Basal Acid Secretion Research Articles

Sustained cholecystokinin-B/gastrin receptor blockade does not impair basal or histamine-stimulated acid secretion in chronic gastric fistula rats.

Gastrin is a physiologically important secretagogue. It is thought to stimulate parietal cells indirectly by mobilizing histamine from enterochromaffin-like (ECL) cells in the oxyntic mucosa. Gastrin stimulates the secretory activity and growth of the ECL cells via an action on cholecystokinin-B/gastrin receptors. Acute cholecystokinin-B/gastrin receptor blockade is known to inhibit gastrin-stimulated acid secretion but whether sustained cholecystokinin-B/gastrin receptor blockade will impair basal, gastrin- and histamine-stimulated acid secretion remains uncertain. The present study was designed to study the effect of long-term (4 weeks) cholecystokinin-B/gastrin receptor blockade on basal and stimulated acid secretion in conscious rats. The selective cholecystokinin-B/gastrin receptor antagonist YM022 (3 mumol.kg-1.hr-1) was given to gastric fistula rats by continuous subcutaneous infusion via osmotic minipumps for various times from 2 hr to 4 weeks. Basal, gastrin- and histamine-stimulated acid secretion were examined during and after cessation of treatment. Basal and histamine-stimulated acid secretion was not affected by YM022 during the 4 week period of administration, whereas gastrin-induced acid secretion was inhibited. YM022 induced hypergastrinaemia in freely fed rats but did not affect the serum gastrin level in fasted rats. The serum gastrin concentration and gastrin-induced acid secretion returned to control levels 3-7 days after termination of YM022 administration.

Inhibition of gastric acid secretion by galanin in rats: Relation to endogenous histamine release

Inhibitory effect of galanin on basal and secretagogs-stimulated gastric acid secretion was investigated in urethane-anesthetized rats. A rat stomach was mounted in an ex-vivo chamber, perfused with saline, and either gastric acid or alkaline secretion was determined by titrating the perfusate. Gastric mucosal blood flow (GMBF) was measured by a laser Doppler flowmeter. Intravenous infusion of galanin dose-dependently inhibited the increase of acid secretion induced by pentagastrin and carbachol but not by histamine, without any influence on the GMBF response. Galanin also reduced basal acid secretion while increasing GMBF, but did not evoke any change in basal gastric alkaline secretion. M15, which is a galanin receptor antagonist in the central nervous system but acts as a full agonist in the gastrointestinal smooth muscle, also suppressed pentagastrin-induced acid secretion, similar to galanin. In addition, pentagastrin increased the release of histamine into the gastric lumen, and this response was significantly inhibited by galanin. These results suggest that the inhibitory effect of galanin on acid secretion is mediated by suppression of endogenous histamine release from enterochromaffin-like cells and that the process may be related to the activation of the same subtype of galanin receptors as in the central nervous system and pancreatic β-cells.

Gastric antisecretory drug-induced achlorhydria causes decreases in serum vitamin B12 levels in patients with zollinger-ellison syndrome (ZES): A prospective study

Markedly decreased acid secretion is known to decrease vitamin B~2 absorption. However, it is controversial whether prolonged treatment with potent gastric antisecretory drugs will caused decreased serum vitamin Btz levels (Bt2 levels). This could be a potentially important problem in conditions such as GERD or ZES, requiring continuous long-term treatment. In a previous study we reported that B~z levels, but not serum folate levels, determined at one time correlated inversely with the length of omeprazole treatment in patients with ZES. In the present study to provide insights into the possible effects of long-term acid suppression on B~2 levels in a given patient, we have analyzed sequential results from 68 patients with ZES who were followed for at least 5 years. Patients had yearly B~ levels and determinations of acid secretory control taken one hour before the next dose of antisecretory drug. The mean age of the patients was 55 ± 1 yrs, there were 22 females and 46 males, and the total duration of gastric antisecretory treatment was 14 _+0.5 yrs. Fifty-two patients were being treated with omeprazole (mean time ± 1SEM=5 ± 1 yrs) and 17 patients with histamine Hz inhibitors. The mean initial B~2 level was 439 ± 21 pg/ml (normal=165-1000 pg/ml) and the last Ba2 level, a mean of 6.3 ± 1.2 yrs later, was 427 ± 21 pg/ml, was not significantly different. The patients had a mean basal acid output of 25 ± 2 mEq/h and M An of 54-+ 4 mEq/h. The patients' acid secretory rate on antisecretory drug for each of the last 5 years was reviewed and 21/68 (30%) had complete achlorhydria defined as no basal acid secretion during each of the last 3 years. The B~ levels over the 6.3 ± 1.1 yrs from the first to the last Bl~ level in the achlorhydric patients showed a highly significant (p=0.001) decrease from 419 _+ 38 to 305 ± 24 pg/ml. In contrast, for the 47 patients without complete achlorhydria over a 6.3 ± 1.2 year period of antisecretory drug treatment, the B~2 levels did not change significantly (447 ± 26 vs 480 ± 35 pg/ml). A significantly higher proportion (p=0.002) [18/21 (86%)] of patients with complete achlorhydria had a decrease in their B~2 levels over this time period compared to the patients without achlorhydria [22/47 (47%)]. These results demonstrate that profound acid inhibition, which occurs in 32% of patients with ZES, lead to a highly significant decrease in serum vitamin levels over a 6-year period. In other studies > 80% of patients with GERD treated long-term with potent antisecretory drugs also have such acid hyposecretion that hypergastrinemia develops. These results suggest that in patients with such conditions as ZES or GERD undergoing prolonged daily treatment with potent gastric acid suppressants such as omeprazole or lansoprazole, routine monitoring of B~2 levels should be considered.

PYY-preferring receptor in the dorsal vagal complex and its involvement in PYY stimulation of gastric acid secretion in rats.

1. Microinjection of peptide YY (PYY, 7-46 pmol) into the dorsal vagal complex (DVC) stimulated gastric acid secretion in urethane-anaesthetized rats. Using a variety of neuropeptide Y (NPY) and PYY derivatives, we characterized the pharmacological profile of the receptor mediating the acid secretory response to PYY. 2. [Pro34]rat(r)/porcine(p)PYY and [Pro34]human(h)PYY (23-117 pmol), microinjected unilaterally into the DVC resulted in a similar maximal increase in net acid secretion reaching 68+/-11 and 89+/-31 micromol 90 min(-1) respectively. 3. Rat/hNPY and pNPY (47 pmol) microinjected into the DVC induced a similar net gastric acid secretion (27+/-8 and 23+/-8 micromol 90 min(-1) respectively) and a higher dose (116 pmol) tended to reduce the response. 4. Pancreatic polypeptide (PP, 4-46 pmol), [Leu31,Pro34]r/hNPY (47 and 117 pmol) and the Y2 selective agonists, hPYY3-36, pNPY5-36 and PNPY13-36 (25-168 pmol) microinjected into the DVC failed to influence basal gastric acid secretion. 5. The rank order of potency of PYY > or = [Pro34]r/pPYY = [Pro34]hPYY> r/hNPY = pNPY to stimulate gastric acid secretion upon injection into the DVC and the ineffectiveness of PP, [Leu31,Pro34]NPY and C-terminal NPY/PYY fragments suggest that a PYY-preferring receptor subtype may be involved in mediating the stimulating effect.

Model to study gastric acid secretion in mice: Effect of secretagogues and inhibitors on basal gastric acid secretion

Model to study gastric acid secretion in mice: Effect of secretagogues and inhibitors on basal gastric acid secretion

Role of nitric oxide in regulation of gastric acid secretion in rats: effects of NO donors and NO synthase inhibitor.

1. The role of nitric oxide (NO) in the regulation of acid secretion was examined in the anaesthetized rat. 2. A rat stomach was mounted in an ex vivo chamber, instilled with 2 ml of saline every 15 min, and the recovered sample was titrated at pH 7.0 against 0.1 N NaOH by use of an automatic titrator for acid secretion. Gastric mucosal blood flow (GMBF) was measured simultaneously by laser Doppler flowmeter. 3. Intragastric application of NO donors such as FK409 (3 and 6 mg ml[-1]) and sodium nitroprusside (SNP; 6 and 12 mg ml[-1]) as well as i.p. administration of cimetidine (60 mg kg[-1]), a histamine H2-receptor antagonist, significantly inhibited the increase in acid secretion in response to pentagastrin (60 microg kg(-1) h(-1), i.v.), in doses that increased gastric mucosal blood flow (GMBF). 4. Intragastric application of FK409 (6 mg ml[-1]) increased both basal and stimulated acid secretion induced by YM-14673 (0.3 mg kg(-1), i.v.), an analogue of thyrotropin-releasing hormone (TRH), but had no effect on the acid secretory response induced by histamine (4 mg kg(-1) h(-1), i.v.). 5. Pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME; 10 mg kg(-1), i.v.) did not affect basal acid secretion, but significantly potentiated the increase in acid secretion induced by YM-14673 and slightly augmented the acid secretory response to pentagastrin. 6. Both pentagastrin and YM-14673 increased the release of nitrite plus nitrate (NOx), stable NO metabolites, into the gastric lumen, and these changes were completely inhibited by prior administration of L-NAME (10 mg kg(-1), i.v.). 7. Pentagastrin caused an increase in luminal release of histamine and this response was significantly suppressed by intragastric application of FK409 (6 mg ml[-1]). 8. These results suggest that either exogenous or endogenous NO has an inhibitory action on gastric acid secretion through suppression of histamine release from enterochromaffin-like (ECL) cells.

Impaired gastric acid secretion in gastrin-deficient mice.

To further understand the role of the peptide hormone gastrin in the development and function of the stomach, we have generated gastrin-deficient mice by gene targeting in embryonic stem cells. Mutant mice were viable and fertile, without obvious visible abnormalities. However, gastric function was severely affected by the loss of gastrin. Basal gastric acid secretion was abolished and could not be induced by histamine, carbachol, or gastrin. Histological analysis revealed alterations in the two cell types primarily involved in acid secretion, parietal and enterochromaffin-like (ECL) cells. Parietal cells were reduced in number with an accumulation of immature cells lacking H(+)-K(+)-adenosinetriphosphatase (H(+)-K(+)-ATPase). ECL cells were positioned closer to the base of the gastric glands, with markedly lower expression of histidine decarboxylase. Gastrin administration for 6 days reversed the effects of the gastrin deficiency, leading to an increase in the number of mature, H(+)-K(+)-ATPase-positive parietal cells and a partial restoration of acid secretion. The results show that gastrin is critically important for the function of the acid secretory system.

Effects of keratinocyte growth factor (KGF) on gut growth and repair.

Keratinocyte growth factor (KGF) is a mitogen found throughout the gastrointestinal tract, but its role in gastrointestinal pathophysiology is unclear. The effect of recombinant KGF on gut growth and repair has been examined using a variety of in vivo models. Rats receiving total parenteral nutrition had co-infusions of KGF or control for 6 days. Changes in gut growth (wet weight and vincristine-induced metaphase arrest) were then assessed. The effects of KGF on gastric repair and acid secretion in rats were determined using an indomethacin (20 mg/kg)/restraint model and animals fitted with chronic gastric fistulae. KGF at 0.1, 1, and 3 mg/kg increased gut growth as assessed by wet weight throughout the gastrointestinal tract and increased vincristine-induced accumulation of metaphases in the stomach and small intestine but not in the colon. Plasma gastrin, peptide YY, enteroglucagon, and glucagon-like peptide-1 were all increased, whereas insulin was lowered by KGF (all P < 0.01). KGF was ineffective in reducing indomethacin-induced gastric damage but caused a reduction in basal acid secretion of about 35 and 50 per cent when administered at 0.2 or 5 mg/kg (P < 0.05). These studies support the idea that KGF is involved in the control of proliferation of the gastrointestinal tract. They do not provide evidence, however, for a role in the early reparative process invoked during short-term models of gastrointestinal injury.

Interleukin 1β and tumour necrosis factor α inhibit acid secretion in cultured rabbit parietal cells by multiple pathways

Background—The cytokines interleukin 1β (IL-1β) and tumour necrosis factor α (TNF-α) are inhibitors of gastric acid secretion when administered systemically.Aims—To investigate the inhibitory effect of IL-1β and TNF-α on cultured,...

Similarities and differences in oxynticopeptic cell ultrastructure of one marine teleost, Gadus morhua and one freshwater teleost, Oncorhynchus mykiss, during basal and histamine-stimulated phases of acid secretion

Oxynticopeptic cells (OC) from rainbow trout, Oncorhynchus mykiss, and Atlantic cod, Gadus morhua, were studied during basal acid secretion and during stimulation with histamine. An in vitro method for measuring acid secretion from isolated stomac a was used. The OC ultrastructure was studied using electron microscopy. During basal acid secretion, the OC had short apical microvilli, an extensive tubulovesicular network, large electron-dense vesicles and many mitochondria. Stimulation of acid s tion with histamine and ultrastructural changes in the OC occurred simultaneously. The acid stimulation promoted large increases in the length of microvilli, a decrease in the size of the tubulovesicular network and an increase in the diameter of the ndular lumen in cod. Large vacuoles were found to characterize the histamine-stimulated OC. These were located close to the apical membrane and sometimes opened into the lumen. During stimulation, electron-dense vesicles were often observed close to apical membrane and the large vacuoles. Sometimes these vesicles were observed inside the glandular lumen and/or the large vacuoles. It is concluded that the ultrastructure of the OC in the saltwater cod and the freshwater trout show similar characte ics as OC in other animal groups both during basal and high rates of acid secretion. In addition, vacuoles were found in both species OC during basal rates of acid secretion and they significantly increased in size during high rates of acid secretion propose that the OC vacuole have a part in the osmoregulation, since the increase was tenfold in cod but less then one-fold in trout, this difference was statistically significant.

Effects of YJA20379-4 on gastric secretion, Helicobacter pylori growth and various gastric and duodenal lesions in rats.

Effects of a newly synthesized antiulcer agent, YJA20379-4, on gastric proton pump (H+/K+-ATPase) activity, Helicobacter pylori (H. pylori) growth, gastric acid secretion, and gastro-duodenal lesions, were examined in comparison with those of omeprazole. YJA20379-4 markedly inhibited the H+/K+-ATPase activity in a concentration-dependent manner and the inhibitory effect was increased under a weak acidic condition; the IC50 values were 32 and 81 microM at pH 6.4 and 7.4, respectively. The inhibition was completely antagonized by 0.5 mM dithiothreitol (DTT). In addition, YJA20379-4 showed a significant anti-H. pylori activity determined by the agar dilution method. The value of minimum inhibitory concentration (MIC, 3.9-11.7 microg/ml) was at least 3 times more potent than that of omeprazole. In pylorus ligated rats, YJA20379-4 inhibited basal gastric acid secretion when administered by the intraduodenal route (ED50: 23.6 mg/kg). In experimental ulcer models, YJA20379-4 administered by the oral route dose-dependently prevented the development of gastro-duodenal lesions in rats. Moreover, repeated administration of YJA20379-4 promoted the healing of gastric ulcers induced by acetic acid. On the basis of the data obtained, it is suggested that YJA20379-4 has a wide spectrum of antiulcer activities, and its mode of antiulcer actions is dependent on the inhibition of H+/K+-ATPase activity and H. pylori growth and the enhancement of a mucosal defense. Thus, YJA20379-4 might prove to be a beneficial therapy for gastritis and peptic ulcer diseases.

Gastric effects of the CCK-B/gastrin receptor ligand CI-988 in cynomolgus monkeys

We have previously demonstrated that the CCK-B/gastrin receptor ligand CI-988 induces gastric gland degeneration and atrophy in cynomolgus monkeys, an effect consistent with gastrin receptor antagonism and inhibition of gastrin's trophic effects on oxyntic mucosa. However, gastrin receptor ligands of the dipeptoid chemical series to which CI-988 belongs have been reported to act as agonists or antagonists towards gastrin-related events, depending on the animal model and the functional endpoint examined. To investigate further these apparently conflicting data, basal gastric acid secretion was monitored acutely in conscious monkeys given CI-988 orally at 10 mg/kg or intravenously at 0.01 μmol/kg/hr and histological changes in gastric mucosa were evaluated in monkeys given CI-988 orally at 5, 25 or 75 mg/kg/day for 4 weeks. Degeneration and atrophy of gastric glands occurred at 25 and 75 mg/kg with statistically significant decrements in gastric mucosal height at 75 mg/kg. In addition, CI-988 stimulated gastric acid secretion when given either orally or intravenously. Co-administration of the structurally unrelated CCK-B/gastrin antagonist L-365 260 completely blocked CI-988-stimulated acid secretion, confirming that CI-988's agonist effect on acid secretion is mediated by the gastrin receptor. Assuming that gastric mucosal degeneration is the result of inhibition of gastrin's trophic activity, CI-988 appears to induce paradoxical agonist and antagonist gastrin-receptor mediated effects.

Effects of Helicobacter pylori Eradication on Gastric Function Indices in Functional Dyspepsia: A Prospective Controlled Study

Background: To date, it is unclear whether Helicobacter pylori infection is associated with disturbances of gastric emptying or acid secretion in patients with functional dyspepsia (FD). Our aim was to investigate whether, in the long run, cure of H. pylori infection significantly influences gastric emptying of solids, acid secretion, and gastrin and pepsinogen I (PGI) release in patients with FD. Methods: Thirty-eight consecutive H. pylori-positive patients with FD, whose complaints were scored for severity and frequency on the basis of a validated symptom questionnaire, were initially enrolled in the study. They were randomized to receive an eradicating regimen consisting of omeprazole plus clarithromycin and tinidazole for 1 week or full-dose ranitidine for 3 weeks. In 33 patients (18 H. pylori-cured and 15 with persistent infection) basal and pentagastrin-stimulated acid secretion, fasting and meal-induced gastrin concentrations, fasting serum PGI levels, and gastric emptying of solids were determined before and 6 months after therapy. Results: In the 18 H. pylori

Antigastric Autoantibodies and Gastric Secretory Function in Helicobacter pylori-Infected Patients with Duodenal Ulcer and Non-Ulcer Dyspepsia

Background: Autoantibodies against epitopes located at the canaliculi of human parietal cells occur in about 30% of Helicobacter pylori-infected patients. This has led to the hypothesis that gastric secretory function could be inhibited by anticanalicular autoantibodies in H. pylori gastritis. Methods: Forty-four H. pylori-infected patients with and without duodenal ulcers were screened for anticanalicular autoantibodies by means of immunohistochemistry. Plasma gastrin levels and basal and maximal gastric acid output were determined. Results: Fasting gastrin levels were significantly increased in the group with anticanalicular autoantibodies. In the group of patients with non-ulcer dyspepsia the presence of anticanalicular autoantibodies was significantly correlated with an impaired basal acid secretion. Conclusions: Antigastric autoimmunity in H. pylori gastritis seems to be relevant for gastric hyposecretion either directly by inhibiting the proton pump or indirectly through the development of gastric mucosa atrophy.

Inhibition of Gastric Acid Secretion by Bunodosoma cavernata Extract

The saline extract of Bunodosoma cavernata (6.0 µg protein/100 g body wt i.v.) did not affect basal acid secretion in rats. The extract, however, completely blocked the induced-release of gastric acid by histamine (0.2 mg/100 g body wt i.v.) and pentagastrin (0.6 µg/kg body wt i.v.). These effects were produced when the extract was administered 50 min before the drugs. Also, the extract abolished the stimulant action of both histamine and pentagastrin when it was administered 50 min before application of the drugs. However, the extract failed to influence the basal acid output.

Effects of extracellular Mg 2+ concentration on intracellular signalling and acid secretion in rat gastric parietal cells

In the present study, the effects of extracellular magnesium concentration ([Mg 2+] ex) on stimulus-secretion coupling processes were investigated in rat gastric parietal cells in vitro. Extracellular magnesium reduction resulted in (1) an increase of basal intracellular free calcium concentration ([Ca 2+] in), (2) an enhancement of both carbachol and thapsigargin-induced calcium responses, (3) an improved filling state of intracellular calcium stores, (4) an increase of both basal and carbachol-induced acid secretion, whereas intracellular adenosine 3′,5′-cyclic monophosphate (cyclicAMP) levels and histamine stimulated acid secretion were not affected. The effects of high [Mg 2+] ex were opposite to the described results, except that high [Mg 2+] ex was able to decrease significantly histamine-stimulated cyclicAMP levels and acid secretion. These findings indicate a modulatory role of [Mg 2+] ex on the intracellular signalling processes and acid secretory properties in rat parietal cells. These effects seemed to be mediated by regulating (1) calcium loading capacity of intracellular stores, (2) the permeability of the calcium influx pathway, and (3) the formation of cyclicAMP.

Increased sensitivity of gastrin cells to gastric distension following antral denervation in the rat.

1. Secretion of the antral hormone gastrin is increased by protein in the gastric lumen and by nervous reflexes. We have examined the relative importance of luminal and neuronal mechanisms, by lesioning the antral innervation using benzalkonium chloride. 2. Benzalkonium chloride was applied to the serosa of the antrum in anaesthetized rats. In some animals, a stainless-steel cannula was also implanted in the corpus. Animals were allowed 10 days to recover. Plasma gastrin was measured by radioimmunoassay and mRNAs encoding gastrin, somatostatin and histidine decarboxylase were measured by Northern blot. 3. Antral denervation was associated with gastric retention after fasting, and elevated plasma gastrin (28.4 +/- 7 pM compared with 7.6 +/- 1.0 pM in controls). When fasted control or denervated rats were refed, plasma gastrin increased 3-fold in both cases. A gastrin-releasing peptide antagonist inhibited the post-prandial rise in plasma gastrin in control rats, but had no effect in antrally denervated rats. 4. In fasted, antrally denervated rats with a gastric fistula, basal gastric acid secretion was depressed 3-fold, and plasma gastrin concentrations were similar to controls. 5. Distension of the stomach with peptone via a barostat attached to the gastric cannula (5 cm H2O, 30 min), produced 3-fold increases in plasma gastrin in both control and denervated rats. However, distension with a non-nutrient solution at pH 6.0 had no effect in controls, but increased gastrin to a similar extent to peptone in denervated rats; distension with 50 mM HCl had no effect in either control or denervated rats. 6. Somatostatin and gastrin mRNA abundances in the antrum were depressed by about 35% by antral denervation, but somatostatin mRNA in the corpus was unchanged; GAPDH mRNA abundance was unaffected by antral denervation. 7. The data suggest that luminal nutrient releases gastrin in the rat, in vivo, via activation of antral neurons secreting gastrin-releasing peptide, and that the antral innervation normally inhibits G-cell responses to non-nutrient distension of the stomach. After antral denervation, gastric distension with a non-nutrient solution is an adequate stimulus for gastrin release.

Effect of somatostatin immunoneutralization on gastric acid and pancreatic enzyme secretion in anesthetized rats

The involvement of somatostatin in urethane-anesthesia-evoked suppression of gastric acid secretion has been described. The present study has examined the role of endogenous somatostatin in diminished pancreatic enzyme secretion during anesthesia, while monitoring acid secretion concurrently. Rats were anesthetized with either urethane or sodium pentobarbital. An indwelling catheter was placed into the right jugular vein. The esophagus and the pylorus were ligated, and the stomach was perfused with saline. The common bile duct was ligated at the hepatic hilum, and cannulated at the duodenal end of the duct for collecting pure pancreatic juice. Purified somatostatin monoclonal antibody (CURE.S6) or control antibody (keyhole limpet hemacyanin, KLH) was injected iv in increasing doses (0.05; 0.15; 0.5; and 1.5 mg) every 30 min ( n = 6). Gastric acid and pancreatic amylase secretions were measured. The effect of the antibodies on CCK-8-stimulated (0.25–2.50 nmol/kg/h) pancreatic amylase secretion was also tested. During urethane anesthesia somatostatin antibody induced a dose-dependent increase in acid output, while control antibody did not change it. Basal pancreatic amylase secretion was not affected by either somatostatin or by control antibody. Pancreatic secretory responses to high but not to low doses CCK-8 were found to be significantly increased following immunoneutralization of somatostatin. In sodium pentobarbital-anesthetized rats somatostatin antibody stimulated basal acid secretion but did not affect basal pancreatic amylase secretion. Our data indicate that in anesthetized rats endogenous somatostatin mediates suppression of basal gastric acid secretion but not that of basal pancreatic amylase secretion, and this action does not depend on the type of anesthesia. Furthermore, endogenous somatostatin may play a physiological role in modulating stimulated pancreatic enzyme secretion in this species.

Substance P in the dorsal vagal complex inhibits medullary TRH-induced gastric acid secretion in rats.

Neurons that contain substance P (SP) and thyrotropin-releasing hormone (TRH) in medullary midline raphe nuclei project to the dorsal vagal complex (DVC). The modulatory role of SP on basal gastric acid secretion (GAS) and TRH on DVC-induced stimulation of GAS was studied in urethan-anesthetized rats. The stable SP agonist, DiMe-C7 ([pGlu5, MePhe8, MeGly9]SP5-11, 50 and 100 pmol), injected unilaterally into the DVC reduced the GAS response (47 +/- 12 mumol/60 min) to coinjected TRH analog, RX 77368 (25 pmol), by 53% and 85%, respectively, whereas DiMe-C7 (100 pmol) alone had no effect on basal and pentagastrin-stimulated GAS. DiMe-C7 (100 pmol/site) inhibited the GAS response to kainic acid injected into the raphe pallidus (Rpa) when it was injected bilaterally into the DVC but not the hypoglossal nuclei. The SP nourokinin-1-receptor antagonist, CP-96,345, injected bilaterally into the DVC (1 nmol/ site) increased basal GAS (33 +/- 8 mumol/90 min) and potentiated the GAS response to kainic acid injected into the Rpa by 40%. These results suggest that SP acts on neurokinin-1 receptors in the DVC to reduce medullary TRH-induced stimulation of GAS in rats.

Gastric ECL-cell hyperplasia produces enhanced basal and stimulated gastric acid output but not gastric erosion formation in the rat

1. 1. The purpose of this study was to examine the change in gastric acid output and gastric erosion formation produced by inducing gastric enterochromaffinlike (ECL) cell hyperplasia in female rats. 2. 2. Rats were treated with vehicle or ranitidine (1,200 μmol/kg/day×4 wks) administered via SC Alzet minipumps. Experiments were performed 24 hours after removing the minipump, when the inhibitory effect of ranitidine on gastric acid secretion had been lost. 3. 3. Basal gastric acid secretion was 7-fold higher in chronic ranitidine animals than in sham control. 4. 4. Both total and net gastric acid secretions stimulated by carbachol/pentagastrin infusion or histamine injection were significantly higher in chronic ranitidine animals than in controls. 5. 5. By contrast, intracisternal injection of the chemical vagal stimulant RX77368 (100 ng) resulted in no net increase in acid output of the recovered ranitidine-pretreated group. 6. 6. No significant changes in gastric erosions produced experimentally by cold exposure plus restraint or indomethacin pretreatment were noted in recovered chronic ranitidine animals compared to sham controls. 7. 7. These findings suggest that achlorhydria-induced ECL cell hyperplasia augments both basal and stimulated gastric acid secretory function. The histamine results implicate an enhanced parietal cell mass, upregulation of H 2 receptors, and/or second-messenger events at the parietal cell as the mechanism for the enhanced gastric secretory response.