Increase In Somatostatin Secretion Research Articles

Paracrine regulation of somatostatin secretion by insulin and glucagon in mouse pancreatic islets.

The endocrine pancreas comprises the islets of Langerhans, primarily consisting of beta cells, alpha cells and delta cells responsible for secretion of insulin, glucagon and somatostatin, respectively. A certain level of intra-islet communication is thought to exist, where the individual hormones may reach the other islet cells and regulate their secretion. Glucagon has been demonstrated to importantly regulate insulin secretion, while somatostatin powerfully inhibits both insulin and glucagon secretion. In this study we investigated how secretion of somatostatin is regulated by paracrine signalling from glucagon and insulin. Somatostatin secretion was measured from perfused mouse pancreases isolated from wild-type as well as diphtheria toxin-induced alpha cell knockdown, and global glucagon receptor knockout (Gcgr-/-) mice. We studied the effects of varying glucose concentrations together with infusions of arginine, glucagon, insulin and somatostatin, as well as infusions of antagonists of insulin, somatostatin and glucagon-like peptide 1 (GLP-1) receptors. A tonic inhibitory role of somatostatin was demonstrated with infusion of somatostatin receptor antagonists, which significantly increased glucagon secretion at low and high glucose, whereas insulin secretion was only increased at high glucose levels. Infusion of glucagon dose-dependently increased somatostatin secretion approximately twofold in control mice. Exogenous glucagon had no effect on somatostatin secretion in Gcgr-/- mice, and a reduced effect when combined with the GLP-1 receptor antagonist exendin 9-39. Diphtheria toxin-induced knockdown of glucagon producing cells led to reduced somatostatin secretion in response to 12mmol/l glucose and arginine infusions. In Gcgr-/- mice (where glucagon levels are dramatically increased) overall somatostatin secretion was increased. However, infusion of exendin 9-39 in Gcgr-/- mice completely abolished somatostatin secretion in response to glucose and arginine. Neither insulin nor an insulin receptor antagonist (S961) had any effect on somatostatin secretion. Our findings demonstrate that somatostatin and glucagon secretion are linked in a reciprocal feedback cycle with somatostatin inhibiting glucagon secretion at low and high glucose levels, and glucagon stimulating somatostatin secretion via the glucagon and GLP-1 receptors. Graphical abstract.

Islet Complexins are Complex

While Ca2+ activity is required for islet hormone secretion, proper glucose stimulated glucagon, insulin and somatostatin secretion requires a synergistic combination of electrical, paracrine, juxtacrine and cell intrinsic signaling pathways. This complexity can be unraveled by reconciling islet cell electrical activity, second messenger response and secretory vesicle mobilization in the presence and absence of paracrine regulatory factors. One molecule of interest is Complexin 2, a Protein Kinase A (PKA) dependent SNARE binding protein known to be expressed in alpha, beta and delta cells. Previous alpha cell studies showed that paracrine signaling by insulin and somatostatin combine to reduce glucagon secretion by lowering cAMP and PKA activity independent of Ca2+ activity. In contrast, beta cell insulin secretion is increased by cAMP/PKA and Ca2+ activity. Here, we test the hypothesis that Complexin 2 regulates insulin and glucagon secretion at the secretory vesicle level via phosphorylation by Protein Kinase A (PKA) which is in turn regulated by somatostatin paracrine signaling. Using islets from mice that are null for Complexin 2 gene (Cplxn2 KO), we measured insulin, glucagon and somatostatin secretion in response to glucose. We found increases in both glucagon and insulin output despite a concomitant increase in somatostatin secretion. In order to image Ca2+ signaling in Cplxn2 KO mice we used 2D confocal and 3D dual inverted selective plane illumination microscopy (diSPIM), which performs at high speed using light sheet illumination and camera detection. Live islet imaging experiments with GCaMP6 expressed in Cplxn 2 KO alpha cells showed that somatostatin, which normally inhibits Ca2+ oscillations, was unable to attenuate Ca2+ oscillations in Cplxn2 KO alpha cells during direct alpha cell cAMP/PKA activation.

The role of somatostatin in GLP-1-induced inhibition of glucagon secretion in mice

Aims/hypothesisGlucagon-like peptide-1 (GLP-1) receptor agonists are currently used for the treatment of type 2 diabetes. Their main mechanism of action is enhancement of glucose-induced insulin secretion (from increased beta cell glucose sensitivity) and inhibition of glucagon secretion. The latter has been demonstrated to account for about half of their blood glucose-lowering activity. Whereas the effect of GLP-1 on insulin secretion is clearly dependent on ambient glucose concentrations and has been described in detail, the mechanism responsible for the inhibitory effect of GLP-1 on glucagon secretion is heavily debated. Glucagon inhibition is also said to be glucose-dependent, although it is unclear what is meant by this. We hypothesise here that GLP-1 does not inhibit glucagon secretion during hypoglycaemia because the inhibition depends on somatostatin secretion, which in turn is dependent on glucose levels.MethodsWe used the perfused mouse pancreas model to investigate this hypothesis.ResultsWe found that, in this model, GLP-1 was able to significantly inhibit glucagon secretion from pancreatic alpha cells at all glucose levels tested: 6.0, 1.5 and 0.5 mmol/l (−27.0%, −37.1%, and −23.6%, respectively), and the decrease in glucagon secretion was invariably accompanied by an increase in somatostatin secretion (+286.8%, +158.7%, and +118.8%, respectively). Specific blockade of somatostatin receptor 2 increased glucagon secretion (+118.8% at 1.5 mmol/l glucose and +162.9% at 6.0 mmol/l glucose) and completely eliminated the inhibitory effect of GLP-1.Conclusions/interpretationWe have shown here that the glucagon-lowering effect of GLP-1 is entirely mediated through the paracrine actions of somatostatin in the perfused mouse pancreas. However, in this model, the inhibitory effect of GLP-1 was preserved at hypoglycaemic levels, leaving unanswered the question of how this is avoided in vivo in individuals treated with GLP-1 receptor agonists.

Cell-to-cell communication and cellular environment alter the somatostatin status of delta cells

IntroductionSomatostatin, released from pancreatic delta cells, is a potent paracrine inhibitor of insulin and glucagon secretion. Islet cellular interactions and glucose homeostasis are essential to maintain normal patterns of insulin secretion. However, the importance of cell-to-cell communication and cellular environment in the regulation of somatostatin release remains unclear. MethodsThis study employed the somatostatin-secreting TGP52 cell line maintained in DMEM:F12 (17.5mM glucose) or DMEM (25mM glucose) culture media. The effect of pseudoislet formation and culture medium on somatostatin content and release in response to a variety of stimuli was measured by somatostatin EIA. In addition, the effect of pseudoislet formation on cellular viability (MTT and LDH assays) and proliferation (BrdU ELISA) was determined. ResultsTGP52 cells readily formed pseudoislets and showed enhanced functionality in three-dimensional form with increased E-cadherin expression irrespective of the culture environment used. However, culture in DMEM decreased cellular somatostatin content (P<0.01) and increased somatostatin secretion in response to a variety of stimuli including arginine, calcium and PMA (P<0.001) when compared with cells grown in DMEM:F12. Configuration of TGP52 cells as pseudoislets reduced the proliferative rate and increased cellular cytotoxicity irrespective of culture medium used. ConclusionsSomatostatin secretion is greatly facilitated by cell-to-cell interactions and E-cadherin expression. Cellular environment and extracellular glucose also significantly influence the function of delta cells.

The antiulcer effect of Croton cajucara Benth in normoproteic and malnourished rats

The aim of the present study is to investigate the antiulcerogenic effects of the essential oil (EO) of Croton cajucara Benth in rats fed with a normal protein (NP) and low-protein diet (MN). NP and MN rats were treated with the essential oil for 15 days after chronic ulceration was induced. The EO accelerated healing of acetic acid-induced gastric lesions in NP and MN rats (p<0.05). In a similar experiment on chronic ulceration, Epidermal Growth Factor (EGF) mRNA expression increased in NP rats but not in MN rats. In assays of acute antiulcerogenic activity, C. cajucara increased somatostatin plasma levels and decreased gastrin plasma levels in both animal groups. The EO significantly prevented ethanol-induced gastric ulcers in NP and MN rats (p<0.001). Histological examination showed initial regeneration, formation of inflammatory infiltrate and angiogenesis in the epithelium surface of acetic acid-induced ulcers in NP and MN rats. C. cajucara prevented gastric lesions in both animal groups when ethanol methodology was used. We concluded that the EO showed an antiulcerogenic activity mediated by increased somatostatin secretion and EGF mRNA expression.

CAPS1 and CAPS2 Regulate Stability and Recruitment of Insulin Granules in Mouse Pancreatic β Cells

CAPS1 and CAPS2 regulate dense-core vesicle release of transmitters and hormones in neuroendocrine cells, but their precise roles in the secretory process remain enigmatic. Here we show that CAPS2(-/-) and CAPS1(+/-);CAPS2(-/-) mice, despite having increased insulin sensitivity, are glucose intolerant and that this effect is attributable to a marked reduction of glucose-induced insulin secretion. This correlates with diminished Ca(2+)-dependent exocytosis, a reduction in the size of the morphologically docked pool, a decrease in the readily releasable pool of secretory vesicles, slowed granule priming, and suppression of second-phase (but not first-phase) insulin secretion. In beta cells of CAPS1(+/-);CAPS2(-/-) mice, the lowered insulin content and granule numbers were associated with an increase in lysosome numbers and lysosomal enzyme activity. We conclude that although CAPS proteins are not required for Ca(2+)-dependent exocytosis to proceed, they exert a modulatory effect on insulin granule priming, exocytosis, and stability.

CONTROL OF SOMATOSTATIN SECRETION BY CCK-1 AND CCK-2 RECEPTORS IN RIN-14B CELLS, A RAT PANCREATIC ISLET CELL LINE

Background: In normal pancreatic islets of seven different species, the CCK-1 receptors were located on insulin and glucagon cells, while the CCK-2 receptors were observed on somatostatin (SS) cells. The objectives of this study were to establish the presence of the CCK receptors (CCKR) subtypes in RIN-14B cells, a SS secreting cell line and determine the implication of these receptors in SS secretion. Methods: RIN-14B cells were grown in RPMI 1640 medium. Western blot (WB) analyses were performed to detect the CCKR subtypes in cell membranes. The localization of the CCKR subtypes, insulin and SS in cells was investigated by immunofluorescence. Effects of either caerulein or pentagastrin (PG) alone or in combinaison with CCKR specific antagonists on SS secretion were evaluated by ELISA over 4 h. Results: WB analyses with specific antibodies identified both CCKR in RIN-14B cells. By immunofluorescence, both subtypes appear on SS cells (95%) and CCK-1R on insulin cells (5%). Cearulein and PG caused a conc.- dependent increase in SS secretion. Cearulein at 10−6 M caused a maximal 3-fold increase (basal 225 pg/mL ± 29) in SS release, whereas PG effect was maximal at 10−5 M with a 2.5-fold increase. Cells release 80-90% of their SS content in the culture medium. Addition of L-364,718 (anti CCK-1R)at 10−7 M and L-365,260 (anti CCK-2R) at 10−5 M, to PG (10−5 M), reduced SS release by 26% and 51%, respectively. Conclusion: CCKR subtypes are present with SS in RIN-14B pancreatic islet cells. The cells displayed high basal SS secretion significantly stimulated by caerulein and PG. This response was mostly CCK-2R dependent. Further investigations on the effect of caerulein and PG on RIN-14B cell growth are presently underway. Future data may clarify the role of CCKR subtypes in endocrine pancreatic SS cells physiology. Funded by NSERC Canada.

Splanchnic and hepatic metabolism of somatostatin: a study in cirrhotic patients with a portacaval shunt.

Experimental data suggest that somatostatin is metabolized by both liver and kidneys. Results in humans are conflicting. By studying a group of cirrhotic patients with surgically induced end-to-side portacaval shunts, basally and during a somatostatin infusion, we have been able to analyze separately the hepatic and splanchnic metabolism of this peptide. After catheterization, samples were obtained from the pulmonary artery, portal and hepatic veins. Basal pulmonary artery immunoreactive somatostatin (IRS) was significantly higher (p less than 0.001) in the cirrhotic patients (96 +/- 11 pg per ml) than in a sex- and age-matched control group (31.4 +/- 5.8 pg per ml). During the infusion of exogenous somatostatin, IRS values were higher in arterial (12,269 +/- 1,198 pg per ml) than in hepatic venous blood (7,648 +/- 1,234 pg per ml), indicating hepatic extraction of the peptide; but there was also a substantial splanchnic extraction demonstrated by higher arterial (12,269 +/- 1,532 pg per ml) than portal values (6,754 +/- 1,040 pg per ml) of IRS. During the somatostatin infusion, at very high circulation IRS levels, the liver was able to extract 38% of the peptide. This suggests that the high basal IRS levels found in liver cirrhosis are not likely to be due to hepatic failure. Possible mechanisms may involve increased somatostatin secretion, predominance of high molecular weight moieties of IRS which may not be as effectively removed by the liver, and/or portal-systemic shunting.

Gastric atrial natriuretic peptide regulates endocrine secretion in antrum and fundus of human and rat stomach.

Atrial natriuretic peptide (ANP) is present in gastric mucosa and preferentially binds to two subtypes of natriuretic peptide receptors (NPR), NPR-A and NPR-C. The present study examines the role of endogenous ANP in regulating endocrine secretion in rat and human stomachs. NPR-A protein expression and transcripts were identified in rat antral and fundic mucosa by Western blot and RT-PCR. In superfused rat and human antral and fundic segments, ANP (0.1 pM to 0.1 microM) caused a concentration-dependent increase in somatostatin secretion. In antrum, this was accompanied by a decrease in gastrin, and in fundus, this was accompanied by a decrease in histamine secretion. Changes in gastrin and histamine secretion reflected changes in somatostatin secretion and were abolished by somatostatin antibody. The NPR-A receptor antagonist anantin 1) inhibited basal somatostatin secretion and 2) abolished the somatostatin, gastrin, and histamine responses to ANP. We conclude that endogenous ANP, acting via the NPR-A receptor, stimulates somatostatin secretion from both antrum and fundus of rat and human stomach. Stimulation of somatostatin secretion is coupled to inhibition of gastrin secretion in the antrum and inhibition of histamine secretion in the fundus.

Adrenomedullin stimulates somatostatin and thus inhibits histamine and acid secretion in the fundus of the stomach

Adrenomedullin has recently been localized to enterochromaffin-like (ECL) and chief cells in the gastric fundus. It has been proposed that adrenomedullin may play a role in gastric mucosal defense and repair. In the present study, we have used the isolated, luminally perfused mouse stomach and superfused rat fundic segments to examine the effect of adrenomedullin on exocrine and endocrine secretion in this region of the stomach. Addition of adrenomedullin (1 pM to 1 μM) to the isolated mouse stomach caused a concentration-dependent decrease in acid secretion. The EC 50 value was 1.4×10 −9 and maximal inhibition of acid secretion was obtained at a concentration of 1 μM (31±4% below basal level, P<0.001). In rat fundic segments, superfusion with adrenomedullin (0.1 pM to 0.1 μM) caused a concentration-dependent increase in somatostatin secretion (EC 50, 1×10 −10) that was accompanied by a reciprocal decrease in histamine secretion (EC 50, 1.2×10 −11). Maximal stimulation of somatostatin secretion (60±5% above basal level, P<0.001) and inhibition of histamine secretion (50±5% below basal level, P<0.01) was obtained at a concentration of 0.1 μM. Changes in acid and histamine secretion induced by adrenomedullin reflected changes in somatostatin secretion and could be abolished by addition of somatostatin antibody. The axonal blocker, tetrodotoxin, also abolished the somatostatin and, consequently, the acid and histamine responses to adrenomedullin, implying that the effect of adrenomedullin on somatostatin secretion was mediated via activation of intramural neurons. We conclude that adrenomedullin, acting via intramural fundic neurons, stimulates somatostatin and thus inhibits histamine and acid secretion. This represents one mechanism by which adrenomedullin might enhance mucosal defense and repair.

Reciprocal paracrine pathways link atrial natriuretic peptide and somatostatin secretion in the antrum of the stomach

Atrial natriuretic peptide (ANP) as well as its receptor, NPR-A, have been identified in gastric antral mucosa, suggesting that ANP may act in a paracrine fashion to regulate gastric secretion. In the present study, we have superfused antral mucosal segments obtained from rat stomach to examine the paracrine pathways linking ANP and somatostatin secretion in this region. ANP (0.1 pM to 0.1 μM) caused a concentration-dependent increase in somatostatin secretion (EC 50, 0.3 nM). The somatostatin response to ANP was unaffected by the axonal blocker tetrodotoxin but abolished by addition of the selective NPR-A antagonist, anantin. Anantin alone inhibited somatostatin secretion by 18±3% ( P<0.005), implying that endogenous ANP, acting via the NPR-A receptor, stimulates somatostatin secretion. Somatostatin (1 pM to 1 μM) caused a concentration-dependent decrease in ANP secretion (EC 50, 0.7 nM) that was abolished by addition of the somatostatin subtype 2 receptor (sst2) antagonist, PRL2903. Neutralization of ambient somatostatin with somatostatin antibody (final dilution 1:200) increased basal ANP secretion by 70±8% ( P<001), implying that endogenous somatostatin inhibits ANP secretion. We conclude that antral ANP and somatostatin secretion are linked by paracrine feedback pathways: endogenous ANP, acting via the NPR-A receptor, stimulates somatostatin secretion, and endogenous somatostatin, acting via the sst2 receptor, inhibits ANP secretion.

Leptin inhibits in vitro hypothalamic somatostatin secretion and somatostatin mRNA levels.

Leptin, the product of the ob gene, is a recently discovered hormone secreted by adipocytes that regulates food intake and energy expenditure. The site of action of leptin is likely to be the hypothalamus, since this area is important in the control of food intake and leptin receptor mRNA is particularly abundant in this area. In order to further unravel the mechanisms by which leptin acts, we have studied the effect of leptin on in vitro somatostatin synthesis and secretion. Leptin administration to fetal rat neurones in monolayer culture led to a time dependent decrease in basal somatostatin secretion and somatostatin mRNA levels, the maximal effect being observed with 6x10(-8) M leptin after 24 h incubation. Furthermore, leptin completely blunted 10(-7) M Neuropeptide Y-induced increase in somatostatin secretion and somatostatin mRNA levels as well as 10(-3) M (Bu)2-cAMP and 10(-6) M A23187-induced somatostatin secretion. Finally, leptin (3x10(-8) M M) also inhibited low glucose (1.1 mM) induced-somatostatin secretion in perifused adult hypothalami. This data indicates that leptin can influence the neuroendocrine system by regulating hypothalamic somatostatin gene expression.

Effects of free fatty acids on somatostatin secretion, content and mRNA levels in cortical and hypothalamic fetal rat neurones in monolayer culture.

The effects of free fatty acids on somatostatin secretion, content and mRNA levels in fetal rat hypothalamic and cortical cell cultures were investigated. Somatostatin secretion and content were quantified by radioimmunoassay. Somatostatin mRNA levels were measured by Northern blot hybridization using a cRNA probe. Treatment with either caprylic acid (5 x 10(-3) M) or oleic acid (5 x 10(-5) M) for 90 min inhibited basal somatostatin secretion in both hypothalamic and cortical cell cultures. In addition, the increase in somatostatin secretion induced by incubation with veratridine (10(-4) M) or carbachol (10(-4) M) for 90 min was significantly reduced by the addition of caprylic acid, but somatostatin release stimulated by 5.6 x 10(-2) M KCl was not affected. Furthermore, treatment with these free fatty acids for 90 min markedly decreased somatostatin mRNA levels in both types of neurone culture. These inhibitory effects were transient, being observed after 90 min, but not after 5 h. These results support the probability that there is a role for free fatty acids in the regulation of somatostatin mRNA levels and somatostatin secretion in both hypothalamic and cortical cell cultures.

NMDA receptor activation stimulates phospholipase A 2 and somatostatin release from rat cortical neurons in primary cultures

We have recently shown that glutamate exerts a stimulatory action on somatostatin secretion in cortical neurons essentially through NMDA receptor sites. Here, we investigated whether arachidonic acid release could be modified after NMDA receptor activation in cortical neurons in primary culture. We also studied whether pharmacological manipulation of phospholipase A 2 could modify somatostatin release. We found that both glutamate and NMDA (N-methyl-D-aspartate) stimulated [ 3H]arachidonic acid release. NMDA-evoked arachidonic acid release was inhibited by MK-801 and TCP (two NMDA receptor-type antagonists), or by mepacrine, an inhibitor of phospholipase A 2. NMDA-induced somatostatin release was inhibited by MK-801, mepacrine and by another phospholipase A 2 inhibitor, p-bromophenacylbromide (pBPB). However, responses to NMDA were unaffected by H7, NDGA (nordihydroguaiaretic acid), indomethacin or by RHC 80267 (inhibitors of protein kinase C, lipooxygenase, cyclooxygenase and diacylglycerol lipase, respectively). Mepacrine (⩾ 100 μM) decreased NMDA-stimulated phosphatidylinositol (PI) hydrolysis and at higher concentrations (250 μM) was also able to inhibit basal release whereas pBPB had no effect in the range of concentrations tested. Neomycin (which inhibits phosphatidylinositol metabolism by binding strongly and selectively to inositol phospholipids) reduced by 30% the NMDA-stimulated somatostatin release, although chronic treatment of neurons with the phorbol ester 12-myristate, 13-acetate (PMA) had no effect on this response. Melittin, an activator of phospholipase A 2, was able to stimulate both arachidonic acid release and somatostatin secretion. High-performance liquid chromatography (HPLC) analysis of tritiated metabolites released from cortical neurons under basal or NMDA-stimulated conditions revealed that [ 3H]arachidonic acid was the only metabolite detectable. Furthermore, external addition of arachidonic acid increased somatostatin secretion. Our results show a correlation between the two parameters studied.

Vagal control of the release of somatostatin, vasoactive intestinal polypeptide, gastrin-releasing peptide, and HCl from porcine non-antral stomach.

We studied the secretion of somatostatin and HCl and the release of vasoactive intestinal polypeptide (VIP) and gastrin-releasing peptide (GRP) from isolated, vascularly perfused, porcine non-antral stomach. Electric vagus stimulation increased acid secretion and the release of VIP and GRP and inhibited somatostatin secretion as determined in the venous effluent. Atropine abolished the HCl response and reversed the somatostatin inhibition to a three-fold increase, whereas GRP and VIP responses were unchanged. Both intra-arterial carbachol (10(-6) M) and GRP (10(-8) M) increased acid secretion and inhibited somatostatin secretion. VIP (10(-8) M) increased somatostatin secretion and had no effect on acid secretion. By immunohistochemistry, somatostatin was localized to both open-type and closed-type cells equally spread in the various parts of the gastric glands without particular relation to the parietal cells. Numerous GRP- and VIP-immunoreactive nerve fibers were seen between the glands. It is concluded that the fundic and antral secretion of somatostatin, investigated in a previous study, are differently regulated. The relation of fundic somatostatin release to acid secretion seems to be complex.

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.

Regulation of Somatostatin Secretion by Gastrin- and Acid-Dependent Mechanisms*

The regulation of gastric somatostatin is linked to changes in gastric acidity, with a number of studies showing a good correlation between somatostatin secretion and gastrin-stimulated luminal acidity. However, gastrin may also have direct effects on somatostatin secretion independent of the concurrent acid status. We have examined the relative contribution of gastrin itself vs. gastric acid on the increase in somatostatin secretion observed after gastrin administration. Pentagastrin administered to conscious sheep for 2 h caused a 10- to 12-fold increase in both portal venous and peripheral jugular venous plasma somatostatin levels. This was associated with a decrease in gastric pH from 3.5 to 1.7. When the sheep were pretreated with the proton pump inhibitor omeprazole to prevent any change in gastric acidity, pentagastrin caused a similar increase in plasma somatostatin. The increase in somatostatin could also be produced by gastrin-17 infusions. Thus, these studies demonstrate that in the conscious animal gastrin can stimulate somatostatin independent of changes in gastric acidity. It is proposed that there is a negative feedback between somatostatin and gastrin, which may modulate the acid secretory response to gastrin.

The effect of vasoactive intestinal polypeptide on gastric acid secretion is predominantly mediated by somatostatin

The mechanism of action of vasoactive intestinal polypeptide on gastric acid secretion was examined in the isolated, luminally perfused mouse stomach. Vasoactive intestinal polypeptide caused a weak, transient increase in basal and histamine-stimulated acid secretion and a sustained increase in somatostatin secretion. The sustained increase in somatostatin despite return of acid to basal levels indicated that somatostatin secretion was a direct response to vasoactive intestinal polypeptide and not mediated by intraluminal acidification. The increase in somatostatin secretion was partly responsible for the weak, transient nature of the acid response since incubation with pertussis toxin, which is known to block the inhibitory effect of exogenous and endogenous somatostatin, converted the acid response to a sustained increase throughout the period of stimulation. The inhibitory influence of somatostatin was confirmed with selective vasoactive intestinal polypeptide antagonists. The antagonists inhibited vasoactive intestinal polypeptide-induced somatostatin secretion but caused a sustained increase in acid secretion. The pattern of response implied that somatostatin secretion was more sensitive than acid secretion to vasoactive intestinal polypeptide and vasoactive intestinal polypeptide antagonists and that suppression of somatostatin eliminated the main inhibitory influence on acid secretion. In addition, both vasoactive intestinal polypeptide antagonists inhibited basal somatostatin secretion, implying that input from tonically active vasoactive intestinal polypeptide neurons is responsible, at least in part, for basal somatostatin secretion.

The Effect of Vasoactive Intestinal Polypeptide on Gastric Acid Secretion Is Predominantly Mediated by Somatostatin

The mechanism of action of vasoactive intestinal polypeptide on gastric acid secretion was examined in the isolated, luminally perfused mouse stomach. Vasoactive intestinal polypeptide caused a weak, transient increase in basal and histamine-stimulated acid secretion and a sustained increase in somatostatin secretion. The sustained increase in somatostatin despite return of acid to basal levels indicated that somatostatin secretion was a direct response to vasoactive intestinal polypeptide and not mediated by intraluminal acidification. The increase in somatostatin secretion was partly responsible for the weak, transient nature of the acid response since incubation with pertussis toxin, which is known to block the inhibitory effect of exogenous and endogenous somatostatin, converted the acid response to a sustained increase throughout the period of stimulation. The inhibitory influence of somatostatin was confirmed with selective vasoactive intestinal polypeptide antagonists. The antagonists inhibited vasoactive intestinal polypeptide-induced somatostatin secretion but caused a sustained increase in acid secretion. The pattern of response implied that somatostatin secretion was more sensitive than acid secretion to vasoactive intestinal polypeptide and vasoactive intestinal polypeptide antagonists and that suppression of somatostatin eliminated the main inhibitory influence on acid secretion. In addition, both vasoactive intestinal polypeptide antagonists inhibited basal somatostatin secretion, implying that input from tonically active vasoactive intestinal polypeptide neurons is responsible, at least in part, for basal somatostatin secretion.

Inhibition of acid secretion by bombesin is partly mediated by release of fundic somatostatin

The effect and mode of action of bombesin on gastric acid secretion was examined in the isolated, luminally perfused mouse stomach. Bombesin caused a concentration-dependent inhibition of basal and histamine-stimulated acid secretion and an increase in somatostatin secretion. Pertussis toxin was used to determine the contribution of somatostatin to the observed inhibition of acid secretion. Previous studies have shown that at a concentration of 125 ng/ml, pertussis toxin reverses completely the inhibition of acid secretion induced by exogenous and endogenous somatostatin. Preincubation of the stomach for 60 min with pertussis toxin (125 and 1250 ng/ml) reversed partially the inhibitory effect of bombesin on basal and histamine-stimulated acid secretion by 51%–59%, implying that bombesininduced inhibition was partly mediated by release of somatostatin. The residual inhibition may represent a direct effect of bombesin on parietal cells.