Increase In Gastric Acid Output Research Articles

Low gastric acid and high plasma gastrin in high-anxiety Wistar Kyoto rats

Objective. Wistar Kyoto (WKY) rats are more susceptible to stress-evoked ulcerations than Sprague-Dawley (SPD) rats. We have already demonstrated that gastrin cells are more active and ghrelin cells less active in WKY rats than in SPD rats. The purpose of this study was to compare endocrine cell activity and gastric acid output in WKY and SPD rats. Material and methods. Gastric acid output was determined in conscious rats with gastric fistula. Plasma gastrin and ghrelin levels were measured after an overnight fast. Acid secretagogues (gastrin, histamine and carbachol) were given by continuous subcutaneous infusion. Results. The volume of gastric juice, and the acidity and acid output were all significantly lower (p <0.05) in fasted WKY rats than in fasted SPD rats. Gastrin evoked a 4-fold (p <0.01) and 3-fold (p <0.05) increase in gastric acid output in SPD rats and WKY rats, respectively. Histamine raised the acid output 1.6-fold in SPD rats (p=0.06) and 3-fold in WKY rats (p <0.05), while carbachol failed to affect the acid output (weak increase, p >0.05). Fasting plasma ghrelin levels were 2-fold higher in SPD rats than in WKY rats (p <0.01) while fasting gastrin levels were 10-fold higher in WKY rats than in SPD rats (p <0.05). Neither the parietal-cell density nor the oxyntic mucosal thickness differed between the two strains. Conclusions. The results of the present study suggest that a high gastrin cell activity in WKY rats is secondary to a low gastric acidity. Whether the high gastrin cell activity is linked to susceptibility to stress ulcer in WKY rats warrants further investigation.

Acute Effect of Gamma Irradiation on Gastric Acid Secretion and Gastric Mucosal Integrity in the Rat

The effect of 3- or 6-Gray (Gy) whole-body gamma irradiation on basal and stimulated gastric acid secretion was studied in pylorus-ligated rats. Different groups of rats were irradiated with a single 3- or 6-Gy fraction and examined 7 days after irradiation. Exposure to 3-Gy fraction led to marked increase in basal (nonstimulated) gastric acid output in the 4-h pylorus-ligated rat (47.5% compared with unirradiated controls). After exposure to 6 Gy, only 18.2% increase in gastric acid output was noted compared with unirradiated controls. Under pentagastrin or histamine stimulation, gastric acid secretion in those irradiated with 3- or 6-Gy fraction was markedly reduced compared to that of unirradiated controls. Exposure to 3- or 6-Gy gamma irradiation intensified the degree of gastric mucosal injury evoked by indomethacin or 50% ethanol in a dose-dependent manner. It is concluded that in the pylorus-ligated rat model, lower doses of gamma irradiation increase basal gastric acid secretion and impair the gastric mucosal barrier with marked increase in its permeability to H+ following stimulation of acid secretion or exposure to barrier breakers. Exposure to irradiation is likely to result in failure of the parietal cell to respond to direct stimulation with histamine or pentagastrin.

Vagal-sparing esophagectomy: a more physiologic alternative.

To evaluate the function of the vagal nerves and the gastric reservoir after vagal-sparing esophagectomy. Esophagectomy as currently performed includes division of the vagal nerves and surgical alteration of the stomach, with attendant postoperative dumping, diarrhea, reduced meal capacity, and weight loss. Vagal-sparing esophagectomy has been introduced as a technique for removal of the esophagus while preserving the vagal nerves and gastric reservoir. The procedure is touted as having a low morbidity and is applicable to patients with end-stage benign or early malignant disease. A random sample of 15 patients at a median of 20 months after a vagal-sparing esophagectomy was compared to 23 asymptomatic normal subjects; 10 randomly selected patients, 29 months after esophagogastrectomy with colon interposition; and 10 randomly selected patients, 47 months after standard esophagectomy with gastric pull-up. Gastric mucosal acidification was tested with Congo red staining. Vagal secretory function was measured by gastric acid output and pancreatic polypeptide response to sham feeding. Vagal motor function was assessed by a technetium gastric emptying scan and a questionnaire to evaluate dumping and diarrhea. Gastric reservoir function was evaluated by measuring meal capacity and postoperative changes in body mass index. Vagal-sparing esophagectomy preserved the function of the vagi, as evident by an increase in gastric acid output, a rise in serum pancreatic polypeptide following sham feeding, and preservation of normal postoperative gastric emptying in 70% of the patients. After vagal-sparing esophagectomy, patients were free of dumping and diarrhea and were analogous to normal subjects in meal capacity but had a slight reduction in the speed of eating. Vagal-sparing esophagectomy preserves gastric secretory, motor, and reservoir function. Postoperatively, patients have normal alimentation, bowel regulation, and no weight loss. It is an ideal procedure for patients with end-stage benign disease, Barrett's esophagus with high-grade dysplasia, or esophageal carcinoma limited to the lamina propria.

Adenosine protects against indomethacin-induced gastric damage in rats.

This study examines the putative gastroprotective effect of adenosine on indomethacin-induced gastric lesions and the possible mechanisms involved. After 24 hr of starvation, the rats were treated either with indomethacin (Indo; 25 mg/kg, subcutaneously) alone or adenosine + Indo (Ado; 7.5 mg/kg, subcutaneously, three times a day), or the vehicle (5% NaHCO3, subcutaneously). The length of hemorrhagic lesions in the stomachs was expressed as the lesion index. The tissue-associated myeloperoxidase (MPO) activity and protein oxidation were measured in gastric tissue samples. Formation of reactive oxygen species in gastric tissues was measured by using luminol- and lucigenin-enhanced chemiluminescence. In other groups of rats, gastric mucosal permeability and gastric acid output were performed following the same treatment regimens. The gastric mucosal permeability was measured by determination of [51Cr]EDTA clearance in a perfused stomach preparation and gastric acid secretion studies were performed following pylorus ligation. The lesion index, the increase in lucigenin-enhanced chemiluminescence, and the increase in gastric mucosal permeability in Indo-treated rats were reversed by Ado pretreatment. Ado pretreatment also prevented the increase in gastric acid output and gastric volume in Indo-treated rats. Thus, these findings implicate that exogenous adenosine has a protective role on indomethacin-induced gastric lesions, possibly by inhibiting gastric hyperacidity and reactive oxygen formation and by preventing disruption of the mucosal integrity.

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.

Effects of intracerebral injections of VIP on jejunal alanine absorption and gastric acid secretion in rats

The effects of intracerebral injections of VIP on jejunal alanine absorption and gastric acid secretion, and its association with vagal outflow were examined in Sprague-Dawley rats. Intracerebroventricular injection of VIP (2 ng) decreased significantly ( P<0.05) alanine absorption across the jejunum, whereas similar injections in vagotomized rats did not show further decrease in absorption beyond that noticed by vagotomy only. Moreover, VIP injected in the Nucleus Tractus Solitarius-Dorsal Motor Nucleus (NTS-DMN) complex (1 ng) produced also a significant inhibition of Ala absorption which was reduced but remained significant ( P<0.05) after vagotomy. Water movement was not affected by VIP injection in the lateral ventricle, while VIP injections in the NTS-DMN inhibited significantly ( P<0.05) jejunal water absorption by 10–12%. Vagotomy increased water absorption by 15–20% above control ( P<0.05) which was not altered by injecting VIP in the NTS-DMN complex. On the other hand, VIP injection in the NTS-DMN produced a 25.7% increase in gastric acid output in the first hour of the experiment followed by a non-significant decrease ( P>0.05) in the second hour. Same injections done in vagotomized animals produced similar effects to those elicited by vagotomy only. It can be suggested that NTS-DMN complex could be a site of action of VIP since injection of VIP in it produced a more pronounced inhibitory effect on water and Ala absorption than that produced by VIP injection in the LV. These effects were reduced or abolished by vagotomy. It is concluded that when VIP is injected in the brain and in particular in the NTS-DMN complex, it can modulate intestinal absorption and gastric secretion, and this modulation is mainly exerted through the vagal outflow.

Inhibition of bombesin-stimulated acid secretion by immunoneutralization of gastrin in dogs

Bombesin-like peptides stimulate gastrin release and gastric acid secretion. The increase in gastric acid output is thought to be secondary to gastrin release. A monoclonal antibody (MAb) directed specifically to gastrin (MAb 28.2) was used to study the role of circulating gastrin in the regulation of bombesin-stimulated acid secretion in dogs. Seven conscious, fasted dogs with gastric fistulas received intravenous bombesin infusions in fourfold increasing doses from 200 to 3,200 pmol.kg-1.h-1. Each dose was given for 45 min. On separate days, dogs were pretreated with an intravenous infusion of 7 mg of MAb 28.2 or vehicle (0.1% canine serum albumin). Samples of gastric effluent were collected by gravity drainage through the gastric fistula, and acid output was measured by titration of gastric effluent to pH 7.0, using 0.2 N NaOH. Plasma gastrin concentrations were determined by radioimmunoassay. Bombesin infusion produced dose-dependent increases in plasma gastrin concentrations and gastric acid output. Administration of gastrin MAb 28.2 abolished bombesin-stimulated gastric acid output. Immunoneutralization of circulating gastrin in vivo using a gastrin monoclonal antibody in dogs indicates that the acid stimulatory response to bombesin is mediated by gastrin.

Effect of Elevated Intracranial Pressure on Gastric Acid Secretion, Mucosal Blood Flow and Mucosal Injury

Head injury is frequently accompanied by an increase in intracranial pressure and gastric lesion formation. We used a model of controlled intracranial pressure to investigate the effect of elevated intracranial pressure on gastric acid secretion and mucosal blood flow and on the susceptibility of the gastric mucosa to lesion formation. With increasing intracranial pressure, there was a corresponding increase in gastric acid output but no significant change in gastric mucosal blood flow. This imbalance between acid secretion and blood flow could be a factor in the pathogenesis of the gastric lesions seen with head injury. Susceptibility to gastric mucosal injury then was studied in a model that is independent of the acid secretory state-exogenous intragastric HCl plus ethanol. Elevated intracranial pressure did render the gastric mucosa more susceptible to injury in this model, but there was no impairment of the increased gastric mucosal blood flow response to the increased acid back-diffusion. In this situation, factors other than altered overall blood flow appear to be responsible for the increased lesion formation.

Effect of duodenal switch procedure on gastric acid production, intragastric pH, gastric emptying, and gastrointestinal hormones

The duodenal switch operation preserves the pylorus and the proximal 3 to 7 cm of duodenum in continuity with the stomach while diverting pancreaticobiliary secretions. We compared it with the Roux-en-Y without vagotomy or antrectomy in 12 dogs with innervated gastric pouches. Acid secretion was inhibited between tests using ranitidine in the Roux-en-Y group only, but two of the six dogs still developed stomal ulcers and the remainder showed stomal hyperemia. This may be due to a significant increase in gastric acid output after Roux-en-Y, but gastric emptying and plasma gastrin, cholecystokinin, secretin, gastric inhibitory polypeptide, peptide YY, and neurotensin were similar after both procedures. In 12 patients and a further 6 dogs, the duodenal switch caused no significant change in the intragastric pH environment as assessed by intragastric pH monitoring. The duodenal switch is a suitable procedure for pancreaticobiliary diversion.

Effect of elevated intracranial pressure on gastric acid secretion, mucosal blood flow and mucosal injury

Head injury is frequently accompanied by an increase in intracranial pressure and gastric lesion formation. We used a model of controlled intracranial pressure to investigate the effect of elevated intracranial pressure on gastric acid secretion and mucosal blood flow and on the susceptibility of the gastric mucosa to lesion formation. With increasing intracranial pressure, there was a corresponding increase in gastric acid output but no significant change in gastric mucosal blood flow. This imbalance between acid secretion and blood flow could be a factor in the pathogenesis of the gastric lesions seen with head injury. Susceptibility to gastric mucosal injury then was studied in a model that is independent of the acid secretory state--exogenous intragastric HCl plus ethanol. Elevated intracranial pressure did render the gastric mucosa more susceptible to injury in this model, but there was no impairment of the increased gastric mucosal blood flow response to the increased acid back-diffusion. In this situation, factors other than altered overall blood flow appear to be responsible for the increased lesion formation.

Telenzepine, a New M1-Receptor Antagonist, Is a More Potent Inhibitor of Pentagastrin-Stimulated Gastric Acid Output Than Pirenzepine in Dogs

In conscious dogs with a gastric fistula we compared the action of different doses of telenzepine (ranging from 1 to 243 nmol/kg/h) and pirenzepine (ranging from 4.7 to 1170 nmol/kg/h) on gastric acid output in response to pentagastrin (1 to 8 micrograms/kg/h). Pentagastrin caused a dose-dependent increase in gastric acid output. A dose of 27 nmol/kg/h and all subsequent doses of telenzepine and a dose of 130 nmol/kg/h and all higher doses of pirenzepine significantly inhibited (up to 74% of control values) the gastric acid response to pentagastrin. Doses above 27 nmol/kg/h of telenzepine and doses above 130 nmol/kg/h of pirenzepine did not further inhibit the gastric acid output. Only the highest doses of telenzepine (243 nmol/kg/h) and pirenzepine (1170 nmol/kg/h) significantly increased heart rate from 66 +/- 3.1 to 77.1 +/- 3.9 and 72.5 +/- 3.2, respectively (beats/min, chi +/- SEM, n = 6). Differences between both drugs were not found with regard to cardiovascular responses of equipotent doses. We conclude that in conscious dogs with an intact stomach, the new M1-receptor antagonist telenzepine is, on a molar basis, more than 4.7 times more potent than pirenzepine in inhibiting pentagastrin-stimulated gastric acid output. This inhibition occurs at doses that do not increase heart rate, and, therefore, probably cause few systemic effects.

Nervous control of gastric and pancreatic secretory response to 2-deoxy-D-glucose in the dog.

The relative contribution of the vagus and splanchnic nerves as mediators of the action of 2-deoxy-D-glucose (2-DG) on the stomach and the pancreas is largely unknown. In conscious dogs with gastric and pancreatic fistulas, the effect of 2-DG (100 mg kg-1, given as an intravenous bolus) on gastric acid and pancreatic exocrine secretion was tested before and after bilateral truncal vagotomy and after truncal vagotomy plus celiac and superior mesenteric ganglionectomy (i.e. extrinsic denervation of the stomach and the pancreas). In another set of dogs, only ganglionectomy was performed and the same experiments were done as in the first set of dogs. With the extrinsic nerves intact, 2-DG caused a rapid (within 15 min) and prolonged increase in gastric acid output as well as in pancreatic flow rate, bicarbonate and protein output. Truncal vagotomy abolished the gastric acid and pancreatic secretory response to 2-DG; additional ganglionectomy had no further effect. Ganglionectomy alone did not significantly alter 2-DG-stimulated gastric acid output, pancreatic flow rate and bicarbonate output; protein output, however, was significantly diminished by 57%. These results indicate that (a) intravenous 2-DG is a potent stimulant of gastric acid and pancreatic bicarbonate and protein output; (b) the vagus nerves are the major mediators of the gastric and pancreatic secretory response to 2-DG; (c) the sympathetic nerve fibers running through the celiac and superior mesenteric ganglia are probably not involved in the mediation of the 2-DG-induced gastric acid and pancreatic bicarbonate secretion. The diminished protein response to 2-DG after ganglionectomy is probably due to cut vagal fibers running through these ganglia.

Intracerebroventricularly Administered Nicotine Inhibits Vagally Stimulated Gastric Acid Output in Rats by Activating the Central Sympatho-Adrenal Outflow

The effect of intracerebroventricularly (i.c.v.) administered nicotine was investigated in urethane-anesthetized rats. I.c.v., but not intravenously, administered nicotine (300 and 600 nmole/animal) inhibited the increase in gastric acid output induced by electrical stimulation of the vagus nerve. This antisecretory effect of nicotine was abolished by combined pretreatment with adrenalectomy and 6-hydroxydopamine (50 mg/kg, i.v., 3 days before). I.c.v.-administered nicotine also raised the blood levels of catecholamines. These observations suggest that i.c.v. administered nicotine leads to excitation of the central sympathoadrenomedullary outflow and inhibits gastric acid output induced by stimulation of the vagus nerve.

Intracerebroventricularly administered nicotine inhibits vagally stimulated gastric acid output in rats by activating the central sympatho-adrenal outflow.

The effect of intracerebroventricularly (i.c.v.) administered nicotine was investigated in urethane-anesthetized rats. I.c.v., but not intravenously, administered nicotine (300 and 600 nmole/animal) inhibited the increase in gastric acid output induced by electrical stimulation of the vagus nerve. This antisecretory effect of nicotine was abolished by combined pretreatment with adrenalectomy and 6-hydroxydopamine (50 mg/kg, i.v., 3 days before). I.c.v.-administered nicotine also raised the blood levels of catecholamines. These observations suggest that i.c.v. administered nicotine leads to excitation of the central sympatho-adrenomedullary outflow and inhibits gastric acid output induced by stimulation of the vagus nerve.

Effects of morphine and naloxone on stress ulcer formation and gastric acid secretion

The effect of both acute and chronic morphine and naloxone on restraint-stress gastric ulcer formation and on basal gastric acid secretion were examined in the conscious rat. Acute morphine administration produced a dose-related decrease in stress ulceration and basal gastric acid secretion. Acute naloxone treatment resulted in a dose-related increase in stress ulcer formation and markedly augmented gastric acid secretion. Naloxone (4.0 mg/kg) antagonized the ulcer-reducing effects at all doses of morphine tested (4.0–32.0 mg/kg). Morphine-dependent rats, restrained during spontaneous or naloxone-precipitated withdrawal, exhibited the most severe ulceration. However, only those subjected to naloxone-precipitated withdrawal produced a significant increase in gastric acid output. Chronic treatment with naloxone or with chronic naloxone followed by morphine (16.0 mg/kg) resulted in augmented stress ulcer formation relative to all acutely treated groups. Both chronic naloxone-treated groups exhibited markedly enhanced gastric secretion. These data suggest that central and/or peripheral opiate receptors can modulate both basal and stress-perturbed gastric function.

Nicotine applied into the dorsal motor nucleus of the vagus inhibits enhanced gastric acid output and mucosal blood flow in rats

The effects of nicotine microinjected into several brain regions on the centrally elevated gastric acid output and mucosal blood flow (MBF) were examined in anesthetized rats. Intravenous administration of 2-deoxy-D-glucose (2-DG) induced increases in gastric acid output and MBF. These increases were inhibited dose dependently by nicotine microinjected into the dorsal motor nucleus of the vagus (NDV) but not into various hypothalamic regions. This effect of nicotine was abolished with concomitantly administered hexamethonium and was not observed in reserpine-pretreated animals. Electrical stimulation of the lateral hypothalamic area (LHA) induced an increase in gastric acid output. This increase was completely inhibited when nicotine was microinjected into the NDV 5 min before stimulation. This inhibitory effect of nicotine was abolished by concomitantly administered hexamethonium and by intraventricular pretreatment with phentolamine, but not with propranolol. These results suggest that activation of nicotinic receptors within the NDV releases noradrenaline and that there is a resultant inhibition of gastric acid output and MBF.

Central Cholinergic Descending Pathway to the Dorsal Motor Nucleus of the Vagus in Regulation of Gastric Functions

AbstractA possible role of the cholinergic mechanism within the dorsal motor nucleus of the vagus (NDV) in the regulation of gastric functions was examined in urethane anesthetized rats. Pretreatment with atropine (1–5 nmole). intracerebroventricularly inhibited the increase in both gastric acid output and mucosal blood flow (MBF). as induced by electrical stimulation of the lateral hypothalamic area (LHA). Bethanechol. micromjected into the dorsal vagal complex (the NDV. the nucleus tractus solitanus and area postrema) induced dose-dependent (5–30 nmole) increases in gastric acid output and MBF, while nicotine was without effect Pretreatment with atropine 3 nmole microinjected into the dorsal vagal complex completely blocked the increases induced by electrical stimulation of the LHA Furthermore, the increases in these gastric parameters induced by the administration of 2-deoxy-D-glucose (2-DG) were also significantly inhibited by atropine micromjected into the dorsal vagal complex. These results suggest that neurotransmission of the central descending pathway to the NDV in excitatory regulation of gastric functions is probably mediated through cholinergic muscarinic receptors.

Cholecystokinin intracerebroventricularly applied stimulates gastric acid secretion.

Intracerebroventricularly applied cholecystokinin-8-sulfate (CCK-8) induced a significant and dose-related increase in gastric acid output in urethane anesthetized rats. On the other hand, cholecystokinin-8-non-sulfate (CCK-8-NS), a non-active analogue of CCK-8, and pentagastrin as one of the cholecystokinin families, had no effect on gastric acid secretion. Pretreatment with atropine 5 min prior to CCK-8 as well as subdiaphragmatic vagotomy completely blocked this peptide-induced increase in gastric acid secretion. These results suggest that centrally applied CCK-8 induced a vagally mediated increase in gastric acid 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.

Inhibition of gastric secretion by fat and hypertonic glucose in the dog: role of gastric inhibitory peptide.

1. The gastric and intestinal phases of gastric secretion were selectively evoked by 'meals' of 5% liver extract or saline in five dogs provided with a special cannula that allowed complete separation of the stomach from the duodenum. 2. The gastric phase in response to liver extract administered into the stomach amounted to an increase in acid output equivalent to about 70% of the maximum output in response to histamine. There was also a significant rise in the concentration of gastrin but not of gastric inhibitory peptide (GIP) in the serum. 3. The addition of fat (2 or 4% corn oil) or glucose (20%) to this liver extract meal inhibited secretion of gastric acid by 50 and 30%, respectively, without affecting the concentration of gastrin or GIP in the serum. 4. The 5% liver extract in the duodenum stimulated an increase in gastric acid output amounting to about 40% of the maximum response to histamine. Serum gastrin and GIP levels were not affected. Additional fat (0.5-4.0%) or glucose (10-20%) reduced acid secretion under these conditions by between 50 and 80% without affecting serum gastrin concentrations. Significant increases in the concentration of GIP in the serum occurred in response to intraduodenal glucose (5%), and to fat at the highest dose used (4%). 5. Intraduodenal infusions of glucose (5-20%) significantly increased serum GIP levels. Gastric secretion in response to 5% liver extract in the stomach was significantly inhibited at the highest dose (10 or 20%) although gastrin release was unaffected. 6. These results show that intraduodenal fat and glucose both exhibit potent inhibitory effects on post-prandial gastric acid secretion but that there is no correlation between the changes in serum GIP concentration and the inhibition of gastric secretion under these conditions. 7. We conclude that GIP is unlikely to mediate fat-induced inhibition of gastric secretion, but it is still possible that it might be involved in the inhibition that occurs during intestinal perfusion with hypertonic glucose solutions.