High basal gastric acid secretion in somatostatin receptor subtype 2 knockout mice

Background & Aims: Somatostatin receptor subtype 2 (sst₂) agonists inhibit gastric secretion. The role of sst₂ in the regulation of acid secretion was assessed using sst₂ knockout mice and urethane to induce somatostatin release. Methods: Acid secretion was monitored every 10 minutes by gastric perfusion and backtitration of perfusates in fasted, urethane-anesthetized C57/129 sst₂ (−/−) mice and wild-type (+/+) mice. The ileal vein was cannulated for drug injection. Intragastric pH and serum gastrin were monitored 1 hour after anesthesia without perfusion. Results: Gastric pH values were lower in sst₂ (−/−) mice (3.8 ± 0.3) than in wild-type mice (7.1 ± 0.1, P < 0.05), and there was no difference in gastrin levels. Basal acid output per 2 hours was 10-fold higher in sst₂ knockout mice compared with wild-type mice. The gastrin antibody abolished the high basal acid secretion in sst₂ (−/−) mice and had no effect in wild-type mice. The somatostatin antibody increased basal secretion by 4-fold in wild-type and had no effect in knockout mice. Somatostatin 14 or the sst₂ agonist DC 32-87 inhibited pentagastrin-stimulated acid secretion in wild-type mice, but did not alter basal secretion in knockout mice. Conclusions: These results indicate that sst₂ is the main subtype whereby endogenous somatostatin suppresses gastric acid secretion through inhibition of gastrin action.GASTROENTEROLOGY 1998;114:1125-1132     

Is somatostatin a humoral regulator of the endocrine pancreas and gastric acid secretion in man?

The effect of low dose infusions of somatostatin on meal stimulated gastric acid secretion was studied in eight healthy volunteers by intragastric titration after a peptone test meal with radioimmunoassay control of the plasma concentrations of somatostatin and the pancreatic hormones glucagon and insulin. Infusion of somatostatin in a dose of 100 ng/kg/h, resulting in a plasma concentration of 13.4 +/- 2.1 pmol/l, inhibited acid secretion significantly, and in a dose of 800 ng/kg/h, with corresponding plasma concentration of 66.5 +/- 12.0 pmol/l the acid secretion was virtually abolished. Plasma concentrations of insulin and pancreatic glucagon decreased significantly during infusion of 200 ng/kg/h (24.5 +/- 7.5 pmol/l) and glucose concentrations increased. Serum gastrin was only significantly decreased during the highest dose of somatostatin. The range of plasma somatostatin concentrations obtained with the lower doses correspond to reported physiological variations. The results support the concept that somatostatin participates in the hormonal control of the pancreatic endocrine and the acid secretion.     

Intraluminal thyrotropin-releasing hormone affects gastric somatostatin and acid secretion through its specific receptor in rats

BACKGROUND: Although thyrotropin-releasing hormone (TRH) is present in the gastric mucosa and juice, the pathophysiologic significance of TRH is poorly understood at the peripheral level of the stomach. In the present study we analyzed the TRH-induced secretion profiles of somatostatin, histamine, and acid in the rat stomach. METHODS: The effects of intraluminal perfusion of TRH on somatostatin, histamine, and acid and the influence of the specific anti-TRH receptor antibody were investigated by using the rat gastric intraluminal perfusion model. RESULTS: Intraluminal TRH caused an immediate decrease in somatostatin secretion in a dose-dependent manner, and this change occurred preceding an increase in acid secretion. In contrast, this treatment did not yield any significant changes in histamine contents in the effluent. Pretreatment of the gastric lumen with the anti-TRH receptor antibody caused a complete inhibition of TRH-induced changes in somatostatin and acid secretion. CONCLUSIONS: These findings suggest that intraluminal TRH affects somatostatin and acid secretion in a paracrine manner via its specific receptor in the rat stomach.     

Amylin,released from the gastric fundus,stimulates somatostatin and thus inhibits histamine and acid secretion in mice

BACKGROUND & AIMS: Amylin, a peptide that displays 50% homology with calcitonin gene-related peptide (CGRP), is colocalized with somatostatin in endocrine cells of the gastric fundus. The present study was designed to determine the mechanism of action of amylin on gastric exocrine and endocrine secretion. METHODS: Acid secretion was measured in the isolated mouse stomach by titration. Somatostatin and histamine secretion were measured in rat fundic segments by radioimmunoassay. RESULTS: In isolated mouse stomach, amylin caused a concentration-dependent decrease in acid secretion. In rat fundic segments, amylin and CGRP each caused a concentration-dependent increase in somatostatin and a decrease in histamine secretion. Changes in histamine secretion induced by amylin reflected changes in somatostatin secretion and could be abolished by addition of somatostatin antibody. Both the somatostatin and the histamine responses to amylin were abolished by the selective amylin antagonist AC187 but were unaffected by the CGRP antagonist CGRP8-37. In contrast, the responses to CGRP were abolished by CGRP8-37 but were unaffected by AC187. AC187 alone decreased somatostatin and increased histamine in fundic segments and increased acid secretion in isolated stomach, indicating that endogenous amylin participates in the regulation of gastric endocrine (somatostatin and histamine) and exocrine (acid) secretion. CONCLUSIONS: In gastric fundus, release of amylin from somatostatin cells interacts with distinct amylin receptors to enhance somatostatin secretion via an autocrine pathway that leads to inhibition of histamine and acid secretion.     

Effect of somatostatin on histamine-stimulated gastric acid and pepsin secretion in dogs

The purpose of the present study was to evaluate the effect of somatostatin on gastric acid secretion and pepsin secretion in conscious dogs with gastric fistula. Infusion of histamine stimulated dose-dependently the acid secretion, whereas pepsin secretion was decreased by the high doses of histamine. Somatostatin inhibited dose-dependently the stimulated acid secretion but only with a maximum of 40%. The pepsin secretion was inhibited by somatostatin dose-dependently and with a higher potency. The acid inhibition was of a competitive type and prostaglandin-independent.     

Morphological support for paracrine inhibition of gastric acid secretion by nitric oxide in humans

BACKGROUND: Functional studies have shown that nitric oxide (NO) inhibits gastric acid secretion in a variety of species, including man. We have performed a morphological study with the intention of localizing the endothelial NO synthase (eNOS) in the human gastric mucosa. METHODS: Fifteen healthy subjects voluntarily participated in the study, and mucosal biopsies were obtained from the cardia, corpus and antrum. The presence and localization of eNOS were studied using immunohistochemical techniques. RESULTS: eNOS-immunoreactivity (eNOS-IR) is found in surface mucous cells of cardia, corpus and antrum. Unique to the oxyntic mucosa is the presence of eNOS-IR in 'endocrine-like' cells, found in close contact with parietal cells. CONCLUSIONS: eNOS-IR cells in close apposition to parietal cells provide morphological support for paracrine inhibition of gastric acid secretion by NO.     

Effect of somatostatin on bethanechol-stimulated gastric acid secretion and gastric antral motility in dogs with gastric fistula

The purpose of the present study was to evaluate the effect of somatostatin on gastric acid secretion and gastric antral motility in conscious dogs with gastric fistula. Infusion of bethanechol stimulated dose-dependently acid secretion, whereas the frequency and strength of antral motility was maintained at a high level. Somatostatin inhibited dose-dependently the stimulated acid secretion, whereas the effect on antral motility was more complex, acting especially on the amplitude of the contractions. The effects of somatostatin were not altered by using alpha-adrenergic, beta-adrenergic, dopaminergic, and serotonergic blocking drugs. The dose-response kinetics with four doses of bethanechol with and without somatostatin showed inhibition of a non-competitive type for gastric acid secretion and of a competitive type for antral motility with regard to amplitude.     

Effect of somatostatin on pentagastrin-stimulated gastric acid secretion and gastric antral motility in dogs with gastric fistula

The purpose of the present study was to evaluate the effect of somatostatin on gastric acid secretion and gastric antral motility in conscious dogs with gastric fistula. Infusion of pentagastrin induced motility with a digestive pattern. Somatostatin inhibited dose-dependently the stimulated acid secretion, whereas the effect on antral motility was more complex, acting especially on the amplitude of the contractions. The effects of somatostatin were not altered by using alpha- and beta-adrenergic, dopaminergic, and serotonergic blocking drugs. The dose-response kinetics with seven doses of pentagastrin with and without somatostatin showed inhibition of a competitive type for gastric acid secretion and of a non-competitive type for antral motility with regard to amplitude.     

Neurohumoral pathways mediating stress-induced inhibition of gastric acid secretion in rats

In awake rats, physical restraint inhibited pentagastrin-stimulated gastric acid secretion by more than 50%. This inhibitory effect was abolished by either ganglionic or noradrenergic blockade. Adrenalectomy, as well as pretreatment with a vasopressin V1-receptor antagonist, significantly attenuated the gastric inhibitory effect in response to stress. In contrast, neither truncal vagotomy nor hypophysectomy or opiate blockade prevented stress-induced inhibition of gastric acid secretion. These findings indicate that stress-induced inhibition of gastric acid secretion in rats is mediated by autonomic, noradrenergic efferents as well as by adrenal and vasopressin-dependent pathways. Vagal efferents, opiate pathways, and the pituitary gland do not seem to be involved.     

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.     

Interactions between secretin and somatostatin on acid secretion and gastric emptying in dogs

Secretin and somatostatin are two peptides released by H+ ions. The fact that blood levels of these peptides increase during the postprandial period makes them the most probable candidates for gastric acid secretion retrocontrol . The aim of our study was to determine whether a potentiation of inhibitory effects exists when the two peptides are administered simultaneously. Seven dogs were provided with a gastric fistula. Gastric acid secretion was stimulated by intragastric infusion of a bactopeptone solution or by pentagastrin (1 microgram X kg-1 X h-1). Acid outputs and gastric emptying rates were measured at regular intervals. The tests were repeated during intravenous infusion of secretin (0.125 micrograms X kg-1 X h-1), somatostatin (0.2 micrograms X kg-1 X h-1) or both peptides together at the same doses. Both secretin and somatostatin inhibited acid secretion and gastric emptying. The inhibition was not greater when both peptides were administered together. Under the conditions used, no potentiation or additive effects between the two peptides were observed on gastric acid secretion or gastric emptying.     

Beta-adrenergic agonists inhibit gastric acid and pepsin secretion through somatostatin release in dogs

The purpose of the present study was to evaluate whether the inhibitory effects of beta-adrenergic agonists on gastric secretory activity in vivo could be mediated through a local release of somatostatin. The gastric secretion was measured during continuous stimulation with pentagastrin (1 microgram/kg/h). The infusion of isoprenaline (beta 1 + beta 2), salmefamol (beta 2), and somatostatin produced inhibitory effects on both acid and pepsin secretion. The reaction patterns were similar for isoprenaline and somatostatin, whereas salmefamol induced an inhibition of longer duration and with dissimilar dose-response kinetics. The gastric somatostatin release was significantly increased after infusion of both beta-adrenergic agonists and somatostatin, with patterns similar to those obtained for the secretory inhibition. There was a significant correlation between the somatostatin release and the acid and pepsin secretion during infusion of the secretory inhibitors but not in the control state. This study shows that beta-adrenergic agonists have inhibitory effects on gastric secretion in vivo similar to those of somatostatin. Both somatostatin and the beta-adrenergic agonists stimulated the release of somatostatin from the gastric mucosa. beta-Adrenergic antagonists were without effects. Somatostatin thereby fulfils the requirements for an endogenous mediator of the beta-adrenergic inhibition.     

Control of gastric acid secretion in health and disease

Recent milestones in the understanding of gastric acid secretion and treatment of acid-peptic disorders include the (1) discovery of histamine H(2)-receptors and development of histamine H(2)-receptor antagonists, (2) identification of H(+)K(+)-ATPase as the parietal cell proton pump and development of proton pump inhibitors, and (3) identification of Helicobacter pylori as the major cause of duodenal ulcer and development of effective eradication regimens. This review emphasizes the importance and relevance of gastric acid secretion and its regulation in health and disease. We review the physiology and pathophysiology of acid secretion as well as evidence regarding its inhibition in the management of acid-related clinical conditions.     

Effect of low-dose exogenous secretin and somatostatin on pentagastrin-stimulated gastric acid secretion in man

The inhibitory effect of intravenous infusion of secretin (0.05 CU kg-1h-1) and somatostatin (60 pmol kg-1h-1), given alone or in combination, on pentagastrin-stimulated (100 ng kg-1 h-1) acid secretion was studied in 10 healthy subjects. Secretin inhibited acid secretion by 54% (p less than 0.05), and somatostatin inhibited by 70% (p less than 0.05). The combined infusion of secretin and somatostatin decreased acid output by 64% (p less than 0.05). The differences between the three groups were not significant (p greater than 0.05). Median plasma concentrations of secretin and somatostatin were of the same magnitude as seen after duodenal acidification. The present study did not demonstrate any interaction between secretin and somatostatin in the inhibition of gastric acid secretion.     

Thyroid hormones modulate the endocrine and autocrine/paracrine actions of leptin on thyrotropin secretion

We investigated the influence of hypo- and hyperthyroidism on the ability of leptin to modulate TSH secretion. Two hours after receiving leptin (8 mug leptin/100 g BW; s.c.), hyperthyroid rats (10 mug thyroxine (T4)/100 g body weight (BW) for 5 days) showed a 1.7-fold increase in serum TSH (P<0.05); in hypothyroid rats, leptin had no effect. Hemi-pituitaries of hyperthyroid rats incubated with 10(-9) and 10(-7)M leptin showed reductions in TSH release of 40 and 50% respectively (P<0.05); incubation with 1:2000 and 1:500 dilutions of antiserum against leptin resulted in 3- and 4-fold higher TSH release (P<0.05 and P<0.001 respectively). However, in hypothyroid pituitaries leptin or the antiserum had no effect. The results suggest that the in vivo and in vitro responsiveness of TSH to leptin is abolished in hypothyroidism and is preserved in short-term hyperthyroidism, in comparison to previous reports in euthyroidism. In addition, the inhibitory action of pituitary leptin is enhanced in hyperthyroid glands, which may suggest a role for locally produced leptin in the suppression of TSH release associated with hyperthyroidism.     

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.     

Somatostatin inhibits insulin and glucagon secretion via two receptors subtypes: an in vitro study of pancreatic islets from somatostatin receptor 2 knockout mice

Somatostatin (SST) potently inhibits insulin and glucagon release from pancreatic islets. Five distinct membrane receptors (SSTR1-5) for SST are known, and at least two (SSTR2 and SSTR5) have been proposed to regulate pancreatic endocrine function. Our current understanding of SST physiology is limited by the receptor subtype selectivity of peptidyl SST analogs, making it difficult to assign a physiological function to an identified SST receptor subtype. To better understand the physiology of SSTRs we studied the in vitro effects of potent subtype-selective nonpeptidyl SST analogs on the regulation of pancreatic glucagon and insulin secretion in wild-type (WT) and in somatostatin receptor 2 knockout (SSTR2KO) mice. There was no difference in basal glucagon and insulin secretion between islets isolated from SSTR2KO and WT mice; however, potassium/arginine-stimulated glucagon secretion was approximately 2-fold higher in islets isolated from SSTR2KO mice. Neither SST nor any SSTR-selective agonist inhibited basal glucagon or insulin release. SST-14 potently inhibited stimulated glucagon secretion in islets from WT mice and much less effectively in islets from SSTR2KO mice. The SSTR2 selective analog L-779,976 inhibited glucagon secretion in islets from WT, but was inactive in islets from SSTR2KO mice. L-817,818, an SSTR5 selective analog, slightly reduced glucagon release in both animal groups, whereas SSTR1, -3, and -4 selective analogs were inactive. SST and L-817,818 inhibited glucose stimulated insulin release in islets from WT and SSTR2KO mice. L-779,976 much less potently reduced insulin secretion from WT islets. In conclusion, our data demonstrate that SST inhibition of glucagon release in mouse islets is primarily mediated via SSTR2, whereas insulin secretion is regulated primarily via SSTR5.     

Quantitation of somatostatin inhibition of insulin-stimulated gastric acid and pepsin secretion in the cat.

Somatostatin inhibition of gastric acid and pepsin secretion stimulated by insulin-hypoglycaemia was quantified in six conscious cats prepared with cannulated gastric fistulae. Somatostatin 0.5-5 microgram kg-1h-1 produced a dose dependent reduction of both acid and pepsin secretions stimulated by insulin 0.2 u kg-1h-1. The doses of somatostatin which produced 50% inhibition of pepsin and acid secretions (ID50) were not significantly different (0.70 +/- 0.16 and 0.93 +/- 0.11 microgram kg-1h-1 respectively). The slope of the calculated correlation line relating % inhibition of pepsin and % inhibition of acid is within experimental error of unity indicating equality of action of somatostatin on insulin-stimulated acid and pepsin secretion. The results indicate that somatostatin is a more potent inhibitor of insulin 0.2 u kg-1h-1 stimulated acid secretion than pentagastrin 8 microgram kg-1h-1 stimulated acid secretion, but is a more potent inhibitor of pentagastrin--than insulin--stimulated pepsin secretion. As insulin stimulates less acid and more pepsin secretion than pentagastrin, the differences in sensitivities to somatostatin of these secretions produced by the two stimulants is thought to be a result of the different absolute amounts of secretion produced by the stimulants.     

Altered control of gastric acid secretion in gastrin-cholecystokinin double mutant mice

BACKGROUND & AIMS: Three pathways control gastric acid secretion: the gastrin-enterochromaffin-like (ECL) cell axis, the vagus-parietal cell axis, and the cholecystokinin (CCK)-D cell axis. Mice lacking gastrin or both gastrin and CCK were examined to determine the role of the hormones. METHODS: Acid was measured after pylorus ligation, and biopsies from gastrin knockout (KO), gastrin-CCK double-KO, and wild-type (WT) mice were collected for biochemical, immunocytochemical, and electron-microscopic examination. RESULTS: The ECL cells were inactive in both groups of mutant mice but the cell number was unaffected. Both parietal cell number and level of H(+)/K(+)-ATPase messenger RNA (mRNA) were reduced in the mutant strains, but gastrin-CCK double-KO mice displayed more active parietal cells and larger acid output than the gastrin KO mice. The acid response to histamine in double-KO mice was unchanged whereas that to gastrin was diminished, but it could be restored by infusion of gastrin. Oxyntic D-cell density was the same in both mutant strains, but the D cells were more active in the gastrin KO than in the double-KO mice. CCK infusion in gastrin-CCK double-KO mice raised the somatostatin mRNA level and inhibited acid secretion to the level seen in gastrin KO mice. Vagotomy and atropine abolished acid secretion in all 3 groups of mice. CONCLUSIONS: Lack of gastrin impairs the gastrin-ECL axis, whereas lack of gastrin and CCK impairs both hormonal pathways. In the gastrin-CCK double-KO mice, acid secretion is only controlled by cholinergic vagal stimulation, which normalizes the acid output.