Gastric Acid Secretion In Response Research Articles

Membrane-bound ATP-dependent Energy Systems, as Extra- and Intracellular Key Signals for Gastrointestinal Functions and their Regulations in the Gastrointestinal Mucosa.

Our research group has carried out various biochemical examinations in rat gastric ulcer models and in human gastrointestinal resecates obtained from patient who underwent gastric intervention due to peptic ulcer disease. Biochemical methods gave excellent possibility to approach the biochemical events taking place in tissues, cellular and subcellular regulatory levels during of ulcer development and of its prevetions. This paper gives a brief summary of these biochemical examinations conducted during this study period started from the 1960's up till now. 1. The decreased action of gastric acid secretory responses is not needed for duodenal and gastric ulcer healing in patients with peptic ulcer; 2. The surgical and chemical vagotomy resulted in various biochemical changes in the rat stomach; 3. The presence of Na+-K+-dependent ATPase and adenylate cyclase can be demostrated both in the rat and human gastric fundic mucosa; 4. The mitocondrial ATP is a common substrate for these membrane-bound ATP-dependent enzymes, and a multiple feedback mechanism existing between these two membrane-bound enzymes altered by mediators, hormones and drugs; 5. This feedback mechanism exists in the GI mucosa under different pathological conditions and during certain drug actions; 6. The development of mucosal damage and prevention depends on the actual regulatory state of above mentioned feedback mechanism between the membrane-bound ATP-dependent energy systems; 7.The drug actions depend on the actual functional state of target organ; 8. Biochemical gradients exist between the biochemical structure of the fundic, antral, duodenal and jejunal mucosa in patients with gastric hyperacidity, which is gradually downregulated by the decrease of gastric acid secretory responses, and totally disappears in patients with hypacidity; 9. No biochemically proven tissue hypoxia - around the chronic ulcer, duodenal and jejunal ulcers - exists in patients with chronic peptic ulcer; 10. The cellular and tissue protection differ from each other in the gastrointestinal tract; 11. Helicobacter pylori does not produce damage at the level of cell membrane, mitochondrion and DNA - given alone or in combination with indomethacin - on freshly isolated rat gastric mucosal cells. 12. A biochemical explanation is given to ulcer development in humans and in different animal models.

Effect of Cannabis sativa extract on gastric acid secretion, oxidative stress and gastric mucosal integrity in rats

Studies were conducted in pylorus-ligated rats to investigate the effect of Cannabis sativa extract on gastric acid secretion, experimental gastric ulcer and on oxidative stress and inflammatory markers in the gastric mucosa. C. sativa (5, 10 and 20 mg/kg, expressed as Δ9-tetrahydrocannabinol) was administered subcutaneously daily for 4 weeks prior to pylorus ligation and different treatments. Under basal conditions, pretreatment with cannabis extract at doses of 5 and 10 mg/kg increased gastric acid secretion and induced minimally visible gastric mucosal lesions in the 4 h pylorus-ligated rat. Malondialdehyde and nitric acid concentration increased, while reduced glutathione decreased by cannabis at doses of 5 and 10 mg/kg in gastric mucosa. TNF-α increased by cannabis extract at doses of 5 and 10 mg/kg but decreased following the high dose of 20 mg/kg. On the other hand, the gastric acid secretory responses stimulated by pentagastrin or carbachol (but not histamine) were inhibited in rats pretreated with cannabis extract. Under these conditions, cannabis decreased pepsin content after pentagastrin and carbachol but not histamine stimulation. Cannabis also decreased lipid peroxidation and nitric oxide content, and increased both reduced glutathione and catalase activity in mucosa. Moreover, cannabis decreased mucosal inflammation (level of TNF-α) and the development of gastric mucosal lesions. Cannabis administered for 1 month prior to pylorus-ligation and either acidified aspirin or ethanol (96 %) decreased the development of gastric mucosal damage in a dose-dependent manner, along with reduction in gastric acid output, gastric mucosal oxidative stress and inflammation (TNF-α). Sections of gastric mucosa stained with periodic acid Schiff showed increased mucus secretion by cannabis in basal conditions and after treatment with aspirin or ethanol. Results indicate that: (1) the effect of cannabis differs in basal conditions and after exposure of the gastric mucosa to high acid concentrations or other chemical noxious agents; (2) cannabis administered systemically exerts gastric mucosal protective effects against mucosal damage evoked by stimulation of gastric acid secretion, acidified aspirin or ethanol. These effects of cannabis are likely to involve inhibition of gastric acid and pepsin secretion, increased mucus, decreased oxidative stress and inflammation in gastric mucosa.

Endoscopic findings for predicting gastric acid secretion status.

Gastric acidic abnormalities are related to various types of diseases in Helicobacter pylori (H. pylori) infection status. However, no studies have shown correlations between many tiny endoscopic findings and the acid secretion level simultaneously. In the present study, we investigated predictive tiny endoscopic findings of hyperchlorhydria and hypochlorhydria. A total of 223 subjects without organic diseases who underwent esophagogastroduodenoscopy and endoscopic gastrin test (EGT) for estimating gastrin-stimulated gastric acid secretory response between 1999 and 2012 at our institution were retrospectively analyzed. Two blinded expert endoscopists reviewed the images independently and recorded the endoscopic findings. According to the EGT values, the enrolled subjects were categorized into hyperchlorhydria, normal acid secretion, and hypochlorhydria groups. In all subjects, hematin (odds ratio [95% confidence interval] = 3.32 [1.40-7.84]) and antral erosion(2.88 [1.24-6.70]) were the predictive endoscopic findings for hyperchlorhydria, and swelling of areae gastricae (14.4 [5.74-36.1]) and open-type atrophy (15.1 [7.35-31.1]) were those for hypochlorhydria. In addition, the predictive endoscopic findings for hyperchlorhydria differed according to the H. pylori infection status, hematin in H. pylori-positive subjects and antral erosion in H. pylori-negative subjects, in contrast to those for hypochlorhydria, which were the same irrespective of the H. pylori infection status. We could predict the acid secretion status based on the endoscopic findings regardless of H. pylori infection status, which would be of some help for evaluating the risk for acid-related diseases.

Su1636 Ginger Ingredient, 6-Gingerol Potentiates Regulatory Effect of Gastric Acid Secretion in Response to Capsaicin Through Activation of TRPV1 Channels in Awake Mice

Su1636 Ginger Ingredient, 6-Gingerol Potentiates Regulatory Effect of Gastric Acid Secretion in Response to Capsaicin Through Activation of TRPV1 Channels in Awake Mice

Inhibition of basal and insulin-stimulated gastric acid secretion by phenoxybenzamine or phentolamine.

The present study in the rat was undertaken to investigate the possible involvement of alpha- and beta-adrenoceptors in mediating gastric acid secretion in response to insulin-hypoglycaemia. Phenoxybenzamine, 15 mg kg-1, depressed the basal acid secretion to a level similar to that associated with vagotomy; phentolamine, 15 mg kg-1, had a similar effect. Insulin (1 unit kg-1) significantly stimulated gastric acid secretion. Vagotomy or phenoxybenzamine or phentolamine, 15 mg kg-1 prevented this action. The beta-adrenoceptor blocking drug, propranolol, 5-15 mg kg-1, had no significant effect on the basal acid secretion or its stimulation by insulin. The similarity in action between vagotomy and large doses of phenoxybenzamine and phentolamine suggests that, in the rat, vagal alpha-adrenoceptor stimulation is involved in the mechanisms of basal and insulin-stimulated gastric acid secretion.

Effect of folic acid supplementation on oxidative gastric mucosa damage and acid secretory response in the rat

Objective:This study investigated the antioxidative and antisecretory properties of folic acid in the rats’ stomach.Materials and Methods:Male Wistar rats were treated with 2 mg/kg diet of folic acid for 21 days. Gastric ulceration was induced by indomethacin, scored, and assayed to determine the concentration of total protein, mucus, malondialdehyde (MDA), catalase (CAT) and superoxide dismutase (SOD) in homogenized samples. Normal saline and Ranitidine treated group served as negative and positive control, respectively. Basal and stimulated acid secretion was measured by continuous perfusion method.Result:Indomethacin caused severe damage to the rats’ stomach with an ulcer index of 4.32 ± 0.13, increase in MDA concentration and reduction in the concentration of protein, mucus, catalase and superoxide dismutase (P < 0.001). Pre-treatment with folic acid prevented the formation of ulcers by 32%, and attenuated the inhibition of mucus by 14%, CAT, 51% and SOD, 150%. Ranitidine afforded 56% prevention in ulcer formation with 67%, 55% and 78% attenuation of the inhibition of mucus, CAT and SOD, respectively, by indomethacin. While indomethacin-induced lipid peroxidation was attenuated by 58% reduction in MDA concentration on pretreatment with folic acid, Ranitidine offered 65% reduction. Basal and stimulated acid secretions were significantly reduced in the treated when compared with control animals. Folic acid produced a 21% reduction in the basal acid output when compared with the control animals (P < 0.05), and 140% reduction in histamine-induced acid response.Conclusion:The results indicate the gastroprotective activity of folic acid due its antioxidative and anti-secretory properties.

Impairment of gastric acid secretion and increase of embryonic lethality in Foxq1-deficient mice

The mouse Foxq1 gene, also known as Hfh1, encodes a winged helix/forkhead transcription factor. In adult mice, Foxq1 is highly expressed in kidney and stomach. Here, we report that Foxq1 is expressed during prenatal and postnatal stomach development and the transcripts are restricted to acid secreting parietal cells. Mice homozygous for a deletion of the Foxq1 locus on a 129/Sv × C57BL/6J hybrid genetic background display variable phenotypes consistent with requirement of the gene during embryogenesis. Approximately 50% of Foxq1^–/– embryos die in utero. Surviving homozygous mutants are normal and fertile, and have a silky shiny coat. Although the parietal cell development is not affected in the absence of Foxq1, there is a lack of gastric acid secretion in response to various secretagogue stimuli. Ultrastructural analysis suggests that the gastric acid secretion defect in Foxq1-deficient mice might be due to impairment in the fusion of cytoplasmic tubulovesicles to the apical membrane of secretory canaliculi.

Decreased hydrogen–potassium-activated ATPase (H +–K +-ATPase) expression and gastric acid secretory capacity in aged mice

Gastric acid secretion in response to chemical stimulation and to mechanical stimulation was investigated in adult and old mice. The protein expression of a proton pump (H +–K +-ATPase), a marker of parietal cell function, was determined by Western blotting. Acid secretion was stimulated by histamine (500 and 1000 μg/kg) or carbachol (10 and 20 μg/kg). To investigate the response to mechanical stimulation, the stomach was distended by an intragastric injection of isotonic saline (0.5, 1.0, 1.5, and 2.0 ml). Administration of two doses of histamine produced a dose-dependent increase in acid secretion in adult mice, whereas a higher dose of histamine failed to produce a further increase in old mice. Gastric acid secretion, whether produced by carbachol or mechanical stimulation, did not differ between the two age groups. The protein expression of H +–K +-ATPase was significantly lower in old mice than in adult. Insofar as histamine increases acid secretion via the cyclic AMP (cAMP) pathway in parietal cells, while carbachol and gastric distention do so via the calcium signaling pathway, the cAMP signaling pathway may be more susceptible to aging than the calcium signaling pathway. The decrease in the secretory capacity of acid secretion in the old mice may be partly attributable to a decrease in parietal cell function, as shown by decrease in H +–K +-ATPase protein expression.

Role of endogenous nitric oxide in mucosal defense of inflamed rat stomach following iodoacetamide treatment

Nitric oxide (NO) plays a role in regulating the mucosal integrity of the stomach. However, its part in the mucosal defense of the inflamed stomach remains unclear. In the present study, we examined the effects of various NO synthase (NOS) inhibitors on gastric ulcerogenic and acid secretory responses following daily exposure of the stomach to iodoacetamide and investigated the role of each NOS isozyme in gastric protection from subchronic mucosal irritation. Gastric mucosal irritation was induced in rats by addition of 0.1% iodoacetamide to drinking water, and the gastric mucosa was examined on the 6th day. L-NAME (a nonselective NOS inhibitor: 20 mg/kg) or aminoguanidine (a selective iNOS inhibitor: 20 mg/kg) was given s.c. twice 24 h and 3 h before the termination of iodoacetamide treatment. Giving iodoacetamide in drinking water for 5 days produced minimal damage in the stomach with an increase in myeloperoxidase (MPO) activity and lipid peroxidation. Iodoacetamide treatment up-regulated the expression of iNOS mRNA and NO production in the stomach, without affecting nNOS expression. Both L-NAME and aminoguanidine markedly aggravated gastric lesions induced by iodoacetamide treatment, with a further enhancement in MPO activity and lipid peroxidation. Basal acid secretion as determined in pylorous-ligated stomachs was decreased following iodoacetamide treatment, but the response was significantly restored by both L-NAME and aminoguanidine. These results suggest that endogenous NO derived from both cNOS and iNOS is involved in mucosal defense of the inflamed stomach, partly by decreasing acid secretion, and contributes to maintaining mucosal integrity under such conditions.

The effect of selective gastric or extragastric vagotomy on gastric secretion in conscious cats.

Abstract Earlier studies in dogs showed that in animals with gastric fistulas, selective gastric vagotomy decreased maximal acid secretion in response to gastrin but not to histamine, and that in animals with Heidenhain pouches, selective extragastric vagotomy increased maximal response to gastrin but not to histamine. The present study sought to determine whether similar changes occurred in cats. In cats with gastric fistulas, selective gastric vagotomy reduced maximal response to pentagastrin and to histamine by about the same extent. In cats with Heidenhain pouches, selective extragastric vagotomy had no effect on the response to pentagastrin. It is concluded that there is a species difference between the dog and the cat regarding the effects of selective gastric and selective extragastric vagotomy on gastric acid secretion in response to gastrin. It is not yet known whether man fits the pattern of the dog or the cat.

Apolipoprotein A‐IV is involved in detection of lipid in the rat intestine

Long chain triglyceride (>C12) in the intestinal lumen potently inhibits gastric emptying and acid secretion via the vagal afferent pathway. While the mechanism of inhibition involves the formation of chylomicrons, the essential role of the apolipoprotein apo A-IV is unclear. Using apo A-IV(-/-) mice, we tested the hypothesis that inhibition of gastric emptying and gastric acid secretion in response to dietary lipid is dependent upon apo A-IV. As measured by nuclear scintigraphy in awake mice, gastric emptying of an ingested whole-egg meal was significantly faster in apo A-IV(-/-) knockout versus A-IV(+/+) controls (34 +/- 1 versus 54 +/- 3 min, P < 0.0001). In anaesthetized A-IV(+/+) mice, meal-stimulated gastric acid secretion was 59% inhibited by intestinal lipid infusion; this was abolished in apo A-IV(-/-) mice. Oral gavage of lipid in awake mice activated neurones throughout the nucleus of the solitary tract (NTS) in A-IV(+/+) mice, measured by immunohistochemical localization of Fos protein expression. However, in the mid region of the NTS (bregma -7.32 to -7.76 mm), Fos expression in response to intestinal lipid was significantly decreased by 50% in apo A-IV(-/-) mice compared to A-IV(+/+) controls. We conclude that activation of the vagal afferent pathway and inhibition of gastric function in response to dietary lipid is partly dependent upon apo A-IV.

Pharmacological Investigation of Trimetazidine in Models of Inflammation, Pain and Gastric Injury in Rodents

The antinociceptive, anti-inflammatory and gastric effects of trimetazidine (2,3,4-trimethoxybenzyl-piperazine dihydrochloride), a novel anti-ischaemic compound, were evaluated in various animal models. In acute pain models, namely acetic acid-induced writhing, hot-plate assay, tail electric stimulation test, capsaicin-induced pain and the formalin test, trimetazidine (1.8–7.2 mg/kg, i.p.) showed marked antinociceptive effects. Trimetazidine did not produce any behavioural impairment as revealed by the mouse rotarod. The inhibition of writhing response by trimetazidine was reduced by yohimbine, theophylline (and to a certain extent by sulpiride) but not by prazosin, guanethidine, naloxone, atropine, propranolol, haloperidol, domperidone, clozapine, glibenclamide or caffeine. The carrageenan-evoked acute paw oedema was reduced by 19.2–21.2 and 17–18.6% by 3.6 and 7.2 mg/kg trimetazidine, respectively. The drug did not alter the oedema-suppressive effect of indomethacin or dexamethasone, but reduced that of rofecoxib. Trimetazidine at 7.2 mg/kg reduced immobility time in Porsolt’s forced-swimming test by 28.9%. The acute gastric mucosal lesions evoked by indomethacin in the rat were inhibited in a dose-dependent manner by co-administration of trimetazidine. In anesthetized rats, trimetazidine potentiated the gastric acid secretory response. This study indicates that trimetazidine possesses antinociceptive and gastric protective properties. The antinociceptive properties of trimetazidine are likely to be centrally mediated, but do not involve opioid pathways.

Cholinergically stimulated gastric acid secretion is mediated by M3 and M5 but not M1 muscarinic acetylcholine receptors in mice

Muscarinic acetylcholine receptors play an important role in the regulation of gastric acid secretion stimulated by acetylcholine; nonetheless, the precise role of each receptor subtype (M(1)-M(5)) remains unclear. This study examined the involvement of M(1), M(3), and M(5) receptors in cholinergic regulation of acid secretion using muscarinic receptor knockout (KO) mice. Gastric acid secretion was measured in both mice subjected to acute gastric fistula production under urethane anesthesia and conscious mice that had previously undergone pylorus ligation. M(3) KO mice exhibited impaired gastric acid secretion in response to carbachol. Unexpectedly, M(1) KO mice exhibited normal intragastric pH, serum gastrin and mucosal histamine levels, and gastric acid secretion stimulated by carbachol, histamine, and gastrin. Pirenzepine, known as an M(1)-receptor antagonist, inhibited carbachol-stimulated gastric acid secretion in a dose-dependent manner in M(1) KO mice as well as in wild-type (WT) mice, suggesting that the inhibitory effect of pirenzepine on gastric acid secretion is independent of M(1)-receptor antagonism. Notably, M(5) KO mice exhibited both significantly lower carbachol-stimulated gastric acid secretion and histamine-secretory responses to carbachol compared with WT mice. RT-PCR analysis revealed M(5)-mRNA expression in the stomach, but not in either the fundic or antral mucosa. Consequently, cholinergic stimulation of gastric acid secretion is clearly mediated by M(3) (on parietal cells) and M(5) receptors (conceivably in the submucosal plexus), but not M(1) receptors.

Gastric parietal cell acid secretion in mice can be regulated independently of H +/K + ATPase endocytosis

Background & Aims: Gastric parietal cells secrete acid into the lumen of the stomach. They express a proton pump, the gastric H +/K + ATPase, the activity of which is tightly regulated. The H +/K + ATPase traffics between an intracytoplasmic compartment (tubulovesicles) in quiescent parietal cells and the apical plasma membrane in activated cells. These trafficking events are considered to contribute to the control of acid secretion by modulating access to apical K + and Cl − conductances that are required for transmembrane H + ion transport by the H +/K + ATPase. Here, we have determined whether the control of acid secretion in vivo requires membrane trafficking of the H +/K + ATPase. Methods: We developed mice that only express an H +/K + ATPase β subunit in which a putative tyrosine-based endocytosis motif in the cytoplasmic tail is mutated. Location of the H +/K + ATPase and parietal cell ultrastructure and gastric acid secretion were then examined. Results: Parietal cells of these mice lacked a tubulovesicular compartment, and the H +/K + ATPase was resident exclusively on the apical plasma membrane. Despite the inability of the H +/K + ATPase to be endocytosed, the gastric acid secretory response to histamine or an antagonist was very similar to that of wild-type mice, indicating that control of H +/K + ATPase activity can occur independently of intracellular trafficking. Conclusions: We were able to dissociate the regulation of H +/K + ATPase activity from intracellular trafficking of the protein. Thus, it is likely that direct regulation of apical K + and Cl − conductances are sufficient to control gastric acid secretion.

Effects of inhibition gastric acid secretion on arterial acid–base status during digestion in the toad Bufo marinus

Digestion affects acid–base status, because the net transfer of HCl from the blood to the stomach lumen leads to an increase in HCO 3 − levels in both extra- and intracellular compartments. The increase in plasma [HCO 3 −], the alkaline tide, is particularly pronounced in amphibians and reptiles, but is not associated with an increased arterial pH, because of a concomitant rise in arterial P co 2 caused by a relative hypoventilation. In this study, we investigate whether the postprandial increase in Pa co 2 of the toad Bufo marinus represents a compensatory response to the increased plasma [HCO 3 −] or a state-dependent change in the control of pulmonary ventilation. To this end, we successfully prevented the alkaline tide, by inhibiting gastric acid secretion with omeprazole, and compared the response to that of untreated toads determined in our laboratory during the same period. In addition, we used vascular infusions of bicarbonate to mimic the alkaline tide in fasting animals. Omeprazole did not affect blood gases, acid–base and haematological parameters in fasting toads, but abolished the postprandial increase in plasma [HCO 3 −] and the rise in arterial P co 2 that normally peaks 48 h into the digestive period. Vascular infusion of HCO 3 −, that mimicked the postprandial rise in plasma [HCO 3 −], led to a progressive respiratory compensation of arterial pH through increased arterial P co 2. Thus, irrespective of whether the metabolic alkalosis is caused by gastric acid secretion in response to a meal or experimental infusion of bicarbonate, arterial pH is being maintained by an increased arterial P co 2. It seems, therefore, that the elevated P co 2, occuring during the postprandial period, constitutes of a regulated response to maintain pH rather than a state-dependent change in ventilatory control.

Expanded Parietal Cell Pool in Transgenic Mice Unable to Synthesize Histamine

Background: The histidine decarboxylase enzyme (HDC) is responsible for the synthesis of histamine in mammals. Histidine decarboxylase-deficient (HDC −/− ) mice have recently been developed by targeted mutation of the HDC gene. Methods: The impact of prolonged histamine deficiency was studied on gastric morphology (by immunohistochemistry and morphometry), gastric acid secretion (by a wash-through method for basal gastric acid secretion and by pylorus ligation for stimulated gastric acid secretion) and gastrin levels (by radioimmunoassay) in homozygous HDC −/− mice kept on a low-histamine diet. Results: A double maximal gastric acid secretory response was found in knockouts after exogenous histamine administration. In contrast, the gastric acid secretion was significantly reduced after gastrinergic and cholinergic stimulation in the absence of histamine. The oxynthic gland area of HDC −/− mice was thickened with an increased parietal cell count compared to wild types. Substantially elevated serum and antral tissue gastrin levels of HDC −/− mice could be possible indications of both an expanded parietal cell mass and/or an increased histamine-induced maximal gastric acid secretory capacity of this genotype. Conclusions: These data suggest that not enough compensatory mechanisms develop in HDC −/− mice during a prolonged low-histamine diet to maintain/restore normal gastric acid secretion. An expanded parietal cell pool was also demonstrated in HDC −/− mice kept on a low-histamine diet, probably caused by a trophic effect of sustained hypergastrinaemia. The HDC −/− strain is a suitable model for studying the effects of achlorhydria and consequent hypergastrinaemia as an approach to human conditions such as atrophic gastritis or long-term antisecretory therapies.

Absorption of biologically active peptide hormones from the small intestine of rat.

Absorption of the 4, 10 and 34 amino acid forms of gastrin from the small intestine has been investigated in anaesthetized rats. The method of assessment of successful absorption of the hormone into the systemic circulation was when the amount of acid secreted by the stomach over consecutive 15-min periods was increased. When the natural hormones were infused into the ileum in a relatively high dose, there was no increase in gastric acid secretion, indicating that they had not been absorbed. Each of the forms of gastrin was conjugated at the free amino terminus to the carboxyl group of cholic acid. Subsequent infusion of the conjugated form of gastrin into the ileum, this time in relatively low doses, resulted in substantial and prolonged increases in gastric acid secretion, indicating that these hormones had been successfully absorbed. In addition, conjugation of the 10 and 34 amino acid forms of gastrin with cholic acid was shown to increase markedly the potency in evoking an increase in gastric acid secretion in response to intravenous injection of the hormone. Absorption of the gastrin conjugates was specific to the ileum thus indicating that they had been absorbed through the bile salt transporters.

Suppression by protease-activated receptor-2 activation of gastric acid secretion in rats

Activation of protease-activated receptor-2 (PAR-2), a receptor activated by trypsin/tryptase, induces neurally mediated gastric mucus secretion accompanied by mucosal cytoprotection. In the present study, we investigated whether PAR-2 could modulate gastric acid secretion in rats. Messenger RNAs for PAR-2 and PAR-1 were detected in the gastric mucosa and smooth muscle. The PAR-2-activating peptide SLIGRL-NH 2, but not the inactive control peptide, when administered i.v., strongly suppressed gastric acid secretion in response to carbachol, pentagastrin or 2-deoxy- d-glucose in the rats with a pylorus ligation. The PAR-2-mediated suppression of acid secretion was resistant to cyclooxygenase inhibition or ablation of sensory neurons by capsaicin. Our results provide novel evidence that in addition to stimulating neurally mediated mucus secretion, activation of PAR-2 suppresses gastric acid secretion independently of prostanoid production or sensory neurons. These dual actions of PAR-2 would result in gastric mucosal cytoprotection.

GRP and Pavlov's dogs

See article on page 23 The cephalic phase of gastric acid secretion has been a topic of great interest to physiologists and physicians since its description by Pavlov 100 years...

The effect of etodolac on bile salt and histamine-mediated gastric mucosal injury in the rat

The effect of the selective cyclo-oxygenase-type-2 (COX-2) inhibitor etodolac on gastric mucosal integrity and gastric acid secretion was investigated in the rat. Etodolac was given in doses comparable with those being used in man for therapy of rheumatic conditions. The effect of etodolac was studied in the presence of a mild barrier breaker and in the presence of increased rates of endogenous acid secretion. In conscious pylorus-ligated rats, etodolac given intragastrically in 16 or 32 mg /kg for 3 h did not by itself give rise to visible gastric mucosal injury. Etodolac, however, exacerbated gastric mucosal injury evoked by intragastric application of acidified sodium taurocholate (5 mM in 150 mM HCl) in a dose-dependent manner. This effect of edotolac was independent of changes in gastric acid secretory responses. In rats whose gastric acid secretion was stimulated by intraperitoneal histamine (5 mg/kg), and etodolac (given i.g. in doses of 16 or 32 mg/kg) also increased gastric mucosal injury caused by histamine dose-dependently in the 3-h pylorus-ligated rats. Etodolac decreased gastric mucus in the saline- and in the sodium taurocholate-treated rats. In urethane-anaesthetized acute gastric fistula rats, intragastric etodolac (32 mg/kg) did not modify basal gastric acid secretion. Our data suggest that etodolac, a selective COX-2 inhibitor, impairs gastric mucosal resistance and can exacerbate gastric mucosal injury caused by other mucosal barrier breaking agents. Cyclooxygenase type-2 thus contributes to the gastric mucosal defences.