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At least 343 records · Page 19Linked to original sources
PubMed1998

Diurnal pattern of rat pancreatic acinar cell replication.

Fully differentiated pancreatic acinar cells can enter the cell cycle under appropriate conditions in the rat. The aim of this study was to analyse the diurnal pattern of acinar cell proliferation as a function of food intake and the release of cholecystokinin (CCK), because the peptide hormone CCK is a major physiological regulator of rat pancreatic acinar cell replication. Pancreatic acinar cell replication was quantitated using an antibody against the S-phase marker proliferating cell nuclear antigen (PCNA). In addition, acinar cells in S-phase were detected after injecting bromodeoxyuridine (BrdU) and subsequent immunohistochemical staining of BrdU-positive nuclei. Rat pancreata were analysed during the day under standard diet conditions, as well as after various schedules of fasting and refeeding and after the application of the CCK receptor antagonist L-364,718. Between 6 a.m. and 6 p.m., the PCNA labeling index was 4.4+/-0.9%, while between 9 p.m. and 3 a.m. the PCNA labeling index was elevated and reached peak values of 11.4% (mean value: 7.8+/-2.5%) around midnight. BrdU-positive cells also doubled around midnight, compared to the 9:00 a.m. value. In fasted rats, acinar cell proliferation was completely suppressed and this suppression could be overcome by injection of the CCK analog cerulein. In addition, the CCK antagonist L-364,718 led to the same results as fasting. Here we show for the first time that there is a diurnal pattern of pancreatic acinar cell proliferation in rats, which is dependent on food intake and is mediated by CCK.

Animals↗
PubMed2003

Medical therapy for chronic pancreatitis pain.

Chronic pancreatitis should be considered in all patients with unexplained abdominal pain. Management of abdominal pain in these patients continues to pose a formidable challenge. The importance of small duct disease without radiographic abnormalities is now a well-established concept. It is meaningful to determine whether patients with chronic pancreatitis have small duct or large duct disease because this distinction has therapeutic implications. Diagnostic evaluation should begin with simple noninvasive and inexpensive tests like serum trypsinogen and fecal elastase, to be followed where appropriate by more complicated measures such as the secretin hormone stimulation test, especially in patients with suspected small duct disease. No universal causal treatment is available. Non-enteric-coated enzyme preparations are useful for treatment of pain, whereas enteric-coated enzyme preparations are preferred for steatorrhea. Octreotide is used increasingly for abdominal pain that is unresponsive to pancreatic enzyme therapy. When medical therapy for chronic pancreatitis pain has failed, endoscopic therapy, endoscopic ultrasound-guided celiac plexus block, and thoracoscopic splanchnicectomy, performed by experts, may be considered for a highly selected patient population. Surgical ductal decompression is appropriate in patients with considerable pancreatic ductal dilation. The role and efficacy of cholecystokinin-receptor antagonists, antioxidants, and antidepressant drugs remain to be defined.

Abdominal Pain↗
PubMed1993

Cibacron blue-induced enhancement of agonist binding to cholecystokinin (CCK) receptors in solubilized pancreatic membranes.

The pancreatic receptor for cholecystokinin (CCK) typifies many G protein-coupled receptors in that its ability to bind agonist can be reduced by GTP or the solubilization of membranes. We found, however, that a dye, cibacron blue, caused up to a 6-fold increase in binding of the CCK receptor agonist, 125I-CCK-8, to rat pancreatic membranes solubilized with digitonin. Binding optimally enhanced in this manner was comparable to binding of 125I-CCK-8 to native membranes with respect to time-course, maximal amount bound, reversibility, and sensitivity to inhibition by various CCK receptor ligands. Increases in affinity of the CCK receptor for CCK-8 accounted fully for the enhancement of binding of 125I-CCK-8. Cibacron blue did not enhance binding of 125I-CCK-8 to native membranes, and also failed to enhance binding of the CCK receptor antagonist, [3H]L-364,718, to solubilized or native membranes. The ability of cibacron blue to enhance binding of agonist but not that of antagonist suggests that this dye may mimic or perhaps stimulate the effects of G protein on CCK receptors. Such a phenomenon may provide new insights into the mechanisms by which receptors distinguish agonists from antagonists.

Animals↗
PubMed1992

Effects of CCK-8 on the cytoplasmic free calcium concentration in isolated rat islet cells.

The C-terminal octapeptide of cholecystokinin (CCK-8) is known to stimulate insulin secretion. We examined its effects on the cytoplasmic free calcium concentration ([Ca2+]IC) in isolated rat pancreatic islet cells. At 8.3 mM glucose and 1.28 mM Ca2+, CCK-8 (100 nM) rapidly increased [Ca2+]IC to a short-lived peak, whereafter the [Ca2+]IC, within 1.5 minutes, fell to values below baseline. CCK-8 also rapidly increased the [Ca2+]IC at 3.3 mM glucose and in a calcium deficient medium. However, either at low glucose or in the absence of extracellular Ca2+, the post-peak [Ca2+]IC did not fall below baseline levels. The CCKA receptor antagonist, L-364,718 (20 nM), inhibited the effects of CCK-8 on [Ca2+]IC. The results suggest that CCK-8 in islet cells liberates calcium from intracellular stores by activating CCKA receptors.

Animals↗
PubMed1987

Characterization of [3H](+/-)L-364,718 binding to solubilized cholecystokinin (CCK) receptors of rat pancreas.

The binding of [3H](+/-)L-364,718 (3S(-)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl )-1H-indole-2-carboxamide), an extremely potent nonpeptide cholecystokinin (CCK) receptor antagonist, to digitonin-solubilized CCK receptors from rat pancreas was characterized. [3H](+/-)L-364,718 binding to digitonin-solubilized receptors was assayed using polyethylene glycol precipitation followed by rapid filtration to separate free and bound [3H](+/-)L-364,718. Specific [3H](+/-)L-364,718 binding to solubilized receptors was dependent on the digitonin and receptor concentration and, under optimal conditions, represented greater than 90% of the total binding. Scatchard analysis indicated a single class of binding sites with a Kd of 0.53 nM and a Bmax of 3.1 pmol/mg protein. Specific [3H](+/-)L-364,718 binding to solubilized CCK receptors was inhibited by both CCK receptor agonists and antagonists in a stereospecific manner. After solubilization, the affinities of various antagonists to displace specific [3H](+/-)L-364,718 binding were similar to those obtained with membrane-bound receptors; however, the affinities of CCK agonists were reduced 10-100 times. Collectively, the data presented indicate that [3H](+/-)L-364,718 represents a new antagonist ligand which has apparent advantages over the agonist ligand [125I]CCK in assaying digitonin-solubilized receptors. Gel filtration of the digitonin-solubilized CCK receptors followed by [3H](+/-)L-364,718 binding determinations revealed an estimated molecular weight of 400,000 daltons.

Animals↗
PubMed1991

"Gastrin" and "CCK" receptors on histamine- and somatostatin-containing cells from rabbit fundic mucosa-II. Characterization by means of selective antagonists (L-364,718 and L-365,260).

In the preceding paper, by means of selective agonists to gastrin (HG-17) and cholecystokinin (CCK-39), we evidenced the existence of "gastrin-type" receptors that could regulate histamine release and "CCK-type" receptors that could stimulate somatostatin release in isolated rabbit fundic non-parietal cells (F1 cells). Furthermore, these receptors could induce phosphoinositide breakdown. To confirm the involvement of these receptor types in these biological and biochemical processes, we used selective antagonists, L-364,718 (3-(benzoylamino)-benzodiazepine) specific to "CCK-A-type" receptor and L-365,260 (3-(acylamino)-benzodiazepine) specific to "gastrin/CCK-B-type" receptor. Neither L-364,718 nor L-365,260 alone caused any significant stimulation of [3H]inositol phosphate ([3H]InsP) production and release of histamine or somatostatin-like immunoreactivity (SLI). Each analogue inhibited in a dose-dependent manner [125I]HG-17 or [125I]CCK-39 binding to F1 cells, [3H]InsP accumulation and histamine and SLI release stimulated by HG-17 or CCK-39. L-365,260 appeared to be 30-70 times more potent than L-364,718 in inhibiting [125I]HG-17 binding to F1 cells, as well as HG-17-induced [3H]InsP accumulation and HG-17-or CCK-39-enhanced histamine release (IC50 values: approximately 5-20 nM for L-365,260 and approximately 200-1500 nM for L-364,718). In contrast, L-364,718 was 200 to 400 times more potent than L-365,260 in inhibiting [125I]CCK-39 binding to F1 cells, CCK-39-induced [3H]-InsP accumulation and SLI release stimulated by CCK-39 or HG-17 (IC50 values: approximately 0.3-1 nM for L-364,718 and 100-200 nM for L-365,260). These results led to conclude: (i) the existence of a "gastrin-type" receptor related to histamine release: (ii) the existence of a "CCK-A-type" receptor related to somatostatin release; (iii) the existence of "gastrin type" and "CCK-A-type" receptors linked to the phosphoinositide breakdown pathway.

Animals↗
PubMed1989

Brain CCK-B receptors mediate the suppression of dopamine release by cholecystokinin.

The sulfated octapeptide of cholecystokinin (CCK-8S) and CCK fragments were administered to mice to determine the subtype and central versus peripheral location of the CCK receptor that modulates dopamine release in the neostriatum. Dopamine release was decreased when unsulfated CCK (CCK-8U) or the butoxycarbonyl tetrapeptide of CCK (t-boc-CCK-4) was infused into the brain ventricles but not when injected subcutaneously. These CCK fragments bind to the brain-type (CCK-B) but not alimentary-type (CCK-A) receptor. Centrally or peripherally administered CCK-8S also lowered dopamine release and this action was not blocked by the selective CCK-A receptor antagonist, L 364,718. The increase in dopamine release following amphetamine administration was attenuated by central injections of t-boc-CCK-4, CCK-8U, or CCK-8S, and this action of CCK-8S was not prevented by L 364,718. These data are the first to demonstrate that CCK-B receptors in brain mediate the suppression of dopamine release by cholecystokinin, especially when release is augmented. CCK-B receptor agonists should be useful for the treatment of psychiatric conditions that result from hyperactive dopamine neurons.

Amphetamines↗
PubMed1990

CCK8 neurons of the ventromedial (VMH) hypothalamus mediate the upper gut motor changes associated with feeding in rats.

The effect of microinfusions of cholecystokinin octapeptide (CCK8) and its antagonist L364,718 on duodenal and jejunal motility were evaluated by electromyography in fasted and fed rats. The rats were chronically fitted with electrodes implanted on the duodeno-jejunal wall. Steel cannulas were placed bilaterally in either the ventromedial (VMH) and lateral (LHA) hypothalamus. In 8 h fasted rats, microinfusion of CCK8 (1 ng/kg) into the VMH disrupted the migrating myoelectric complex (MMC) and replaced it by irregular spiking activity for 45.0 +/- 4.9 min at the duodenal level without affecting the jejunal MMC pattern. The duration of these effects were dose-related between 1 and 50 ng/kg. When injected into the LHA at 1, 10 or 50 ng/kg, CCK8 had no effect on either duodenal or jejunal motility. When infused bilaterally into the VMH 10 min before feeding, L364,718 (1 or 10 micrograms/kg) significantly reduced the duration of the postprandial disruption of MMCs by 29.1% and 35.9%, respectively, in the duodenum but not the jejunum (P less than 0.05). Infused into the LHA at similar and higher dosages (1 and 10 micrograms/kg) L364,718 had no effect on the duration of the duodeno-jejunal fed pattern. These results suggest that, in rats, (i) CCK8 is involved in the maintenance of the typical postprandial disruption of duodenal MMCs observed after a meal, and (ii) these effects are selectively mediated through CCK8 receptors located in the ventromedial hypothalamic nuclei.

Animals↗
PubMed1990

Differentiation of central cholecystokinin receptor binding sites using the non-peptide antagonists MK-329 and L-365,260.

Cholecystokinin (CCK) receptor binding was measured in rodent and primate brain and spinal cord using 125I-Bolton Hunter CCK-8 (125I-BH-CCK) and the selective non-peptide CCK antagonists MK-329 and L-365,260. In homogenate binding studies, L-365,260 displayed nanomolar affinity for CCK-B receptors in the cerebral cortex of several species including man (pIC50 congruent to 8.2) but showed low affinity for CCK-A receptors in the rat pancreas (pIC50 congruent to 6.3). By contrast, the CCK-A antagonist MK-329 showed the reverse selectivity (cortex: pIC50 congruent to 6.9, pancreas: pIC50 = 9.6). In autoradiographs of rat and monkey brain. 125I-BH-CCK binding was localized regionally with high levels being detected in the cerebral cortex, basal ganglia and some mid- and hindbrain nuclei. Specific 125I-BH-CCK binding was also localized to the substantia gelatinosa of the rat, monkey and human spinal cord. L-365,260 inhibited binding to most areas of the brain, but in the rat medial nucleus tractus solitarii and the monkey nucleus tractus solitarii. dorsomedial nucleus and infundibular hypothalamic nuclei together with the dorsomedial aspects of the caudate nucleus, where CCK-A sites are present, L-365,260 failed to displace all 125I-BH-CCK binding. In the primate spinal cord, L-365,260 was a relatively weak inhibitor of 125I-BH-CCK binding (pIC50 congruent to 6.0) whereas MK-329 showed high affinity for the CCK-A sites present there (pIC50 congruent to 9.6).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Cholecystokinin-induced protection of cultured cortical neurons against glutamate neurotoxicity.

The effects of cholecystokinin (CCK) on glutamate-induced neurotoxicity were examined using cultured rat cortical neurons. Brief exposure of glutamate followed by an incubation with normal solution for more than 60 min reduced cell viability by 60-70%, compared with control values. Glutamate-induced neurotoxicity was significantly inhibited by MK-801 and ketamine, which are non-competitive blockers of N-methyl-D-aspartate (NMDA) receptors. Octapeptide CCK-8S and CCK-related decapeptide ceruletide at concentrations of 10(-9)-10(-7) M dose-dependently reduced glutamate-induced neurotoxicity. A desulfated analog CCK-8NS, which acts selectively as an antagonist of CCKB receptors, also reduced glutamate neurotoxicity. The neuroprotective effects of CCK were antagonized by L-365260, a CCKB receptor antagonist, but not by L-364718, a CCKA receptor antagonist. These results suggest that CCK protects cortical neurons against NMDA receptor-mediated glutamate neurotoxicity via CCKB receptors.

Animals↗
PubMed1993

Characterization of type A and type B CCK receptor binding sites in rat vagus nerve.

We employed quantitative receptor autoradiography to analyze pharmacological properties of 125I-Bolton Hunter cholecystokinin (CCK-8)-labeled binding sites in sections of rat cervical vagus nerve that had been ligated 24 h prior to extraction. Binding densities were detected in segments of nerve proximal and distal to the ligature. Analysis was confined to proximal segments. Saturation and competitive binding studies were carried out using sulphated CCK-8 and two selective CCK receptor antagonists: MK-329, to define type-A (CCKA) binding sites; and, L-365,260, to define type-B (CCKB) binding sites. Sulphated CCK-8 was the most potent inhibitor of vagal 125I-CCK binding (IC50 = 2 nM). Nonlinear curve fitting analysis of the CCK binding data favored the presence of a single class of vagal CCK receptors (KDi = 1 nM). However, both MK-329 (IC50 = 18 nM) and L-365,260 (IC50 = 45 nM) competed for vagal 125I-CCK binding indicating the presence of CCKA and CCKB binding sites. Co-analysis of the antagonist binding data suggested that CCKA and CCKB receptors were transported in equal concentrations within the vagus. MK-329 bound with high affinity to CCKA sites (Ki = 3 nM) and low-affinity to CCKB sites (Ki = 462 nM) while L-365,260 bound with high affinity to CCKB sites (Ki = 10 nM) and low-affinity to CCKA sites (Ki = 775 nM). These same ligands were used to characterize the specificity of 125I-CCK binding in the medial and lateral divisions of the nucleus of the solitary tract (NTS), two regions innervated by primary vagal afferents carrying CCK receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Effects of systemically administered ceruletide on the in vivo release and metabolism of dopamine in the medial prefrontal cortex of awake, freely moving rats: an in vivo microdialysis study.

The effects of the cholecystokinin octapeptide-related peptide, ceruletide (CER), on the in vivo release and metabolism of dopamine (DA) in the medial prefrontal cortex were examined in awake, freely moving rats, using in vivo microdialysis. Subcutaneously administered CER (200 micrograms/kg) increased extracellular levels of DA, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA), indicating that extracellular levels of DOPAC and HVA may reflect DA release in the medial prefrontal cortex. Bilateral subdiaphragmatic vagotomy markedly attenuated the CER-induced effect, but did not abolish it completely. CER (10(-7) and 10(-10) M), applied locally via the dialysis tube, had no effect on the extracellular levels of either DOPAC or HVA. The CCK-A receptor antagonist, L-364,718 (3 mg/kg, i.p.), completely prevented CER-induced increases in the extracellular levels of DOPAC and HVA. The CCK-B antagonist, L-365,260 (3 mg/kg, i.p.), however, given 1 h before the CER treatment, slightly attenuated the CER-induced increase in the extracellular levels of DOPAC, but not the CER-induced increase in HVA, 60-180 min after the treatment. These findings indicate that systemically administered CER modulates the in vivo release and metabolism of DA in the medial prefrontal cortex. We suggest that systemically administered CER exerts its action on both vagal afferent nerves and the area postrema via CCK-A receptors, thus enhancing the in vivo release and metabolism of DA in the medial prefrontal cortex.

Administration, Topical↗
PubMed1987

Fasting and L-364,718 prevent cholecystokinin-induced elevations of plasma insulin levels.

Sulfated CCK-8 but not non-sulfated CCK-8 induced a dose-dependent increase in plasma insulin levels in fed mice. In fasted mice, however, the CCK peptides caused a non-significant to minimal elevation of plasma insulin. Refeeding fasted mice for 1 h prior to CCK-8-S administration was sufficient to cause a significant elevation of plasma insulin levels. The peripheral CCK antagonist, L-364,718, prevented the CCK-8-S-induced elevation of plasma insulin observed in fed mice. In conclusion, CCK produces a nutrition-dependent increase in plasma insulin levels in vivo via an action upon peripheral CCK receptors.

Animals↗
PubMed1988

Enhancement of morphine analgesia and prevention of morphine tolerance in the rat by the cholecystokinin antagonist L-364,718.

The potent and selective non-peptide cholecystokinin (CCK) antagonist L-364,718 (0.5-2.0 mg/kg s.c.) enhanced the analgesia induced by acute morphine treatment in the rat tail flick test. Chronic treatment with L-364,718 (1.0 mg/kg) prevented the development of tolerance to morphine analgesia (after a 6 day period of morphine treatment) but did not influence the onset of opioid dependence. Since L-364,718 is considerably more potent in inhibiting CCK binding to peripheral tissues than to brain membranes its interaction with morphine is surprising. The exact locus of this interaction, or whether it involves 'peripheral-type' (CCK-A) or 'central-type' (CCK-B) receptors is not known.

Analgesia↗
PubMed1988

The cholecystokinin antagonist L-364,718 inhibits the action of cholecystokinin but not bombesin on rat pancreatic secretion in vivo.

The action of an antagonist of peripheral CCK receptors, L-364,718 on CCK8 and bombesin-induced pancreatic exocrine secretion was studied in anaesthetized rats. Both CCK8 and bombesin increased the rate of flow and rate of enzyme secretion from the pancreas. Intravenous L-364,718 inhibited the actions of CCK8, but not those of bombesin. It is concluded that bombesin acts on the exocrine pancreas directly rather than through the release of CCK.

Animals↗
PubMed1988

Effect of metoclopramide, bethanechol and the cholecystokinin receptor antagonist, L-364,718, on gastric emptying in the rat.

The prokinetic effects of metoclopramide, bethanechol and L-364,718 on a semisolid meal and solid pellet gastric emptying were evaluated and compared. Each compound increased the rate of meal emptying as measured 90 min post-dose. L-364,718, a non-peptide CCK antagonist, was the most potent of these three agents with statistically significant activity observed at 0.03, 0.1 and 0.3 mg/kg p.o. Only metoclopramide significantly enhanced pellet emptying in a dose-dependent manner (3-30 mg/kg p.o.). The effects of each test agent and the potential physiologic role of cholecystokinin in regulating gastric emptying are discussed.

Animals↗