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PubMed1995

Evidence for autoregulation of cholecystokinin secretion during diversion of bile pancreatic juice in rats.

BACKGROUND & AIMS: The mechanism regulating cholecystokinin (CCK) secretion during prolonged diversion of bile pancreatic juice (BPJ) is unknown. We examined the hypothesis that the decrease of plasma CCK levels after prolonged diversion of BPJ is mediated by an increase in plasma somatostatin levels evoked by hypercholecystokinemia and somatostatin in turn inhibits CCK-releasing peptide (CCK-RP) bioactivity and decreases plasma CCK levels. METHODS: Pancreatic secretion, plasma CCK levels, and somatostatin levels were monitored for 7 hours after diversion of BPJ in anesthetized rats. Secretion of CCK-RP bioactivity during diversion of BPJ was examined in the presence or absence of somatostatin. RESULTS: Diversion of BPJ for 2 hours caused a 13- and 2.5-fold increase in plasma CCK and somatostatin levels. The increase in somatostatin levels was blocked by the CCK antagonist L364,718. At 5 hours after diversion of BPJ, plasma CCK and somatostatin levels and luminal CCK-RP bioactivity decreased to basal levels. The decrease in plasma CCK levels was prevented by the administration of a specific somatostatin antagonist. We also showed that the stimulatory effect of the CCK-RP bioactivity was eliminated when the donor rat was pretreated with somatostatin. CONCLUSIONS: Autoregulation of CCK secretion occurs during the diversion of BPJ and this is mediated by somatostatin, which inhibits the secretion of CCK-RP bioactivity and decreases plasma CCK levels.

Analysis of Variance↗
PubMed1990

Effect of cholecystokinin receptor blockade on human lymphocyte proliferation.

Cholecystokinin is a peptide produced by neuroendocrine cells in gut and neurons in brain and gut. Proliferating human peripheral blood mononuclear cells (H-PBMC) also make small amounts of cholecystokinin. Cholecystokinin increases intracellular calcium (Ca2+) in H-PBMC. This can be blocked with L 364, 718, a non-toxic specific cholecystokinin antagonist. Cholecystokinin is a comitogen for H-PBMC and activates H-PBMC in a cyclosporine-resistant fashion. If cholecystokinin is a critical lymphokine, then L 364, 718 should block H-PBMC mitogenesis. H-PBMC from healthy donors were stimulated in vitro with either phytohemagglutinin or anti-CD3 monoclonal antibody. L 364, 718 was not toxic for H-PBMC, yet inhibited mitogenesis at 10(-7), 10(-6), and 10(-5) M. The small amount of cholecystokinin made by H-PBMC may play a critical role in H-PBMC mitogenesis.

Antibodies, Monoclonal↗
PubMed1992

Cholecystokinin does not mediate glucose's cytoprotective effects.

Cold restraint stress produces acute gastric mucosal injury in association with altered gastric motility. Enteral nutrients prevent this injury in conjunction with inhibition of gastric emptying. Because cholecystokinin (CCK) is released by nutrients known to be cytoprotective and is thought to inhibit gastric emptying, we performed three experiments to see if CCK contributes to the gastric mucosal protection afforded by enteral nutrients. Our data show that enteral glucose protects the gastric mucosa and increases gastric volume, gastric luminal pH, and gastric mucin. Neither physiologic nor pharmacologic doses of CCK protected the mucosa. None of the other significant effects of glucose on gastric function during cold restraint were affected by exogenous CCK. Furthermore, antagonism of CCK receptors with L-364,718 did not have any independent effects, nor did it diminish the protection associated with enteral glucose. We conclude that enteral glucose protects the gastric mucosa from cold restraint injury in association with a number of potentially beneficial effects on gastric physiology, but none of the effects of glucose in this model appear to be mediated by CCK.

Animals↗
PubMed1992

Effect of CCK receptor antagonist on growth of pancreatic adenocarcinoma.

Cholecystokinin (CCK) exerts an influential effect on the growth of normal pancreas. It is postulated that carcinoma arising from the pancreas may retain some normal pancreatic properties as far as hormone dependency is concerned. In an effort to examine the effect of CCK on the growth of pancreatic cancer, we evaluated the effect of CCK receptor antagonist on the growth of a transplantable adenocarcinoma of the pancreas. For this study we utilized three groups of hamsters with adenocarcinoma of the pancreas transplanted subcutaneously on the right flank. Group I (n = 15) served as control. Group II (n = 15) received CCK receptor antagonist (L-364,718), 0.1 mg/100 g body wt subcutaneously BID. Group III received CCK receptor antagonist in the same dose but treatment was started after tumors became palpable. All animals were examined daily. Latency for tumor growth, tumor size, and body weight were recorded. Animals were sacrificed after 3 weeks and final tumor volume and weight were measured. CCK receptor antagonist (L-364,718) significantly reduced pancreatic carcinoma growth when given immediately after transplantation and also in animals with established tumor. However, this inhibitory effect of L-364,718 was only partial and effective only for a brief time. This finding suggests CCK may have only a minimal influence on the biologic behavior of exocrine pancreatic cancer.

Adenocarcinoma↗
PubMed1986

A new simple mouse model for the in vivo evaluation of cholecystokinin (CCK) antagonists: comparative potencies and durations of action of nonpeptide antagonists.

A new simple mouse assay for the in vivo evaluation of CCK antagonists which is based upon visual determination of the gastric emptying of a charcoal meal is described. CCK-8 (24 micrograms/kg s.c.) but not various other peptide and nonpeptide agents effectively inhibited gastric emptying in this test system. The effect of CCK-8 was antagonized by established peripheral CCK antagonists but not representative agents of various other pharmacological classes. The rank order of potency of the CCK antagonists were: L-364,718 (ED50 = 0.01 mg/kg, i.v.; 0.04 mg/kg, p.o.) greater than Compound 16 (ED50 = 1.5 mg/kg, i.v.; 2.0 mg/kg p.o.) greater than asperlicin (ED50 = 14.8 mg/kg i.v.) greater than proglumide (ED50 = 184 mg/kg i.v.; 890 mg/kg, p.o.). Duration of action studies based upon ED50 values determined at various time intervals after oral administration showed that L-364,718 and proglumide are considerably longer acting than Compound 16. Asperlicin (ED50 greater than 300 mg/kg, p.o.) was ineffective as a CCK antagonist when administered orally. These data provide the first direct comparisons of the in vivo potencies of current CCK antagonists and demonstrate the utility of a new simple mouse assay for the in vivo characterization of peripheral CCK antagonists.

Administration, Oral↗
PubMed1988

Potency of L-364,718 as an antagonist of the behavioral effects of peripherally administered cholecystokinin.

A new antagonist of the peripheral cholecystokinin receptor, L-364,718, was found to block the reductions in food intake and exploratory activity induced by intraperitoneal administration of cholecystokinin octapeptide sulfate. L-364,718 significantly reversed the cholecystokinin-induced reduction in feeding at doses of 10 micrograms/kg - 10 mg/kg i.p. L-364,718 significantly reversed the cholecystokinin-induced reduction in exploratory activity at doses of 500 ng/kg - 10 mg/kg i.p. The time course of antagonist activity of L-364,718 was immediate to 90 minutes after intraperitoneal administration. L-364,718 had no significant effect on food intake or exploratory activity when administered alone, over the dose range of 100 ng/kg-10 mg/kg i.p. This compound appears to be at least one hundred times more potent than proglumide or benzotript as an antagonist of the behavioral effects of peripherally administered cholecystokinin.

Animals↗
PubMed1989

Bombesin reverses bleeding-induced hypovolemic shock, in rats.

In an experimental model of bleeding-induced hypovolemic shock causing the death of all saline-treated rats within 26 +/- 4 min, the intravenous injection of bombesin (2.5, 5 or 10 micrograms/kg) dose-dependently restored blood pressure, pulse amplitude, heart rate and respiratory function, and improved survival rate as assessed at the end of the experiment (2 h). The effect on cardiovascular and respiratory functions was prompt (within 1-2 min) and sustained. The release of cholecystokinin seems to be the main mechanism of action, because the anti-shock effect of bombesin is largely prevented by the CCK-antagonist, L-364,718.

Animals↗
PubMed1993

CGRP 8-37[correction of 8-27] blocks the inhibition of gastric emptying induced by intravenous injection of alpha-CGRP in rats.

The receptor subtype mediating rat alpha-calcitonin gene-related peptide (alpha-CGRP)-induced inhibition of gastric emptying of a non nutrient solution was tested in conscious rats using the CGRP1 receptor antagonist, CGRP 8-37, and the CCK antagonist, MK-329. Intravenous injection of alpha-CGRP (0.5 micrograms) decreased gastric emptying to 26.5 +/- 5.8% from 46.4 +/- 3.9% in vehicle-treated group. Intravenous injection of CGRP 8-37 (15 micrograms) did not influence gastric emptying but completely prevented alpha-CGRP inhibitory effect whereas the 47% delay in gastric emptying induced by intravenous cholecystokinin-8 (CCK, 0.25 microgram) was not modified. The CCK antagonist, MK-329 (1 mg) reversed CCK- but not alpha-CGRP-induced delay in gastric emptying. These results demonstrate that CGRP 8-37 is a specific tool to block alpha-CGRP inhibitory action on gastric motor function and suggest that gastric stasis elicited by peripheral injection of alpha-CGRP may involve an interaction with a CGRP1 receptor subtype.

Animals↗
PubMed1996

L-364,718 and L-365,260, two CCK antagonists, have no affinity for central benzodiazepine binding sites in chickens.

It has recently been demonstrated that L-365,260, a CCK-B antagonist in mammals, causes an increase in food intake in chickens. In contrast, L-364, 718, a CCK-A antagonist in mammals, shows this effect only at very high dose levels. It has been shown that L-365,260 has very low affinity for chicken CCK receptors. Thus, the mechanism of action of L-365,260 remains unknown. As L-365,260 is a benzodiazepine derivative, one may hypothesize that it would be acting on benzodiazepine binding sites. The aims of this work were to establish the existence of benzodiazepine binding sites in the chicken brain, and to check the possibility that L-365,260 was acting on these receptors, determining the affinity of L-364,718 and L-365,260 for them. We have found specific binding for tritiated flunitrazepam (a benzodiazepine agonist) ([3H]-flunitrazepam) in chicken brain membranes. A single binding site was detected with a Kd of 3.58 +/- 0.97 nM and a Bmax of 451.6 +/- 23.3 fmol/mg protein L-365,260 and L-364,718 exhibited very low affinity for these binding sites (Ki = 1.17 x 10(-6) +/- 0.16 x 10(-6) M and Ki > 10(-5) M, respectively). Thus, these results demonstrate that the increase in food intake caused by L-365,260 in the chicken is not due to a direct action on benzodiazepine receptors. Other possible explanations for its effect are discussed.

Animals↗
PubMed1988

Synergistic impact of cholecystokinin and gastric inhibitory polypeptide on the regulation of insulin secretion.

The modulation of insulin output from isolated perifused rat islets by the intestinal peptides cholecystokinin (CCK) and gastric inhibitory polypeptide (GIP) was assessed. In the presence of 7 mmol/L (126 mg/dL) glucose, but not 2.75 mmol/L (50 mg/dL) glucose, CCK (5 nmol/L) or GIP (50 ng/mL) alone evoke small insulin secretory responses. However, the combination of GIP (50 ng/mL) plus CCK (5 nmol/L) together with 7 mmol/L glucose results in a markedly amplified insulin secretory response. CCK (50 nmol/L) alone increases phosphoinositide (PI) hydrolysis in islets, an event reflected by an increase in 3H efflux from myo[2-3H]inositol prelabeled islets and parallel accumulations of labeled inositol phosphates. GIP (50 ng/mL) alone has no effect on PI hydrolysis. However, GIP reduces the quantitative impact of CCK on PI turnover, an effect attributable to the capacity of GIP to elevate islet cAMP levels. CCK has no significant effect on islet cAMP levels. The results support the concept that the synergistic action of these peptides on insulin output is mediated by their ability to generate separate beta cell second messenger molecules. Nutrient-regulated intestinal release of various peptides represents a remarkable control system to ensure the release of insulin from the beta cell in amounts commensurate with both the quantity and quality of nutrient intake.

Animals↗
PubMed1989

Morphine-induced analgesia in the rat paw pressure test is blocked by CCK and enhanced by the CCK antagonist MK-329.

The effects of cholecystokinin octapeptide sulphated (CCK) and the potent CCK antagonist MK-329 (L-364, 718) on analgesia induced by morphine in the paw pressure test in the rat were examined. Both CCK (4-16 micrograms/kg) and MK-329 (0.1-8.0 mg/kg) had no significant effect on thresholds for pain when given alone, whereas morphine (2-16 mg/kg) induced dose-dependent analgesia. Cholecystokinin (4-16 micrograms/kg) abolished the analgesia induced by 8 mg/kg morphine. In contrast, doses of 1 and 2 mg/kg MK-329 enhanced the analgesia induced by 8 and 4 mg/kg morphine, respectively. The present data are consistent with previous reports that CCK blocks, and CCK antagonists enhance, opiate-induced analgesia in response to thermal pain stimuli. In addition, the results show that CCK/opiate interactions extend to mechanical pain stimuli. Recent ligand binding studies have shown that CCK receptors in the spinal cord of the rat (where CCK/opiate interactions are thought to occur) are predominantly of the CCK-B subtype. The drug MK-329 has a relatively weak (micromolar) affinity for CCK-B receptors and a high affinity (nanomolar) for CCK-A receptors. As relatively large doses (1-2 mg/kg) of MK-329 are required to enhance opiate-induced analgesia in the paw pressure test and tail flick test in rats it appears that CCK/opiate interactions in this species involve CCK-B receptors.

Animals↗
PubMed1989

Differential effects of the CCK antagonist, MK-329, on analgesia induced by morphine, social conflict (opioid) and defeat experience (non-opioid) in male mice.

The effects of the potent and selective CCK antagonist, MK-329, on morphine- and environmentally-induced analgesia were examined in male mice. The results show that MK-329 (0.005-0.1 mg/kg) was devoid of intrinsic analgetic activity on the mouse tail-flick assay and, over the dose range 0.01-0.5 mg/kg, was without significant effect upon non-opioid analgesia, induced by defeat experience. However, opposite effects of MK-329 on analgesia induced by morphine and opioid-mediated social conflict analgesia were observed. That is, 0.05-0.01 mg/kg MK-329 (but not smaller doses) enhanced, and modestly prolonged, the duration of analgesia induced by 5 mg/kg morphine. In direct contrast, 0.0001-0.5 mg/kg of the CCK antagonist very potently inhibited opioid-typical analgesia in mice exposed to intense conspecific attack. In the latter studies, a residual short-lasting analgesia in mice, treated with MK-329, was found to be resistant to naloxone (5 mg/kg), indicating its non-opioid nature and confirming the lack of effect of the CCK antagonist on opioid-independent analgesia. It is suggested that the variable effects of MK-329 on morphine-induced and opioid-mediated social conflict analgesia may reflect differential, dose-dependent effects at CCK-B and CCK-A sites respectively, a proposal consistent with the 500-fold potency difference observed between the two models.

Analgesia↗
PubMed1989

Duodenal infusion of fat, cholecystokinin secretion and satiety in the pig.

The influence of the cholecystokinin (CCK) antagonist L-364,718 (0.1 mg/kg) on short-term control of food intake was studied in 6 pigs. Arterial injection of L-364,718 abolished the inhibition of intake to CCK octapeptide infusion (4 micrograms/kg/hr; from 42% p less than 0.001, to 97% of control intake), but did not alter control intake (99%). Injection of L-364,718 also abolished the inhibition of intake to duodenal infusion of emulsified fat (12 g/hr; from 76% p less than 0.001 to 105%) and of monoglyceride (24 g/hr; from 64% p less than 0.001 to 101%), but did not alter the inhibition to oleic acid (60 g/hr; 48% p less than 0.01 and 61% p less than 0.02), to glycerol (127 g/hr; 84% p less than 0.05 and 89%) or to glucose (144 g/hr; 78% p less than 0.02 and 69% p less than 0.001). These results suggest that monoglyceride-induced CCK secretion is mainly responsible for the satiety to duodenal fat in the pig, but that there is also a CCK-independent effect via the fatty acid. The results further indicate that intake of a normal barley-based diet (2% fat) is controlled via CCK-independent mechanisms.

Animals↗
PubMed1990

Effects of the CCK receptor antagonist MK-329 on food intake in pigs.

The cholecystokinin (CCK) receptor antagonist MK-329 (previously L364,718) was administered intravenously (IV) (17.5-140 micrograms/kg) to pigs trained to make operant responses for food reinforcements after 4 hr of food deprivation. MK-329 produced a dose-related increase in food intake during the 2-hr test period, with maximum increases occurring at a dose of 70 micrograms/kg. CCK (1 micrograms/kg IV) produced a short-term reduction in feeding and this effect was completely abolished by pretreating the animals with MK-329 (70 micrograms/kg). The present results lend support to the hypothesis that endogenous CCK is involved in satiety.

Animals↗
PubMed1992

Cholecystokinin antagonist and lipid intake as a function of caloric density and familiarity.

The effect of treatment with the cholecystokinin antagonist L364,718 on intake of different dilutions of corn oil emulsion was tested under two levels of familiarity with the oil emulsion. No increase in intake was observed. To see if the CCK antagonist was effective under our conditions, exogenous CCK was administered under the same conditions. A complete suppression of the large reduction produced by CCK on intake was found.

Animals↗
PubMed1993

The role of cholecystokinin in interleukin-1-induced anorexia.

Anorexia is a common response to infection which is thought to be mediated, at least in part, by interleukin (IL-1), an immunoregulatory peptide secreted by activated monocytes. Cholecystokinin (CCK) is a neuropeptide that suppresses food intake and gastric emptying when injected into healthy animals. There is increasing evidence of bidirectional interactions between neuropeptides, immune cell function, and secretion of immunoregulatory cytokines. Therefore, the present study was undertaken to determine if administration of L364,718 (L364), a CCK receptor antagonist, might block the anorexigenic effects of recombinant human IL-1 alpha (IL-1 alpha) in rats. We report that injection of IL-1 alpha significantly increased plasma CCK 1 h after injection, and decreased food intake and emptying of gastric contents. Pretreatment with 1 mg/kg L364 partially blocked the decrease in food intake and gastric stasis induced by IL-1 alpha. We conclude CCK may mediate, at least in part, IL-1 alpha-induced anorexia.

Animals↗
PubMed1993

Voluntary intake and gastric emptying in pigs: effects of fat and a CCK inhibitor.

The influence of the cholecystokinin (CCK) antagonist MK-329 (0.1 mg/kg) on short-term control of voluntary food intake and gastric emptying was studied in five pigs. Arterial injection of MK-329 abolished the inhibition of intake resulting from duodenal infusion of emulsified fat (Intralipid, 24 g/h). However, MK-329 only reduced the inhibition of dry matter (DM) and liquid emptying, and hence increased stomach volume at satiety. Intralipid infusion decreased the rise in gastric pressure during feeding. All these changes are consistent with endogenous CCK, released by Intralipid, inhibiting intake independent of the concomitant slowing of gastric emptying. MK-329 alone significantly increased intake using two different diets, but had no effect on gastric emptying so that gastric volume at satiety was significantly increased. These results suggest that endogenous CCK may be part of short-term satiety control in the pig.

Animals↗
PubMed1989

CCK8 effects on motivational and emotional states of rats involve CCKA receptors of the postero-median part of the nucleus accumbens.

Administration of 3 fmol of cholecystokinin octapeptide (CCK8) into the postero-median nucleus accumbens (NAS) induced an hypoexploration measured using the four-hole box and an increase in the emotional states of rats observed in the elevated plus maze. These effects seem likely to involve CCKA receptors since they were reversed by the selective CCKA antagonist L364,718 (100 micrograms/kg, 200 micrograms/kg IP) and not observed after injection of 0.1 to 1000 fmol unsulfated cholecystokinin octapeptide (CCK8NS) in the same region. On the other hand, CCK8 or CCK8NS injected into the anterior NAS did not significantly modify these behaviors. These results support the neuroanatomical heterogeneity in the distribution of CCK and its binding sites in the NAS, but raise the question of the presence of CCKA receptors not detected in binding studies and of the behavioral effects mediated by CCKB receptor stimulation in this structure.

Animals↗