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V. Martínez - One of the best experts on this subject based on the ideXlab platform.

  • Peripheral PACAP inhibits gastric acid secretion through Somatostatin release in mice
    British journal of pharmacology, 2004
    Co-Authors: Laura Piqueras, Yvette Taché, V. Martínez
    Abstract:

    Studies in rats suggest that PACAP modulates gastric acid secretion through the release of both histamine and Somatostatin. We characterized the effects of exogenous PACAP on gastric acid secretion in urethane-anesthetized mice implanted with a gastric cannula and in conscious 2-h pylorus ligated mice, and determined the involvement of Somatostatin and Somatostatin receptor type 2 (SSTR2) by using Somatostatin immunoneutralization, the SSTR2 antagonist, PRL-2903, and SSTR2 knockout mice. Urethane-anesthetized wild-type mice had low basal acid secretion (0.10±0.01 μmol (10 min)−1) compared with SSTR2 knockout mice (0.93±0.07 μmol (10 min)−1). Somatostatin Antibody and PRL-2903 increased basal secretion in wild-type mice but not in SSTR2 knockout animals. In wild-type urethane-anesthetized mice, PACAP-38 (3–270 μg kg−1 h−1) did not affect the low basal acid secretion, but inhibited the acid response to pentagastrin, histamine, and bethanechol. In wild-type urethane-anesthetized mice pretreated with Somatostatin Antibody or PRL-2903 and in SSTR2 knockout mice, peripheral infusion of PACAP-38 or Somatostatin-14 did not inhibit the increased basal gastric acid secretion. In conscious wild-type mice, but not in SSTR2 knockout mice, PACAP-38 inhibited gastric acid secretion induced by 2-h pylorus ligation. The antisecretory effect of PACAP-38 was prevented by immunoneutralization of Somatostatin. These results indicate that, in mice, peripheral PACAP inhibits gastric acid secretion through the release of Somatostatin and the activation of SSTR2 receptors. There is no evidence for stimulatory effects of PACAP on acid secretion in mice. British Journal of Pharmacology (2004) 142, 67–78. doi:10.1038/sj.bjp.0705739

  • Galanin inhibits gastric acid secretion through a Somatostatin-independent mechanism in mice.
    Peptides, 2004
    Co-Authors: Laura Piqueras, Yvette Taché, V. Martínez
    Abstract:

    The role of Somatostatin in galanin-induced inhibition of gastric acid secretion in urethane-anesthetized mice was investigated by using immunoneutralization of endogenous Somatostatin and Somatostatin receptor type 2 (SSTR2) knockout mice. Intravenous galanin (10 and 20 μg/kg/h) inhibited pentagastrin-stimulated gastric acid secretion by 47 and 33%, respectively. Somatostatin Antibody injected i.v. increased acid secretion by 3.5-fold over basal levels but did not modify the antisecretory effects of galanin. Urethane-anesthetized SSTR2 knockout mice had a basal secretion 14-fold higher than wild-type animals, that was inhibited by galanin (10 and 20 μg/kg/h) by 49 and 31% respectively. In mice galanin inhibits gastric acid secretion through a Somatostatin-independent mechanism.

  • Somatostatin receptor type 2 mediates bombesin-induced inhibition of gastric acid secretion in mice
    The Journal of Physiology, 2003
    Co-Authors: Laura Piqueras, Yvette Taché, V. Martínez
    Abstract:

    Studies in isolated mouse stomach showed that bombesin releases Somatostatin. We characterized the effects of exogenous bombesin on gastric acid secretion in mice and determined the involvement of Somatostatin and Somatostatin receptor type 2 (SSTR2) by using Somatostatin immunoneutralization, the SSTR2 antagonist, PRL-2903, and SSTR2 knockout mice. Gastric acid secretion was monitored under basal and pentagastrin-, histamine- or bethanechol-stimulated conditions in urethane-anaesthetized mice. Bombesin (10–40 μg kg−1 h−1) and Somatostatin-14 (20 μg kg−1 h−1) were infused i.v. 10 and 30 min after PRL-2903 or Somatostatin Antibody pretreatment, respectively. Urethane-anaesthetized wild-type mice had low basal acid secretion (0.12 ± 0.01 μmol (10 min)−1) compared with SSTR2 knockout mice (1.43 ± 0.10 μmol (10 min)−1). Somatostatin Antibody and PRL-2903 increased basal secretion in wild-type mice but not in SSTR2 knockout animals. In wild-type mice, bombesin inhibited secretagogue-stimulated acid secretion in a dose-dependent manner, and Somatostatin-14 inhibited pentagastrin-stimulated secretion. In wild-type mice pretreated with Somatostatin Antibody or PRL-2903 and in SSTR2 knockout mice, bombesin and Somatostatin-14 i.v. infusion did not alter the increased gastric acid secretion. These results indicate that, in mice, bombesin inhibits gastric acid secretion through the release of Somatostatin and the activation of SSTR2. These observations strengthen the important role of SSTR2 in mediating Somatostatin inhibitory actions on gastric acid secretion.

  • High basal gastric acid secretion in Somatostatin receptor subtype 2 knockout mice
    Gastroenterology, 1998
    Co-Authors: V. Martínez, John H. Walsh, Annette P. Curi, Behrooz Torkian, James M. Schaeffer, Hilary A. Wilkinson, Y. Tache
    Abstract:

    Abstract Background & Aims: Somatostatin receptor subtype 2 (sst 2 ) agonists inhibit gastric secretion. The role of sst 2 in the regulation of acid secretion was assessed using sst 2 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 sst 2 (−/−) 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 sst 2 (−/−) mice (3.8 ± 0.3) than in wild-type mice (7.1 ± 0.1, P 2 knockout mice compared with wild-type mice. The gastrin Antibody abolished the high basal acid secretion in sst 2 (−/−) 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 sst 2 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 sst 2 is the main subtype whereby endogenous Somatostatin suppresses gastric acid secretion through inhibition of gastrin action. GASTROENTEROLOGY 1998;114:1125-1132

  • Somatostatin Antibody does not influence bombesin-induced inhibition of gastric acid secretion in rats
    Peptides, 1995
    Co-Authors: V. Martínez, Hong Yang, Helen Wong, John H. Walsh, Yvette Taché
    Abstract:

    Abstract The influence of peripheral Somatostatin immunoneutralization on intravenous (IV) and intracerebroventricular (ICV) bombesin-induced inhibition of gastric acid secretion (GAS) was investigated with the Somatostatin monoclonal Antibody, CURE.S6, in rats. The Somatostatin Antibody, injected IV in conscious rats with a chronic gastric fistula and IV catheter, did not modify basal GAS, whereas in urethane-anesthetized rats the basal GAS was increased by 150%. In conscious rats, Somatostatin (15 μg/kg/h, IV) inhibited basal GAS by 50% after injection of control Antibody but not after pretreatment with the Somatostatin Antibody. With pretreatment with a control Antibody, bombesin (10 μg/kg/h, IV) inhibited basal GAS by 60% in conscious rats and by 50% the acid response to pentagastrin infusion in urethane-anesthetized rats. Bombesin injected ICV (3 and 10 ng/10 μl/rat) inhibited basal GAS by 50% and 70%, respectively, in conscious rats pretreated with a control Antibody. The Somatostatin Antibody injected IV before IV or ICV injection of bombesin did not influence bombesin-induced inhibition of GAS in conscious or anesthetized rats. These results show that peripheral Somatostatin does not play a major role in the inhibition of gastric acid secretion induced either by ICV or IV administration of bombesin or basal acid secretion in conscious rats.

Mitchell L Schubert - One of the best experts on this subject based on the ideXlab platform.

  • adrenomedullin stimulates Somatostatin and thus inhibits histamine and acid secretion in the fundus of the stomach
    Regulatory Peptides, 2003
    Co-Authors: Ari Hirsch, Akira Arimura, Robert W Mccuen, Mitchell L Schubert
    Abstract:

    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 EC50 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 (EC50, 1×10−10) that was accompanied by a reciprocal decrease in histamine secretion (EC50, 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
    Regulatory Peptides, 2003
    Co-Authors: William R Gower, Robert W Mccuen, Akira Arimura, John R Dietz, Carol S Landon, Mitchell L Schubert
    Abstract:

    Abstract 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 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 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.

  • Amylin, released from the gastric fundus, stimulates Somatostatin and thus inhibits histamine and acid secretion in mice.
    Gastroenterology, 2002
    Co-Authors: Muhammad Zaki, Lokesh Vuyyuru, Robert W Mccuen, Shashi Koduru, Mitchell L Schubert
    Abstract:

    Abstract 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. GASTROENTEROLOGY 2002;123:247-255

  • histamine acting via h3 receptors inhibits Somatostatin and stimulates acid secretion in isolated mouse stomach
    Gastroenterology, 1997
    Co-Authors: Lokesh Vuyyuru, Mitchell L Schubert
    Abstract:

    Abstract BACKGROUND & AIMS: The role of histamine H3 receptors in the regulation of gastric acid secretion is unclear. The present study was designed to characterize the location of H3 receptors in the fundus of the stomach and the mechanism by which these receptors regulate acid secretion. METHODS: Acid, Somatostatin, and histamine secretions were measured in the isolated mouse stomach. RESULTS: Thioperamide (H3 antagonist) increased Somatostatin and decreased histamine and acid secretion in a concentration-dependent manner. (r)-alpha-Methylhistamine (H3 agonist) had the opposite effect, decreasing Somatostatin and increasing histamine and acid secretion. The pattern implies that endogenous histamine, acting via H3 receptors, exerts an inhibitory paracrine influence on Somatostatin secretion. Somatostatin Antibody increased basal histamine secretion and abolished the decrease in histamine and acid secretion induced by thioperamide, confirming that changes in histamine and acid secretion induced by the activation of H3 receptors reflected changes in Somatostatin secretion. Similar effects were obtained when acid secretion was stimulated by histamine: thioperamide augmented Somatostatin and thus inhibited acid secretion, and (r)-alpha- methylhistamine attenuated Somatostatin and increased acid secretion. CONCLUSIONS: Reciprocal inhibitory paracrine pathways link histamine and Somatostatin cells in the gastric fundus. Histamine, acting via H3 receptors, augments acid secretion by eliminating the inhibitory influence of Somatostatin. (Gastroenterology 1997 Nov;113(5):1545-52)

  • Reciprocal inhibitory paracrine pathways link histamine and Somatostatin secretion in the fundus of the stomach.
    The American journal of physiology, 1997
    Co-Authors: Lokesh Vuyyuru, Akira Arimura, L Harrington, Mitchell L Schubert
    Abstract:

    The present study was designed to examine the functional linkage between histamine and Somatostatin secretion in the fundus of the stomach. In segments of rat fundic mucosa, superfusion with thioperamide (H3 antagonist) increased Somatostatin and decreased histamine secretion; superfusion with (R)(-)-alpha-methylhistamine (H3 agonist) had the opposite effect, decreasing Somatostatin and increasing histamine secretion. The pattern implied that endogenous histamine, acting via H3 receptors, exerts an inhibitory paracrine influence on Somatostatin secretion. Superfusion with Somatostatin Antibody (1:250) increased histamine secretion, implying that endogenous Somatostatin, in turn, exerts an inhibitory paracrine influence on histamine secretion. Somatostatin Antibody also abolished the decrease in histamine secretion induced by thioperamide and the increase in histamine secretion induced by (R)(-)-alpha-methylhistamine, implying that changes in histamine secretion induced by activation of H3 receptors reflect changes in Somatostatin secretion. Superfusion with the muscarinic agonist methacholine alone and in the presence of either H3 agonist or H3 antagonist confirmed the existence of reciprocal inhibitory pathways linking Somatostatin and histamine. We conclude that fundic histamine and Somatostatin secretion are linked via reciprocal inhibitory paracrine pathways that serve to amplify the regulatory influence of Somatostatin.

John H. Walsh - One of the best experts on this subject based on the ideXlab platform.

  • immunoneutralization of Somatostatin insulin and glucagon causes alterations in islet cell secretion in the isolated perfused human pancreas
    Pancreas, 2001
    Co-Authors: F. C. Brunicardi, John H. Walsh, Robert Kleinman, Stefan Moldovan, Thuha Nguyen, P C Watt, Ronald L Gingerich
    Abstract:

    Introduction In this study, immunoneutralization of endogenous insulin, glucagon, and Somatostatin with specific antibodies was used in an isolated perfused human pancreas (IPHP) model. Aims To study intrapancreatic cellular interactions and pancreatic hormonal secretion. Methodology Randomized, sequential 10-minute test intervals of single-pass perfusion with each Antibody were performed at 3.9 m M or 11.5 m M steady-state glucose concentrations. Somatostatin, insulin, and glucagon levels were measured in the effluent during basal and immunoneutralization intervals. Results At 3.9 m M glucose concentration, Somatostatin Antibody (SS-Ab) stimulated insulin and glucagon secretion, insulin Antibody (IN-Ab) inhibited glucagon secretion, and glucagon Antibody (GN-Ab) stimulated insulin secretion. At 11.5 m M glucose concentration, SS-Ab stimulated insulin secretion, IN-Ab stimulated glucagon and inhibited Somatostatin secretion, and GN-Ab stimulated insulin secretion. Conclusion The variation in hormonal responses to immunoneutralization during stimulated and nonstimulated glucose conditions suggests that a dynamic association exists between the pancreatic cells.

  • PACAP type I receptor activation regulates ECL cells and gastric acid secretion.
    The Journal of clinical investigation, 1999
    Co-Authors: Ningxin Zeng, John H. Walsh, Gordon Ohning, Christoph Athmann, T Kang, Rong-ming Lyu, George Sachs, Joseph R. Pisegna
    Abstract:

    Pituitary adenylate cyclase activating polypeptide (PACAP) is present in gastric nerves, and PACAP receptors (PAC1) are found on gastric enterochromaffin-like (ECL) cells. Expression of PAC1 splice variants in purified ECL cells was determined by RT-PCR. PACAP effects on ECL cells were analyzed by video imaging of [Ca2+]i and histamine release; its effects on gastric glands were examined by confocal microscopy of [Ca2+]i in ECL and parietal cells. PACAP action on D cells was measured by [Ca2+]i and radioimmunoassay. PACAP effects on acid secretion were determined in fistula rats with or without neutralizing anti-Somatostatin antibodies. All splice variants of PAC1 were found, but vasoactive intestinal polypeptide (VIP) receptor (VPAC) products were absent. PACAP-27 and -38 dose-dependently raise [Ca2+]i in ECL cells, and stimulated histamine release. VIP had a much lower affinity, which demonstrates the presence of PAC1 but not VPAC. PACAP elevated [Ca2+]i in ECL and parietal cells of superfused gastric glands, but only the parietal cell signal was inhibited by ranitidine, showing the absence of PAC1 on parietal cells, and demonstrating functional coupling between the cell types. PACAP and VIP stimulated calcium signaling and Somatostatin release from D cells with almost equal efficacy. Acid secretion was stimulated after intravenous injection of PACAP into rats treated with Somatostatin Antibody. PACAP is a candidate as a mediator of neural regulation of acid secretion. J. Clin. Invest. 104:1383–1391 (1999).

  • High basal gastric acid secretion in Somatostatin receptor subtype 2 knockout mice
    Gastroenterology, 1998
    Co-Authors: V. Martínez, John H. Walsh, Annette P. Curi, Behrooz Torkian, James M. Schaeffer, Hilary A. Wilkinson, Y. Tache
    Abstract:

    Abstract Background & Aims: Somatostatin receptor subtype 2 (sst 2 ) agonists inhibit gastric secretion. The role of sst 2 in the regulation of acid secretion was assessed using sst 2 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 sst 2 (−/−) 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 sst 2 (−/−) mice (3.8 ± 0.3) than in wild-type mice (7.1 ± 0.1, P 2 knockout mice compared with wild-type mice. The gastrin Antibody abolished the high basal acid secretion in sst 2 (−/−) 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 sst 2 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 sst 2 is the main subtype whereby endogenous Somatostatin suppresses gastric acid secretion through inhibition of gastrin action. GASTROENTEROLOGY 1998;114:1125-1132

  • Somatostatin Antibody does not influence bombesin-induced inhibition of gastric acid secretion in rats
    Peptides, 1995
    Co-Authors: V. Martínez, Hong Yang, Helen Wong, John H. Walsh, Yvette Taché
    Abstract:

    Abstract The influence of peripheral Somatostatin immunoneutralization on intravenous (IV) and intracerebroventricular (ICV) bombesin-induced inhibition of gastric acid secretion (GAS) was investigated with the Somatostatin monoclonal Antibody, CURE.S6, in rats. The Somatostatin Antibody, injected IV in conscious rats with a chronic gastric fistula and IV catheter, did not modify basal GAS, whereas in urethane-anesthetized rats the basal GAS was increased by 150%. In conscious rats, Somatostatin (15 μg/kg/h, IV) inhibited basal GAS by 50% after injection of control Antibody but not after pretreatment with the Somatostatin Antibody. With pretreatment with a control Antibody, bombesin (10 μg/kg/h, IV) inhibited basal GAS by 60% in conscious rats and by 50% the acid response to pentagastrin infusion in urethane-anesthetized rats. Bombesin injected ICV (3 and 10 ng/10 μl/rat) inhibited basal GAS by 50% and 70%, respectively, in conscious rats pretreated with a control Antibody. The Somatostatin Antibody injected IV before IV or ICV injection of bombesin did not influence bombesin-induced inhibition of GAS in conscious or anesthetized rats. These results show that peripheral Somatostatin does not play a major role in the inhibition of gastric acid secretion induced either by ICV or IV administration of bombesin or basal acid secretion in conscious rats.

  • Regulatory role of intraislet Somatostatin on insulin secretion in the isolated perfused human pancreas.
    Pancreas, 1994
    Co-Authors: Kleinman R, John H. Walsh, H Wong, Gordon Ohning, F. Charles Brunicardi
    Abstract:

    This study was undertaken to determine whether intraislet Somatostatin inhibits insulin secretion in the human islet. A high-affinity monoclonal Somatostatin Antibody was used to immunoneutralize Somatostatin in the isolated, perfused human pancreas. Single pass perfusion was performed in pancreata obtained from cadaveric organ donors using a modified Krebs medium with either 3.9 or 12.9 mM glucose. Sequential test periods separated by basal periods were performed with either Somatostatin-14 (SS-14), Somatostatin monoclonal Antibody (CURE.S6), or a combined infusion. Infusion of SS-14 resulted in inhibition of insulin secretion under both low glucose (delta X = -712 +/- 212 pM) (p < 0.05) and high glucose (delta X = -21,913 +/- 10,003 pM) (p = 0.06) conditions. Immunoneutralization of intraislet Somatostatin with CURE.S6 resulted in a significant increase in insulin secretion under both low glucose (454 +/- 162 pM) (p < 0.05) and high glucose (2,177 +/- 829 pM) (p < 0.05) conditions. Combined infusion of SS-14 and CURE.S6 resulted in a reversal of the inhibitory effect of exogenous SS-14. The data suggest that intraislet Somatostatin has an inhibitory role in the regulation of insulin secretion in the human islet.

F. C. Brunicardi - One of the best experts on this subject based on the ideXlab platform.

  • immunoneutralization of Somatostatin insulin and glucagon causes alterations in islet cell secretion in the isolated perfused human pancreas
    Pancreas, 2001
    Co-Authors: F. C. Brunicardi, John H. Walsh, Robert Kleinman, Stefan Moldovan, Thuha Nguyen, P C Watt, Ronald L Gingerich
    Abstract:

    Introduction In this study, immunoneutralization of endogenous insulin, glucagon, and Somatostatin with specific antibodies was used in an isolated perfused human pancreas (IPHP) model. Aims To study intrapancreatic cellular interactions and pancreatic hormonal secretion. Methodology Randomized, sequential 10-minute test intervals of single-pass perfusion with each Antibody were performed at 3.9 m M or 11.5 m M steady-state glucose concentrations. Somatostatin, insulin, and glucagon levels were measured in the effluent during basal and immunoneutralization intervals. Results At 3.9 m M glucose concentration, Somatostatin Antibody (SS-Ab) stimulated insulin and glucagon secretion, insulin Antibody (IN-Ab) inhibited glucagon secretion, and glucagon Antibody (GN-Ab) stimulated insulin secretion. At 11.5 m M glucose concentration, SS-Ab stimulated insulin secretion, IN-Ab stimulated glucagon and inhibited Somatostatin secretion, and GN-Ab stimulated insulin secretion. Conclusion The variation in hormonal responses to immunoneutralization during stimulated and nonstimulated glucose conditions suggests that a dynamic association exists between the pancreatic cells.

  • The effect of intraislet Somatostatin immunoneutralization on insulin secretion in the isolated perfused rat pancreas.
    International journal of surgical investigation, 2000
    Co-Authors: F. C. Brunicardi, D. Wen, John C. Bradley, D. Elahi, Charles C. Miller, J. Hanks
    Abstract:

    BACKGROUND There is evidence of a local inhibitory effect of Somatostatin on insulin secretion in the isolated human pancreas, but this has not been shown in a rat model. The possible phasic effect of Somatostatin on insulin secretion has not been demonstrated. AIMS This study was undertaken to determine if Somatostatin has a local regulatory effect on phasic insulin secretion within a rat pancreas model. METHODS The basal and glucose stimulated secretion of insulin was compared with and without immunoneutralization of Somatostatin using a Somatostatin Antibody in an isolated perfused rat pancreas model. High concentration, high affinity monoclonal Somatostatin Antibody was perfused through isolated rat pancreata. Radioimmunoassay for insulin was performed on the portal effluent. RESULTS Immunoneutralization of Somatostatin during basal insulin secretion produced a rise in insulin secretion of 551 +/- 163% that approached significance. Immunoneutralization during glucose stimulated insulin secretion produced a significant rise in insulin secretion compared to the control group of 2,678 +/- 187% vs. 535 +/- 39% (p < 0.05). The phase I vs. the phase II response in the glucose stimulated pancreas was similar in the presence of control Antibody, 867 +/- 351% vs. 900 +/- 398% (p = NS). With Somatostatin immunoneutralization, the glucose stimulated pancreas had a significantly higher phase II response than phase I; 3,832 +/- 688% vs. 2,516 +/- 431% (p < 0.05). CONCLUSION These data indicate that intraislet Somatostatin is an inhibitor of insulin secretion in the isolated perfused rat pancreas. This effect occurs primarily in phase II of insulin secretion.

  • differential inhibition of insulin and islet amyloid polypeptide secretion by intraislet Somatostatin in the isolated perfused human pancreas
    Pancreas, 1999
    Co-Authors: Robert Kleinman, H Wong, J H Walsh, Shawn P Fagan, Thomas E Adrian, David K Imagawa, F. C. Brunicardi
    Abstract:

    Islet amyloid polypeptide (IAPP) and insulin are co-stored and generally secreted in parallel; however, studies have demonstrated that the IAPP/insulin molar secretory ratio may be altered in response to certain stimuli. Because we previously demonstrated that intraislet Somatostatin is an inhibitory regulator of basal insulin secretion in the isolated perfused human pancreas, this study was designed to determine the relative influence on the regulation of IAPP versus insulin secretion. Single-pass perfusion was performed in pancreata obtained from cadaveric organ donors with continuous perfusion of a modified Krebs media with the glucose level maintained at constant 3.9 mM. Intraislet Somatostatin was immunoneutralized by the infusion of either a highly sensitive monoclonal Somatostatin Antibody (SAb) or its FAb fragment (SFAb). Sequential test periods separated by basal periods were performed by infusion of either of the following: glucose, SAb, SFAb, or appropriate controls. IAPP/insulin molar secretory ratio decreased by 33% in response to infusion of either SAb or the SFAb, respectively (p < 0.01), and decreased by 67% in response to glucose infusion (p < 0.01). An alteration of the IAPP/insulin secretory ratio is seen in response to infusion of exogenous glucose or in response to the neutralization of intraislet Somatostatin.

Yvette Taché - One of the best experts on this subject based on the ideXlab platform.

  • Peripheral PACAP inhibits gastric acid secretion through Somatostatin release in mice
    British journal of pharmacology, 2004
    Co-Authors: Laura Piqueras, Yvette Taché, V. Martínez
    Abstract:

    Studies in rats suggest that PACAP modulates gastric acid secretion through the release of both histamine and Somatostatin. We characterized the effects of exogenous PACAP on gastric acid secretion in urethane-anesthetized mice implanted with a gastric cannula and in conscious 2-h pylorus ligated mice, and determined the involvement of Somatostatin and Somatostatin receptor type 2 (SSTR2) by using Somatostatin immunoneutralization, the SSTR2 antagonist, PRL-2903, and SSTR2 knockout mice. Urethane-anesthetized wild-type mice had low basal acid secretion (0.10±0.01 μmol (10 min)−1) compared with SSTR2 knockout mice (0.93±0.07 μmol (10 min)−1). Somatostatin Antibody and PRL-2903 increased basal secretion in wild-type mice but not in SSTR2 knockout animals. In wild-type urethane-anesthetized mice, PACAP-38 (3–270 μg kg−1 h−1) did not affect the low basal acid secretion, but inhibited the acid response to pentagastrin, histamine, and bethanechol. In wild-type urethane-anesthetized mice pretreated with Somatostatin Antibody or PRL-2903 and in SSTR2 knockout mice, peripheral infusion of PACAP-38 or Somatostatin-14 did not inhibit the increased basal gastric acid secretion. In conscious wild-type mice, but not in SSTR2 knockout mice, PACAP-38 inhibited gastric acid secretion induced by 2-h pylorus ligation. The antisecretory effect of PACAP-38 was prevented by immunoneutralization of Somatostatin. These results indicate that, in mice, peripheral PACAP inhibits gastric acid secretion through the release of Somatostatin and the activation of SSTR2 receptors. There is no evidence for stimulatory effects of PACAP on acid secretion in mice. British Journal of Pharmacology (2004) 142, 67–78. doi:10.1038/sj.bjp.0705739

  • Galanin inhibits gastric acid secretion through a Somatostatin-independent mechanism in mice.
    Peptides, 2004
    Co-Authors: Laura Piqueras, Yvette Taché, V. Martínez
    Abstract:

    The role of Somatostatin in galanin-induced inhibition of gastric acid secretion in urethane-anesthetized mice was investigated by using immunoneutralization of endogenous Somatostatin and Somatostatin receptor type 2 (SSTR2) knockout mice. Intravenous galanin (10 and 20 μg/kg/h) inhibited pentagastrin-stimulated gastric acid secretion by 47 and 33%, respectively. Somatostatin Antibody injected i.v. increased acid secretion by 3.5-fold over basal levels but did not modify the antisecretory effects of galanin. Urethane-anesthetized SSTR2 knockout mice had a basal secretion 14-fold higher than wild-type animals, that was inhibited by galanin (10 and 20 μg/kg/h) by 49 and 31% respectively. In mice galanin inhibits gastric acid secretion through a Somatostatin-independent mechanism.

  • Somatostatin receptor type 2 mediates bombesin-induced inhibition of gastric acid secretion in mice
    The Journal of Physiology, 2003
    Co-Authors: Laura Piqueras, Yvette Taché, V. Martínez
    Abstract:

    Studies in isolated mouse stomach showed that bombesin releases Somatostatin. We characterized the effects of exogenous bombesin on gastric acid secretion in mice and determined the involvement of Somatostatin and Somatostatin receptor type 2 (SSTR2) by using Somatostatin immunoneutralization, the SSTR2 antagonist, PRL-2903, and SSTR2 knockout mice. Gastric acid secretion was monitored under basal and pentagastrin-, histamine- or bethanechol-stimulated conditions in urethane-anaesthetized mice. Bombesin (10–40 μg kg−1 h−1) and Somatostatin-14 (20 μg kg−1 h−1) were infused i.v. 10 and 30 min after PRL-2903 or Somatostatin Antibody pretreatment, respectively. Urethane-anaesthetized wild-type mice had low basal acid secretion (0.12 ± 0.01 μmol (10 min)−1) compared with SSTR2 knockout mice (1.43 ± 0.10 μmol (10 min)−1). Somatostatin Antibody and PRL-2903 increased basal secretion in wild-type mice but not in SSTR2 knockout animals. In wild-type mice, bombesin inhibited secretagogue-stimulated acid secretion in a dose-dependent manner, and Somatostatin-14 inhibited pentagastrin-stimulated secretion. In wild-type mice pretreated with Somatostatin Antibody or PRL-2903 and in SSTR2 knockout mice, bombesin and Somatostatin-14 i.v. infusion did not alter the increased gastric acid secretion. These results indicate that, in mice, bombesin inhibits gastric acid secretion through the release of Somatostatin and the activation of SSTR2. These observations strengthen the important role of SSTR2 in mediating Somatostatin inhibitory actions on gastric acid secretion.

  • Somatostatin Antibody does not influence bombesin-induced inhibition of gastric acid secretion in rats
    Peptides, 1995
    Co-Authors: V. Martínez, Hong Yang, Helen Wong, John H. Walsh, Yvette Taché
    Abstract:

    Abstract The influence of peripheral Somatostatin immunoneutralization on intravenous (IV) and intracerebroventricular (ICV) bombesin-induced inhibition of gastric acid secretion (GAS) was investigated with the Somatostatin monoclonal Antibody, CURE.S6, in rats. The Somatostatin Antibody, injected IV in conscious rats with a chronic gastric fistula and IV catheter, did not modify basal GAS, whereas in urethane-anesthetized rats the basal GAS was increased by 150%. In conscious rats, Somatostatin (15 μg/kg/h, IV) inhibited basal GAS by 50% after injection of control Antibody but not after pretreatment with the Somatostatin Antibody. With pretreatment with a control Antibody, bombesin (10 μg/kg/h, IV) inhibited basal GAS by 60% in conscious rats and by 50% the acid response to pentagastrin infusion in urethane-anesthetized rats. Bombesin injected ICV (3 and 10 ng/10 μl/rat) inhibited basal GAS by 50% and 70%, respectively, in conscious rats pretreated with a control Antibody. The Somatostatin Antibody injected IV before IV or ICV injection of bombesin did not influence bombesin-induced inhibition of GAS in conscious or anesthetized rats. These results show that peripheral Somatostatin does not play a major role in the inhibition of gastric acid secretion induced either by ICV or IV administration of bombesin or basal acid secretion in conscious rats.

  • Potent inhibition of gastric acid secretion by intravenous interleukin-1β and -1α in rats
    Peptides, 1992
    Co-Authors: E. Saperas, F. Cominelli, Yvette Taché
    Abstract:

    The influence of human and rat recombinant interleukin-1 (hIL-1 beta and -1 alpha and rIL-1 beta) on acid secretion was investigated in conscious pylorus-ligated rats. Intravenous injection of either hIL-1 beta, hIL-1 alpha or rIL-1 beta dose dependently inhibited gastric acid output with an ED50 of 0.05 microgram, 0.5 microgram and 2.2 micrograms, respectively. The antisecretory action of IL-1 beta was associated with an increase in circulating levels of gastrin. hIL-1 beta-induced inhibition of acid secretion was dose dependently reversed by peripheral injection of the IL-1 receptor antagonist, IL-RA, with a dose ratio of 1:10(3) for complete reversal. The inhibitory effect of hIL-1 beta was blocked by indomethacin and was not modified by IV injections of the CRF receptor antagonist, alpha-helical CRF(9-41), or the monoclonal Somatostatin Antibody CURE.S6, or by systemic capsaicin pretreatment. These results show that systemic hIL-1 beta-induced inhibition of gastric acid secretion is mediated through IL-1 receptors and prostaglandin pathways, and does not involves CRF receptors, afferent fibers, or changes in circulating gastrin or Somatostatin levels.