Stimulation Of Pancreatic Enzyme Secretion Research Articles

Melatonin as an organoprotector in the stomach and the pancreas

Melatonin was thought to originate primarily from the pineal gland and to be secreted during the night, but recent studies revealed that gastrointestinal (GI) tract presents another, many times larger, source of melatonin that contributes significantly to the circulating concentration of this indole. Melatonin may exert a direct effect on GI tissues but its major influence on GI organs seems to occur indirectly, via the brain-gut axis including peripheral receptors, sensory afferent (vagal or sympathetic) pathways and central nervous system (CNS) acting on these organs via autonomic efferents and neuromediators. This article reviews and updates our experience with the fascinating molecule, as related to GI organs, with special focus on secretory activity of the stomach and pancreas and the maintenance of their tissue integrity. In addition to being released into the circulation, melatonin is also discharged into the gut lumen and this appears to be implicated in the postprandial stimulation of pancreatic enzyme secretion, mediated by melatonin-induced release of cholecystokinin, acting through entero-gastro-pancreatic reflexes. Although exerting certain differences in the mechanism of action on gastric and pancreatic secretory activities, melatonin derived from its precursor L-tryptophan, exhibits similar highly protective actions against the damage of both the stomach and the pancreas and accelerates the healing of chronic gastric ulcerations by stimulating the microcirculation and cooperating with arachidonate metabolites such as prostaglandins, with nitric oxide released from vascular endothelium, and/or sensory nerves and with their neuropeptides such as calcitonin gene related peptide. The beneficial effects of melatonin results in gastro- and pancreato-protection, prevents various forms of gastritis and pancreatitis through the activation of specific MT2-receptors and scavenges reactive oxygen species (ROS). Melatonin counteracts the increase in the ROS-induced lipid peroxidation and preserves, at least in part, the activity of key anti-oxidizing enzymes such as superoxide dismutase. It is proposed that melatonin should be considered as the agent exerting an important role in prevention of gastric and pancreatic damage and in accelerating healing of gastric ulcers.

Melatonin and its precursor, L-tryptophan: influence on pancreatic amylase secretion in vivo and in vitro.

Melatonin, considered as a main pineal product, may be also synthetized in the gastrointestinal tract from L-tryptophan. Melatonin has been recently shown to affect insulin release and its receptors have been characterized in the pancreas however, the effects of melatonin on the pancreatic enzyme secretion have not been examined. The aim of this study was to investigate the effects of melatonin or L-tryptophan on amylase secretion in vivo in anaesthetized rats with pancreato-biliary fistulas, and in vitro using isolated pancreatic acini. Melatonin (1, 5 or 25 mg/kg) or L-tryptophan (10, 50 or 250 mg/kg) given to the rats as a intraperitoneal (i.p.) bolus injection produced significant and dose-dependent increases in pancreatic amylase secretion under basal conditions or following stimulation of enzyme secretion by diversion of bile-pancreatic juice. This was accompanied by a dose-dependent rise in melatonin plasma level. Stimulation of pancreatic enzyme secretion caused by melatonin or L-tryptophan was completely abolished by vagotomy, deactivation of sensory nerves with capsaicin or pretreatment with CCK1 receptor antagonists (tarazepide or L-364,718). Pretreatment with luzindole, an antagonist of melatonin MT(2) receptor failed to affect melatonin- or L-tryptophan-induced amylase secretion. Administration of melatonin (1, 5 or 25 mg/kg i.p.) or L-tryptophan (10, 50 or 250 mg/kg i.p.) to the rats resulted in the dose-dependent increase of cholecystokinin (CCK) plasma immunoreactivity. Enzyme secretion from isolated pancreatic acini was not significantly affected by melatonin or L-tryptophan used at doses of 10(-8) -10(-5) M. We conclude that exogenous melatonin, as well as that produced endogenously from L-tryptophan, stimulates pancreatic enzyme secretion in vivo while increasing CCK release. Stimulatory effect of melatonin or L-tryptophan on the exocrine pancreas involves vagal sensory nerves and the CCK release by these substances.

Appetite regulation: from the gut to the hypothalamus.

these proportions had increased to 26% and 22%, respectively, with 55% of women and 66% of men being overweight (BMI > 25 kg/m 2 ; Health Survey for England, 2001), reflecting a worldwide trend which is most marked in, but not restricted to, the developed world. Most of us in affluent countries live in a privileged land of plenty where high calorie foods are easily available and in which we have a limited need for exercise. The rising prevalence of obesity in children is of particular concern (Chinn & Rona, 2001).

On the Measurement of Cholecystokinin

A hormone is a chemical transmitter that is secreted from one part of the body and circulates in the bloodstream to reach a distant target in another part of the body where it exerts its biologic effect. At its inception, this was a revolutionary concept that gave birth to an entire physiological and, later, medical discipline. Early on, hormones were discovered by their biologic actions. However, the physiology of hormones could not be assessed without quantification. Fundamental to the study of hormones was the ability to measure concentrations in the blood. Although biological assays have been the cornerstone of endocrinologic measurements, the development of the radioimmunoassay (RIA) completely changed the field of endocrinology (1). The attractive features of RIA include (a) applicability to most hormones, (b) ease of performance, and (c) relatively low cost, as well as high degrees of (d) accuracy, (e) sensitivity, and (f) specificity. Cholecystokinin (CCK) was discovered in 1928 on the basis of the ability of intestinal extracts to stimulate gallbladder contraction in dogs (2). Later it was recognized that CCK was a potent stimulant of pancreatic enzyme secretion (3). However, it was not until 1966, when CCK was purified, that the primary sequence was determined (4)(5). Early estimates of CCK-like activity in blood were based on biological assays such as pancreatic secretion or gallbladder contraction. However, these estimates were fraught with confounding problems that existed in whole animals, such as the effects of other hormones or neural influences. To circumvent these problems, a sensitive and specific in vitro bioassay was developed (6), but …

Changes in messenger RNA of pancreatic enzymes and intestinal cholecystokinin after a 7-day bile-pancreatic juice diversion from the proximal small intestine in rats.

We have previously demonstrated the bile-pancreatic juice (BPJ)-independent stimulation of pancreatic enzyme secretion in chronic BPJ-diverted rats. Pancreatic and intestinal adaptation to 7-day BPJ diversion was next examined. Pancreatic enzyme mRNA and cholecystokinin mRNA in the jejunal mucosa were measured in rats with BPJ diverted into the ileum (PBD rats) in comparison with the figures for rats with BPJ returned to the duodenum (normal rats) or laparotomized (Intact) rats under well-nourished conditions. Amylase mRNA in the pancreas was lower and trypsinogen plus chymotrypsinogen mRNA was higher in the PBD rats than in the intact rats. The change in pancreatic mRNA was similar to that in the specific activities of the enzymes after a chronic BPJ diversion. This finding suggests that these pancreatic enzymes were regulated by the mRNA level. The portal concentration of cholecystokinin in the postabsorptive period (exogenously non-stimulated status) was 4-fold higher in the PBD group than in the normal and intact groups. Cholecystokinin mRNA in the jejunal mucosa of PBD rats was somewhat higher than that of intact rats. These results suggest that intestinal cholecystokinin was predominantly increased at the translational or later stage by chronic BPJ diversion.

Role of Cholecystokinin in the Regulation of Gastrointestinal Motility

Cholecystokinin, a hormone released from endocrine cells of the upper small intestine in response to amino acids and fatty acids in chyme, has potent effects on gut smooth muscle contractility. Depending on the region of the gut, the effect of cholecystokinin may be neurally mediated, direct, or both. Neurally-mediated effects may be relaxant or contractile depending on the transmitter released by cholecystokinin. Based on mimicry by infusion of cholecystokinin to postprandial levels and the ability of specific cholecystokinin receptor antagonists to abolish effects of endogenous cholecystokinin released in response to a meal, three physiological effects of cholecystokinin, all of which are neurally-mediated, have been identified: contraction of the gallbladder mediated by cholecystokinin-induced release of acetylcholine, relaxation of the sphincter of Oddi mediated by cholecystokinin-induced release of vasoactive intestinal peptide and inhibition of gastric emptying mediated by cholecystokinin-induced activation of an inhibitory vago-vagal reflex involving vasoactive intestinal peptide-induced relaxation of the gastric fundus. Gallbladder contraction and relaxation of the sphincter of Oddi regulate the flow of bile, and inhibition of gastric emptying regulates the flow of chyme into the duodenum. Combined with the potent stimulation of pancreatic enzyme secretion by cholecystokinin, these effects insure optimal conditions for digestion and absorption of nutrients by the intestine.

Supramaximal inhibition of cholecystokinin-induced pancreatic amylase release involves desensitization to cytoplasmic Ca2+.

Cholecystokinin (CCK) is a major stimulant of pancreatic enzyme secretion. The dose-response relationship for CCK-induced secretion is bell-shaped, with a characteristic supramaximal inhibition. The mechanism for this inhibition has now been studied. The kinetics of amylase release and the changes of the cytoplasmic Ca2+ concentration ([Ca2+]i) were recorded during stimulation of guinea-pig pancreatic acinar cells with different concentrations of cholecystokinin octapeptide (CCK-8) and the Ca2+ ionophore ionomycin. Individual cells reacted with [Ca2+]i oscillations at 10(-11)-10(-10) M CCK-8 and with an initial peak followed by a sustained suprabasal level at 10(-9)-10(-8) M of the agonist. The latter response was also seen in suspensions of acinar cells at all tested concentrations of CCK-8 and at 10(-6)-10(-5) M of ionomycin. With increases of extracellular Ca2+ from 0.5 to 5.0 mM there was a rise of [Ca2+]i during exposure to 10(-9)-10(-8) M CCK-8 or 10(-5) M ionomycin but a paradoxical decrease at lower concentrations of CCK-8 or ionomycin. A dose-dependent increase of amylase release was seen at CCK-8 concentrations from 10(-11) to 10(-9) M. At 10(-9)-10(-8) M CCK-8 secretion was characterized by an initial peak followed by a sustained phase. Whereas the initial peak of secretion remained unaffected by increasing CCK-8 from 10(-9) to 10(-8) M, the sustained phase was inhibited (supramaximal inhibition). Increasing extracellular Ca2+ from 0.5 to 5.0 mM transiently enhanced secretion in response to 10(-9) M but lacked effect during supramaximal inhibition of secretion by 10(-8) M CCK-8. Both initial and sustained CCK-8-stimulated amylase release increase with [Ca2+]i. However, supramaximal inhibition of secretion was not due to a decrease of [Ca2+]i but was characterized by desensitization to the stimulatory effect of [Ca2+]i.

Mechanism of bombesin-induced pancreatic secretion in unanesthetized rats

It is unclear whether stimulation of pancreatic enzyme secretion by intravenously administered bombesin is a direct effect on acinar cells or is mediated by release of CCK; this distinction is important for defining the potential role of bombesin-like peptides as regulators of pancreatic secretion. The role of CCK in bombesin-induced pancreatic secretion was examined in rats using CCK radioimmunoassay and the CCK receptor antagonist L-364,718. A biphasic pancreatic response occurred to sequential doubling doses of bombesin (31 to 2000 pmol/kg/h, each for 30 min; n = 9 rats); amylase secretion increased to a peak at 250 pmol/kg/h ( 11.5 ± 1.7 kU/30 min ; 4.2 ± 0.6 kU/30 min , basal) and then declined to basal levels at 2000 pmol/kg/h. The ED 50 dose of bombesin for stimulation was 31 pmol/kg/h, and the maximal response did not differ significantly from that to exogenous CCK-8 ( 10.6 ± 1.5 kU/30 min ) in the same rats. When single doses of bombesin were infused for 2 h (31, 62, 125, 250 pmol/kg/h; one dose per day; order randomized; n = 8), a similar dose-response relationship was seen, both for peak amylase response and cumulative output over basal. L-364,718 (0.5 mg/kg IV) had no effect on the pancreatic response to ED 50 or maximal doses of bombesin. Neither dose of bombesin altered plasma CCK levels. In contrast, other stimulants of pancreatic secretion (food ingestion, soybean trypsin inhibitor) caused marked elevations in plasma CCK levels. These results indicate that the potent stimulation of pancreatic secretion by exogenous bombesin in rats is not mediated by CCK, similar to findings in humans.

Actions of novel bombesin receptor antagonists on pancreatic secretion in

Recently synthezised highly specific and potent bombesin receptor antagonist permit study of the role of endogenous bombesin-like peptides in the physiological regulation of pancreatic secretion. We now tested the action of three novel pseudononapeptide bombesin/gastrin releasing peptide (GRP) antagonists (RC-3095, RC-3100 and RC-3120) on amylase release in vitro from isolated rat pancreatic acini and on protein secretion in vivo in chronic pancreatic fistula rats. In isolated pancreatic acini, all three bombesin receptor antagonists inhibited the amylase secretion induced by bombesin by shifting to the right the amylase response to bombesin without altering the maximal response. These antagonists also reduced concentration dependently the near-maximal amylase response to bombesin, the concentration required for 50% reduction (IC 50) being about 10 −7 M for RC-3095 and RC-3100 and 10 −6 M for RC-3120. None of the bombesin/GRP anatagonists used affected the amylase response to CCK, pentagastrin or urecholine. In conscious rate witha chronic pancreatic fistula, all three bombesin antagonists shifted to the right the pancreatic protein response to graded doses of bombesin without changing the maximal response. These antagonists inhibited the protein response to constant background stimulation with bombesin in a dose-dependent manner, the ID 50 being about 20 nmol/kg per h for RC-3095 and RC-3100 and about 160 nmol/kg per h for RC-3120. None of the antagonists significantly affected basal pancreatic secretion or secretion induced by sham-feeding, ordinary feeding or the diversion of pancreatic juice from the duodenum. These results indicate that exogenous bombesin is a potent direct stimulant of pancreatic enzyme secretion. However, the results do not support the view that endogenous bombesin/GRP-like peptides are involved in the physiological regulation of pancreatic secretion in rats.

Effects of atropine on pancreatic response to bethanechol, cholecystokinin, and food intake in rats

Atropine was used to examine the role of cholinergic mechanisms in the pancreatic secretory response to food intake. Unanesthetized rats with gastric, jugular vein, bile-pancreatic, and duodenal cannulas were used; bile-pancreatic juice was recirculated. The maximal response to bethanechol (4 mg.kg-1.h-1) was similar to cholecystokinin (CCK)-8-induced maximal secretion. Atropine (25-200 micrograms.kg-1.h-1) markedly inhibited basal amylase output and caused dose-related inhibition of the incremental response to a maximal dose of bethanechol. Atropine (50 micrograms.kg-1.h-1) shifted the dose-response curve to bethanechol (1-32 mg.kg-1.h-1) to the right but did not alter maximal amylase output. L 364718 (0.5 mg/kg), a CCK receptor antagonist, had no effect on bethanechol-stimulated pancreatic secretion. Atropine (50 micrograms.kg-1.h-1) did not affect the incremental responses to low doses of CCK-8; the maximal response occurred at a higher CCK-8 dose because atropine decreased basal secretion. Atropine (50 or 200 micrograms.kg-1.h-1) did not decrease the amylase response to ingestion of a liquid meal. We conclude that 1) bethanechol is a full agonist for stimulation of pancreatic enzyme secretion and its effects are not mediated by CCK release; 2) atropine is a competitive antagonist of bethanechol-induced pancreatic secretion in vivo but does not directly affect responses to CCK-8; 3) cholinergic mechanisms do not mediate the pancreatic enzyme response to a liquid meal in rats.

Effect of the cholecystokinin-receptor antagonist lorglumide on pancreatic enzyme secretion stimulated by bombesin, food, and caerulein, giving similar plasma cholecystokinin concentrations in the dog.

This study was undertaken to determine the role of cholecystokinin in pancreatic enzyme secretion stimulated by bombesin and a meal by (a) comparing the pancreatic enzyme output during bombesin infusion and after a meal to output during caerulein infusion and (b) comparing the inhibitory effect of the cholecystokinin-receptor antagonist lorglumide (CR-1409) on enzyme output in response to bombesin and food with the response to caerulein. Bombesin (90 pmol/kg per h) and caerulein (30 pmol/kg per h) were infused into seven dogs in doses giving similar plasma cholecystokinin peak increments as a meal (mean (SEM) 6.8 (0.8), 6.3 (1.2), and 5.7 (0.8) pM, respectively), together with either saline or 2 mg/kg per h of lorglumide. A background infusion of synthetic secretin 20.5 pmol/kg per h was given in each experiment. In addition, gastric acid secretion was determined in the experiments with bombesin and caerulein infusion. Pancreatic protein responses to bombesin (1231 (247) mg/h) and food (1430 (220) mg/h) were similar to the responses to caerulein (1249 (201) mg/h). Lorglumide inhibited pancreatic protein output during stimulation with bombesin by 60%, after the meal by 45%, and during caerulein infusion by 68%. Pancreatic bicarbonate output by bombesin, caerulein, and food was inhibited by lorglumide by 28%, 40%, and 38%, respectively. In contrast, lorglumide significantly increased gastric acid secretion from 1.12 to 7.98 mmol/h during bombesin infusion and from 0.52 to 7.62 mmol/h during caerulein infusion. In conclusion, cholecystokinin plays an important part in the stimulation of pancreatic enzyme secretion by bombesin and a meal in conscious dogs and it is involved in the regulation of gastric acid during stimulation by infusions of caerulein and bombesin.

Feedback regulation of pancreatic exocrine secretion in animal and man

This chapter focuses on studies dealing with the feedback mechanism of pancreatic exocrine secretion in animal and man. Clear evidence is presented that this feedback mechanism is working in the rat and the pig and that this feedback is mediated in the rat by the gastrointestinal hormones pancreozymin (enzyme secretion) and secretin (volume and bicarbonate secretion). Two novel peptides have been described--the 'CCK-releasing peptide' originating from the small intestinal mucosa, and the 'monitor peptide' cosecreted together with the enzymes in the pancreatic juice--to account for the stimulation of pancreatic enzyme secretion by the release of CCK. A similar feedback regulation of pancreatic secretion is working in man. It remains as yet controversial whether the feedback in humans is regulated via hormonal or neural pathways. It is also a matter of debate whether this feedback regulation of pancreatic enzyme secretion could be utilized for therapeutic aims in the treatment of pain in patients with chronic pancreatitis.

Human pancreatic secretion and intestinal motility: effects of ileal nutrient perfusion

To study the effects of intraileal nutrients on human pancreatic secretion and gastrointestinal motility, nine healthy subjects were intubated with an oroileal multilumen tube for ileal perfusion, duodenal juice aspiration, and intestinal motility recording. The duodenum was perfused continuously with essential amino acids to induce submaximal stimulation of pancreatic enzyme secretion and fed motility pattern. Additional ileal perfusion with carbohydrate at quantities similar to those observed under physiological late postprandial conditions or fat at isocaloric loads significantly decreased pancreatic enzyme outputs by greater than 80% (P less than 0.001) compared with saline. Ileal carbohydrate or fat induced a duodenal motor activity front that migrated distally and was followed by reduced motility. In summary, ileal delivery of small quantities of nutrient markedly decreased endogenously stimulated pancreatic enzyme secretion in humans. This was associated with specific changes in fed intestinal motility that converted to patterns characteristic of the interdigestive state. Our findings suggest that the distal small intestine may participate in the late postprandial regulation of gastrointestinal function in humans.

Evidence for an Intraluminal Mediator in Rat Pancreatic Enzyme Secretion: Reconstitution of the Pancreatic Response with Dietary Protein, Trypsin and the Monitor Peptide

New evidence has been obtained suggesting that the "monitor" peptide is an essential intraluminal mediator in the stimulation of pancreatic enzyme secretion in response to protein intake in rats. Experiments were performed in vivo using a mixture of 50 mg of ovalbumin, alpha-lactalbumin or casein, 2 micrograms of purified protease-sensitive, cholecystokinin-releasing monitor peptide and 1 mg of porcine trypsin which was infused by cannula into the duodenum of atropine-treated rats. The small intestine had previously been washed with bicarbonate to eliminate proteases and the pancreatic juice was diverted. The amount of trypsin secreted in 2 h was comparable to that of rats in which the pancreatic juice was returned into the duodenum. However, in the presence of a monitor peptide--specific antibody which recognizes the N-terminal region of the peptide, the monitor peptide did not induce any pancreatic response. Therefore, the characteristic pattern of pancreatic enzyme secretion in response to protein intake can be reproduced by infusing only three components--dietary proteins, porcine trypsin and the purified monitor peptide.

Two hypotheses on the feedback regulation of pancreatic enzyme secretion.

We review the mechanisms underlying the feedback regulation of pancreatic enzyme secretion in response to a meal. Pancreatic enzyme secretion in the rat and pig is known to be regulated by a negative feedback mechanism mediated by intestinal trypsin and chymotrypsin. Such a mechanism has recently been noted in humans. The presence of these enzymes in the small intestine suppresses pancreatic enzyme secretion, whereas their removal increases it. Two novel peptides have been proposed to account for the stimulation of pancreatic enzyme secretion in response to feeding trypsin inhibitor. One was assumed to be present in rat pancreatic juice and the other to be spontaneously secreted from the rat small intestine. In either case, trypsin and trypsin inhibitors do not directly interact with the luminal surface of the small intestine, but their actions are mediated by a trypsin-sensitive, cholecystokinin-releasing peptide. This is a novel explanation of the well-recognized stimulation of pancreatic enzyme secretion in response to dietary protein intake.

Effect of neural blockers and CR-1392 on the pancreatic enzyme secretion in response to soybean trypsin inhibitor and hydrochloric acid.

The effects of neural blockers on the pancreatic enzyme secretion in response to an intraluminal infusion of soybean trypsin inhibitor and HCl were investigated. The stimulation of pancreatic enzyme secretion upon the intraluminal infusion of soybean trypsin inhibitor was not blocked by atropine, but was completely blocked by guanethidine. The intraluminal infusion of 0.08 N HCl, which is known as a potent secretagogue of secretin, caused a rapid augmentation of trypsin output, which was not blocked by atropine or guanethidine. Preinjection of CR-1392 (1.5mg/kg, i.p.), which is a strong cholecystokinin receptor antagonist, completely blocked the pancreatic response to soybean trypsin inhibitor, but not that to 0.08 N HCl. This inferred that guanethidine specifically suppressed the CCK-release from the small intestine. These findings suggest that the pancreatic enzyme secretion in response to soybean trypsin inhibitor is mainly mediated by CCK, and that adrenergic modulation would be involved in the CCK-mediated pancreatic enzyme secretion in response to soybean trypsin inhibitor.

Atropine-Nonsensitive Feedback Regulatory Mechanism of Rat Pancreatic Enzyme Secretion in Response to Food Protein Intake

The effect of atropine on pancreatic enzyme secretion in response to removal of intraluminal protease was investigated using rats with an indwelling bile-pancreatic cannula. Stimulation of pancreatic enzyme secretion by diversion of bile-pancreatic juice was blocked by intravenous atropine [100 µg/(kg·h)] injection. On the other hand, stimulation of pancreatic enzyme secretion by intraluminal infusion of soybean trypsin inhibitor (SBTI) was not blocked by atropine administration. These results suggest that the feedback response of pancreatic enzyme secretion after removal of the intraluminal protease is controlled by at least two different systems, an atropine-sensitive mechanism and an atropine-nonsensitive mechanism. We detected and purified a peptide from rat bile-pancreatic juice that enhanced pancreatic enzyme secretion when the peptide was infused into the proximal intestine. In the atropine-administered rat whose small intestine was deprived of protease after intraluminal washing with saline containing SBTI, intraluminal infusion of the purified peptide stimulated pancreatic enzyme secretion markedly. These findings suggest that the atropine-nonsensitive feedback response of pancreatic enzyme secretion is at least in part mediated by the peptide.

Intracellular Ca2+ in pancreatic acinar cells: regulation and role in stimulation of enzyme secretion.

Evidence for a primary role for intracellular Ca2+ in the stimulation of pancreatic enzyme secretion is reviewed. Measurements of cytoplasmic free Ca2+ concentration have allowed direct demonstration of its importance in triggering enzyme secretion and defined the concentration range over which membrane Ca2+ pumps must work to regulate intracellular Ca2+. Current evidence suggests a key role for the Ca2+, Mg-ATPase of rough endoplasmic reticulum in regulating intracellular Ca2+ and accumulating a Ca2+ store which is released by the action of inositol-1,4,5 trisphosphate following stimulation of secretion.

Stimulation of Pancreatic Enzyme Secretion by a Peptide Purified from Rat Bile-Pancreatic Juice

We purified a peptide from rat pancreatic juice that enhances pancreatic enzyme secretion in a manner different from that of exogenous trypsin inhibitors, such as soybean trypsin inhibitor, when it is infused into the rat intestine. In this paper, we present evidence for the release of gut hormone(s) into the blood of rats after intestinal administration of the peptide. In the presence of atropine, an anesthetized rat small intestine was washed out with saline containing soybean trypsin inhibitor (Kunitz type) to eliminate proteases. Under these conditions, the rat small intestine was divided into four equal parts by ligation. Administration of the peptide into the first quarter of the small intestine stimulated pancreatic enzyme secretion. However, administrations into the more distal parts did not stimulate the enzyme secretion. Moreover, intravenous injection of 1 mL of plasma from rats in which the peptide had been infused into the duodenum caused stimulation of pancreatic enzyme secretion in the recipient rats. It was suggested that the purified peptide acts in the proximal small intestine and that it stimulates the release of gut hormone(s) into the blood to enhance pancreatic enzyme secretion. These findings support the hypothesis that the peptide we purified is responsible in part for the humoral control of pancreatic enzyme secretion in the response to food intake.

Cholecystokinin is not a peripheral satiety signal in the dog.

The doses of cholecystokinin (CCK) that have been shown to cause satiety after peripheral administration are pharmacological and whether "physiological" doses of exogenous CCK or endogenously released CCK have a satiety effect is not known. The purpose of the present study is threefold: to compare the potency of endogenous and exogenous CCK for their satiety, cholecystokinetic, and pancreozyminic actions; to determine whether small doses of CCK in the presence of gastric distension cause satiety; and to test the satiety effect of CCK administered centrally into the lateral cerebral ventricle. Dogs were prepared with cerebroventricular guides and esophageal and duodenal fistulas (n = 4), with chronic bile fistulas (n = 8), and chronic pancreatic fistulas (n = 7). Satiety effect was quantified in the esophageal fistula dog by the amount of blenderized food sham fed within 7.5 min. Duodenal perfusion of fat, used as a releaser of endogenous CCK, stimulated pancreatic protein, and gallbladder contraction with D50 values of 1.5 and 0.3 mmol/h, respectively, but had no effect on the volume sham fed (316 +/- 82 ml/min without and 371 +/- 41 ml/min with the maximal dose of sodium oleate infused). The D50 values of CCK-8 (pmol X kg-1 X h-1) for satiety and for stimulation of pancreatic enzyme secretion and gallbladder contraction were 440, 120, and 22, respectively. Injection of CCK-8 into the lateral cerebral ventricle inhibited sham feeding in a dose-dependent manner. We conclude that duodenal fat in doses producing maximal gallbladder and pancreatic stimulation has no satiety effect in the dog.(ABSTRACT TRUNCATED AT 250 WORDS)