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PubMed1993

The effect of endogenous cholecystokinin released by bombesin and trypsin inhibitor on the regeneration of the pancreas.

OBJECTIVE: This study examined the effects of endogenous cholecystokinin (CCK) released by bombesin and FOY-305 (a synthetic inhibitor of trypsin on pancreatic regeneration in rats). SUMMARY BACKGROUND DATA: Trophic gut hormones (CCK and bombesin) stimulate the growth of the normal rat pancreas. However, the influence of endogenous gut hormones on pancreatic regeneration is unclear. METHODS: Male Fisher rats (n = 6 to 8 per group) were fed a protein-free diet and given ethionine (700 mg/kg intraperitoneally daily) for 8 to 9 days to induce degeneration of the pancreas. Regeneration was stimulated by giving the rats a regular chow diet. The effects of bombesin (10 micrograms/kg three times a day for 7 days) or FOY-305 (200 mg/kg daily for 8 days) on the process of regeneration were examined. RESULTS: At the end of the degeneration phase, there was near-total destruction of pancreatic acinar cells. Both bombesin and FOY-305 stimulated pancreatic regeneration. Growth measurements (weight and total content of DNA and protein) were significantly increased (p < 0.05) in the bombesin- and FOY-305-treated rats compared with controls. Histologic examination revealed widespread repopulation of the pancreas with acinar cells in the bombesin- and FOY-305-treated groups. The stimulating effects of both bombesin and FOY-305 on pancreatic regeneration were blocked completely by the CCK-receptor antagonist L-364,718. Growth measurements were not significantly increased in the groups of control rats or rats given L-364,718 alone. CONCLUSIONS: These results show that bombesin and FOY-305 significantly stimulated pancreatic regeneration. Because the stimulating effects of bombesin and FOY-305 on regeneration were blocked by the specific CCK-receptor antagonist L-364,718, it was concluded that this effect was mediated by endogenous CCK.

Animals↗
PubMed2002

Total gastrectomy severely alters the central regulation of food intake in rats.

OBJECTIVE: To investigate the central regulation of food intake by quantifying neuron activation of the nucleus of the solitary tract (NTS) after injection of cholecystokinin (CCK) or food intake in gastrectomized rats. SUMMARY BACKGROUND DATA: Total gastrectomy is followed by early satiety, low calorie intake, and weight loss in the majority of patients. The etiology of these effects is unknown. Sixty percent to 70% of patients remain underweight after total gastrectomy, the weight loss averaging 25% of preoperative body weight. About two thirds of gastrectomized patients report early satiety, and about 60% do not reach the recommended daily calorie intake. The NTS is a brain stem center involved in the regulation of food intake; thus, the extent and pattern of neuronal activation provide information on the process involved in the initiation of satiation and the regulation of food intake. METHODS: The authors investigated neuronal activation in the NTS using c-fos immunohistochemistry following CCK injection or food intake in healthy control rats, sham-operated control rats, age-matched control rats, weight-matched control rats, and vagotomized or gastrectomized rats. RESULTS: Neuronal activation in the NTS after CCK injection was significantly decreased 21 days after total gastrectomy, but increased by up to 51% 3 months and by up to 102% 12 months after surgery compared to age-matched unoperated control rats. Neuronal activation in the NTS in response to feeding was markedly increased up to fivefold in gastrectomized rats. This increase was early in onset and sustained, and occurred despite significantly reduced food intake. Administration of MK329, a CCK-A receptor antagonist, significantly reduced the number of postprandially activated neurons in both gastrectomized and control rats. CONCLUSIONS: The early postprandial activation of NTS neurons after total gastrectomy in rats may correspond to early satiety reported by patients, while the sustained activation of NTS neurons after a meal could contribute to a reduced daily calorie intake. These data suggest that a disturbed central regulation of food intake might contribute to early satiety, reduced food intake, and weight loss after total gastrectomy.

Animals↗
PubMed1992

CCKB receptor stimulation mediates [Ca2+]i increase but no PKC activation in Jurkat T-cells.

We have investigated the effect of cholecystokinin-octapeptide (CCK-8) on [Ca2+]i and protein kinase C (PKC) activity in Jurkat T-cells. CCK-8 produced a transient [Ca2+]i increase in the presence of extracellular Ca2+. While CCKB receptor antagonist L-365,260 abolished the elevation of [Ca2+]i, CCKA receptor antagonist L-364,718 was without effect. Moreover, the dihydropyridine calcium channel blocker nitrendipine was shown to block the observed calcium response. Results suggest that the calcium effect is caused by an interaction of CCK-8 with CCKB binding sites and an influx of external Ca2+ via dihydropyridine sensitive calcium channels might serve as a source for the increased [Ca2+]i. Because CCK-8 induced no PKC activation CCKB receptor mediated rise of intracellular calcium seems not to include activation of phospholipase C.

Benzodiazepinones↗
PubMed1992

CCK modulates inhibitory synaptic transmission in the solitary complex through CCKB sites.

The CCKB antagonists L-365, 260 and PD134308 and the CCKA antagonist L-364, 718 were applied to neurones of the rat solitary complex (SC) isolated in brainstem slices, while recording either intracellularly or by whole-cell patch-clamp. The CCKB antagonists increased the amplitude of spontaneous or solitary tract-evoked Cl(-)-dependent inhibitory synaptic events by 25 +/- 5% in 5/7 neurones. These events were identified as (1) reversed spontaneous potentials, (2) reversed multisynaptic potentials and (3) outward currents blocked by the GABAA antagonist bicuculline. The CCKB antagonists had no postsynaptic action and increased excitatory synaptic events by 16 +/- 5% in only 3/9 neurones. The CCKA antagonist depolarized neurones but had no effect on synaptic events. Results suggest that CCK, released from the SC tissue, modulates GABAergic interneurones through CCKB sites. This mechanism could contribute to panic attacks, probably mediated by CCKB receptors.

Animals↗
PubMed1992

Evidence for an endogenous cholecystokininergic balance in social memory.

The cholecystokinin (CCK) peptide family is involved in a variety of physiological processes, including neurotransmission in the brain. Pharmacological responses to CCK are mediated through at least two receptor subtypes termed CCK-A and CCK-B. Studies with CCK agonists suggest a possible role for CCK in cognition. Using selective antagonists and a behavioural recognition test based on the olfactory discriminative capacities of rats, we found that endogenous CCK acting at CCK-A and CCK-B receptors modulates olfactory recognition positively and negatively, respectively. CCK-B receptor antagonists therefore have facilitatory potentialities on memory processes.

Animals↗
PubMed1993

Association of the peptidase inhibitor RB 101 and a CCK-B antagonist strongly enhances antinociceptive responses.

The brain peptide cholecystokinin (CCK) has been shown to counteract the analgesic effects of morphine suggesting a physiological antagonism between opioid and CCK neural systems. This has been definitely demonstrated in this study by co-administration of the CCK-B selective antagonist L-365,260 with RB 101, a systemically active inhibitor of peptidases, which fully protects the endogenous opioids, the enkephalins, from their inactivation. The naloxone reversible analgesic effects induced by RB 101 in the mouse hot-plate and rat tail-flick tests were strongly increased by low doses of L-365,260. These results could have important clinical applications by reducing the efficient dose of RB 101, which has recently been shown to be practically devoid of morphine-like side-effects.

Analgesics↗
PubMed1999

CCK-8 can inhibit ingestive behavior by acting on the liver.

The possibility that cholecystokinin octapeptide (CCK-8) can inhibit ingestive behavior by acting on the liver was investigated. Male rats were trained to ingest an intraorally infused 1 M solution of sucrose and then injected with 10 microg CCK-8/kg. Intraperitoneal or hepatic portal vein, but not jugular vein, injection suppressed intake of the sucrose solution. Intraperitoneal injection was more potent than hepatic portal vein injection. Inhibition by hepatic portal vein injection was blocked by i.p. injection of 80 microg/kg of the CCK-A receptor antagonist L-364,718 or by hepatic vagotomy. The results support the hypothesis that CCK-8 can inhibit ingestive behavior via a hormonal action on the liver.

Animals↗
PubMed2000

Cholecystokinin-B receptor antagonists attenuate morphine dependence and withdrawal in rats.

The possible effect of a cholecystokinin-8 agonist (caerulein) and antagonists (MK-329 and L365,260) on the development of morphine dependence and withdrawal were investigated in rats. Caerulein treatment (0.01 and 0.1 mg/kg) increased the incidence of naloxone-induced withdrawal syndromes and delayed the extinction of morphine-conditioned place preference in morphine-dependent animals. The signs of the morphine withdrawal syndromes and the formation of morphine-conditioned place preference were suppressed by pretreatment with L365,260 (0.1 and 1 mg/kg) and not affected by pretreatment with MK-329 (0.1 and 1 mg/kg). The present study demonstrated CCK, acting on CCK-B receptors, participates in the development of the opiate dependence. These findings suggest that CCK-B receptor antagonists might be of some value in the treatment and prevention the relapse of opiate addicts.

Animals↗
PubMed1988

Effect of L364718, a new CCK antagonist, on amylase secretion in isolated rat pancreatic acini.

We examined the effect of L364718, a new cholecystokinin (CCK) receptor antagonist, on amylase release stimulated by CCK or different secretagogues in isolated rat pancreatic acini. L364718 caused a parallel rightward shift of the dose-response curve of CCK8. Schild plots showed a slope of 1.05 +/- 0.15 and a pA2 value of 10.01 +/- 0.31. L364718 inhibited maximally stimulated amylase release by CCK in a dose-dependent manner, with half maximal inhibition (ID50) at 1.7 nM and complete inhibition at 30 nM. Asperlicin, a prototype compound of L364718, also caused dose-dependent inhibition, but L364718 was approximately 400 times more potent than asperlicin (ID50 = 761 nM). L364718 significantly inhibited amylase release in response to CCK33 and CCK8 but had no effect on amylase release stimulated by other receptor secretagogues or agents by passing receptors. The results indicate that L364718 acts as an extremely potent, competitive, and specific antagonist of CCK's action on pancreatic acini.

Amylases↗
PubMed1989

Effect of L-364,718 on GRP-stimulated pancreatic and gastric secretions and GI peptides in conscious dogs.

The effect of L-364,718, a cholecystokinin (CCK) receptor antagonist, on exocrine pancreatic secretion, gastric secretion, and plasma levels of gastrointestinal (GI) peptides stimulated by gastrin-releasing peptide (GRP) was examined in five conscious dogs. Intravenous infusion of graded doses of synthetic porcine GRP (18, 36, and 178 pmol/kg/h) caused significant and dose-dependent increases in pancreatic and gastric juice secretion and in plasma levels of pancreatic polypeptide (PP), CCK, and gastrin. Intravenous injection of L-364,718 (20 nmol/kg) significantly inhibited GRP-stimulated pancreatic outputs of juice volume, protein, and amylase and plasma PP release. L-364,718, however, did not affect gastric juice volume and plasma levels of CCK and gastrin. The results suggest that endogenously released CCK is, at least in part, responsible for GRP-stimulated pancreatic protein and enzyme secretions and PP release in dogs. The results further suggest that GRP-stimulated pancreatic secretion might be, in part, a direct response of GRP to exocrine pancreas.

Animals↗
PubMed1989

Failure of a potent cholecystokinin antagonist to protect against diet-induced pancreatitis in mice.

The effects of a potent cholecystokinin (CCK) receptor antagonist, L-364,718, on two forms of experimental acute pancreatitis in mice were evaluated. The antagonist prevented the hyperamylasemia, pancreatic edema, and acinar cell vacuolization that followed administration of a supramaximally stimulating dose of the cholecystokinin analogue cerulein. In contrast, the same dose of L-364,718 (1 mg/kg/6 h) and an even higher dose (10 mg/kg/6 h) failed to prevent the hyperamylasemia, acinar cell necrosis, and mortality that followed administration of a choline-deficient ethionine-supplemented diet. These observations are at variance with those previously reported to follow administration of the relatively weak cholecystokinin antagonist proglumide (Niederau C et al. J Clin Invest 1986;78:1056-63). The observations reported in this communication suggest that cholecystokinin does not play an important role in diet-induced pancreatitis and that CCK receptor antagonists are unlikely to be of benefit in the treatment of clinical acute pancreatitis.

Animals↗
PubMed1990

Effects of L-364,718 on pancreatic exocrine and endocrine secretion in the rat.

We examined the inhibitory effect of L-364,718, a nonpeptide cholecystokinin (CCK) antagonist, on CCK stimulation of pancreatic exocrine and endocrine secretion in both the isolated pancreatic acini and the isolated perfused pancreata of rats. In the isolated acini, L-364,718 inhibited CCK octapeptide (CCK-8)-stimulated amylase release and binding of 125I-CCK-8 in a dose-dependent manner without appreciable effects on the basal amylase secretion. L-364,718 also inhibited amylase release in response to caerulein and gastrin I, but had no effect on amylase release stimulated by other secretagogues or by agents bypassing receptors. Similarly, binding of N-methylscopolamine to pancreatic acini was not inhibited by L-364,718. In the isolated perfused pancreata, L-364,718 inhibited CCK-8-stimulated pancreatic exocrine secretion and insulin release. The inhibitory effects of L-364,718 were more potent for insulin release than for exocrine secretion and persisted even after the removal of L-364,718 infusion. These results clearly demonstrate that L-364,718 is a specific, potent, and prolonged antagonist of CCK's stimulatory actions on pancreatic acinar and B cells.

Amylases↗
PubMed1990

Chronic administration of a potent cholecystokinin receptor antagonist, L-364,718, fails to inhibit pancreas growth in preweanling rats.

We examined whether endogenous cholecystokinin (CCK) is involved in growth of the preweanling rat pancreas. Twice daily for 14 days, 7-day-old neonatal rats received an oral gavage of either 2.5 mg/kg or 5.0 mg/kg of the potent and specific CCK receptor antagonist L-364,718 (the 2.5 mg/kg dose of antagonist was shown in the present study to abolish totally the pancreas growth-promoting effects of exogenously administered caerulein (CR) in neonatal rats). Control pups received oral gavages of the L-364,718 vehicle alone. The final body weights, pancreas weights, total pancreatic DNA contents, and total pancreatic protein contents did not differ significantly between the 21-day-old control pups and the 21-day-old pups that were pretreated for 14 days with either the low or the high doses of L-364,718. These findings suggest that endogenous CCK is not required for growth of the neonatal rat pancreas.

Amylases↗
PubMed1990

Cholecystokinin antagonist prevents hyperamylasemia and improves pancreatic exocrine function in cerulein-induced acute pancreatitis.

Supramaximal cerulein administration induces acute pancreatitis, which markedly impairs pancreatic secretion in conscious rats. We hypothesized that pretreatment with the potent cholecystokinin antagonist, L-364,718, improves the pancreatic secretory impairment associated with cerulein-induced acute pancreatitis. Rats were surgically prepared with gastric, duodenal, bile, and pancreatic fistulas and jugular vein catheters. On postoperative day 4, groups of rats were administered (a) L-364,718 1 mg/kg intraduodenally, (b) cerulein 5 micrograms/kg/h for 6 h intravenously, (c) L-364,718 1 mg/kg intraduodenally followed by cerulein 5 micrograms/kg/h for 6 h intravenously, and (d) safflower oil carrier intraduodenally. On postoperative day 5, we studied cholecystokinin (CCK)-stimulated pancreatic secretion. Plasma amylase was measured at the time of surgery and at the conclusion of experiments on postoperative days 4 and 5. The duodenally administered CCK antagonist had no effect, 24 h later, on CCK-evoked protein secretion and prevented the pancreatic exocrine impairment and hyperamylasemia caused by supramaximal cerulein administration. These observations suggest that cerulein-induced acute pancreatitis is mediated by a CCK-receptor mechanism.

Acute Disease↗
PubMed1990

Effect of synthetic human cholecystokinin-33 on pancreatic blood flow in dogs.

We have examined the effect of synthetic human cholecystokinin (CCK-33 and CCK-8) on pancreatic blood flow and protein output in anesthetized dogs. Human CCK-33 and CCK-8 increased pancreatic blood flow and protein output in a dose-related manner. There were no significant differences in increasing pancreatic blood flow between human CCK-33 and CCK-8, and increases in blood flow were closely related to the increase of the pancreatic enzyme secretion. L-364,718 (20 nmol/kg) caused a potent inhibition of CCK-stimulated pancreatic blood flow as well as protein output. The degree of inhibition by L-364,718 was dependent on the amount of CCK infused. This study demonstrates that increasing effect on pancreatic blood flow may be one of the biological actions of CCK mediated via CCK receptor. The CCK-33, one of longer molecular forms of CCK, is an important biological stimulator of pancreatic blood flow as well as of exocrine pancreatic secretion.

Animals↗
PubMed1991

Synthetic CCK8 analogs with antagonist activity on pancreatic receptors: in vivo study in the rat, compared to non-peptidic antagonists.

The cholecystokinin octapeptide (CCK8)-derived synthetic peptides Boc-Tyr(SO3H)-Nle-Gly-DTrp-Nle-Asp-O-CH2-CH2-C6H5 (JMV179) and Boc-Tyr(SO3H)-Nle-Gly-DTrp-Nle-Asp-NH-CH2-CH2-C6H5 (JMV167) are antagonists of peripheral cholecystokinin (CCK) receptors in vitro. In the present study, antagonist activity of these peptides was studied on rat pancreatic secretion in vivo, and compared to those of other peptidic molecules and to the non-peptidic antagonists L364718, D-, L-, DL-lorglumide, and proglumide. The decreasing order of antagonist potencies on amylase release in vitro was L364718 greater than JMV179 greater than lorglumide greater than JMV167 greater than proglumide; JMV179 was 25 times less potent than L364718 and 300 times more potent than JMV167. The decreasing order of antagonist potencies on protein output in pancreatic juice in vivo was L364718 greater than JMV167 greater than JMV179 greater than lorglumide greater than proglumide; JMV167 was two times more potent than JMV179 and only 8 times less potent than L364718. Increased potency of JMV167, relative to JMV179 under in vivo conditions, is probably due to the slower rate of catabolism of the phenylethylamide group, relative to the phenylethylester group, since the metabolite issued from hydrolysis of the ester bond was totally inactive. This study shows that it is possible to obtain peptidic CCK antagonists, which are active and potent in vivo, and provides a quantitative measurement of potency changes occurring in vivo for several peptidic and non-peptidic antagonists.

Amino Acid Sequence↗
PubMed1991

Role of cholecystokinin in cholestyramine-induced changes of the exocrine pancreas.

This study was an investigation of the role of cholecystokinin (CCK) in the stimulatory action of cholestyramine on rat exocrine pancreas. Postprandial CCK release was significantly enhanced by acute administration of cholestyramine (12.7 +/- 1.8 vs 3.7 +/- 0.5 pmol/L in controls). Over four weeks, rats were fed either regular diet or diet containing 6% cholestyramine, and were treated with the specific CCK receptor antagonist L-364,718 (2 x 0.5 mg/kg body weight/day s.c.) or DMSO (vehicle for the antagonist). Cholestyramine significantly increased pancreatic weight and trypsin and chymotrypsin contents. L-364,718 abolished these effects. Concomitant administration of antagonist and cholestyramine elevated amylase content, compared to controls. CCK levels in fasted animals did not differ between the four groups. The effect of the same dose of L-364,718 on pancreatic enzyme depletion, induced by the protease inhibitor camostate, was studied in a control experiment. A single dose of camostate (200 mg/kg) caused a 44-68% decrease in enzyme content. L-364,718 reversed this effect for all enzymes. We conclude that CCK is the mediator of cholestyramine-induced pancreatic hypertrophy and increase in content of proteases. After long-term administration, the CCK receptor antagonist, in combination with cholestyramine revealed an agonistic effect on individual, pancreatic enzyme content.

Administration, Oral↗
PubMed1992

A pilot clinical trial of the cholecystokinin receptor antagonist MK-329 in patients with advanced pancreatic cancer.

MK-329 is a nonpeptidal, highly specific cholecystokinin (CCK) receptor antagonist, with affinity for pancreatic and gallbladder CCK receptors similar to CCK itself. MK-329 and its progenitor, asperlicin, can inhibit the growth of CCK receptor-positive human pancreatic cancer in athymic mice. Based on these activities and the ability of MK-329 to transiently increase food intake and enhance morphine analgesia in murine models, we conducted an open trial of MK-329 in 18 patients with advanced pancreatic cancer in whom the CCK receptor status of the tumors was unknown. Tumor response, pain control, and nutritional parameters (hunger rating, caloric intake, body weight, and anthropometrics) were serially assessed. The results of the study failed to demonstrate any impact of MK-329 on tumor progression, pain, or nutrition. Toxicity was mild and limited to nausea, vomiting, diarrhea, and abdominal cramps, with 17 of 18 patients able to tolerate treatment. While a role for MK-329 in the management of patients with advanced pancreatic cancer cannot be supported by the results of this trial, additional studies of this agent in patients with known CCK receptor-positive tumors, at escalated doses, and possibly in conjunction with other growth antagonists, appear warranted.

Adenocarcinoma↗