The effect of vasoactive intestinal peptide, secretin, and glucagon on human duodenal bicarbonate secretion

Duodenal luminal acidification increases duodenal mucosal bicarbonate production and also releases both secretin and vasoactive intestinal peptide (VIP). The effect of these two structurally similar peptides on human duodenal bicarbonate production has not been examined in humans. Our purpose was therefore to assess the effect of VIP and secretin and also glucagon, a homologous hormone, on human duodenal bicarbonate secretion. A 4-cm portion of either proximal or distal duodenum was isolated and perfused with iso-osmolar NaCl. Pure porcine VIP (200 and 400 pmol/kg-h intravenously) significantly increased proximal duodenal bicarbonate secretion. Although secretin (0.01 to 0.18 CU/kg-h intravenously) markedly increased pancreatic bicarbonate secretion, it failed to alter duodenal mucosal bicarbonate output in either the proximal or the distal duodenum. Glucagon (1 to 8 micrograms/kg-h intravenously) did not affect proximal duodenal mucosal bicarbonate output. It is concluded that VIP, but neither secretin nor glucagon, significantly stimulates human duodenal mucosal bicarbonate secretion.     

Studies on the localization of secretin release from canine intestine

In conscious dogs with chronic pancreatic fistulas, duodenal perfusion with HCl (16 mmol/h) stimulated pancreatic HCO-3 secretion to a similar degree as exogenous secretin (2 U/kg X h), while meat feeding (500 g) and duodenal perfusion with oleate (16 mmol/h) increased this secretion to about 58 and 43% of the highest response to secretin. Plasma secretin increments with duodenal HCl, feeding and duodenal oleate amounted to about 45, 13 and 8% of that achieved with secretin, producing the highest HCO-3 response. Perfusion of the in situ intestine with HCl at gradually increasing rates produced HCO-3 responses similar to those induced by exogenous secretin in graded doses, but the increments in plasma secretin with duodenal HCl were only about half those obtained with exogenous secretin, producing an equal rate of HCO-3 secretion. HCl perfusion of isolated Thiry loops made of the duodenojejunal portion also stimulated the HCO-3 secretion in a dose-dependent way, but raised plasma secretin only to about half that attained with secretin, producing a similar secretory rate. HCl in the proximal duodenal and distal jejunal loop slightly stimulated the HCO-3 secretion without affecting plasma secretin, and that in the ileal loop was without any effect on the pancreatic or plasma secretin. This study provides evidence that (a) endogenous secretin is released by feeding and duodenal perfusion with HCl and oleate, but only HCl appears to release sufficient amounts of secretin to drive the HCO-3 secretion, and (b) the release of secretin is confined mainly to the distal duodenum and proximal jejunum.     

Identification, characterization, and distribution of secretin immunoreactivity in rat and pig brain.

Secretin immunoreactivity was detected in the central nervous system of the rat and pig with a highly specific radioimmunoassay. The secretin immunoreactivity in the rat and pig brain and duodenum extracts was fractionated by using a reverse-phase high-pressure liquid chromatographic system. The immunoreactive secretin from pig brain and duodenum coeluted precisely with synthetic porcine secretin. However, immunoreactive secretin extracted from rat brain and duodenum eluted slightly before porcine secretin. These data suggest a slight difference in the structure of rat and pig secretin. The detection of secretin in the brain lays the groundwork for studies to determine the role of the peptide in central nervous system function.     

Plasma secretin concentrations in fasting and postprandial state in man

Plasma immunoreactive secretin concentrations were determined in both healthy subjects and patients with duodenal ulcer. The modified radioimmunoassay method could detect significant increases in the plasma secretin concentrations when 0.05 N HCl was infused intraduodenally at a rate of 1.1 and 2.2 ml/min. The mean fasting plasma secretin concentration of 13 normal healthy subjects was 4.4±0.38 pg/ml which was significantly less (P<0.01) than that of 13 duodenal ulcer patients, 6.9±0.64 pg/ml. In both groups ingestion of a meat-containing meal resulted in significant increase in the plasma secretin concentrations. Recording of pH from proximal duodenum indicated that pH fell periodically below 4.5 during the postprandial period, indicating that only a short segment of proximal duodenum was exposed to acid after meal. The postprandial rise in plasma secretin levels was abolished when antral pH was raised above 5.5 by intragastric infusion of 0.3 N NaHCO₃ solution. These observations indicate that although fasting plasma secretin levels are low, the plasma secretin levels increase significantly after ingestion of a meal. This increase appears to be attributable to an increased amount of acid delivered to the proximal duodenum, and patients with duodenal ulcer were found to release more secretin during the postprandial period than normal subjects.     

Activation of human adenylate cyclase in the upper gastrointestinal tract by vasoactive intestinal polypeptide.

The effects of various polypeptide hormones known to inhibit gastric acid secretion were tested on the adenylate cyclase system in human gastric and duodenal mucosal homogenates. Glucagon and secretin failed to stimulate the enzyme system in the stomach. The latter hormone produced a small but significant activation of the duodenal cyclase. The vasoactive intestinal polypeptide (VIP), however, induced a dose-dependent increase of enzyme activity throughout the stomach and the duodenum. Maximal effects (1.8 to 3.0-fold increase) were observed at a VIP-concentration of about 10 microgram per ml. Because the entire physiological role of VIP in gastric function has not been defined, ipt cannot be discerned whether the VIP-stimulated adenylate cyclase is linked to inhibition of gastric acid secretion or to another as yet unrecognized effect of this hormone in human gastric function.     

Tolerance of rat duodenum to luminal acid

The tolerance of the duodenal mucosa to luminal acid was investigated by measuring with a liquid sensor pH microelectrode technique the epithelial surface pH (pH_s) and subepithelial tissue pH (pH_t) in rat proximal (duodenal bulb, Brunner gland area) and distal duodenum exposed to luminal acid. Under basal conditions, pH_s was roughly equal in both parts of the duodenum; proximal duodenum, 7.40 ± 0.14 (mean ± sem) at the villus tip and 7.54 ± 0.16 at the depth of crypt; distal duodenum, 7.46 ± 0.19 and 7.55 ± 0.09, respectively. Yet, exposure of the mucosa to luminal acid (10 mM HCl) provoked a significantly lesser decrease of pH_s (0.25 ± 0.13 vs 0.42 ± 0.12 pH units) in the proximal duodenum, suggesting that the response of epithelial HCO₃ secretion to luminal acid is stronger in that part of the duodenum. Further, the initial acidification of pH_s was followed in the proximal duodenum by a secondary alkalinization of pH_s, leading to normalization of pH_s, which may suggest activation of compensatory protective mechanisms. pH_t at the villus tip was likewise roughly equal in both parts of duodenum (7.29 ± 0.05 vs 7.17 ± 0.04), but, again, acidification of the luminal perfusate progressively from 10 to 100 mM HCl induced a much earlier and significantly more profound acidification in the distal than in the proximal duodenum. The possible contribution of Brunner glands to the greater mucosal tolerance to acid in the proximal duodenum was assessed by investigating whether stimulation or inhibition of Brunner gland secretion modulates the response of the duodenal mucosa to acid. It appeared that even though stimulation of Brunner gland secretion by secretin increased slightly but significantly pH_s (0.10 ± 0.03 pH units), it did not alleviate intramucosal acidosis during exposure to luminal acid. In contrast, inhibition of Brunner gland secretion by somatostatin had no influence on pH_s but markedly enhanced the susceptibility of the mucosa to tissue acidosis during acid exposure. This suggests that Brunner glands may, indeed, have a role in the mucosal defense against acid but that this protective action is mediated by some other mechanisms than stimulation of alkaline secretion. The data indicate that the proximal duodenum has a greater tolerance against luminal acid than distal duodenum, presumably due to a stronger stimulatory response of HCO₃ secretion to luminal acid. In addition, the action of the Brunner glands may contribute to the enhanced capacity of the proximal duodenum to withstand luminal acid.This study was supported by grants from the Medical Research Council of the Academy of Finland, Sigrid Jusélius Foundation, and University of Helsinki, Helsinki, Finland.     

Nerve cell density in submucous plexus throughout the gut of cat and opossum

Quantitative differences in submucous plexus density were sought in cat and opossum gut by examining full-thickness whole mounts of the submucosa stained with silver, and counting ganglia per square centimeter and nerve cell bodies per ganglion in order to compute density of innervation (nerve cell bodies per square centimeter). In the cat, the nerve cell bodies per square centimeter in the 12 named regions were as follows: proximal esophagus, 0; mid-esophagus, 0; distal esophagus, 0; fundus, 84; gastric antrum, 18; duodenum, 5831; jejunum, 4632; ileum, 3191; proximal colon, 1275; mid-colon, 689; distal colon, 359; rectum, 144. In the opossum, values were as follows: proximal esophagus, 37; mid-esophagus, 52; distal esophagus, 84; duodenum, 1812; jejunum, 2234; ileum, 1488; proximal colon, 206; mid-colon, 197; distal colon, 121; rectum, 61. Adequate specimens could not be obtained from opossum stomach. Differences were due more to variations in distribution density of ganglia than in ganglionic size. The relatively dense submucous plexus of the intestine probably is related to the capacity of the intestinal mucosa for peptide secretion as well as to its absorptive function.     

Renal handling of secretin in dogs: Free and stop flow analyses

Renal handling of secretin was studied in anesthetized dogs. Highly purified porcine secretin was infused into the renal artery and its concentration in plasma and urine was measured by a radioimmunoassay. Free flow experiments demonstrated that secretin appeared in urine above 10 ng/ml of plasma secretin and that its urinary excretion was increased in proportion to the plasma level of the hormone. Clearance of secretin was less than 0.05% of creatinine clearance and nearly constant over the plasma range of 10–170 ng/ml. In stop flow studies secretin appeared in urine in the same manner as inulin when both substances were injected simultaneously. This indicates that the hormone is filtered through glomerular capillary membranes. The maximal fall of secretin concentration during an infusion of the hormone appeared around the distal portion of the nephron where the dip of Na concentration was present. This suggests, although not entirely excludes the possibility of proximal reabsorption of secretin, that the hormone is reabsorbed around the distal portion of the nephron. It may be concluded that secretin, once filtered by the glomerulus, is reabsorbed by the tubular epithelium.     

Study of the characteristics of transcortin and the progesterone binding protein of the plasma of pregnant guinea pig]

Experiments were conducted with the plasma of pregnant guinea pigs; it was shown that the corticosteroid-binding protein (CBP) of the plasma in a pregnant guinea pig (in difference from the CBP of other species) bound cortisol only, and not progesterone. Progesterone-binding protein (PBP) of these animals bound progesterone, but not glucocorticoids and their metabolites. The binding capacity of CBP proved to be several hundred microgram per cent of cortizol and of PBP--about 100 microgram per cent of progesterone. The association constant of the CBP with cortisol constituted 10(6) M-1, and of the PBP-10(-8) M-1. These proteins are also analysed according to a number of other parameters.     

Localization of the duodenal pacemaker and its role in the organization of duodenal myoelectric activity

In two series of conscious healthy dogs, a study of duodenal electric activity was made to locate the pacemaker or site of the greatest intrinsic frequency of the pacesetter potential. In three dogs, an annular myotomy of the duodenum about 1 cm proximal (orad) to the biliary ampulla caused a reduction in the frequency of the pacesetter potential distal (caudad) to the conduction block and demonstrated that the pacemaker was not in the region of the ampulla, as had been suggested previously. Annular myotomy of the duodenum at increasing intervals distal to the pylorus in a second series of eight dogs showed that the pacemaker was present in the proximal 5 to 6 mm of duodenum. The greater frequency of the pacemaker was found to maintain constant distal conduction of the pacesetter potential. Distal conduction of the pacesetter potential was shown on occasion to be associated with the distal propagation of action potentials along the duodenum.     

Inhibition of secretin release and pancreatic bicarbonate secretion by somatostatin infusion in man.

Five healthy students were investigated on two different days with or without a constant infusion of somatostatin (500 microgram/h) into an arm vein a fluoroscopically placed Lagerl?f tube was used for the collection of gastric and duodenal juice. After 30-min basal period, 40 ml 100 mmol/l HCl was infused into the midpart of the duodenum over 5 min through a thin catheter attached to the tube. Plasma immunoreactive secretin was measured by radioimmunoassay employing 125I-labelled synthetic secretin, antibody against synthetic secretin, and standards prepared from pure natural porcine secretin. Secretin levels without somatostatin infusion were 4.6+/-0.7 pmol/l (mean+/-S.E.M.) basally and rose to a peak of 21.8+/-6.2 pmol/l after duodenal acidification (p less than 0.05) and with somatostatin infusion were 4.4+/-0.4 pmol/l basally and rose to a peak of 6.7+/-1.7 pmol/l (n.s.) after duodenal acidification. Pancreatic bicarbonate output increased from 8.0+/-2.5 mumol/min (mean+/-S.E.M.) to 283+/-44 mumol/min without somatostatin infusion (p less than 0.05) and from 6.7+/-2.1 mumol/min to 70+/-13 mumol/min somatostatin (p less than 0.05). This study shows that somatostatin (500 microgram/h can inhibit the release of secretin and the pancreatic bicarbonate secretion after duodenal acidification in man.     

Duodenal gastrinoma—clinical features and usefulness of selective arterial secretin injection test

Duodenal gastrinoma is recognized as a relatively common cause of Zollinger-Ellison syndrome, but its clinical and biological features are not well known. Here we report a case of duodenal gastrinoma with lymph node metastasis which was confirmed by pathology examinations. Hypergastrinemia and gastric acid hypersecretion were documented, but the secretin test showed negative results. An enlarged peripancreatic lymph node lying close to the pancreas head was the only positive finding on preoperative imaging studies. The results of the selective arterial secretin injection (SASI) test suggested that the primary tumor was located in the gastrinoma triangle. Finally, surgical exploration was carried out and a submucosal tumor, approximately 15mm in size, was detected by intraoperative palpation at the posterior wall of the proximal portion of the duodenum. Intraoperative pathology examination demonstrated metastases to regional lymph nodes. The present case calls attention to the unique features of duodenal gastrinomas, which differ from those of pancreatic origin: a highly malignant potential for its small size, and submucosal location in the proximal duodenum. The SASI test is recommended for assessing the location of a primary lesion if it cannot be identified by various conventional imaging studies. (Received Dec. 17, 1997; accepted Jan. 23, 1998)     

Patterns of pancreatic secretion in the anaesthetised guinea pig following stimulation with secretin, cholecystokinin octapeptide, or bombesin

The guinea pig is frequently used for studies of the cellular mechanisms of pancreatic secretion. Despite this, little is known about the control of pancreatic secretion in this species. To remedy this omission, we have studied the effects of secretin, cholecystokinin (CCK) octapeptide, and bombesin on the secretion of fluid, electrolytes, and amylase in the anaesthetised guinea pig. While the actions of secretin were similar to those in other species, the actions of CCK were not. As well as stimulating amylase release, CCK evoked a marked fluid secretion whose electrolyte composition differed little from that evoked by secretin. Bombesin had actions similar to those of CCK. It is suggested that this fluid secretion is derived from pancreatic acini. Whether a similar secretory component exists in other species (including humans), albeit as a minor component, needs to be determined.     

Epidermal growth factor increases intestinal calbindin-D9k and 1,25-dihydroxyvitamin D receptors in neonatal rats

Epidermal growth factor (EGF) has been reported to increase intestinal calcium absorption in suckling rats. The mechanism of this effect is unknown, as are the roles of vitamin D-dependent and independent pathways. The present studies were undertaken to investigate the ability of EGF to accelerate the postnatal induction of the vitamin D-dependent intestinal calcium-binding protein, calbindin-D9k. Subcutaneous administration of EGF increased duodenal calbindin-D9k in suckling rats by more than 100% (P less than 0.001). The effect of EGF was not seen in older weaned animals or when EGF was given to suckling rats by gavage. Administration of EGF simulated the changes of normal development. 1) It increased calbindin-D9k, and the effect was greater in proximal than distal duodenum. 2) EGF increased alkaline phosphatase activity to the same extent in proximal and distal duodenum. 3) EGF increased sucrase more markedly in distal than in proximal epithelium. Maximal and half-maximal effects of EGF on each of these proteins were observed at twice daily doses of 0.1 and 0.04 microgram/g BW, respectively. 4) EGF at the maximally effective dose produced a small (30%) but statistically significant (P less than 0.005) increase in serum 1,25-dihydroxyvitamin D. 5) Most importantly, EGF treatment resulted in a 2-fold increase in intestinal 1,25-dihydroxyvitamin D receptors (VDR) in the proximal segments of the small intestine (P less than 0.001). EGF effects on calbindin-D9k and VDR were specific for the intestine, as EGF did not change kidney calbindin-D9k or kidney VDR. Thus, EGF was able to prematurely initiate a complex series of molecular changes that occur during normal development. The mechanism of EGF's action to stimulate calcium absorption appears to involve a maturation effect on the vitamin D-dependent pathway.     

Influence of parasitism on secretin-inhibited gastric secretion.

This study tested the hypothesis that the inhibitory action of secretin on gastrin-stimulated gastric acid and pepsin secretion is comprised in animals harboring intestinal stages of the parasite Trichinella spiralis. Pentagastrin-stimulated acid and pepsin secretion, and the influence of secretin on these processes, were measured in dogs prepared with gastric fistulas and Heidenhain pouches. Dogs were studied before and after infection with 10(4) T. spiralis larvae/kg body weight. Gastric secretion was stimulated by constant intravenous infusion of pentagastrin, 1 microgram/kg per hour. Exogenous secretin inhibited pentagastrin-stimulated acid and pepsin output from both the main stomach and Heidenhain pouch in infected as well as in the uninfected dogs. Identical inhibition was observed in uninfected dogs during duodenal infusion with HCl to release endogenous secretin. In contrast, duodenal stimulation with HCl did not inhibit acid and pepsin secretion in dogs tested during the 1st week following infection. Results support the conclusion that the regulatory effect of secretin on gastrin-stimulated gastric secretion is impaired during the early phase of infection, and is due to depressed synthesis or release of secretin from duodenal mucosa.     

Distribution and postprandial release of porcine peptide YY

Peptide YY (PYY), a thirty-six amino acid intestinal hormonal peptide with a tyrosine residue at each end (hence YY as Y represents tyrosine in the new peptide nomenclature), was found throughout the gastrointestinal tract of the pig. Concentrations were very low in the foregut (antrum, 3.4 +/- 0.3 pmol/g; duodenum, 1.1 +/- 1.5 pmol/g), higher in the distal small intestine (ileum, 100 +/- 13 pmol/g) and very high in the large bowel (descending colon, 270 +/- 45 pmol/g). Peptide YY was found to circulate in plasma and concentrations rose substantially in response to eating (fasting, 138 +/- 15 pmol/l; postprandial, 263 +/- 21 pmol/l; P less than 0.001). There was a small but significant portal/arterial gradient in postprandial PYY levels. More than 90% of the immunoreactive PYY in gut extracts eluted, on gel permeation chromatography, in an identical position to pure PYY standard, but small amounts of higher molecular weight material, possibly precursors, were detected. In contrast, plasma from fasting pigs contained a large proportion (60-70%) of these large molecular forms. These findings suggest that the putative pro-PYY may be cleared more slowly from the circulation than the 36 amino acid hormonal peptide. The high concentrations of immunoreactive PYY in the circulation of the young pig may reflect a species difference between pig and man or may indicate an important role for PYY in the developing animal.     

Biliary and pancreatic secretions influence experimental duodenal ulcer without affecting gastric secretion in the rat

The effect of the absence of biliary and/or pancreatic secretions in the duodenum or the enhanced presence of bile at the proximal duodenum on the incidence, severity, number, and location of cysteamine-induced duodenal ulcers was investigated in the rat. Cysteamine produced ulcers on the anterior wall of the duodenum in 75% and on the posterior wall (kissing ulcers) in 50% of the animals. Diversion of biliary and/or pancreatic secretions from the duodenum increased both the severity and the incidence of the posterior duodenal ulcers. Diversion of bile to the proximal duodenum, on the other hand, decreased the severity as well as the incidence of the anterior duodenal ulcers. Mortality in rats receiving cysteamine correlated with the severity of ulcers. Taurocholic acid at nontoxic doses given subcutaneously or orally to nonoperated rats and rats which had bile diverted to the proximal duodenum aggravated the cysteamine-caused duodenal ulcers. Neither proximal nor distal diversion of bile had a major effect on gastric secretion of acid and pepsin in normal or cysteamine-treated rats. We conclude that both bile and pancreatic secretions may directly influence the development of cysteamine-induced duodenal ulcers in the rat.These studies were supported in part by a grant (AM25229) and Research Career Development Award (AM00600) to S. Szabo from NIH and U.S. Public Health Service.     

Comparative assessment of secretin and motilin responses to graded duodenal acidification in anaesthetised pigs

The effects of graded duodenal acidification on plasma concentration of immunoreactive secretin, and motilin in portal vein (PV) and carotid artery (CA) were investigated in 6 anaesthetised pigs in which the proximal duodenum was excluded and sequentially irrigated with isotonic saline (pH 7.0) and with hydrochloric acid (HCl) delivered at successive rates of 2, 8 and 40 mM H+/40 min (pH of 2.8, 1.9 and 1.0, respectively) under a constant flow of 10 ml/min. The release of secretin was first observed at pH 1.9 (from basal 4.2 +/- 0.3 to a peak of 26.6 +/- 9.8 pM in PV and from 3.4 +/- 0.3 to 6.8 +/- 0.9 pM in CA) and further increased at pH 1.0 (peaks of 60.9 +/- 16.3 in PV and 16.8 +/- 2.6 pM in CA). In contrast, only the highest HCl concentration (pH of effluent: 1.0) induced significant increases of plasma motilin (PV: peak of 25.2 +/- 4.9 for basal 13.3 +/- 1.1 pM, CA: 14.3 +/- 2.4 for basal 10.5 +/- 0.6 pM). A sharp decrease of the plasma secretin and motilin concentration was observed when the venous drainage of the duodenal segment was occluded, followed by a rapid increase when the clamp was released. In the present experimental conditions, duodenal motilin-producing sites were less sensitive to graded luminal acidification than secretin cells. Thus, the release of duodenal motilin in response to variations of luminal pH may be expected to occur primarily from the most proximal part of the duodenum in physiological conditions.     

Human duodenal mucosal bicarbonate secretion. Evidence for basal secretion and stimulation by hydrochloric acid and a synthetic prostaglandin E1 analogue

The factors responsible for prevention of duodenal mucosal injury are not known. This series of experiments was performed to determine whether the human duodenum secretes bicarbonate that could prevent mucosal damage. To isolate a 4-cm segment of proximal (i.e., the duodenal bulb) or distal duodenum free of contamination from either gastric or pancreaticobiliary secretion, or both, methods were developed using occlusive balloons. The test segment was perfused with NaCl (2 ml/min, 37 degrees C) containing [14C]PEG as a nonabsorbable marker, and bicarbonate output was quantitated. Mean (+/- SE) basal proximal duodenal bicarbonate output was 143 +/- 17 mumol/cm X h. A 5-min infusion of 25, 50, and 100 mM HCl directly into the isolated proximal duodenal test segment increased bicarbonate output to 167 +/- 29, 199 +/- 19, and 278 +/- 49 mumol/cm X h, respectively, during the hour after acidification. Distal duodenal acidification (25, 50, and 100 mM) also increased bicarbonate output from the isolated proximal duodenal test segment. A synthetic prostaglandin E1 analogue, misoprostol (1.67-13.3 micrograms/min), infused directly into proximal or distal test segments significantly stimulated bicarbonate outbreak; peak responses were 644 +/- 35 mumol/cm X h and 171 +/- 20 mumol/cm X h (p less than 0.001), respectively. Thus, in humans, the proximal and distal duodenal mucosa secretes bicarbonate at rest; direct acidification of the proximal duodenum stimulates bicarbonate output; acidification of the distal duodenum beyond the isolated test segment also increased proximal duodenal bicarbonate output; and a synthetic prostaglandin E1 analogue stimulated both proximal and distal bicarbonate output; however, distal duodenal bicarbonate output was significantly less, indicating a proximal-to-distal gradient in bicarbonate secretion.     

Inhibition of bombesin-stimulated gastric acid secretion by secretin, glucagon and caerulein in patients with duodenal ulcer.

The inhibitory effects of intravenous infusions of secretin, glucagon and caerulein on the gastric acid response to bombesin were studied in 8 duodenal ulcer patients. Bombesin was found to be a very potent stimulator of gastric acid secretion in patients with duodenal ulcer. There were no significant differences in acid outputs per 15-min period between bombesin infused in a dose of 0.9 microgram/kg/h and pentagastrin infusion administered in a maximal dose, at a rate of 6.0 microgram/kg/h. Secretin (1 U/kg/h), glucagon (30 microgram/kg/h) and caerulein (0.1 microgram/kg/h) produced significant decreases in gastric acid secretion evoked by bombesin given in a dose of 0.9 microgram/kg/h. Percentages of inhibition were 48.6, 45.2 and 35.5, respectively. It is supposed that secretin and glucagon given in pharmacological doses are capable of interfering with the action of gastrin released from antrum by means of bombesin on the parietal cell by noncompetitive kinetics. Caerulein administered in a pharmacological dosis, however, can inhibit the effect of gastrin released by bombesin on the parietal cells by a competitive kinetic.