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The aetiology of dental erosion may be of both extrinsic and intrinsic origin. The aim of the present study was to test the ability of various neutralizing products to raise the low intra-oral pH after an erosive exposure, in this case to gastric acid, which was simulated using hydrochloric acid (HCl). Eleven adults participated. They rinsed with 10 ml of 10 mM HCl (pH 2) or 10 ml of 100 mM HCl (pH 1) for 1 min, after which the pH was measured intra-orally for up to 30 min at four sites (two approximal, one buccal, and the dorsum of the tongue). After rinsing with the two acid solutions (pH 1 and pH 2), the following products were used: (i) antacid tablet; (ii) gum arabic lozenge; (iii) mineral water; (iv) milk; and (v) tap water (positive control). The negative control was no product use. The five test products were used for 2 min after the erosive challenge. All the products produced an initially higher pH compared with the negative control. The antacid tablet resulted in the greatest and most rapid increase in pH, followed by the lozenge. In dental practice, the use of any of the neutralizing products tested, especially the antacid tablet, could be recommended in order to increase the intra-oral pH after an erosive challenge.

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1. Nociceptin/orphanin FQ (N/OFQ) is the endogenous peptide ligand for a specific G-protein coupled receptor, the N/OFQ peptide receptor (NOP). The N/OFQ-NOP receptor system has been reported to play an important role in pain, anxiety and appetite regulation. In airways, N/OFQ was found to inhibit the release of tachykinins and the bronchoconstriction and cough provoked by capsaicin. 2. Here we evaluated the effects of NOP receptor activation in bronchoconstriction and airway microvascular leakage induced by intraesophageal (i.oe.) hydrochloric acid (HCl) instillation in rabbits. We also tested the effects of NOP receptor activation in SP-induced plasma extravasation and bronchoconstriction. 3. In anesthetized New Zealand rabbits bronchopulmonary function (total lung resistance (R(L)) and dynamic compliance (C(dyn))) and airway microvascular leakage (extravasation of Evans blue dye) were evaluated. 4. Infusion of i.oe. HCl (1 N) led to a significant increase in bronchoconstriction and plasma extravasation in the main bronchi and trachea of rabbits pretreated with propranolol, atropine and phosphoramidon. 5. Bronchoconstriction and airway microvascular leakage were inhibited by N/OFQ (3-30 microg kg(-1) i.v.) in a dose-dependent manner. The NOP receptor agonist [Arg14,Lys15]N/OFQ mimicked the inhibitory effect of N/OFQ, being 10-fold more potent, UFP-101, a peptide selective NOP receptor antagonist, blocked the inhibitory effects of both agonists. 6. Under the same experimental conditions, N/OFQ and [Arg14,Lys15]N/OFQ did not counteract the bronchoconstriction and airway microvascular leakage induced by substance P. 7. These results suggest that bronchoconstriction and airway plasma extravasation induced by i.oe. HCl instillation are inhibited by activation of prejunctional NOP receptors.

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1. Gastro-oesophageal acid reflux may cause airway responses such as cough, bronchoconstriction and inflammation in asthmatic patients. Our previous results suggest that microvascular leakage induced, in the guinea-pig airways, by intra-oesophageal hydrochloric acid (HCl) infusion was mainly dependent on the release of tachykinins. Nociceptin, an endogenous ligand of the opioid receptor NOP, has been shown to inhibit bronchoconstriction and cough in guinea-pig or cat by inhibiting tachykinin release. 2. The purpose of this study was to investigate the effects of nociceptin on the intra-oesophageal HCl-induced airway microvascular leakage evaluated by Evans blue dye extravasation measurement in anaesthetised guinea-pigs pretreated with propranolol, atropine and phosphoramidon. 3. Infusion of intra-oesophageal HCl led to a significant increase in plasma extravasation in the main bronchi and trachea. This increase was abolished when animals underwent a bilateral vagotomy. 4. Airway microvascular leakage was inhibited by nociceptin (3-30 microg x kg(-1) i.v.) in a dose-dependent manner (maximal inhibition at the dose of 30 microg x kg(-1): 19.76+/-1.13 vs 90.92+/-14.00 ng x mg(-1) tissue for nociceptin and HCl infusion, respectively, in the main bronchi, P<0.01). The NOP receptor agonist [Arg(14),Lys(15)]N/OFQ mimicked the inhibitory effect of nociceptin, but at a 10-fold lower dose (3 microg x kg(-1) i.v). The NOP receptor antagonist J-113397 had no effect on plasma protein extravasation by itself, but was able to block the inhibitory effect of nociceptin. 5. Morphine (1 mg x kg(-1)) had a similar inhibitory effect as that of nociceptin. Naloxone pretreatment abolished the effect of morphine, but was enable to block the inhibitory effect of nociceptin. 6. Under similar conditions, nociceptin, in the previous range of concentration, was unable to counteract the airway microvascular leakage induced by substance P (SP). 7. These results suggest that airway plasma extravasation induced by intra-oesophageal HCl instillation might be inhibited by specific stimulation of the NOP receptor with nociceptin. Nociceptin is likely to act at a pre-junctional level, by inhibiting tachykinin release, since it was unable to prevent SP-induced airway plasma extravasation.

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Prostaglandin (PG) and nitric oxide (NO) have been known to inhibit the lesion formation induced by necrotic agents. However, no clear correlation between PG and NO has been shown in the gastroprotective action against necrotic agent-induced gastric mucosal lesions in rats. Thus, the present study was performed to clarify this correlation. Gastric mucosal lesions were induced by the oral administration of 0.6 M HCl in rats. 16,16-Dimethyl PGE2 (0.3-3 microg/kg, p.o.; dim-PGE2), sodium nitrite (0.3 and 1 mg/kg, s.c.) and sodium nitroprusside (30 and 100 microg/kg, i.v.; SNP) dose-dependently inhibited the lesion formation. Orally administered sodium nitrite or SNP (3 mg/kg) also significantly inhibited the lesion formation. The gastroprotective action by dim-PGE2 was not affected by the pre-treatment with N(G)-nitro-L-arginine methylester (10 mg/kg, i.v.). The gastroprotective effect by sodium nitrite or SNP was markedly attenuated by the pre-treatment with indomethacin (10 mg/kg, s.c.). These findings suggest that NO donating compounds inhibit the HCl-induced mucosal lesions mainly through prostaglandin, but dim-PGE2 directly inhibits the lesions without involvement of NO in rats.

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The mesenteric hyperemia induced by intraduodenal application of hydrochloric acid (HCl) is mediated in part by capsaicin-sensitive afferent nerves. Antagonist of capsaicin-sensitive receptors (capsazepine) and blocker of capsaicin-sensitive cation channels (ruthenium red) have been described. We employed these tools to dissect the mechanism of regulation of mesenteric hyperemia induced by intraduodenal administration of HCl. Subcutaneous 100 micromol/kg capsazepine or intraduodenal 0.1% ruthenium red was administered to pentobarbital anesthetized rats. Then, 2.5 ml/kg of 640 microM capsaicin or 0.1 N HCl was administered intraduodenally. The mesenteric hyperemic responses were recorded. The results demonstrated that in a dose that decreased the mesenteric hyperemia induced by intraduodenal capsaicin, capsazepine failed to attenuate the mesenteric vasodilatory effect of intraduodenal HCl. Ruthenium red significantly attenuated the mesenteric hyperemia after intraduodenal capsaicin and HCl. These in vivo data provide the first functional evidence for the existence of capsazepine-sensitive capsaicin receptors and cation channel complexes in the rat duodenal and intestinal mucosa. The capsaicin- and HCl-sensitive receptors are unlikely to be functionally identical in these locations. The ruthenium red-sensitive cation channels appear to mediate the capsaicin- and HCl-induced mesenteric hyperemia.

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BACKGROUND: Neutrophils play a crucial role in the pathogenesis of acid-induced acute lung injury. Lidocaine inhibits the function of neutrophils. This study aimed to determine whether lidocaine attenuates acute lung injury induced by hydrochloric acid (HCl) instillation. METHODS: In study 1, rabbits were divided into four groups (n = 7 each). Lung injury was induced by intratracheal HCl (0.1 N, 3 ml/kg) in two groups. The other two groups received saline intratracheally. Lidocaine given intravenously (2 mg/ g bolus + 2 mg x kg(-1) x h(-1) infusion) was started 10 min before intratracheal instillation in one HCl and one saline group, and saline was given intravenously in the other two groups. In study 2, rabbits (four groups of seven animals each) received HCl (0.1 N, 3 ml/kg) intratracheally. Treatment with intravenous lidocaine was started 10 min before, 10 min after, or 30 min after acid instillation, or saline was given intravenously 10 min before instillation. RESULTS: In study 1, HCl caused deterioration of the partial pressure of oxygen (PaO2), lung leukosequestration, decreased lung compliance, and increased the lung wet-to-dry weight ratio and albumin, interleukin-6 (IL-6), and IL-8 levels in bronchoalveolar lavage fluid. Lidocaine pretreatment attenuated these changes. Hydrochloric acid increased superoxide anion production by neutrophils and caused morphologic lung damage, both of which were lessened by lidocaine. In study 2, lidocaine given 10 min after acid instillation was as effective as pretreatment in PaO2, lung mechanics, and histologic examination. However, PaO2 changes in lidocaine 30 min after injury were similar to those in saline given intravenously. CONCLUSIONS: Intravenous lidocaine started before and immediately after acid instillation attenuated the acute lung injury, in part by inhibiting the sequestration and activation of neutrophils.

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The aggravation of acid-induced gastric damage and its prevention by glucose, ascorbate or glutathione precursors was studied in fed and food-deprived rats. The stomachs of fed rats and those starved for 1, 3 or 5 d were vagotomized just before irrigating for 3 h with solutions containing 0-150 mmol HCI/L. Mucosal glutathione, mucus, lipid peroxides and acid back-diffusion were measured. Stomach ulcers were evaluated by morphological and histological examination. The preventive effects of glucose, ascorbate and a mixture of L-glutamine, L-glycine and L-cysteine were evaluated in the stomachs of rats that were starved for 5 d, vagotomized, then perfused for 3 h with 100 mmol HCI/L. Greater acid back-diffusion and ulcer formation, and lower glutathione and mucus levels in starved rats were dependent on the duration of starvation and luminal acidity. Increased acid back-diffusion and decreased glutathione and mucus production were negatively correlated (r < -0.80, P < 0.05) with ulcer formation. A significant enhancement in mucosal lipid peroxide concentration and serious damage of forestomach and corpus mucosal cells were observed in starved rats exposed to 100 mmol HCI/L. These ulcerogenic factors were effectively inhibited in acid-perfused stomachs of food-deprived rats by daily intraperitoneal injection of the amino acid mixture (150 mg/kg) or by an average daily consumption via drinking water of glucose (10 g) or ascorbate (1.2 g). Starvation aggravated acid-induced gastric damage and was associated with greater acid back-diffusion and oxygen radical generation, and lower mucosal glutathione and mucus production.

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The aim was to investigate whether prostaglandins affect HCl-induced mucosal permeability and to elucidate the role of mucosal bicarbonate secretion in protection. Proximal duodenum of anaesthetized rats were perfused with hydrochloric acid and the effects on luminal alkalinization, mucosal permeability and morphology examined in the absence and in the presence of prostaglandin E2 and/or indomethacin. Luminal alkalinization was determined by back titration of the perfusate and mucosal permeability assessed by measuring the clearance of 51Cr-labelled ethylenediaminetetraacetat ([51Cr]EDTA) from blood-to-intestinal lumen. Perfusion with 100 mM HCl for 5 min increased mucosal permeability sixfold and caused villus tip damage. Luminal administration of PGE2 at a concentration of 10(-6) M had no effect whereas 10(-4) M increased alkalinization by 100% but neither concentration affected the HCl-induced increase in mucosal permeability. PGE2 (10(-4) M), however, improved the ability of the duodenal mucosa to recover from the HCl-induced increase in mucosal permeability. Indomethacin (5 mg kg-1, i.v.) increased alkalinization, augmented HCl-induced mucosal permeability and aggravated mucosal injury. In animals pre-treated with PGE2 plus indomethacin, the HCl-induced increases in mucosal permeability were lower and injury less pronounced than in animals treated with indomethacin alone. No correlation was found between the rate of alkalinization and the HCl-induced increase in mucosal permeability. It is concluded that endogenous prostaglandins reduced the extent of 100 mM HCl-induced duodenal mucosal damage by a mechanism other than the stimulation of alkaline secretion.

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While cimetidine (CIM) is strikingly effective in inhibiting gastric acid secretion, its effect on the defensive mechanisms of the gastric mucosa has been controversial. The aims of the present study were to test if administration of CIM at an antisecretory dose is protective against acid-induced injury and to assess its effect on adaptive cytoprotection induced by non-necrotizing concentrations of HCl in rats. A dose of 100 mg/kg of CIM was administered once, or twice a day for 5 days intraperitoneally. To study the effect of CIM on HCl-induced damage, 0.6 N HCl was given orally one hour after the last administration of CIM. To study the effect of CIM on adaptive cytoprotection, 0.35 N HCl was given orally one hour after the last administration of CIM. Fifteen minutes later, 0.6 N HCl was given orally. Thirty minutes after the administration of 0.6 N HCl, the stomach was removed and ulcer indices were calculated. Pretreatment with CIM did not prevent 0.6 N HCl induced gastric damage. Prior administration of 0.35 N HCl significantly reduced ulcer indices caused by 0.6 N HCl. Short or long term treatment with CIM did not have significant effects on the reduction of ulcer indices. These results suggest that CIM at an antisecretory dose neither acts as a protective agent nor modulates the protective process of the gastric mucosa.

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The mechanisms of acid damage to oesophageal epithelium are incompletely understood. In particular, it is unclear whether luminal acid enters and damages the oesophageal epithelium by traversing the paracellular and/or transcellular route. The present paper describes studies of the role of serosal bicarbonate ions (HCO3-) in oesophageal protection against acid damage, the results of which have direct implications regarding the route of H+ entry. The results indicate that HCO3- protects by buffering H+ within the intercellular compartment of the extracellular space, and that this protection can be mimicked almost completely by replacement of serosal HCO3- with HEPES (N-2-hydroxyethylpiperazine-N'-2-ethane sulphonic acid), a buffer that cannot permeate cells. These findings support the hypothesis that luminal acid damages oesophageal epithelium primarily by H+ diffusion through the paracellular pathway.

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Aluminium hydroxide gels were precipitated from aluminium isopropoxide by addition of water or aqueous solutions of Na2SO4, NaCl and NaNO3. The antacid activity of the gels was assessed on the basis of determinations of their total capacity to neutralize HCl, while structure of the gels was studied by X-ray diffraction analysis and IR spectrometry. It has been stated that prolonged storage, higher storage temperature and presence of water promote conversion of the active form of aluminium hydroxide gels in pharmaceutical preparations into less active forms.

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Usefulness of the pH-stat method for assaying the neutralizing activity of antacids was compared with the ones of the methods based on the determination of the action time by dynamic methods. A high level of correlation between the antacid dose and the neutralization capacity has been stated. The found relationships proved to enable optimization of the antacid dosage as well as prediction of the therapeutic effect.

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UNLABELLED: It was earlier known that PGI2 and beta-carotene have a cytoprotective effect, but the similarities and the differences of their mechanisms were not clear. The gastric mucosal lesions were produced by ig. administration of 1 ml 96% ethanol and 1 ml 0.6 N HCl in rats. The 5 and 50 micrograms/kg dose of PGI2 and the 1 and 10 mg dose of beta-carotene was given 30 min. earlier. The animals were sacrified 1, 5, 15, 30 and 60 minutes after the administration of the necrotizing agent. The number and the severity of gastric mucosal lesions were noted. It was found that the number and the severity of gastric ulcers were dose-dependently decreased in each model after using either PGI2 or beta-carotene. The inhibiting effect of PGI2 appeared in the first last 15 minutes while beta-carotene was effective from 15 to 60 minutes. CONCLUSION: The mechanism of the cytoprotection induced by PGI2 differ from the beta-carotene induced one. PGI2 plays a part in the earlier vascular phase. beta-carotene modulates the repair mechanisms.

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Effects of acetaminophen against gastric mucosal lesions induced by three different necrotizing agents were studied. Acetaminophen (30, 100 mg/kg), given p.o. 0.5 hr before absolute ethanol, HCl . ethanol, or HCl . aspirin administration, afforded no cytoprotection against gastric mucosal lesions induced by the above agents in 24 hr fasted rats. However, 16,16-dimethyl prostaglandin E2 (3 micrograms/kg), given p.o. 0.5 hr before these necrotizing agents, completely prevented development of these lesions.

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Effects of troxipide on several acute gastric lesions in rats were investigated in comparison with those of cetraxate. Troxipide (100, 200, 300 mg/kg) and cetraxate (100, 300, 1,000 mg/kg), given orally, dose-dependently protected the gastric mucosa from damage due to ethanol. Aspirin- and 0.6 N HCl-induced gastric lesions were dose-dependently inhibited by troxipide (200, 300 mg/kg), but only significantly inhibited by cetraxate at high dose (1,000 mg/kg). Troxipide (100, 200, 300 mg/kg) dose-dependently prevented the formation of gastric lesions induced by water-immersion stress, whereas cetraxate (600, 1,000 mg/kg) also significantly prevented gastric lesions. That is, protective effects of troxipide were much more potent than those of cetraxate against aspirin-, 0.6 N HCl- and water-immersion stress-induced gastric lesions, whereas both were almost equal against ethanol-induced gastric lesions. In addition, cytoprotective effects of troxipide against ethanol-induced lesions were most remarkable at 10, 30, 60 min after administration (100, 300 mg/kg) and lasted for up to 240 min. These results suggested that troxipide might be useful for the treatment of acute gastric lesions in humans.

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Effects of TKG01 on gastric ulcers and gastric secretion in rats were investigated in comparison with those of TA903, which is the equimolar clathrate compound of TKG01 anhydride with beta-cyclodextrin. The doses were adjusted on a molecular weight basis to include the same amount of TKG01 anhydride. Water-immersion stress ulcers were dose-dependently (100, 300 mg/kg) inhibited by TA903 given orally, but only significantly inhibited by TKG01 (300 mg/kg). TA903, given orally, even in low doses (30, 100 mg/kg) potently inhibited HCl-ethanol ulcers, whereas TKG01 did not inhibit these ulcers. Both TA903 and TKG01, given orally (100, 300 mg/kg), showed similar inhibition of indomethacin ulcers. TA903, given intraduodenally (100, 300 mg/kg), dose-dependently inhibited gastric secretion (volume, acid output and pepsin output) in pylorus-ligated rats, but TKG01 only inhibited pepsin output (100, 300 mg/kg). These results showed that TA903 had a broader spectrum of anti-ulcer effects than TKG01 and the mechanism of TA903 could involve both its cytoprotective activity and its anti-secretory effect.

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The incidence of mucosal hemorrhage induced in rats by the oral administration of taurocholic acid (TCA) and hydrochloric acid (HCl) both singly and in combination was investigated. The effect of prostaglandin 15 (R) 15 methyl-PGE2 methyl ester (Me-PGE2) on the occurrence of hemorrhage induced by TCA with HCl was also studied. The incidence of hemorrhage induced by TCA (10 mM) alone and HCl (160 mM) alone was minimal and not different from that induced by the control solution. The combination of TCA (10 mM) and HCl (160 mM) produced bleeding in 67.7% of animals. The addition of 15 (R) 15 methyl-PGE2 methyl ester (9.9 micronM, corresponding to 50 microng/Kg) significantly reduced the incidence of hemorrhage induced by the combination of TCA with HCl from 67.7% to 31.3%. This suggests that this synthetic prostaglandin may be of value in conditions thought to be associated with reflux of bile into the stomach.

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