Gastric Acid Response Research Articles

Thyrotropin releasing hormone (TRH) in the brainstem: Role of Pavlov’s vagally mediated cephalic phase of gastric secretion

Pavlov’s seminal observation that sham feeding in dogs stimulates gastric acid secretion through the vagus nerve pioneered the concept of the cephalic phase of digestion. This has been subsequently extended to a wide range of mammals including humans. In the last decades, experimental evidence in rats established that the three amino acid peptide thyrotropinreleasing hormone (TRH) expressed in the brainstem plays a key role in the vagal stimulation of digestive secretory-motor function. The dorsal motor nucleus of the vagus (DMN) neurons expresses TRH receptor subtype 1 (TRH-R1) and receives input of TRH containing fibers arising from TRH synthesizing neurons in medullary raphe nuclei. The activation of TRHTRH-R1 signaling excites the firing of DMN neurons leading to the activation of vagal efferent discharges and gastric myenteric cholinergic neurons. This results in a vagally mediated and atropine-sensitive stimulation of gastric secretory and propulsive motor function, along with duodenal and pancreatic secretion. Importantly, the blockade of TRH or TRH-R1 in the brainstem inhibits the gastric acid response to sham feeding in rats. Collectively, these convergent data support the physiological relevance of medullary TRHTRH-R1 signaling as the end effector of the vagally mediated stimulation of digestive process in the cephalic phase.

Accelerated gastric ulcer healing in thyroxine-treated rats: roles of gastric acid, mucus, and inflammatory response.

The roles of gastric acid, mucus, and inflammation on the pro-ulcer-healing effect of thyroid hormone were investigated. Male Wistar rats were randomly divided into four groups: control, thyroidectomised, thyroidectomised with thyroxine treatment (100 μg·kg-1·day-1), and sham-operated animals treated with thyroxine. Thirty-five days after thyroidectomy, sham surgery, or thyroxine treatment, an ulcer was experimentally induced. Healing was assessed 3, 7, and 10 days post-ulceration by measurement of the ulcer area, gastric mucus and acid secretion, and neutrophil lymphocyte ratio (NLR) as an index of inflammation. By day 10, the ulcer area had decreased in all groups. Recovery was significantly greater (P < 0.05) in thyroxine-treated rats (78.5% ± 1.6% reduction in ulcer area) than in controls (72.3% ± 1.2% reduction) or thyroidectomised rats (63.3% ± 1.9% reduction). Thyroxine-treated animals also had the highest reduction in NLR (65.0% ± 2.5%). Mucus secretion was significantly lower (P < 0.05) in thyroidectomised rats by days 3 and 7. Furthermore, by day 10, the concentration of basal acid decreased by 77.4% ± 2.6% in thyroxine-treated, 65.0% ± 0.0% in control, and 51.5% ± 3.3% in thyroidectomised rats. We conclude that thyroxine accelerates gastric ulcer healing by altering mucus and acid secretion and reducing NLR.

Gastric acid response to acute exposure to hypergravity.

The influence of environmental stressors on the pathogenesis of gastrointestinal disease has received increased awareness. Stress affects different physiological functions of the gastrointestinal tract, including gastric acid secretion and mucosal blood flow. Repeated exposures of rapid-onset, highly-sustained hypergravity cause severe physical stress in the pilot. Although the effects of exposure to hypergravity on cardiovascular and cerebral functions have been the subjects of numerous studies, crucial information regarding pathophysiological changes in the gastrointestinal tract following hypergravity exposure is lacking. In this study, we investigated the effects of acute exposure to hypergravity on gastric secretory activity and gastrin release. Male Sprague-Dawley rats were exposed to +10Gz three times for 3 min. Gastric juice and blood were collected. The volume and total acidity of gastric juice, and the plasma gastrin level was measured. Acute exposure to +10Gz significantly decreased the gastric juice parameters. The gastric juice volume and total acidity of hypergravity-exposed rats were 3.54 ± 0.32 mL/100 g and 84.90 ± 5.17 mEq/L, respectively, which were significantly lower than those of the nonexposed rats (4.62 ± 0.39 mL/100 g and 97.37 ± 5.42 mEq/L; P < 0.001 and P < 0.001, respectively). In contrast, plasma gastrin level was not significantly altered following hypergravity exposure. We demonstrated that acute exposure to hypergravity led to a significant decrease in the gastric juice volume and acidity but did not alter the plasma gastrin level.

The Microbiota and infectious diarrhea

Understanding the importance of the fecal microbiota has been key in understanding the pathophysiology of some infectious diarrheas. In addition to normal protective measures of bile, gastric acid, and immune response, among others, we now know that the healthy gut flora protects us from some infectious diarrheas. Antibiotic associated diarrhea (AAD) is an excellent example, as antibiotics perturb the normal flora; the resulting diarrhea may be due to changes in short chain fatty acid metabolism. A severe form of AAD is due to Clostridium difficile, a pathogen that can cause severe diarrhea, colitis and even death. Recurrent Clostridium difficile diarrhea is a difficult clinical problem to treat successfully because one recurrence makes further recurrences more likely, probably because antibiotics are still needed to treat and thus the fecal flora remains abnormal. There is no single effective treatment but therapies include pulsed and tapered antibiotics, the probiotic Saccharomyces boulardii as an adjunct to antibiotics, and even fecal flora reconstitution. It is likely that we will learn even more in the future about the beneficial effect of our microbiota.

The role of cAMP and prostaglandins in gastric acid secretion after pentagastrin administration.

The role of cAMP and prostaglandins as specific intracellular effectors of gastrin action at the level of the parietal cells has not been sufficiently clarified. For this reason we studied the responses of the parietal cells to stimulation with pentagastrin (6 micrograms/kg i.m.) during theophylline infusion (which causes an increase in the intracellular cAMP) and during acetylsalicylic acid infusion (which inhibits the prostaglandin synthesis) in 28 healthy volunteers. Both theophylline and acetylsalicylic acid provoked a significant increase of gastric acid secretion after pentagastrin. Our results suggest that: 1. an increase in intracellular cAMP may be the basis of the stimulatory effect of gastrin on gastric acid secretion 2. a decrease in the synthesis of prostaglandins may lead to a greater gastric acid response after pentagastrin.

Plasma gastrin concentration related to acid secretion during insulin hypoglycaemia

The release of gastrin by insulin hypoglycaemia was studied in man before and after vagotomy. Completeness of vagotomy was judged by the gastric acid response to the same hypoglycaemia, using several criteria including one that allows for pyloric losses and duodenogastric reflux. A total of 137 tests was performed on 10 subjects. The plasma gastrin concentration was found to rise in the preoperative studies and also in the postoperative studies no matter what type of vagotomy had been performed or what criteria of completeness of vagotomy were used. We concluded that gastrin can be released in response to hypoglycaemia in the absence of the vagus nerve.

The delayed insulin test and recurrent duodenal ulceration.

Abstract It has previously been shown that insulin tests of gastric secretion carried out within 2 weeks of vagotomy and pyloroplasty give no indication of the patient's liability to recurrent duodenal ulceration. Delayed insulin tests (done 6 or more months postoperatively) have been compared in 100 patients without and 50 patients with recurrence after operation for duodenal ulceration. Complete discrimination between the groups was not achieved but the incidence of recurrence was related to the magnitude of the acid response. As no dividing line could be established to separate tests into positive and negative results, it is preferable that the actual figures for the gastric acid response to insulin be quoted. It is suggested that the peak acid concentration should be selected for this purpose. Separate estimates of the probability of recurrence associated with various levels of peak acid concentration have been made for routine insulin tests and for tests performed in patients with clinical evidence suggestive of recurrent ulceration.

Galanin in vivo immunoneutralization partly prevents intraduodenal lipid-induced inhibition of gastric acid response to intracisternal TRH analog in urethane-anesthetized rats

Galanin in vivo immunoneutralization partly prevents intraduodenal lipid-induced inhibition of gastric acid response to intracisternal TRH analog in urethane-anesthetized rats

Synthesis of nitric oxide in the dorsal motor nucleus of the vagus mediates the inhibition of gastric acid secretion by central bombesin.

1. Central administration of bombesin inhibits gastric acid production independently of the centrally or peripherally-acting stimuli employed. This study evaluates the role and location of the cerebral nitric oxide (NO) implicated in the inhibitory effect of central bombesin on in vivo rat gastric acid secretion, as induced by distension with 15 cm H2O, insulin (0.75 u.i. kg-1 i.p.) TRH (1.2 microg kg-1, i.c.) or pentagastrin (100 microg kg-1, i.p.). 2. The acid-inhibitory effect of i.c. bombesin (40 ng kg-1) was prevented by prior administration of L-NAME (80 microg kg-1) in the dorsal motor nucleus of the vagus (DMN). This dose of L-NAME when administered into the nucleus of the tractus solitarious (NTS) did not influence the effects of bombesin. Administration of L-arginine (400 microg kg-1) into the DMN restored the acid-inhibitory effect of i.c. bombesin in animals treated with L-NAME. 3. Microinjection of bombesin (12 ng kg-1) into the paraventricular nucleus of the hypothalamus (PvN) inhibits acid secretion stimulated by pentagastrin. This inhibitory effect was prevented by a previous injection of L-NAME (80 microg kg-1) into the DMN. 4. The release of NO in the DMN following i.c. administration of bombesin was confirmed by in vivo electrochemical detection. 5. Administration by microdialysis in the DMN of the NO-donor SNAP (25 mM in 1.5 microl min-1) into the DMN inhibits pentagastrin-stimulated gastric acid secretion. 6. The present study suggests that nNOS-containing neurons in the DMN have an inhibitory role in the control of gastric acid responses.

What Are the Host Factors That Place an Individual at Risk for Helicobacter pylori-Associated Disease?

Helicobacter pylori infection is associated with duodenal and gastric ulcer disease, gastric cancer, and gastric mucosa-associated lymphoid tissue lymphoma. Although more than half the world's population harbors H. pylori, only a proportion will develop clinically significant disease. The specific clinical outcome of an individual can be examined as the modulation of host factors by H. pylori infection. Host acid-secretory status and sensitivity to gastrin can be modulated by H. pylori infection. Once H. pylori has established itself in the stomach, virtually everyone develops gastritis, and variations in gastritis patterns have been associated with different gastric acid responses to H. pylori infection. The patterns of gastritis are important because they seem to determine disease outcome. Blood group antigens have been implicated in studies of ulcer disease. Receptors to Lewis antigens in gastric mucosa indicate that host mucosal factors influence H. pylori attachment. Conversely, H. pylori strains express Lewis antigen-like molecules, suggesting an autoimmune component for some H. pylori-associated diseases. HLA genotypes may influence the host response to H. pylori infection, and those of H. pylori infected individuals have been correlated with histological features. The clinical outcome of H. pylori infection is most likely a result of complex interactions among host, bacterial, and environmental factors. The mechanisms by which these diverse factors influence the pathogenesis of different clinical outcomes remain under investigation.

5-CT or DOI augments TRH analog-induced gastric acid secretion at the dorsal vagal complex.

Serotonin (5-HT) interacts with thyrotropin-releasing hormone (TRH) at the dorsal vagal complex (DVC) to augment TRH-induced stimulation of gastric acid secretion. To investigate the 5-HT receptor family involved in the augmentation response, prototypical 5-HT receptor-selective agonists (146 pmol) were coinjected with the TRH analog RX-77368 (RX; 12 pmol) into the rat DVC in a 30-nl volume. The DVC coordinates were 0.2 mm anterior, 0.2 mm right, 0.6 mm ventral with respect to the calamus scriptorius. Coinjection of RX with the 5-HT agonists 5-carboxyamidotryptamine (5-CT) or (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (DOI; 5-HT2 agonist) produced a 183 or 103% increase in gastric acid output compared with the RX injection alone. In contrast, coinjection of 2-methyl-5-HT (5-HT3 agonist) with RX produced no effect on RX-induced increase in gastric acid secretion. Moreover, coinjection of SC-53116 (5-HT4 agonist) decreased the gastric acid output by 45% compared with the RX response itself. Examination of the RX/5-HT agonist coinjection response in more rostral regions of the DVC using the same doses (5-CT/RX or DOI/RX) revealed that only 5-CT was effective in producing the augmented response to TRH analog. The results suggest that activation of 5-CT- or DOI-sensitive receptors augments, and of 5-HT4 receptors inhibits, the gastric acid response to TRH analog injected into the DVC. Thus the integrated response to several serotonin receptor subtypes may mediate changes to the TRH response induced by 5-HT at the DVC.

Mechanisms mediating gastric hyperemic and acid responses to central TRH analog at a cytoprotective dose.

Gastric hyperemic and acid responses to the stable thyrotropin-releasing hormone (TRH) analog RX-77368 injected intracisternally at a cytoprotective dose were investigated, as well as the underlying mechanisms of the responses. Gastric acid secretion (GAS), mucosal blood flow (GMBF; measured by the hydrogen gas clearance technique), and mucosal vascular resistance (GMVR) and mean arterial pressure (MAP) were assessed simultaneously for 30 min before and after RX-77368 (1.5 ng) administration in urethan-anesthetized rats. RX-77368 increased GMBF from 46.8 +/- 5.3 to 100.6 +/- 20.9 ml.min-1.100 g-1 and MAP from 70.3 +/- 2.1 to 84.3 +/- 5.9 mmHg and decreased GMVR from 1.50 +/- 0.33 to 0.84 +/- 0.08 mmHg.ml-1.min.100 g, whereas GAS was not significantly altered (1.8 +/- 0.4 vs. 4.7 +/- 1.7 mumol/30 min) in vehicle-pretreated rats. The GMBF, MAP, and GMVR responses to RX-77368 were not modified by indomethacin (5 mg/kg ip), whereas GAS was increased. In rats pretreated with capsaicin (125 mg/kg sc) or calcitonin gene-related peptide (CGRP) antagonist hCGRP-(8-37), intracisternal RX-77368 did not increase GMBF or decrease GMVR but did stimulate GAS. These data show that vagal stimulation by the TRH analog RX-77368 injected intracisternally at a nonacid secretory dose increases GMBF. Gastric hyperemia is mediated by CGRP contained in capsaicin-sensitive afferent fibers, whereas acid secretion is under the inhibitory influence of prostaglandins and CGRP.

Caloric restriction causes secretagogue specific changes of gastric acid secretion in rats

The purpose of this study was to examine the effects of short-term caloric restriction (CR) for 4, 8 and 16 weeks on gastric acid secretion in rats. CR rats were fed 60% of normal food intake for 4, 8 or 16 weeks and then prepared with gastric fistulas. Histamine- and carbachol-stimulated gastric acid secretion were significantly ( P<0.05) decreased after more than 4 weeks and 8 weeks of caloric restriction, respectively. In contrast, gastrin-stimulated acid secretion was unaffected by CR. The 1-h-integrated acid output to a submaximal dose of gastrin (40 μg·kg −1) was significantly higher than that of histamine (5 mg·kg −1) after 8 weeks of CR (63±13 and 27±4 μEq·h −1, respectively). Gastrin treatment (5 μg·kg −1·h −1) of CR rats restored the gastric acid responses to both histamine and carbachol. These results suggest that CR can selectively decrease the gastric acid responses to both histamine and carbachol by depletion of the endogenous tissue stores of gastrin. More importantly, these results indicate that under an in vivo gastrin-diminished condition, histamine is not the final secretagogue for gastric acid secretion.

Rat stomach enterochromaffin-like cells are not stimulated by pylorus ligation. A biochemical and ultrastructural study.

The enterochromaffin-like (ECL) cells in the rat oxyntic mucosa produce histamine and contain cytoplasmic granules, microvesicles, and secretory vesicles. The cells respond to gastrin by the release of histamine (associated with loss of secretory vesicles), which is thought to mediate the gastrin-induced stimulation of the parietal cells. Gastric acid secretion is stimulated also by vagal excitation, which can be induced, for instance, by pylorus ligation. The present study addresses the question whether the ECL cells are involved in the acid response to pylorus ligation. Rats were subjected to pylorus ligation and killed 4 or 16 h later. Other rats were subjected to sham operation (laparotomy). Some of the rats received human Leu15-gastrin-17 (5 nmol/kg/h) by intravenous infusion for 30 or 60 min before being killed. The serum gastrin concentration, the oxyntic mucosal histidine decarboxylase (HDC) activity, HDC mRNA concentration, histamine concentration, and gastric acid output were measured. Specimens from the oxyntic mucosa were processed for transmission electron microscopy. Electron micrographs of ECL cells were analyzed planimetrically. The gastric acid output was high, but the serum gastrin concentration was not affected by the pylorus ligation. The HDC activity and the level of HDC mRNA in the oxyntic mucosa were reduced, but the histamine concentration was unchanged. The secretory vesicles and granules of the ECL cells were unaffected, whereas the number and volume density of the microvesicles were reduced. Gastrin administration to sham-operated and pylorus-ligated rats lowered the oxyntic mucosal histamine concentration and increased the HDC activity in both groups. ECL cells in the rat stomach do not mediate the gastric acid response to pylorus ligation, and ECL cells in the pylorus-ligated stomach retain their ability to respond to gastrin with activation.

Serotonin enhances gastric acid response to TRH analogue in dorsal vagal complex through 5-HT2 receptors in rats

The effect of serotonin (5-HT) and thyrotropin-releasing hormone (TRH) analogue, p-Glu-His-[3,3'-dimethyl]-Pro-NH2 (RX-77368), injected into the dorsal vagal complex (DVC) on gastric acid secretion was assessed in urethan-anesthetized rats with gastric cannula. 5-HT (0.1, 0.2, 1, or 10 nmol into the DVC) enhanced the acid response to RX-77368 (25 pmol, DVC) by 54, 100, 147, and 144%, respectively, whereas 5-HT given alone had no effect. The 5-HT2 receptor agonists (1 nmol, DVC), ( +/- )-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride, 1-(alpha, alpha, alpha-trifluoro-m-tolyl)-piperazine hydrochloride, and alpha-methyl-5-HT increased the gastric acid response to coinjection of RX-77368 (25 pmol) by 153, 108, and 96%, respectively, whereas 8-hydroxy-2-(di-n-propylamino)tetralin (5-HT1A), 7-trifluoromethyl-4(4-methyl-1-piperazinyl)- pyrrolo[1,2-a]quinoxaline (5-HT1A/1B), and 3-(2-aminoethyl)-2-methyl-1-H-indol-5-ol hydrochloride hydrate (2-methyl-5-HT3) did not. The 5-HT2 receptor antagonist, 3-[2-(4-fluorobenzoyl)-1-piperdinyl]ethyl]-2,4(1H,3H)-quinazoli nedone tartrate (ketanserin; 20 nmol), injected intracisternally abolished the potentiating action of 5-HT injected into the DVC with RX-77368, whereas the 5-HT antagonists 8-[4-(4-fluorophenyl)-4-oxobutyl]-1-phenyl-1,3,8-triazaspiro[4,5]- decan-4-one (spiperone; 5-HT2/1A) and 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1- yl)methyl]-4H-carbazol-4-one hydrochloride dihydrate (ondansetron; 5-HT3) did not. Ketanserin (1 nmol/site bilaterally into the DVC) decreased the acid response to kainic acid injected into the raphe pallidus by 62%. These data suggest that 5-HT acting at 5-HT2 receptors in the DVC potentiates the gastric acid response to exogenous and endogenous TRH.

Influence of intracisternal injection of somatostatin analog receptor subtypes 2, 3 and 5 on gastric acid secretion in conscious rats

Somatostatin (SST) and its analogs injected into the CSF induce different gastric acid response patterns. Five SST receptors have been characterized (SSTR-1 to -5). We studied the influence of selective SSTR-2, -3 and -5 ligands on basal gastric acid secretion after intracisternal (i.c.) injection in conscious rats equipped with chronic gastric and i.c. cannulae. Compared with pre-injection level, the SSTR-3 agonist, BIM-23056 (1 μg) increased acid secretion by 274 ± 43% while the SSTR-2 agonist, DC 32–87 (1 μg) inhibited acid secretion by 50.7 ± 13.3%. SST-14 (1 μg), the SSTR-5 agonist, BIM-23052, (0.5–1 μg), SSTR-3 (0.5 μg) and −2 (0.5 μg) or vehicle injected i.c. did not modify basal acid secretion. These results show that the activation of brainstem SSTR-3 receptors stimulate and SSTR-2 inhibit basal gastric acid secretion in conscious rats with chronic gastric fistulae.

CGRP antagonists enhance gastric acid secretion in 2-h pylorus-ligated rats

The influence of calcitonin gene-related peptide (CGRP) antagonists on gastric acid secretion was investigated in rats. Intravenous injection of the CGRP receptor antagonist, CGRP(8-37) (128 nmol/kg) or the CGRP antibody #4901 (4.8 mg/kg, IV) completely prevented alpha-CGRP (3.9 nmol/kg/h)-induced inhibition of acid response to pentagastrin in urethane-anesthetized rats with gastric fistula. CGRP antibody (4.8 mg/kg, IV) increased by 93% gastric acid secretion in conscious rats with pylorus ligation for 2 h. (CGRP(8-73) (128 nmol/kg, IV) also enhanced the acid response measured 2 h after pylorus ligation in conscious rats and in urethane-anesthetized rats infused with pentagastrin by 91% and 56%, respectively. These results suggest that endogenous CGRP attenuates the gastric acid response measured 2 h after pylorus ligation.

Nitric oxide donors preferentially inhibit neuronally mediated rat gastric acid secretion

Continous i.v. infusion of the nitric oxide (NO) donors, S-nitroso-glutathione (10–50 μg kg −1 min −1) and S-nitrroso- N- acetyl-penicillamine (10 μg kg −1 min −1) inhibited neuronally mediated gastric acidsecretion, as induced by gastric distension (20 cm water) or i.v. bolus administration of 2-deoxy- D-glucose (150 mg kg −1) in the anaesthetized rat. By contrast, gastric acid responses to i.v. infusion of submaximal doses of pentagastrin (8 μg kg −1 h −1) or histamine (1 mg kg −1 h −1) were not influenced by these NO donors. These findings suggest that NO does not directly influence acid secretion in vivo but could play an inhibitory modulator role in neuronally mediated acid responses.

Neuropeptide Y functions as a physiologic regulator of cephalic phase acid secretion

Neuropeptide Y (NPY) has been established as a potent orexigenic peptide, and recent studies suggest that NPY stimulates cephalic phase secretion as well. However, it is not known whether NPY's effects are pharmacologic or physiologic. In order to determine the physiologic significance of NPY, we examined the effects of two putative NPY receptor antagonists, PYX-1 and PYX-2, on sham feeding and gastric acid secretion in dogs. Our results demonstrate that intracerebroventricular (i.c.v.) injection of PYX-1 and PYX-2 at 1000 pmol/kg doses significantly suppresses the gastric acid response to sham feeding in dogs. The volumes sham fed were not significantly altered with i.c.v. administration of the antagonists. Peripheral administration did not affect acid secretion nor sham feeding volumes. Our data suggest that central administration of the novel NPY antagonists, PYX-1 and PYX-2, results in significant suppression of acid secretion in dogs. This supports our hypothesis that NPY functions as a physiologic modulator of cephalic phase acid secretion.

Effect of resiniferatoxin on stimulated gastric acid secretory responses in the rat

The effect of the capsaicin analogue ‘resiniferatoxin’ (RTX) was studied on basal and stimulated gastric acid secretory responses following sc bethanechol (1.5 mg/kg), sc pentagastrin (50 μg/kg) and sc histamine (0.5 and 2.5 mg/kg) in the 1-h pylorusligated plus saline (2 ml ig)-treated rats. Resiniferatoxin applied intragastrically in doses of 0.6 and 1 μg/kg at time of pylorus-ligation and administration of the above secretagogues reduced acid secretory respones to bethanechol by 18.3 and 26.4%, to 0.5 mg/kg histamine by 39.9 and 44.6%, to 2.5 mg/kg histamine by 21.3 and 40.8% and to pentagastrin by 10.2 and 30.9% respectively. A single sc injection of 0.4 μg/kg of RTX abolished basal secretion in pylorus ligated rats (which did not receive ig saline). Our results indicate that locally applied RTX is capable of inhibiting basal secretory responses and modifying gastric acid responses stimulated with histamine, bethanechol or pentagastrin in the rat.