Role of histamine and acid back-diffusion in modulation of gastric microvascular permeability and hemorrhagic ulcers in Salmonella typhimurium-infected rats

Documentation concerning the pathogenesis of gastric hemorrhagic ulcer in Salmonella typhimurium (Salmonella typhi)-infective disease is lacking. This research first proposed that alterations of mast cell histamine release, gastric acid back-diffusion and mucosal microvascular permeability are important in modulating gastric ulcer and hemorrhage in Salmonella typhi-infected rats. Additionally, effects of several histamine-related drugs on this ulcer model were evaluated. Male Wistar rats were deprived food for 36 h. Live cultures of Salmonella typhi (OU 5045, 1 x 10(10) CFU in 1.0 mL of sterilized phosphate buffer saline) were challenged, intrajejunally to rats just before withdrawal of food. Control rats received the same volume of sterilized vehicle only. Rat stomachs were irrigated for 3 h with either normal saline or simulated gastric juice. Gastric acid back-diffusion, mucosal histamine concentration, microvascular permeability as well as luminal hemoglobin content and ulcer areas were determined. Severe gastric hemorrhage and mucosal ulcerations, particularly in acidic stomachs, were observed in Salmonella typhi-infected rats. A positive correlation of histamine to gastric hemorrhage and ulcer was found in those rats with Salmonella typhi-infection. This hemorrhagic ulcer in Salmonella typhi-infected rats was effectively ameliorated by intraperitoneal ketotifen, diphenhydramine and ranitidine but was worsen by exogenous histamine or diamine oxidase. In conclusion, enhancement of acid back-diffusion, mast cell histamine release and microvascular permeability is important in modulating gastric hemorrhage and ulcer in Salmonella typhi-infected rats.     

Role of histamine in aggravation of gastric acid back-diffusion and vascular permeability in septic rats

The aim of the present study was to investigate the role of histamine in aggravation of gastric acid back-diffusion and vascular permeability in lipopolysaccharide (LPS)-induced septic rats. Male specific pyrogen-free Wistar rats were deprived food for 24 h before the experiment. Intravenous LPS (3 mg/kg dissolved in sterilized saline) was given to rats 12 h after food removal. Control rats received sterilized saline only. Under diethylether-anesthesia, the pylorus and esophageal sphincters of rats were ligated. Vagotomy also was performed. The stomachs were then irrigated for 3 h with physiological acid solutions containing 0-150 mM HCl plus adequate amount of NaCl. Increases in various ulcerogenic parameters, such as gastric acid back-diffusion, mucosal histamine concentration, luminal hemoglobin (Hb) content and stomach ulcer, were dependent on the concentration of acid solutions irrigated in stomachs of those LPS rats. Gastric vascular permeability also was increased in an acid concentration-related manner. In those LPS rats, high correlation was found between extents of acid back-diffusion and mucosal ulceration. Increased vascular permeability also closely related to the luminal Hb content. Moreover, these ulcerogenic parameters were dose-dependently ameliorated by intraperitoneal ketotifen and ranitidine. Diamine oxidase also was effective in inhibition, but exogenous histamine on the contrary, produced exacerbation of these ulcerogenic parameters. In conclusion, histamine plays a pivotal role in modulating gastric acid back-diffusion and vascular permeability that are greatly associated with hemorrhagic ulcer in septic rats.     

Effect of taurine on gastric oxidative stress and hemorrhagic erosion in brain ischemic rats

The effect of taurine on gastric hemorrhage and mucosal erosion in the brain ischemia (BI) is unknown. The aim of the research was to study the involvement of gastric oxidative stress in hemorrhagic erosion produced in BI rats. The protective effect of taurine on this erosion model was evaluated. Male Wistar rats were deprived of food for 24 h. Under chloral hydrate -anesthesia, bilateral carotid artery ligation (BCAL) was performed 12, 18 and 21 h after removal of food to obtain 12, 6 and 3 h of BI duration. The pylorus and carotid esophagus of rats also were ligated. The stomachs were then irrigated for 3 h with normal saline or simulated gastric juice containing 100 mM HCl plus 17.4 mM pepsin and 54 mM NaCl. The stomach was dissected. Gastric samples were harvested. The rat brain was dissected for examination of ischemia by using triphenyltetrazolium chloride staining method. Changes in gastric ulcerogenic parameters, such as decreased mucosal GSH level as well as enhanced gastric acid back-diffusion, mucosal lipid peroxide generation, histamine concentration, luminal hemoglobin content and mucosal erosion in gastric samples were measured. The results indicated that BCAL could produce severe BI in rats. Moreover, a BI- duration-dependent exacerbation of various ulcerogenic parameters also was observed in these rats. Intraperitoneal taurine (0-300 mg/kg) dose-dependently ameliorated gastric oxidative stress and hemorrhagic erosion in BI rats. Taken together, BI could produce gastric oxidative stress and hemorrhagic erosions that was ameliorated by taurine through stimulation of GSH biosynthesis and inhibition of oxidative stress.     

Protective effects of several amino acid-nutrients on gastric hemorrhagic erosions in acid-irrigated stomachs of septic rats

Our previous report demonstrates that severe gastric mucosal damage is produced in lipopolysaccharide (LPS)-intoxicated rats. In the present study, we examined protective effects of several amino acids including taurine, phenylalanine and L-Arginine on gastric hemorrhagic erosions in acid-irrigated stomachs of LPS rats. The animals were deprived of food for 24 hr. Intravenous LPS (3 mg/kg) was challenged 12 hr after withdrawal of food. Gastric vagotomy was performed, followed by irrigation the stomachs for 3 hr with a physiological acid solution containing 100 mM HCl and 54 mM NaCl. The ulcerogenic parameters including increased gastric acid back-diffusion, mucosal histamine concentrations, lipid peroxide productions, luminal hemoglobin contents, stomach erosions and the lowered glutathione levels were markedly enhanced in LPS rat stomachs irrigated with acid solution. Both phenylalanine and taurine caused dose-dependent attenuations of these ulcerogenic parameters in LPS rats. L-arginine also was effective in inhibition. The inhibitory effect was restored by pretreatment of nitric oxide synthase inhibitors, such as N(G)-nitro-L-arginine-methyl ester or L-N(G)-(1-iminoethyl)-lysine. Furthermore, marked amelioration of hemorrhagic erosions in LPS rats was observed when a combination of these amino acid nutrients was used. The results provide evidence that these amino acid nutrients may ameliorate gastric hemorrhagic erosion via GSH synthesis stimulation, histamine cell membrane stabilization and antioxidant actions in LPS rat stomachs.     

Gastric mucosal damage induced by arecoline seizure in rats

In an attempt to know the relation of seizure and gastric mucosal damage, we challenged arecoline (ACL) centrally to induce seizure and investigated gastric hemorrhagic injury in acid-irrigated stomachs of rats. The protective effects of several drugs also were evaluated. After deprivation of food for 24 h, rats were received laparotomy under diethylether-anesthesia. Both pylorus sphincters and carotid esophagus were ligated. The forestomach was equipped with a cannula for gastric irrigation. After recovery from anesthesia (approximately 1 h), the stomach was irrigated for 2 h with an acid solution containing 100 mM HCl and 54 mM NaCl or the same volume of normal saline. Intracerebroventricular (i.c.v.) ACL (0, 1, 3 or 10 mg/kg dissolved in 10 microl of CSF) was challenged to rats immediately after gastric irrigation. The seizure in rats was produced by ACL in a dose-related manner. The ulcerogenic parameters such as decrease of gastric mucosal glutathione levels and increase of histamine concentrations and lipid peroxide generations as well as the raise of luminal hemoglobin contents and exacerbated mucosal lesions were obtained depending on the doses of ACL challenged. These ulcerogenic parameters produced in ACL (10 mg/kg, i.c.v.) seizure rats were markedly ameliorated by gastric vagotomy or central anticholinergics. Intraperitoneal ketotifen, zinc sulfate, diphenhydramine or cimetidine also produced significant (p<0.05) inhibitions of these ulcerogenic parameters in ACL seizure rats. In conclusion, central ACL seizure may produce gastric oxidative stress and hemorrhagic lesions via vagal nervous activation and histamine release in acid-irrigated stomachs of rats.     

Histamine in stress ulcer prophylaxis in rats.

BACKGROUND: Gastrin and its analogues increase the gastric acid secretion, but also enhance mucosal defense mechanisms. On the other hand, increased formation of histamine leading to an increase in gastric acid secretion is accompanied with gastroprotection and acceleration of gastric ulcer healing. AIM: Of this study was to examine the effect of histamine on stress induced gastric ulcers in rats. METHODS: Male Wistar rats were exposed to water immersion and restrain stress (WRS) for 3.5 h at 23 degrees C. Before WRS rats were pretreated with saline, histamine, ranitidine or omeprazole. RESULTS: WRS produces gastric lesions which were strongly reduced by ranitidine or omeprazole. Also treatment with histamine markedly reduced ulcer area evoked by WRS. Addition of histamine to ranitidine or omeprazole caused an additional reduction in ulcer area. Gastroprotective effect of histamine was accompanied with the increase in gastric blood flow (GBF). Administration of omeprazole or ranitidine alone was without significant effect on GBF. Histamine caused an slight decrease in gastric luminal pH, whereas ranitidine or omeprazole significantly increased gastric luminal pH. Plasma interleukin-1beta was significantly reduced after administration of omeprazole, ranitidine, or histamine, however, the effect of histamine was less pronounced. DNA synthesis was increased after administration of omeprazole, ranitidine or histamine when compared with WRS alone. Administration of histamine in combination with ranitidine or omeprazole caused an additional increase in DNA synthesis. CONCLUSIONS: Histamine exhibits protective effect and increases gastroprotective effect of ranitidine and omeprazole against stress-induced gastric lesions. This effect of histamine seems to be independent on gastric acid secretion but related to the increase in gastric blood flow and the reduction in activation of cytokine cascade.     

The pharmacological differences and similarities between stress- and ethanol-induced gastric mucosal damage.

Stress- and ethanol-induced gastric mucosal damage are the two commonly used ulcer models in animals. They share some of the similarities but also have differences in the etiology of gastric ulceration. This article reviews the influences of various protective drugs on these two types of gastric damage in rats. Verapamil (a calcium antagonist) or N-ethylmaleimide (a sulfhydryl depletor) prevents cold restraint-, but potentiates ethanol-provoked gastric lesion formation. N-Acetylcysteine (a mucolytic agent) and acetaminophen (an antipyretic analgesic) have the opposite actions. Prostaglandins provide a much better antiulcer effect on ethanol-induced lesions. Cimetidine (a histamine H2-receptor antagonist) prevents only stress-induced mucosal damage. These differences in drug actions indicate that stress and ethanol may have dissimilar ulcerogenic mechanisms in rats. On the other hand, carbenoxolone (a mucus inducer), histamine H1-receptor antagonists, leukotriene inhibitors (FPL 55712 and nordihydroguaiaretic acid) and mast cell stabilizers (like zinc compounds, sodium cromoglycate, FPL 52694 and ketotifen), all protect against gastric mucosal damage by stress or ethanol in rats. However, the role of gastric sulfhydryls in both types of gastric lesions is still controversial. These findings imply that the two types of lesion formation share some of the ulcerogenic mechanisms. This communication attempts to analyze the various findings and to relate them to the etiology of stress and ethanol-induced gastric lesions. It also summarizes the uses, and the antiulcer mechanisms, of the drugs that have been studied utilizing these two animal ulcer models, and suggests their possible implications in man.     

Effects of desensitization of capsaicin-sensitive afferent neurons on gastric microcirculation in rats depend on the blood glucocorticoid hormone level

The effects of desensitization of capsaicin-sensitive afferent neurons on gastric microcirculation were investigated before and after administration of indomethacin at ulcerogenic dose in adrenalectomized rats with or without corticosterone replacement and in sham-operated animals. We estimated the blood flow velocity in submucosal microvessels; the diameters and permeability of mucosal venous microvessels as parameters of gastric microcirculation. Desensitization of capsaicin-sensitive neurons was performed with capsaicin at the dose 100 mg/kg two weeks before the experiment. Adrenalectomy was created one week before experiment. In vivo microscopy technique for the direct visualization of gastric microcirculation and the analysis of the blood flow was employed. Indomethacin at ulcerogenic dose decreased the blood flow velocity in submucosal microvessels, caused dilatation of superficial mucosal microvessels and increased their permeability. Desensitization of capsaicin-sensitive afferent neurons potentiated indomethacin-induced microvascular disturbances in gastric submucosa-mucosa. These potentiated effects of the desensitization are obviously promoted by concomitant glucocorticoid deficiency. Thus, glucocorticoid hormones have a beneficial effect on gastric microcirculation in rats with desensitization of capsaicin-sensitive afferent neurons.     

Study of the damaging effects of acetazolamide on gastric mucosa in rats

The present study demonstrated that acetazolamide (100 and 200 mg/kg, s.c.) induced severe gastric hemorrhagic ulceration in rats. The ulceration was aggravated by oral administration of HCl, but was inhibited by NaHCO3. Furthermore, the severity of ulceration was also decreased by pretreatment with methysergide, chlorpheniramine, or cimetidine. These protective effects were accompanied by an increase in serotonin and histamine released from the stomach. Acetazolamide injection also increased the protein level but reduced the sialic acid content in the gastric secretion, indicating that the gastric mucosal barrier may have been damaged. Prostaglandin E2 content of the gastric mucosa was not affected by the drug; however, carbonic anhydrase activity was markedly reduced in a dose-dependent manner. Thus, it is suggested that the ulceration induced by acetazolamide is mainly due to the inhibition of carbonic anhydrase activity and mucus secretion. The increase in serotonin and histamine release also may have been the contributing factors for gastric ulcer formation.     

Prostaglandin E2 aggravates gastric mucosal injury induced by histamine in rats through EP1 receptors

We demonstrated that prostaglandin (PG) E2 aggravates gastric mucosal injury caused by histamine in rats, and investigated using various EP agonists which EP receptor subtype is involved in this phenomenon. Rats were used after 18 hr fasting. Histamine (80 mg/kg) dissolved in 10% gelatin, was given s.c., either alone or in combination with i.v. administration of PGE2 or various EP agonists such as 17-phenyl PGE2 (EP1), butaprost (EP2), sulprostone (EP1/EP3), ONO-NT012 (EP3) and ONO-AE1-329 (EP4). The animals were killed 4 hr later, and the mucosa was examined for lesions. The mucosal permeability was determined using Evans blue (1%). Histamine alone induced few lesions in the gastric mucosa within 4 hr. PGE2 dose-dependently worsened the lesions induced by histamine, the response being inhibited by tripelennamine but not cimetidine. The effect of PGE2 was mimicked by 17-phenyl PGE2 and sulprostone, but not other EP agonists, including EP2, EP3, and EP3/EP4 agonists. The mucosal vascular permeability was slightly increased by histamine, and this response was markedly enhanced by co-administration of 17-phenyl PGE2 as well as PGE2. The mucosal ulcerogenic and vascular permeability responses induced by histamine plus PGE2 were both suppressed by pretreatment with ONO-AE829, the EP1 antagonist. These results suggest that PGE2 aggravates histamine-induced gastric mucosal injury in rats. This action of PGE2 is mediated by EP1 receptors and functionally associated with potentiation of the increased vascular permeability caused by histamine through stimulation of H1-receptors.     

Role of bradykinin in gastric vasodilation caused by hypertonic saline and acid back diffusion

Protective vasodilation in response to tissue injury and acid back diffusion is associated with release of bradykinin in the rat stomach. We hypothesized that bradykinin might be involved in mechanisms behind such vasodilation via influence on mast cells and sensory neurons. Acid back diffusion after mucosal barrier disruption with hypertonic saline evoked degranulation of mast cells in the rat stomach wall. Acid back diffusion was also associated with increased luminal release of histamine and gastric blood flow in normal rats, but not in mast cell-deficient rats. Bradykinin (BK(2)) receptor blockade inhibited degranulation of submucosal mast cells in the stomach and attenuated gastric vasodilation both in response to acid back diffusion and after stimulation of sensory neurons with capsaicin. Gastric vasodilation caused by mucosal injury with hypertonic saline alone was associated with degranulation of mucosal mast cells. These events were unaffected by inhibition of prostaglandin synthesis, whereas bradykinin (BK(2)) receptor blockade was associated with abolished vasodilation and inhibition of mucosal mast cell degranulation. We conclude that bradykinin is involved in gastric vasodilation caused by hypertonic injury alone via influence on mast cells, and by acid back diffusion via influence on both sensory neurons and mast cells.     

Gastroprotective effect of leptin on gastric mucosal injury induced by ischemia-reperfusion is related to gastric histamine content in rats

Leptin has cytoprotective effect to gastric mucosal injury in rats. We aimed to test the hypothesis that leptin induced histamine is involved in the prevention of ischemia-reperfusion (I/R) induced gastric mucosal injury in rats. At the end of the 30 min celiac artery occlusion and 12h reperfusion process, serum and gastric tissue samples were taken from three group of rats to measure oxidative status, histamine levels and for histological examinations. Leptin decreased ulcer and polymorphonuclear leukocyte (PMNL) index, and serum malondialdehyde (MDA) and protein carbonyl content but increased gastric tissue histamine levels. We concluded that leptin exerts a protective effect on gastric mucosa to I/R induced gastric injury probably through increasing tissue histamine content which, in turn, maintain the gastric mucosal blood flow.     

Activation of hypothalamic-pituitary-adrenocortical system as important gastroprotective component of stress reaction

The review is focused on the action of glucocorticoids released during activation of hypothalamic-pituitary-adrenocortical axis, on the susceptibility of gastric mucosa to injury. The data support the idea that glucocorticoids produced in response to acute stress or other ulcerogenic stimuli have a gastroprotective action but not ulcerogenic one as it has generally been considered for some decades. It has been shown that gastroprotective action of glucocorticoids may be mediated by multiple actions, including maintenance of glucose homeostasis, gastric mucosal blood flow, mucus production and attenuation of enhanced gastric motility and microvascular permeability. For maintenance of gastric mucosal integrity glucocorticoids may cooperate with other gastroprotective factors. Glucocorticoid hormones exert a pivotal role in the maintenance of gastric mucosal integrity in the case of impaired gastroprotective mechanisms provided by prostaglandins, nitric oxide and capsaicin-sensitive sensory neurons. These findings indicate that activation of hypothalamic-pituitary-adrenocortical system could be considered as a significant hormonal gastroprotective component of stress reaction and therefore glucocorticoid hormones are natural gastroprotective factors.     

Various ulcerogenic stimuli are potentiated by glucocorticoid deficiency in rats

The effects of glucocorticoid deficiency with or without corticosterone replacement on susceptibility to gastric mucosal injury by various ulcerogenic stimuli have been evaluated in rats. Gastric erosions were induced in male rats by stimuli of different modalities and intensities: 20% ethanol (po), aspirin (300 mg/kg, ip), acidified aspirin (40 mM, po) and 100% acetic acid (applied to gastric serosa). Glucocorticoid supply was decreased by adrenalectomy or by delayed inhibitory action after a single pharmacological dose of cortisol (300 mg/kg, ip) injected one week before the onset of ulcerogenic stimulus. Corticosterone for replacement (4 mg/kg, sc) was injected in rats with glucocorticoid deficiency 15 min before the onset of ulcerogenic stimulus. Plasma corticosterone levels were measured by fluorometry. Gastric erosions were quantitated by measuring the area of damage. Ulcerogenic stimuli induced both plasma corticosterone rise and gastric mucosal injury. The area of mucosal damages induced various stimuli ranged from small to extensive. Glucocorticoid deficiency significantly potentiated an ulcerogenic action of every ulcerogenic stimulus. Replacing corticosterone prevented or significantly decreased erosion-potentiating effect of glucocorticoid deficiency. These results show that endogenous glucocorticoids released during ulcerogenic influences help gastric mucosa to resist a harmful action of both weak and strong ulcerogenic stimuli.     

The effect of rebamipide on gastric xanthine oxidase activity and type conversion in ethanol-treated rats

Rebamipide, a novel antipeptic ulcer drug, 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinone-4-yl]-propionic acid, was studied for its inhibitory effect on gastric xanthine oxidase activity and type conversion of the enzyme that has a profound role in free radical generation. Intraperitoneal administration of rebamipide at 60 mg/kg body weight reduced gastric mucosal hemorrhagic lesions and lipid peroxidation, which was proportional to the inhibitory effect of rebamipide on alcohol-induced xanthine oxidase-type conversion and enzyme activity. It was also observed that the activity of xanthine oxidase was significantly inhibited by administration of rebamipide at 60 mg/kg body weight, leading to a significant reduction of lipid peroxide content in alcohol-treated rats. The results suggest that alcohol-induced gastric mucosal lesions might be, in part, due to the increased activity of xanthine oxidase and type conversion rate of the enzyme and the protective effect of rebamipide on gastric mucosal lesions would result from its ability to protect against oxidative stress on gastric mucosal lesions of alcohol-treated rats.     

Current concepts in gastric microcirculatory pathophysiology.

When the barrier to acid back-diffusion is disrupted, there is a protective increase in gastric mucosal blood flow to help remove the back-diffusing acid. Only recently has the mechanism for calling forth this protective hyperemia been determined. The gastric mucosa and submucosa are innervated by many capsaicin-sensitive sensory nerve fibers containing vasodilator peptides. The gastric mucosal sensory neurons monitor for acid back-diffusion, and, when this process occurs, signal for a protective increase in blood flow via release of calcitonin gene-related peptide from the submucosal periarteriolar fibers. The endothelium-derived vasodilator, nitric oxide, plays an important role both in the maintenance of basal gastric mucosal blood flow and in the increase in blood flow that accompanies pentagastrin-stimulated gastric acid secretion. It also interacts with the capsaicin-sensitive sensory nerves in the modulation of the microcirculation to maintain mucosal integrity. Finally, it has been shown that neutrophils play an important role in various forms of mucosal injury. The leukocytes adhere to the vascular endothelium and contribute to injury by reducing blood flow via occlusion of microvessels, as well as by releasing mediators of tissue damage.     

Atropine-induced gastrointestinal cytoprotection dependences to the intact of vagal nerve against indomethacin-induced gastrointestinal mucosal and microvascular damage in rats

The non-steroidal antiinflammatory drugs, such as an indomethacin (IND), cause mucosal ulceration and increase the mucosal vascular permeability in the gastrointestinal (GI) tract. Some exogenous agents, e.g. the atropine, can protect the GI mucosa against these ulcerogenic effects. The gastrointestinal functions and mucosal protection, however, are regulated by the vagal nerve. The aims of this study was to examine the dependence of atropine-induced GI cytoprotection to the vagal innervation against the development of IND-caused ulcers and microvascular damage in the mucosa of stomach and small intestine in rats. METHODS: the observations were carried out on CFY-strain rats. The mucosal damage was produced by subcutaneous administration of IND in a 20 mg/kg dose 24 h prior to the killing of animals at the same time as the start of atropine-application, which was given in a small dose (0.1 mg/kg) every 5 h. The subdiaphragmatic bilateral surgical vagotomy was done 24 h before the experiment. The vascular permeability, indicated by the microvascular endothel damage, was measured by the appearance and concentration of intravenously administered Evans blue into the GI mucosa. The number and severity of mucosal lesions and the Evans blue content of mucosa were determined in the stomach and small intestine. RESULTS: (1) The IND caused mucosal ulcers and Evans blue extravasation into the mucosa of the stomach and small intestine. (2) The IND-induced mucosal ulceration and vascular permeability significantly decreased after atropine-administration in the same parts of GI tract. (3) The extent of cytoprotective effect of atropine against the IND was decreased after bilateral surgical vagotomy. CONCLUSIONS: (1) The IND causes microvascular endothel damage in the stomach and small intestinal. (2) The atropine has a cytoprotective effect in the stomach and small intestine against the aggressive effects of IND without decrease of gastric acid secretion. (3) The intact vagal nerve is necessary to the function of cytoprotective mechanisms of atropine against the IND.     

Cyclooxygenase-2 selective and nitric oxide-releasing nonsteroidal anti-inflammatory drugs and gastric mucosal responses.

Occurrence of gastrointestinal damage and delayed healing of pre-existing ulcer are commonly observed in association with clinical use of nonsteroidal antiinflammatory drugs (NSAIDs). We examined the effects of NS-398, the cyclooxygenase (COX)-2 selective inhibitor, and nitric oxide (NO)- releasing aspirin (NCX-4016) on gastric mucosal ulcerogenic and healing responses in experimental animals, in comparison with those of nonselective COX inhibitors such as indomethacin and aspirin. Indomethacin and aspirin given orally were ulcerogenic by themselves in rat stomachs, while either NS-398 or NCX-4016 was not ulcerogenic at the doses which exert the equipotent antiinflammatory action with indomethacin or aspirin. Among these NSAIDs, only NCX-4016 showed a dose-dependent protection against gastric lesions induced by HCl/ethanol in rats. On the other hand, the healing of gastric ulcers induced in mice by thermal-cauterization was significantly delayed by repeated administration of these NSAIDs for more than 7 days, except NCX-4016. Gastric mucosal prostaglandin contents were reduced by indomethacin, aspirin and NCX-4016 in both normal and ulcerated mucosa, while NS-398 significantly decreased prostaglandin generation only in the ulcerated mucosa. Oral administration of NCX-4016 in pylorus-ligated rats and mice increased the levels of NO metabolites in the gastric contents. In addition, both NS-398 and NCX-4016 showed an equipotent anti-inflammatory effect against carrageenan-induced paw edema in rats as compared with indomethacin and aspirin. These results suggest that both indomethacin and aspirin are ulcerogenic by themselves and impair the healing of pre-existing gastric ulcers as well. The former action is due to inhibition of COX-1, while the latter effect may be accounted for by inhibition of COX-2 and mimicked by NS-398, the COX-2 selective NSAID. NCX-4016, despite inhibiting both COX-1 and COX-2, protects the stomach against damage and preserves the healing response of gastric ulcers, probably because of the beneficial action of NO.     

Evaluation of early gastric mucosal permeability induced by central thyrotropin-releasing hormone administration

Accumulating evidence suggests that central thyrotropin-releasing hormone (TRH) administration induces gastric erosion 4 h after administration through the vagal nerves. However, early changes in the gastric mucosa during these 4 h have not been described. To assess early changes in the gastric mucosa after intracisternal injection of a stable TRH analog, pGlu-His-(3,3'-dimethyl)-ProNH2 (RX-77368), we measured the blood-to-lumen 51Cr-labeled EDTA clearance and examined the effects of vagotomy, atropine, omeprazole, and hydrochloric acid (HCl) on RX-77368-induced mucosal permeability. A cytoprotective dose of RX-77368 (1.5 ng) did not increase mucosal permeability. However, higher doses significantly increased mucosal permeability. Permeability peaked within 20 min and gradually returned to control levels in response to a 15-ng dose (submaximal dose). Increased mucosal permeability was not recovered after a 150-ng dose (ulcerogenic dose). This increase in permeability was inhibited by vagotomy or atropine. Intragastric perfusion with HCl did not change the RX-77368 (15 ng)-induced increase in permeability, but completely inhibited the recovery of permeability after the peak. Pretreatment with omeprazole did not change the RX-77368 (15 ng)-induced increase in permeability, but quickened the recovery of permeability after the peak. These data indicate that the RX-77368-induced increase in permeability is mediated via the vagal-cholinergic pathway and is not a secondary change in RX-77368-induced acid secretion. Inhibited recovery of permeability on exposure to an ulcerogenic RX-77368 dose or on exposure to HCl plus a submaximal dose of RX-77368 may be crucial for the induction of gastric mucosal lesions by central RX-77368 administration.     

Mast cells are involved in the gastric hyperemic response to acid back diffusion via release of histamine

Acid back diffusion into the rat stomach mucosa leads to gastric vasodilation. We hypothesized that histamine, if released from the rat mucosa under such conditions, is mast cell derived and involved in the vasodilator response. Gastric blood flow (GBF) and luminal histamine were measured in an ex vivo chamber. Venous histamine was measured from totally isolated stomachs. Mucosal mast cells (MMC), submucosal connective tissue mast cells (CTMC), and chromogranin A-immunoreactive cells (CgA IR) were assessed morphometrically. After mucosal exposure to 1.5 M NaCl, the mucosa was subjected to saline at pH 5.5 (control) or pH 1.0 (H(+) back diffusion) for 60 min. H(+) back diffusion evoked a marked gastric hyperemia, increase of luminal and venous histamine, and decreased numbers of MMC and CTMC. CgA IR cells were not influenced. Depletion of mast cells with dexamethasone abolished (and stabilization of mast cells with ketotifen attenuated) both hyperemia and histamine release in response to H(+) back diffusion. GBF responses to H(+) back diffusion were attenuated by H(1) and abolished by H(3) but not H(2) receptor blockers. Our data conform to the idea that mast cells are involved in the gastric hyperemic response to acid back diffusion via release of histamine.