Because of prior difficulties in measuring plasma cholecystokinin (CCK) levels, it has not been established which components of food stimulate CCK secretion in rats. In the present study, we used a sensitive and specific bioassay for measuring plasma CCK and determined the effects of proteins, protein hydrolysates, amino acids, fats, starch, and glucose on CCK secretion in this species. Intact proteins were the only stimulants of CCK release. Solutions of 18% casein and 0.2% soybean trypsin inhibitor caused prompt increases in plasma CCK levels from 0.5 +/- 0.2 to 7.9 +/- 1.9 and 8.0 +/- 2.0 pM, respectively, within 5 min of orogastric administration. The proteins lactalbumin and bovine serum albumin caused smaller elevations in circulating CCK. In contrast, hydrolysates of casein and lactalbumin and the amino acids L-phenylalanine and L-tryptophan did not stimulate CCK release. In addition, plasma CCK levels did not increase with the feeding of fat, starch, or glucose. The ability of proteins to stimulate CCK secretion paralleled their ability to inhibit trypsin activity in vitro. Furthermore, the plasma CCK response to casein was completely abolished by the simultaneous administration of trypsin. These studies indicate that proteins are the major food stimulants of CCK release in the rat and that the effects of proteins are related to inhibition of intraluminal protease activity.

Peptide YY (PYY) and pancreatic polypeptide (PP) have been shown to inhibit exocrine pancreatic secretion in vivo in a variety of species. This study evaluates the type of stimulation inhibited by PYY and PP by examining, in urethan-anesthetized rats, the inhibition of pancreatic secretion when stimulated to a comparable extent by cholecystokinin (CCK), 2-deoxy-D-glucose (2DG), bethanecol, and electrical vagal nerve stimulation. PYY at maximal infusion rates inhibited stimulation by CCK by 83%, bethanecol by 55%, and electrical nerve stimulation by 40%. The inhibition of CCK stimulation was half maximal at 250 pmol.kg-1.h-1. By contrast, PYY totally inhibited 2DG-stimulated secretion with half-maximal inhibition at 10 pmol. kg-1.h-1. PP acted similarly to PYY in inhibiting CCK and 2DG-stimulated pancreatic protein secretion but was fivefold weaker in each case. These findings indicate that PYY and PP have multiple actions but preferentially inhibit neurally mediated pancreatic secretion at a preacinar cell locus, possibly at a central site of action.

SUMMARY The effects on pancreatic growth and plasma CCK concentration of chronic feeding of camostate (400 mg/kg day for 10 days), a potent inhibitor of serine proteases including trypsin, were assessed in the mouse. For comparison, the trophic effects of chronic exogenous administration of CCK octapeptide (sc injection of 1 jug/kg day every eight hours for 10 days) were also studied. In addition, the effects of a proglumide-analogue CCK-receptor antagonist (CR1409) on the stimulatory actions of camostate feeding and chronic administration of exogenous CCK were studied. The effects of the combination of chronic camostate feeding and sc injections of CCK, the effects of acute camostate feeding, and the effects of the CCK-receptor antagonist given without camostate or CCK were also studied. The results show that chronic camostate feeding markedly increased CCK plasma concentrations eight-fold over control values, and that acute camostate feeding increased plasma CCK concentration to four fold of control values. Correspondingly, chronic camostate feeding markedly increased pancreatic weight, protein and DNA content. Exogenous CCK-8 also had qualitatively similar, but quantitatively less potent stimulatory effects. The combination of camostate and CCK-8 resulted in an additive stimulatory effect. The trophic actions of exogenous and endogenous CCK grossly increased chymotrypsinogen content, but left amylase content unaffected. The CCK-receptor antagonist CR1409 completely abolished the trophic effects of exogenous CCK and greatly inhibited the effects of chronic camostate feeding. The CCK antagonist decreased pancreatic weight, DNA and protein content compared to control values when given without any CCK or camostate. We conclude that the protease inhibitor camostate is a very strong release effector of CCK and exerts a powerful trophic effect on mouse pancreas which is probably mediated by CCK. Furthermore, physiological increases of CCK during feeding of regular chow appear to exert trophic effects on the exocrine pancreas.It is well established that exogenous cholecystokinin and cholecystokinin analogues, like caerulein, stimulate pancreatic growth in the experimental animal.' 2 It is also well known that feeding of trypsin inhibitors markedly stimulates pancreatic growth.3-4 It has been shown recently, that pancreaticobiliary diversion also stimulates pancreatic growth.5 -6 Both feeding of trypsin inhibitors and pancreaticobiliary diversion may stimulate pancreatic growth by the same mechanism of decreasing intraduodenal activity of pro-

The relationship among plasma cholecystokinin (CCK), pancreatic growth, and food intake was studied in rats over a 2-wk period of adaptation from a very low-protein to a very high-protein diet. Rats adapted to a control diet (5% casein) were killed at 0900 (without fasting) at 0 h, 12 h, 24 h, 48 h, 7 days, or 14 days after transfer to a high-protein diet (75% casein). CCK was measured by bioassay using isolated pancreatic acini. Plasma CCK in high protein-fed rats was increased approximately threefold in the first 24 h, but returned to control (approximately 2.5 pM) values by day 7. Pancreatic weight, DNA, protein, and chymotrypsin(ogen) significantly increased to maximal values by day 7 in high protein-fed rats. Food intake in high protein-fed rats was inhibited by 47% after 24 h but returned to control values by day 7. The results indicate that high-protein diets initially increase CCK release and increase pancreatic protease secretory capacity and that, when pancreatic protease secretion is sufficient to match protein digestive requirements, the stimulus for CCK secretion is reduced and plasma CCK returns to normal. The pronounced but transient inhibition of food intake in high protein-fed rats is consistent with a role for CCK in regulation of food intake.

Page G70: Gary M. Green, Van H. Levan, and Roger A. Liddle. “Plasma cholecystokinin and pancreatic growth during adaptation to dietary protein.” Page G70: sentence beginning on line 7, second column, should read “Therefore we hypothesized that increased dietary protein would raise plasma CCK levels only transiently, the levels returning to normal when pancreatic synthesis and secretion of proteases increased sufficiently to inhibit CCK release”.

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Cholecystokinin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on CCK receptors [89]) are activated by the endogenous peptides cholecystokinin-8 ( CCK-8), . There are only two distinct subtypes of CCK receptors, CCK 1 and CCK 2 receptors [63,123], with some alternatively spliced forms most often identified in neoplastic cells. The CCK receptor subtypes are distinguished by their peptide selectivity, with the CCK 1 receptor requiring the carboxyl-terminal heptapeptideamide that includes a sulfated tyrosine for high affinity and potency, while the CCK 2 receptor requires only the carboxyl-terminal tetrapeptide shared by each CCK and gastrin peptides. These receptors have characteristic and distinct distributions, with both present in both the central nervous system and peripheral tissues. ContentsThis is a citation summary for Cholecystokinin receptors in the Guide to Pharmacology database (GtoPdb). It exists purely as an adjunct to the database to facilitate the recognition of citations to and from the database by citation analyzers. Readers will almost certainly want to visit the relevant sections of the database which are given here under database links.GtoPdb is an expert-driven guide to pharmacological targets and the substances that act on them. GtoPdb is a reference work which is most usefully represented as an on-line database. As in any publication this work should be appropriately cited, and the papers it cites should also be recognized. This document provides a citation for the relevant parts of the database, and also provides a reference list for the research cited by those parts.Please note that the database version for the citations given in GtoPdb are to the most recent preceding version in which the family or its subfamilies and targets were substantially changed. The links below are to the current version. If you need to consult the cited version, rather than the most recent version, please contact the GtoPdb curators.