Pancreastatin inhibits pancreatic enzyme secretion by presynaptic modulation of acetylcholine release

1992 ◽  
Vol 262 (1) ◽  
pp. G113-G117 ◽  
Author(s):  
K. H. Herzig ◽  
D. S. Louie ◽  
K. Tatemoto ◽  
O. Y. Chung
Keyword(s):  
Acetylcholine Release ◽  
Pancreatic Enzyme ◽  
Exocrine Secretion ◽  
Enzyme Secretion ◽  
Neural Pathways ◽  
Amylase Release ◽  
Pancreatic Acini ◽  
Presynaptic Modulation ◽  
Pancreatic Enzyme Secretion ◽  
Pancreatic Fistulas

Pancreastatin (PST), a 49-amino acid polypeptide, inhibits endocrine and exocrine pancreatic functions. In this study, we examined the mechanism of the inhibitory action of PST on exocrine pancreatic secretion in the rat. In anesthetized rats prepared with pancreatic fistulas, intravenous administration of PST (500 pM.kg-1.h-1) completely inhibited 2-deoxyglucose (75 mg/kg)-stimulated amylase output to below basal levels. Because 2-deoxyglucose acts to stimulate the vagus, we assessed the ability of PST to inhibit carbachol-stimulated amylase release from isolated rat pancreatic acini. PST suppressed neither carbachol- nor cholecystokinin-stimulated amylase release, indicating that PST inhibits exocrine secretion via indirect mechanisms. To examine neural pathways for inhibition, we used pancreatic lobules to examine the action of PST on intrapancreatic neurons. Incubation of pancreatic lobules in 75 mM potassium buffer stimulated amylase release by a cholinergic pathway. PST dose dependently inhibited potassium-evoked amylase release, with maximal inhibition of 49.6 +/- 11%. In addition, when lobules were incubated with [3H]choline, PST inhibited KCl-stimulated release of synthesized [3H]acetylcholine by 43 +/- 5.7%. Other studies demonstrate that PST inhibits rat pancreatic enzyme secretion via presynaptic modulation of acetylcholine release.

Pancreatic polypeptide inhibits pancreatic enzyme secretion via a cholinergic pathway

1987 ◽  
Vol 253 (5) ◽  
pp. G706-G710 ◽  
Author(s):  
G. Jung ◽  
D. S. Louie ◽  
C. Owyang
Keyword(s):  
Pancreatic Polypeptide ◽  
Acetylcholine Release ◽  
Pancreatic Enzyme ◽  
Enzyme Secretion ◽  
Dependent Manner ◽  
Amylase Release ◽  
Opioid Receptor Antagonists ◽  
Cholinergic Pathway ◽  
Pancreatic Enzyme Secretion ◽  
Dose Dependent

In rat pancreatic slices, rat pancreatic polypeptide (PP) or C-terminal hexapeptide of PP [PP-(31-36)] inhibited potassium-stimulated amylase release in a dose-dependent manner. The inhibition was unaffected by addition of hexamethonium but blocked by atropine. In contrast, PP(31-36) did not have any effect on acetylcholine- or cholecystokinin octapeptide-stimulated amylase release. In addition, when pancreatic slices were incubated with [3H] choline, PP(31-36) inhibited the potassium-evoked release of synthesized [3H] acetylcholine in a dose-dependent manner. The inhibitory action of PP was unaffected by adrenergic, dopaminergic, or opioid receptor antagonists. Thus PP inhibits pancreatic enzyme secretion via presynaptic modulation of acetylcholine release. This newly identified pathway provides a novel mechanism for hormonal inhibition of pancreatic enzyme secretion via modulation of the classic neurotransmitter function.

Cholecystokinin at physiological levels evokes pancreatic enzyme secretion via a cholinergic pathway

1992 ◽  
Vol 263 (1) ◽  
pp. G102-G107 ◽  
Author(s):  
H. C. Soudah ◽  
Y. Lu ◽  
W. L. Hasler ◽  
C. Owyang
Keyword(s):  
Acetylcholine Release ◽  
Pancreatic Enzyme ◽  
Exocrine Secretion ◽  
Cholinergic Innervation ◽  
Enzyme Secretion ◽  
Healthy Humans ◽  
Cholinergic Pathway ◽  
Pancreatic Enzyme Secretion ◽  
Stimulation Of

The mechanism by which physiological concentrations of cholecystokinin (CCK) evoke pancreatic exocrine secretion in humans was investigated. CCK octapeptide (CCK-8) dose dependently increased trypsin and lipase output in healthy humans. Atropine inhibited CCK-8 (10 ng.kg-1.h-1)-stimulated trypsin output by 84.0 +/- 7.7% and lipase output by 78.6 +/- 9.2%. The inhibition with atropine was much less with a CCK-8 dose of 40 ng.kg-1.h-1 (41.8 +/- 6.6% for trypsin and 46.3 +/- 7.3% for lipase). CCK-8 at 10 ng.kg-1.h-1 produced plasma CCK levels similar to postprandial levels (6.0 +/- 1.3 vs. 6.9 +/- 0.8 pM), whereas the 40-ng.kg-1.h-1 dose produced supraphysiological levels (18.4 +/- 3.1 pM). To evaluate if CCK might act via stimulation of cholinergic nerves, in vitro studies were performed using rat pancreas. CCK-8 (10 nM-10 microM) stimulated [3H]acetylcholine release from pancreatic lobules that was blocked by tetrodotoxin, a calcium-free medium, and the CCK antagonist L364,718. In conclusion, CCK-stimulated pancreatic enzyme secretion is dependent on cholinergic neural and noncholinergic pathways. In humans, CCK infusions, which produce plasma CCK levels similar to those seen postprandially, stimulate the pancreas predominantly via a pathway dependent on cholinergic innervation. Correlative in vitro experiments suggest that CCK may act by stimulation of neural acetylcholine release. In contrast, supraphysiological CCK infusions act in part via noncholinergic pathways.

Cholecystokinin-induced restricted stimulation of pancreatic enzyme secretion

1982 ◽  
Vol 242 (5) ◽  
pp. G464-G469 ◽  
Author(s):  
N. Barlas ◽  
R. T. Jensen ◽  
J. D. Gardner
Keyword(s):  
Dose Response ◽  
Incubation Time ◽  
Response Curve ◽  
Pancreatic Enzyme ◽  
Enzyme Secretion ◽  
Enzyme Release ◽  
Pancreatic Acini ◽  
Basal Rate ◽  
Pancreatic Enzyme Secretion ◽  
Stimulation Of

During a 5-min incubation with increasing concentrations of cholecystokinin, enzyme secretion from pancreatic acini increased, became maximal at 1 nM cholecystokinin, and then decreased progressively to 65% of maximal with concentrations of cholecystokinin above 1 nM. During a 20-min incubation with increasing concentrations of cholecystokinin, enzyme secretion increased, became maximal at 0.3 nM cholecystokinin, and then decreased progressively to 40% of maximal with concentrations of cholecystokinin above 0.3 nM. The configuration of the dose-response curve for cholecystokinin-stimulated enzyme secretion did not change when the incubation time was increased from 20 to 30, 45, or 60 min. Concentrations of cholecystokinin that were supramaximal for stimulating enzyme secretion abolished the stimulation caused by other secretagogues that promote mobilization of cellular calcium (e.g., carbamylcholine, bombesin, physalaemin, or A23187), as well as that caused by secretagogues that elevate cellular cAMP (e.g., vasoactive intestinal peptide or secretin). The submaximal stimulation caused by supramaximal concentrations of cholecystokinin reflects what we have termed "restricted stimulation" of enzyme secretion. Secretion is than the basal rate of release and is "restricted" in the sense that enzyme release is submaximal and cannot be increased by adding another secretagogue.

Prostaglandin E2 inhibits secretagogue-induced enzyme secretion from rat pancreatic acini

1991 ◽  
Vol 260 (5) ◽  
pp. G711-G719
Author(s):  
J. Mossner ◽  
R. Secknus ◽  
G. M. Spiekermann ◽  
C. Sommer ◽  
M. Biernat ◽  
...  
Keyword(s):  
Prostaglandin E2 ◽  
Pancreatic Enzyme ◽  
Enzyme Secretion ◽  
Amylase Secretion ◽  
Binding Studies ◽  
Pancreatic Acini ◽  
Inositol 1,4,5 Trisphosphate ◽  
Pancreatic Enzyme Secretion ◽  
Hcl Secretion ◽  
Specific Receptors

Prostaglandins of the E type may have a potential role in pancreatic physiology and pathophysiology. Because prostaglandins of the E type inhibit HCl secretion in parietal cells via a specific receptor by inhibition of adenylylcyclase, we studied whether a similar mechanism exists in the exocrine pancreas. Isolated rat pancreatic acini were incubated with various concentrations of secretagogues, such as cholecystokinin-octapeptide (CCK-8), bombesin, carbachol, and vasoactive intestinal peptide (VIP), in the absence or presence of prostaglandin E2 (PGE2), and amylase secretion was measured. For receptor binding studies, acini and pancreatic membranes were incubated with [3H]PGE2 and either unlabeled PGE2 or other types of prostaglandins. PGE2 (10(-13) to 10(-5) M) did not inhibit basal amylase secretion. However, CCK-8-stimulated secretion was significantly inhibited. Stimulation of secretion by bombesin, carbachol, VIP, and secretin was also inhibited by PGE2, but not as pronounced as CCK-8-stimulated secretion. The formation of inositol 1,4,5-trisphosphate induced by CCK-8 was markedly inhibited by simultaneous incubation with PGE2. Furthermore, PGE2 slightly but significantly reduced the CCK-8-induced efflux of 45Ca2+ from prelabeled acini. Intact acini and a membrane fraction bound [3H]PGE2 and this function could be equally competed by either unlabeled PGE2 or PGE1 in contrast to less-related prostaglandins such as PGF2 alpha, PGD2, and prostacyclin. We conclude that prostaglandins of the E type inhibit pancreatic enzyme secretion stimulated by various secretagogues. This function is mediated via specific receptors for PGE. With regard to CCK-8-stimulated secretion this function may be mediated by an inhibition of formation of inositol 1,4,5-trisphosphate.

Postreceptor modulation of action of VIP and secretin on pancreatic enzyme secretion by secretagogues that mobilize cellular calcium

1982 ◽  
Vol 242 (4) ◽  
pp. G423-G428 ◽  
Author(s):  
M. J. Collen ◽  
V. E. Sutliff ◽  
G. Z. Pan ◽  
J. D. Gardner
Keyword(s):  
Vasoactive Intestinal Peptide ◽  
Pancreatic Enzyme ◽  
Enzyme Secretion ◽  
Secretory Process ◽  
Amylase Secretion ◽  
Pancreatic Acini ◽  
Rat Pancreas ◽  
Cellular Calcium ◽  
Twofold Increase ◽  
Pancreatic Enzyme Secretion

In dispersed acini from rat pancreas, secretagogues that act through or mimic the action of AMP [vasoactive intestinal peptide (VIP), secretin, or 8-bromo-AMP] caused a twofold increase in amylase secretion. Secretagogues that mobilize cellular calcium (carbamylcholine, C-terminal octapeptide of cholecystokinin, bombesin, or A23187) caused a sevenfold augmentation of the actions of VIP, secretin, or 8-bromo-cAMP on enzyme secretion. Carbamylcholine and the C-terminal octapeptide of cholecystokinin also augmented the action of VIP on amylase secretion from mouse pancreatic acini. Secretagogues that mobilize cellular calcium did not alter binding of 125I-VIP, cellular cAMP, or the increase in cellular cAMP caused by VIP or secretin. Similarly, secretagogues that increase cellular cAMP did not alter 45Ca outflux or the increase in 45Ca outflux caused by carbamylcholine, C-terminal octapeptide of cholecystokinin, bombesin, or A23187. These results indicate that in dispersed acini from rat pancreas there is postreceptor modulation of the actions of VIP and secretin on enzyme secretion by secretagogues that mobilize cellular calcium and that this modulation is a major determinant of the magnitude of the effect of VIP and secretin on enzyme secretion. This modulation, in turn, reflects the ability of cellular calcium, mobilized from intracellular stores, to amplify the action of cellular cAMP on the enzyme secretory process.

Action of pancreatic polypeptide on rat pancreatic secretion: in vivo and in vitro

1985 ◽  
Vol 249 (4) ◽  
pp. G489-G495 ◽  
Author(s):  
D. S. Louie ◽  
J. A. Williams ◽  
C. Owyang
Keyword(s):  
Protein Secretion ◽  
Pancreatic Polypeptide ◽  
Pancreatic Secretion ◽  
Specific Binding ◽  
Pancreatic Enzyme ◽  
Enzyme Secretion ◽  
Amylase Release ◽  
Pancreatic Acini

The biological activity of bovine pancreatic polypeptide (BPP) on rat exocrine pancreatic secretion was compared in vivo and in vitro. In anesthetized rats prepared with a bile-pancreatic duct cannula, BPP inhibited cholecystokinin (CCK)-stimulated (10 IDU . kg-1 X h-1) protein secretion in a dose-related manner (P less than 0.001). CCK, from 5-20 IDU . kg-1 X h-1, did not alter the degree of inhibition by BPP at 40 micrograms . kg-1 X h-1, suggesting a nonsurmountable inhibition. Analogues of BPP, including rat pancreatic polypeptide, neuropeptide Y, peptide YY, and the C-terminal hexapeptide of PP, also inhibited CCK-stimulated protein secretion. To determine whether BPP acts directly on acinar cells to suppress enzyme secretion, in vitro studies were performed. BPP and its analogues did not suppress octapeptide of CCK (CCK-8)-stimulated amylase release from either isolated rat pancreatic acini or preparations of pancreatic lobules. Specific binding of 125I-BPP to pancreatic acini was also not observed. From our data we conclude that BPP acts to inhibit pancreatic enzyme secretion in the rat in a noncompetitive manner. Absence of an effect by BPP or its analogues in vitro coupled with an absence of 125I-BPP binding to acini suggest that the inhibitory action of PP on exocrine pancreatic function is mediated by indirect mechanisms.

Selective modification of the ability of cholecystokinin to cause residual stimulation of pancreatic enzyme secretion

1982 ◽  
Vol 243 (3) ◽  
pp. G214-G217
Author(s):  
M. L. Villanueva ◽  
J. Martinez ◽  
M. Bodanszky ◽  
S. M. Collins ◽  
R. T. Jensen ◽  
...  
Keyword(s):  
Aspartic Acid ◽  
Pancreatic Enzyme ◽  
Terminal Region ◽  
Enzyme Secretion ◽  
Aspartic Acid Residue ◽  
Pancreatic Acini ◽  
Pancreatic Enzyme Secretion ◽  
Stimulation Of

In the C-terminal heptapeptide of cholecystokinin (-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2), replacing the aspartic acid residue by beta-aspartic acid did not alter the ability of the peptide to cause stimulation, desensitization, or residual stimulation of enzyme secretion from dispersed pancreatic acini. Replacing the tyrosine sulfate residue by hydroxynorleucine sulfate did not alter the ability of the heptapeptide to cause stimulation or desensitization, but caused a 50-fold decrease in the potency with which the peptide caused residual stimulation of enzyme secretion. These findings suggest that a modification of the N-terminal region of cholecystokinin heptapeptide, which does not alter the ability of the peptide to bind to its receptor on pancreatic acini and by so doing cause stimulation and desensitization of enzyme secretion, can increase the rate at which the bound peptide dissociates when the acini are washed and reincubated. This increased dissociation is reflected by a reduction in the potency with which the peptide causes residual stimulation of enzyme secretion.

Mechanism of action of calcitonin gene-related peptide in stimulating pancreatic enzyme secretion

1986 ◽  
Vol 251 (3) ◽  
pp. G391-G397 ◽  
Author(s):  
Z. C. Zhou ◽  
M. L. Villanueva ◽  
M. Noguchi ◽  
S. W. Jones ◽  
J. D. Gardner ◽  
...  
Keyword(s):  
Pancreatic Enzyme ◽  
Phosphodiesterase Inhibitors ◽  
Calcitonin Gene Related Peptide ◽  
Enzyme Secretion ◽  
Maximal Effect ◽  
Response Curves ◽  
Amylase Release ◽  
Pancreatic Acini ◽  
Related Peptide ◽  
Calcitonin Gene

In guinea pig pancreatic acini rat calcitonin gene-related peptide (CGRP) caused an eightfold increase in amylase release with various phosphodiesterase inhibitors present. Rat CGRP and rat [Tyro]CGRP caused half-maximal effect at 2 nM, and were threefold more potent than human CGRP. CGRP-stimulated amylase release was not inhibited by VIP-(10-28) or secretin-(5-27). CGRP stimulated cAMP and was augmented by phosphodiesterase inhibitors with the order of sensitivity being Ro-20-1724 greater than isobutylmethylxanthine greater than theophylline. CGRP did not increase 45Ca outflux or effect of 125I-VIP binding. CGRP specifically inhibited 125I-CGRP binding. The dose-response curves were broad and each peptide accelerated dissociation of bound 125I-CGRP. Computer analysis demonstrated two classes of CGRP-binding sites. Occupation of a high-affinity class (Kd 20 nM) correlated with stimulation of enzyme secretion and cAMP, and occupation of the low-affinity class (Kd 1 microM) correlated with accelerated dissociation. These studies demonstrate that CGRP interacts with specific pancreatic receptors, CGRP-stimulated cAMP is in a different compartment from that stimulated by other secretagogues, and CGRP differs from other agents that increase cAMP and amylase release in the relationship among receptor occupation, cAMP generation, and enzyme secretion.

Reversal of cholecystokinin-induced persistent stimulation of pancreatic enzyme secretion by dibutyryl cyclic GMP

1981 ◽  
Vol 240 (6) ◽  
pp. G466-G471 ◽  
Author(s):  
S. M. Collins ◽  
S. Abdelmoumene ◽  
R. T. Jensen ◽  
J. D. Gardner
Keyword(s):  
Cyclic Gmp ◽  
Pancreatic Enzyme ◽  
Enzyme Secretion ◽  
Amylase Secretion ◽  
Pancreatic Acini ◽  
Incubation Solution ◽  
Complete Reversal ◽  
Pancreatic Enzyme Secretion ◽  
Derivatives Of ◽  
Stimulation Of

When pancreatic acini are first incubated with cholecystokinin, washed to remove free cholecystokinin, and then reincubated in fresh incubation solution, there is a significant residual stimulation of amylase secretion. Butyryl derivatives of cyclic GMP can prevent as well as reverse this cholecystokinin-induced residual stimulation. At 37 degrees C the nucleotide-induced reversal is complete within a few minutes, but at 4 degrees C complete reversal requires 90 min of incubation. The ability of butyryl cyclic GMP to reverse cholecystokinin-induced residual stimulation is itself fully reversible, and the nucleotide-induced reversal is accompanied by restoration of full responsiveness to cholecystokinin. The ability of dibutyryl cyclic GMP to reverse cholecystokinin-induced residual stimulation appears to result from the ability of the nucleotide to displace cholecystokinin from its receptors in pancreatic acini.

Central CGRP inhibits pancreatic enzyme secretion by modulation of vagal parasympathetic outflow

1998 ◽  
Vol 275 (5) ◽  
pp. G957-G963 ◽  
Author(s):  
Ying Li ◽  
Yi Cheng Jiang ◽  
Chung Owyang
Keyword(s):  
Nervous System ◽  
Protein Secretion ◽  
Pancreatic Secretion ◽  
Inhibitory Action ◽  
Pancreatic Enzyme ◽  
Enzyme Secretion ◽  
Intravenous Route ◽  
Neural Pathways ◽  
Vagus Nerves ◽  
Pancreatic Enzyme Secretion

Calcitonin gene-related peptide (CGRP) is a potent inhibitor of pancreatic enzyme secretion in vivo. Recent studies have shown that CGRP exerts its inhibitory action at a central vagal site. The present study investigates the mechanism responsible for the central action of CGRP. Rats were fitted with lateral cerebroventricular cannulas, using stereotaxic instruments, 4 days before pancreatic secretion studies. In anesthetized rats, administration of 2-deoxy-d-glucose (2-DG) (75 mg/kg iv) or CCK-8 (40 pmol ⋅ kg−1 ⋅ h−1) produced a 100 and 75% increase in protein secretion, respectively, which was completely blocked by atropine. Intracerebroventricular (ICV) administration of CGRP (0.03–0.6 nmol/h) resulted in a dose-related inhibition of pancreatic protein secretion evoked by 2-DG or CCK-8. CGRP administered by the ICV route was 10–40 times more potent than CGRP given by the intravenous route. In contrast, ICV administration of CGRP had no significant effect on pancreatic protein secretion evoked by electrical vagal stimulation or bethanechol, which directly activates the pancreatic muscarinic receptor. Chemical sympathectomy induced by pretreatment with guanethedine (20 mg/kg ip, 2 days) or α-adrenergic receptor blockade with phentolamine did not alter the inhibitory effects of CGRP. We recently demonstrated that CCK stimulated the enteropancreatic neural pathways to mediate pancreatic secretion in rats with a chronic vagotomy. ICV-administered CGRP did not affect CCK-stimulated pancreatic secretion in rats with a chronic vagotomy. In conclusion, CGRP in the central nervous system inhibits pancreatic enzyme secretion stimulated by 2-DG and CCK-8, which act through vagal pathways. The inhibitory action of CGRP is not mediated by the sympathetic nervous system but appears to depend on intact vagus nerves.

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