Skip to main content

Search form
Search

Pancreapedia

About

Publications

Pathways & Structures

Methods

Directory

Resources

Account

Regulation of Pancreatic Secretion

inShare

Rashmi Chandra and Rodger A. Liddle

Department of Medicine, Division of Gastroenterology, Duke University and VA Medical
Centers, Durham North Carolina 27710, USA
rodger.liddle@duke.edu

Entry Version:
Version 1.0, September 14, 2015

Citation:
Chandra, Rashmi. Liddle, Rodger A. (2015). Regulation of Pancreatic Secretion.
Pancreapedia: Exocrine Pancreas Knowledge Base, DOI: 10.3998/panc.2015.38
Attachment
Regulation of Pancreatic Secretion

Size
709.75 KB

1. Introduction
The exocrine pancreas secretes digestive enzymes, fluid, and bicarbonate in response to food
ingestion. This is a critical digestive process that is regulated by neural reflexes,
gastrointestinal hormones, and absorbed nutrients. Secretion is highly regulated by both
stimulatory and inhibitory influences that coordinate the delivery of digestive enzymes with
food emptying into the intestine to assure adequate digestion of a meal. In the absence of
proper pancreatic secretion, maldigestion and malabsorption of nutrients may cause
malnutrition and associated complications. This review describes the physiological processes
that regulate pancreatic exocrine secretion.

2. Phases of Meal Response

Pancreatic secretion in response to a meal occurs in four distinct but overlapping phases
which are named based on the location of ingested food. The four phases of pancreatic
secretion are cephalic, gastric, intestinal, and absorbed nutrient. Considerable crosstalk and
inter-regulation is associated within the phases, thereby ensuring adequate, but not excessive,
enzyme and bicarbonate secretion. Each phase is regulated by a complex network of neural,
humoral, and paracrine feedback mechanisms which help to maintain an optimal environment
for food digestion and absorption.
Cephalic Phase
Sensory inputs such as sight, smell, taste, and mastication (prior to swallowing) lead to the
anticipation of food. These sensations initiate the first phase of pancreatic secretion known as
the cephalic phase. In addition to sensory input, interaction of certain food molecules such as

long chain fatty acids (but not triglycerides or medium chain fatty acids) with receptors in the
oral cavity also induce the cephalic phase (119). Furthermore, studies in animals have
implicated a gustatory vago-pancreatic reflex in mediating the cephalic phase of pancreatic
secretion (247, 271).
Approximately 20-25% of the total pancreatic exocrine secretion occurs during the cephalic
phase (8, 54, 163). This estimate is based on data obtained by sham feeding, a process by
which food is anticipated by sight, smell, and taste, but not ingested. Sham feeding in animals
such as dogs, has been evaluated by inserting a surgically prepared gastric fistula that diverts
food from the esophagus, allowing swallowing but not entry of food into the stomach. In
humans sham feeding involves chewing but not swallowing. The pancreatic response to sham
feeding in humans lasts approximately 60 minutes while in dogs it can last for more than 4
hours (288, 302). Sham feeding stimulates pancreatic secretion which is low in bicarbonate
but rich in enzymes, suggesting that pancreatic acinar, rather than ductal cells are stimulated
in this phase (8).
The cephalic phase of exocrine secretion is under the control of the vagus nerve. Sensory
inputs arising from anticipation of food are integrated in the dorsal vagal complex (located in
the brainstem) and transmitted to the exocrine pancreas via the vagus nerve (83, 256).
Cholinergic agonists produce secretory responses similar to cephalic stimulation while
vagotomy blocks the cephalic responses, suggesting that acetylcholine released by vagal
efferents is the primary mechanism by which sensory inputs lead to exocrine secretion (18,
125). Secretion of the islet hormone, pancreatic polypeptide (PP), increases with sham
feeding and serves as an indicator of vagal innervation of the pancreas, as its secretion is
inhibited by cholinergic blockers (149, 293). When sham feeding is accompanied by
swallowing, the pancreatic secretory and PP responses are much greater implying that
chewing and swallowing stimulate PP secretion by cholinergic mechanisms (294).
The exocrine pancreas contains peptidergic nerve terminals and there is some evidence to
suggest that neuropeptides such as vasoactive intestinal peptide (VIP) and gastrin-releasing
peptide (GRP) may influence the cephalic phase. In addition, thyrotropin-releasing hormone
stimulates pancreatic exocrine secretion of protein and bicarbonate through vagal efferents
and this process involves both muscarinic and VIP receptors (8, 121, 160). In contrast, the
effects of inhibitory cerebral calcitonin gene-related peptide (CGRP) are mediated by
sympathetic noradrenergic efferents acting upon -adrenergic receptors (160, 211). Sham
feeding and electrical vagus nerve stimulation in dogs triggers the release of cholecystokinin
(CCK) although this response may be absent in humans (8, 155, 291). Endogenous CCK was
shown to enhance PP release in humans during sham feeding (149). Therefore, although
peptidergic neurotransmitters are released during vagal stimulation, acetylcholine is believed
to be the main neurotransmitter which regulates the cephalic phase.
A number of G protein-coupled receptors (GPCRs) located on acinar cells also mediate the
cephalic phase of enzyme secretion. Interaction of CCK with CCK-1 receptors has been
shown to induce protein secretion in new born calves (352). This response is possibly
dependent upon neural CCK release as cephalic stimulation does not increase blood levels of
CCK. Thus, both neural and hormonal mechanisms play an important role in regulating the
cephalic phase of pancreatic secretion.
Gastric Phase

Entry of food into the stomach initiates the gastric phase of pancreatic secretion. This phase
has been difficult to study in unanesthetized animals because presence of food in the stomach
initiates neural reflexes and release of hormones. Therefore, physiological data regarding this
phase has been collected by gastric distention induced either by balloon dilation or instillation
of inert substances in the antrum.
Experiments in which gastric contents were prevented from emptying into the duodenum
demonstrated that the gastric phase accounted for approximately 10% of pancreatic secretion.
Secretions induced during this phase consist mainly of enzymes with minimal release of
bicarbonate suggesting that acinar cells are primarily involved in the induction of this phase
(8, 37, 331, 338).
The role of gastrin in this phase of pancreatic secretion remains unclear. It was demonstrated
that step-wise alkaline distension of the antrum induced graded release of gastrin and
pancreatic enzymes (53). However, when exogenous gastrin was administered to dogs the
amount required to stimulate exocrine secretion was much greater than normal postprandial
gastrin levels, suggesting that gastrin did not have a physiological role (160). These findings
are supported by other studies demonstrating that gastrin release is not required for pancreatic
enzyme secretion during this phase.
The vagus nerve plays an important role in the gastric phase of pancreatic secretion. Early
experiments in anesthetized cats demonstrated that stimulation of the antrum resulted in vagal
stimulation of pancreatic amylase release (25). Antral distension in dogs also increased
pancreatic secretion by long route vagal pathways (53). An antropancreatic short reflex
pathway which is blocked by hexamethonium and atropine also mediates this phase (82). In
addition, atropine and vagotomy block the gastric phase providing further evidence that
gastric contributions to pancreatic secretion are mediated by vagovagal cholinergic reflexes
that originate in the stomach and terminate in the pancreas (173, 338, 339). CCK release
plays an important role in antral motility and gastrin release in humans as suggested by sham
feeding experiments (149).
In the stomach, pepsin and gastric lipases catabolize proteins and fats into peptides and
triglycerides plus fatty acids, respectively, while salivary amylase contributes to the
continued digestion of carbohydrates. Peptic digests of proteins are effective in stimulating
the intestinal phase (100). Thus when gastric chyme enters the duodenum, it stimulates the
intestinal phase of pancreatic secretion. In a clinical setting, surgical procedures that slow the
rate of gastric emptying reduce pancreatic secretion (200, 207). Therefore, the rate of gastric
emptying regulates the discharge of nutrients into the intestine and consequently the
activation of the intestinal phase through neural and hormonal pathways.s
Intestinal Phase
As mentioned above, digestion of food in the stomach is followed by release of acidic chyme
into the duodenum which initiates the intestinal phase of pancreatic secretion. By this phase,
the pancreas has already been primed by cephalic and gastric influences, which enhance
blood flow and initiate exocrine secretion. A majority of the pancreatic secretory response (50
- 80%) occurs during the intestinal phase and is regulated by hormonal and neural
mechanisms.

The intestinal phase is more easily studied than the gastric phase as food can be instilled
directly into the intestinal lumen without concern for gastric emptying. Stimulation of both
acinar and ductal cells results in the production of enzyme and bicarbonate secretion.
Pancreatic amylase secretion is stimulated by food molecules such as sodium oleate,
monoglycerides, peptides, and amino acids (particularly tryptophan and phenylalanine) (50,
88, 188, 215-217). In the duodenum the high volume of bicarbonate released neutralizes the
acidity of gastric chyme, while pancreatic enzymes catabolize partially digested food into
molecules that are easily absorbed by intestinal enterocytes.
In the intestinal phase, pancreatic response is regulated primarily by the hormones secretin
and CCK, and by neural influences including the enteropancreatic reflex which is mediated
by the enteric nervous system and amplifies the pancreatic secretory response. Entry of low
pH gastric chyme into the intestine stimulates release of secretin from S cells into the blood
(164). The main action of secretin is to stimulate bicarbonate release from pancreatic duct
cells, but it also has a direct effect on acinar cells and potentiates enzyme secretion. The role
of secretin in pancreatic secretion is addressed later in this review. CCK is released by
proteins and fats and their partial digestion products: peptides and fatty acids. Experiments in
dogs with chronic pancreatic fistulae have shown that CCK antagonism diminishes pancreatic
protein response to a meal and duodenal perfusion suggesting that CCK plays an important
role in this phase (169). Similar results were also obtained in humans, where CCK receptor
antagonism reduced pancreatic enzyme secretion during the intestinal phase (85, 116).
Cholinergic regulation plays a critical role during this phase of pancreatic secretion. In the
absence of secretin, atropine partially inhibits pancreatic bicarbonate secretion stimulated by
low pH due to acidic chyme in the duodenum (306, 349). In addition, the amount of
bicarbonate produced by infusion of secretin is lower than that released by entry of food into
the duodenum suggesting that other factors contribute to meal-stimulated pancreatic
bicarbonate secretion (30). Atropine inhibited pancreatic enzyme secretion from 30 -120
minutes following meal ingestion, implicating cholinergic mechanisms (30). Vagovagal
enteropancreatic reflexes mediated by M1 and M3 muscarinic receptors and CCK receptors
play an important role in the intestinal phase of secretion (302, 304). These vagovagal
enteropancreatic reflexes are modulated by input from the dorsal motor nucleus of the vagus
projecting into the pancreas. Thus, vagal stimulation activates pancreatic bicarbonate
secretion through both cholinergic muscarinic and noncholinergic transmission.
Role of Gastric Acid
The physiological effects of acid on pancreatic secretion have been evaluated by various
methods such as diversion of gastric and pancreatic contents with fistulae, and instillation of
acidic solutions into the duodenum. Both gastric acid and exogenous HCl are powerful
regulators of postprandial pancreatic bicarbonate secretion and their effects are potentiated by
intrapancreatic and vagovagal neural pathways as well as by hormones such as secretin and
CCK (303) indicating that the physiological effects of gastric acid are due to its pH.
Intraduodenal infusion of hydrochloric acid elicited a concentration-dependent increase in
both the amount of bicarbonate and volume of pancreatic secretion. Secretion was similar to
that attained with intravenous infusion of exogenous secretin suggesting that pH changes
resulting from entry of acidic contents into the duodenum are important in inducing
pancreatic secretion. Administration of a peptone meal of varying pH (pH 1 to 5) produced a
maximal secretory response at pH 3.0, which was comparable in magnitude to that obtained

with exogenous secretin (58). Acid infusion in both the duodenum and upper jejunum elicited
pancreatic secretion suggesting that the proximal small intestine responds to this stimulus
(164).
Entry of gastric contents into the duodenum creates an acidic environment with a pH of 2.0 3.0 in the initial segment of the duodenum, while the pH of the distal segment remains
alkaline (32, 279). This difference in pH is due to pancreatic bicarbonate release, which is
augmented in large part by gastric acid-induced secretin release from the intestinal mucosa.
In conscious rats with gastric and pancreatic fistulae, diversion through a gastric fistula
produced a small increase in pancreatic secretion. However, instilling hydrochloric acid into
the duodenum with an open gastric fistula augmented pancreatic secretion (22, 94). In
addition, pancreatic bicarbonate secretion was much greater when pancreatic juice was
diverted from the intestine signifying a correlation between intestinal pH and quantity of
pancreatic bicarbonate release (48, 113).
The pancreatic bicarbonate response is dependent on the concentration of free unbuffered
hydrogen ions and not on the total load of buffered acid entering the duodenum. Inhibition of
gastric acid production by cimetidine (an histamine H2 receptor blocker) or omeprazole (an
H+/K+ ATPase inhibitor) substantially reduced the pancreatic bicarbonate response to a meal
(22, 232). The pH of a liquid gastric meal also plays a significant role in pancreatic
bicarbonate secretion; in cats and dogs, pH > 4.5 resulted in little pancreatic bicarbonate
secretion, while at pH <4.0 secretion increased substantially suggesting that a pH threshold of
< 4.5 is critical for stimulation of pancreatic secretion (58, 219).
This evidence implies that gastric acid is an important regulator of pancreatic bicarbonate
secretion which neutralizes the acid to create an alkaline environment optimal for the action
of pancreatic enzymes and continued digestion of food.
Role of Dietary Fat in Pancreatic Secretion
Dietary fats stimulate pancreatic enzyme and bicarbonate secretion. Perfusion of monoolein
stimulated pancreatic enzyme secretion in humans and this effect was similar in potency to
that observed with intravenous CCK injection (202). In contrast, triglycerides administered
directly into the duodenum (in the absence of endogenous lipase) were unable to induce
pancreatic secretion. However, following lipase digestion of fatty acids, monoglycerides
stimulated pancreatic secretion but glycerol was ineffective indicating that fatty acids are the
major component of ingested fats that stimulate pancreatic secretion (202, 214).
There is some evidence to suggest that both free and saponified fatty acids induce pancreatic
secretion, while other experiments suggest effectiveness only in a micellar form. Secretion
has been shown to be dependent on fatty acid chain length, with C4 being least effective and
C18 being most effective (59). Although the reason for this difference in potency is not
entirely clear, it is not believed to be related to the efficiency of absorption (201). Other
studies have demonstrated that intraduodenal administration of propionate (C3) was more
effective than oleate (C18) in stimulating acinar cell secretion (241). The reason for the
differences between the two studies is not entirely clear but could be species related as these
experiments have been performed in humans, rats, and rabbits. Both oleate and neutral fats
stimulate bicarbonate and fluid secretion, whereas only neutral fats stimulate pancreatic
enzyme secretion. In dogs, oleic acid was shown to potentiate acidified protein-meditated
pancreatic enzyme and bicarbonate secretion (75). Fat emulsions given to conscious rats

produced a 3-fold increase in pancreatic protein secretion. The route of fat administration also
has an impact on pancreatic secretion. Intravenous administration of fat did not produce
pancreatic secretion, whereas intraduodenal administration led to elevated protein,
bicarbonate, and fluid secretion (246, 315).
Administration of fat emulsions increases plasma CCK and secretin levels. Fat-mediated
pancreatic secretion was blocked by proglumide, a CCK receptor antagonist, implicating the
importance of CCK in stimulating pancreatic secretion (97). Both C12 and C18 fatty acids
augment the effects of secretin-induced bicarbonate secretion (74). In humans, introduction of
different concentrations of oleic acid into the duodenum induce pancreatic secretion, although
the threshold for CCK stimulation is much lower than for secretin (252). Secretin release is
physiologically important since injection of anti-secretin antibodies in conscious rats greatly
reduce fat-mediated protein and bicarbonate secretion (101).
A critical fatty acid chain length of C12 was required for CCK release from STC-1 cells, a
neuroendocrine tumor cell line. Fatty acids with less than ten carbon atoms did not augment
secretion. This dependence on fatty acid chain length is similar to that observed previously
for in vivo CCK release in humans. In addition to the fatty acid carbon chain length, a free
carboxyl terminus is also important as esterification of the carboxylic terminus abolished
CCK secretion, while modification of the methyl terminus had no effect (208-210). Two cell
surface receptors have been identified and demonstrated to promote fat-mediated CCK
release. Mice with global deletion of GPR40 show partial reduction in CCK secretion
following fatty acid administration (193). The recently discovered immunoglobulin-like
domain containing receptor (ILDR) is expressed in I cells of the duodenum. ILDR appears to
play an essential role in fat-stimulated CCK release as deletion of ILDR in mice completely
eliminates fatty acid-stimulated CCK secretion (39).
Thus fats and fatty acids are important regulators of pancreatic secretion. Experimental
evidence suggests that the degree and extent of acinar and ductal cell activation may vary
depending on the animal species and the route of fat administration.
Contributions of Proteins, Peptides and Amino Acids to Pancreatic Secretion
Studies performed in dogs, rats, and humans have shown that proteins, peptides, and amino
acids stimulate pancreatic secretion while the magnitude of this effect may be dependent on
the species being evaluated (311). In dogs, intact, undigested proteins such as casein,
albumin, and gelatin did not stimulate pancreatic secretion, whereas protease digests of these
proteins were very effective (215). In contrast, studies in rats suggested that intestinal
administration of hydrolyzed casein produced a smaller response than some of the other
proteins which potently stimulated pancreatic enzyme secretion, suggesting that the amino
acid composition of a protein is relevant in determining the extent of stimulation (96, 189).
Although intravenous infusion of amino acids in humans stimulated pancreatic enzyme and
bicarbonate secretion, a mixture of L-amino acids when infused intravenously in dogs was
not effective. In contrast to intravenous infusion, intraduodenal delivery of amino acids in
dogs induced pancreatic fluid, bicarbonate and protein secretion which was comparable to an
elemental diet suggesting the importance of the route of administration on pancreatic
secretion (315, 344). Only L-amino acids stimulate pancreatic secretion which is consistent
with the overall physiological importance of these stereoisomers. Of all the amino acids,

aromatic amino acids such as phenylalanine and tryptophan have the greatest potency (76,
213, 217).
Although aromatic amino acids are highly effective in stimulating pancreatic secretion,
peptides may be more physiologically relevant as they are more abundant than amino acids in
the intestinal lumen (46). Oligopeptides and longer peptides containing the amino acids
phenylalanine and tryptophan are effective stimulants of pancreatic secretion (215, 216).
Acidification of amino acid (166, 213) and peptide (76) preparations with hydrochloric acid
potentiates the bicarbonate response but pancreatic enzyme secretion is not influenced
beyond that observed in the absence of acid. Aromatic amino acids are capable of inducing
maximal secretory response as potentiation of pancreatic enzyme secretion is not observed
when amino acids or peptides are administered concomitantly with lipid molecules such as
oleate or monoolein (75, 202).
The pancreatic secretory response to intraduodenal administration of amino acids appears to
be concentration dependent. A minimal concentration of 8 mM is necessary for stimulation by
most amino acids (217) although the more potent aromatic amino acids such as tryptophan
stimulate secretion at concentrations as low as 3 mM (305). The length of the intestine
exposed to amino acids also plays a critical role in pancreatic secretion. In dogs, exposure of
the first 10 cm was least effective, while perfusion of the whole intestine produced significant
enzyme output (217) suggesting that the pancreatic response was dependent upon the entire
load of nutrients, not just their concentration. The majority of stimuli responsible for
pancreatic stimulation originate in the proximal small intestine. In humans, amino acids
stimulated pancreatic secretion only when perfused into the duodenum and no response was
observed upon perfusion in the ileum (63). Therefore, similar to fats, the primary mechanisms
that stimulate pancreatic secretion are limited to the proximal regions of the small intestine.
The amount of bicarbonate released by intraluminal administration of tryptophan is similar to
that produced by maximal doses of exogenously infused CCK indicating that release of CCK
by tryptophan leads to pancreatic secretion (52, 202, 215). Similarly, intraduodenal
administration of liver extracts in dogs mediated CCK release along with pancreatic enzyme
and bicarbonate secretion, both of which were blocked by CCK receptor antagonists (234).
Bile acids released from the gallbladder can significantly inhibit pancreatic stimulation
induced by intraluminal amino acids. This inhibition of pancreatic secretion by bile acids
appears to be due to inhibition of CCK release and serves as a feedback mechanism in
regulating pancreatic and gallbladder function (202). By using a sensitive bioassay for CCK
measurement, it was shown that one of the pathways by which proteins stimulate CCK
release is by their ability to inhibit intraluminal trypsin activity (189). Another mechanism by
which aromatic amino acids mediate CCK release is by activation of the calcium sensing
receptor (CaSR), a known nutrient sensor (117, 194, 240, 336). In addition to stimulating the
release of hormones such as CCK and secretin, amino acids also activate cholinergic neural
mechanisms which regulate pancreatic bicarbonate secretion (305).
Hence proteins, peptides, and amino acids stimulate pancreatic secretion but the magnitude of
stimulation depends upon the mode of administration and the species being evaluated.
Role of Bile and Bile Acids in Pancreatic Secretion
Bile is produced by hepatocytes as a complex mixture of bile acids, cholesterol, and organic
molecules. It is stored and concentrated in the gall bladder and released into the duodenum

upon entry of chyme. Bile acids such as cholate, deoxycholate, and chenodeoxycholate are
conjugated with glycine or taurine amino acids which increase their solubility. In the
intestine, bile acids assist in the emulsification and absorption of fatty acids,
monoacylglycerols, and lipids and stimulate lipolysis by facilitating binding of pancreatic
lipase with its co-lipase.
Under basal conditions, intraduodenal administration of physiological concentrations of bile
or the bile salt sodium taurocholate, elevated plasma secretin and stimulated pancreatic fluid
secretion in cats (104, 105). Secretin was released only in response to perfusion of sodium
taurocholate in the duodenum. Perfusion in the upper jejunum produced a significantly
diminished pancreatic response, while no response was observed upon ileal perfusion (107).
Pancreatic fluid secretion was stimulated by the free ionized form of taurocholate and was not
dependent on its detergent properties (98). In humans, infusion of bovine bile augmented
secretin release along with pancreatic exocrine secretions of fluid, bicarbonate, and enzymes
(253, 254).
In addition to secretin, infusion of bovine bile and bile acids in humans and dogs was shown
to stimulate the release several hormones and neuropeptides such as CCK, neurotensin, VIP,
gastric inhibitory peptide (GIP), PP, and somatostatin (34, 42, 274, 276). Fluid and
bicarbonate release was enhanced when elevated levels of VIP were present in the plasma,
suggesting that bile activates peptidergic nerves resulting in pancreatic secretion.
Additionally, cholinergic mechanisms are also important as atropine blocked bile- and
taurocholate-stimulated exocrine pancreatic secretion (276). The composition of bile is
important in mechanisms regulating this secretory response as some differences in
hydrokinetic and ecbolic responses were observed with administration of bile versus various
bile acids (273).
However, a stimulatory effect of bile acids on pancreatic fluid secretion was not observed in
the presence of digestive intraluminal contents (27). In some studies where bile acids were
administered concomitantly with amino acids or fat, an inhibition of pancreatic enzyme
secretion was observed. The mechanism underlying this observation is not completely
understood, although it is possible that bile acids inhibit CCK release by a negative feedback
mechanism which helps to relax and refill the gallbladder (24, 171, 202, 248). Chemical
sequestration of bile acids in dogs augmented the release of CCK and pancreatic enzyme
secretion in response to amino acids and addition of taurocholate reversed this effect (89).
Long term diversion of bile in dogs also augmented basal and oleate-stimulated pancreatic
fluid, bicarbonate, and enzyme secretion along with plasma CCK levels, further supporting
the role of bile acids in inhibiting CCK release (319).
Other studies have shown that the bile salt chenodeoxycholate when infused in humans,
inhibited bombesin- and CCK-stimulated gallbladder emptying along with elevation of
plasma CCK levels. These results led the authors to hypothesize that chenodeoxycholate, by a
yet unknown mechanism, reduced the sensitivity of the gall bladder to stimulation by
bombesin and CCK (326).
In contrast to many species including mice and humans, rats do not possess a gallbladder and
multiple pancreatic ducts join the lower end of the common bile duct. In rats, diversion of
bile and pancreatic juice stimulates the release of pancreatic enzymes. This augmentation of
enzyme secretion has been suggested to compensate for the increased degradation of
proteolytic enzymes in the absence of bile. Thus exocrine secretion in rats is regulated by a

luminal feedback mechanism (93, 225). Additional experiments have shown that certain bile
salts stimulate bicarbonate secretion via CCK release whereas other bile salts inhibit exocrine
secretion (223, 226, 227). Two inhibitory mechanisms have been proposed one dependent
on the stabilization of luminal proteases and the other independent of protease activity (228).
Stimulation of pancreatic fluid secretion in anesthetized rats has been demonstrated to be
mediated by taurocholate induced transcription of Na+/K+/2Cl- cotransporter, which plays a
key role in regulating the entry of Cl- from the basolateral surface of acinar cells.
The physiological role of bile and bile salts in regulating pancreatic secretions is not
completely understood and appears to be dependent on multiple factors, including the
chemical properties of bile salts, the animal model being evaluated, and prandial status of the
animal being studied (275).
Absorbed Nutrient Phase
Once nutrients are absorbed from the intestinal lumen, they may directly stimulate pancreatic
secretion leading to the absorbed nutrient phase. Nutrients can either directly stimulate
pancreatic acinar cells, or they may indirectly activate hormonal and neural pathways to
further regulate exocrine secretion. Little conclusive evidence is available for intravenous
lipids and glucose in stimulating pancreatic secretion (187). However, intravenous
administration of amino acids increases the amount of trypsin and chymotrypsin secretion,
but not lipase or amylase (88). Amino acids appear to have a substantial indirect effect on
pancreatic secretion, since intraduodenal administration of amino acids produces large
increases in pancreatic secretion (168, 218, 278). The role of nutrients after absorption on
pancreatic secretion is not well understood and additional studies are needed to fully
investigate these effects. One effect is to stimulate synthesis of new digestive enzymes to
replenish the pancreatic supply.
Feedback Regulation of Pancreatic Secretion
The concept of feedback regulation of pancreatic secretion emanated from a series of studies
demonstrating that (1) instillation of trypsin inhibitor into the upper small intestine or (2)
surgical diversion of the bile-pancreatic duct removing bile and pancreatic juice from the
duodenum of rats stimulated pancreatic enzyme secretion (95). Conversely, infusion of
trypsin into the duodenum during bile-pancreatic juice diversion suppressed pancreatic
enzyme release. Thus, the protease concentration in the upper small intestine appears to be
intimately linked to pancreatic secretion through a negative feedback system in which active
proteases within the duodenum limit pancreatic secretion but reduced protease activity
stimulates pancreatic secretion. When assays for CCK became available, it was shown that
CCK mediated the effects of proteases on pancreatic secretion (186) through proteasesensitive CCK releasing factors (115, 314) (see Figure 1). In the absence of proteases, CCK
releasing factor can stimulate CCK cells, but in the presence of proteases, the releasing
factors are inactivated and CCK secretion is low. Negative feedback regulation of pancreatic
secretion has been shown to exist in many species although other proteases such as elastase
may be more important in regulating pancreatic secretion in humans.

Figure 1. Feedback regulation of pancreatic exocrine secretion is mediated by positive and

negative mechanisms. Positive feedback: Monitor peptide is secreted by acinar cells and
directly stimulates CCK cells in the small intestine and amplifies pancreatic secretion once it
has been initiated. Negative feedback: Trypsin-sensitive CCK releasing factors are produced
by the intestine and stimulate CCK secretion when trypsin is temporarily consumed by
ingested protein or other trypsin inhibitors.
Pancreatic exocrine secretion is also influenced through a positive feedback mechanism.
Monitor peptide is a 61 amino acid peptide produced by pancreatic acinar cells and
possessing CCK releasing activity. Although monitor peptide has modest trypsin inhibitor
capability, its ability to stimulate CCK is independent of this action because monitor peptide
can directly stimulate CCK secretion from isolated CCK cells in vitro (28, 190).
Monitor peptide is secreted in pancreatic juice, therefore, it does not stimulate CCK secretion
unless pancreatic secretion is underway. Thus, monitor peptide cannot account for the
increase in CCK in during bile-pancreatic juice diversion, but it may serve to reinforce
pancreatic secretion once the process has been initiated.

3. Pancreatic Exocrine Secretion

The exocrine pancreas delivers its secretions of digestive enzymes, fluid, and bicarbonate
ions to the duodenum following ingestion of food. The pancreas is composed of both
endocrine and exocrine components. The endocrine pancreas is comprised of , , , , and
PP (F) cells, which
are located in the islets of Langerhans. These specialized cells secrete the hormones insulin,
glucagon, somatostatin, ghrelin, amylin, and pancreatic polypeptide into the blood, which
exert endocrine and paracrine actions within the pancreas. Ninety percent of the pancreas is
composed of acinar cells which secrete digestive enzymes such as trypsin, chymotrypsin, and
amylase for digestion of food in the small intestine. The acinar cells are triangular in shape

and arranged in clusters with the apex of the cell opening into a centrally located terminal
duct. The terminal or intercalated ducts merge to form interlobular ducts, which in turn
congregate to form the main pancreatic duct. The pancreatic duct delivers exocrine secretions
into the duodenum. The ductal cells secrete fluid and bicarbonate ions, which neutralize
acinar cell secretions, as well as the acidic gastric contents entering the duodenum (110). The
pancreas is heavily innervated by sympathetic and parasympathetic peripheral nerves and
contains a dense network of blood vessels which regulate blood flow and modulate pancreatic
secretion.

Pancreatic exocrine secretion is a highly integrated process mediated by neural and hormonal
signals arising from the gut as well as by factors secreted by other tissues and hormones
released from pancreatic islets. The secretory pathways can be stimulatory or inhibitory in
nature, and represent a highly regulated system that responds to ingestive signals. The agents
that modulate pancreatic exocrine secretion are discussed below (Table 1).
Neural Mechanisms
Neural Innervation
The pancreas is innervated by parasympathetic nerve fibers, postganglionic sympathetic
neurons, as well as a network of intrapancreatic nerves. Together these nerves regulate
pancreatic exocrine function by releasing neurotransmitters such as acetylcholine and
neuropeptides such as VIP, GRP, serotonin, and neuropeptide Y (NPY). The pancreatic
ganglia receive input from pre- and post-ganglionic nerve fibers and regulate exocrine and
endocrine secretion.
Intrapancreatic postganglionic neurons are activated by central input during the cephalic
phase and by vagovagal responses initiated during the gastric and intestinal phases of
stimulation. They stimulate enzyme and bicarbonate secretion primarily by releasing
acetylcholine, which activates muscarinic receptors located on acinar and duct cells.
Vagal Innervation
The dorsal vagal complex in the brainstem is comprised of the nucleus of the solitary tract
and the dorsal motor nucleus of the vagus (DMV) and exerts parasympathetic control on
pancreatic secretion. Information relayed by sensory vagal afferent nerves innervating the
pancreas is first processed in the nucleus of the solitary tract, which then projects onto the
preganglionic motor neurons of the DMV. The DMV receives inputs from other regions of

the brain such as the hypothalamus and from numerous hormones and neuropeptides through
the afferent limb of the vagus nerve.
Parasympathetic preganglionic efferent vagal nerves innervating the pancreas originate
primarily from the DMV and terminate in the pancreatic ganglion. Electrical and chemical
stimulation of the DMV induces rapid pancreatic secretion, and this response is inhibited by
vagotomy or blockade of muscarinic receptors by atropine (239). It has been suggested that
vagal cholinergic neurons mediate pancreatic secretion during low loads of intestinal
stimulants whereas hormones mediate the response during high loads of intestinal stimuli
(245, 304).
CCK affects pancreatic secretion through both a direct effect on pancreatic acinar cells and an
indirect effect on the vagus nerve (Figure 2). However, the effects on the vagus nerve are
complex and the firing response of neurons in the DMV complex appears to be dictated by
their spatial location. In one study, neurons in the caudal region were activated, those in the
rostral region were unaffected, while neurons in the intermediate region were inhibited by a
direct action of CCK (238). Although it is not fully understood, it appears that CCKs effects
on the vagus nerve influences the overall pancreatic secretory response.
The exocrine pancreas is regulated directly by the vagus. Studies with muscarinic receptor
knockout mice demonstrated that both M1 and M3 receptors mediate amylase release from
dispersed acini. It is likely that M3 receptors are more relevant physiologically since the level
of M3 receptor expression was significantly higher in acinar cells (87) and M1 receptors were
found to have only a minor effect on bicarbonate secretion in conscious dogs (325).
The vagus nerve also possesses group II metabotropic glutamate receptors that couple
primarily to Gi/o. These receptors are located on excitatory and inhibitory pre-synaptic
terminals of pancreas-projecting DMV neurons (10) that are also activated by CCK and
pancreatic polypeptide. Thus, in addition to -amino butyric acid, glutamate also modulates
pancreatic exocrine secretion through distinct vagal neurons.
Vasoactive Intestinal Peptide
VIP is a 28 amino acid neuropeptide that is found throughout the body. Immunocytochemical
evidence suggests that VIP is localized in pancreatic nerve fibers and functions as a vagal
neurotransmitter. In the chick, VIP immunoreactive nerve endings are found in close
proximity to acinar cells and epithelial cells of arterioles. Small clear vesicles were present in
VIP-positive nerves indicating that these neurons are were also cholinergic in nature (118).

Figure 2. CCK stimulates pancreatic secretion through hormonal and neuronal pathways.
CCK is released from I cells of the small intestine and diffuses into the blood stream where it
is carried to the pancreas. CCK binds to receptors on acinar cells to stimulate pancreatic
enzyme secretion. Secreted CCK also diffuses through the paracellular space and binds to
CCK1 bearing nerves in the submucosa. Vagal afferent signals are integrated in the dorsal
vagal complex which also receives signals from other regions of the brain (e.g.,
hypothalamus). Vagal efferent fibers transmit cholinergic signals to the pancreas to stimulate
pancreatic secretion.
In normal human pancreas, autonomic ganglia receive an abundant supply of VIP-positive
fiber plexi, and VIP-positive nerves and appeared to innervate acinar cells, ducts, and blood
vessels (204). After atropine treatment, electrical stimulation of the vagus still increased
bicarbonate secretion concurrent with detection of VIP in pancreatic venous effluent
suggesting that VIP release is coupled with bicarbonate secretion (70). The effects of VIP are
especially prominent in the pig as perfusion of the pancreas with VIP antibodies inhibited
fluid and bicarbonate secretion, and treatment of rats with a VIP antagonist reduced

bicarbonate secretion concomitant with vasodepression further supporting a direct

relationship (120, 337). High and low affinity VIP receptors have been identified on
pancreatic acinar membranes. The high affinity receptors are coupled to cAMP-mediated
amylase release, while activation of low affinity receptors did not cause cAMP elevation or
amylase release, suggesting that only high affinity receptors are important in protein secretion
(23). These effects of VIP were attenuated by somatostatin and galanin, which reduced VIPmediated fluid and protein output (123). One ofthe main functions of VIP appears to be
increasing blood flow by vasodilation, and as a result its effects on pancreatic secretion
independent of blood flow in the pancreas are difficult to evaluate (9, 170).
Gastrin Releasing Peptide
Gastrin releasing peptide (GRP) is a 27 amino acid neuropeptide that is present in postganglionic vagal afferents and has been detected in neurons innervating the feline, porcine,
rodent, and human pancreas (231). Receptors responsive to GRP have been identified in rat
pancreatic membranes and cancer cells where they mediate enzyme secretion (103, 146). In
the cat, GRP is present in intrapancreatic ganglia, acinar and stromal regions, and
occasionally on the vasculature and ducts (51). In humans, the pattern of GRP expression was
similar to that of VIP; GRP was localized on nerve fibers in proximity to pancreatic acini,
capillaries, ductules, and arterial walls (298). Several studies in different species have
demonstrated that GRP modulates exocrine secretion (342). Vagal stimulation of porcine
pancreas resulted in GRP release which enhanced pancreatic exocrine secretion (157). In
isolated perfused rat pancreatic preparations, electrical field-stimulated GRP release
potentiated secretin-mediated fluid and amylase secretion through a non-cholinergic pathway
(264). The effects of GRP on rat pancreatic exocrine secretion were enhanced by -amino
butyric acid (266). Neuromedin C, a decapeptide of GRP, also enhanced pancreatic secretion
by direct action on canine acinar cells as well as indirectly by stimulating CCK release (128,
129). However, since bombesin (GRP analog) does not stimulate pancreatic secretion in dogs,
it appears that its effects may be dependent on the species being evaluated (167). For more
details on bombesin see (342).
Other Peptide Neurotransmitters
Immunohistochemical staining has revealed that the neuropeptides listed below are present in
pancreatic nerves and their functional significance and ability to regulate pancreatic secretion
has been demonstrated by in vitro and/or in vivo studies.
PACAP: Pituitary adenylate cyclase-activating polypeptide (PACAP) has been identified in
nerve fibers and intrapancreatic ganglion in rodents (79). PACAP has been shown to evoke
bicarbonate and enzyme secretion from the pancreas albeit with a slower time course than
VIP (7, 337). In the acinar cell line AR42J, PACAP activated phospholipase C, which led to
elevation of intracellular Ca2+ and amylase release (13). For more details on PACAP and
pancreatic secretion see (91).
Neurotensin: Neurotensin is a 13 amino acid neuropeptide that is widely expressed in the
central nervous system and is also present in pancreatic nerves. It stimulates amylase
secretion and its effects are potentiated by carbachol (a cholinergic agonist), secretin, and
caerulein (a CCK analog) (11, 73). Other studies demonstrated that neurotensin stimulates
bicarbonate, but not protein secretion in dogs and may act indirectly by stimulating dopamine
release (134).

Substance P: Substance P is expressed in periductal nerves in the guinea pig pancreas and
inhibits ductal bicarbonate secretion by modulating neurokinin 2 and 3 receptors (111, 152,
159). It enhanced caerulein-stimulated enzyme secretion in isolated perfused pancreas as well
as in anesthetized rodents (148).
CGRP: CGRP is a 37-amino acid peptide that is present in central and peripheral neurons.
The effect of CGRP on exocrine secretion is not clear and may be species specific. Interaction
of CGRP with receptors on guinea pig acinar cells led to amylase release, although its effect
was not as potent as VIP (295). In rat acinar cell preparations, CGRP inhibited amylase
release by a mechanism involving cholinergic (muscarinic) neural pathways (33).
NPY: NPY, a 36 residue peptide, is expressed in intrapancreatic ganglia and nerve fibers that
surround exocrine pancreatic tissue (296). NPY inhibited CCK- and vagally-mediated
amylase secretion from intact pancreas and lobules, but not from dispersed acini, suggesting
that its actions were mediated by neurons innervating the exocrine pancreas (235). Other
evidence suggests that NPY plays at best only a modest role in pancreatic exocrine secretion
(122).
CCK: The presence of CCK in intrapancreatic nerves has led to the suggestion that it may
serve a dual role as neurotransmitter and hormone in pancreatic secretion. However, CCK
could not be detected in the venous effluent of isolated perfused porcine pancreas after vagal
stimulation following a meal (120) suggesting that synaptic release of CCK does not occur
within the pancreas. Therefore, the role of CCK as a neurotransmitter in pancreatic secretion
merits further investigation.
Peptide Histidine Isoleucine: Peptide histidine isoleucine (PHI) is a 27 amino acid peptide
with an N-terminal histidine and C-terminal isoleucine, and is derived from the same
precursor molecule as VIP. It is present in pancreatic nerves and ganglia and stimulates fluid
and bicarbonate secretion in a cAMP-dependent fashion (136, 296).
Adrenergic Nerves
Compared to cholinergic stimulation, adrenergic nerves play a relatively minor role in
pancreatic exocrine secretion. Catecholamine-containing nerves are found in the celiac
ganglion, and extend to intrapancreatic ganglia, blood vessels, ducts, and islets (176).
Epinephrine and norepinephrine (NE) evoked amylase release from superfused rat pancreatic
preparations, similar to that induced by electrical stimulation in the presence of cholinergic
blockade (309). This process is dependent on elevated intracellular Ca2+ and inhibited by
propranolol, suggesting that -adrenergic receptors are involved (268). Catecholamines also
interact with -adrenergic receptors expressed in pancreatic acini and inhibit amylase
secretion (333). NPY is coexpressed with NE in some nerve fibers, and stimulation of
splanchnic nerves leads to the release of NPY and NE (38, 296). Infusion of PACAP into the
pancreatoduodenal artery enhanced release of NE after electrical stimulation of nerves.
However, the physiological relevance of this observation is not clear (347).
Celiac denervation reduces pancreatic secretion by ~70% while increasing blood flow by
350%. This dissonance presumably occurs by the disruption of stimulatory fibers and
sympathetic fibers that maintain tonic constriction of pancreatic vessels (156). The effect of
adrenergic transmitters on pancreatic secretion has been difficult to discern due to the wideranging effects of norepinephrine on multiple processes including blood pressure, blood flow,

neural reflexes, and release of hormones. Even though high concentrations of norepinephrine
have been found in rabbit pancreatic ganglia, ducts, and blood vessels, its effects are
controversial (348). Norepinephrine has been reported to stimulate, inhibit, or have no effect
on pancreatic secretion (12, 41, 60, 84, 176, 183, 312). Unfortunately - and - adrenergic
receptor agonists and antagonists have not provided information that could be used to
delineate mechanisms important in adrenergic regulation of pancreatic secretion (40, 61).
Dopamine
Dopamine was detected in pancreatic ducts and ampullae and dopamine -hydroxylase
(DBH) -positive fibers were identified along the vasculature, ducts, and ganglia suggesting it
may play some role in pancreatic secretion (198, 348). There is conflicting evidence
regarding the role of dopamine in pancreatic secretion. Dopamine stimulates pancreatic
secretion in anesthetized dogs and rats although the effect is negligible in conscious animals
(17, 55, 60, 84, 131, 135). Other data suggest that the secretory response to dopamine differs
between dogs, cats, rabbits and rats, and species specific effects must be taken into
consideration when evaluating its effects (109).
Serotonin
Like dopamine, serotonin is present in pancreatic ducts and ampullae. Autoradiography of
tissue sections after tritiated serotonin uptake demonstrated the presence of serotonergic
innervation of blood vessels, but not exocrine parenchyma in rats, suggesting a limited role in
pancreatic secretion (158, 348). However, phenylbiguanide, a 5-HT3 receptor agonist,
activated preganglionic neurons located in the caudal DMV, inhibited those in the
intermediate DMV, and had no effect on rostral DMV neurons, suggesting complex spatial
regulation of pancreatic vagal neurons by serotonin (238). Intraduodenal infusion of
melatonin (a serotonin derivative) increased pancreatic amylase secretion, while pretreatment
with 5-HT2 serotonin antagonist ketanserin or the 5-HT3 antagonist MDL72222 decreased
amylase release. Serotonin-induced amylase release was blocked by bilateral vagotomy
supporting a role for serotonergic mechanisms on exocrine secretion (243).
Nitric Oxide
Nitric oxide (NO) is a gaseous signaling molecule that is synthesized by NO synthase (NOS)
from L-arginine in the presence of nicotinamide adenine dinucleotide hydrogen phosphate
(NADPH). It is a potent vasodilator and modulates secretory activity as well as pancreatic
blood flow in the pancreas (44). Because it is not practical to directly measure NO in
biological tissues, the presence of NO has been identified by expression of NOS or
histochemistry of NADPH diaphorase (NADPH-d), since NOS and NADPH-d colocalize in
neurons of the peripheral and central nervous systems. The actions of NO in tissues have
been identified by the use of NO donors, NOS inhibitors, and agents that inactivate (e.g.
superoxide-generating compounds) or stabilize NO (e.g., superoxide dismutase). Unlike
ligands that signal through cell surface receptors, NO penetrates cells and activates guanylate
cyclase to generate the second messenger cGMP (345).
Immunostaining of pancreas from a wide range of mammals (mouse, rat, hamster, guinea-pig,
cat and man) indicates that NOS is expressed in the cell bodies of intrapancreatic ganglia,
interlobular nerve fibers, and along blood vessels. VIP is sometimes co-expressed with NOS
in ganglia and nerve fibers. These studies suggest that NO is important in pancreatic exocrine

secretion (66). In newborn guinea pig, nitrergic neurons were present primarily in the head
and body of the pancreas, along blood vessels, the main pancreatic duct, and in association
with pancreatic acini (195). These nerves also immunostained with antibodies against NPY,
VIP, and DBH indicating complex co-regulation of pancreatic secretion by various
neurotransmitters.
In rat pancreas, the NO donor sodium nitroprusside and cGMP analog 8-bromo cGMP,
inhibited basal and vagal amylase secretion through a Ca2+-dependent mechanism (68, 346).
The G protein-coupled receptor, protease-activated receptor-2 (PAR-2) modulates NOmediated amylase release in mice, and inhibition of NOS abolished PAR-2 mediated amylase
release suggesting that the effects of NO may be mediated by neuronal release of a PAR-2
agonist. Ablation of sensory nerves by capsaicin did not affect PAR-2 mediated amylase
release, suggesting that TRPV1-expressing sensory vagal fibers are not involved in this
pathway (150). Analysis of the effects of NO on pancreatic secretions in pigs support the
findings that NO is essential for pancreatic fluid and amylase secretion mediated by the vagus
nerve (124). Thus, in addition to maintaining the vascular tone, nitrergic nerves play an
important role in pancreatic fluid and amylase release.
Stimulatory Hormones
Cholecystokinin
CCK is released from specialized enteroendocrine cells (I cells) located mainly in the upper
small intestine. The major stimulants of CCK release are dietary fats and proteins. In the rat,
intraluminal proteases via an active feedback system participate in the release of a putative
intestinal CCK releasing factor (e.g., LCRF) which in turn causes CCK secretion (115, 314).
Various molecular forms of CCK, ranging in size from CCK-8 [CCK-(26-33)-NH2] to CCK58, have been described in dogs, rats, and humans (65, 69, 329). CCK-58, was determined to
be the predominant peptide in dogs and humans, and the only form detected in rats after
employing CCK isolation techniques that prevented degradation of CCK in blood (272). The
actions of CCK-8 and CCK-58 appear to be functionally identical suggesting that CCK-8
retains the biological activity ascribed to this hormone (49). CCK is post-translationally
modified and has an amidated C-terminus. A sulfated tyrosine residue in CCK-8 is important
for its biological actions including exocrine secretion (141, 285). C-terminal amidation is
critical for binding of CCK to its receptors and removal of the amide group decreases CCK
activity. Other studies have reported that deamidation and desulfation, do not significantly
impair the ability of CCK to stimulate amylase release and these discrepancies may arise
from differences between species. Shorter forms of CCK such as the tetrapeptide CCK-4, are
generally much less effective in mediating exocrine secretion than CCK-8, while longer
forms of CCK, such as CCK-33 are equally effective (64, 86, 251, 255).
CCK mediates its hormonal effects through two G-coupled protein receptors, CCK-1 and
CCK-2, previously known as CCK-A and CCK-B, respectively. The contribution of these
receptors to pancreatic secretion has been evaluated in order to delineate the molecular
mechanisms of CCK action. CCK receptors have been proposed to exist in two states, a high
affinity (picomolar) but low capacity state, and a low affinity (nanomolar) but high capacity
state (322, 332). Autoradiography of pancreatic membranes incubated with radioiodinated
CCK-8 demonstrated that CCK-1 receptors are highly expressed in rat pancreas, while CCK2 receptors are less abundant. CCK-1 receptors appear to modulate pancreatic secretion as
oral administration of loxiglumide, a potent CCK-1 receptor antagonist, reduces protein and

fluid output in rats (132). Similarly, caerulein-induced pancreatic amylase release was
blocked by CCK-1 receptor antagonists (99). CCK-8 also did not induce amylase release in
CCK-1 receptor knockout mice confirming that CCK-1 receptors are critical for CCKmediated protein secretion (172). Since bicarbonate secretion was not observed from
dispersed acinar cells this effect is not believed to be regulated by CCK receptors (320).
Pancreatic responses in CCK-2 receptor knockout mice were similar to wild type mice
suggesting that CCK-2 is not important for amylase release, although it may be involved in
augmenting vascular flow (99, 230). In pigs, where a majority of receptors are of the CCK-2
subtype, acinar cells demonstrated a low responsivity to CCK and did not secrete amylase in
response to caerulein or a CCK-1 agonist (233). In humans, the actions of CCK on pancreatic
secretion have been variously reported. Infusion of CCK, caerulein, and secretin in the
presence of amino acids substantially increased output of fluid, bicarbonate, and enzyme
(162, 318). Similar to porcine pancreas, CCK-2 is the major CCK receptor subtype expressed
in human pancreas, although interestingly CCK-1 receptor antagonists are able to inhibit
amylase secretion (3, 270, 321). In dispersed human acini which responded to
carbamylcholine and neuromedin C, CCK did not stimulate amylase release presumably
because of a paucity of cellular membrane receptors. It has been proposed that the effects of
CCK on human pancreatic secretion are mediated through CCK-1 receptors on nerves which
innervate the pancreas (142, 229). However, recent data demonstrated that application of
physiologic concentrations of CCK-8 and CCK-58 to human acinar cells produced
intracellular Ca2+ oscillations and normal exocytosis of pancreatic enzyme, suggesting that
functional CCK receptors are expressed on human pancreas (237). Thus, it appears that CCK
receptors are expressed on acinar cells of both human and rodent pancreas, and the
differences between the two may not be as great as previously predicted.
Recently it was shown that rat and human pancreatic stellate cells express CCK receptors and
secrete acetylcholine in response to CCK stimulation. This source of acetylcholine was
sufficient to stimulate amylase release from acinar cells. Pancreatic stellate cells may
represent a previously unrecognized intrapancreatic pathway regulating CCK-induced
pancreatic exocrine secretion (269).
Several hormones and neuropeptides regulate CCK-mediated exocrine secretion. Locally,
insulin has been shown to influence exocrine secretion. Intra-arterial infusion of canine
pancreas with anti-insulin antibodies, prevented CCK stimulation as well as secretinmediated protein and fluid secretion from canine pancreas (178). Secretin potentiated, as well
as attenuated, CCK-mediated amylase secretion by the inositol signaling pathway while VIP
enhanced CCK-mediated enzyme secretion (35, 36). Peptide YY (PYY), PP, and somatostatin
also inhibited CCK-mediated protein secretion and their effects are discussed later in this
review.
The mechanism of CCK-induced amylase secretion, involves transient elevation in
intracellular Ca2+ (257). It also requires phospholipase C activation and generation of second
messengers inositol trisphosphate and diacylglycerol (259). In some instances, CCK activates
secretion by elevation of cAMP, as 8-bromo-cAMP and a phosphodiesterase inhibitor
augmented CCK-mediated amylase release (35). Heterotrimeric G proteins G13 and Gq
through downstream interactions with small GTP binding proteins RhoA and Rac1 regulate
actin cytoskeleton reorganization which is required for exocytosis (280, 343).
Secretin

Secretin is a 27 amino acid hormone released by S cells of the small intestine (340). Secretin
release is stimulated during the intestinal phase upon entry of gastric acid and ingested fatty
acids into the duodenum (71). It augments fluid and bicarbonate secretion and is one of the
most potent stimulators of pancreatic secretion (43). Examination of pancreatic ultrastructure
shortly after secretin injection revealed that fluid is secreted by duct as well as acinar cells
(26).
Large increases in pancreatic fluid and bicarbonate secretion have been demonstrated with
secretin infusions as low as 1-2.8 pmol/kghr (19, 102, 290, 350). In humans, bolus injections
of secretin as low as 0.125 pmol/kg stimulated fluid and bicarbonate secretion (145, 289).
Although secretin is believed to be the single most powerful stimulator of pancreatic
bicarbonate secretion, infusion of exogenous secretin equivalent to postprandial blood levels
only produced 10% of the maximal pancreatic bicarbonate secretory response suggesting that
other hormones and neurotransmitters play important roles in postprandial pancreatic
bicarbonate secretion in humans (289, 290). Secretin receptors have been localized in acinar
and duct cells in the rat pancreas (330).
Secretin stimulates the release of fluid and bicarbonate, and to a lesser extent, protein from
acinar cells by a cholinergic mechanism. Perfusion of acetic and lactic acids in the duodenum
of anesthetized rats increased fluid and protein output from the pancreas concomitant with
elevation of plasma secretin levels. In addition, treatment of rats with atropine decreased
plasma secretin levels and inhibited fluid (but not protein) secretion, indicating that only fluid
secretion is dependent on cholinergic input (286). Electrical field stimulation of isolated
perfused rat pancreas demonstrated that secretin-mediated exocrine secretion was sensitive to
tetrodotoxin and atropine blockade, further suggesting cholinergic regulation. Nicotinic
acetylcholine receptors are not involved in this mechanism as hexamethonium did not exert
an inhibitory effect on pancreatic secretion (265).
Both cAMP-dependent and independent pathways contribute to secretin-mediated exocrine
secretion. Interaction of secretin with its receptor induced a 3-4 fold increase in adenylate
cyclase activity which was abolished in the presence of secretin antagonists (212). Secretin
did not stimulate pancreatic fluid release or elevate acinar cell cAMP levels in secretin
receptor knockout mice (287). Exocrine protein secretion by secretin was associated with
phospholipase C activation in one report (327). At secretin concentrations >10-8 M, inositol
trisphosphate and diacylglycerol were generated in acinar cells, which caused release of Ca2+
from intracellular stores and activated protein kinase C. However, not all investigators have
observed this effect.
Several hormones and peptides modulate the effects of secretin on pancreatic secretion. CCK
augmented secretin-induced pancreatic fluid and protein output by stimulating acetylcholine
release and this effect was blocked by atropine or by dispersion of acini (6, 313). Venous
drainage from pancreatic islets bathes the exocrine pancreas with high concentrations of islet
hormones. Several of these hormones have potent effects on pancreatic secretion. Insulin
enhances secretin-mediated fluid and protein secretion through an ouabain-sensitive Na+,K+ATPase while glucagon inhibits secretin-stimulated release of fluid and protein (108).
Addition of anti-somatostatin antibodies increased secretion from perfused rat pancreas
implying that somatostatin inhibits secretin-induced fluid and enzyme secretion (108, 265).
Atrial Natriuretic Factor and C-Natriuretic Peptide

Atrial natriuretic factor (ANF) is a peptide hormone that is secreted by atrial stretch and
regulates blood pressure and volume by inhibiting reabsorption of sodium by the kidney
(334). Immunochemical studies showed that ANF is present in acinar cells. Early studies
suggested that ANF did not influence protein or fluid secretion. However, incubation of rat
acini with ANF caused a dose-dependent elevation of cellular cGMP (112) showing that
guanylate cyclase receptors transduce ANF signaling (199). Injection of human ANF in dogs
induced bicarbonate but not sodium or protein secretion (249). ANF also stimulates
pancreatic natriuretic peptide receptor-C (NPR-C)-mediated phosphoinositide-dependent
pathway in rats, causing the release of fluid and protein (284). NPR-C is a non-guanylyl
cyclase receptor and is coupled to adenylyl cyclase inhibition or phospholipase C activation
through Gi proteins. ANF attenuated secretin- and VIP-induced elevation of intracellular
cAMP and this effect was blocked by inhibitors of protein kinase C and phospholipaseC
(283). Along with elevating intracellular cAMP, secretin mediates the efflux of cAMP from
intact pancreas and acinar cells. ANF augmented secretin-induced cAMP efflux and caused
the rapid elimination of cAMP from cells. The multidrug resistance protein 4 (MRP4) has
been reported to play a role in the extrusion of cAMP in many cellular systems. MRP4 is also
expressed in the pancreas and genetic knockdown of MRP4 expression reduced intracellular
cAMP levels in acinar cells by ANF and an NPR-C dependent mechanism (277).
C-natriuretic peptide (CNP) is structurally similar to ANF and is expressed in the CNS and
gastrointestinal tract. CNP increases pancreatic protein, chloride, and fluid secretion (without
influencing bicarbonate output) suggesting that it acts on acinar rather than duct cells. Truncal
vagotomy or perivagal application of capsaicin or hexamethonium attenuated chloride
secretion, demonstrating that the effect of CNP is modulated by the parasympathetic nervous
system (282). At low concentrations, CNP induced protein secretion by activation of NPR-C.
Similar to ANF, CNP-induced amylase release was inhibited by PLC and PKC inhibitors.
CNP also elevated intracellular cGMP and reduced cAMP concentrations suggesting that
CNP can interact directly with receptors located on pancreatic acini (281).
Insulin
Insulin modulates pancreatic exocrine function and insulin receptors are present in high
density on the basolateral surfaces of acinar cells (21). Insulin increases pancreatic enzyme
synthesis and secretion and its effects are enhanced by CCK and secretin (4, 154, 179, 181,
205). Since CCK induces insulin release in the presence of glucose and amino acids, it is
possible that these two hormones act in conjunction on exocrine stimulation following food
intake (191, 285).
Limited data suggest that insulin regulates exocrine secretion by potentiation of ouabainsensitive Na+,K+-ATPase and by vagal cholinergic input (108, 205, 267). The action of insulin
on exocrine secretion is modulated by PP which exerts an inhibitory effect on pancreatic
secretion (263). Since galanin, pancreastatin, and somatostatin are known to inhibit insulin
secretion, it is possible that these peptides also regulate insulin-mediated amylase release (16,
180, 224).
Bombesin
Bombesin is a 14 amino acid peptide homolog of GRP and neuromedin B and has the ability
to suppress appetite (342). The effects of bombesin on pancreatic exocrine secretion appear to
vary based on the species. In pigs, administration of bombesin alone or in combination with

secretin induced protein but not fluid secretion (185). In guinea pigs, bombesin was very
effective in inducing bicarbonate release from interlobular ducts, and this effect was blocked
by a GRP receptor antagonist (318). Administration of bombesin to rats resulted in pancreatic
hypertrophy with increased pancreatic weight, protein, RNA, and enzyme content and this
effect was not regulated by CCK or secretin (184, 316).
Melatonin
Melatonin is a lipophilic hormone produced by the pineal gland as well as by certain
neuroendocrine cells located in the gastrointestinal tract. Melatonin receptors are present on
acinar cells and melatonin protects the pancreas against caerulein-induced acute pancreatitis
(140). Initial studies showed that melatonin induced pancreatic amylase release which was
mediated by CCK, vagal sensory nerves, and melatonin type 2 receptors. However, melatonin
did not appear to have a direct effect on pancreatic acinar cells (138, 139, 182, 244). The
extent and importance of melatonin-induced pancreatic secretion is not well understood and
merits further investigation.
Amylin
Amylin is a 37 amino acid hormone that is co-secreted along with insulin from pancreatic cells in response to nutrients. Amylin stimulates CCK-independent pancreatic secretion in
rats, and this effect is blocked by proton pump inhibitors and atropine, perhaps due to
inhibition of somatostatin release (80).Amylin was also shown to stimulate protein secretion
from pancreatic AR42J cells by a mechanism involving activation of GPCRs and release of
Ca2+ from intracellular stores (130). Others investigations have suggested that amylin has no
effect on pancreatic exocrine secretion from isolated perfused pancreas, acinar preparations,
or AR42J cells (72, 153, 351). Hence the effects of amylin on exocrine secretion remain
unresolved.
Histamine
The amino acid histamine is a potential mediator of pancreatic exocrine secretion, although it
may have a gender-dependent role (308). Activation of H1 receptors and inhibition of H2
receptors in the rabbit pancreas led to an increase in fluid and protein secretion suggesting
differential action based on regulation and coupling of the two receptors (262). The effect of
histamine on pancreatic secretion is considered to be minor at best under normal
physiological conditions.
Inhibitory Hormones
Peptide YY and Pancreatic Peptide
The NPY family of peptides consists of three hormones: NPY, PYY, and PP (90, 341). All
three peptides contain 36 residues several of which are tyrosines and share a tertiary
structural motif known as the PP fold. The N-terminal amino acids of PYY and NPY can be
cleaved by peptidases to generate truncated forms, PYY3-36 and NPY3-36,which are
biologically active. NPY has been localized to sympathetic pancreatic nerves and its role has
been discussed previously in this review (38). In islets, PYY is coexpressed with glucagon in
cells, whereas PP is secreted postprandially by F cells of the islets of Langerhans. In certain
species, PP immunopositive cells are also present in the exocrine pancreas and some of these

PP cells also express PYY (67). These three hormones exert their effects through a family of
five GPCRs denoted Y1-5. NPY and PYY possess similar affinity for Y1, Y2 and Y5, PYY3-36
interacts preferentially with Y2, whereas PP is the preferred ligand for Y4 (126).
PYY levels in blood are elevated postprandially and following instillation of fatty acids into
the distal small intestine (203). Physiologically relevant concentrations of PYY in the
circulation inhibit both meal- and hormone-stimulated pancreatic secretion (260, 261, 323).
Intravenous administration of PYY significantly diminishes secretin- and secretin plus CCKmediated pancreatic protein and fluid secretion concomitant with a reduction in pancreatic
blood flow (133, 143, 261, 317). However, PYY does not inhibit 2-diacylglycerol stimulated
pancreatic secretion, suggesting that suppression of CCK-stimulated exocrine secretion
occurs prior to activation by 2-diacylglycerol or does not involve protein kinase C-activated
signaling (62). In denervated pancreas, PYY1-36 but not PYY3-36,reduced CCK-stimulated
amylase release suggesting that hormonal effects of PYY are mediated by Y1 receptors (57,
92). Autoradiographic analysis of rat pancreas with radioiodinated PYY ligand demonstrated
that Y1 receptors are present primarily on smooth muscle cells of blood vessels. Specific
staining was not observed in acinar cells indicating that decreased protein and fluid secretion
could be due to reduced blood flow (297).
PP secretion is also stimulated by ingesting a meal and can be reproduced by intraduodenal
infusion of acid, aromatic amino acids, or fatty acids (20, 45, 151, 292, 324). Like PYY, PP
attenuated secretin- and CCK-mediated exocrine secretion in dogs independent of cholinergic
blockade (56, 57, 161). PP decreased secretin- and secretin plus CCK-mediated amylase
release in dispersed acini, suggesting that PP can act directly on acinar cells (144). However,
although bovine and rat PP inhibited CCK-stimulated protein secretion in vivo, both peptides
were ineffective in vitro, and binding of bovine PP to rat acinar cells or lobules was not
observed (197). In humans, unlike dogs, infusion of PP decreased pancreatic protein output,
but did not influence bicarbonate secretion suggesting species-specific differences in PP
action (165). However, unlike PYY, PP does not affect pancreatic blood flow and therefore
inhibits exocrine secretion by a different mechanism (56, 57, 161).
Somatostatin
Somatostatin is composed of 14 or 28 amino acids and is produced by cells of pancreatic
islets. It is also secreted by certain intestinal cells and by the hypothalamus. It is released into
the blood after a meal but functions primarily through a paracrine mechanism. It has broad
inhibitory actions on the release of several hormones and their target organs.
Somatostatin and its analogs inhibited secretin- and CCK-induced protein secretion in a dosedependent fashion. Low doses of somatostatin exerted a greater inhibitory effect on CCKstimulated pancreatic secretion compared to secretin-stimulated secretion (180, 192, 300,
301). Secretin-mediated activation of slowly-activating voltage-dependent K+ channels
(present on the basolateral surface of pancreatic acini) resulted in cAMP generation and
secretion of chloride ions. Addition of somatostatin to acini, decreased intracellular cAMP
production as well as secretin-mediated enhancement of K+ current suggesting that
somatostatin regulates exocrine secretion through this pathway (177). Additionally,
somatostatin inhibited Ca2+-dependent and cAMP-stimulated amylase release by inhibiting
exocytosis through a Gi protein-dependent mechanism (250).

Somatostatin also inhibits exocrine secretion via a neural mechanism. Based on atropine,
hexamethonium, and tetrodotoxin sensitivities it appears that peptidergic but not cholinergic
and nicotinic acetylcholine receptors present on sympathetic and parasympathetic ganglia
mediate somatostatin action (236). Somatostatin-mediated inhibition of secretin-stimulated
fluid and protein secretion was not influenced by denervation, suggesting that extrapancreatic
nerves are not involved. Bethanechol, a muscarinic receptor agonist, reversed the inhibitory
effects of somatostatin, indicating that its actions are mediated primarily by intrapancreatic
cholinergic neurons (174).
The mechanisms by which somatostatin inhibits pancreatic secretion are not completely
understood. However, it is believed that somatostatin has an inhibitory effect on the release of
hormones and neurotransmitters that normally stimulate pancreatic secretion.
Galanin
Galanin is a 29 amino acid peptide that plays diverse roles including inhibition of insulin,
somatostatin, and PP secretion from the pancreas (14). It is found in the secretory granules of
central and peripheral neurons suggesting that it functions as a neurotransmitter. Galanin
immunoreactivity was present in nerve fibers surrounding acini, ductules, and blood vessels,
with 73% of fibers being dual positive for galanin and VIP (299). Galanin receptor 3 mRNA
is present in acinar cells indicating that galanin can act directly on acini (15). Consistent with
this finding, galanin inhibited CCK- and carbachol-stimulated amylase release from acinar
cells (5). Galanin inhibited the sustained phase of amylase release stimulated by carbachol,
suggesting that it attenuates cholinergic action possibly by a mechanism that involves
pertussis toxin-sensitive Gi proteins (16, 77, 114, 147). Extrapancreatic nerves are not
involved in its action since galanin inhibited food-, secretin- and CCK-mediated fluid release,
as well as food- and CCK-mediated protein release in both innervated and denervated dogs
(31).
Pancreastatin
Pancreastatin is derived from the cleavage of chromogranin A and is expressed in many
neuroendocrine tissues. It has been localized to duct cells of the exocrine pancreas and its
numerous roles include inhibition of pancreatic exocrine secretion (1). Initial studies showed
that pancreastatin inhibited postprandial fluid and protein secretion in rats with bilepancreatic juice diversion. No effect was observed on basal secretion, secretin-stimulated
secretion in conscious rats, or CCK-stimulated secretion from dispersed acini. However,
pancreastatin inhibited CCK-stimulated pancreatic secretion in conscious rats although it did
not influence plasma CCK levels. These results suggest that pancreastatin does not have a
direct effect on acinar cells, but may regulate the intestinal phase of pancreatic secretion (81,
222, 224, 335). Pancreastatin inhibited caerulein-induced blood flow in the exocrine pancreas
raising the possibility that its inhibitory effects are derived from its role in regulating
pancreatic blood flow (220).
Glucagon
Glucagon is released from the endocrine pancreas after ingestion of a meal ((29).Early
investigations suggested that glucagon inhibited secretin- or secretin- and CCK-stimulated
pancreatic protein but not bicarbonate secretion (47, 221). However other studies have
demonstrated that glucagon inhibits postprandial protein and bicarbonate secretion (78, 106,

307). The effect of glucagon on isolated pancreatic lobules and acini appears to be direct and
stimulatory, instead of inhibitory, suggesting complex action at the cellular versus
physiological levels (2, 127, 258, 310). The experimentally observed effects of glucagon on
exocrine secretion are inconclusive and merit further investigation.
Ghrelin
Ghrelin is a 28 amino acid orexigenic hormone released by gastric endocrine cells under
fasting conditions. Ghrelin stimulates acid secretion by oxyntic cells in the stomach, and
plasma levels of ghrelin rise immediately before a meal suggesting a role in modulating
ingestive behavior. In the pancreas both ghrelin and its receptor have been identified in acini
by evaluation of protein and mRNA expression. Ghrelin expression was not altered by gastric
acid inhibition, acute pancreatitis, or food deprivation although its receptor was upregulated
by gastric acid inhibition and downregulated during acute pancreatitis (175). Experimentally,
ghrelin did not affect basal or CCK-stimulated amylase release from dispersed acini.
However, ghrelin inhibited CCK-stimulated protein secretion in normal and vagotomized rats
and amylase secretion from lobules exposed to depolarizing potassium concentrations,
suggesting that it modulates intrapancreatic neurons (353).
Leptin
Leptin is a 16 kDa orexigenic peptide that is secreted by adipocytes and regulates energy
homeostasis by reducing food intake while increasing energy expenditure. In the pancreas,
intravenous or intraperitoneal administration of leptin reduced basal and CCK-stimulated
protein output in vivo. This effect was attenuated by CCK-1 receptor blockade, vagotomy,
and capsaicin pretreatment suggesting that it inhibited pancreatic exocrine secretion through a
CCK-dependent vagal pathway. Leptin had no effect on dispersed acini in vitro, further
supporting a neural mechanism of action (137, 206). In contrast, intraduodenal infusion of
leptin in fasted rats augmented pancreatic protein output possibly by elevating plasma CCK
levels leading to activation of sensory neurons (242).
Adrenomedullin
Adrenomedullin is colocalized with PP in F cells of pancreatic islets and inhibits insulin
(196). It interacts directly with acinar cells and inhibits CCK-stimulated pancreatic amylase
release possibly by modulating intracellular Ca2+ levels and exocytosis (328). The mechanism
of adrenomedullin action is not well understood.

4. Conclusion
Pancreatic secretion is a complex process that is initiated by the sight and smell of food and
progresses until food enters the duodenum. At each level of food digestion, this process is
regulated by a various stimuli which affect neuronal and hormonal pathways. These pathways
are both stimulatory and inhibitory and optimize the release of enzymes, bicarbonate, and
fluid.

5. References
1. Adeghate E, Ember Z, Donath T, Pallot DJ, and Singh J. Immunohistochemical
identification and effects of atrial natriuretic peptide, pancreastatin, leucine-

enkephalin, and galanin in the porcine pancreas. Peptides 17:503-509, 1996. PMID:
8735979.
2. Adler G. Effect of glucagon on the secretory process in the rat exocrine pancreas.
Cell Tissue Res 182:193-204, 1977. PMID: 902302.
3. Adler G, Beglinger C, Braun U, Reinshagen M, Koop I, Schafmayer A, et al.
Interaction of the cholinergic system and cholecystokinin in the regulation of
endogenous and exogenous stimulation of pancreatic secretion in humans.
Gastroenterology 100:537-543, 1991. PMID: 1702077.
4. Adler G, and Kern HF. Regulation of exocrine pancreatic secretory process by
insulin in vivo. Horm Metab Res 7:290-296, 1975. PMID: 807510.
5. Ahren B, Andren-Sandberg A, and Nilsson A. Galanin inhibits amylase secretion
from isolated rat pancreatic acini. Pancreas 3:559-562, 1988. PMID: 2460854.
6. Alcon S, Rosado JA, Garcia LJ, Pariente JA, Salido GM, and Pozo MJ. Secretin
potentiates guinea pig pancreatic response to cholecystokinin by a cholinergic
mechanism. Can J Physiol Pharmacol 74:1342-1350, 1996. PMID: 9047045.
7. Alonso RM, Rodriguez AM, Garcia LJ, Lopez MA, and Calvo JJ. Comparison
between the effects of VIP and the novel peptide PACAP on the exocrine pancreatic
secretion of the rat. Pancreas 9:123-128, 1994. PMID: 7509062.
8. Anagnostides A, Chadwick VS, Selden AC, and Maton PN. Sham feeding and
pancreatic secretion. Evidence for direct vagal stimulation of enzyme output.
Gastroenterology 87:109-114, 1984. PMID: 6724252.
9. Ashton N, Argent BE, and Green R. Effect of vasoactive intestinal peptide,
bombesin and substance P on fluid secretion by isolated rat pancreatic ducts. J
Physiol (Lond) 427:471-482, 1990. PMID: 1698981.
10. Babic T, Browning KN, Kawaguchi Y, Tang X, and Travagli RA. Pancreatic
insulin and exocrine secretion are under the modulatory control of distinct
subpopulations of vagal motoneurones in the rat. J Physiol 590:3611-3622, 2012.
PMID: 22711959.
11. Baca I, Feurle GE, Haas M, and Mernitz T. Interaction of neurotensin,
cholecystokinin, and secretin in the stimulation of the exocrine pancreas in the dog.
Gastroenterology 84:556-561, 1983. PMID: 6295872.
12. Barlow TE, Greenwell JR, Harper AA, and Scratcherd T. The effect of adrenaline
and noradrenaline on the blood flow, electrical conductance and external secretion of
the pancreas. J Physiol 217:665-678, 1971. PMID: 4398605.
13. Barnhart DC, Sarosi GA, Jr., and Mulholland MW. PACAP-38 causes
phospholipase C-dependent calcium signaling in rat acinar cell line. Surgery 122:465474, 1997. PMID: 9288154.

14. Barreto SG. Galanin. Pancreapedia: Exocrine Pancreas Knowledge Base.

10.3998/panc.2015.21 10.3998/panc.2015.21
15. Barreto SG, Bazargan M, Zotti M, Hussey DJ, Sukocheva OA, Peiris H, et al.
Galanin receptor 3--a potential target for acute pancreatitis therapy.
Neurogastroenterol Motil 23:e141-151, 2011. PMID: 21303427.
16. Barreto SG, Woods CM, Carati CJ, Schloithe AC, Jaya SR, Toouli J, et al.
Galanin inhibits caerulein-stimulated pancreatic amylase secretion via cholinergic
nerves and insulin. Am J Physiol Gastrointest Liver Physiol 297:G333-339, 2009.
PMID: 19497960.
17. Bastie MJ, Vaysse N, Brenac B, Pascal JP, and Ribet A. Effects of catecholamines
and their inhibitors on the isolated canine pancreas. II. Dopamine. Gastroenterology
72:719-723, 1977. PMID: 838228.
18. Becker S, Niebel W, and Singer MV. Nervous control of gastric and pancreatic
secretory response to 2-deoxy-D-glucose in the dog. Digestion 39:187-196, 1988.
PMID: 3209002.
19. Beglinger C, Fried M, Whitehouse I, Jansen JB, Lamers CB, and Gyr K.
Pancreatic enzyme response to a liquid meal and to hormonal stimulation. Correlation
with plasma secretin and cholecystokinin levels. J Clin Invest 75:1471-1476, 1985.
PMID: 3998145.
20. Beglinger C, Taylor IL, Grossman MI, and Solomon TE. Pancreatic polypeptide
release: role of stimulants of exocrine pancreatic secretion in dogs. Gastroenterology
87:530-536, 1984. PMID: 6146550.
21. Bergeron JJ, Rachubinski R, Searle N, Sikstrom R, Borts D, Bastian P, et al.
Radioautographic visualization of in vivo insulin binding to the exocrine pancreas.
Endocrinology 107:1069-1080, 1980. PMID: 6997018.
22. Bilski J, Konturek PK, Krzyzek E, and Konturek SJ. Feedback control of
pancreatic secretion in rats. Role of gastric acid secretion. J Physiol Pharmacol
43:237-257, 1992. PMID: 1493255.
23. Bissonnette BM, Collen MJ, Adachi H, Jensen RT, and Gardner JD. Receptors
for vasoactive intestinal peptide and secretin on rat pancreatic acini. Am J Physiol
Gastrointest Liver Physiol 246:G710-717, 1984. PMID: 6204536.
24. Bjornsson OG, Maton PN, Fletcher DR, and Chadwick VS. Effects of duodenal
perfusion with sodium taurocholate on biliary and pancreatic secretion in man. Eur J
Clin Invest 12:97-105, 1982. PMID: 6807694.
25. Blair EL, Brown JC, Harper AA, and Scratcherd T. A gastric phase of pancreatic
secretion. J Physiol (Lond) 184:812-824, 1966. PMID: 5912208.

26. Blomfield J, and Settree PJ. Ultrastructural responses of rat exocrine pancreas to
cholecystokinin octapeptide and secretin. Exp Mol Pathol 38:389-397, 1983. PMID:
6303836.
27. Bondesen S, Christensen H, Lindorff-Larsen K, and Schaffalitzky De Muckadell
OB. Plasma secretin in response to pure bile salts and endogenous bile in man. Dig
Dis Sci 30:440-444, 1985. PMID: 3987477.
28. Bouras EP, Misukonis MA, and Liddle RA. Role of calcium in monitor peptidestimulated cholecystokinin release from perifused intestinal cells. Am J Physiol
Gastrointest Liver Physiol 262:G791-796, 1992. PMID: 1590389.
29. Bozadjieva N, Williams JA, and Bernal-Mizrachi E. Glucagon. Pancreapedia:
Exocrine Pancreas Knowledge Base. 10.3998/panc.2013.23 10.3998/panc.2013.23
30. Bozkurt T, Adler G, Koop I, and Arnold R. Effect of atropine on intestinal phase of
pancreatic secretion in man. Digestion 41:108-115, 1988. PMID: 2464512.
31. Brodish RJ, Kuvshinoff BW, Fink AS, and Mcfadden DW. Inhibition of pancreatic
exocrine secretion by galanin. Pancreas 9:297-303, 1994. PMID: 7517543.
32. Brooks AM, and Grossman MI. Postprandial pH and neutralizing capacity of the
proximal duodenum in dogs. Gastroenterology 59:85-89, 1970. PMID: 5426993.
33. Bunnett NW, Mulvihill SJ, and Debas HT. Calcitonin gene-related peptide inhibits
exocrine secretion from the rat pancreas by a neurally mediated mechanism. Exp
Physiol 76:115-123, 1991. PMID: 2015068.
34. Burhol PG, Lygren I, Waldum HL, and Jorde R. The effect of duodenal infusion of
bile on plasma VIP, GIP, and secretin and on duodenal bicarbonate secretion. Scand J
Gastroenterol 15:1007-1011, 1980. PMID: 7233065.
35. Burnham DB, Mcchesney DJ, Thurston KC, and Williams JA. Interaction of
cholecystokinin and vasoactive intestinal polypeptide on function of mouse pancreatic
acini in vitro. J Physiol 349:475-482, 1984. PMID: 6204039.
36. Camello PJ, and Salido GM. Inhibitory interactions between stimulus-secretion
pathways in the exocrine rat pancreas. Biochem Pharmacol 46:1005-1009, 1993.
PMID: 8216342.
37. Cargill JM, and Wormsley KG. Effect of gastric distension on human pancreatic
secretion. Acta Hepatogastroenterol (Stuttg) 26:235-238, 1979. PMID: 484173.
38. Carlei F, Allen JM, Bishop AE, Bloom SR, and Polak JM. Occurrence, distribution
and nature of neuropeptide Y in the rat pancreas. Experientia 41:1554-1557, 1985.
PMID: 2866975.
39. Chandra R, Wang Y, Shahid RA, Vigna SR, Freedman NJ, and Liddle RA.
Immunoglobulin-like domain containing receptor 1 mediates fat-stimulated
cholecystokinin secretion. J Clin Invest 123:3343-3352, 2013. PMID: 23863714.

40. Chariot J, Appia F, Del Tacca M, Tsocas A, and Roze C. Central and peripheral
inhibition of exocrine pancreatic secretion by alpha-2 adrenergic agonists in the rat.
Pharmacol Res Commun 20:707-717, 1988. PMID: 2905481.
41. Chariot J, Roze C, De La Tour J, Souchard M, and Vaille C. Modulation of
stimulated pancreatic secretion by sympathomimetic amines in the rat. Pharmacology
26:313-323, 1983. PMID: 6878424.
42. Chayvialle JA, Miyata M, Rayford PL, and Thompson JC. Effects of test meal,
intragastric nutrients, and intraduodenal bile on plasma concentrations of
immunoreactive somatostatin and vasoactive intestinal peptide in dogs.
Gastroenterology 79:844-852, 1980. PMID: 6106620.
43. Chey WY, and Chang T-M. Secretin, 100 years later. J Gastroenterol 38:1025-1035,
2003. PMID: 14673718.
44. Chey WY, and Chang T. Neural hormonal regulation of exocrine pancreatic
secretion. Pancreatology 1:320-335, 2001. PMID: 12120211.
45. Choi BR, and Palmquist DL. High fat diets increase plasma cholecystokinin and
pancreatic polypeptide, and decrease plasma insulin and feed intake in lactating cows.
J Nutr 126:2913-2919, 1996. PMID: 8914965.
46. Chung YC, Kim YS, Shadchehr A, Garrido A, Macgregor IL, and Sleisenger
MH. Protein digestion and absorption in human small intestine. Gastroenterology
76:1415-1421, 1979. PMID: 437440.
47. Clain JE, Barbezat GO, Waterworth MM, and Bank S. Glucagon inhibition of
secretin and combined secretin and cholecystokinin stimulated pancreatic exocrine
secretion in health and disease. Digestion 17:11-17, 1978. PMID: 627317.
48. Cooke AR, Nahrwold DL, and Grossman MI. Diversion of pancreatic juice on
gastric and pancreatic response to a meal stimulus. Am J Physiol Gastrointest Liver
Physiol 213:637-639, 1967. PMID: 6036779.
49. Criddle DN, Booth DM, Mukherjee R, Mclaughlin E, Green GM, Sutton R, et al.
Cholecystokinin-58 and cholecystokinin-8 exhibit similar actions on calcium
signaling, zymogen secretion, and cell fate in murine pancreatic acinar cells. Am J
Physiol Gastrointest Liver Physiol 297:G1085-G1092, 2009. PMID: 19815626.
50. Dale WE, Turkelson CM, and Solomon TE. Role of cholecystokinin in intestinal
phase and meal-induced pancreatic secretion. Am J Physiol Gastrointest Liver Physiol
257:G782-790, 1989. PMID: 2480719.
51. De Giorgio R, Sternini C, Brecha NC, Widdison AL, Karanjia ND, Reber HA, et
al. Patterns of innervation of vasoactive intestinal polypeptide, neuropeptide Y, and
gastrin-releasing peptide immunoreactive nerves in the feline pancreas. Pancreas
7:376-384, 1992. PMID: 1594560.

52. Debas HT, and Grossman MI. Pure cholecystokinin: pancreatic protein and
bicarbonate response. Digestion 9:469-481, 1973. PMID: 4787845.
53. Debas HT, and Yamagishi T. Evidence for pyloropancreatic reflux for pancreatic
exocrine secretion. Am J Physiol Endocrinol Metab 234:E468-471, 1978. PMID:
645898.
54. Defilippi C, Solomon TE, and Valenzuela JE. Pancreatic secretory response to sham
feeding in humans. Digestion 23:217-223, 1982. PMID: 6183160.
55. Delcenserie R, Devaux MA, and Sarles H. Action of dopamine on the exocrine
pancreatic secretion of the intact dog. Br J Pharmacol 88:189-195, 1986. PMID:
2871881.
56. Demar AR, Lake R, and Fink AS. The effect of pancreatic polypeptide and peptide
YY on pancreatic blood flow and pancreatic exocrine secretion in the anesthetized
dog. Pancreas 6:9-14, 1991. PMID: 1994383.
57. Demar AR, Taylor IL, and Fink AS. Pancreatic polypeptide and peptide YY inhibit
the denervated canine pancreas. Pancreas 6:419-426, 1991. PMID: 1876598.
58. Dembinski A, Konturek SJ, and Thor P. Gastric and pancreatic responses to meals
varying in pH. J Physiol 243:115-128, 1974. PMID: 4449058.
59. Demol P, and Sarles H. Action of fatty acids on the exocrine pancreatic secretion of
the conscious rat: further evidence for a protein pancreatic inhibitory factor. J Physiol
275:27-37, 1978. PMID: 633115.
60. Demol P, and Sarles H. Action of catecholamines on exocrine pancreatic secretion of
conscious rats. Arch Int Pharmacodyn Ther 243:149-163, 1980. PMID: 7387257.
61. Demol P, and Sarles H. Inhibition of exocrine pancreatic secretion by alphaadrenergic blocking agents in conscious rats. Arch Int Pharmacodyn Ther 243:164176, 1980. PMID: 6104476.
62. Deng X, Guarita DR, Wood PG, Kriess C, and Whitcomb DC. PYY potently
inhibits pancreatic exocrine secretion mediated through CCK-secretin-stimulated
pathways but not 2-DG-stimulated pathways in awake rats. Dig Dis Sci 46:156-165,
2001. PMID: 11270780.
63. Dimagno EP, Go VL, and Summerskill HJ. Intraluminal and postabsorptive effects
of amino acids on pancreatic enzyme secretion. J Lab Clin Med 82:241-248, 1973.
PMID: 4721379.
64. Doi R, Inoue K, Kogire M, Sumi S, Yun M, Futaki S, et al. Effect of synthetic
human cholecystokinin-33 on exocrine pancreas. Biochem Biophys Res Commun
150:1251-1255, 1988. PMID: 3342068.

65. Eberlein GA, Eysselein VE, Hesse WH, Goebell H, Schaefer M, and Reeve JR,
Jr. Detection of cholecystokinin-58 in human blood by inhibition of degradation. Am
J Physiol Gastrointest Liver Physiol 253:G477-482, 1987. PMID: 3661709.
66. Ekblad E, Alm P, and Sundler F. Distribution, origin and projections of nitric oxide
synthase-containing neurons in gut and pancreas. Neuroscience 63:233-248, 1994.
PMID: 7534882.
67. Ekblad E, and Sundler F. Distribution of pancreatic polypeptide and peptide YY.
Peptides 23:251-261, 2002. PMID: 11825640.
68. Ember Z, Yago MD, and Singh J. Distribution of nitric oxide synthase and secretory
role of exogenous nitric oxide in the isolated rat pancreas. Int J Pancreatol 29:77-84,
2001. PMID: 11876252.
69. Eysselein VE, Eberlein GA, Hesse WH, Singer MV, Goebell H, and Reeve JR, Jr.
Cholecystokinin-58 is the major circulating form of cholecystokinin in canine blood.
J Biol Chem 262:214-217, 1987. PMID: 3793725.
70. Fahrenkrug J, Schaffalitzky De Muckadell OB, Holst JJ, and Jensen SL.
Vasoactive intestinal polypeptide in vagally mediated pancreatic secretion of fluid and
HCO3. Am J Physiol Gastrointest Liver Physiol 237:E535-540, 1979. PMID: 517650.
71. Faichney A, Chey WY, Kim YC, Lee KY, Kim MS, and Chang TM. Effect of
sodium oleate on plasma secretin concentration and pancreatic secretion in dog.
Gastroenterology 81:458-462, 1981. PMID: 7250635.
72. Fehmann H-C, Weber V, Gke R, Gke B, Eissele R, and Arnold R. Islet amyloid
polypeptide (IAPP;Amylin) influences the endocrine but not the exocrine rat
pancreas. Biochem Biophys Res Commun 167:1102-1108, 1990. PMID: 1690993.
73. Feurle GE, and Reinecke M. Neurotensin interacts with carbachol, secretin, and
caerulein in the stimulation of the exocrine pancreas of the rat in vitro. Regul Pept
7:137-143, 1983. PMID: 6197722.
74. Fink AS, Luxenburg M, and Meyer JH. Regionally perfused fatty acids augment
acid-induced canine pancreatic secretion. Am J Physiol Gastrointest Liver Physiol
245:G78-84, 1983. PMID: 6869548.
75. Fink AS, and Meyer JH. Intraduodenal emulsions of oleic acid augment acidinduced canine pancreatic secretion. Am J Physiol Gastrointest Liver Physiol
245:G85-91, 1983. PMID: 6869549.
76. Fink AS, Miller JC, Jehn DW, and Meyer JH. Digests of protein augment acidinduced canine pancreatic secretion. Am J Physiol Gastrointest Liver Physiol
242:G634-641, 1982. PMID: 6807099.
77. Flowe KM, Lally KM, and Mulholland MW. Galanin inhibits rat pancreatic
amylase release via cholinergic suppression. Peptides 13:487-492, 1992. PMID:
1381828.

78. Fontana G, Costa PL, Tessari R, and Labo G. Effect of glucagon on pure human
exocrine pancretic secretion. Am J Gastroenterol 63:490-494, 1975. PMID: 1146806.
79. Fridolf T, Sundler F, and Ahren B. Pituitary adenylate cyclase-activating
polypeptide (PACAP): occurrence in rodent pancreas and effects on insulin and
glucagon secretion in the mouse. Cell Tissue Res 269:275-279, 1992. PMID:
1423494.
80. Funakoshi A, Miyasaka K, Kitani K, Nakamura J, Funakoshi S, Fukuda H, et al.
Stimulatory effects of islet amyloid polypeptide (amylin) on exocrine pancreas and
gastrin release in conscious rats. Regul Pept 38:135-143, 1992. PMID: 1574608.
81. Funakoshi A, Miyasaka K, Nakamura R, Kitani K, and Tatemoto K. Inhibitory
effect of pancreastatin on pancreatic exocrine secretion in the conscious rat. Regul
Pept 25:157-166, 1989. PMID: 2474177.
82. Furukawa N, and Okada H. Effects of antral distension on pancreatic exocrine
secretion in dogs: evidence for a short reflex. Jpn J Physiol 37:671-685, 1987. PMID:
3430872.
83. Furukawa N, and Okada H. Effects of stimulation of the hypothalamic area on
pancreatic exocrine secretion in dogs. Gastroenterology 97:1534-1543, 1989. PMID:
2684723.
84. Furuta Y, Hashimoto K, and Washizaki M. beta-Adrenoceptor stimulation of
exocrine secretion from the rat pancreas. Br J Pharmacol 62:25-29, 1978. PMID:
202364.
85. Gabryelewicz A, Kulesza E, and Konturek SJ. Comparison of loxiglumide, a
cholecystokinin receptor antagonist, and atropine on hormonal and meal-stimulated
pancreatic secretion in man. Scand J Gastroenterol 25:731-738, 1990. PMID:
2396088.
86. Gardner JD, Knight M, Sutliff VE, Tamminga CA, and Jensen RT. Derivatives of
CCK-(26-32) as cholecystokinin receptor antagonists in guinea pig pancreatic acini.
Am J Physiol Gastrointest Liver Physiol 246:G292-295, 1984. PMID: 6199984.
87. Gautam D, Han SJ, Heard TS, Cui Y, Miller G, Bloodworth L, et al. Cholinergic
stimulation of amylase secretion from pancreatic acinar cells studied with muscarinic
acetylcholine receptor mutant mice. J Pharmacol Exp Ther 313:995-1002, 2005.
PMID: 15764735.
88. Go VL, Hofmann AF, and Summerskill WH. Pancreozymin bioassay in man based
on pancreatic enzyme secretion: potency of specific amino acids and other digestive
products. J Clin Invest 49:1558-1564, 1970. PMID: 5431665.
89. Gomez G, Upp JR, Jr., Lluis F, Alexander RW, Poston GJ, Greeley GH, Jr., et al.
Regulation of the release of cholecystokinin by bile salts in dogs and humans.
Gastroenterology 94:1036-1046, 1988. PMID: 3345873.

90. Gomez GA, and Greeley GHJ. Peptide YY. Pancreapedia: Exocrine Pancreas
Knowledge Base. 10.3998/panc.2013.6 10.3998/panc.2013.6
91. Goyal D, and Pisegna JR. Pituitary Adenylate Cyclase Activating Polypeptide
(PACAP). Pancreapedia: Exocrine Pancreas Knowledge Base 2014.
10.3998/panc.2014.12
92. Grandt D, Siewert J, Sieburg B, Al Tai O, Schimiczek M, Goebell H, et al. Peptide
YY inhibits exocrine pancreatic secretion in isolated perfused rat pancreas by Y1
receptors. Pancreas 10:180-186, 1995. PMID: 7536329.
93. Green G, and Nasset ES. Effect of bile duct obstruction on pancreatic enzyme
secretion and intestinal proteolytic enzyme activity in the rat. Am J Dig Dis 22:437444, 1977. PMID: 857664.
94. Green GM. Role of gastric juice in feedback regulation of rat pancreatic secretion by
luminal proteases. Pancreas 5:445-451, 1990. PMID: 2199966.
95. Green GM, and Lyman RL. Feedback regulation of pancreatic enzyme secretion as
a mechanism for trypsin inhibitor-induced hypersecretion in rats. Proc Soc Exp Biol
Med 140:6-12, 1972. PMID: 5033119.
96. Green GM, and Nasset ES. Role of dietary protein in rat pancreatic enzyme
secretory response to a meal. J Nutr 113:2245-2252, 1983. PMID: 6685174.
97. Green GM, Taguchi S, Friestman J, Chey WY, and Liddle RA. Plasma secretin,
CCK, and pancreatic secretion in response to dietary fat in the rat. Am J Physiol
Gastrointest Liver Physiol 256:G1016-1021, 1989. PMID: 2735407.
98. Gries E, Hotz J, and Goebell H. Pancreatic exocrine secretion in response to
intraduodenal infusion of different detergent agents in anesthetized cats. Digestion
34:61-67, 1986. PMID: 3732639.
99. Griesbacher T, Rainer I, Heinemann A, and Groisman D. Haemodynamic and
exocrine effects of caerulein at submaximal and supramaximal levels on the rat
pancreas: role of cholecystokinin receptor subtypes. Pancreatology 6:65-75, 2006.
PMID: 16327284.
100.
Guan D, and Green GM. Significance of peptic digestion in rat pancreatic
secretory response to dietary protein. Am J Physiol Gastrointest Liver Physiol
271:G42-47, 1996. PMID: 8760105.
101.
Guan D, Spannagel A, Ohta H, Nakano I, Chey WY, and Green GM. Role
of secretin in basal and fat-stimulated pancreatic secretion in conscious rats.
Endocrinology 128:979-982, 1991. PMID: 1989876.
102.
Hacki WH, Bloom SR, Mitznegg P, Domschke W, Domschke S,
Belohlavek D, et al. Plasma secretin and pancreatic bicarbonate response to
exogenous secretin in man. Gut 18:191-195, 1977. PMID: 852751.

103.
Hajri A, Koenig M, Balboni G, and Damge C. Expression and
characterization of gastrin-releasing peptide receptor in normal and cancerous
pancreas. Pancreas 12:25-35, 1996. PMID: 8927617.
104.
Hanssen LE, Hotz J, Hartmann W, Nehls W, and Goebell H.
Immunoreactive secretin release following taurocholate perfusions of the cat
duodenum. Scand J Gastroenterol 15:89-95, 1980. PMID: 7367827.
105.
Hanssen LE, Hotz J, Layer P, and Goebell H. Bile-stimulated secretin
release in cats. Scand J Gastroenterol 21:886-890, 1986. PMID: 3775254.
106.
Harada H, Kochi F, Hanafusa E, Kobayashi T, Oka H, and Kimura I.
Studies on the effect of glucagon on human pancreatic secretion by analysis of
endoscopically obtained pure pancreatic juice. Gastroenterol Jpn 20:28-36, 1985.
PMID: 4018495.
107.
Hartmann W, Hotz J, Ormai S, Aufgebauer J, Schneider F, and Goebell
H. Stimulation of bile and pancreatic secretion by duodenal perfusion with Nataurocholate in the cat compared with jejunal and ileal perfusion. Scand J
Gastroenterol 15:433-442, 1980. PMID: 7433905.
108.
Hasegawa H, Okabayashi Y, Koide M, Kido Y, Okutani T, Matsushita K,
et al. Effect of islet hormones on secretin-stimulated exocrine secretion in isolated
perfused rat pancreas. Dig Dis Sci 38:1278-1283, 1993. PMID: 8325188.
109.
Hashimoto K, Oguro K, and Furuta Y. Species difference in the secretory
response to dopamine in the pancreas of dogs, cats, rabbits and rats. Arch Histol Jpn
40 Suppl:129-132, 1977. PMID: 209761.
110.
Hegyi P, Maleth J, Venglovecz V, and Rakonczay Z, Jr. Pancreatic ductal
bicarbonate secretion: challenge of the acinar acid load. Front Physiol 2:36, 2011.
PMID: 21808623.
111.
Hegyi P, Rakonczay Z, Jr., Tiszlavicz L, Varro A, Toth A, Racz G, et al.
Protein kinase C mediates the inhibitory effect of substance P on HCO3- secretion
from guinea pig pancreatic ducts. Am J Physiol Cell Physiol 288:C1030-1041, 2005.
PMID: 15625303.
112.
Heisler S, Kopelman H, Chabot JG, and Morel G. Atrial natriuretic factor
and exocrine pancreas: effects on the secretory process. Pancreas 2:243-251, 1987.
PMID: 2442744.
113.
Henriksen FW, and Worning H. External pancreatic response to food and its
relation to the maximal secretory capacity in dogs. Gut 10:209-214, 1969. PMID:
5781141.
114.
Herzig KH, Brunke G, Schon I, Schaffer M, and Folsch UR. Mechanism of
galanin's inhibitory action on pancreatic enzyme secretion: modulation of cholinergic
transmission--studies in vivo and in vitro. Gut 34:1616-1621, 1993. PMID: 7694889.

115.
Herzig KH, Schon I, Tatemoto K, Ohe Y, Li Y, Folsch UR, et al. Diazepam
binding inhibitor is a potent cholecystokinin-releasing peptide in the intestine. Proc
Natl Acad Sci U S A 93:7927-7932, 1996. PMID: 8755579.
116.
Hildebrand P, Beglinger C, Gyr K, Jansen JB, Rovati LC, Zuercher M, et
al. Effects of a cholecystokinin receptor antagonist on intestinal phase of pancreatic
and biliary responses in man. J Clin Invest 85:640-646, 1990. PMID: 2312719.
117.
Hira T, Nakajima S, Eto Y, and Hara H. Calcium-sensing receptor mediates
phenylalanine-induced cholecystokinin secretion in enteroendocrine STC-1 cells.
FEBS J 275:4620-4626, 2008. PMID: 18691347.
118.
Hiramatsu K, and Oshima K. Immunocytochemical study on the innervation
of the chicken pancreas by vasoactive intestinal polypeptide (VIP)-containing nerves.
Histol Histopathol 12:961-965, 1997. PMID: 9302555.
119.
Hiraoka T, Fukuwatari T, Imaizumi M, and Fushiki T. Effects of oral
stimulation with fats on the cephalic phase of pancreatic enzyme secretion in
esophagostomized rats. Physiol Behav 79:713-717, 2003. PMID: 12954413.
120.
Holst JJ, Fahrenkrug J, Knuhtsen S, Jensen SL, Poulsen SS, and Nielsen
OV. Vasoactive intestinal polypeptide (VIP) in the pig pancreas: role of VIPergic
nerves in control of fluid and bicarbonate secretion. Regul Pept 8:245-259, 1984.
PMID: 6379759.
121.
Holst JJ, Knuhtsen S, Jensen SL, Fahrenkrug J, Larsson LI, and Nielsen
OV. Interrelation of nerves and hormones in stomach and pancreas. Scand J
Gastroenterol Suppl 82:85-99, 1983. PMID: 6138853.
122.
Holst JJ, Orskov C, Knuhtsen S, Sheikh S, and Nielsen OV. On the
regulatory functions of neuropeptide Y (NPY) with respect to vascular resistance and
exocrine and endocrine secretion in the pig pancreas. Acta Physiol Scand 136:519526, 1989. PMID: 2675536
123.
Holst JJ, Rasmussen TN, Harling H, and Schmidt P. Effect of intestinal
inhibitory peptides on vagally induced secretion from isolated perfused porcine
pancreas. Pancreas 8:80-87, 1993. PMID: 7678328.
124.
Holst JJ, Rasmussen TN, and Schmidt P. Role of nitric oxide in neurally
induced pancreatic exocrine secretion in pigs. Am J Physiol Gastrointest Liver
Physiol 266:G206-213, 1994. PMID: 8141293.
125.
Holtmann G, Singer MV, Kriebel R, Stacker KH, and Goebell H.
Differential effects of acute mental stress on interdigestive secretion of gastric acid,
pancreatic enzymes, and gastroduodenal motility. Dig Dis Sci 34:1701-1707, 1989.
PMID: 2582983.
126.
Holzer P, Reichmann F, and Farzi A. Neuropeptide Y, peptide YY and
pancreatic polypeptide in the gut-brain axis. Neuropeptides 46:261-274, 2012. PMID:
22979996.

127.
Horiuchi A, Iwatsuki K, Ren LM, Kuroda T, and Chiba S. Dual actions of
glucagon: direct stimulation and indirect inhibition of dog pancreatic secretion. Eur J
Pharmacol 237:23-30, 1993. PMID: 7689468.
128.
Hosotani R, Inoue K, Fujii N, Yajima H, and Tobe T. Effect of synthetic
neuromedin C, a decapeptide of gastrin-releasing peptide (GRP [18-27]), on blood
flow and exocrine secretion of the pancreas in dogs. Life Sci 36:2429-2434, 1985.
PMID: 3892215.
129.
Hosotani R, Inoue K, Kogire M, Suzuki T, Otsuki M, Rayford PL, et al.
Synthetic neuromedin C stimulates exocrine pancreatic secretion in dogs and rats.
Pancreas 2:414-421, 1987. PMID: 2442749.
130.
Huang Y, Fischer JE, and Balasubramaniam A. Amylin mobilizes [Ca2+]i
and stimulates the release of pancreatic digestive enzymes from rat acinar AR42J
cells: evidence for an exclusive receptor system of amylin. Peptides 17:497-502,
1996. PMID: 8735978.
131.
Iijima F, Iwatsuki K, and Chiba S. Effects of dopamine on exocrine
secretion and cyclic nucleotide concentration in the dog pancreas. Eur J Pharmacol
92:191-197, 1983. PMID: 6313394.
132.
Imoto I, Yamamoto M, Jia DM, and Otsuki M. Effect of chronic oral
administration of the CCK receptor antagonist loxiglumide on exocrine and endocrine
pancreas in normal rats. Int J Pancreatol 22:177-185, 1997. PMID: 9444548
133.
Inoue K, Hosotani R, Tatemoto K, Yajima H, and Tobe T. Effect of natural
peptide YY on blood flow and exocrine secretion of pancreas in dogs. Dig Dis Sci
33:828-832, 1988. PMID: 3378477.
134.
Iwatsuki K, Horiuchi A, Ren LM, and Chiba S. Direct and indirect
stimulation of pancreatic exocrine secretion by neurotensin in anaesthetized dogs.
Clin Exp Pharmacol Physiol 18:475-481, 1991. PMID: 1914248.
135.
Iwatsuki K, Horiuchi A, Ren LM, and Chiba S. D-1 dopamine receptors
mediate dopamine-induced pancreatic exocrine secretion in anesthetized dogs.
Hypertens Res 18 Suppl 1:S173-174, 1995. PMID: 8529053.
136.
Iwatsuki K, Ren LM, and Chiba S. Effects of peptide histidine isoleucine on
pancreatic exocrine secretion in anaesthetized dogs. Clin Exp Pharmacol Physiol
20:501-507, 1993. PMID: 8403531.
137.
Jaworek J, Bonior J, Konturek SJ, Bilski J, Szlachcic A, and Pawlik WW.
Role of leptin in the control of postprandial pancreatic enzyme secretion. J Physiol
Pharmacol 54:591-602, 2003. PMID: 14726613.
138.
Jaworek J, Nawrot-Porabka K, Leja-Szpak A, Bonior J, Szklarczyk J,
Kot M, et al. Melatonin as modulator of pancreatic enzyme secretion and
pancreatoprotector. J Physiol Pharmacol 58 Suppl 6:65-80, 2007. PMID: 18212401.

139.
Jaworek J, Nawrot K, Konturek SJ, Leja-Szpak A, Thor P, and Pawlik
WW. Melatonin and its precursor, L-tryptophan: influence on pancreatic amylase
secretion in vivo and in vitro. J Pineal Res 36:155-164, 2004. PMID: 15009505.
140.
Jaworek J, Szklarczyk J, Jaworek AK, Nawrot-Porabka K, Leja-Szpak A,
Bonior J, et al. Protective effect of melatonin on acute pancreatitis. Int J Inflam
2012:173675, 2012. PMID: 22606640.
141.
Jensen SL, Holst JJ, Nielsen OV, and Rehfeld JF. Effect of sulfation of
CCK-8 on its stimulation of the endocrine and exocrine secretion from the isolated
perfused porcine pancreas. Digestion 22:305-309, 1981. PMID: 6277714
142.
Ji B, Bi Y, Simeone D, Mortensen RM, and Logsdon CD. Human
pancreatic acinar cells lack functional responses to cholecystokinin and gastrin.
Gastroenterology 121:1380-1390, 2001. PMID: 11729117.
143.
Jin H, Cai L, Lee K, Chang TM, Li P, Wagner D, et al. A physiological role
of peptide YY on exocrine pancreatic secretion in rats. Gastroenterology 105:208215, 1993. PMID: 8514036.
144.
Joehl RJ, and Dejoseph MR. Pancreatic polypeptide inhibits amylase release
by rat pancreatic acini. J Surg Res 40:310-314, 1986. PMID: 2422440.
145.
Jowell PS, Robuck-Mangum G, Mergener K, Branch MS, Purich ED, and
Fein SH. A double-blind, randomized, dose response study testing the
pharmacological efficacy of synthetic porcine secretin. Aliment Pharmacol Ther
14:1679-1684, 2000. PMID: 11121918.
146.
Kane MA, Kelley K, Ross SE, and Portanova LB. Isolation of a gastrin
releasing peptide receptor from normal rat pancreas. Peptides 12:207-213, 1991.
PMID: 1648710.
147.
Kashimura J, Shimosegawa T, Kikuchi Y, Yoshida K, Koizumi M,
Mochizuki T, et al. Effects of galanin on amylase secretion from dispersed rat
pancreatic acini. Pancreas 9:258-262, 1994. PMID: 7514793.
148.
Katoh K, Murai K, and Nonoyama T. Effects of substance P on fluid and
amylase secretion in exocrine pancreas of rat and mouse. Res Vet Sci 36:147-152,
1984. PMID: 6201966.
149.
Katschinski M, Dahmen G, Reinshagen M, Beglinger C, Koop H, Nustede
R, et al. Cephalic stimulation of gastrointestinal secretory and motor responses in
humans. Gastroenterology 103:383-391, 1992. PMID: 1634057.
150.
Kawabata A, Kuroda R, Nishida M, Nagata N, Sakaguchi Y, Kawao N, et
al. Protease-activated receptor-2 (PAR-2) in the pancreas and parotid gland:
Immunolocalization and involvement of nitric oxide in the evoked amylase secretion.
Life Sci 71:2435-2446, 2002. PMID: 12231404.

151.
Kayasseh L, Haecki WH, Gyr K, Stalder GA, Rittmann WW, Halter F, et
al. The endogenous release of pancreatic polypeptide by acid and meal in dogs. Effect
of somatostatin. Scand J Gastroenterol 13:385-391, 1978. PMID: 675146.
152.
Kemeny LV, Hegyi P, Rakonczay Z, Jr., Borka K, Korompay A, Gray MA,
et al. Substance P inhibits pancreatic ductal bicarbonate secretion via neurokinin
receptors 2 and 3 in the guinea pig exocrine pancreas. Pancreas 40:793-795, 2011.
PMID: 21673544.
153.
Kikuchi Y, Koizumi M, Shimosegawa T, Kashimura J, Suzuki S, and
Toyota T. Islet amyloid polypeptide has no effect on amylase release from rat
pancreatic acini stimulated by CCK-8, secretin, carbachol and VIP. Tohoku J Exp Med
165:41-48, 1991. PMID: 1724710.
154.
Kim C, Kim K, Lee H, Song C, Ryu H, and Hyun J. Potentiation of
cholecystokinin and secretin-induced pancreatic exocrine secretion by endogenous
insulin in humans. Pancreas 18:410-414, 1999. PMID: 10231848.
155.
Kim CK, Lee KY, Wang T, Sun G, Chang TM, and Chey WY. Role of
endogenous cholecystokinin on vagally stimulated pancreatic secretion in dogs. Am J
Physiol Gastrointest Liver Physiol 257:G944-949, 1989. PMID: 2481981.
156.
Klein E, Salinas A, Shemesh E, and Dreiling DA. Effects of autonomic
denervation on canine exocrine pancreatic secretion and blood flow. Int J Pancreatol
3:165-170, 1988. PMID: 3361158.
157.
Knuhtsen S, Holst JJ, Jensen SL, Knigge U, and Nielsen OV. Gastrinreleasing peptide: effect on exocrine secretion and release from isolated perfused
porcine pancreas. Am J Physiol Gastrointest Liver Physiol 248:G281-286, 1985.
PMID: 3976887.
158.
Koevary SB, Mcevoy RC, and Azmitia EC. Specific uptake of tritiated
serotonin in the adult rat pancreas: evidence for the presence of serotonergic fibers.
Am J Anat 159:361-368, 1980. PMID: 6971051.
159.
Koh YH, and Bhatia M. Substance P. Pancreapedia: Exocrine Pancreas
Knowledge Base 2011. 10.3998/panc.2011.23
160.
Kohler E, Beglinger C, Eysselein V, Grotzinger U, and Gyr K. Gastrin is
not a physiological regulator of pancreatic exocrine secretion in the dog. Am J Physiol
Gastrointest Liver Physiol 252:G40-44, 1987. PMID: 3812686.
161.
Khler H, Nustede, R., Barthel, M., Mller, C., Schafmayer, A. Total
denervation of the pancreas does not alter the pancreatic polypeptide-induced
inhibition of pancreatic exocrine secretion in dogs. Res Exp Med (Berl) 191:359-369,
1991. PMID: 8446771.
162.
Konturek JW, Gabryelewicz A, Kulesza E, Konturek SJ, and Domschke
W. Cholecystokinin (CCK) in the amino acid uptake and enzyme protein secretion by
the pancreas in humans. Int J Pancreatol 17:55-61, 1995. PMID: 8568335.

163.
Konturek SJ, Bielanski W, and Solomon TE. Effects of an antral
mucosectomy, L-364,718 and atropine on cephalic phase of gastric and pancreatic
secretion in dogs. Gastroenterology 98:47-55, 1990. PMID: 2403431.
164.
Konturek SJ, Dubiel J, and Gabrys B. Effect of acid infusion into various
levels of the intestine on gastric and pancreatic secretion in the cat. Gut 10:749-753,
1969. PMID: 5386632.
165.
Konturek SJ, Meyers CA, Kwiecien N, Obtulowicz W, Tasler J, Oleksy J,
et al. Effect of human pancreatic polypeptide and its C-terminal hexapeptide on
pancreatic secretion in man and in the dog. Scand J Gastroenterol 17:395-399, 1982.
PMID: 7134866.
166.
Konturek SJ, Radecki T, Mikos E, and Thor J. The effect of exogenous and
endogenous secretin and cholecystokinin on pancreatic secretion in cats. Scand J
Gastroenterol 6:423-428, 1971. PMID: 5093529.
167.
Konturek SJ, Tasler J, Bilski J, Cieszkowski M, Cai RZ, and Schally AV.
Antagonism of receptors for gastrin, cholecystokinin and GRP/bombesin in
postprandial stimulation of exocrine pancreas in dogs. J Physiol Pharmacol 44:43-53,
1993. PMID: 8390873.
168.
Konturek SJ, Tasler J, Cieszkowski M, Jaworek J, and Konturek J.
Intravenous amino acids and fat stimulate pancreatic secretion. Am J Physiol Physiol
Endocrinol Meta 236:E678-684, 1979. PMID: 443422.
169.
Konturek SJ, Tasler J, Cieszkowski M, Szewczyk K, and Hladij M. Effect
of cholecystokinin receptor antagonist on pancreatic responses to exogenous gastrin
and cholecystokinin and to meal stimuli. Gastroenterology 94:1014-1023, 1988.
PMID: 3345871.
170.
Konturek SJ, Yanaihara N, Pawlik W, Jaworek J, and Szewczyk K.
Comparison of helodermin, VIP and PHI in pancreatic secretion and blood flow in
dogs. Regul Pept 24:155-166, 1989. PMID: 2922493.
171.
Koop I, Schindler M, Bosshammer A, Scheibner J, Stange E, and Koop H.
Physiological control of cholecystokinin release and pancreatic enzyme secretion by
intraduodenal bile acids. Gut 39:661-667, 1996. PMID: 9026479.
172.
Kopin AS, Mathes WF, Mcbride EW, Nguyen M, Al-Haider W, Schmitz F,
et al. The cholecystokinin-A receptor mediates inhibition of food intake yet is not
essential for the maintenance of body weight. J Clin Invest 103:383-391, 1999.
PMID: 9927499.
173.
Kreiss C, Schwizer W, Erlacher U, Borovicka J, Lochner-Kuery C, Muller
R, et al. Role of antrum in regulation of pancreaticobiliary secretion in humans. Am J
Physiol Gastrointest Liver Physiol 270:G844-851, 1996. PMID: 8967497.

174.
Kuvshinoff BW, Brodish RJ, James L, Mcfadden DW, and Fink AS.
Somatostatin inhibits secretin-induced canine pancreatic response via a cholinergic
mechanism. Gastroenterology 105:539-547, 1993. PMID: 8101500.
175.
Lai KC, Cheng CH, and Leung PS. The ghrelin system in acinar cells:
localization, expression, and regulation in the exocrine pancreas. Pancreas 35:e1-8,
2007. PMID: 17895831.
176.
Larsson LI, and Rehfeld JF. Peptidergic and adrenergic innervation of
pancreatic ganglia. Scand J Gastroenterol 14:433-437, 1979. PMID: 384501.
177.
Lee E, Gerlach U, Uhm DY, and Kim J. Inhibitory effect of somatostatin on
secretin-induced augmentation of the slowly activating K+ current (IKs) in the rat
pancreatic acinar cell. Pflugers Arch 443:405-410, 2002. PMID: 11810210.
178.
Lee KY, Krusch D, Zhou L, Song Y, Chang TM, and Chey WY. Effect of
endogenous insulin on pancreatic exocrine secretion in perfused dog pancreas.
Pancreas 11:190-195, 1995. PMID: 7479678.
179.
Lee KY, Lee YL, Kim CD, Chang TM, and Chey WY. Mechanism of action
of insulin on pancreatic exocrine secretion in perfused rat pancreas. Am J Physiol
Gastrointest Liver Physiol 267:G207-212, 1994. PMID: 7915495.
180.
Lee W, Miyazaki K, and Funakoshi A. Effects of somatostatin and
pancreatic polypeptide on exocrine and endocrine pancreas in the rats. Gastroenterol
Jpn 23:49-55, 1988. PMID: 2895031.
181.
Lee YL, Kwon HY, Park HS, Lee TH, and Park HJ. The role of insulin in
the interaction of secretin and cholecystokinin in exocrine secretion of the isolated
perfused rat pancreas. Pancreas 12:58-63, 1996. PMID: 8927620.
182.
Leja-Szpak A, Jaworek J, Nawrot-Porabka K, Palonek M, Mitis-Musiol
M, Dembinski A, et al. Modulation of pancreatic enzyme secretion by melatonin and
its precursor; L-tryptophan. Role of CCK and afferent nerves. J Physiol Pharmacol 55
Suppl 2:33-46, 2004. PMID: 15608359.
183.
Lenz HJ, Messmer B, and Zimmerman FG. Noradrenergic inhibition of
canine gallbladder contraction and murine pancreatic secretion during stress by
corticotropin-releasing factor. J Clin Invest 89:437-443, 1992. PMID: 1737835.
184.
Lhoste E, Aprahamian M, Pousse A, Hoeltzel A, and Stock-Damge C.
Combined effect of chronic bombesin and secretin or cholecystokinin on the rat
pancreas. Peptides 6 Suppl 3:83-87, 1985. PMID: 2421268.
185.
Lhoste EF, Levenez F, Chabanet C, Fiszlewicz M, and Corring T. Effect of
bombesin at low doses on the secretion of the exocrine pancreas and on plasma
gastrin concentration in the conscious pig. Regul Pept 74:41-45, 1998. PMID:
9657358.

186.
Liddle RA. Regulation of cholecystokinin secretion by intraluminal releasing
factors. Am J Physiol Gastrointest Liver Physiol 269:G319-G327, 1995. PMID:
7573441.
187.
Liddle RA. Regulation of Pancreatic Secretion. In: Physiology of the
Gastrointestinal Tract, edited by Leonard R. Johnson FKG, Jonathan D. Kaunitz,
Juanita L. Merchant, Hamid M. Said, and Jackie D. Wood London: Academic Press,
2012, pp. 1425-1460.
188.
Liddle RA, Goldfine ID, Rosen MS, Taplitz RA, and Williams JA.
Cholecystokinin bioactivity in human plasma. Molecular forms, responses to feeding,
and relationship to gallbladder contraction. J Clin Invest 75:1144-1152, 1985. PMID:
2580857.
189.
Liddle RA, Green GM, Conrad CK, and Williams JA. Proteins but not
amino acids, carbohydrates, or fats stimulate cholecystokinin secretion in the rat. Am
J Physiol Gastrointest Liver Physiol 251:G243-248, 1986. PMID: 3740265.
190.
Liddle RA, Misukonis MA, Pacy L, and Balber AE. Cholecystokinin cells
purified by fluorescence-activated cell sorting respond to monitor peptide with an
increase in intracellular calcium. Proc Natl Acad Sci U S A 89:5147-5151, 1992.
PMID: 1594624.
191.
Liddle RA, Rushakoff RJ, Morita ET, Beccaria L, Carter JD, and
Goldfine ID. Physiological role for cholecystokinin in reducing postprandial
hyperglycemia in humans. J Clin Invest 81:1675-1681, 1988. PMID: 3290250.
192.
Lin TM, Evans DC, Shaar CJ, and Root MA. Action of somatostatin on
stomach, pancreas, gastric mucosal blood flow, and hormones. Am J Physiol
Gastrointest Liver Physiol 244:G40-45, 1983. PMID: 6129805.
193.
Liou AP, Lu X, Sei Y, Zhao X, Pechhold S, Carrero RJ, et al. The Gprotein-coupled receptor GPR40 directly mediates long-chain fatty acid-induced
secretion of cholecystokinin. Gastroenterology 140:903-912, 2011. PMID: 20955703.
194.
Liou AP, Sei Y, Zhao X, Feng J, Lu X, Thomas C, et al. The extracellular
calcium-sensing receptor is required for cholecystokinin secretion in response to Lphenylalanine in acutely isolated intestinal I cells. Am J Physiol Gastrointest Liver
Physiol 300:G538-546, 2011. PMID: 21252045.
195.
Liu HP, Tay SS, and Leong SK. Nitrergic neurons in the pancreas of
newborn guinea pig: their distribution and colocalization with various neuropeptides
and dopamine-beta-hydroxylase. J Auton Nerv Syst 61:248-256, 1996. PMID:
8988482.
196.
Lopez J, and Cuesta N. Adrenomedullin as a pancreatic hormone. Microsc
Res Tech 57:61-75, 2002. PMID: 11921357.

197.
Louie DS, Williams JA, and Owyang C. Action of pancreatic polypeptide on
rat pancreatic secretion: in vivo and in vitro. Am J Physiol Gastrointest Liver Physiol
249:G489-495, 1985. PMID: 2413769.
198.
Love JA, and Szebeni K. Morphology and histochemistry of the rabbit
pancreatic innervation. Pancreas 18:53-64, 1999. PMID: 9888661.
199.
Maack T. Role of atrial natriuretic factor in volume control. Kidney Int
49:1732-1737, 1996. PMID: 8743487.
200.
Macgregor I, Parent J, and Meyer JH. Gastric emptying of liquid meals and
pancreatic and biliary secretion after subtotal gastrectomy or truncal vagotomy and
pyloroplasty in man. Gastroenterology 72:195-205, 1977. PMID: 830568.
201.
Malagelada JR, Dimagno EP, Summerskill WH, and Go VL. Regulation of
pancreatic and gallbladder functions by intraluminal fatty acids and bile acids in man.
J Clin Invest 58:493-499, 1976. PMID: 956380.
202.
Malagelada JR, Go VL, Dimagno EP, and Summerskill WH. Interactions
between intraluminal bile acids and digestive products on pancreatic and gallbladder
function. J Clin Invest 52:2160-2165, 1973. PMID: 4727454.
203.
Mannon P, and Taylor IL. The pancreatic polypeptide family. In: Gut
peptides: Biochemistry and Physiology, edited by Walsh JH, and Dockray GJ. New
York: Raven Press, 1994, Pp. 341-370.
204.
Marongiu L, Perra MT, Pinna AD, Sirigu F, and Sirigu P. Peptidergic
(VIP) nerves in normal human pancreas and in pancreatitis: an immunohistochemical
study. Histol Histopathol 8:127-132, 1993. PMID: 8443423.
205.
Matsushita K, Okabayashi Y, Koide M, Hasegawa H, Otsuki M, and
Kasuga M. Potentiating effect of insulin on exocrine secretory function in isolated rat
pancreatic acini. Gastroenterology 106:200-206, 1994. PMID: 7506218.
206.
Matyjek R, Herzig KH, Kato S, and Zabielski R. Exogenous leptin inhibits
the secretion of pancreatic juice via a duodenal CCK1-vagal-dependent mechanism in
anaesthetized rats. Regul Pept 114:15-20, 2003. PMID: 12763635.
207.
Mayer EA, Thompson JB, Jehn D, Reedy T, Elashoff J, and Meyer JH.
Gastric emptying and sieving of solid food and pancreatic and biliary secretion after
solid meals in patients with truncal vagotomy and antrectomy. Gastroenterology
83:184-192, 1982. PMID: 6919504.
208.
Mclaughlin J. Long-chain fatty acid sensing in the gastrointestinal tract.
Biochem Soc Trans 35:1199-1202, 2007. PMID: 17956311.
209.
Mclaughlin J, Grazia Luca M, Jones MN, D'amato M, Dockray GJ, and
Thompson DG. Fatty acid chain length determines cholecystokinin secretion and
effect on human gastric motility. Gastroenterology 116:46-53, 1999. PMID: 9869601.

210.
Mclaughlin JT, Lomax RB, Hall L, Dockray GJ, Thompson DG, and
Warhurst G. Fatty acids stimulate cholecystokinin secretion via an acyl chain lengthspecific, Ca2+-dependent mechanism in the enteroendocrine cell line STC-1. J Physiol
513:11-18, 1998. PMID: 9782155.
211.
Messmer B, Zimmerman FG, and Lenz HJ. Regulation of exocrine
pancreatic secretion by cerebral TRH and CGRP: role of VIP, muscarinic, and
adrenergic pathways. Am J Physiol Gastrointest Liver Physiol 264:G237-242, 1993.
PMID: 8447406.
212.
Meuth-Metzinger VL, Philouze-Rome V, Metzinger L, Gespach C, and
Guilloteau P. Differential activation of adenylate cyclase by secretin and VIP
receptors in the calf pancreas. Pancreas 31:174-181, 2005. PMID: 16025005.
213.
Meyer JH, and Grossman MI. Comparison of D- and L-phenylalanine as
pancreatic stimulants. Am J Physiol Gastrointest Liver Physiol 222:1058-1063, 1972.
PMID: 5027085.
214.
Meyer JH, and Jones RS. Canine pancreatic responses to intestinally
perfused fat and products of fat digestion. Am J Physiol Gastrointest Liver Physiol
226:1178-1187, 1974. PMID: 4824870.
215.
Meyer JH, and Kelly GA. Canine pancreatic responses to intestinally
perfused proteins and protein digests. Am J Physiol Gastrointest Liver Physiol
231:682-691, 1976. PMID: 970450.
216.
Meyer JH, Kelly GA, and Jones RS. Canine pancreatic response to
intestinally perfused oligopeptides. Am J Physiol Gastrointest Liver Physiol 231:678681, 1976. PMID: 970449.
217.
Meyer JH, Kelly GA, Spingola LJ, and Jones RS. Canine gut receptors
mediating pancreatic responses to luminal L-amino acids. Am J Physiol Gastrointest
Liver Physiol 231:669-677, 1976. PMID: 970448.
218.
Meyer JH, Spingola J, and Grossman MI. Endogenous cholecystokinin
potentiates exogenous secretin on pancreas of dog. Am J Physiol Gastrointest Liver
Physiol 221:742-747, 1971. PMID: 5570331.
219.
Meyer JH, Way LW, and Grossman MI. Pancreatic bicarbonate response to
various acids in duodenum of the dog. Am J Physiol Gastrointest Liver Physiol
219:964-970, 1970. PMID: 5459498.
220.
Migita Y, Nakano I, Goto M, Ito T, and Nawata H. Effect of pancreastatin
on cerulein-stimulated pancreatic blood flow and exocrine secretion in anaesthetized
rats. J Gastroenterol Hepatol 14:583-587, 1999. PMID: 10385069.
221.
Miller TA, Watson LC, Rayford PL, and Thompson JC. The effect of
glucagon on pancreatic secretion and plasma secretin in dogs. World J Surg 1:93-97,
1977. PMID: 17233.

222.
Miyasaka K, Funakoshi A, Nakamura R, Kitani K, Shimizu F, and
Tatemoto K. Effects of porcine pancreastatin on postprandial pancreatic exocrine
secretion and endocrine functions in the conscious rat. Digestion 43:204-211, 1989.
PMID: 2612743.
223.
Miyasaka K, Funakoshi A, Shikado F, and Kitani K. Stimulatory and
inhibitory effects of bile salts on rat pancreatic secretion. Gastroenterology 102:598604, 1992. PMID: 1343077.
224.
Miyasaka K, Funakoshi A, Yasunami Y, Nakamura R, Kitani K,
Tamamura H, et al. Rat pancreastatin inhibits both pancreatic exocrine and
endocrine secretions in rats. Regul Pept 28:189-198, 1990. PMID: 1693005.
225.
Miyasaka K, and Green GM. Effect of partial exclusion of pancreatic juice
on rat basal pancreatic secretion. Gastroenterology 86:114-119, 1984. PMID:
6689654.
226.
Miyasaka K, and Kitani K. A difference in stimulatory effects on pancreatic
exocrine secretion between ursodeoxycholate and trypsin inhibitor in the rat. Dig Dis
Sci 31:978-986, 1986. PMID: 2426065.
227.
Miyasaka K, and Kitani K. Effects of bile salts on pancreatic secretion in
rabbits: ursodeoxycholate infused into the duodenum stimulates pancreas. Pancreas
1:264-269, 1986. PMID: 3575308.
228.
Miyasaka K, Sazaki N, Funakoshi A, Matsumoto M, and Kitani K. Two
mechanisms of inhibition by bile on luminal feedback regulation of rat pancreas.
Gastroenterology 104:1780-1785, 1993. PMID: 8500737.
229.
Miyasaka K, Shinozaki H, Jimi A, and Funakoshi A. Amylase secretion
from dispersed human pancreatic acini: neither cholecystokinin A nor cholecystokinin
B receptors mediate amylase secretion in vitro. Pancreas 25:161-165, 2002. PMID:
12142739.
230.
Miyasaka K, Shinozaki H, Suzuki S, Sato Y, Kanai S, Masuda M, et al.
Disruption of cholecystokinin (CCK)-B receptor gene did not modify bile or
pancreatic secretion or pancreatic growth: a study in CCK-B receptor gene knockout
mice. Pancreas 19:114-118, 1999. PMID: 10438156.
231.
Moghimzadeh E, Ekman R, Hakanson R, Yanaihara N, and Sundler F.
Neuronal gastrin-releasing peptide in the mammalian gut and pancreas. Neuroscience
10:553-563, 1983. PMID: 6355896.
232.
Moore EW, Verine HJ, and Grossman MI. Pancreatic bicarbonate response
to a meal. Acta Hepatogastroenterol (Stuttg) 26:30-36, 1979. PMID: 34310.
233.
Morisset J, Levenez F, Corring T, Benrezzak O, Pelletier G, and Calvo E.
Pig pancreatic acinar cells possess predominantly the CCK-B receptor subtype. Am J
Physiol Endocrinol Metab 271:E397-402, 1996. PMID: 8770035.

234.
Moriyasu M, Lee YL, Lee KY, Chang TM, and Chey WY. Effect of
digested protein on pancreatic exocrine secretion and gut hormone release in the dog.
Pancreas 9:129-133, 1994. PMID: 8108365.
235.
Mulholland MW, Lally K, and Taborsky GJ, Jr. Inhibition of rat pancreatic
exocrine secretion by neuropeptide Y: studies in vivo and in vitro. Pancreas 6:433440, 1991. PMID: 1715087.
236.
Mulvihill SJ, Bunnett NW, Goto Y, and Debas HT. Somatostatin inhibits
pancreatic exocrine secretion via a neural mechanism. Metabolism 39:143-148, 1990.
PMID: 1698248.
237.
Murphy JA, Criddle DN, Sherwood M, Chvanov M, Mukherjee R,
Mclaughlin E, et al. Direct activation of cytosolic Ca2+ signaling and enzyme
secretion by cholecystokinin in human pancreatic acinar cells. Gastroenterology
135:632-641, 2008. PMID: 18555802.
238.
Mussa BM, Sartor DM, and Verberne AJM. Dorsal vagal preganglionic
neurons: Differential responses to CCK1 and 5-HT3 receptor stimulation. Auton
Neurosci 156:36-43, 2010. PMID: 20346737.
239.
Mussa BM, and Verberne AJ. Activation of the dorsal vagal nucleus
increases pancreatic exocrine secretion in the rat. Neurosci Lett 433:71-76, 2008.
PMID: 18241988.
240.
Nakajima S, Hira T, and Hara H. Calcium-sensing receptor mediates dietary
peptide-induced CCK secretion in enteroendocrine STC-1 cells. Mol Nutr Food Res
56:753-760, 2012. PMID: 22648622.
241.
Navas JM, Calvo JJ, Lopez MA, and De Dios I. Exocrine pancreatic
response to intraduodenal fatty acids and fats in rabbits. Comp Biochem Physiol
Comp Physiol 105:141-145, 1993. PMID: 8099868.
242.
Nawrot-Porabka K, Jaworek J, Leja-Szpak A, Palonek M, Szklarczyk J,
Konturek SJ, et al. Leptin is able to stimulate pancreatic enzyme secretion via
activation of duodeno-pancreatic reflex and CCK release. J Physiol Pharmacol 55
Suppl 2:47-57, 2004. PMID: 15608360.
243.
Nawrot-Porabka K, Jaworek J, Leja-Szpak A, Szklarczyk J, Konturek SJ,
and Reiter RJ. Luminal melatonin stimulates pancreatic enzyme secretion via
activation of serotonin-dependent nerves. Pharmacological Reports : PR 65:494-504,
2013. PMID: 23744434.
244.
Nawrot-Porabka K, Jaworek J, Leja-Szpak A, Szklarczyk J, Kot M,
Mitis-Musiol M, et al. Involvement of vagal nerves in the pancreatostimulatory
effects of luminal melatonin, or its precursor L-tryptophan. Study in the rats. J
Physiol Pharmacol 58 Suppl 6:81-95, 2007. PMID: 18212402.

245.
Niebergall-Roth E, and Singer MV. Central and peripheral neural control of
pancreatic exocrine secretion. J Physiol Pharmacol 52:523-538, 2001. PMID:
11787756.
246.
Niederau C, Sonnenberg A, and Erckenbrecht J. Effects of intravenous
infusion of amino acids, fat, or glucose on unstimulated pancreatic secretion in
healthy humans. Dig Dis Sci 30:445-455, 1985. PMID: 2580678.
247.
Niijima A. Effect of umami taste stimulations on vagal efferent activity in the
rat. Brain Res Bull 27:393-396, 1991. PMID: 1959036.
248.
Nustede R, Schmidt WE, Kohler H, Folsch UR, and Schafmayer A. The
influence of bile acids on the regulation of exocrine pancreatic secretion and on the
plasma concentrations of neurotensin and CCK in dogs. Int J Pancreatol 13:23-30,
1993. PMID: 8454915.
249.
Oguchi H, Iwatsuki K, Horiuchi A, Furuta S, and Chiba S. Effects of
human atrial natriuretic polypeptide on pancreatic exocrine secretion in the dog.
Biochem Biophys Res Commun 146:757-763, 1987. PMID: 2956951.
250.
Ohnishi H, Mine T, and Kojima I. Inhibition by somatostatin of amylase
secretion induced by calcium and cyclic AMP in rat pancreatic acini. Biochem J 304
( Pt 2):531-536, 1994. PMID: 7528010.
251.
Okabayashi Y, Otsuki M, Ohki A, Sakamoto C, and Baba S. Effects of Cterminal fragments of cholecystokinin on exocrine and endocrine secretion from
isolated perfused rat pancreas. Endocrinology 113:2210-2215, 1983. PMID: 6196184.
252.
Olsen O, Schaffalitzky De Muckadell OB, and Cantor P. Fat and pancreatic
secretion. Scand J Gastroenterol 24:74-80, 1989. PMID: 2928726.
253.
Osnes M, Hanssen LE, Flaten O, and Myren J. Exocrine pancreatic
secretion and immunoreactive secretin (IRS) release after intraduodenal instillation of
bile in man. Gut 19:180-184, 1978. PMID: 631638.
254.
Osnes M, Hanssen LE, Lehnert P, Flaten O, Larsen S, Londong W, et al.
Exocrine pancreatic secretion and immunoreactive secretin release after repeated
intraduodenal infusions of bile in man. Scand J Gastroenterol 15:1033-1039, 1980.
PMID: 6165067.
255.
Otsuki M, Okabayashi Y, Ohki A, Oka T, Fujii M, Nakamura T, et al.
Action of cholecystokinin analogues on exocrine and endocrine rat pancreas. Am J
Physiol Gastrointest Liver Physiol 250:G405-411, 1986. PMID: 2421584.
256.
Pandol SJ. The Exocrine Pancreas. San Rafael (CA): Morgan & Claypool
Life Sciences 2010. PMID: 21634067.
257.
Pandol SJ, Schoeffield MS, Sachs G, and Muallem S. Role of free cytosolic
calcium in secretagogue-stimulated amylase release from dispersed acini from guinea
pig pancreas. J Biol Chem 260:10081-10086, 1985. PMID: 2410419.

258.
Pandol SJ, Sutliff VE, Jones SW, Charlton CG, O'donohue TL, Gardner
JD, et al. Action of natural glucagon on pancreatic acini: due to contamination by
previously undescribed secretagogues. Am J Physiol Gastrointest Liver Physiol
245:G703-710, 1983. PMID: 6195929.
259.
Pandol SJ, Thomas MW, Schoeffield MS, Sachs G, and Muallem S. Role
of calcium in cholecystokinin-stimulated phosphoinositide breakdown in exocrine
pancreas. Am J Physiol Gastrointest Liver Physiol 248:G551-560, 1985. PMID:
2581457.
260.
Pappas TN, Debas HT, Goto Y, and Taylor IL. Peptide YY inhibits mealstimulated pancreatic and gastric secretion. Am J Physiol Gastrointest Liver Physiol
248:G118-123, 1985. PMID: 3838121.
261.
Pappas TN, Debas HT, and Taylor IL. Peptide YY: metabolism and effect on
pancreatic secretion in dogs. Gastroenterology 89:1387-1392, 1985. PMID: 3840443.
262.
Pariente JA, Madrid JA, and Salido GM. Role of histamine receptors in
rabbit pancreatic exocrine secretion stimulated by cholecystokinin and secretin. Exp
Physiol 75:657-667, 1990. PMID: 1978780.
263.
Park HJ, Lee YL, and Kwon HY. Effects of pancreatic polypeptide on
insulin action in exocrine secretion of isolated rat pancreas. J Physiol 463:421-429,
1993. PMID: 7504106.
264.
Park HS, Kwon HY, Lee YL, Chey WY, and Park HJ. Role of GRPergic
neurons in secretin-evoked exocrine secretion in isolated rat pancreas. Am J Physiol
Gastrointest Liver Physiol 278:G557-562, 2000. PMID: 10762609.
265.
Park HS, Lee YL, Kwon HY, Chey WY, and Park HJ. Significant
cholinergic role in secretin-stimulated exocrine secretion in isolated rat pancreas. Am
J Physiol Gastrointest Liver Physiol 274:G413-418, 1998. PMID: 9486197.
266.
Park YD, Cui ZY, and Park HJ. Effects of gamma-aminobutyric acid on
action of gastrin-releasing peptidergic neurons in exocrine secretion of isolated,
perfused rat pancreas. Pancreas 25:308-313, 2002. PMID: 12370544.
267.
Patel R, Singh J, Yago MD, Vilchez JR, Martinez-Victoria E, and Manas
M. Effect of insulin on exocrine pancreatic secretion in healthy and diabetic
anaesthetised rats. Mol Cell Biochem 261:105-110, 2004. PMID: 15362492.
268.
Pearson GT, Singh J, and Petersen OH. Adrenergic nervous control of
cAMP-mediated amylase secretion in the rat pancreas. Am J Physiol Gastrointest
Liver Physiol 246:G563-573, 1984. PMID: 6202157.
269.
Phillips PA, Yang L, Shulkes A, Vonlaufen A, Poljak A, Bustamante S, et
al. Pancreatic stellate cells produce acetylcholine and may play a role in pancreatic
exocrine secretion. Proc Natl Acad Sci USA 107:17397-17402, 2010. PMID:
20852067.

270.
Pisegna JR, De Weerth A, Huppi K, and Wank SA. Molecular cloning of
the human brain and gastric cholecystokinin receptor: structure, functional expression
and chromosomal localization. Biochem Biophys Res Commun 189:296-303, 1992.
PMID: 1280419.
271.
Powers MA, Schiffman SS, Lawson DC, Pappas TN, and Taylor IL. The
effect of taste on gastric and pancreatic responses in dogs. Physiol Behav 47:12951297, 1990. PMID: 2395936.
272.
Reeve JR, Jr., Green GM, Chew P, Eysselein VE, and Keire DA. CCK-58
is the only detectable endocrine form of cholecystokinin in rat. Am J Physiol
Gastrointest Liver Physiol 285:G255-265, 2003. PMID: 12686511.
273.
Riepl RL, Fiedler F, Kowalski C, Teufel J, and Lehnert P. Exocrine
pancreatic secretion and plasma levels of cholecystokinin, pancreatic polypeptide, and
somatostatin after single and combined intraduodenal application of different bile
salts in man. Ital J Gastroenterol 28:421-429, 1996. PMID: 9032583.
274.
Riepl RL, Fiedler F, Teufel J, and Lehnert P. Effect of intraduodenal bile
and taurodeoxycholate on exocrine pancreatic secretion and on plasma levels of
vasoactive intestinal polypeptide and somatostatin in man. Pancreas 9:109-116, 1994.
PMID: 7509061.
275.
Riepl RL, and Lehnert P. The role of bile in the regulation of exocrine
pancreatic secretion. Scand J Gastroenterol 27:625-631, 1992. PMID: 1439544.
276.
Riepl RL, Reichardt B, Rauscher J, Tzavella K, Teufel J, and Lehnert P.
Mediators of exocrine pancreatic secretion induced by intraduodenal application of
bile and taurodeoxycholate in man. Eur J Med Res 2:23-29, 1997. PMID: 9049590.
277.
Rodrguez MR, Diez F, Ventimiglia MS, Morales V, Copsel S, Vatta MS, et
al. Atrial Natriuretic Factor Stimulates Efflux of cAMP in Rat Exocrine Pancreas via
Multidrug ResistanceAssociated Proteins. Gastroenterology 140:1292-1302, 2011.
PMID: 21237168.
278.
Rothman SS. Molecular regulation of digestion: short term and bond specific.
Am J Physiol Gastrointest Liver Physiol 226:77-83, 1974. PMID: 4809890.
279.
Rune SJ. pH in the human duodenum. Its physiological and
pathophysiological significance. Digestion 8:261-268, 1973. PMID: 4721705.
280.
Sabbatini ME, Bi Y, Ji B, Ernst SA, and Williams JA. CCK activates RhoA
and Rac1 differentially through G13 and Gq in mouse pancreatic acini. Am J Physiol
Cell Physiol 298:C592-C601, 2010. PMID: 19940064.
281.
Sabbatini ME, Rodriguez M, Di Carlo MB, Davio CA, Vatta MS, and
Bianciotti LG. C-type natriuretic peptide enhances amylase release through NPR-C
receptors in the exocrine pancreas. Am J Physiol Gastrointest Liver Physiol
293:G987-994, 2007. PMID: 17702953.

282.
Sabbatini ME, Rodriguez MR, Dabas P, Vatta MS, and Bianciotti LG. Ctype natriuretic peptide stimulates pancreatic exocrine secretion in the rat: role of
vagal afferent and efferent pathways. Eur J Pharmacol 577:192-202, 2007. PMID:
17900562.
283.
Sabbatini ME, Vatta MS, Davio CA, and Bianciotti LG. Atrial natriuretic
factor negatively modulates secretin intracellular signaling in the exocrine pancreas.
Am J Physiol Gastrointest Liver Physiol 292:G349-357, 2007. PMID: 16973919.
284.
Sabbatini ME, Villagra A, Davio CA, Vatta MS, Fernandez BE, and
Bianciotti LG. Atrial natriuretic factor stimulates exocrine pancreatic secretion in the
rat through NPR-C receptors. Am J Physiol Gastrointest Liver Physiol 285:G929-937,
2003. PMID: 12829435.
285.
Sakamoto C, Otsuki M, Ohki A, Yuu H, Maeda M, Yamasaki T, et al.
Glucose-dependent insulinotropic action of cholecystokinin and caerulein in the
isolated perfused rat pancreas. Endocrinology 110:398-402, 1982. PMID: 6173205.
286.
Sanchez-Vicente C, Rodriguez-Nodal F, Minguela A, Garcia LJ, San
Roman JI, Calvo JJ, et al. Cholinergic pathways are involved in secretin and VIP
release and the exocrine pancreatic response after intraduodenally perfused acetic and
lactic acids in the rat. Pancreas 10:93-99, 1995. PMID: 7899466.
287.
Sans MD, Sabbatini ME, Ernst SA, D'Alecy LG, Nishijima I, and
Williams JA. Secretin is not necessary for exocrine pancreatic development and
growth in mice. Am J Physiol Gastrointest Liver Physiol 301:G791-G798, 2011.
PMID: 21852360.
288.
Sarles H, Dani R, Prezelin G, Souville C, and Figarella C. Cephalic phase
of pancreatic secretion in man. Gut 9:214-221, 1968. PMID: 5655031.
289.
Schaffalitzky De Muckadell OB, Fahrenkrug J, Matzen P, Rune SJ, and
Worning H. Physiological significance of secretin in the pancreatic bicarbonate
secretion. II. Pancreatic bicarbonate response to a physiological increase in plasma
secretin concentration. Scand J Gastroenterol 14:85-90, 1979. PMID: 424692.
290.
Schaffalitzky De Muckadell OB, Fahrenkrug J, Watt-Boolsen S, and
Worning H. Pancreatic response and plasma secretin concentration during infusion of
low dose secretin in man. Scand J Gastroenterol 13:305-311, 1978. PMID: 755275.
291.
Schafmayer A, Nustede R, Pompino A, and Kohler H. Vagal influence on
cholecystokinin and neurotensin release in conscious dogs. Scand J Gastroenterol
23:315-320, 1988. PMID: 3387897.
292.
Schmid R, Schulte-Frohlinde E, Schusdziarra V, Neubauer J, Stegmann
M, Maier V, et al. Contribution of postprandial amino acid levels to stimulation of
insulin, glucagon, and pancreatic polypeptide in humans. Pancreas 7:698-704, 1992.
PMID: 1448457.

293.
Schwartz TW. Pancreatic polypeptide: a hormone under vagal control.
Gastroenterology 85:1411-1425, 1983. PMID: 6138294
294.
Schwartz TW, Stenquist B, and Olbe L. Cephalic phase of pancreaticpolypeptide secretion studied by sham feeding in man. Scand J Gastroenterol 14:313320, 1979. PMID: 441680.
295.
Seifert H, Sawchenko P, Chesnut J, Rivier J, Vale W, and Pandol SJ.
Receptor for calcitonin gene-related peptide: binding to exocrine pancreas mediates
biological actions. Am J Physiol Gastrointest Liver Physiol 249:G147-151, 1985.
PMID: 2409816.
296.
Sheikh SP, Holst JJ, Skak-Nielsen T, Knigge U, Warberg J, TheodorssonNorheim E, et al. Release of NPY in pig pancreas: dual parasympathetic and
sympathetic regulation. Am J Physiol Gastrointest Liver Physiol 255:G46-54, 1988.
PMID: 3389414.
297.
Sheikh SP, Roach E, Fuhlendorff J, and Williams JA. Localization of Y1
receptors for NPY and PYY on vascular smooth muscle cells in rat pancreas. Am J
Physiol Gastrointest Liver Physiol 260:G250-257, 1991. PMID: 1847590.
298.
Shimosegawa T, Asakura T, Kashimura J, Yoshida K, Meguro T, Koizumi
M, et al. Neurons containing gastrin releasing peptide-like immunoreactivity in the
human pancreas. Pancreas 8:403-412, 1993. PMID: 8361958.
299.
Shimosegawa T, Moriizumi S, Koizumi M, Kashimura J, Yanaihara N,
and Toyota T. Immunohistochemical demonstration of galaninlike immunoreactive
nerves in the human pancreas. Gastroenterology 102:263-271, 1992. PMID: 1370157.
300.
Shiratori K, Watanabe S, and Takeuchi T. Somatostatin analog, SMS 201995, inhibits pancreatic exocrine secretion and release of secretin and cholecystokinin
in rats. Pancreas 6:23-30, 1991. PMID: 1704631.
301.
Shiratori K, Watanabe S, and Takeuchi T. Inhibitory effect of intraduodenal
administration of somatostatin analogue SDZ CO 611 on rat pancreatic exocrine
secretion. Pancreas 8:471-475, 1993. PMID: 8361968.
302.
Singer M. Neurohormonal Control of Pancreatic Enzyme Secretion in
Animals. In: The Pancreas : Biology, Pathobiology, and Disease, edited by Go VLW.
New York: Raven Press, 1993 pp 425-448.
303.
Singer MV. Pancreatic secretory response to intestinal stimulants: a review.
Scand J Gastroenterol Suppl 139:1-13, 1987. PMID: 3324297.
304.
Singer MV, and Niebergall-Roth E. Secretion from acinar cells of the
exocrine pancreas: role of enteropancreatic reflexes and cholecystokinin. Cell Biol Int
33:1-9, 2009. PMID: 18948215.

305.
Singer MV, Solomon TE, and Grossman MI. Effect of atropine on secretion
from intact and transplanted pancreas in dog. Am J Physiol Gastrointest Liver Physiol
238:G18-22, 1980. PMID: 6986796.
306.
Singer MV, Solomon TE, Rammert H, Caspary F, Niebel W, Goebell H, et
al. Effect of atropine on pancreatic response to HCl and secretin. Am J Physiol
Gastrointest Liver Physiol 240:G376-380, 1981. PMID: 7235024.
307.
Singer MV, Tiscornia OM, Mendes De Oliveiro JP, Demol P, Levesque D,
and Sarles H. Effect of glucagon on canine exocrine pancreatic secretion stimulated
by a test meal. Can J Physiol Pharmacol 56:1-6, 1978. PMID: 638847.
308.
Singh J, Pariente JA, and Salido GM. The physiological role of histamine in
the exocrine pancreas. Inflamm Res 46:159-165, 1997. PMID: 9197985.
309.
Singh J, and Pearson GT. Effects of nerve stimulation on enzyme secretion
from the in vitro rat pancreas and 3H-release after preincubation with catecholamines.
Naunyn Schmiedebergs Arch Pharmacol 327:228-233, 1984. PMID: 6208490.
310.
Singh M. Effect of glucagon on digestive enzyme synthesis, transport and
secretion in mouse pancreatic acinar cells. J Physiol 306:307-322, 1980. PMID:
6162027.
311.
Solomon TE. Regulation of pancreatic secretion. Clin Gastroenterol 13:657678, 1984. PMID: 6386236.
312.
Solomon TE, Solomon N, Shanbour LL, and Jacobson ED. Direct and
indirect effects of nicotine on rabbit pancreatic secretion. Gastroenterology 67:276283, 1974. PMID: 4847707.
313.
Sommer H, and Kasper H. The action of synthetic secretin, cholecystokininoctapeptide and combinations of these hormones on the secretion of the isolated
perfused rat pancreas. Hepatogastroenterology 28:311-315, 1981. PMID: 6178671.
314.
Spannagel AW, Green GM, Guan D, Liddle RA, Faull K, and Reeve JR,
Jr. Purification and characterization of a luminal cholecystokinin-releasing factor
from rat intestinal secretion. Proc Natl Acad Sci U S A 93:4415-4420, 1996. PMID:
8633081.
315.
Stabile BE, Borzatta M, Stubbs RS, and Debas HT. Intravenous mixed
amino acids and fats do not stimulate exocrine pancreatic secretion. Am J Physiol
Gastrointest Liver Physiol 246:G274-280, 1984. PMID: 6322595.
316.
Stock-Damge C, Lhoste E, Aprahamian M, and Loza E. Influence of
repeated administration of bombesin on rat pancreatic secretion. Pancreas 2:658-663,
1987. PMID: 3438303.
317.
Sumi S, Inoue K, and Tobe T. Experimental studies on the interrelationship
between organs mediated by peptide YY: effect on splanchnic circulation and

exocrine pancreas in dogs. Nihon geka hokan Archiv fur japanische Chirurgie 59:224233, 1990. PMID: 2130785.
318.
Szalmay G, Varga G, Kajiyama F, Yang XS, Lang TF, Case RM, et al.
Bicarbonate and fluid secretion evoked by cholecystokinin, bombesin and
acetylcholine in isolated guinea-pig pancreatic ducts. J Physiol 535:795-807, 2001.
PMID: 11559776.
319.
Takahashi M, Naito H, Sasaki I, Funayama Y, Shibata C, and Matsuno S.
Long-term bile diversion enhances basal and duodenal oleate-stimulated pancreatic
exocrine secretion in dogs. Tohoku J Exp Med 203:87-95, 2004. PMID: 15212143.
320.
Takiguchi S, Suzuki S, Sato Y, Kanai S, Miyasaka K, Jimi A, et al. Role of
CCK-A receptor for pancreatic function in mice: a study in CCK-A receptor knockout
mice. Pancreas 24:276-283, 2002. PMID: 11893936.
321.
Tang C, Biemond I, and Lamers CB. Cholecystokinin receptors in human
pancreas and gallbladder muscle: A comparative study. Gastroenterology 111:16211626, 1996. PMID: 8942742.
322.
Tang C, Biemond I, and Lamers CB. Visualization and characterization of
CCK receptors in exocrine pancreas of rat with storage phosphor autoradiography.
Pancreas 13:311-315, 1996. PMID: 8884854.
323.
Tatemoto K. Isolation and characterization of peptide YY (PYY), a candidate
gut hormone that inhibits pancreatic exocrine secretion. Proc Natl Acad Sci U S A
79:2514-2518, 1982. PMID: 6953409.
324.
Taylor IL, Byrne WJ, Christie DL, Ament ME, and Walsh JH. Effect of
individual l-amino acids on gastric acid secretion and serum gastrin and pancreatic
polypeptide release in humans. Gastroenterology 83:273-278, 1982. PMID: 6806140.
325.
Teyssen S, Niebergall E, Chari ST, and Singer MV. Comparison of two
dose-response techniques to study the pancreatic secretory response to intraduodenal
tryptophan in the absence and presence of the M1-receptor antagonist telenzepine.
Pancreas 10:368-373, 1995. PMID: 7792293.
326.
Thimister PW, Hopman WP, Tangerman A, Rosenbusch G, Willems HL,
and Jansen JB. Effect of intraduodenal bile salt on pancreaticobiliary responses to
bombesin and to cholecystokinin in humans. Hepatology 28:1454-1460, 1998. PMID:
9828206.
327.
Trimble ER, Bruzzone R, Biden TJ, and Farese RV. Secretin induces rapid
increases in inositol trisphosphate, cytosolic Ca2+ and diacylglycerol as well as cyclic
AMP in rat pancreatic acini. Biochem J 239:257-261, 1986. PMID: 3028367.
328.
Tsuchida T, Ohnishi H, Tanaka Y, Mine T, and Fujita T. Inhibition of
stimulated amylase secretion by adrenomedullin in rat pancreatic acini.
Endocrinology 140:865-870, 1999. PMID: 9927317.

329.
Turkelson CM, Solomon TE, Bussjaeger L, Turkelson J, Ronk M, Shively
JE, et al. Chemical characterization of rat cholecystokinin-58. Peptides 9:1255-1260,
1988. PMID: 3247248.
330.
Ulrich CD, 2nd, Wood P, Hadac EM, Kopras E, Whitcomb DC, and
Miller LJ. Cellular distribution of secretin receptor expression in rat pancreas. Am J
Physiol Gastrointest Liver Physiol 275:G1437-1444, 1998. PMID: 9843782.
331.
Vagne M, and Grossman MI. Gastric and pancreatic secretion in response to
gastric distention in dogs. Gastroenterology 57:300-310, 1969. PMID: 4897231.
332.
Van Dijk A, Richards JG, Trzeciak A, Gillessen D, and Mohler H.
Cholecystokinin receptors: biochemical demonstration and autoradiographical
localization in rat brain and pancreas using [3H] cholecystokinin8 as radioligand. J
Neurosci 4:1021-1033, 1984. PMID: 6325601.
333.
Varga G, Papp M, and Vizi ES. Cholinergic and adrenergic control of
enzyme secretion in isolated rat pancreas. Dig Dis Sci 35:501-507, 1990. PMID:
1690631.
334.
Ventimiglia MS, Najenson AC, Rodrguez MR, Davio CA, Vatta MS, and
Bianciotti LG. Natriuretic Peptides and Their Receptors. Pancreapedia: Exocrine
Pancreas Knowledge Base. 10.3998/panc.2011.36 10.3998/panc.2011.36
335.
Von Schonfeld J, Muller MK, Runzi M, Geling M, Neisius I, Kleimann J,
et al. Pancreastatin--a mediator in the islet-acinar axis? Metabolism 42:552-555,
1993. PMID: 8492708.
336.
Wang Y, Chandra R, Samsa LA, Gooch B, Fee BE, Cook JM, et al. Amino
acids stimulate cholecystokinin release through the Ca2+-sensing receptor. Am J
Physiology Gastrointest Liver Physiol 300:G528-537, 2011. PMID: 21183662.
337.
Wheeler S, Eardley JE, Mcnulty KF, Sutcliffe CP, and Morrison JD. An
investigation into the relative merits of pituitary adenylate cyclase-activating
polypeptide (PACAP-27) and vasoactive intestinal polypeptide as vagal neurotransmitters in exocrine pancreas of rats. Exp Physiol 82:729-747, 1997. PMID:
9257115.
338.
White TT, Lundh G, and Magee DF. Evidence for the existence of a
gastropancreatic reflex. Am J Physiol Gastrointest Liver Physiol 198:725-728, 1960.
PMID: 13844402.
339.
White TT, Mc AR, and Magee DF. Gastropancreatic reflex after various
gastric operations. Surg Forum 13:286-288, 1962. PMID: 14000361.
340.
Williams JA. Secretin. Pancreapedia: Exocrine Pancreas Knowledge Base.
10.3998/panc.2013.5 10.3998/panc.2013.5
341.
Williams JA. Pancreatic Polypeptide. Pancreapedia: Exocrine Pancreas
Knowledge Base. 10.3998/panc.2014.4 10.3998/panc.2014.4

342.
Williams JA. Bombesin. Pancreapedia: Exocrine Pancreas Knowledge Base.
10.3998/panc.2015.10 10.3998/panc.2015.10
343.
Williams JA, Chen X, and Sabbatini ME. Small G proteins as key
regulators of pancreatic digestive enzyme secretion. Am J Physiol Endocrinol Metab
296:E405-414, 2009. PMID: 19088252.
344.
Wolfe BM, Keltner RM, and Kaminski DL. The effect of an intraduodenal
elemental diet on pancreatic secretion. Surg Gynecol Obstet 140:241-245, 1975.
PMID: 1124475.
345.
Yago MD, Manas M, Ember Z, and Singh J. Nitric oxide and the pancreas:
morphological base and role in the control of the exocrine pancreatic secretion. Mol
Cell Biochem 219:107-120, 2001. PMID: 11354241.
346.
Yago MD, Tapia JA, Salido GM, Adeghate E, Juma LM, MartinezVictoria E, et al. Effect of sodium nitroprusside and 8-bromo cyclic GMP on nervemediated and acetylcholine-evoked secretory responses in the rat pancreas. Br J
Pharmacol 136:49-56, 2002. PMID: 11976267.
347.
Yamaguchi N, and Fukushima Y. PACAP enhances stimulation-induced
norepinephrine release in canine pancreas in vivo. Can J Physiol Pharmacol 76:788797, 1998. PMID: 10030460.
348.
Yi E, Smith TG, Baker RC, and Love JA. Catecholamines and 5hydroxytryptamine in tissues of the rabbit exocrine pancreas. Pancreas 29:218-224,
2004. PMID: 15367888.
349.
You CH, Rominger JM, and Chey WY. Effects of atropine on the action and
release of secretin in humans. Am J Physiol Gastrointest Liver Physiol 242:G608-611,
1982. PMID: 7091334.
350.
You CH, Rominger JM, and Chey WY. Potentiation effect of
cholecystokinin-octapeptide on pancreatic bicarbonate secretion stimulated by a
physiologic dose of secretin in humans. Gastroenterology 85:40-45, 1983. PMID:
6303892.
351.
Young AA, Jodka C, Pittner R, Parkes D, and Gedulin BR. Dose-response
for inhibition by amylin of cholecystokinin-stimulated secretion of amylase and lipase
in rats. Regul Pept 130:19-26, 2005. PMID: 15982756.
352.
Zabielski R, Lesniewska V, Borlak J, Gregory PC, Kiela P, Pierzynowski
SG, et al. Effects of intraduodenal administration of tarazepide on pancreatic
secretion and duodenal EMG in neonatal calves. Regul Pept 78:113-123, 1998.
PMID: 9879754.
353.
Zhang W, Chen M, Chen X, Segura BJ, and Mulholland MW. Inhibition
of pancreatic protein secretion by ghrelin in the rat. J Physiol 537:231-236, 2001.
PMID: 11711576.

Privacy Guidelines

Terms of Service

Contact Us

About
o How to Cite
o Editorial Board
o Production Staff
o Our Name
o Contribute Content

Publications
o The Pancreas
o eBooks

Pathways & Structures

o Pathways
o Molecules
o Cell Structures

Methods
o Antibodies
o Mouse Models
o Viral Vectors

Directory
o Search People

Resources

o Introduction to Pancreatic Disease

o Classic Books and Papers
o History of the Pancreas
o Living History
o Links
2015 Collective work, copyright Regents of the University of Michigan. Individual
contributions copyight authors | Powered by Michigan Publishing at the University of
Michigan Library
Except where otherwise noted, this work is subject to a Creative Commons
Attribution-NonCommercial License. Please contact us to use this work in a way not covered
by the license.