The effect of somatostatin on bombesin-stimulated serum gastrin and gastric acid secretion in man

The effect of intravenous somatostatin on bombesin-stimulated serum gastrin and gastric acid secretion was studied in 5 healthy subjects. Somatostatin, 100 ng/kg/min, significantly inhibited serum gastrin and gastric acid responses to infusion of bombesin-tetradecapeptide in a dose of 2.5 ng/kg/min. Inhibition of gastrin release could not fully account for the inhibition of gastric acid secretion. Since both bombesin and somatostatin are present in the antrum of man, interrelations between these peptides might be involved in gastrin release from the antrum.     

Effect of atropine and somatostatin on bombesin-stimulated plasma immunoreactive trypsin release in man

This study was undertaken to determine the effect of atropine and somatostatin, two inhibitors of intraduodenal pancreatic enzyme secretion, on bombesin-stimulated release of plasma immunoreactive trypsin in 6 healthy volunteers. Infusion of 5 ng/kg.min bombesin during 30 min induced significant increases in plasma trypsin from 206 +/- 20 to 334 +/- 44 ng/ml (p less than 0.01). Atropine (15 ng/kg as i.v. bolus followed by 5 ng/kg.h) had no influence on the bombesin-stimulated increase in plasma immunoreactive trypsin (207 +/- 20 to 326 +/- 54 ng/ml). Somatostatin (125 micrograms as i.v. bolus followed by 125 micrograms/h) also failed to inhibit the plasma trypsin response to bombesin (207 +/- 18 to 663 +/- 166 ng/ml). These results point to major differences in the regulation of plasma and intraduodenal trypsin secretion.     

Postreceptor inhibition of antral gastrin release by somatostatin

This study was performed to examine the effects of somatostatin on antral gastrin release stimulated by postreceptor increases in adenosine cyclic nucleotide. Increases in intracellular levels of cyclic adenosine monophosphate were achieved through the use of the dibutyryl derivative of cyclic adenosine monophosphate and the phosphodiesterase inhibitor theophylline. The effects of somatostatin on basal and stimulated gastrin release were examined in rat antral organ culture experiments. Inclusion of somatostatin in the culture medium (1 X 10(-8) to 1 X 10(-4) M) resulted in significant inhibition of gastrin release at somatostatin concentrations of 1 X 10(-5) and 1 X 10(-4) M: both doses of somatostatin inhibited gastrin release by approximately 52% at 30 min and by 32% at 6 h. Gastrin release stimulated by dibutyryl cyclic adenosine monophosphate was significantly inhibited by 1 X 10(-5) and 1 X 10(-4) M somatostatin to 133% and 121% at 30 min and 77% and 98% at 6 h, respectively. Gastrin release stimulated by theophylline (1 mM) was also significantly inhibited by somatostatin in doses ranging from 1 X 10(-6) to 1 X 10(-4) M. The degree of inhibition by somatostatin of dibutyryl cyclic adenosine monophosphate- and theophylline-stimulated gastrin release declined over the duration of culture. In conclusion, these results suggest that somatostatin inhibits adenosine cyclic nucleotide-stimulated gastrin release by acting at a point distal to the formation of cyclic adenosine monophosphate.     

Adrenergic control of rat gastric somatostatin and gastrin release

The effect of adrenergic agonists and antagonists on the secretion of gastric somatostatin-like immunoreactivity (SLI) and gastrin was investigated in an isolated, vascularly perfused rat stomach preparation. Two- to six-fold increases in SLI secretion induced by isoproterenol, epinephrine, and norepinephrine were completely abolished by propranolol but were not influenced by phentolamine. Propranolol did not alter glucagon- and DB-cAMP-induced stimulation of SLI release. Experiments in which the beta 2-agonist salbutamol and the beta 1- and beta 2-blockers practolol and H35/25 were used showed that both subtypes of beta receptors are involved. Gastrin secretion revealed only minor changes in dose-response studies with a wide range of isoproterenol concentrations (2 X 10(-8) to 1.5 X 10(-4) M). The results obtained in this study suggest that in rats 1) the SLI response to adrenergic agonism is predominantly mediated by beta receptors; 2) both beta 1- and beta 2-adrenergic receptors are involved; 3) under in vitro conditions, adrenergic agonism is a weak stimulus for gastrin secretion.     

Participation of antral somatostatin in the local regulation of gastrin release

In anaesthetized pigs gastrin release was stimulated by irrigation of the antrum with bicarbonate and by instillation of a meat extract. The concentration of gastrin and somatostatin was measured by radioimmunoassay both in the antral and peripheral venous blood. The increase in gastrin was coupled to a significant decrease in somatostatin immunoreactivity as measured in the antral venous blood both during instillation of alkali and meat extract. In peripheral blood, the differences were much less evident and not statistically significant. It is speculated that the decrease in release of antral somatostatin during alkalinization and instillation of meat extract is the primary event which is followed by a diminished inhibition of gastrin liberation. Thus, the present data support the hypothesis that antral somatostatin participates in the local regulation of gastrin release.     

Influence of vagal integrity on gastrin and somatostatin release in dogs

Plasma gastrin and somatostatin responses to ingestion of a solid meal, to insulin hypoglycemia, and to intravenous infusion of gastrin-releasing peptide were measured in 4 conscious dogs with and without bilateral cryogenic blockade of the cervical vagus nerves. Vagal cooling to -2 degrees C abolished meal-stimulated rises in plasma gastrin and somatostatin. Atropine did not modify the gastrin response to cooling but bethanechol reduced the magnitude of inhibition to 37% +/- 9% without influencing plasma somatostatin. Gastrin-releasing peptide elevated postprandial plasma gastrin during vagal blockade to levels comparable to those with the vagus intact but did not alter the nadir plasma somatostatin response. The plasma gastrin and somatostatin rises associated with insulin hypoglycemia were similarly inhibited by cooling to -2 degrees C. Cooling to 12 degrees C, which selectively blocks vagal inhibitory pathways, had no effect on meal-stimulated gastrin release and partially decreased the plasma gastrin response to insulin hypoglycemia. Thus, gastrin release by food and by insulin hypoglycemia is mediated by a vagal nonmuscarinic excitatory pathway that is independent of changes in circulating plasma somatostatin but may include participation by the candidate neurotransmitter gastrin-releasing peptide.     

Adrenergic and cholinergic interactions in rat gastric somatostatin and gastrin release

The interactions of adrenergic and cholinergic influences on the gastric D cell were studied using an isolated perfused rat stomach in vitro. The sevenfold increase in the release of somatostatin-like immunoreactivity (SLI) in response to isoproterenol (4 . 10(-8) M) was dose-dependently inhibited by acetylcholine (10(-5) to 10(-8) M) whereas gastrin levels increased in a dose-dependent manner. Both inhibition of stimulated SLI and augmentation of gastrin release were completely abolished by atropine (10(-6) M). Isoproterenol (8 . 10(-9) M)-induced stimulation of SLI secretion was not altered by atropine. Antral exclusion completely eliminated gastrin secretion but basal and beta-adrenergic stimulated SLI release was not influenced. It is concluded that (1) cholinergic agonism reverses the stimulatory action of adrenergic agonists on the D cell, and (2) SLI from the rat stomach in vitro originates almost exclusively in the fundic region.     

Effects of somatostatin on gastric secretion and gastrin release in man.

Somatostatin, a recently synthesized hypothalamic growth hormone release-inhibiting factor (GIF), was used in the cyclic and linear form. In all subjects studied, the cyclic GIF inhibited gastrin secretion during basal conditions as well as during a standard food stimulus, with immediate rebound after the infusion was stopped. Similar responses were observed in a hypophysectomized patient, indicating that this effect of GIF was independent of suppression of growth hormone secretion. Cyclic and linear GIF, when administered in normal subjects during an infusion of synthetic human gastrin I, almost totally suppressed gastric secretion. The results indicate that GIF is a potent inhibitor of gastric secretion and gastrin release.     

Effects of carbachol on gastrin and somatostatin release in rat antral tissue culture

Recent studies have demonstrated that somatostatin-containing cells are in close anatomic proximity to gastrin-producing cells in antral mucosa, suggesting a potential local regulatory role for somatostatin. The purpose of this study was to examine further the relationships between gastrin and somatostatin and the effects of the cholinergic agonist carbachol on content and release of gastrin and somatostatin using rat antral mucosa in tissue culture. Antral mucosa was cultured at 37 degrees C in Krebs-Henseleit buffer, pH 7.4, gassed with 95% O2-5% CO2. After 1 h, the culture medium was decanted and the tissue was boiled to extract mucosal gastrin and somatostatin. Inclusion of carbachol 2.5 X 10(-6) M in the culture medium decreased medium somatostatin from 1.91 +/- 0.28 (SEM) ng/mg tissue protein to 0.62 +/- 0.12 ng/mg (p less than 0.01), extracted mucosal somatostatin from 2.60 +/- 0.30 to 1.52 +/- 0.16 ng/mg (p less than 0.001), and percentage of somatostatin released from 42% +/- 2.6% to 27% +/- 2.2% (p less than 0.01). Carbachol also increased culture media gastrin from 14 +/- 2.5 to 27 +/- 3.0 ng/mg protein (p less than 0.01). Tissue content and release of gastrin and somatostatin were also examined during culture of rat antral mucosa in culture media containing antibodies to somatostatin in the presence and in the absence of carbachol. Incubation with somatostatin antisera, both with and without carbachol, markedly increased culture media concentrations of somatostatin, all of which was effectively bound by antibodies present in the media. Antibody binding of somatostatin was accompanied by significant increases in culture media gastrin concentrations, both in the presence and in the absence of carbachol. Results of these studies support the hypothesis that antral somatostatin exerts a local regulatory effect on gastrin release and that cholinergic stimulation of gastrin release is mediated, at least in part, through inhibition of somatostatin synthesis and release.     

Effects of somatostatin and acid on inhibition of gastrin release in newborn rats

Newborn dogs, humans, and rats have elevated gastric luminal pH values and significantly elevated serum gastrin levels compared to adults. In the adult, acidification of the antral mucosa to pH 3.0 or lower inhibits gastrin release. Somatostatin is released by acid and may mediate this effect. We examined the effects of gastric acidification and somatostatin injection in rats aged 10 days to adult. Gastric gavage with 0.15 M HCl significantly lowered serum gastrin in animals of all ages. Somatostatin injection (400 micrograms/kg) significantly decreased serum gastrin in rats aged 18 days or older, but not in 10- and 15-day-old animals. These data indicate that 1) the mechanism whereby antral acidification inhibits gastrin release is at least partially developed in unweaned rats, 2) somatostatin is not a necessary mediator of the inhibition of gastrin release, and 3) at least part of the hypergastrinemia found in newborn animals is of antral origin.     

Antral release of gastrin and somatostatin in duodenal ulcer and control subjects.

Organ culture was used to compare gastrin and somatostatin release from cultured antral mucosa obtained from duodenal ulcer and non-ulcer (control) subjects. In response to dibutyryl cyclic AMP (DBCAMP) cultured antral mucosal explants from patients with a history of duodenal ulcer released a greater proportion of antral gastrin into the medium than did antral mucosal explants from non-ulcer subjects. Somatostatin release from antral mucosa from duodenal ulcer patients was substantially less than somatostatin released by antral explants from non-ulcer subjects. In the non-ulcer subjects there was a direct positive correlation between the amounts of antral somatostatin and gastrin released into the culture medium (r = 0.64, less than p 0.01). In the duodenal ulcer patients, however, there was no correlation between gastrin release and somatostatin release from antral mucosa ( r = 0.09; p greater than 0.2). Results of these studies identify enhanced gastrin release in response to stimulation and decreased release of somatostatin from antral mucosa of duodenal ulcer patients. These alterations in paracrine relationships of antral somatostatin and gastrin in duodenal ulcer subjects may contribute, at least in part, to the pathogenesis of duodenal ulcer disease.     

Cholinergic mediation of gamma-aminobutyric acid-induced gastrin and somatostatin release from rat antrum

Addition of gamma-aminobutyric acid (GABA) to antral mucosal fragments in short-term incubation results in dose-dependent and bicuculline-sensitive stimulation of gastrin release and inhibition of somatostatin release, respectively. These effects of GABA on antral gastrin and somatostatin release closely resembled the actions of cholinergic agonists on G- and D-cell function. The present study examines the possibility that the effects of GABA on antral peptide release may be mediated, in part, through stimulation of antral cholinergic neurons. Inclusion of either atropine or pirenzepine in incubation medium prevented GABA-induced stimulation of gastrin release and inhibition of somatostatin release. Addition of the acetylcholinesterase inhibitor, physostigmine, caused a leftward shift in the GABA dose-response curve and increased by 10-fold the sensitivity of the antral preparation to GABA stimulation. Studies with tetrodotoxin suggest that GABA-stimulated gastrin release is mediated through activation of neurons contained within the antral mucosal/submucosal fragments. Hexamethonium, the ganglionic nicotinic receptor antagonist, did not affect GABA-induced gastrin release. These results indicate that GABA affects antral gastrin and somatostatin release through stimulation of antral postganglionic cholinergic neurons.     

Effects of somatostatin-14 and somatostatin-28 on bombesin-stimulated release of gastrin, insulin, and glucagon in the dog

The effects of somatostatin-14 (S14) and somatostatin-28 (S28), a novel intestinal peptide containing somatostatin tetradecapeptide in its C-terminal position, on the bombesin-stimulated release of gastrin, insulin, and glucagon were tested. On iv infusion of bombesin, the increase in the level of glucagon was seen to be twice that of gastrin, and the insulin increase was 8 times that of gastrin. Plasma concentrations of somatostatin were not modified. S14 and S28 inhibited the release of gastrin, insulin, and glucagon; insulin release was inhibited most effectively, with glucagon release next, and gastrin release least inhibited. Based on the exogenous dose needed to produce equal effects, S28 was more potent than S14 on a molar basis, but based on the plasma concentrations needed to produce equal effects, S14 and S28 were equipotent.     

Effect of gastrin receptor antagonists on gastric acid secretion and gastrin and somatostatin release in the rat stomach.

The effects of two recently developed gastrin receptor antagonists, PD 136450 and L-365,260, on pentagastrin-stimulated acid secretion were investigated in rats. PD 136450 at a dose of 6 mg/kg s.c. (9.6 mumol) completely abolished acid secretion induced by pentagastrin. The inhibition of 18 mg/kg PD 136450 s.c. lasted for at least 8 h and was still effective after 14 days of treatment (18 mg/kg s.c. every 8 h). Acute application of L-365,260 at a dose of 3.8 mg/kg, which is equimolar (9.6 mumol) to 6 mg/kg PD 136450 reduced acid responses slightly. However, when L-365,260 was administered intravenously at a dose of 3 mg/kg, this antagonist completely abolished the pentagastrin-stimulated acid secretion. Furthermore, the effect of PD 136450 on endogenous gastric somatostatin and gastrin releases was tested in the isolated, vascularly perfused rat stomach. PD 136450 perfused at a concentration of 1 microM slightly increased somatostatin secretion after stimulation with a high dose of isoproterenol (10(-7) M). There was no effect of PD 136450 on basal or acetylcholine-stimulated gastrin secretion.     

Role of calcium in the stimulus-secretion coupling of antral gastrin release

The role of calcium in the stimulus-secretion coupling of antral gastrin release was examined in isolated sheets of canine antral mucosa. Mucosa was obtained from 137 dogs and mounted in Ussing chambers to separate the luminal from nutrient surfaces. The influence of verapamil, LaCl3, A23187, and EGTA on the release of gastrin by luminal calcium and ethyl alcohol was examined and the release of immunoreactive gastrin (IG) was measured in luminal perfusates. Release of IG by luminal calcium was dose-related, unsaturable, and impaired by verapamil and by LaCl3. Release of IG by alcohol was prevented by leaching the mucosa of calcium and restored by repletion of the calcium. IG release induced by alcohol was prevented by topical, but not by nutrient, application of LaCl3. Molecular sieve and affinity chromatography of the endogenous IG released in the absence of luminal calcium, and of the exogenous gastrin added, indicated that antral gastrin was released as heptadecapeptide gastrin, and that which was released in the presence of CaCl2 degraded rapidly into a C-terminal fragment. The data indicate that calcium may participate in the stimulus-secretion coupling of canine antral gastrin release in vitro.     

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.     

Effect of peptide YY on gastric acid secretion, gastrin and somatostatin release in the rat

The influence of PYY on stimulated gastric acid secretion and the possible role of gastric somatostatin was measured in rats. PYY, infused intravenously at a dose of 800 pmol/kg/h, reduced pentagastrin (20.8 nmol/kg/h) stimulated gastric acid secretion by 34 +/- 3%, whereas in controls acid secretion remained constant throughout the 90 min observation period. In a second series the effect of PYY on the endogenous gastric somatostatin-like immunoreactivity and gastrin-release was tested in the isolated, vascularly perfused rat stomach. PYY perfused at concentrations of 10 pM to 100 nM did not change either somatostatin or gastrin secretion from the rat stomach in vitro. The study shows that PYY suppressed acid secretion in the rat. Endogenous somatostatin or gastrin is unlikely to mediate the inhibitory effect of PYY on acid production.     

Mechanisms for regulation of gastrin and somatostatin release from isolated rat stomach during gastric distention

AIM: To investigate the intragastric mechanisms forregulation of gastric neuroendocrine functions during gastricdistention in isolated vascularly perfused rat stomach.METHODS: Isolated vascularly perfused rat stomach wasprepared, then the gastric lumen was distended with either5,10 or 15 ml pH7 isotonic saline during a period of 20 min.During the distention, the axonal blocker tetrodotoxin (TTX),the cholinergic antagonist atropine, or the putativesomatostatin-antagonist cyclo [7-aminoheptanoyl-Phe-D-Trp-Lys-Thr(Bzl)] were applied by vascular perfusion. Thereleases of gastrin and somatostatin were then examinedby radioimmunoassay.RESULTS: The graded gastricdistention caused a significantvolume-dependent decrease in gastrin secretion [-183±75 (5ml), -385±86 (10 ml) and -440±85 (15 ml) pg/20 min] and asignificant increase of somatostatin secretion [260±102 (5 ml),608±148 (10 ml) and 943±316 (15 ml) pg/20 min]. In responseto 10 ml distention, the infusion of either axonal blocker TTX(10-6 M) or cholinergic blocker atropine (10-7 M) had a similaraffect. They both attenuated the decrease of gastrin releaseby approximately 50 %, and attenuated the increase ofsomatostatin release by approximately 40 %. The infusion ofsomatostatin-antagonist cyclo [7-aminoheptanoyl-Phe-D-Trp-Lys-Thr (Bzl)] (10-6M) attenuated the decrease of gastrin releaseby about 60 %. Furthermore, combined infusion of thesomatostatin-antagonist and atropine completely abolisheddistention-induced inhibition of gastrin release.CONCLUSION: The present data suggest that distention ofisolated rat stomach stimulates somatostatin release viacholinergic and non-cholinergic TTX-insensitive pathways. Bothsomatostatin and intrinsic cholinergic pathways are responsiblefor distention-induced inhibition of gastrin release.     

Effects of [Asu1,7]-eel calcitonin on gastric somatostatin and gastrin release.

Effects of [Asu1,7]-eel calcitonin on gastric somatostatin and gastrin secretion were studied by using the isolated perfused rat stomach. [Asu1,7]-eel calcitonin (10(-9)--10(-7)M) caused a simultaneous dose-dependent increase of gastric somatostatin release and decrease of gastrin secretion, with a significant correlation between these two. The demonstration of calcitonin stimulation of gastric somatostatin release raises the possibility of somatostatin-mediated suppression of gastrin secretion by calcitonin.