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PubMed1996

Secretory response of cultured acinar cells of rat pancreas to cholecystokinin.

To determine the adequate models for studying the functions of pancreatic acinar cells, secretory responses to CCK and to CCK receptor antagonist, L-364, 718 were examined in freshly isolated cells and confluent monolayer cells. The results showed that as CCK concentration increased, releases of amylase and lipase increased dose-dependently reaching a maximum at 10(-9) M in acinar cells cultured in serum-containing media as well as in serum-free media. Acinar response to CCK was partially inhibited by L-364, 718, L-364, 718 itself had no effect on the releases of both amylase and lipase. Confluent monolayer of acinar cells released relatively low levels of enzymes and exhibited less response to CCK. In conclusion, short-term culture of acinar cells would be suitable to study the regulation of pancreatic enzyme secretion, and serum factors do not influence acinar response to the secretagogues. However, confluency of the acinar cells resulted in the loss of their secretory potential in the aspect of amylase and lipase release.

Amylases↗
PubMedDate not supplied

Small synthetic ligands of the cholecystokinin-B/gastrin receptor can mimic the function of endogenous peptide hormones.

The gastric cholecystokinin-B/gastrin receptor (CCK-BR) is a key regulator of enterochromaffin-like cell function and proliferation. Over the last decade, a number of small non-peptide CCK-BR "antagonists" have been discovered. Here, we demonstrate that some of these non-peptide ligands in fact possess significant ability to activate the human CCK-BR, and are, therefore, more properly categorized as partial agonists. When tested in COS-7 cells transiently expressing the recombinant human CCK-BR, saturating concentrations of the small "peptoid" ligands PD 135,158 and PD 136,450 stimulated inositol phosphate formation to 23 and 43 percent, respectively, of the maximum response induced by a considerably larger endogenous peptide agonist, cholecystokinin octapeptide. In contrast, the benzodiazepine-derived CCK-BR ligand, YM022, acted as a "true" high-affinity antagonist of cholecystokinin-induced inositol phosphate formation (pA2 = 9.69). Consistent with recent findings in animal experiments, our data reveal that small synthetic ligands have the potential to function as either CCK-BR agonists or antagonists. These dual properties of synthetic molecules must be considered when evaluating candidate drugs for human disease.

Animals↗
PubMed2000

Effects of spinal cholecystokinin receptor antagonists on morphine antinociception in a model of visceral pain in the rat.

The objective of the present study was to determine the effects of spinal cholecystokinin (CCK) receptor antagonists on morphine antinociception in a model of visceral nociception, colorectal distension, in rats with chronic colonic inflammation and vehicle-treated controls. Three to five days after intracolonic instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS), an enhanced visceromotor response to all pressures of colorectal distension (10-80 mm Hg) was evident. The ED(50) of intrathecal morphine (0.93 microgram) in vehicle-treated rats produced significantly greater antinociception in TNBS-treated rats. Intrathecal proglumide, a nonselective CCK receptor antagonist, dose dependently enhanced the antinociceptive effect of morphine in vehicle-treated rats, but not in TNBS-treated rats. Similarly, L-365, 260, a specific CCK(B) receptor antagonist, dose dependently increased morphine's antinociceptive effects in vehicle-treated rats but had no effect in rats with TNBS-induced colonic inflammation. L-364,718, a specific CCK(A) receptor antagonist, had no effect on morphine antinociception in either vehicle-treated or TNBS-treated rats. These data indicate that CCK, acting at the CCK(B) receptor, is involved in modulating morphine antinociception following a noxious visceral stimulus. However, CCK receptor antagonists no longer enhance morphine antinociception after instillation of intracolonic TNBS, suggesting that visceral inflammation may lead to a reduction in spinal CCK release.

Analgesics↗
PubMed2002

[The effects of cholecystokinin octapeptide on PKC activity in rat cerebral cortex neurocytes].

OBJECTIVE: To investigate the effects of CCK8 on protein kinase C activity in rat cerebral cortex. METHODS: The cerebral cortex neurocytes were isolated and used as a model. The effects of CCK8, L-364, 718 and L-365, 260 on PKC activities were detected by using a non-radioactive method. RESULTS: CCK8 caused a detectable increase in PKC activity at 10(-11) mol/L, and a peak increase of PKC activity was observed at 10(-5) mol/L (about 4.5 U/mg protein). PKC activity was increased in dose-dependent manner by CCK8(10(-11)-10(-6) mol/L). The CCKB-selective receptor antagonist L-365, 260 with a higher efficiency, and the CCKA-selective receptor antagonist L-364, 718 with a lower efficiency were able to block a maximal effect of CCK8-induced PKC activation. CONCLUSIONS: CCK8 may regulate PKC activities in rat cerebral cortex through CCKB receptor.

Animals↗
PubMed1992

[Effect of CCK receptor antagonists on plasma CCK bioassay].

Fasting and postprandial plasma CCK levels of 102 normal subjects were measured by bioassay with dispersed rat pancreatic acini. The reference values ranged from 0 to 4.2 pmol/L (CCK-8 equivalents) for fasting and from 1.1 to 13.5 pmol/L for postprandial state. There was no significant difference between male and female, or in different age groups. The effects of CCK receptor antagonists of 3 different categories on CCK bioactivity in plasma measured by the bioassay were investigated. L 364,718 (5 nmol/L), proglumide (1.0 mmol/L), or Bt2-cGMP (0.1 mmol/L) was either extracted by SEP-PAK C18 cartridges together with human plasma containing 8 pmol/L of CCK-8, or added into the plasma extracts before the assay. The CCK bioactivity was inhibited by all of the 3 CCK antagonists. The action of L364,718 could be eliminated by the procedure of plasma extraction, but not of proglumide or Bt2-cGMP. It was suggested that CCK bioassay can be used even if L364,718 was administered. However, CCK cannot be measured accurately if there are proglumide or Bt2-cGMP in the plasma.

Adolescent↗
PubMed1992

Effect of somatostatin analogue and cholecystokinin receptor antagonist on bile-induced acute canine pancreatitis.

To determine whether a synthetic somatostatin analogue, octreotide, and a cholecystokinin receptor antagonist, L-364,718, may be beneficial in acute pancreatitis, 33 dogs were assigned to four groups. Each dog underwent laparotomy with injection of autologous bile into the dorsal pancreatic duct. Thirty minutes after the induction of pancreatitis, Group 1 received a subcutaneous injection of octreotide (200 micrograms/kg), Group 2 received an equal volume of the octreotide carrier, Group 3 received an hourly intravenous bolus of L-364,718 (60 micrograms/kg), and Group 4 received an equal volume of the L-364,718 carrier. Hemodynamic profiles, arterial blood gases, plasma glucose, and serum amylase were obtained before laparotomy, at bile injection, and at hourly intervals. The pancreas was removed after 8 hours for gross evaluation, measurement of water content, and histologic examination. A significant decrease in cardiac index and a significant increase in serum amylase and pancreatic edema occurred in all four groups 8 hours after the induction of pancreatitis (P less than 0.05), but there was no statistical difference between any group. Likewise, there was no difference in gross or histologic changes in the pancreas of any group. The somatostatin analogue, octreotide, and the cholecystokinin receptor antagonist, L-364,718, did not ameliorate the effects of severe, bile-induced pancreatitis in dogs.

Acute Disease↗
PubMed1992

Feedback control of pancreatic secretion in rats. Role of gastric acid secretion.

Pancreatic secretion in rats is regulated by feedback inhibition of cholecystokinin (CCK) release by proteases in the gut lumen, but little is known about the role of gastric acid in this regulation. This study, carried out on conscious rats with large gastric fistulas (GF) and pancreatic fistulas, shows that diversion of pancreatic juice results in the progressive stimulation of pancreatic secretion only in rats with the GF closed. When the GF was kept open, the diversion resulted in only small increment in pancreatic secretion and this was accompanied by progressive increase in gastric acid outputs. Similar amounts of HCl instilled into the duodenum in rats with the GF open fully reproduced the increase in pancreatic secretion observed after the diversion of pancreatic juice. Pretreatment with omeprazole (15 mumol/kg) to suppress gastric acid secretion or with L-364,718 (5 mumol/kg) to antagonize CCK receptors in the diverted state, resulted in the decline in pancreatic secretion similar to that observed after opening the GF. CCK given s.c. (20-320 pmol/kg) failed to cause any significant rise in the post-diversion pancreatic secretion in rats with the GF closed, but stimulated this secretion dose-dependently when the GF was open. Camostate (6-200 mg/kg) in rats with pancreatic juice returned to the duodenum caused dose-dependent increase in pancreatic secretion, but after opening the GF or after omeprazole this increase was reduced by about 75%. This study provides evidence that gastric acid plays a crucial role in the pancreatic response to diversion of pancreatic juice or inhibition of luminal proteases, and that factors that eliminate gastric acid secretion reduce this response.

Animals↗
PubMed1992

Subtype-selective cholecystokinin receptor antagonists block cholecystokinin modulation of dopamine-mediated behaviors in the rat mesolimbic pathway.

Subtype-selective antagonists of the peripheral-type (CCK-A) and the central-type (CCK-B) cholecystokinin (CCK) receptors were employed to determine the receptor subtype(s) mediating the modulatory actions of CCK on dopamine-induced changes in exploratory activity at three sites in the mesolimbic pathway of the rat. The CCK-A antagonist L-364,718 (10 ng) blocked CCK potentiation of dopamine-induced hyperlocomotion in the medial posterior nucleus accumbens. The CCK-B antagonist CI-988 (20 ng) blocked CCK inhibition of dopamine-induced hyperlocomotion in the anterior nucleus accumbens. The CCK-B antagonists CI-988 (20 ng) and L-365,260 (10 ng) blocked CCK potentiation of dopamine-induced hypolocomotion in the ventral tegmental area. These data indicate a CCK-B pharmacology in the cell body and anterior terminal field, and a CCK-A pharmacology in the posterior terminal field, of the mesolimbic dopamine pathway. Behavioral analyses using the selective CCK antagonists did not detect a contribution of endogenous CCK to exploratory locomotion. L-364,718 (10 ng), L-365,260 (10 ng), and CI-988 (20 ng or 2 micrograms), microinjected into the medial posterior nucleus accumbens, anterior nucleus accumbens, or ventral tegmental area, had no effect on baseline exploratory locomotion or on dopamine-induced changes in exploratory locomotion. Using a dark-induced hyperlocomotion paradigm, the CCK antagonists at these doses at these sites and intraperitoneally had no effect on the high levels of exploratory locomotor activity exhibited by the rats in the dark testing environment, or the lower levels of exploratory activity in the lighted environment. Endogenous CCK may not be released during dopamine-induced hyperlocomotion or dark-induced hyperlocomotion, or endogenous CCK may not contribute significantly to exploratory behaviors mediated through the mesolimbic dopamine pathway. Utilization of these potent, selective, nonpeptide CCK antagonists, with the doses, vehicles, and routes of administration developed in the present studies, will guide further investigations into the role of endogenous CCK in other facets of mesolimbic function.

Animals↗
PubMed1992

CholecystokininA and cholecystokininB receptors in neurons of the brainstem solitary complex of the rat: pharmacological identification.

The brainstem solitary complex, which receives projections from primary sensory afferents of the vagus nerve, appears to be a crucial site for the action of the cholecystokinin octapeptide (CCK8), because both peripheral-type (CCKA) and central-type (CCKB) binding sites are present in this structure. In the present study, we investigated the effects of recently developed receptor-specific pharmacological tools on neurons recorded in rat coronal brainstem slices, to ascertain whether CCK acts differently on each type of receptor. CCK8, which interacts with both binding sites, had three effects on neuronal discharge, brief excitation, prolonged excitation and delayed inhibition. BC 264, a novel CCK analog endowed with high affinity and selectivity for CCKB receptors, produced exclusively prolonged excitation. L-365,260, a novel nonpeptide antagonist of CCKB receptors, blocked the prolonged excitation induced by BC 264 or CCK8. L-364,718, a potent antagonist of CCKA receptors, blocked delayed inhibition and replaced brief CCK8-induced excitation by prolonged excitation. Altogether, these results show that CCK8 exerts, on neurons of the solitary complex, mixed effects due to simultaneous activation of CCKA inhibitory and CCKB excitatory binding sites. The hypothesis that exogenous CCK8 acts, in the solitary complex, through CCKA sites to slow down the motility of the digestive tract and through CCKB sites to modulate anxiety will be developed.

Animals↗
PubMed1992

Use of a specific cholecystokinin receptor antagonist (L-364,718) to determine the role of cholecystokinin on feeding and body weight in rats with obstructive jaundice.

We conducted a study to examine the role of cholecystokinin in feeding behavior and weight change in rats with obstructive jaundice. Daily food and water intake, body weight, and short-term food intake were determined in two groups of rats with surgically induced obstructive jaundice and in control rats. One group of rats with obstructive jaundice was given L-364,718, a selective cholecystokinin receptor antagonist. Plasma bilirubin and cholecystokinin levels were measured in each rat before and 7 days after surgery. Daily food intake and body weight were decreased in obstructive jaundice rats compared with control rats during the first week after surgery (P less than .05); however, obstructive jaundice rats treated with L-364,718 had increased food intake and body weight (P less than .05). Short-term food intake measured for 30 minutes and 120 minutes in food-deprived obstructive jaundice rats was decreased when compared with control rats (P less than .05), but the obstructive jaundice rats given L-364,718 had increased short-term food intake (P less than .05). Water intake was similar between the two groups of rats. Plasma levels of cholecystokinin and bilirubin were increased in obstructive jaundice rats with and without L-364,718 treatment (P less than .05). The results support the concept that endogenously elevated levels of plasma cholecystokinin play an important role in decreased food intake and subsequent loss of body weight in rats with obstructive jaundice.

Animals↗
PubMed1992

Evidence for two cholecystokinin receptors mediating the contraction of the guinea pig isolated ileum longitudinal muscle myenteric plexus.

In guinea pig isolated ileum longitudinal muscle myenteric plexus, cholecystokinin octapeptide (CCK-8S) produced a rapid (phasic) contraction followed by a slower tonic phase. The tetrapeptide derivative CCK-4 and pentagastrin elicited only the phasic response up to 10(-6) M, whereas the tonic phase was also apparent at higher concentrations. The rank order of potency for the effect of agonists on the tonic and phasic responses were CCK-8S much greater than gastrin greater than CCK-8US congruent to pentagastrin greater than CCK-4 and CCK-8S greater than gastrin congruent to pentagastrin greater than CCK-4 greater than CCK-8US, respectively. Phasic responses of CCK-8S and CCK-4 were sensitive to atropine, whereas the tonic response could be completely abolished with the neurokinin-1 antagonist GR82334. The CCK-A receptor antagonist L-364,718 up to 10(-7) M had little effect on the phasic contracture of CCK-4. The CCK-B/gastrin receptor antagonist L-365,260 had no effect on the CCK-8S phasic response up to 10(-7) M, but antagonized the phasic response induced by low concentrations of CCK-4 in a competitive manner with an estimated pKB of 8.51. This value is close to that of 8.53 found in a guinea pig cortical binding assay. Both the second phase of the CCK-4 phasic concentration response curve (CRC) and the tonic contraction were insensitive to L-365,260.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Postprandial peptide YY release is mediated by cholecystokinin.

Peptide YY (PYY), a 36 amino acid peptide, is a member of the structurally and functionally related pancreatic polypeptide (PP) family of gastrointestinal and neurally active peptides. Peptide YY is released postprandially from the distal small intestine and colon and has been shown to inhibit many physiologic actions of cholecystokinin (CCK), an integral foregut hormonal stimulant of pancreatic and gastric secretion. The specific signals for the release of PYY have not been ascertained, although foregut signals, both neural and hormonal, are likely. In this study, we evaluated the possible role for CCK in postprandial PYY release in eight conscious dogs. Conscious dogs were given a fat meal or a one hour intravenous infusion of CCK-8. On separate days, the dogs were pretreated with the specific CCK receptor antagonist L-364,718. Peripheral blood samples were collected for radioimmunoassay for PYY, PP and neuropeptide Y. The fat meal and exogenous CCK stimulated PYY and PP release, effects that were abolished by pretreatment with the CCK receptor antagonist. The results provide support for a physiologic role of CCK in the mediation of postprandial PYY and PP release. Furthermore, an inhibitory feedback loop is suggested between the hindgut (PYY) and the foregut (CCK).

Animals↗
PubMed1991

The effect of antagonist of receptors for gastrin, cholecystokinin and bombesin on growth of gastroduodenal mucosa and pancreas.

The effects of gastrin, cholecystokinin (CCK) and bombesin on the DNA synthesis, as a biochemical indicator of trophic action in the gastroduodenal mucosa and the pancreas, have been examined in rats fasted for 48 h and in rats refed for 16 h with or without administration of specific receptor antagonists for bombesin, gastrin and CCK. Bombesin and gastrin administered three times daily for 48 h in fasted rats significantly increased the rate of DNA synthesis as measured by the incorporation of [3H] thymidine into DNA in each tissue tested. CCK significantly increased DNA synthesis in the duodenal mucosa and pancreatic tissue, but not in the gastric mucosa. The stimulation of DNA synthesis induced by bombesin in the gastroduodenal mucosa and pancreas was abolished by bombesin/GRP receptor antagonist, RC-3095. RC-3095 did not affect DNA synthesis stimulated by gastrin and CCK in these tissues. L-365,260, a receptor antagonist for gastrin suppressed the DNA synthesis induced by gastrin but not by CCK or bombesin in the gastrointestinal mucosa and pancreas. L-364,718, a specific antagonist for CCK receptors was effective only against CCK stimulated duodenal mucosa and pancreatic growth. Refeeding of 48 h fasting rats strongly enhanced the DNA synthesis in all tissues tested, and this effect was significantly reduced in the gastroduodenal mucosa by blocking only gastrin receptors (with L-365, 260) and that in the duodenal mucosa and the pancreas by antagonizing of CCK receptors (with L-364,718). Antagonism of bombesin receptors (with RC-3095) did not significantly affect the stimulation of DNA synthesis induced by refeeding in all tissues tested. This study indicates that the stimulation of DNA synthesis can be achieved by exogenous gastrin, CCK and bombesin acting through separate receptors, but that only gastrin and CCK play the major role in the postprandial stimulation of the growth of gastroduodenal mucosa and pancreatic tissue.

Animals↗
PubMed1990

A novel micromethod for pancreatic acinar secretion. Time course of CCK stimulation and its inhibition by L-364,718.

Dispersed acini have proven to be particularly valuable in the study of pancreatic enzyme secretion. Complex time course studies or experiments requiring large numbers of replicates have proven difficult, however, with currently available techniques. Using a custom-designed incubation chamber, a miniaturized incubation method has been devised, which allows for continuous oxygenation of acini in 96-well microtiter plates and rapid separation of medium from acini by vacuum filtration. The filtrates from individual wells are collected into the wells of a second microtiter plate for pancreatic enzyme measurement. Using the above method, the dose response and time course of cholecystokinin (CCK-8)-stimulated amylase secretion was investigated. During a 1-h incubation, unstimulated amylase secretion was 4.1 +/- 0.3% of total acini content. Response to CCK was very sensitive, being detected at 10(-13) M (p less than 0.05), half-maximal at 10(-11) M CCK (14.0 +/- 0.6%, p less than 0.001) and maximal at 10(-9) M CCK (24.8 +/- 1.0%, p less than 0.001). In the time course experiments, an increase in amylase secretion was detected by 2.5 min and continued to increase steadily to a plateau at 40 min, with both submaximal (10(-11) M) and maximal (10(-9) M) CCK concentrations. The potent and specific CCK-receptor antagonist, L-364,718, caused a dose-dependent decrease in CCK-stimulated amylase secretion, with a half-maximal effect at 10(-10) M. The receptor antagonist, L-364,718, at 10(-8) M completely abolished CCK-stimulated amylase secretion. This microtechnique provides a simple, reliable, and reproducible method for the study of dispersed pancreatic acini.(ABSTRACT TRUNCATED AT 250 WORDS)

Amylases↗
PubMed1991

CCK-8, CCK-4 and gastrin-induced contractions in guinea pig ileum: evidence for differential release of acetylcholine and substance P by CCK-A and CCK-B receptors.

The cholecystokinin (CCK) receptor involved in contraction of guinea pig ileal longitudinal muscle to cholecystokinin is poorly understood; some studies have suggested that contraction was mediated via a CCK-A receptor whereas other studies have implicated CCK-B receptors in ileal contraction to CCK. To clarify this, we compared the effects of CCK-8 sulfate, CCK-4 and gastrin in radioligand binding studies and longitudinal ileal contractility in vitro. Contraction to all three peptides was abolished by tetrodotoxin (3 x 10(-7)M), confirming the neuronal nature of the CCK receptors mediating contraction to all three peptides. Maximal CCK-8S contractions were inhibited by 80% in the presence of atropine (10(-6)M), and entirely by the combination of atropine and a substance P receptor antagonist (3 x 10(-5)M). CCK-4 and gastrin-induced contractions were unaffected by substance P receptor blockade, but were abolished by atropine. Two selective CCK-A and CCK-B receptor antagonists, L-364,718 and L-365,260, respectively, were used to probe further the receptors involved in ileal contraction to this peptide family. Radioligand binding studies in mouse brain, rat pancreas and guinea pig stomach confirmed the selectivity of these antagonists. The CCK-A selective antagonist, L-364,718, potently inhibited ileal contractions to CCK-8S (-log KB = 9.35) with 10-fold lower affinity at receptors mediating contraction to CCK-4 (-log KB = 8.25). In contrast, the CCK-B receptor antagonist, L-365,260, did not affect contraction to CCK-8S (-log KB less than 7) but potently inhibited contraction to CCK-4 (-log KB = 9.24).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1991

The role of cholecystokinin in the pathogenesis of acute pancreatitis in the isolated pancreas preparation.

In a variety of animal models of acute pancreatitis, cholecystokinin-receptor antagonists have ameliorated the injury response. These results suggest that cholecystokinin may play a primary role in the pathogenesis of pancreatitis initiated by multiple stimuli. In an effort to test this theory, a sensitive and high affinity cholecystokinin-receptor antagonist L364,718 was administered to four different models of acute pancreatitis that were produced in the ex vivo perfused canine pancreas preparation. The four models of pancreatitis were initiated by cerulein infusion, partial duct obstruction with secretin stimulation, oleic acid infusion, and a 2-hour period of ischemia. In each model, pancreatitis was manifest by edema formation, weight gain, and hyperamylasemia during a 4-hour perfusion. In cerulein infusion-induced pancreatitis L364,718 inhibited edema formation and weight gain (31 +/- 5 gm versus 7 +/- 6 gm; p less than 0.05) and significantly decreased plasma amylase activity (36,605 +/- 21,216 U/dl versus 9421 +/- 5149 U/dl; p less than 0.05). The acute pancreatitis induced by the other three stimuli was not ameliorated by L364,718 treatment. We conclude that in the ex vivo-perfused canine pancreas preparation cerulein-induced pancreatitis is mediated at least in part by the cholecystokinin receptor. Early blockade of the cholecystokinin receptor was of no benefit in treating the other models of pancreatitis, suggesting that cholecystokinin is not involved in the early pathogenesis.

Acute Disease↗