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PubMedDate not supplied

Cholecystokinin-B (CCK-B) receptor antagonists improve "aged" sleep: a new class of sleep modulators?

Sleep disorders are a major, although often minimized and underdiagnosed, medical problem. Current therapy is based on the use of hypnotics, mainly benzodiazepines, which disrupt the sleep pattern often suppressing rapid-eye-movement (REM) sleep. Here, new types of pharmacological tools such as cholecystokinin (CCK) receptor antagonists are examined. In particular, since the awake-sleep rhythm is mainly altered in old age in humans, the influence of these compounds over REM and non-REM sleep has been studied in aged rats (21 months) vs. young rats (5 months) prepared for electroencephalographic (EEG) recordings. Basal EEG data indicated that REM and non-REM sleep was reduced in aged rats vs. young rats. GV-150013, a selective CCK-B receptor antagonist, was found to increase REM sleep, as well as non-REM sleep, and therefore total sleep (non-REM + REM) mainly in aged rats. The dose-range of activity (0.5-60 micrograms/kg) together with the evidence that another CCK-B receptor antagonist, L-365,260 (5 micrograms/kg) increased, while devazepide (a CCK-A receptor antagonist; 20 micrograms/kg) decreased non-REM sleep and total sleep time, support the original hypothesis that the activity of GV-150013 on sleep progress through CCK-B receptors. Furthermore, no tolerance was detected after chronic treatments with GV-150013. In contrast, typical EEG modifications (decrease of REM) and the development of tolerance towards benzodiazepines were monitored following chronic treatment with triazolam (400 micrograms/kg). These results suggest that the CCKergic compounds studied are involved via a different mechanism of action than benzodiazepines in the modulation of the awake-sleep rhythm. A further observation is that the total sleep time recorded in aged rats after treatment with GV-150013 reached the value of the total sleep time of young untreated rats also prepared for EEG. Finally, this work suggests that CCK receptor antagonists, GV-150013 in particular, are more effective in aged resulting in an improvement of sleep quality towards that of young rats.

Adamantane↗
PubMed2006

Activation of neural cholecystokinin-1 receptors induces relaxation of the isolated rat duodenum which is reduced by nitric oxide synthase inhibitors.

Cholecystokinin (CCK) influences gastrointestinal motility, by acting on central and peripheral receptors. The aim of the present study was to determine whether CCK has any effect on isolated duodenum longitudinal muscle activity and to characterize the mechanisms involved. Isolated segments of the rat proximal duodenum were mounted for the recording of isometric contractions of longitudinal muscle in the presence of atropine and guanethidine. CCK-8S (EC50: 39; 95% CI: 4.1-152 nM) and cerulein (EC50: 58; 95% CI: 18-281 nM) induced a concentration-dependent and tetrodotoxin-sensitive relaxation. Nomeganitro-L-arginine (L-NOARG) reduced CCK-8S- and cerulein-induced relaxation (IC50: 5.2; 95% CI: 2.5-18 microM) in a concentration-dependent manner. The magnitude of 300 nM CCK-8S-induced relaxation was reduced by 100 microM L-NOARG from 73 +/- 5.1 to 19 +/- 3.5% in an L-arginine but not D-arginine preventable manner. The CCK-1 receptor antagonists proglumide, lorglumide and devazepide, but not the CCK-2 receptor antagonist L-365,260, antagonized CCK-8S-induced relaxation in a concentration-dependent manner. These findings suggest that CCK-8S and cerulein activate intrinsic nitrergic nerves acting on CCK-1 receptors in order to cause relaxation of the rat duodenum longitudinal muscle.

Animals↗
PubMed1993

Enterochromaffin-like cells in rat stomach respond to short-term infusion of high doses of cholecystokinin but not to long-term, sustained, moderate hyperCCKemia caused by continuous cholecystokinin infusion or pancreaticobiliary diversion.

The histamine-producing enterochromaffin-like (ECL) cells in the oxyntic mucosa are controlled by gastrin. An acute gastrin challenge induces release and accelerated resynthesis of ECL cell histamine. Long-term stimulation with gastrin causes ECL cell hyperplasia. We set out to study whether the ECL cells respond not only to gastrin but also to cholecystokinin (CCK). A wide dose range of gastrin-14 sulfated and -17 non-sulfated and CCK-8 sulfated (CCK-8s) and non-sulfated (CCK-8) was infused intravenously to rats for 3 h. The activity of the histamine-forming enzyme was measured at termination of infusion. Gastrins and CCK-8s were equally effective in activating the enzyme, whereas sulfated CCK-8 was notably less potent than the other three peptides. Clearly, the receptor responsible for activation of the ECL cells distinguishes poorly between gastrin-17 and CCK-8s, which is in line with the characteristics of the CCK-B receptor. Moreover, neither the response to gastrin-17 nor that to CCK-8s was affected by concomitant infusion of devazepide (200 micrograms/kg/h), a selective CCK-A-receptor antagonist. One group of rats received CCK-8s continuously via a minipump. Another group of rats was subjected to pancreaticobiliary diversion (PBD), which increases the plasma CCK concentration 10- to 20-fold. The rats were killed 7 or 10 weeks later, respectively, and the stomachs were analyzed with regard to mucosal growth and ECL cell hyperplasia. HyperCCKemic rats had increased pancreatic weights but showed no signs of growth stimulation in the stomach and no ECL cell hyperplasia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Cholecystokinin-induced anxiety in rats: relevance of pre-experimental stress and seasonal variations.

OBJECTIVE: To examine the influence of pre-experimental stress on the anxiogenic-like action of caerulein, an agonist of cholecystokinin (CCK) receptors. Differences in the anxiety levels of rats in summer and winter, and the role of CCK in these behavioural alterations, were also examined. DESIGN: Prospective animal study. INTERVENTIONS: Male Wistar rats were injected with the CCK agonist caerulein, or the CCK antagonists L-365,260 or devazepide, after being exposed to pre-experimental stress (handling and isolation). OUTCOME MEASURES: Performance in the plus-maze model of anxiety; serum levels of prolactin, thyrotropin and growth hormone; brain density and affinity of dopamine D2, serotonin 5-HT2 and CCK receptors. RESULTS: Caerulein (5 micrograms/kg, subcutaneous injection) caused the strongest action in animals brought to the experimental room immediately before the experiment and kept in isolation after the administration of caerulein. Caerulein did not cause any reduction of exploratory activity in rats made familiar with the experimental room and kept in the home-cage after the injection of the CCK agonist. The anti-exploratory action of caerulein in stressed rats was reversed by the CCK antagonist L-365,260 (100 micrograms/kg, intraperitoneal injection), demonstrating the involvement of the CCKB receptor subtype. In addition, seasonal fluctuations occur in the exploratory activity of rats; such activity was much lower in July than in November. The rats displaying the reduced exploratory activity had an increased number of CCK receptors in the frontal cortex and hippocampus. Simultaneously, the density of serotonin 5-HT2 receptors in the frontal cortex, but not that of dopamine D2 receptors in the striatum, was elevated. The blood level of growth hormone was also higher in July. CONCLUSIONS: The anti-exploratory action of caerulein appears to be dependent on the pre-experimental stress of rats. Moreover, the seasonal variations of exploratory behaviour of rats are evident in the plus-maze model of anxiety. The reduced exploratory activity in summer appears to be related to the elevated density of CCK and 5-HT2 receptors in the brain.

Animals↗
PubMed1992

Neuropeptide Y and sigma ligand (JO 1784) suppress stress-induced colonic motor disturbances in rats through sigma and cholecystokinin receptors.

The effects of neuropeptide Y (NPY), sigma ligand (JO 1784) and sulfated cholecystokinin octapeptide (CCK8s) on emotional stress (ES) and corticotropin-releasing hormone (CRH)-induced colonic hypermotility were evaluated in rats equipped with chronically implanted electrodes on the colon and a small catheter into the lateral ventricle of the brain. A 139% (97-172%) increase in colonic spike burst frequency was observed in rats placed in a test cage in which they had previously received electric footshocks, an event assimilated to an ES. Intracerebroventricular injection of CRH (0.5 microgram/kg) mimicked the effects of ES by increasing colonic spike burst frequency by 89.0%. Given i.c.v., both JO 1784 (0.1 microgram/kg) and NPY (0.15 microgram/kg) blocked these stimulatory effects. Similarly, i.c.v. administration of CCK8s (0.1 microgram/kg) abolished both ES and CRH stimulated colonic motility, an effect reproduced by central injection of JMV 180, a cholecystokinin (CCK) derivative with high affinity for CCKA receptors, (1 microgram/kg), but not by JMV 170, a CCK derivative with low affinity for CCKA receptor at similar or higher dose. BMY 14802 (a sigma receptor antagonist) injected s.c. (1 mg/kg) abolished the antagonistic effects of JO 1784 and NPY on the ES-induced colonic hyperkinesia. Injected i.c.v., devazepide (L 364,718), a CCKA receptor antagonist, at 0.1 and 1 microgram/kg, abolished the effect of both JO 1784 and NPY; by contrast L365,260, a CCKB antagonist, required a dose of 10 micrograms/kg to block the antagonistic effect of NPY and JO 1784.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

A further analysis of the contraction induced by activation of cholecystokinin A receptors in guinea pig isolated ileum longitudinal muscle-myenteric plexus.

The activity of a selective cholecystokinin (CCK)-A receptor agonist, N-acetyl derivative of A71623 (Ac-Trp-Lys(epsilon-N-[2-methylphenylamino-carbonyl]) -Asp-(NMe)Phe-NH2) was investigated in the guinea pig isolated ileum longitudinal muscle myenteric plexus. NAA caused both a phasic and tonic contraction at all concentrations tested (1-1000 nM). The selective CCK-A antagonist L-364,718 (Devazepide) antagonized both types of contraction with a pKB of 10.10 and 9.95, respectively. The CCK-B selective antagonist L-365,260 ((3R(+)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1, 4-benzodiazepine-3yl)-N-(3-methylphenyl)-urea) was inactive up to a concentration of 30 nM. Atropine at 300 nM and 1000 nM reduced the maximal response of NAA by only 17% and 50%, respectively. The selective neurokinin (NK)-1 antagonists GR 82334 ([D-pro9[Spiro-gamma-Lactam] Leu10, Trp11]-Phys (1-11)9) at 300 and 1000 nM and (+-) CP-96,345 [(2S, 3S)-cis- 2-(diphenylmethyl)-N- [(2-methoxyphenyl)-methyl] -1-azabici-clo [2.2.2]octan-3-amine] at 10 nM were inactive or partially active. When atropine and GR 82334 or (+/-) CP-96,345 were combined, they produced a dose-dependent synergistic inhibition of both phasic and tonic contractions induced by NAA. The selective NK-3 receptor agonist senktide induced both phasic and tonic contractions that were blocked by tetrodotoxin. In the presence of atropine and GR 82334, both 300 nM, a synergistic depression of the response to senktide similar to that observed for the agonist NAA was disclosed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Characterization of SNF 9007, a novel cholecystokinin/opoid ligand in mouse ileum in vitro: evidence for involvement of cholecystokininA and cholecystokininB receptors in regulation of ion transport.

The effects of cholecystokinin (CCK) fragments and Asp-Tyr-D-Phe-Gly-Trp-[N-Me]Nle-Asp-Phe-NH2 1(SNF 9007), a synthetic CCK analog which binds with high affinity to CCKB and opioid delta receptors, were evaluated in isolated sheets of mouse ileum mounted in Ussing flux chambers. Serosal, but not mucosal, administration of cholecystokinin octapeptide-sulfated [CCK8(s)] and cholecystokinin tetrapeptide (30-33) [CCK4(30-33)] produced a brief, concentration-related increase in short circuit current (Isc) without changing tissue conductance. Serosal, but not mucosal, SNF 9007 produced a similar concentration-related increase in Isc which was followed by an immediate concentration-related and sustained decrease in Isc; no decrease in Isc was observed for either CCK8 or CCK4(30-33). The increase and subsequent decrease in the SNF 9007 Isc response were respectively classified as phase I (i.e., CCK-like) and phase II (opioid-like) activity. CCK8(s) and SNF 9007 (phase I) were active at low nanomolar concentrations, whereas CCK4(30-33) was active only at high nanomolar concentrations: the rank order of potencies to increase Isc was CCK8(s) > SNF 9007 > CCK4(30-33). Devazepide (L364,718), a selective antagonist of CCKA receptors, effectively blocked the action of CCK8(s), but not that of CCK4(30-33) or SNF 9007 (phase I). In contrast, 3R[+]-N-[2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-benzodiazepin-3-yl ]-N'- [3-methyl-phenyl]urea (L365,260), a selective CCKB receptor antagonist, blocked the action of CCK4(30-33) and SNF 9007 (phase I), and also antagonized CCK8(s), though to a lesser degree.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1994

Molecular modelling of CCK-A receptors.

Recently, the primary structure of the cholecystokinin A-type (CCK-A) receptor has been determined. From the Kyte-Doolittle-predicted hydrophobic stretches of this sequence and the transmembrane domains of bacteriorhodopsin, a membrane-bound protein of known tertiary structure, a three-dimensional model of the membrane-embedded part of this receptor was built. Subsequently, the modelled receptor pore was searched for a binding site that matches the structural and conformational characteristics of the parent classes of the antagonists devazepide and lorglumide. In addition, the binding mode of hybrid analogues of these reference compounds was examined. The proposed antagonist, binding site includes regions in which hydrophobic, hydrogen-bonding and aromatic interactions stabilize the receptor-ligand complex.

Amino Acid Sequence↗
PubMed1989

Cholecystokinin augmentation of 'surgical' pancreatitis. Benefits of receptor blockade.

The management of acute pancreatitis has not changed appreciably throughout several decades. Recent evidence has suggested that cholecystokinin (CCK) may play an important role in pancreatic disease. Investigations into the precise role of CCK in acute pancreatitis have been hampered by the lack of a specific CCK receptor antagonist. Using a newly described, highly potent and specific CCK receptor antagonist, L-364,718, the effect of CCK in two models of acute "surgical" pancreatitis was examined: (1) the bile salt ductal perfusion model in the rat and (2) a traumatic model in the guinea pig. At a suboptimal dose for pancreatic enzyme secretion (25 pmol/kg/h), CCK was found to potentiate the severity of the ensuing pancreatitis in both models. Continuous CCK receptor blockade with L-364,718 (25 nmol/kg/h) improved biochemical, morphologic, and survival indexes. This study suggests that physiologic levels of CCK play an important permissive role in the evolution of acute pancreatitis. The use of L-364,718 as an investigative probe or therapeutic tool for acute pancreatitis is worthy of further consideration.

Acute Disease↗
PubMed1997

Sustained gallbladder stasis promotes cholesterol gallstone formation in the ground squirrel.

Although gallbladder stasis exists in most patients with cholesterol gallstones, it is unknown whether stasis is a causative factor of gallstone disease or merely a consequence of it. We studied the impact of sustained gallbladder stasis induced by a cholecystokinin (CCK)-A receptor antagonist (MK-329) on gallstone formation in ground squirrels fed either a trace or a high-cholesterol diet. MK-329 markedly inhibited gallbladder contraction in vitro in response to CCK (at EC100, control: 3.6 +/- 0.5 vs. MK-329: 1.1 +/- 0.3 g; P < .05) and increased gallbladder fasting volume in vivo (control: 462 +/- 66 vs. MK-329: 1,004 +/- 121 microL; P < .05). Whereas the high-cholesterol diet alone (1%-cholesterol diet + placebo) increased the cholesterol saturation index (CSI) in control animals (trace-cholesterol diet + placebo), MK-329 significantly (P < .05) decreased the CSI in both hepatic and gallbladder bile in animals on the trace-(trace-cholesterol diet + MK-329) as well as on the high-cholesterol diets (1%-cholesterol diet + MK-329). The mucin content of the mucus layer on the epithelial surface of the gallbladder wall more than doubled (P < .05) with the high-cholesterol diet; adding MK-329 to the latter group produced a further 82% increase (P < .05). The cholesterol diet + MK-329 group had the highest (100%) incidence of cholesterol crystals that were evident in fresh gallbladder bile, coincident with a shortened nucleation time (2.5 +/- 0.6 days; P < .05 vs. the cholesterol diet + placebo group, 5.8 +/- 1.0 days or the other 2 groups, >21 days). Bile from animals on the trace-cholesterol diet, whether or not receiving MK-329, lacked crystals in bile and exhibited a normal nucleation time (>21 days). Thus, stasis per se may lower the CSI, but its detrimental effect on the gallbladder predominates locally, and so accelerates cholesterol crystal formation in this model.

Animals↗
PubMed1992

Characterization of interactions between CCK-33 and CCK receptors in isolated dispersed pancreatic acini.

In isolated dispersed pancreatic acini, we have characterized the interactions between cholecystokinin (CCK) and CCK receptors by simultaneously measuring CCK-33 immunoreactivity and CCK bioactivity. Incubation of acinar cells with CCK-33 at cell density of 0.2-0.3 mg acinar protein per ml resulted in stimulation of amylase release concomitant with significant and time-dependent decrease of the immunoreactive CCK. With L-364,718 (0.1 microM), a specific CCK receptor antagonist, immunoreactive CCK levels in the media were not significantly altered during incubation; however, CCK-stimulated amylase release was almost completely abolished (94% inhibition). Vasoactive intestinal peptide (1 nM) significantly potentiated CCK stimulated amylase release without affecting immunoreactive CCK in the media. Insulin (167 nM) did not affect the CCK stimulated amylase release or immunoreactive CCK in the media. Incubation of acinar cells with CCK-33 at 4 degrees C did not affect the levels of immunoreactive CCK; however, a significant change in levels of immunoreactive CCK were found at 37 degrees C at 90 min. Incubation of cell free medium with CCK-33 in the presence or absence of secreted enzymes revealed no changes in CCK immunoreactivity in the medium at 90 min. Addition of bacitracin in the incubation media did not affect the CCK immunoreactivity or bioactivity. These findings indicate that in isolated rat pancreatic acini, CCK-33 stimulates amylase release through a receptor that is specifically blocked by L-364,718. Specificity of the interactions of CCK-33 with acinar cells in the media appears to be receptor-mediated and time- and temperature-dependent.

Amylases↗
PubMed1991

Receptor selectivity of cholecystokinin effects on mesoaccumbens dopamine neurons.

Extracellular recording techniques were combined with antidromic stimulation to examine the effects of C-terminal cholecystokinin (CCK) fragments and CCK antagonists on the activity of identified mesoaccumbens dopamine (MADA) neurons in chloral hydrate-anesthetized rats. These experiments were designed to determine the receptor selectivity of sulfated CCK octapeptide (CCK-8S) effects on MADA cells. Neither CCK tetrapeptide (CCK-4) nor unsulfated CCK octapeptide (CCK-8U) significantly altered MADA cell basal firing rate or responsiveness to the inhibitory effects of the D2 DA agonist quinpirole. As reported previously for ventral tegmental area DA cells, CCK-8S produced increases or decreases in the firing rate of most MADA cells sampled. CCK-8S also enhanced the sensitivity of MADA neurons to quinpirole-induced inhibition. This increase in sensitivity to quinpirole was blocked by pretreatment with the nonselective CCK receptor antagonist proglumide and the preferential CCK-A receptor antagonist CR 1409 but not by the preferential CCK-B receptor antagonist L-365,260. The inactivity of CCK-4 and CCK-8U in these tests and the results with the antagonists suggest that the effects of CCK-8S on MADA neuronal activity are mediated by CCK-A receptors.

Animals↗
PubMed1993

Comparison of the effects of the cholecystokinin-B receptor antagonist, PD 134308, and the cholecystokinin-A receptor antagonist, L-364,718, on dopamine neuronal activity in the substantia nigra and ventral tegmental area.

Extracellular single-unit recording techniques were used to study the effects of the cholecystokinin-A (CCK-A) antagonist, L-364,718, and the CCK-B antagonist, PD 134308, on DA neuronal activity in chloral hydrate anesthetized rats. Neither L-364,718 (0.1-1.6 mg/kg i.v.) nor PD 134308 (0.1-6.4 mg/kg) altered the basal firing rate of substantia nigra or ventral tegmental area DA neurons. The ability of PD 134308 and L-364,718 to alter the apomorphine-induced inhibition of substantia nigra DA neurons was assessed. Pretreatment with L-364,718 (0.6 or 4.16 mg/kg i.v.) did not shift the apomorphine dose-response curve (0.5-32 micrograms/kg i.v.). In contrast, PD 134308 (0.6 or 6.4 mg/kg i.v.) produced dose-related, significant shifts to the right of the apomorphine dose-response curves. However, these effects were small in comparison to the haloperidol (0.1 mg/kg i.p.)-induced shift of the apomorphine curve. These data suggest that in the substantia nigra there may be a tonic level of CCK release that, through actions on CCK-B receptors, may modulate DA agonist-induced inhibition of DA neuronal activity.

Animals↗
PubMed1994

The seventh transmembrane domain of gastrin/CCK receptors contributes to non-peptide antagonist binding.

The related rat cholecystokinin (CCK)-A and gastrin/CCK-B receptors can be selectively blocked by the antagonists L364718 and L365260, respectively. In order to determine receptor domains which are important in conferring specificity for L365260 and L364718 we constructed by overlap-PCR a rat gastrin/CCK-B receptor chimaera which contained the seventh transmembrane domain of the rat CCK-A receptor. Receptor binding assays on transiently transfected COS cells demonstrated a selective reduction in the affinity of the chimaeric receptor for L364718, so that the L365260 and L364718 affinities were of a similar order. Since the chimaera differs from the wild-type gastrin/CCK-B receptor by only six amino acids we conclude that one or more of these six amino acids contributes to L364718 binding and that the affinity determinants of L365260 and L364718 must, at least in part, be different. Furthermore, the affinity of the chimaera for gastrin is essentially the same as the gastrin/CCK-B receptor, indicating that the six different amino acids probably do not contribute to peptide agonist binding.

Animals↗
PubMed1994

Extrapancreatic cholinergic nerves mediate cholecystokinin-stimulated pancreatic polypeptide release.

Although vagal cholinergic stimulation is the predominant regulatory mechanism governing the release of pancreatic polypeptide (PP), recent studies suggest that cholecystokinin (CCK) is also an important mediator. The present study examined the role of cholinergic neural pathways in the PP response to exogenous CCK-8 using a selectively denervated canine pancreas model. Chronic denervated pancreatic preparations were created in five dogs, while five dogs underwent sham laparotomy as controls. On study days, the fasted animals were infused intravenous CCK-8 (40 or 400 pmole/kg/hr) for 60 min both with and without atropine (20 micrograms/kg/hr). Plasma was collected at 20-min intervals and PP levels were determined by radioimmunoassay. CCK-8 elicited a dose-dependent increase in circulating PP in dogs with a neurally intact pancreas. Atropine and pancreatic denervation eliminated the PP response to CCK-8 at 40 pmole/kg/hr (P < 0.01) and inhibited the PP response to CCK-8 at 400 pmole/kg/hr (P < 0.05). The high dose of CCK-8 still elicited a small PP response in the denervated dogs (P < 0.05), which was subsequently abolished by the addition of atropine. These findings suggest that extrapancreatic cholinergic nerves are essential components of CCK-stimulated PP release, and that intrapancreatic cholinergic activity may play a limited role.

Animals↗
PubMed1995

Cholecystokinin effect on human lymphocyte ionized calcium and mitogenesis.

Cholecystokinin (CCK) is a peptide present in large amounts in gut, brain, and neurons innervating lymphatic tissues. Plasma CCK levels increase in enterally alimented patients. Enteral alimentation is also associated with enhanced immune function. The effects of CCK and a CCK antagonist were studied on human peripheral blood mononuclear cells (H-PBMC), lymphocyte intracellular ionized calcium ([Ca2+]i), and lymphocyte mitogenesis. CCK receptors transduce their signal via the release of [Ca2+]i. CCK octapeptide caused a specific increase in [Ca2+]i measured by Fura-2 fluorometry in H-PBMC and human T helper lymphocytes. Neither gastrin-17 nor pentagastrin produced a signal. While the highly specific CCK antagonist MK329 blocked the CCK [Ca2+]i signal, it had no effect on the PHA-mediated signal. At high dosages (10(-7)-10(-8) M), CCK was a comitogen with "complete" lymphocyte mitogens such as anti-CD3 monoclonal antibody (mAb) or low-dose PHA, but not for "partial" mitogens such as phorbol esters. CCK comitogenic effect occurred even in the presence of cyclosporine. CCK radioimmunoassay demonstrated that H-PBMC contained CCK and that anti-CD3 mAb- or PHA-mediated H-PBMC mitogenesis caused release of CCK. MK329 blocked PHA and anti-CD3 mAb mitogenesis and CCK comitogenic effects. We conclude that CCK octapeptide may be a coregulator of lymphocyte Ca2+ activation signals. The immunologically beneficial effect of enteral nutrition may, in part, be mediated by increased levels of CCK.

Benzodiazepinones↗
PubMed1996

Exocrine effects of the CCK antagonist L-364,718 in canine pancreatic autografts.

This study evaluated the effect of the cholecystokinin antagonist L-364,718 on exocrine secretion in canine pancreatic autografts with pancreaticocystostomies. Urinary (autograft) amylase (U/min) and bicarbonate (mmole/min) secretion, over a 6 hr interval, were determined in the basal state (Group A), after a bolus injection of 20 nmoles/kg of L-364,718 (Group B), during a continuous cholecystokinin octapeptide (OP-CCK) infusion at 125 ng/kg/hr either alone (Group C), with a bolus injection of 20 nmoles/kg (Group D), or 30 nmoles/kg (Group E), of L-364,718 1 hr before initiating OP-CCK, or 20 nmoles/kg of L-364,718 1 hr after initiating OP-CCK (Group F). L-364,718 had no effect on basal or OP-CCK-stimulated secretion of bicarbonate. Basal amylase secretion was decreased 1 hr after L-364,718 and remained significantly lower than controls throughout the study interval. When compared to Group C (280.3 +/- 48.6), OP-CCK-stimulated amylase secretion was significantly lower for the first hour after L-364,718 in both Group D (157 +/- 46.7) and Group E (31.9 +/- 11.6). In Group E, 2, 3, and 4 hr post-L-364,718 amylase releases were 60.2 +/- 19.7, 77.7 +/- 25.1, and 87.2 +/- 28.3 compared to 335.5 +/- 85.9, 291.0 +/- 21.8, and 289.9 +/- 45.7 in Group C indicating a sustained significant inhibition of stimulated autograft amylase secretion with the higher L-364,718 dosage. In Group F, no significant change in amylase secretion was demonstrated, indicating that L-364,718 must be administered prior to CCK stimulation to be effective. These studies demonstrate that L-364,718 has a dose dependent, inhibitory effect on basal, and OP-CCK-stimulated amylase secretion in a denervated autograft model. The therapeutic potential of L-364,718 and other CCK receptor antagonists in pancreatic transplantation warrants further study.

Amylases↗