Plasma Somatostatin-like Immunoreactivity Research Articles

Evidence for a novel, neurohumoral antinociceptive mechanism mediated by peripheral capsaicin-sensitive nociceptors in conscious rats

Stimulation of capsaicin-sensitive peripheral sensory nerve terminals induces remote anti-inflammatory effects throughout the body of anesthetized rats and guinea-pigs mediated by somatostatin. As somatostatin has also antinociceptive effects, the study aimed at investigating whether similar remote antinociceptive effects can be demonstrated in awake animals.In conscious rats, nociceptive nerve endings of the right hind paw decentralized by cutting the sciatic and saphenous nerves 18h before were chemically stimulated, and drop of the noxious heat threshold (heat hyperalgesia) induced by prior (18h before) plantar incision was measured on the contralateral, left hind paw using an increasing-temperature water bath. 18h after nerve transection, mustard oil-evoked plasma extravasation was not significantly reduced in the right hind paw as tested by in vivo fluorescence imaging. Applying agonist of either transient receptor potential vanilloid 1 (TRPV1) or transient receptor potential ankyrin 1 (TRPA1) receptor (capsaicin or mustard oil, respectively) to the nerve-transected paw inhibited the plantar incision-induced drop of the noxious heat threshold on the contralateral paw. The onset of these remote antihyperalgesic effects was 10–20min. A similar contralateral inhibitory effect of capsaicin or mustard oil treatment was observed on neuropathic mechanical hyperalgesia evoked by partial sciatic nerve injury 2days before nerve transection and measured by a Randall–Selitto apparatus. The remote thermal antihyperalgesic effect was prevented by chronic (5days) denervation or local capsaicin desensitization of the stimulated paw; reduced by intraperitoneally applied antagonist of somatostatin (cyclosomatostatin) or opioid receptors (naloxone). The response was mimicked by intraperitoneally applied somatostatin and associated with a 72±27% increase in plasma somatostatin-like immunoreactivity that was absent after chronic (5days) denervation.In conclusion, chemical activation of decentralized peripheral capsaicin-sensitive nociceptors evokes remote antihyperalgesic responses initiated outside the central nervous system and mediated by somatostatin and endogenous opioids.

Plasma somatostatin-like immunoreactivity increases in the plasma of septic patients and rats with systemic inflammatory reaction: Experimental evidence for its sensory origin and protective role

Alterations of somatostatin-like immunoreactivity (SST-LI) in the plasma of 11 systemic inflammatory response syndrome (SIRS) patients were investigated in correlation with cytokines, adhesion molecules and coagulation markers repeatedly during 4 days. The origin and role of SST were studied in the cecum ligation and puncture (CLP) rat SIRS model. Capsaicin-sensitive peptidergic sensory nerves were defunctionalized by resiniferatoxin (RTX) pretreatment 2 weeks earlier, in a separate group animals were treated with the somatostatin receptor antagonist cyclo-somatostatin (C-SOM). Plasma SST-LI significantly elevated in septic patients compared to healthy volunteers during the whole 4-day period. Significantly decreased Horowitz score showed severe lung injury, increased plasma C-reactive protein and procalcitonin confirmed SIRS. Soluble P-selectin, tissue plasminogen activator and the interleukin 8 and monocyte chemotactic protein-1 significantly increased, interleukin 6 and soluble CD40 ligand did not change, and soluble Vascular Adhesion Molecule-1 decreased. SST-LI significantly increased in rats both in the plasma and the lung 6h after CLP compared to sham-operation. After RTX pretreatment SST-LI was not altered in intact animals, but the SIRS-induced elevation was absent. Lung MPO activity significantly increased 6h following CLP compared to sham operation, which was significantly higher both after RTX-desensitization and C-SOM-treatment. Most non-pretreated operated rats survived the 6h, but 60% of the RTX-pretreated ones died showing a significantly worse survival. This is the first comprehensive study in humans and animal experiments providing evidence that SST is released from the activated peptidergic sensory nerves. It gets into the bloodstream and mediates a potent endogenous protective mechanism.

Inhibition of the Function of TRPV1-Expressing Nociceptive Sensory Neurons by Somatostatin 4 Receptor Agonism: echanism and Therapeutical Implications

Release of somatostatin into the circulation from the activated TRPV1-expressing nociceptors revealed by antidromic stimulation of dorsal roots in the rat pinpointed to a novel potential drug target on these nociceptors. The review summarizes the functional, biochemical and pharmacological evidence for a novel somatostatin-mediated counter-regulatory antiinflammatory/antinociceptive "sensocrine" function in rats and guinea-pigs. To identify the somatostatin receptor subtype(s) responsible for this function, experiments were focused on actions of sstR4 receptor agonists as this subtype, similarly to sstR1, is not involved in endocrine regulation. Involvement of somatostatin and the sstR4 was revealed by using pretreatment with somatostatin antibody, depletion of somatostatin with cysteamine, measuring the plasma somatostatin-like immunoreactivity, release from nerves in vitro from isolated trachea, detection of sstR4 receptors in animal and human tissue specimens, using sstR4 gene-deleted mice and investigating in detail effects of a stable peptide analogue of somatostatin (TT-232) and of an ultrapotent non-peptide agonist of sstR4 receptors. Promising antinociceptive, antihyperalgesic effects of these sstR4 agonists were observed in various experimental models of inflammatory and neuropathic conditions which are mediated both by TRPV1-expressing nociceptors and non-neural cells involved in mediation of inflammation. In sstR4 receptor knockout mice an aggravation of inflammation and hyperalgesia was observed.

Surgery and sepsis increase somatostatin-like immunoreactivity in the human plasma

We have previously shown in animals that somatostatin released from capsaicin-sensitive afferents in response to inflammation and tissue damage exerts systemic anti-nociceptive and anti-inflammatory actions. Since peptidergic sensory innervation of the airways and the joints are particularly dense, we aimed at investigating the alterations of plasma somatostatin-like immunoreactivity (SST-LI) in response to thoracic and orthopedic surgery, as well as sepsis. Thoracotomy, video-assisted thoracoscopy, hip and knee endoprosthesis were performed under general anesthesia. Blood was taken before, during and after the surgical procedures, as well as at admission and every consecutive morning from septic patients receiving exclusively total parenteral nutrition. SST-LI was determined from the plasma with specific and sensitive radioimmunoassay developed in our laboratory. Plasma SST-LI in healthy volunteers and preoperatively was 8–12 fmol/ml. Both thoracotomy and thoracoscopy significantly increased SST-LI by 55–60% at the end of the procedures when the thoracic cavity and the skin were closed. Hip endoprosthesis implantation elevated SST-LI by 30% after skin incision, which increased further to 55% by the time the surgery was completed. In contrast, knee operations performed under tourniquet did not alter SST-LI in the systemic circulation. SST-LI was almost 3-fold higher in the plasma of septic patients than in healthy volunteers. This human study revealed that thoracic/hip surgery and sepsis elevate SST-LI in the systemic circulation, presumably by inducing its release from sensory fibres. It is concluded, that the endogenous protective mechanism mediated by neural somatostatin, which has been evidenced in animals, is likely to operate in patients.

Low-dose infusion of somatostatin in man--no effect upon intestinal calcium absorption but a fall in blood insulin.

We studied the role of low plasma somatostatin (SRIF) levels in intestinal calcium absorption (CaA) in man. Plasma somatostatin-like immunoreactivity (SLI; pg X ml-1) rose after a 600-cal test meal (from 22.9 +/- 2 basally to 30.6 +/- 3.6 at 45 min, p less than 0.05), but was not affected by an oral Ca load (264 mg). Under intravenous SRIF (0.15 microgram kg-1 h-1) plasma SLI rose from 3.3 +/- 0.4 basally to 24.5 +/- 3 at 45 min (p less than 0.001). CaA was not influenced under these conditions, whereas insulin levels fell significantly and the levels of PTH, calcitonin, glucagon and GH were not changed. A regulating role of SRIF in CaA seems therefore unlikely for human physiology, since neither SLI is influenced by an oral Ca load, nor is CaA changed under postprandial SLI. The fall in insulin under postprandial-like SLI levels favors the view of a hormonal role of SRIF in man.

Systemic anti-inflammatory effect of somatostatin released from capsaicin-sensitive vagal and sciatic sensory fibres of the rat and guinea-pig

The systemic anti-inflammatory effect induced by antidromic sensory nerve stimulation was investigated in rats and guinea-pigs. In atropine-pretreated rats, bilateral antidromic stimulation of vagal afferent fibres (8 Hz, 20 min, at C-fibre strength) inhibited plasma extravasation induced by 1% mustard oil on the acutely denervated hindlegs by 36.45±3.95%. Both the prevention of this inhibitory effect by cysteamine pretreatment and the stimulation-evoked rise of plasma somatostatin-like immunoreactivity in the two species suggest a mediator role of neural somatostatin. Since this response was blocked by systemic capsaicin pretreatment and slightly reduced after subdiaphragmal vagotomy, participation of thoracic capsaicin-sensitive afferents is indicated. In guinea-pigs pretreated with guanethidine and pipecuronium, antidromic sciatic nerve stimulation induced 45.46±5.08% inhibition on the contralateral leg and increased plasma somatostatin-like immunoreactivity. It is concluded that somatostatin released from the activated vagal capsaicin-sensitive sensory nerve terminals of the rat and somatic nerves of the guinea-pigs exerts a systemic humoral function.

In Vivo and in Vitro Effects of Adenosine-5???-0-(2-thiodiphosphate) on Pancreatic Hormones in Dogs

Adenosine-5'-O-(2-thiodiphosphate) (ADP beta S), a P2y purinergic agonist, has been shown to be a potent insulin secretagogue on the isolated rat pancreas. In the present work the effects of ADP beta S on insulin somatostatin, and glucagon secretions were investigated in dogs. In vivo, in anesthetized fasted dogs, i.v. ADP beta S (0.1 mg kg-1) induced an immediate increase in insulin and somatostatin-like immunoreactivity (SLI) but not in glucagon pancreaticoduodenal outputs. In conscious fasted dogs, i.v. ADP beta S (0.1 mg kg-1) produced an immediate and transient augmentation in plasma insulin levels but not in plasma SLI and glucagon levels. In vitro, the effects of ADP beta S were investigated on the isolated uncinate process of dog pancreas, from normal and alloxan-diabetic animals. In normal uncinate process, in presence of 8.3 mM glucose, ADP beta S (1 microM) stimulated insulin and SLI releases but not glucagon release. On uncinate process from diabetic animals, ADP beta S (1 microM) retained its stimulating effects but the responses were impaired as compared with normal dogs: Insulin response was drastically diminished and SLI response strongly enhanced. In conclusion, ADP beta S is a potent insulin secretory agent in dog. This P2y purinoceptor agonist, which exerts a direct stimulatory effect on pancreatic SLI, is interestingly devoid of direct glucagonotropic properties.

Effect of intraduodenal bile and taurodeoxycholate on exocrine pancreatic secretion and on plasma levels of vasoactive intestinal polypeptide and somatostatin in man.

Intraduodenal (i.d.) application of bile or Na-taurodeoxycholate (TDC) dose dependently enhances basal exocrine pancreatic secretion. The hydrokinetic effect is mediated at least in part by secretin. This study should show, whether vasoactive intestinal polypeptide (VIP), a partial agonist of secretin, may also be involved in the mediation of the hydrokinetic effect. Furthermore, plasma concentrations of somatostatin-like immunoreactivity (SLI) were measured in order to check whether this counterregulating hormone is also released by bile and TDC. Twenty investigations were carried out on 10 fasting healthy volunteers provided with a double-lumen Dreiling tube. Bile and TDC were intraduodenally applied in doses of 2-6 g and 200-600 mg, respectively, at 65-min intervals. Plasma samples were withdrawn at defined intervals for radioimmunological determination of VIP and SLI. Duodenal juice was collected in 10-min fractions and analyzed for volume, pH, bicarbonate, lipase, trypsin, and amylase. I.d. application of bile or TDC dose dependently stimulated hydrokinetic and ecbolic pancreatic secretion. Bile exerted a slightly stronger effect than TDC. Pancreatic response was simultaneously accompanied by a significant increase of plasma VIP and SLI concentrations. The effect of bile on integrated plasma VIP and SLI concentrations seems to be dose dependent; the effect of TDC on integrated SLI, too. For the increase of integrated plasma VIP concentrations after TDC no dose-response relation could be established. We conclude that VIP may be a further mediator of bile-induced volume and bicarbonate secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential neural regulation of circulating somatostatin-14 and somatostatin-28 in conscious dogs

Somatostatin-like immunoreactivity (SLI) released into the circulation after nutrients or secretagogues is heterogeneous. To determine whether similar neural pathways regulate secretion of SLI molecular forms, circulating somatostatin-28 (S-28) and somatostatin-14 (S-14) responses to ingestion of a solid meal, intraduodenal perfusion of a liquid defined formula meal, and intravenous infusion of cholecystokinin octapeptide (CCK-OP, 250 pmol.kg-1.h-1) were measured in four conscious dogs with and without cryogenic blockade of the cervical vagus nerves. SLI was separated by gel-filtration chromatography of extracted, acidified plasma and quantified by radioimmunoassay. Basal plasma concentrations of S-28 were 4.1 +/- 0.6 fmol/ml and of S-14 were 3.8 +/- 0.4 fmol/ml. Ingestion of the solid meal increased plasma SLI threefold, and elevations of S-28 and S-14 were equivalent. After the intraduodenal liquid meal or infusion of CCK-OP, plasma SLI rose twofold, but increments of S-28 exceeded S-14, comprising approximately 70% of SLI released. Vagal blockade by cooling reversibly inhibited both the S-28 and S-14 responses to the solid meal, intraduodenal liquid meal, and CCK-OP. In contrast, atropine (50 micrograms/kg iv), given after solid food, intraduodenal nutrients, and CCK-OP, suppressed S-28 but further increased S-14 responses. Atropine did not, however, alter the suppression of S-14 and S-28 by vagal cooling.(ABSTRACT TRUNCATED AT 250 WORDS)

Selective release of somatostatin by calcitonin gene-related peptide and influence on pancreatic secretion.

Calcitonin gene-related peptide is a potent inhibitor of stimulated pancreatic exocrine secretion in vivo. The mechanism of this inhibitory action was studied in dogs and rats. The questions examined were: (1) is the inhibitory action of CGRP on pancreatic secretion mediated by somatostatin? (2) is the inhibition direct, via action on acinar cells, or indirect? and (3) is a neuronal mechanism involved, and, if so, by what pathway? In dogs with chronic pancreatic fistulae, CGRP caused significant inhibition of the outputs of pancreatic protein (63-68%) and of pancreatic bicarbonate (74-89%) and a simultaneous dose-related rise (40-102 fmol/ml) in plasma somatostatin-like immunoreactivity. A similar degree of inhibition was found when exogenous somatostatin was infused to achieve similar levels of plasma somatostatin-like immunoreactivity. More direct evidence of somatostatin mediation of CGRP action was sought in conscious rats with pancreatic fistulae using a potent and specific monoclonal antibody to somatostatin. The latter studies suggest that CGRP has both a somatostatin-dependent and a somatostatin-independent mechanism of action. In isolated rat acini, CGRP did not inhibit CCK-stimulated amylase release, suggesting that its in vivo action is indirect. In the isolated vascularly perfused rat pancreas, CGRP (10(-10)-10(-7) M) inhibited in a dose-dependent manner volume and protein output stimulated by a mixture of CCK-8 and secretin. The inhibitory action of CGRP was blocked by tetrodotoxin (10(-7) M) and by atropine (10(-7) M), but not by hexamethonium (10(-7) M). We conclude that CGRP action: (1) is partly explained by release of somatostatin; (2) is indirect; (3) is neurally mediated; and (4) involves cholinergic muscarinic neurons within the pancreas.

Plasma Somatostatin-Like Immunoreactivity during Growth-Hormone-Releasing Hormone Therapy in Non-Growth-Hormone-Deficient Children

To date, the effects of long-term growth hormone (GH)-releasing hormone [GHRH(1-29)-NH2] treatment on the plasma concentrations of somatostatin-like immunoreactivity (SLI) remain undefined. In the present study, the effect of GHRH(1-29)-NH2 therapy on plasma SLI levels has been studied in 11 non-GH-deficient children. The pattern of administration was 5 micrograms/kg body weight, given subcutaneously once every day. There was no significant change in plasma SLI levels after bolus injection of GHRH(1-29)-NH2 before and during GHRH(1-29)-NH2 therapy. However, plasma SLI rose in basal plasma and nocturnal sleep after 3 months of GHRH(1-29)-NH2 therapy and remained the same during 6 months of treatment with GHRH(1-29)-NH2. The reason for this finding is uncertain, but an increase in SLI release from the enteroinsular axis is a possible explanation. The association of our findings with the role of the circulating SLI on nutrient homeostasis and the effects of GNRH on growth velocity is discussed.

A Characterization of Immunoreactive Somatostatin in Human Milk

In the present work, somatostatin-like immunoreactivity (SLI) in human milk was characterized. In the early postpartum period, SLI levels were highest on the first day after delivery, and then gradually declined. From the fifth day postpartum, SLI levels in milk seemed unchanged. On the fifth day after delivery, milk SLI was significantly (p less than 0.01) higher than plasma SLI (126.3 +/- 11.7 vs. 17.6 +/- 1.1 pmol/L). The results indicate an active transport from blood or synthesis of somatostatin within the mammary gland. Gel filtration studies of skimmed milk, as well as milk exposed to urea and HCl, and aspirated milk from the human premature newborn, revealed that the main portion of milk SLI either represents somatostatin covalently bound to a larger protein, or more likely, a high molecular weight variant of somatostatin.

A Characterization of Immunoreactive Somatostatin in Human Milk

In the present work, somatostatin‐like immunoreactivity (SLI) in human milk was characterized. In the early postpartum period, SLI levels were highest on the first day after delivery, and then gradually declined. From the fifth day postpartum, SLI levels in milk seemed unchanged. On the fifth day after delivery, milk SLI was significantly (p < 0.01) higher than plasma SLI (126.3 ± 11.7 vs. 17.6 ± 1.1 pmol/L). The results indicate an active transport from blood or synthesis of somatostatin within the mammary gland. Gel filtration studies of skimmed milk, as well as milk exposed to urea and HCl, and aspirated milk from the human premature newborn, revealed that the main portion of milk SLI either represents somatostatin covalently bound to a larger protein, or more likely, a high molecular weight variant of somatostatin.

Relationship between gastric acid and elevated plasma somatostatinlike immunoreactivity after a mixed meal

The aim of this study was to examine whether hydrochloric acid plays a role mediating the postprandial increase in plasma somatostatinlike immunoreactivity in normal subjects. Intravenous infusion of cimetidine was found to reduce by 45% the postprandial increment in plasma somatostatin-like immunoreactivity. This effect was reversed by concomitant intragastric administration of 0.1 N hydrochloric acid, which in previous studies in fasted subjects had not affected plasma somatostatinlike immunoreactivity. The effects of cimetidine on postprandial plasma gastrin were the inverse of those observed on postprandial somatostatin. There was a greatly enhanced increment in postprandial plasma gastrin during cimetidine infusion, which was reduced significantly toward control levels by concomitant intragastric infusion of hydrochloric acid. To exclude direct inhibition by cimetidine of nutrient-stimulated plasma somatostatinlike immunoreactivity we studied the effect of cimetidine on plasma somatostatinlike immunoreactivity stimulated by an intraduodenal infusion of fat. Cimetidine did not alter the incremental response of somatostatinlike immunoreactivity to intraduodenal fat infusion. These data show that cimetidine does not invariably reduce nutrient-stimulated plasma somatostatinlike immunoreactivity and are consistent with the hypothesis that the action of cimetidine in reducing the plasma somatostatin response to ingestion of a meal is a consequence of reduction of postprandial acid secretion. These data suggest that the postprandial elevation in plasma somatostatin observed in humans is mediated in part through postprandial secretion of gastric acid, which in turn acts to elevate plasma somatostatin.

Inhibition of Pancreatic Exocrine Secretion in the Rat by Calcitonin Gene-Related Peptide: Involvement of Circulating Somatostatin*

Calcitonin gene-related peptide (CGRP), a 37-amino acid peptide, has been shown to be a potent inhibitor of pancreatic exocrine secretion when administered exogenously The present study was performed to determine if this inhibitory effect is due to the direct actions of exogenous CGRP on the exocrine pancreas or to the effects of another inhibitor released by CGRP. To this end, we first confirmed the inhibitory effects of the peptide on exocrine function by infusing the peptide into conscious rats previously prepared with bile-pancreatic fistulas and measuring cholecystokinin-stimulated amylase and protein outputs. CGRP produced a dose-dependent inhibition of both protein and amylase outputs in vivo. In marked contrast, CGRP in vitro had no direct inhibitory effect on amylase output from either the isolated buffer-perfused pancreas or dispersed acinar cells. Thus, the inhibitory effects of exogenous CGRP on pancreatic exocrine function appear to be indirect. In an attempt to determine the mediator of the inhibitory effects of CGRP, we assessed the ability of similar doses of CGRP to stimulate the release of a potential endogenous inhibitor of pancreatic exocrine function, circulating somatostatin. In conscious rats, iv CGRP dose-dependently increased circulating plasma somatostatin-like immunoreactivity from 35 +/- 5 to 86 +/- 7 fmol/ml. To determine if these increments in circulating somatostatin were sufficient to impair exocrine function, the isolated pancreas was exposed in vitro to a similar concentration of somatostatin. Somatostatin perfusion resulted in a significant inhibition of pancreatic amylase output (73%). Overall, these results support the hypothesis that 1) the inhibitory effect of exogenous CGRP on pancreatic exocrine function is indirect; 2) exogenous CGRP stimulates the release of endogenous somatostatin into the systemic circulation; and 3) the concentration of circulating somatostatin is sufficient to mediate the effect of exogenous CGRP on the exocrine pancreas.

A Case of Somatostatinoma

Plasma somatostatin response to food and the administration of the long-acting somatostatin analogue SMS 201-995, as well as pituitary responses to insulin-induced hypoglycemia, growth hormone-releasing hormone (GHRH) and thyrotropin-releasing hormone (TRH), were assessed in a 60-year-old woman with biopsy-proven metastatic somatostatinoma. SMS 201-995 alone did not change plasma somatostatin-like immunoreactivity (SRIF), but levels of low-molecular-weight forms (SRIF-14 and SRIF-28) more than doubled in response to a standard meal. This postprandial response was not affected by pretreatment with SMS 201-995. Although a growth hormone response to insulin-induced hypoglycemia and supramaximal GHRH was absent, the patient's thyroid-stimulating hormone response to TRH was normal. These results suggest that somatostatin analogues may not influence tumor autonomy and that a SRIF response to food may contribute to early satiety in patients with somatostatinoma. In addition, the long-term use of somatostatin analogues to suppress hormone production by other peptide-secreting tumors may not have predictable results.

Thyrotrophin-releasing hormone-induced growth hormone secretion in ducks: Independence of peripheral plasma somatostatin, insulin, and glucagon

In young, but not old, ducks the iv infusion of thyrotrophin-releasing hormone (TRH) markedly increased peripheral plasma growth hormone (GH) concentrations, which remained elevated throughout the 30-min period of infusion. This GH response to TRH was suppressed by the simultaneous infusion of somatostatin, which increased the level of circulating somatostatin-like immunoreactivity (SLI) to supraphysiological levels. Basal concentrations of plasma SLI in both young and old birds were suppressed by TRH infusion. Concentrations of glucagon-like immunoreactivity (GLI) were increased by the infusion of TRH in young birds but not in adults, whereas plasma immunoreactive insulin (IRI) was decreased in young birds and increased in adults following TRH infusion. These results indicate that TRH-induced GH secretion in ducks is unrelated to changes in peripheral plasma SLI, GLI, or IRI induced by TRH infusion.

Effect of GABA on basal and vagally mediated gastric acid secretion and hormone release in dogs.

To stimulate peripheral gamma-aminobutyric acid (GABA) receptors, GABA, which does not cross the blood-brain barrier, was administered to dogs with vagally innervated gastric fistulas at intravenous doses of 0, 0.66, 2, 6, 18, and 54 micrograms.kg-1.min-1. Mean gastric acid output increased from zero basally to 3.0 +/- 1.4 mmol/h during infusion of 54 micrograms.kg-1.min-1 GABA. Plasma somatostatin-like immunoreactivity decreased significantly below basal levels during infusion of 54 micrograms.kg-1.min-1 GABA (P less than 0.05). To stimulate central nervous system GABA receptors as well as peripheral GABA receptors, progabide, a GABA-receptor agonist, which readily crosses the blood-brain barrier, was injected intravenously. Mean acid output was 3.5 +/- 1.3 mmol/h after 20 mg/kg progabide and 0.6 +/- 0.5 mmol/h after its vehicle (P less than 0.05). Basal serum gastrin concentration increased significantly after progabide injection. Acid output during insulin-induced hypoglycemia was inhibited 59% by 30 mg/kg intravenous progabide. Progabide infusion also diminished or abolished circulating gastrin, somatostatin, and pancreatic polypeptide responses during insulin-induced hypoglycemia (P less than 0.05). Further studies were performed in dogs with a gastric fistula and a vagally denervated Heidenhain pouch to confirm that GABA-receptor stimulation affects acid secretion via peripheral pathways. Intravenous injection of baclofen (0.5 mg/kg), a GABAB-receptor agonist, increased acid secretion significantly from the gastric fistula and the Heidenhain pouch. These studies suggest that GABA may play a role in regulating gastric acid secretion and gastrointestinal and pancreatic endocrine function by both central and peripheral mechanisms.

Somatostatin may not be a hormonal messenger of fat-induced inhibition of gastric functions

The present study was designed to evaluate somatostatin as a hormonal inhibitor of gastric functions in humans. Seven healthy volunteers were investigated on 6 separate days. Peptone meal-stimulated gastric acid secretion was measured by intragastric titration for 2 h and gastric emptying was estimated with a dye-dilution technique. The effect of intravenous administration of somatostatin at 0, 12.5, 50, 100, and 200 pmol/kg · h was investigated and related to the effect of intragastric administration of 100 ml of vegetable oil. Plasma somatostatinlike immunoreactivity was elevated during intravenous administration of somatostatin at 100 and 200 pmol/kg · h, whereas no increase was detected in response to the oil. Somatostatin infusion at 100 and 200 pmol/kg · h significantly inhibited the acid secretion by 25% and 65%, and the oil reduced the acid output by 41%. Somatostatin at 100 and 200 pmol/kg · h significantly enhanced gastric emptying, whereas the oil inhibited gastric emptying. These observations suggest that somatostatin may not be an important hormonal messenger of fat-induced inhibition of acid secretion or gastric emptying.

Degradation and conversion of somatostatin in normal and diabetic rats in vivo and in vitro

Plasma somatostatin-like immunoreactivity in the portal and jugular veins of streptozotocin diabetic rats was compared with that in normal control rats. In the diabetic group, somatostatin levels in the portal (p less than 0.05) and jugular (p less than 0.01) veins were both elevated compared with those in the control group. Moreover, the degree of elevation was greater in the jugular vein than in the portal vein. To further investigate the role of the liver in the clearance of somatostatin-28 in vivo, 2 micrograms of somatostatin-28 was administered as a bolus into the external jugular vein of intact and functionally hepatectomized rats. The mean half-time of somatostatin-28 was significantly longer in intact diabetic rats than in controls (p less than 0.05). The functional hepatectomy did not cause a significant difference in the half-time in diabetic rats but made it longer in control rats. These results suggest that the longer half-time of somatostatin-28 in diabetic rats in vivo is due to its slower hepatic clearance. The hepatic clearance of somatostatin-28 and somatostatin-14 was further studied in vitro using a recirculating liver perfusion method. The hepatic clearance of 1.2 nM of either somatostatin-28 or somatostatin-14 was significantly lower in diabetic rats than in controls (p less than 0.01). This indicates that elevated plasma somatostatin levels in diabetic rats are caused at least in part by decreased hepatic clearance of somatostatin.(ABSTRACT TRUNCATED AT 250 WORDS)