Physiological mechanisms of cholecystokinin action on pancreatic secretion

1996 ◽  
Vol 271 (1) ◽  
pp. G1-G7 ◽  
Author(s):  
C. Owyang
Keyword(s):  
Pancreatic Secretion ◽  
Pancreatic Enzyme ◽  
Experimental Studies ◽  
Sensory Information ◽  
Pancreatic Acini ◽  
Gastroduodenal Mucosa ◽  
Wide Range ◽  
Cholinergic Pathway ◽  
Pancreatic Enzyme Secretion ◽  
The Central Nervous System

Recent experimental studies in animals and humans provide strong evidence that cholecystokinin (CCK) acts via cholinergic pathways to mediate pancreatic enzyme secretion. These studies indicate that the sites of CCK's action to stimulate pancreatic secretion are dose dependent. Doses of CCK that produce physiological plasma CCK levels act via stimulation of the vagal afferent pathway originating from the gastroduodenal mucosa, whereas doses that produce supraphysiological CCK levels act to stimulate intrapancreatic neurons and pancreatic acini. These CCK-sensitive fibers are also responsive to a wide range of chemical and osmotic stimuli. In this manner, gastrointestinal afferents responding to hormones such as CCK and the ever-changing chemical and physical luminal environment provide sensory information to the central nervous system, which in turn stimulates pancreatic secretion via a vagal cholinergic pathway.

CK-independent increases in pancreatic secretion induced by dietary protein in chronic BPJ-diverted rats

1996 ◽  
Vol 271 (3) ◽  
pp. G501-G508
Author(s):  
H. Hara ◽  
T. Nishi ◽  
H. Narakino ◽  
T. Kasai
Keyword(s):  
Dietary Protein ◽  
Pancreatic Secretion ◽  
Pancreatic Enzyme ◽  
Oral Feeding ◽  
Enzyme Secretion ◽  
Cholinergic Pathway ◽  
Protein Ingestion ◽  
Pancreatic Enzyme Secretion ◽  
Cck Antagonist ◽  
Very High

Previously, we demonstrated that, in rats with chronic bile-pancreatic juice (BPJ) diversion, pancreatic enzyme secretion was increased after feeding animals a 25% casein fat-free diet. We determined whether cholecystokinin (CCK) or the cholinergic pathway is associated with the response of pancreatic secretion after protein ingestion in the diverted rats, using a potent CCK antagonist, MK-329 or FK-480, and a cholinergic blocker, atropine. Secretion rates of chymotrypsin and trypsin in the fasting state were very high 7 days after a BPJ diversion, and the hypersecretion of the proteases was markedly reduced with an injection of MK-329, FK-480, or atropine and was further reduced by combined injection of FK-480 and atropine. The lowered secretion of the proteases in CCK-antagonized rats was increased after oral feeding of a protein diet and after a duodenal instillation of some protein sources, especially hydrolysate of guanidinated casein (HGC). The CCK-independent increases by HGC instillation are completely depressed by atropine. In rats treated with only atropine, the lowered secretion tended to be increased by a duodenal instillation of HGC. Increases in secretion after an administration of the protein source in CCK-antagonized rats were not affected by bestatin, an inhibitor of brush-border peptidases. We conclude that the stimulatory effects of dietary protein on the pancreatic enzyme secretion partially do not depend on CCK in chronic BPJ-diverted rats and that the CCK-independent increase is atropine sensitive.

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.

Somatostatin inhibits pancreatic enzyme secretion at a central vagal site

1993 ◽  
Vol 265 (2) ◽  
pp. G251-G257 ◽  
Author(s):  
Y. Li ◽  
C. Owyang
Keyword(s):  
Effective Dose ◽  
Protein Secretion ◽  
Pancreatic Secretion ◽  
Inhibitory Action ◽  
Pancreatic Enzyme ◽  
Enzyme Secretion ◽  
Afferent Pathway ◽  
Pancreatic Enzyme Secretion ◽  
Vagal Afferent ◽  
Somatostatin 14

The mechanisms and site of action of somatostatin-induced inhibition of pancreatic enzyme secretion were investigated using different stimulants of pancreatic secretion acting on different sites in anesthetized rats. Administration of graded doses of somatostatin-14 resulted in a dose-related inhibition of pancreatic protein secretion evoked by 2-deoxy-D-glucose, a central vagal stimulant that acts by stimulating the dorsal vagal nuclei. The lowest effective dose of somatostatin-14 was 1.0 microgram.kg-1 x h-1; maximal effective dose was 25 micrograms.kg-1 x h-1, which resulted in complete inhibition of protein output. Similarly, somatostatin-14 at a dose of 25 micrograms.kg-1 x h-1 also completely inhibited pancreatic protein secretion in response to a physiological concentration of cholecystokinin octapeptide (CCK-8), which acts via a vagal afferent pathway. In contrast, pancreatic protein outputs evoked by bethanechol, which directly stimulates pancreatic muscarinic receptors, or electrical stimulation of the vagal trunk, which activates the vagal efferent pathway, were unaffected by somatostatin-14. In separate studies, we demonstrated that perivagal treatment with the sensory neurotoxin capsaicin impaired pancreatic responses to CCK-8 but had no effect on the inhibitory action of somatostatin-14 on pancreatic secretion evoked by 2-deoxy-D-glucose, ruling out an effect of somatostatin on the vagal afferent pathway. Similarly we also demonstrated that perineural capsaicin treatment of the celiac-superior mesenteric ganglia did not affect the inhibitory action of somatostatin. These findings indicate that somatostatin inhibits 2-deoxy-D-glucose- and CCK-8-evoked pancreatic enzyme secretion via a vagal pathway.(ABSTRACT TRUNCATED AT 250 WORDS)

Physiological role and localization of cholecystokinin release in dogs

1986 ◽  
Vol 250 (4) ◽  
pp. G391-G397 ◽  
Author(s):  
S. J. Konturek ◽  
J. Tasler ◽  
J. Bilski ◽  
A. J. de Jong ◽  
J. B. Jansen ◽  
...  
Keyword(s):  
Protein Secretion ◽  
Pancreatic Secretion ◽  
Pancreatic Enzyme ◽  
Physiological Role ◽  
Amino Acid Mixture ◽  
Acid Mixture ◽  
Elevated Plasma ◽  
Pancreatic Enzyme Secretion ◽  
Pancreatic Fistulas ◽  
Dose Dependent

In dogs with pancreatic fistulas, meat feeding and intestinal perfusion with a sodium oleate or amino acid mixture increased pancreatic protein secretion to approximately 110, 100, and 50%, respectively, of the response to cholecystokinin (CCK) at a dose of 85 pmol X kg-1 X h-1. Plasma CCK response increased in these studies to approximately 100, 180, and 40%, respectively, of the value obtained with exogenous CCK, suggesting that, in addition to CCK, other neurohormonal factors contribute to pancreatic enzyme secretion in response to endogenous stimulants. Feeding and duodenal oleate or amino acids also stimulate the release of pancreatic polypeptide (PP), which may be involved in the control of pancreatic secretion in response to endogenous stimulants, including CCK. Perfusion of the intact intestine with graded amounts of oleate (0.5-16 mmol/h) produced dose-dependent increments in plasma CCK and pancreatic protein similar to those obtained with intravenous infusion of graded doses of CCK (0.85-255 pmol X kg-1 X h-1). Oleate perfusion of isolated Thiry loops (30 cm long) made of duodenojejunal (D-J) and ileal (I) segments also stimulated protein secretion but elevated plasma CCK only after perfusion of the D-J but not of the I loop. We conclude that 1) the endogenous CCK released by various luminal stimulants drives the pancreatic protein secretion; 2) the release of CCK is confined to the foregut; and 3) PP concomitantly released by various intestinal stimulants may contribute to the control of pancreatic secretion induced by endogenous CCK.

Gastrin is not a physiological regulator of pancreatic exocrine secretion in the dog

1987 ◽  
Vol 252 (1) ◽  
pp. G40-G44
Author(s):  
E. Kohler ◽  
C. Beglinger ◽  
V. Eysselein ◽  
U. Grotzinger ◽  
K. Gyr
Keyword(s):  
Pancreatic Secretion ◽  
Pancreatic Enzyme ◽  
Exocrine Secretion ◽  
Exocrine Pancreatic Secretion ◽  
Response Curves ◽  
Blood Concentrations ◽  
Pancreatic Enzyme Secretion ◽  
Pancreatic Exocrine ◽  
Bicarbonate Output

The role of gastrin as a regulator of exocrine pancreatic secretion has not been proven adequately. In the present study we therefore compared the relative molar potencies of sulfated and unsulfated gastrin 17 with structurally related CCK peptides (synthetic CCK-8 and natural porcine CCK-33) in stimulating exocrine pancreatic secretion in conscious dogs. Dose response curves were constructed for pancreatic and gastric acid secretion. Plasma gastrin levels after exogenous gastrin 17-I and -II were compared with postprandial gastrin concentrations (meal: ground beef 20 g/kg body wt). The molar potency estimates calculated with synthetic CCK8 as standard (potency = 1.00) for pancreatic protein secretion were natural porcine 50% pure CCK-33 1.60, gastrin 17-I 0.12, and gastrin 17-II 0.16. All four peptides induced a dose-dependent increase in pancreatic bicarbonate output. However, the blood concentrations needed to stimulate pancreatic secretion were above the postprandial gastrin levels. Our data indicate that both gastrin 17 peptides are not physiological regulators of pancreatic enzyme secretion in dogs.

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.

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.

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.

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