, the gastroprotective potential of histamine H 2 receptor antagonists is controversial. Most clinical studies in fact indicate that these drugs do not substantially protect the gastric mucosa from aggressive factors. Nitric oxide (NO) has been recently recognized as a fundamental mediator in gastric defence mechanisms, due to its ability to increase gastric mucosal blood flow and mucus production and to inhibit neutrophils adherence to endothelial cells. The aim of this study was to investigate the gastroprotective and H 2 receptor antagonistic activity of a series of lamtidine analogues which contain different NO-releasing moieties (furoxan, nitroxy and nitrosothiol). These compounds were tested, in comparison with related H 2 antagonists devoid of NO-donor structures, in different H 2 receptor assays and in the conscious rat against 0.6 N HCl-induced gastric lesions. All the compounds tested were able to antagonize histamine-mediated responses at cardiac and gastric H 2 receptors; however, furoxan and nitroxy derivatives were 10-fold less potent than the analogues devoid of NO-donor properties. By contrast, NO-donor compounds were more active than reference H 2 antagonists as gastroprotective agents against mucosal injury induced by 0.6 N HCl. Among the different NO-donor moieties, the furoxan group conferred to the H 2 antagonist molecule the highest gastroprotective potential; this finding closely correlates with the characteristics of NO release. In conclusions, lamtidine-analogue H 2 antagonists combined with NO-donor moieties are endowed with gastric antisecretory and protective activity and could be the prototypes of a new class of anti-ulcer drugs. Finally, the furoxan NO donor group seems to be the most favourable among the different moieties tested.

Role of mucus reduction and luminal acid elevation in increased susceptibility of stomach to nonsteroidal antiinflammatory drug-induced injury in arthritic rats.

We investigated the role of gastric mucus and acid secretion in the increase of nonsteroidal antiinflammatory drug-induced gastric lesions in adjuvant-induced arthritic rats. Both aspirin- and indomethacin-induced gastric injury were remarkably worsened in the arthritic rats. In the arthritic rats, the amounts of mucus glycoprotein in both the mucosa and adherent gel layer were respectively decreased to 70% and 34% of those in normal rats, while gastric acid secretion was augmented to 1.5-fold. The gastroprotective antiulcer agent ecabet sodium, which increased the mucus content in the gel layer but did not affect the luminal acid contents, prevented the increase of both lesions induced by aspirin and indomethacin. Cimetidine also inhibited the formation of aspirin- and indomethacin-induced damage as well as the acid secretion in the arthritic rats. In conclusion, an imbalance between gastric defensive and aggressive systems due to the loss of adherent mucus glycoprotein and the elevation of the luminal acid contents seems to account for the increased susceptibility of the lesion-inducing properties of nonsteroidal antiinflammatory drugs in arthritic rats.

Co-regulation of mucosal nitric oxide and prostaglandin in gastric adaptive cytoprotection.

The correlation between mucosal generation of nitric oxide (NO) and prostaglandin E2 (PGE2) in gastric adaptive cytoprotection was investigated. Male Sprague-Dawley rats were pretreated with either N(w)-nitro-L-arginine methyl ester (L-NAME, 12.5 mg/kg i.v.) or indomethacin (5 mg/kg s.c.). Following that, mild irritant 20% ethanol was administered, 15 min prior to 100% ethanol challenge. Macroscopic gastric mucosal damage, NO synthase activity, mucosal PGE2 and leukotriene C4 (LTC4) levels were measured. Administration of L-NAME and indomethacin significantly reduced the protective action of 20% ethanol against 100% ethanol-induced gastric mucosal damage. Besides, mucosal activity of constitutive NO (cNO) synthase, but not of the inducible isozyme (iNO synthase), was elevated following 20% ethanol treatment. This was accompanied by a reduction in mucosal leukotriene C4 level. Indomethacin significantly inhibited mucosal PGE2 biosynthesis but increased cNO synthase activity. Nevertheless, L-NAME reduced both cNO and iNO formation and prevented the increase in cNO formation caused by 20% ethanol, while enhancing mucosal PGE2 production. Combined L-NAME and indomethacin treatment markedly potentiated ethanol-induced mucosal damage, and completely prevented the increase in cNO or PGE2 biosynthesis when either compound was given alone. These findings suggest a co-regulatory relationship between mucosal NO and PG in the gastric defense system, which will be released after activation by the mild irritants to induce cytoprotection.

Upper gastrointestinal diseases in the elderly

The aim of this article is to summarize the recent progress in geriatric/gastroenterological topics, particularly of the upper gastrointestinal tract, which were the focus of the First International Meeting on Upper Gastrointestinal Diseases in the Elderly, held in Vicenza, Italy, in March 1998. The Meeting was divided into three sections: gastro-oesophageal reflux disease (GORD) in the elderly, Helicobacter pylori infection in the elderly, and nonsteroidal anti-inflammatory drugs (NSAIDs) and the upper gastrointestinal tract in the elderly. GORD presents unique clinical features in elderly patients. The changes in oesophageal function, particularly disorders of motility, only partially explain its unique clinical manifestation. The diagnostic, clinical and therapeutic characteristics of GORD in the elderly need to be studied with attention to avoid its severe local complications, i.e. bleeding, stenosis and Barrett's oesophagus, as well as the more generalized risks of disability, impairment of nutritional status and reduction in the quality of life. Epidemiological studies have demonstrated that the prevalence of H. pylori infection increases with ageing and that subjects living in nursing homes have discrete epidemiological characteristics which render them a high-risk group. The incidence of some histological modifications of the gastric mucosa, particularly intestinal metaplasia, gastric atrophy and gastric cancer, seems to be both age- and H. pylori-related; their study in elderly subjects could give the key to understanding the pathophysiological mechanisms of H. pylori gastric damage. NSAID-related gastroduodenal damage, particularly haemorrhage, increases with age. Ageing, per se, does not modify significantly gastric aggressive factors, such as acid and pepsin secretions; however, a selective and specific reduction in some gastric defensive mechanisms seems to occur with ageing. Clinical studies on prevention of NSAID damage have rarely been performed in an elderly population, and meta-analyses of published data can lead to conflicting conclusions from a pharmaco-economic perspective. The identification of risk factors of NSAID-related gastroduodenal damage must be the foundation of preventive medical care for elderly subjects.

Dynamic regulation of gastric surface pH by luminal pH.

In vivo confocal imaging of the mucosal surface of rat stomach was used to measure pH noninvasively under the mucus gel layer while simultaneously imaging mucus gel thickness and tissue architecture. When tissue was superfused at pH 3, the 25 microm adjacent to the epithelial surface was relatively alkaline (pH 4.1 +/- 0.1), and surface alkalinity was enhanced by topical dimethyl prostaglandin E2 (pH 4.8 +/- 0.2). Luminal pH was changed from pH 3 to pH 5 to mimic the fasted-to-fed transition in intragastric pH in rats. Under pH 5 superfusion, surface pH was relatively acidic (pH 4.2 +/- 0.2). This surface acidity was enhanced by pentagastrin (pH 3.5 +/- 0.2) and eliminated by omeprazole, implicating parietal cell H,K-ATPase as the dominant regulator of surface pH under pH 5 superfusion. With either pH 5 or pH 3 superfusion (a) gastric pit lumens had the most divergent pH from luminal superfusates; (b) qualitatively similar results were observed with and without superfusion flow; (c) local mucus gel thickness was a poor predictor of surface pH values; and (d) no channels carrying primary gastric gland fluid through the mucus were observed. The model of gastric defense that includes an alkaline mucus gel and viscous fingering of secreted acid through the mucus may be appropriate at the intragastric pH of the fasted, but not fed, animal.

Central vagal activation increases mucus gel thickness and surface cell intracellular pH in rat stomach

BACKGROUND & AIMS: Central vagal stimulation induced by the thyrotropin- releasing hormone analogue RX 77368 injected intracisternally in urethane-anesthetized rats is gastroprotective. In an in vivo system, the effects of central RX 77368 on discrete components of the rat gastric mucosal barrier were studied to determine if these effects were prostaglandin synthesis dependent.METHODS: Using intravital microscopy, intracellular pH of gastric surface cells, mucus gel thickness, gastric mucosal blood flow, and acid output were measured simultaneously in vivo.RESULTS: Intracisternal RX 77368 significantly increased acid output, gel thickness, and blood flow. Indomethacin enhanced the RX 77368-induced increase in acid output but had no effect on measures of gastric defense during mucosal superfusion with neutral solutions. During acid superfusion, RX 77368 delayed acidification and enhanced recovery of surface cell intracellular pH. These latter effects were reversed partially by indomethacin. Omeprazole abolished RX 77368-induced acid secretion but did not alter its effects on gastric defense mechanisms.CONCLUSIONS: In response to central vagal stimulation with RX 77368, gastric defense mechanisms were enhanced through prostaglandin-dependent and -independent pathways, in contrast to the prostaglandin-independent effects of intravenous pentagastrin. RX 77368-induced enhancements of gastric defense mechanisms did not occur as a result of acid secretion.(Gastroenterology 1997 Feb;112(2):409-17)

Nitric oxide enhances cytotoxicity of cultured rabbit gastric mucosal cells induced by hydrogen peroxide

While NO has been reported to act as a protective factor to gastric mucosa, it has been shown to be cytotoxic to various cells. NO also has been demonstrated to stimulate prostaglandin (PG) release and mucous glycoprotein secretion which could result in the activation of gastric defensive mechanisms. We examined the effect of NO on cytotoxicity induced by hydrogen peroxide, and mucous glycoprotein secretion and PGE2 release from cultured rabbit gastric mucosal cells. NO enhanced cytotoxicity induced by hydrogen peroxide. Defensive prostaglandin E2 release and mucous glycoprotein secretion were not altered by NO. Under certain circumstances, NO might behave as an aggressive factor in gastric mucosal injury.

Indomethacin does not alter the effect of pentagastrin on rat gastric defense mechanisms

We studied the effect of the prostaglandin synthesis inhibitor, indomethacin, on pentagastrin-associated enhancements of gastric mucosal defense mechanisms, using a microfluorometric technique in which mucus gel thickness, intracellular pH (pHi), gastric mucosal blood flow, and acid secretion were measured simultaneously in vivo. Intravenous infusion with pentagastrin (80 micrograms/kg/h) increased mucus gel thickness, induced a hyperemic response to luminal acid, and enhanced pHi homeostasis during acid superfusion. Indomethacin, (5 mg/kg, IP) did not alter the effects of pentagastrin on acid output, mucus gel thickness, mucosal blood flow, and pHi homeostasis. Indomethacin alone did not affect any of these measures. We conclude that the enhancement of gastric defense mechanisms due to pentagastrin is independent of prostaglandin synthesis.

2020 Coexistence of cgrp- and substance p-containing fibers in the spermatic nerve

It has been proposed that capsaicin-sensitive nerves might participate in a gastric defence mechanism, possibly via a local release of sensory neuropeptides. In this study, it was examined whether capsaicin might induce the release of neurokinin A (NKA), substance P (SP) and calcitonin gene-related peptide (CGRP) from different regions of rat stomach. Firstly, the tissue content of NKA-, SP- and CGRP-like immunoreactivity (LI) was measured in the fundus, in the corpus, in the muscle layer and in the mucosa of corpus of control rats and rats pre-treated with systemic capsaicin, s.c. (50 mg/kg as newborn). A large depletion (about 80%) of CGRP-LI following capsaicin treatment was observed in all regions examined, while no difference was observed for NKA-LI and SP-LI, NKA-LI, SP-LI and CGRP-LI release induced by capsaicin was measured in different regions of the rat stomach. Both in the gastric fundus and in the corpus, capsaicin (10 μM) produced a remarkable release of CGRP-LI and NKA-LI, but not of SP-LI. A second administration of the drug had no longer effect, indicating desensitization. In the gastric corpus, the capsaicin-induced NKA-LI and CGRP-LI release was larger from the muscle layer than from the mucosa. The present findings provide neurochemical evidence that both NKA-LI and CGRP-LI are released from different regions of the rat stomach and both peptides should therefore be taken into account when considering the efferent function of capsaicin-sensitive primary afferents at gastric level.

Prostaglandin E2 enhances gastric defense mechanisms against acid injury in uremic rats

Background/Aims: Uremia increases gastric mucosal H+ permeability and acid back-diffusion-related injury in rats. The aim of this study was to examine the effect of the synthetic gastroprotective compound 16,16-di-methyl prostaglandin E2 (16,16-dm PGE2) on the gastric barrier to acid injury in uremic rats. Methods: Chronic renal failure was induced by subtotal nephrectomy. Acid back-diffusion injury was induced by superfusion with 15% ethanol in 0.15N HCl and was assessed by image analysis. Intracellular pH, initial surface cell acidification rate, and thickness of mucous gel layer were measured with in vivo microscopy. Gastric mucosal blood flow was measured in separate experiments by laser-Doppler flowmetry. Results: Pretreatment with 16,16-dm PGE2 attenuated H+ back-diffusion and prevented the production of gross lesions. 16,16-dm PGE2 increased gastric mucous gel thickness, decreased initial acidification rate, and maintained intracellular pH homeostasis during exposure to luminal acid. Gastric mucosal blood flow was not changed during superfusion with a neutral buffer but increased during acid exposure in rats treated with 16,16-dm PGE2. Conclusions: 16,16-dm PGE2 attenuated H+ back-diffusion injury in uremic rats. This effect was associated with blunting of the initial decrease of intracellular pH and enhanced surface cell intracellular pH homeostasis during acid exposure. These effects were associated with an increased mucous gel layer thickness and an acid-related increase in blood flow.

Pentagastrin enhances gastric mucosal defenses in vivo: luminal acid-dependent and independent effects

Stimulation of acid secretion is associated with enhanced resistance of the gastric mucosa to damage by luminal acid. We studied the mechanism by which gastric mucosal defenses are modulated in a system in which mucus gel thickness, intracellular pH (pHi), gastric mucosal blood flow, and acid secretion can be measured simultaneously in vivo, using a recently developed microfluorometric technique. Intravenous infusion of pentagastrin in a dose associated with maximal acid secretion increased mucus gel thickness, pHi, and mucosal blood flow during superfusion with a neutral solution. Subsequent superfusion with an acidic buffer (pH 1.7) further increased blood flow to nearly three times basal. During superfusion with luminal acid, pHi fell more slowly and recovered toward baseline more quickly in pentagastrin-infused rats than in controls. Pretreatment with the H2-receptor antagonist cimetidine abolished the increased blood flow associated with pentagastrin, impairing pHi homeostasis, although cimetidine increased mucus gel thickness in the absence of pentagastrin. We conclude that gastric defense mechanisms at the preendothelial and postepithelial levels are enhanced during acid secretion as part of a histamine-dependent homeostatic mechanism that balances gastric protective mechanisms with acid secretion. The net result of these enhanced defenses is the preservation of gastric surface cell pHi despite the presence of a large proton gradient between lumen and blood.

Gastric damage and body weight loss in LHA-lesioned rats: effects of cytoprotective geranylgeranylacetone.

We investigated the development of gastric damage and body weight (BW) loss in lateral hypothalamic area (LHA)-lesioned rats, measured 2 h and 1 and 3 days after the lesioning (experiment 1), as well as the effects of geranylgeranylacetone (GGA), a cytoprotective antiulcer agent, on these disorders (experiment 2). In experiment 1, BW of LHA-lesioned rats decreased throughout the 3-day experiment. In LHA-lesioned rats, gastric mucosal lesions appeared 1 day after lesioning in the glandular portion and persisted, whereas those in the rumenal portion appeared only after 3 days. Gastric transepithelial potential differences (PDs) of glandular portion began to decrease after 2 h and had decreased in both portions. Gastric acid output was increased transiently at 2 h but it was not high after 1 day and after 3 days was lower than that in sham-LHA-lesioned rats. In experiment 2, PDs of the rumenal decreased more in LHA-lesioned rats than in sham-LHA-lesioned rats pair fed to LHA-lesioned rats after 3 days. Three days of treatment with GGA (200 mg/kg ip) improved PDs of rumenal and glandular portions in LHA-lesioned rats and reduced lesions of the rumenal portion. Loss of BW in LHA-lesioned rats was significantly but not completely inhibited by GGA. These results indicate that disturbance to the gastric defensive mechanism plays an important role in the development of gastric lesions after LHA lesions and that the impairment of gastric functions may be a partial cause of the loss of BW in LHA-lesioned rats.

How Helicobacter pylori acquired its name, and how it overcomes gastric defence mechanisms

At Royal Perth Hospital, Western Australia in April 1982, spiral bacteria were first cultured from a gastric biopsy specimen. Several important taxonomic features were identified which indicated that these bacteria represented a new genus. In October 1989 the new genus name Helicobacter was published. Helicobacter pylori overcomes gastric defence mechanisms by means of its powerful urease enzyme, by its spiral shape allowing it to penetrate mucus, by adherence to the gastric mucosa and by various mechanisms which enable it to evade the immune response.

Effects of GABA and l-glutamate on the gastric acid secretion and gastric defensive mechanisms in rat lateral hypothalamus

The effects of administration of an inhibitory GABAergic or excitatory glutaminergic neurotransmitter into the lateral hypothalamic area (LHA) on gastric acids, an aggressive mechanism, and transepithelial potential difference (PD) and mucosal blood flow (MBF), defensive mechanisms, were examined in anesthetized rats, since lesions of LHA in these animals cause gastric mucosal damage and electrical stimulation stimulates gastric acids and antral contractions. Microinfusion of the inhibitory neurotransmitter, muscimol (GABA agonist) resulted in an increase in gastric acid secretion and in PD and MBF. The GABA antagonists picrotoxin and bicuculline methiodide, in contrast, decreased these three factors. The excitatory neurotransmitter l-glutamate induced only an increase of MBF. Thus, the GABAergic system in LHA stimulates the gastric functions, both defensive and aggressive mechanisms, while the glutaminergic system increases only a portion of the defensive system. The results suggest that there is a significant interaction between LHA and stomach functions.

Gastric cytoprotection: morphological perspectives.

In 1979, a new mechanism of gastric defense named cytoprotection was followed by numerous reports elucidating this interesting and important phenomenon. During this decade, however, the concept and definition of gastric cytoprotection have been modified from the morphological and ultrastructural viewpoints. This review attempts to describe the concept and mechanisms of cytoprotection as well as its pathophysiological features. Specifically, in vitro studies using isolated cells or monolayer cultured cells as well as molecular investigations of signal transduction system have been documented.

Capsaicin-induced release of neurokinin A from muscle and mucosa of gastric corpus: Correlation with capsaicin-evoked release of calcitonin gene-related peptide

It has been proposed that capsaicin-sensitive nerves might participate in a gastric defence mechanism, possibly via a local release of sensory neuropeptides. In this study, it was examined whether capsaicin might induce the release of neurokinin A (NKA), substance P (SP) and calcitonin gene-related peptide (CGRP) from different regions of rat stomach. Firstly, the tissue content of NKA-, SP- and CGRP-like immunoreactivity (LI) was measured in the fundus, in the corpus, in the muscle layer and in the mucosa of corpus of control rats and rats pre-treated with systemic capsaicin, s.c. (50 mg/kg as newborn). A large depletion (about 80%) of CGRP-LI following capsaicin treatment was observed in all regions examined, while no difference was observed for NKA-LI and SP-LI, NKA-LI, SP-LI and CGRP-LI release induced by capsaicin was measured in different regions of the rat stomach. Both in the gastric fundus and in the corpus, capsaicin (10 μM) produced a remarkable release of CGRP-LI and NKA-LI, but not of SP-LI. A second administration of the drug had no longer effect, indicating desensitization. In the gastric corpus, the capsaicin-induced NKA-LI and CGRP-LI release was larger from the muscle layer than from the mucosa. The present findings provide neurochemical evidence that both NKA-LI and CGRP-LI are released from different regions of the rat stomach and both peptides should therefore be taken into account when considering the efferent function of capsaicin-sensitive primary afferents at gastric level.

Intragastric capsaicin protects against aspirin-induced lesion formation and bleeding in the rat gastric mucosa

Previous work has indicated that capsaicin-sensitive afferent neurons are involved in gastric mucosal defense mechanisms. The present study investigated whether stimulation of these neurons by intragastric administration of capsaicin would protect against aspirin-induced mucosal damage in the luminally perfused rat stomach. Capsaicin (25–640 μM), administered together with acidified (pH 1.5) aspirin (25 mM), inhibited macroscopically visible lesion formation and gastric bleeding in a concentration-dependent fashion. Capsaicin (160 μM) also attenuated the aspirin-induced fall in the gastric potential difference. An inhibitory effect of capsaicin (160 μM) on aspirin-induced gastric injury was also seen by light and scanning electron microscopy. Aspirin alone caused a vast ablation of the gastric surface epithelium, resulting in exposure of the lamina propria. In the presence of capsaicin, the depth of mucosal injury, the area totally deprived of surface epithelial cells, and the severity of surface desquamation were diminished. As capsaicin is a selective stimulant of thin afferent neurons, it would appear that these neurons participate in mechanisms of gastric defense against aspirin injury. Prevention of hemorrhagic damage seems to be the primary effect of afferent nerve-mediated gastroprotection, although injury to the surface epithelium is also reduced to some degree.

Capsaicin-induced release of substance P-like immunoreactivity from the guinea pig stomach in vitro and in vivo

Capsaicin induced a release of substance P-like immunoreactivity (SP-LI) in superfusates from gastric fundic mucosa of guinea pig in vitro and from gastric perfusates of anaesthetized guinea pigs in vivo. Tissue SP-LI from the gastric fundus was reduced (43.4%) by systemic capsaicin desensitization. These findings provide direct neurochemical evidence which supports the hypothesis for the involvement of local neuropeptide release in the ‘gastric defence mechanism’ played by capsaicin-sensitive nerves.

AM and PM measurement of gastric potential difference and prostacyclin production in humans: effects of ranitidine.

It has been previously documented that aspirin induced gastric injury of healthy male volunteers was greater in the morning than in the evening. We have also reported that fasting gastric acid secretion rates and gastric retention times for solids were lower in the morning hours of the circadian cycle. We hypothesized, therefore, that defensive factors in the human stomach may exhibit circadian rhythmicity with greater vulnerability to noxious agents during the morning hours. It has also been hypothesized that an antisecretory agent, with reported protective effects, such as Ranitidine, would affect gastric defense mechanisms differently at different times in the circadian cycle. Transmural electrical potential difference (PD) and prostacyclin (PGI2) production by mucosal biopsy specimens were chosen as putative indicators of gastric defensive status. Accordingly, morning (1000) and evening (2200) studies were performed on 10 fasting healthy male subjects with and without oral Ranitidine (150 mg) given 3 hr before oro-gastric intubation for the measurement of PD and the removal of mucosal biopsy samples.(ABSTRACT TRUNCATED AT 250 WORDS)

Gastric mucosal protection against ulcerogenic factors in the rat mediated by capsaicin-sensitive afferent neurons

Treatment of newborn rats with capsaicin (0.16 mmol/kg) is known to cause a permanent degeneration of certain, primarily unmyelinated, afferent neurons. In this study, experimentally induced gastric ulceration was investigated in adult rats treated with capsaicin as neonates. It was found that in capsaicin-treated animals the formation of gastric mucosal lesions in response to indomethacin, ethanol, or cysteamine was significantly enhanced as compared with vehicle-treated controls. The duodenal ulceration caused by cysteamine was not altered after capsaicin treatment. In further experiments the possible pathways involved in the effect of capsaicin treatment on gastric mucosal protection were explored. It was found that the capacity of gastric tissue to release prostaglandins E2 and I2 was unchanged after capsaicin treatment. Atropine, hexamethonium, cimetidine, or terbutaline all reduced gastric ulceration in response to indomethacin in both solvent- and capsaicin-treated rats but did not counteract the enhancement of the ulcerogenic effect of indomethacin in capsaicin-treated rats. Guanethidine enhanced the ulcerogenic effect of indomethacin in solvent-treated but not in capsaicin-treated animals. Ethanol-induced formation of gastric lesions remained unaltered by guanethidine in both solvent- and capsaicin-treated rats. These results indicate that capsaicin-sensitive afferent neurons are involved in gastric mucosal protection against ulcerogenic factors. The data further suggest that this type of gastric defense is primarily due to a local mechanism initiated by sensory nerve endings in the gastric mucosa.