Gastric Acid Secretion In Dogs Research Articles

Eosinophils in the lamina propria of the rat stomach bind a biotinylated gastrin analog

Gastrin is a small peptide known to function as both a stimulator of gastric acid secretion and as a growth factor. Eosinophils are white blood cells which form a part of the body's defenses against invading microorganisms. Douglas et al. have reported staining, using a biotinylated gastrin analog (biotinyl-L-Trp-L-Leu-ß-Ala), of unidentified cells in the lamina propria of the rat fundic stomach. This gastrin analog has been shown to suppress gastric acid secretion in dogs. We here identify the cells binding this analog as eosinophils. We have perfused and fixed small pieces of fundic stomach with 2% paraformaldehyde/0.5% glutaraldehyde in 0.1 M phosphate buffer, pH 7.4 for 1 hour. The tissue was then embedded in 5% agar and 50 ¼m sections were cut on a vibratome. Sections were incubated for 30 min. with 1.63 x 10-6 M biotinylated gastrin analog, rinsed, and exposed to an avidin-biotin-glucose oxidase complex (ABC-GO; Vector).

Role of cholecystokinin in the inhibition of gastric acid secretion in dogs.

1. This study was designed to determine the involvement of cholecystokinin (CCK) in the gastric secretory responses to exogenous and endogenous secretagogues in conscious dogs with chronic gastric fistulae (GF), pancreatic fistulae (PF) and Heidenhain pouches (HP). 2. A meal of meat or intragastric application of peptone (300 mosM) increased secretion of HCl from the HP and pancreatic secretion of protein and plasma levels of gastrin, CCK and somatostatin. 3. The CCK receptor antagonist L-364,718 caused a further increase in the postprandial HCl secretion from the HP and in the plasma levels of gastrin and CCK but pancreatic output of protein and plasma concentration of somatostatin were significantly reduced. 4. Addition to intragastric peptone of 10% oleate or its acidification to pH 3.0 profoundly inhibited the HP secretion and gastrin release but significantly increased pancreatic secretion of protein and plasma levels of CCK and somatostatin. Administration of L-364,718 reversed the fall in the HP secretion and plasma gastrin while significantly attenuating pancreatic protein secretion and plasma somatostatin levels. 5. Intragastric administration of hyperosmolar (1200 mosM) peptone also inhibited HCl secretion from the HP but this was not affected by L-364,718. 6. Exogenous CCK and bombesin (but not gastrin) caused a small increase in HCl secretion from the HP and marked stimulation of pancreatic protein secretion accompanied by a significant rise in plasma levels of gastrin, CCK and somatostatin. Administration of L-364,718 resulted in a further increase in the HCl response of HP to bombesin and in plasma levels of gastrin and CCK but caused a reduction in plasma levels of somatostatin. 7. We conclude that CCK released by a meal of meat, intragastric peptone, oleate or acidified peptone and intravenous bombesin exerts tonic inhibitory influences on gastric acid secretion and that this effect is mediated, at least in part, by somatostatin.

Effect of somatostatin analogs on gastric acid secretion in dogs and rats

The effects of several superactive analogs of somatostatin on gastric acid response to various exogenous and endogenous stimulants were investigated in conscious dogs and rats with gastric fistulae (GF). The inhibition was compared to that induced by somatostatin-14 (S-S-14) at two dose levels. Several octapeptide analogs of somatostatin including D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160) and D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 (RC-121), which were superactive in tests on suppression of GH levels, were 4-5 times more potent than S-S-14 in inhibiting desglugastrin-stimulated gastric acid secretion in GF dogs. The analog RC-160 also reduced the rise in serum gastrin levels and gastric acid secretion induced by sham feeding (SF) in dogs with gastric and esophageal fistulae (EF), but did not decrease food consumption. Gastric acid secretion induced by histamine (80 micrograms/kg/h) in dogs was not affected by 1-5 micrograms/kg/h of analog RC-121 or by 5 micrograms/kg/h of S-S-14. Analogs RC-160, RC-121, and RC-98-I (D-Trp-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2) and others also powerfully inhibited desglugastrin-induced potent as S-S-14 in dogs but its activity was higher in rats. The results indicate that octapeptide analogs which are superactive in GH-inhibition tests are also more potent than S-S-14 in suppressing gastric acid secretion. These findings may be of clinical value.

Canine gastric muscarinic receptors up-regulate after vagotomy

Postvagotomy (PV) gastroparesis is an infrequent but troublesome problem. To test the hypothesis that the rarity of the PV syndrome is due to compensatory up-regulation of muscarinic cholinergic receptors (mAChR), we measured changes in stomach mAChR and gastric acid secretion in dogs before and three weeks after truncal vagotomy. Maximum acid output dropped significantly one week PV and then partially recovered by three weeks PV. mAChR density changed in parallel and was significantly increased in body mucosa, body muscle, and antrum mucosa. In the body, changes in mAChR in mucosa correlated positively with changes in muscle, suggesting that mAChR binding in pinch biopsies of gastric mucosa might become useful in evaluating patients for postvagotomy syndrome. PV up-regulation of mAChR in the mucosa of the canine gastric body might explain PV recovery of gastric acid secretion.

The action of a β‐adrenoreceptor agonist on gastric acid secretion in dogs

1. In conscious dogs with gastric fistulae and Heidenhain pouches, isoprenaline (0.75 microgram kg-1 h-1) brought about an increase in methacholine stimulated gastric acid and pepsin secretion from the innervated mucosa. 2. The increase in acid consisted for the most part of the replacement of the usual post-peak fade by a sustained plateau and of the replacement of the usual wait for the spontaneous peak by immediate stimulation of secretion.

Influence of Endogenous Prostaglandins on Secretin-Mediated Inhibition of Gastric Acid Secretion in Dogs

The influence of endogenous prostaglandins on secretin-mediated inhibition of gastric acid secretion was examined in 6 mongrel dogs with Thomas gastric and Herrera pancreatic cannulas. The dogs were given intravenous pentagastrin (1 μg/kg · h) during the 180-min experiment, and graded doses of secretin (0.3–1.5 μ/kg · h) (1–5 CU/kg · h) were infused intravenously between 60 and 120 min. In alternate, otherwise identical experiments, a prostaglandin synthesis inhibitor, either indomethacin or meclofenamate, was also administered throughout the experiment. Increasing doses of secretin led to increasing inhibition of gastric acid output with the maximum inhibition at 1 μg/kg · h (3.3 CU/kg · h) of secretin. Both indomethacin and meclofenamate abolished the inhibitory effects of secretin on gastric acid secretion. The inhibitors of prostaglandin generation had no effect on the serotonin system. We concluded that secretin mediates its inhibitory action on gastric acid secretion, at least in part, through endogenous prostaglandins.

Immunoreactive gastric inhibitory polypeptide.

IN 1906 extracts of mucosa from the upper small intestine from pigs were tested as a treatment of diabetes in the hope that “the internal secretion of the pancreas might be stimulated and initiated by the substance of the nature of a hormone yielded by the duodenal mucous membrane” (1). La Barre (2) introduced the name incretin for an unidentified substance that was thought to exert this effect. With the advent of insulin RIAs in the early 1960s (3), it was shown that insulin levels in the blood after ingestion of glucose were elevated out of proportion to the concentration of blood glucose when compared with the response to glucose given iv (4, 5). It was suggested that the potentiation of insulin secretion after oral glucose was mediated by a humoral substance which was released from the gut during glucose absorption and which stimulated insulin secretion (4, 5). Some years later a polypeptide was found (6, 7), which, due to its inhibitory effect on gastric acid secretion in dogs (8), was named gastric ...

Effects of omeprazole and ranitidine on gastric acid secretion, blood gastrin levels and [3H]-thymidine incorporation in the oxyntic mucosa from dogs and rats.

Dogs provided with a gastric fistula were treated orally for 1 week either with the H+, K+-ATPase inhibitor omeprazole, 80 mumol/kg once daily, or with the histamine H2 receptor antagonist ranitidine, 85-175 mumol/kg every 8 h. Acid secretion, serum gastrin levels and [3H]-thymidine incorporation in the corpus mucosa were determined before, during and after the treatment period. In order to examine differences between species, plasma gastrin levels and [3H]-thymidine incorporation in the oxyntic mucosa were also determined in female rats treated up to 1 week with omeprazole, 400 mumol/kg orally once daily. Histamine-stimulated gastric acid secretion in dogs treated with omeprazole or ranitidine was almost completely inhibited during the whole treatment period. As a consequence of that, the meal-stimulated gastrin levels were increased (7-fold) during treatment by both compounds. [3H]-thymidine incorporation in the dog corpus mucosa was increased approximately 4 times on day 5 both with omeprazole and ranitidine. After the treatment was stopped, gastric acid secretion, serum levels of gastrin and the rate of [3H]-thymidine incorporation were back to control level in both groups within 11 days. In the rats, the plasma gastrin levels increased 10-fold and the rate of [3H]-thymidine incorporation in the corpus mucosa increased 3-fold during treatment with omeprazole. In conclusion, a pronounced suppression of gastric acid secretion over the day with antisecretagogues results in hypergastrinemia in both dogs and rats. As a consequence of the trophic effect of gastrin, the incorporation of [3H]-thymidine in the oxyntic mucosa is increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of gastric acid secretion in dogs by detomidine.

Inhibition of gastric acid secretion in dogs by detomidine.

Anterior gastric stapling combined with posterior truncal vagotomy: an experimental technique for gastric acid reduction.

An operative technique using a mechanical stapling device has been developed to simplify proximal gastric vagotomy. A series of gastric fistula dogs underwent posterior truncal vagotomy and anterior lesser curvature stapling. The basal and pentagastrin-stimulated acid secretion was measured before surgery and 2 weeks and 3 and 9 months after surgery. During the whole period, no change in body weight was noticed. Gastric acid secretion in dogs remained low and stable during the first year after the procedure.

Alpha chain unsaturated derivatives of misoprostol

Misoprostol, a 15-deoxy-16-hydroxy-16-methyl analog of PGE 1, is an effective agent for the treatment of peptic ulcer disease. Efforts to impede metabolic degradation of the alpha chain of misoprostol led to the discovery of a second clinical candidate in this series. Enisoprost, a Δ 4Z derivative of misoprostol, is more potent as a gastric antisecretory agent and longer acting than misoprostol. These findings prompted further work to determine the effects that two double bonds in the alpha chain might have on the activity profile of misoprostol. The most promising structure in this series was a 1:1 mixture of 3E, 5z and 3z, 5z dienes which was about three times more potent than misoprostol in inhibiting gastric secretion in dogs, while the separation of the diarrheogenic effect was significantly improved. Chromatographic separation of the mixture was very difficult, but small amounts of each isomer were obtained by HPLC, and preliminary antisecretory studies indicated that most of the activity resided in the 3E, 5Z isomer. A stereospecific synthesis of the 3E, 5z isomer was carried out to provide sufficient quantities for complete pharmacological assessment. The 3E, 5z diene was about three times more potent than misoprostol in inhibiting gastric acid secretion in dogs and also in producing diarrhea in rats.

Inhibition of gastric acid secretion by brain peptides in the dog: Role of the autonomic nervous system and gastrin

We have studied the effects of 30 peptides administered intracerebroventricularly on basal and pentagastrin-stimulated (8 μg/kg s.c.) gastric acid secretion in conscious dogs. None of the peptides significantly increased basal gastric acid secretion. Twelve peptides (2 nmol/kg) significantly (p < 0.01) decreased the pentagastrin-stimulated 2-h acid output (percentage inhibition in parentheses): human calcitonin (CT) (36%), neurotensin (NT) (52%), rat corticotropin-releasing factor (CRF) (59%), human calcitonin gene-related peptide (CGRP) (59%), ovine CRF (66%), β-endorphin (β-End) (80%), urotensin-I (81%), rat CT (81%), porcine gastrin-releasing peptide (GRP) (83%), sauvagine (Svg) (85%), rat CGRP (87%), and bombesin (Bom) (95%). Blockade of the autonomic nervous system with chlorisondamine abolished the gastric inhibitory action induced by CRF, β-End, CT, and NT, but not by CGRP and Bom (1 nmol/kg each). Corticotropin-releasing factor, βEnd, CT, NT, CGRP, and Bom significantly inhibited gastric acid secretion stimulated by an intragastric 8% peptone meal for 2 h. None of these six peptides significantly altered plasma gastrin concentrations in response to the peptone meal as compared with control experiments. A rise of plasma concentrations of gastrin, CT, CRF, and CGRP could not be detected by radioimmunoassay in animals after intracerebroventricular administration of these four peptides. The results of this study indicate that CT, CGRP, NT, β-End, and peptides of the CRF and Bom families act within the brain to inhibit pentagastrinand meal-stimulated gastric acid secretion in conscious dogs. None of the 30 peptides administered intracerebroventricularly increased basal gastric acid secretion in the dog. Inhibition of gastric acid secretion induced by CRF, β-End, CT, and NT, but not by CGRP and Bom is mediated by the autonomic nervous system. Gastrin does not appear to play a role in gastric acid inhibition induced by the six brain peptides studied.

Inhibitory effects of beta-adrenergic agonists on gastric acid secretion in dogs.

We evaluated the effect of two beta-adrenergic agonists, isoproterenol (nonselective agonist) and terbutaline (selective beta 2-agonist), on gastric acid secretion stimulated by intravenous pentagastrin, bethanechol, or histamine in dogs with gastric fistulas. Intravenous infusion of isoproterenol or terbutaline inhibited pentagastrin-stimulated acid secretion to a significantly greater extent than they inhibited bethanechol- or histamine-stimulated acid secretion. For example, isoproterenol (12 micrograms X kg-1 X h-1) reduced mean pentagastrin-, bethanechol-, and histamine-stimulated acid output by 86, 63, and 14%, respectively. Percent inhibition of acid secretion with terbutaline (30 micrograms X kg-1 X h-1) averaged 60, 17, and 24% for pentagastrin, bethanechol, and histamine, respectively. Terbutaline also inhibited pentagastrin-stimulated acid secretion from vagally denervated fundic pouches in a dose-related manner. Plasma somatostatin-like immunoreactivity was significantly higher during infusion of terbutaline plus pentagastrin than during infusion of pentagastrin alone. However, an intravenous infusion of 0.3 microgram X kg-1 X h-1 somatostatin-14 had no effect on pentagastrin-stimulated acid secretion from the gastric fistula, even though this infusion increased plasma somatostatin-like immunoreactivity to the same extent as terbutaline plus pentagastrin infusion. Thus the amount of somatostatin released during terbutaline infusion was not sufficient to explain the inhibition of pentagastrin-stimulated acid secretion observed.

Influence of the stimulation state of the parietal cells on the inhibitory effect of omeprazole on gastric acid secretion in dogs

The relationship between the stimulation state of the parietal cells and the gastric antisecretory properties of omeprazole has been evaluated in dogs with gastric fistulas maximally stimulated with pentagastrin. Intravenous administration of omeprazole (5 μmol/kg) 4 h before the start of stimulation with pentagastrin inhibited the acid response by 71%. This inhibition was prevented when omeprazole was given during an infusion of somatostatin at a dose that completely inhibited acid secretion. When given 18 h before stimulation with pentagastrin, omeprazole inhibited the acid response by 50%. This inhibitory effect was almost completely suppressed when omeprazole was administered during an infusion of somatostatin or after the administration of cimetidine, and was increased when omeprazole was given during an infusion of pentagastrin. These data indicate that the inhibitory effect of omeprazole given by rapid intravenous injection is related to the activity of the parietal cells at the moment of administration of the drug. They suggest that, in the intact animal as well as in the isolated gastric glands, the uptake of omeprazole by the parietal cells is related to the stimulation state of these cells.

Structure and Function of the Dog Gastric Mucosa During and After a 1–Year Treatment with Omeprazole. II. Effects on Gastric Acid Secretion and Blood Levels of Gastric Hormones

Omeprazole is known to be a potent inhibitor of gastric acid secretion in dogs in acute experiments (1). The aim of the present study was to evaluate the effects of long-term treatment with omeprazole on acid secretion and blood levels of gastrointestinal hormones, and to correlate these functional parameters with possible structural changes. The parameters were studied before, during, and after a 1–year period of treatment with two dose levels of omeprazole.

Calcitonin gene-related peptide-induced selective inhibition of gastric acid secretion in dogs.

Calcitonin gene-related peptide (CGRP) is a 37-residue peptide recently characterized in the brain and found in high concentrations in the gut, particularly in the stomach and pancreas. The effects of intravenous infusion of human and rat CGRP (260 pmol . kg-1 . h-1) on gastric secretion and emptying and pancreatic exocrine secretion were studied in conscious dogs. CGRP inhibited by 60-75% gastric acid secretion stimulated by a meal, sham feeding, or step doses of bombesin but did not modify acid response to step doses of histamine or bethanechol. The inhibitory effect of CGRP is not due to blockage of postprandial or bombesin-stimulated gastrin release. CGRP did not influence basal or meal-stimulated pancreatic exocrine secretion or the rate of gastric emptying of a saline meal. These results indicate that CGRP is a potent and selective inhibitor of gastrin-mediated acid secretion in dogs and, under these conditions, did not alter other gastrointestinal functions such as gastric emptying or pancreatic exocrine secretion.

Cerebroventricular bombesin inhibits gastric acid secretion in dogs

Bolus injections of bombesin into a lateral cerebral ventricle of conscious beagle dogs inhibited pentagastrin-stimulated gastric acid secretion from both the innervated stomach (gastric fistula) and the vagally denervated Heidenhain pouch in a dose-dependent manner. Bombesin (300 ng/kg), injected into the lateral ventricle, inhibited acid secretion from the gastric fistula and Heidenhain pouch by 66% ± 5% and 93% ± 4%, respectively. Central administration of bombesin also suppressed acid secretion in response to a meal by 52% ± 15%; postprandial gastrin response was not affected. By contrast, intravenous infusion of bombesin stimulated both gastrin release and acid secretion without affecting the acid response to a submaximal dose of pentagastrin. The opposing effects of central and peripheral bombesin on acid secretion indicate that the gastric response to intracerebrally administered bombesin is mediated by the central nervous system. Furthermore, the inhibitory action of bombesin injected into the lateral cerebral ventricle is independent of the vagus and is not mediated by the inhibition of gastrin release. These observations demonstrate that bombesinlike peptides may act centrally to alter gastric secretion.

Effects of antibodies to gastric inhibitory peptide on gastric acid secretion and gastrin release in the dog

Previous studies have questioned the physiological role of gastric inhibitory peptide in inhibiting gastric acid secretion. The present study was designed to examine and compare peptone meal-stimulated gastric acid secretion in dogs after intravenous infusion of rabbit serum containing antibodies to gastric inhibitory peptide or normal rabbit serum (as control). Five dogs were prepared with gastric fistulas. Basal acid output was collected for 90 min through the gastric fistula. After 30 min of basal acid output collection, either rabbit serum containing antibodies to gastric inhibitory peptide or normal control rabbit serum (0.1 ml/kg) was infused intravenously over 1 min. After the basal acid output collection, a 10% peptone meal was infused into the stomach. Gastric acid output was measured by intragastric titration (pH 5.0) for 60 min. Peripheral venous plasma was collected for measurement of gastrin and gastric inhibitory peptide and for binding of endogenous plasma gastric inhibitory peptide by administered antibodies to gastric inhibitory peptide before and at 2, 5, 10, 15, 30, 60, 90, and 120 min after the meal. After intravenous administration of antibodies to gastric inhibitory peptide, 98% ± 3% (SEM) of endogenous plasma gastric inhibitory peptide was bound by administered antibodies to gastric inhibitory peptide. No binding of endogenous plasma gastric inhibitory peptide was detected after infusion of normal rabbit serum. In dogs receiving intravenous antibodies to gastric inhibitory peptide, both peptone-stimulated gastric acid output and integrated gastrin release responses were increased when compared with dogs receiving normal rabbit serum. With infusion of antibodies to gastric inhibitory peptide, there was a high degree of correlation between the increase in gastric acid output and the increase in integrated gastrin response (r = 0.900, p < 0.04) that followed the peptone meal. This study, using antibodies to bind endogenous gastric inhibitory peptide, demonstrates the capacity of circulating gastric inhibitory peptide to inhibit meal-stimulated gastric acid secretion. Furthermore, these results support the conclusion that this enterogastrone effect of gastric inhibitory peptide is due, at least in part, to inhibition of gastrin release.

Effect of Dopamine on Bethanechol-Stimulated Gastric Mucosal Blood Flow and Gastric Acid Secretion in Dogs with Gastric Fistula

The aim of the present study was to investigate the effect of Dopamine on bethanechol-stimulated gastric acid secretion and mucosal blood flow. dopamine was used alone and in conjunction with selective blockade of the alpha, beta, and dopaminergic receptors. An increasing and dose-dependent stimulation of gastric acid secretion was found for dopamine at 1, 5, and 10 micrograms/kg/min. A significant inhibition of gastric acid secretion was found with the highest dose of dopamine (40 micrograms/kg/min). the stimulatory effect seems to be mediated by more than one receptor, whereas the inhibition by high dopamine doses could be explained by a beta 1 stimulation. Dopamine (10 micrograms/kg/min) was found to increase the bethanechol-stimulated gastric mucosal blood flow. Phentolamine (alpha blackade) increased this dopamine-elevated blood flow further, with a significant increase in the ratio between blood flow and acid secretion, indicating a primary action of the alpha receptors on blood flow. Bethanechol stimulated the gastric acid secretion and blood flow in a parallel manner. It is concluded that alpha-receptor stimulation is the predominant directly acting factor in the regulation of gastric mucosal blood flow, whereas stimulation of beta, muscarinic, and 'gastrinergic' receptors mainly occurs indirectly via changes in parietal cell function. The main effect of dopamine seems to be on gastric motility, whereas the effect on gastric acid secretion is of minor importance.

Effect of a beta2-sympathomimetic on urecholine-stimulated gastric acid secretion in dogs.

The effect of a selective beta2-adrenoceptor agonist on urecholine-stimulated gastric acid secretion was studied in conscious gastric fistula dogs. A dose-dependent inhibition was found, most pronounced for the highest doses of urecholine. The inhibition was primarily on volume, whereas the acidity showed a decreasing tendency only. The pulse rate was increased by the beta2-agonist and by urecholine in high doses. Propranolol prevented both the inhibition of acid secretion and the increase in pulse rate. Practolol had no effect on the inhibition of acid secretion and the increase in pulse rate. Practolol had no effect on the inhibition of acid secretion but prevented the increase in pulse rate. Dose-response experiments with five doses of urecholine and two doses of the beta2-agonist showed a decrease in maximal response, and transformation of the curve suggested an unchanged D50. It is concluded that the beta2-agonist inhibits urecholine-stimulated acid secretion in the dog to the same degree as pentagastrin-induced acid secretion, and much stronger than found for histamine-induced acid secretion in earlier experiments. The inhibition seems to follow a noncompetitive kinetic, and beta2-receptors are probable involved.