Effect of Antrectomy and Vagiscretion on Gastric Acid Output and Gastrin Secretion

In three dogs with denervated Heidenhain pouches, ingestion of cooked beef liver caused increased acid output and gastrin secretion. After antrectomy and gastrojejunal anastomosis, ingestion of the liver did not increase sernm gastrin levels throughout the experiment. Acid output, however, although markedly reduced, was elevated over basal levels during the last three hours of the four-hour experiment. Total abdominal vagotomy did not alter gastrin secretion but further inhibited acid output in response to the test meal. These results indicate that in the dog intestinal gastrin is not released in response to a beef liver meal. Acid output postantrectomy, although reduced, does respond to the meal and is further decreased after vagotomy. A hormonal mechanism other thati tlie re-lease of intestinal gastrin is responsible for the intestinal phase of gastric acid secretion.     

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.     

Effects of omeprazole, a substituted benzimidazole, on gastrointestinal secretions, serum gastrin, and gastric mucosal blood flow in dogs

In dogs with gastric fistulas and vagally denervated Heidenhain pouches, omeprazole, a benzimidazole derivative infused intravenously or given intraduodenally, dose-dependently inhibited gastric acid secretion, which had been induced by histamine, pentagastrin, or urecholine. It also suppressed gastric acid response to physiologic stimulants such as sham-feeding and gastric peptone meal without affecting serum gastrin level. The inhibition of histamine-induced acid secretion was accompanied by a parallel reduction in the mucosal blood flow, but no significant alteration in the ratio (R) value, indicating that omeprazole primarily affected gastric acid secretion but did not limit gastric mucosal microcirculation. Omeprazole, infused into the Heidenhain pouch, caused a dose-dependent inhibition of the Heidenhain pouch response to intravenous histamine without any significant change in the acid response of the main stomach and plasma concentrations of the drug. This indicates that omeprazole may exhibit local inhibitory action on the oxyntic glands. Omeprazole did not affect gastric mucosal integrity or the rate of alkaline secretion from the gastroduodenal mucosa or the pancreas stimulated by duodenal acidification or secretin.     

Effects of gonadotropin-releasing hormone (GnRH) on gastric secretion and gastrin release in the dog

The effects of GnRH on gastric secretion and gastrin release from dogs provided with gastric fistulae and Heidenhain pouches have been investigated. A transient yet significant inhibition of pentagastrin-stimulated secretion from gastric fistulae was observed, while secretion from Heidenhain pouches was unchanged. The maximal inhibitory effect of GnRH on both acid and pepsin secretion stimulated by 2-deoxy-D-glucose was obtained from gastric fistulae. On the contrary, GnRH failed to affect either acid secretion stimulated by bethanechol or acid secretion and gastrin release induced by bombesin. The present results indicate that GnRH possesses an inhibitory action on gastric secretion from the vagally innervated stomach of the dog. The most likely inhibitory mechanism seems to be represented by a decrease of the vagal activity.     

Gastric acid and pancreatic polypeptide responses to modified sham feeding. Effects of truncal and parietal cell vagotomy.

The effects of truncal vagotomy and parietal cell vagotomy on gastric acid secretion and plasma gastrin and pancreatic polypeptide release were studied in 28 duodenal ulcer patients under basal conditions and after modified sham feeding and infusion of pentagastrin (2 micrograms/kg/h). Before vagotomy gastric acid output in response to modified sham feeding was significantly higher than basal acid secretion in all subjects tested and reached about 45% of the pentagastrin maximum. No difference in the increase in acid response, or in the pancreatic polypeptide response to modified sham feeding was found between patients with high and low basal secretion. Plasma gastrin concentration was unaltered by modified sham feeding before and after truncal vagotomy or parietal cell vagotomy, although after vagotomy it tended to reach higher values than before this procedure. After truncal vagotomy, basal pancreatic polypeptide concentration was decreased and modified sham feeding-induced pancreatic polypeptide increment was completely eliminated. Four weeks after parietal cell vagotomy, the modified sham feeding-induced increment in plasma pancreatic polypeptide was significantly decreased and observed only in seven of 12 patients. Four to five years after parietal cell vagotomy all subjects responded to modified sham feeding with pancreatic polypeptide increment similar to that before vagotomy and in three of 12 patients acid response to modified sham feeding was seen. This study indicates that truncal vagotomy eliminates gastric acid and plasma pancreatic polypeptide responses to vagal excitation while parietal cell vagotomy abolishes gastric acid response and reduces temporarily the pancreatic polypeptide response to modified sham feeding (possibly because of transient impairment of the vagal innervation of the pancreas). (2) A high ratio of basal to maximal acid output in non-operated duodenal ulcer patients is not associated with a low acid response to modified sham feeding, nor with a high pancreatic polypeptide concentration, and (3) Restitution of the pancreatic polypeptide response to modified sham feeding five years after parietal cell vagotomy does not indication ineffective denervation of the parietal cells.     

After vagotomy atropine suppresses gastrin release by food.

Changes in serum gastrin in response to feeding a meal of beef liver (15 g kg(-1)) were studied in 5 gastric fistula dogs with and without administration of atropine sulfate (0.2 mg kg(-1) intravenously). The studies were repeated after a truncal vagotomy that abolished acid secretion in response to 2-deoxyglucose. Before vagotomy atropine had little effect on the gastrin response to a meal. After vagotomy the gastrin response to feeding was greatly enhanced, but now atropine depressed the gastrin response at all times after the meal. It is concluded that vagotomy enhances the serum gastrin response to feeding and that atropine counteracts this enhancement.     

Effect of ninety-five percent pure cholecystokinin on gastrin-stimulated acid secretion in man and dog.

In 5 human subjects, 95% pure cholecystokinin (CCK) given as a background infusion in doses of 42, 84, or 168 pmol kg-1 h-1 did not significantly alter acid secretion in response to graded doses (11-300 pmol kg-1 h-1) of synthetic human gastrin-17-I. The 168 pmol kg-1 h-1 dose of CCK produced maximal pancreatic amylase output. In 3 subjects, 337 pmol kg-1 h-1 of CCK slightly stimulated acid secretion when given alone and tended to reduce acid secretion in response to gastrin, but each of the subjects experienced cramping abdominal pain. The increment in acid secretion produced by CCK alone was similar to that produced by maximally effective doses of carboxyl-terminal octapeptide of CCK. In dogs with gastric and pancreatic fistulas, 168 pmol kg-1 h-1 of CCK produced maximal pancreatic protein output and slightly stimulated gastric acid secretion. In dogs with gastric fistulas and Heidenhain pouches, the lowest dose of CCK that inhibited gastrin-stimulated acid secretion was 674 pmol kg-1 h-1. We conclude that in man and dog 95% pure CCK weakly stimulates gastric acid secretion and inhibits gastrin-stimulated acid secretion but these actions occur only with doses of CCK that are maximal or supramaximal for pancreatic enzyme secretion. Because of the high dose requirement, these effects are unlikely to be physiologically significant.     

Comparison of methionine-enkephalin and morphine in the stimulation of gastric acid secretion in the dog

In dogs with Heidenhain pouches and gastric fistulas, we studied acid secretion in response to systemic or portal infusion of methionine-enkephalin (met-enkephalin), enkephalin-analog, or morphine. All these opiate compounds caused a dose-dependent increase in acid secretion under basal conditions and resulted in a significant rise in pentagastrin- or histamine-induced acid secretion. The stimulation by opiates of gastric secretion was accompanied by an increase in the mucosal blood flow but without any significant change in serum gastrin concentration. Gastric acid stimulation by met-enkephalin and morphine was strongly inhibited not only by naloxone, an opiate antagonist, but also by blockers of H2-receptors (metiamide) or cholinergic receptors (atropine), suggesting a cooperative interaction between opiates and other stimuli of parietal cells. The gastric stimulation by met-enkephalin and its analog, but not by morphine, was markedly reduced by portal administration of these compounds, indicating a marked inactivation of opiate peptides by hepatic transit. This study shows that enkephalin and morphine stimulate gastric acid secretion by a gastrin-independent mechanism sensitive to atropine and H2-blocker and probably involving opiate receptors.     

Effect of Medical Vagotomy on Acid and Pepsin Responses to Histamine and Pentagastrin in Man

Acid and pepsin secretion in response to graded doses of pentagastrin (ICI 50123) and histamine was studied before and after medical vagotomy in six duodenal ulcer patients.

Before medical vagotomy the mean maximal pepsin response to pentagastrin was reached at a dose causing a submaximal rate of acid secretion, whereas maximal responses of acid and pepsin to histamine occurred at the same doses.

Vagotomy reduced acid and pepsin responses to pentagastrin and histamine at all dose levels and shifted the dose response curve to the right.     

The effect of endogenous gastrin on histamine-induced gastric secretion

Conclusion The release of endogenous gastrin through irrigation of isolated antrum pouches in dogs produced stimulation but no inhibition of acid secretion from Heidenhain pouches when a plateau of secretion had been established by the continuous intravenous injection of histamine. These experiments together with the secretory data on man secured from patients with Ellison-Zollinger tumors are interpreted as supporting the view that the inhibitory effect of the intravenous injection of exogenous gastrin represents an effect of marked overdosage of gastrin or rapidity of injection and that the normal response to the release of gastrin from the antrum during a meal is stimulation of secretion.This work has been aided by Grant AM-04178 from the National Institutes of Health, U. S. Public Health Service.     

Effect of duodenal acidification on gastric mucus and acid secretion in conscious cats.

In cats with gastric fistulae and Heidenhein pouches, the effect of acid entering the duodenum on secretion of acid, pepsin, and mucus from the Heidenhain pouch during maximal acid stimulation with pentagastrin or histamine, was studied. Duodenal acidification produced stimulation of pepsin and mucus secretion comparable to that induced by exogenous hormones (secretin and the combination of secretin with cholecystokinin). In addition, duodenal acidification caused an increase in acid secretion, thus suggesting that, in addition to secretin and cholecystokinin, a factor that stimulates acid secretion was also released by acid.     

Psychosensory initiation of gastric secretion in dogs. Inter-relation of vagal component, gastrin, histamine and somatostatin

The effects of vagal stimulation on gastric secretion and on blood gastrin, histamine and somatostatin release have been assessed in three esophagostomized dogs equipped with gastric fistula and Heidenhain pouch. The animals were submitted to sham feeding of variable duration (from 2.5 to 12.5 min) and composition. In response to standard composition of the sham feeding, acid and pepsin responses were observed in the gastric fistula only; they were closely related to the sham feeding duration. Integrated histamine responses were also closely related to sham feeding duration and were correlated with acid or pepsin responses. Gastrin was released by sham feeding induced-vagal stimulation, but there were no relationship between gastrin and secretory responses. Somatostatin release decreased as duration of sham feeding stimulation increased and correlated negatively with acid or pepsin responses. Modified standard sham feeding, by adding either lipids or glucids resulted in the same gastric and hormonal responses as standard sham feeding. It appears that 1 degree) vagal stimulation resulting in the psychosensorial receptors stimulation can be quantified, 2 degrees) histamine reduces somatostatin release and could represent a non cholinergic vagal mediator, capable of controlling somatostatin release in the cephalic phase of gastric secretion.     

'Non-active' pepsin secretion compared with stimulated secretion by bethanechol, histamine, pentagastrin, and 2-deoxy-D-glucose. The role of vagal innervation

The present studies were performed on a double-pouch dog with one vagally innervated Amdrup pouch (AP) and one denervated Heidenhain pouch (HP), allowing comparison of pepsin secretion from innervated and denervated mucosa at the same time in the same animal. 'Non-active' secretion of pepsin was determined by instillation in the pouches of 0.1 M and 0.005 M HCl, 0.15 M NaCl, and 0.03 M phosphate buffer, and well-known stimulators of gastric secretion such as histamine, pentagastrin, bethanechol, and 2-deoxy-D-glucose (2-DG) were tested as pepsigogues. Cholinergic stimulation by 2-DG and bethanechol (Urecholine) was clearly the most potent stimulus of pepsin secretion. 2-DG elicited secretion only from innervated mucosa, whereas the responses to bethanechol were similar in the two pouches. Histamine and pentagastrin were weak stimulators, but both provoked active and sustained secretion of pepsin when given in small doses. Higher doses of histamine strongly inhibited pepsin output. The effects of histamine were independent of vagal innervation. By contrast, the active stimulation by pentagastrin only took place in innervated mucosa. The highest outputs were seen in the lowest doses, but also very high doses of pentagastrin elicited active pepsin secretion in the AP. Medium doses of pentagastrin brought the secretion down the the 'non-active' level. The chief cells in the denervated mucosa were quite insensible to pentagastrin, and the pepsin output in the HP equalled the non-active' response at all dose levels.     

Comparison of the effect of omeprazole--a substituted benzimidazole--and ranitidine--a potent H2-receptor antagonist--on histamine-induced gastric acid secretion and the ultrastructure of canine parietal cells

Gastric acid secretion and mucosal biopsy findings in canine stomach were evaluated after administration of omeprazole or ranitidine with and without histamine stimulation. Pretreatment with omeprazole (1 mg/kg) or ranitidine (0.5 mg/kg) almost completely prevented subsequent stimulation of acid secretion by histamine (40 micrograms/kg-h). Only ranitidine pretreatment, however, prevented post-histamine morphological transformation of parietal cells into the active state after histamine. Omeprazole pretreatment did not prevent the development of canaliculi and the reduction in the number of tubulovesicles in parietal cells after histamine. This canalicular expansion was, however, only partial with microvilli tightly packed together. Injection of omeprazole or ranitidine during half maximal stimulation by histamine effectively inhibited gastric acid secretion both in gastric fistulas (GF) and Heidenhain pouches (HP), and transformed the morphology of parietal cells into the resting state. In addition, omeprazole treatment with and without histamine stimulation increased the number of parietal cells with condensed mitochondria. This study demonstrates that omeprazole and ranitidine, while both potent inhibitors of gastric acid secretion, affect the parietal cell ultrastructure in different ways. Omeprazole does not prevent the formation of canaliculi in histamine-stimulated cells. This underscores the relative value of morphometrical studies of parietal cells.     

Serum disappearance rate of gastrin-17 after vagotomy

Six duodenal ulcer patients were investigated before and after truncal vagotomy and pyloroplasty. Four doses of gastrin-17 were injected intravenously (15.625, 31.25, 62.5, and 125 micrograms/kg body weight); the gastric secretory response and the disappearance rate of gastrin were measured. After vagotomy the basal level of gastrin increased from 64 pg/ml to 106 pg/ml. When corrected for the basal levels of gastrin, the peak levels and disappearance rate of gastrin-17 were observed to be the same after vagotomy as before (half-life before vagotomy, 5.6 min; after, 5.8 min). This indicates that vagus does not influence the metabolism of exogenous gastrin-17. The gastric secretion of acid was reduced to 30% after vagotomy, which shows that there is a synergism between vagus and gastrin-17.     

Gastric secretion of acid in response to right and left atrial infusion of gastrin

The purpose of this study was to evaluate the possible role of the lung as an organ for inactivation of exogenous gastrin. Human synthetic gastrin was infused into the right and left atria of 4 mongrel dogs with Heidenhain pouches. The mean rate of acid secretion in response to right atrial gastrin infusion was 0.39 mEq/15 min, as compared to the mean rate of 0.36 mEq/15 min when the gastrin was infused via the left atrium. The difference in gastric acid secretory response to infusion of gastrin into the right or left atrium was not statistically significant.Supported by Research Grant AM 04487-08, US Public Health Service.     

Relationship between amino acid dose and gastric secretory response.

Gastric secretory dose-response studies, using an 8.5% mixed L-amino acid solution as the agonist, were carried out in three dogs with Heidenhain pouches and gastric fistulae. Secretory responses of the Heidenhain pouches were measured during two hour infusions of amino acids given at rates of 0, 0.05, 0.1, 0.2, 0.4, 0.8, and 1.6 g/kg/h and plasma amino nitrogen was measured before and during the infusion. Three separate studies at each dose level were made in each dog. The maximum secretory response occurred at the dose of 0.4 g/kg/h and amounted to approximately 20% of the maximal histamine response. Larger doses produced no additional increase in secretion or an actual decrease in secretory rate. It is concluded that the solution of amino acids used acts as a modest gastric agonist and that increases in plasma amino nitrogen such as may be observed after a protein meal are capable of eliciting a slight, but definite, gastric secretory response.     

Effect of antrectomy on gastric secretion following duodenal exclusion

The effect of antrectomy on acid secretion was studied in Pavlov-pouch dogs from which the duodenal inhibitory mechanism was excluded prior to antrectomy. The secretion was stimulated with graded doses of histamine, gastrin, and a combination of graded doses of histamine and gastrin plus a fixed dose of Urecholine.Following exclusion of the duodenum from the normal gastrointestinal continuity, the maximal acid response of the Pavlov-pouch dogs was significantly increased. Subsequent antrectomy produced a highly significant decrease in the acid response to histamine, while the acid output of dogs stimulated with graded doses of gastrin was reduced only slightly following antrectomy. Resection of the duodenal bulb produced a small decrease in the acid output of the Pavlov pouches in response to graded doses of histamine and a highly significant decrease in acid response to graded doses of gastrin.These findings demonstrate the importance of the duodenal inhibitory mechanism in regulating the gastric acid secretory response, and the potentiating effect of spontaneously released gastrin from the antrum to injected histamine. Our results lend support to the theory that endogenous gastrin is located in the duodenal bulb, and that these minute amounts of gastrin are significant in the production of acid secretion.     

Effects of truncal vagotomy and antrectomy on bombesin-stimulated pancreatic secretion,release of gastrin,and pancreatic polypeptide in the anesthetized dog

The short-term effects of truncal vagotomy and antrectomy on bombesin-stimulated pancreatic secretion and release of gastrin and pancreatic polypeptide (PP) were studied in 18 anesthetized dogs. Together with an intravenous infusion of secretin (250 ng/kg/hr) bombesin (500 ng/kg/hr) was given before and after truncal vagotomy, antrectomy, and sham operation (N=6 dogs per group). Peak incremental pancreatic protein output in procedures (tachyphylaxis). Neither truncal vagotomy nor antrectomy significantly altered the pancreatic protein response to bombesin when compared with sham operation. Bombesin produced a mean 1-hr increase over basal of 196 pM for gastrin, which was abolished by antrectomy but not appreciably affected by truncal vagotomy and sham operation. The mean 1-hr increment (207 pM) for PP in response to bombesin was not changed by truncal vagotomy, antrectomy, and sham operation. This study shows in the anesthetized dog that exogenous bombesin stimulates release of PP as well as gastrin; that the release of gastrin by bombesin is not vagally dependent; that neither truncal vagotomy nor antrectomy alter the release of PP by bombesin; and that the action of bombesin on pancreatic protein secretion does not depend on release of gastrin or on intact vagal nerves.Parts of this paper have been presented at the 12th European Pancreatic Club Meeting, Copenhagen, Denmark, October 11–13, 1979, and at the 3rd International Symposium on Gastrointestinal Hormones, Cambridge, England, September 15–18, 1980.