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At least 325 records · Page 18Linked to original sources
PubMed1996

Effect of L-364,718 on pancreatic endocrine function following partial pancreatectomy.

This study was designed to determine the effect of a potent cholecystokinin antagonist, L-364,718, on canine pancreatic endocrine function following partial pancreatectomy. Plasma glucose, insulin, and glucagon were determined over a 2-hr interval following an intravenous bolus of 0.5 g/kg glucose in a 50% solution. The following groups were established: normal animals (group A, n = 5), normal animals pretreated with 20 nmole/kg L-364,178 (group B, n = 5), partially pancreatectomized animals (group C, n = 5), and partially pancreatectomized animals pretreated with 20 nmole/kg L-364,178 (group D, n = 5). In contrast to animals with an intact pancreas, pretreatment with L-364,718 following partial pancreatectomy resulted in a significant decrease in peak insulin (group C = 132.8 +/- 13.0 microU/ml vs Group D = 90.4 +/- 16.1 microU/ml, P < 0.05) and the basal-to-peak insulin difference (group C = 111.9 +/- 11.5 microU/ml vs group D = 77.5 +/- 16.6 microU/ml, P < 0.05). Despite this, the rate of glucose utilization (K value) was significantly increased in the partially pancreatectomized animals given the antagonist (group C = -1.22 +/- 0.22%/min vs group D = -2.79 +/- 0.427%/min) and there were no significant differences in basal or peak glucose when comparing the groups given L-364,718 with the groups given placebo (group A vs B and group C vs D). Thus, the CCK antagonist L-364,718 significantly decreases peak insulin in partially pancreatectomized animals but not in nonoperative control animals. There is a paradoxical increase in the rate of glucose utilization but no effect on glucose homeostasis. The effect of this antagonist in other models of reduced islet cell reserve (i.e., pancreas transplantation) remains to be determined.

Animals↗
PubMed1997

Evidence that A8947 enhances pancreas growth via a trypsin inhibitor mechanism.

A8947 is a member of the sulfonyl urea class of compounds and is the active ingredient in a commercial broad leaf herbicide. This compound has been shown to produce pancreatic hypertrophy in rats, mice, and dogs. The objectives of this study were to investigate the mechanism(s) for the A8947 induction of pancreatic acinar cell hypertrophy and proliferation and to evaluate whether these pancreatic changes are reversible. A8947 was fed to male Crl:CD BR rats for up to 28 days (0, 300, 10,000, 30,000 ppm) or 56 days (0, 30,000 ppm). Rats were terminated on Test Days 7, 14, and 28 to assess the time course and dose response for the A8947-induced pancreatic changes, while rats terminated on Test Day 56 were used to assesss the reversibility of the pancreas effects at 30,000 ppm A8947. A8947 produced significant increases in pancreatic weight and acinar cell proliferation and diffuse acinar cell hypertrophy in 7 days at 10,000 and 30,000 ppm dose levels. By Day 14, absolute pancreas weights in the 10,000 and 30,000 ppm groups were maximally increased and remained at these levels throughout the study. In contrast, acinar cell proliferation in the 30,000 ppm group was still elevated at Test Day 14, but attenuated relative to the 7-day response, and returned to control levels by Test Day 28. No effects were observed at 300 ppm after a 28-day exposure period, while complete reversibility of A8947-induced pancreatic effects was demonstrated at 30,000 ppm following a 1-month recovery period (Test Day 56). Cholecystokinin (CCK) levels were increased by A8947 and closely followed the time course for pancreatic changes. MK-329, a specific CCKA receptor antagonist, completely ablated the ability of 30,000 ppm A8947 to increase pancreas weight following 7 days of exposure. A8947 did not bind the CCKA receptor in a receptor competition assay, negating any potential agonist mechanism. A8947 did, however, inhibit trypsin in vitro, suggesting a mechanism of action similar to that of raw soy protein, in which trypsin inhibition in vivo results in increased CCK levels followed by pancreatic acinar cell hypertrophy and proliferation.

Animals↗
PubMed1989

Chronic neuroleptic-induced mouth movements in the rat: suppression by CCK and selective dopamine D1 and D2 receptor antagonists.

Fluphenazine decanoate (25 mg/kg IM every 3 weeks x 6) resulted in spontaneous vacuous chewing mouth movements and jaw tremor in male Sprague-Dawley rats. These movements could be suppressed by the selective D1 or D2 dopamine antagonists SCH 23390 (0.5 mg/kg) and raclopride (0.5 mg/kg), respectively, and by CCK-8S (50 micrograms/kg). Fluphenazine-induced mouth movements were unaffected by the selective CCK antagonist MK-329, and by a dose of physostigmine (50 micrograms/kg) sufficient to stimulate mouth movements in placebo treated rats. Scopolamine (0.1 mg/kg) suppressed spontaneous mouth movements in placebo-treated rats, but the effect on fluphenazine-induced mouth movements was not significant. A higher dose of scopolamine (0.5 mg/kg) did suppress the neuroleptic-induced mouth movements, but also induced hyperactivity, characterized by increased sniffing and grooming. These findings indicate that mouth movements resulting from the chronic administration of neuroleptics to the rat may serve as a useful pharmacological model of tardive dyskinesia in the human, and suggest that a relative increase of D1 activity as well as impaired CCK function may contribute to the pathogenesis of this disorder.

Animals↗
PubMed1994

Enhancement of the cytotoxicity of cisplatin by the cholecystokinin antagonist MK-329 in a human pancreatic cancer cell line.

Cholecystokinin (CCK) is an important trophic hormone for the pancreas, and CCK receptors are present on pancreatic carcinoma cells. We sought to determine whether either CCK itself or an antagonist of CCK could modulate the sensitivity of the human pancreatic cell line MIA-PaCa2 to cisplatin (DDP). The IC50 for a 1-h exposure to DDP was 35.3 +/- 3.2(SD) microM. Exposure to CCK8 octapeptide at physiologic and supra-physiologic concentrations did not alter the sensitivity of MIA-PaCa2 cells to DDP. The CCK receptor antagonist MK-329 was directly cytotoxic to the MIA-PaCa2 cells on a constant exposure schedule with an IC50 of 9.5 +/- 1.4 (SD) microM. MK-329 enhanced the sensitivity of MIA-PaCa2 cells to DDP by a factor of 3.5, and the interaction between DDP and MK-329 was shown to be synergistic by median-effect analysis. At a level of 50% cell kill, the combination index was 0.58 +/- 0.10. The ability of MK-329 to sensitize cells to DDP was schedule-dependent and required prolonged exposure to the antagonist following a 1-h exposure to DDP. MK-329 had no effect on the uptake of a radiolabeled analog of cisplatin ([3H]-dichloro(ethylenediamine)platinum) and did not affect intracellular glutathione content. MK-329 had no effect on the cell-cycle-phase distribution of MIA-PaCa2 cells and did not alter the DDP-induced cell-cycle perturbations. The cytotoxic effect of MK-329 and its ability to interact synergistically with DDP could not be reversed by CCK. We conclude that MK-329 is directly cytotoxic to pancreatic carcinoma cells and can enhance their sensitivity to DDP by a mechanism not related to its ability to antagonize the CCK receptor.

Antineoplastic Agents↗
PubMed1989

L-364,718, a new CCK antagonist, inhibits postprandial pancreatic secretion and PP release in dogs.

The effects of L-364,718, a new CCK receptor antagonist, on food-stimulated exocrine pancreatic secretion and plasma levels of PP, insulin, CCK, and gastrin were examined in four conscious dogs with pancreatic fistulas. Intravenous injections of L-364,718 (20 nmol/kg) significantly inhibited pancreatic protein and enzyme responses by food (33% inhibition) but not juice volume output. Both rapid and secondary prolonged postprandial rises of plasma PP were also significantly suppressed by L-364,718 (50% inhibition); however, plasma levels of insulin were not altered. Postprandial levels of gastrin were not affected by L-364,718 administration, whereas 3-hr integrated CCK response was significantly enhanced by L-364,718. This study indicates that L-364,718 inhibits pancreatic protein and enzyme secretion and the release of pancreatic polypeptide stimulated by food in conscious dogs. This inhibition might be due to the selective blockage of receptor binding of circulating CCK molecules. The results suggest that L-364,718 may be useful for the physiological and pathophysiological studies associated with CCK.

Animals↗
PubMed1990

Effects of CCK-receptor antagonists on CCK-stimulated pepsinogen secretion and calcium increase in isolated guinea pig gastric chief cells.

The effects of CCK-receptor antagonists such as dibutyryl cyclic GMP (dbcGMP), L-364,718, and CR1409 on COOH-terminal octapeptide of CCK (CCK-8)-stimulated chief cell responses were examined using isolated guinea pig gastric chief cells. L-364,718 and CR1409 inhibited CCK-8-stimulated pepsinogen secretion over the same concentration range as they inhibited CCK-8-stimulated increases in intracellular Ca2+ concentration ([Ca2+]i), respectively. Schild analysis of the CCK dose-response curve indicates that L-364,718 and CR1409 exert their inhibitory effects on CCK-8-stimulated chief cell responses in a competitive manner. By contrast, dbcGMP inhibited not only CCK-8- but also carbachol-stimulated pepsinogen secretion. Furthermore, dbcGMP inhibited CCK-8-stimulated pepsinogen secretion more potently than the increases in [Ca2+]i. These results suggest that L-364,718 and CR1409 act as CCK-receptor antagonists, but dbcGMP has another inhibitory effect on pepsinogen secretion in addition to the effect as a CCK-receptor antagonist in guinea pig gastric chief cells.

Animals↗
PubMed1990

Feline cholescintigraphy. Studies on role of cholecystokinin in regulation of gallbladder function.

Quantitative cholescintigraphy using technetium-99m-disofenin was employed to study the kinetics of gallbladder filling and emptying in cats. The radionuclide rapidly visualizes the gallbladder, with activity continuing to rise during the 60 minutes after injection. The gallbladder emptied in a dose-response manner to the intravenous administration of the octapeptide of cholecystokinin (CCK-OP). An infusion of 10 ng/kg/min of CCK-OP resulted in 75% emptying of the gallbladder at 30 min compared to control. This was significantly greater emptying than with an infusion of either 0.1 or 1.0 ng/kg/min. After administration of a fatty meal, the 30-min gallbladder emptying was 73% of control, similar to the response to CCK-OP at a dose of 10 ng/kg/min. Intravenous administration of 1 mg/kg of L-364,718 (a CCK-receptor antagonist) completely inhibited the gallbladder response to a fatty meal but had no effect on gallbladder filling in the fasting state. These results suggest that feline cholescintigraphy can be used for the quantitative study of gallbladder emptying. While CCK appears to be the primary modulator of gallbladder contraction after a fatty meal, no influence of CCK was detected in the interdigestive (fasting) state.

Animals↗
PubMed1990

Effects of a high-fat diet and L364,718 on growth of human pancreas cancer.

The effects of a high-fat diet and the CCK-receptor antagonist, L364,718, were examined on growth of human pancreas cell line SW-1990 xenografted to nude mice. Sixty animals were fed either low-fat (4.3%) or high-fat (20.25%) diet. Fifteen mice in each diet group were treated with L364,718 (2 mg/kg) subcutaneously twice daily for 23 days. On day 24 the animals were sacrificed. Tumor and animal pancreases were dissected and evaluated for weight, protein, and DNA content. When comparing within each diet group, L364,718 significantly decreased tumor volume, weight, protein, and DNA content compared to untreated mice (P less than 0.005). Tumor volume and protein content were significantly larger in untreated animals on the high-fat diet (P less than 0.05) compared to the low-fat diet. Mouse pancreatic weight, protein, and DNA content per kilogram of animal weight were all significantly lower (P less than 0.005) in mice on the low-fat diet treated with L364,718. Pancreatic DNA content was also decreased in both groups of animals on the high-fat diet compared to untreated mice on the low-fat diet. These findings suggest that diets high in unsaturated fat promote the growth of human pancreatic cancer. Since both tumor and pancreas growth are inhibited by the specific CCK-antagonist, L364,718, it is possible that endogenous CCK promotes the growth.

Animals↗
PubMed1989

CCK receptors in release of pancreatic polypeptide (PP) in dogs.

Pancreatic polypeptide (PP) is released after ingestion of protein-fat meals and following administration of some gut hormones (CCK and bombesin), but the hormonal contribution to the physiological release of PP has not been elucidated. We used specific and potent CCK-receptor antagonist, L-364,718, administered intravenously in a dose of 0.5 mumol/kg or intraduodenally in a dose of 2 mumol/kg to assess the role of CCK in the release of PP. Exogenous CCK-8 infused intravenously in gradually increasing doses (12.5-400 pmol/kg/hr) caused a dose-dependent increase in plasma PP from basal 28 +/- 4 pM to 136 +/- 18 pM, and this PP increase was completely suppressed by both intravenous and intraduodenal administration of L-364,718. Meat feeding caused a dramatic increase in plasma PP from a basal level of 26 +/- 4 pM to a peak of about 190 +/- 32 pM, and the pretreatment with intravenous or intraduodenal L-364,718 reduced this PP increase by about 60%. Duodenal perfusion with oleate (0.12-4.0 mmol/hr) or L-Trp (0.12-4.0 mmol/hr) also increased plasma PP, reaching, respectively, 180 +/- 28 pM and 76 +/- 6 pM. Pretreatment with intravenous or intraduodenal L-364,718 completely abolished the plasma PP responses to oleate and L-Trp. Bombesin (100 pmol/kg/hr) raised plasma PP to the level similar to that achieved by meat feeding and L-364,718 given intravenously or intraduodenally blocked completely these plasma PP increments.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Cholecystokinin-induced contraction of opossum sphincter of Oddi. Mechanism of action.

In this study, we evaluated the mechanism of action whereby cholecystokinin increases spike-burst rate of the opossum sphincter of Oddi (SO). Each spike burst corresponds to a peristaltic SO contraction. Two types of animal preparations were evaluated: (1) awake chronic animal preparations and (2) anesthetized animals. A total of 19 chronic animals were prepared by implantation of electrodes on the SO, gastric antrum, duodenum, and jejunum. SO spike-burst rate was stimulated by intravenous infusion of CCK-OP (10 ng/kg/min), feeding, or intraduodenal infusion of fat-containing nutrient. Each stimulus was begun 20 min after cessation of phase III duodenal MMC activity and caused an increase in SO spike-burst rate from about 2 to 6/min that lasted for less than or equal to 1 hr. Such increases were antagonized substantially by hexamethonium, atropine, or methysergide. The CCK antagonist, L364718, antagonized the excitatory SO response to CCK-OP infusion or intraduodenal infusion of fat-containing nutrient (Isocal) but did not antagonize the response to feeding; CR1409 had no antagonistic effect on SO response to any of the three types of stimuli. In the acute studies in anesthetized animals, an intravenous bolus dose of CCK-OP (800 ng/kg) caused a substantial increase in SO spike-burst rate that was antagonized by CR1409 but not by atropine, hexamethonium, methysergide, L364718, or TTX.(ABSTRACT TRUNCATED AT 250 WORDS)

Ampulla of Vater↗
PubMed1995

Cholecystokinin is a potent protective agent against alcohol-induced gastric injury in the rat. Role of endogenous prostaglandins.

Cholecystokinin is a gastrointestinal hormone known to physiologically regulate pancreatic protein secretion and gallbladder contractility. Some evidence suggests that cholecystokinin is also involved in the maintenance of gastrointestinal mucosal integrity. This study was undertaken to ascertain whether cholecystokinin could prevent the gastric mucosal injury induced by acidified ethanol and what role prostaglandins, and type A and type B cholecystokinin receptors might play in this process. Conscious, fasted rats were given subcutaneous saline or cholecystokinin octapeptide (10-100 micrograms/kg) 30 min before a 1-ml oral gastric bolus of acidified ethanol (150 mM HCl/50% ethanol). Five minutes later, rats were sacrificed and the total area of macroscopic injury quantitated (square millimeters). In additional experiments using a similar protocol, 1 ml of either the cyclooxygenase inhibitor, indomethacin (5 mg/kg), a type A cholecystokinin receptor antagonist, L-364,718 (0.01-1 mg/kg), or the type B cholecystokinin receptor antagonist, L-365,260 (12.5-25 mg/kg) was given intraperitoneally 30 min prior to pretreatment with cholecystokinin octapeptide. Cholecystokinin octapeptide dose-dependently prevented mucosal injury from acidified ethanol (corroborated by histology). The protective effect of cholecystokinin octapeptide was completely negated by L-364,718 and partially reversed by indomethacin, while L-365,260 had no discernible effect in this process. In a further study, cholecystokinin was unable to prevent the damaging effects of aspirin and the inhibition of endogenous prostaglandins. This, it appears that cholecystokinin is able to maintain mucosal integrity in the face of a damaging insult by activation of type A cholecystokinin receptors, an effect mediated, at least in part, through the release of endogenous prostaglandins.

Animals↗
PubMed1990

Effect of intracerebroventricular and systemic injections of caerulein, a CCK analogue, on electrical self-stimulation and its interaction with the CCKA receptor antagonist, L-364,718 (MK-329).

Systemic administration of caerulein (10-100 micrograms/kg SC), a potent analogue of cholecystokinin, caused a profound dose-related depression of variable-interval self-stimulation, followed by progressive recovery within 60 min. Intracerebroventricular injection of caerulein (3-1000 ng) was not more effective than systemic injection, while injections into the nucleus accumbens (3-100 ng bilaterally) were without detectable effect. Systemic injections of L-364,718 (70-700 micrograms/kg IP), a specific competitive antagonist of CCKA ("peripheral-type") receptors, had no effect on self-stimulation when given alone. When given in combination with caerulein, L-364,718 (200 micrograms/kg IP) significantly reduced the inhibitory effect of caerulein (30 micrograms/kg SC); however, this dose, and higher doses of L-364,718, failed to confer complete protection. It is concluded that self-stimulation performance may be subject to modulation by CCK receptors distributed predominantly in the peripheral nervous system and that some but not all of these receptors are CCKA receptors.

Animals↗
PubMed1994

A new CCK-B/gastrin receptor antagonist acts as an agonist on the rat pancreas.

The new CCK-B/gastrin receptor antagonist PD 136450 is of potential value in treating neurologic and psychiatric disorders. We investigated possible side effects on the rat pancreas using acute and chronic administration schedules. In chronic experiments, four groups of rats were given either PD 136450, the proton pump inhibitor BY 308 (in order to induce hypergastrinemia), a combination of both, or control solutions over 14 d. Pancreatic growth, DNA, and protein content were significantly increased in rats given PD 136450 irrespective of circulating gastrin levels. Furthermore, an anticoordinate shift in pancreatic enzyme content in favor of trypsin and chymotrypsin at the expense of amylase and lipase was observed. Plasma CCK levels remained unchanged in this group making a role of circulating hormone unlikely. In order to investigate a possible direct agonist effect of the CCK-B/gastrin receptor antagonist, we studied amylase release from isolated rat pancreatic acini in response to PD 136450 and sulfated CCK8 alone and in combination with the specific CCK-A receptor antagonist MK 329. Increasing concentrations of PD 136450 caused a monophasic dose-response curve in contrast to the well-known biphasic amylase release in response to CCK8. Addition of increasing doses of PD 136450 to a concentration of CCK causing maximal stimulation of amylase release (0.1 nM) further enhanced amylase release from pancreatic acini. The specific CCK-A receptor antagonist MK 329 dose-dependently inhibited CCK8- and PD 136450-induced amylase release. In conclusion, the new CCK-B/gastrin receptor antagonist PD 136450 exhibited profound agonist actions on the rat pancreas mediated via CCK-A receptors.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1997

Cholecystokinin-8S increases dynorphin B, aspartate and glutamate release in the fronto-parietal cortex of the rat via different receptor subtypes.

The effect of sulphated cholecystokinin-8 (CCK-8S) on extracellular dynorphin B, aspartate, glutamate and GABA levels in the rat fronto-parietal cortex was investigated with in vivo microdialysis. The peptide was infused through the microdialysis probe trying to mimic local CCK-8S release. Basal levels of dynorphin B were around 20 pM, aspartate 100 nM, glutamate 600 nM and GABA 30 nM. CCK-8S (10 microM) induced a approximately 3-fold increase in extracellular dynorphin B, aspartate and glutamate levels, while GABA levels were only slightly increased. The effect of CCK-8S was restricted to the stimulated neocortex. Systemic pretreatment with the CCKB antagonist, L-365, 260, but not with the CCKA antagonist, L-364, 718, significantly antagonised the effect of CCK-8S on cortical dynorphin B and aspartate release. However, both CCKA and CCKB antagonists inhibited the increase in cortical glutamate levels. Thus, the present results indicate that cortical CCK release exerts a stimulatory modulation on cortical dynorphin B and aspartate release via the CCKB receptor subtype, and on glutamate release via both CCKA and CCKB receptor subtypes. Considering electrophysiological evidence that CCK increases neuronal firing rates in many brain regions, it may be suggested that CCK represents a stimulatory system modulating the function of the neocortex.

Animals↗
PubMed1998

Evidence for CCK(B) receptors in the guinea-pig kidney: localization and characterization by [125I]gastrin binding studies and by RT-PCR.

Two types of receptors for gastrin and cholecystokinin (CCK) have been identified in the gastrointestinal tract and in the central nervous system: CCK(A) and CCK(B) receptors. Here we report evidence for the expression of CCK(B) receptors in the guinea-pig kidney. Specific binding sites for [125I]gastrin were detected in sections of the guinea-pig kidney: Binding was saturable, pH-, temperature- and time-dependent, and specific for gastrin-related peptides. The potencies for inhibition of binding of [125I]gastrin were CCK-8 > gastrin 17-I > CCK(B) receptor antagonist L-365,260 > des(SO3)CCK-8 > CCK(A) receptor antagonist L-364,718. Autoradiography demonstrated specific [125I]gastrin binding to medullary collecting ducts and to a much lesser extent to glomeruli, but not over other structures. CCK(B) receptor cDNA fragments were amplified by RT-PCR from total kidney, isolated tubuli and from tissues known to express CCK(B) receptors such as stomach and brain. The kidney might therefore be a previously unidentified site of action for gastrin and cholecystokinin-related peptides.

Aldosterone↗
PubMed1996

Cholecystokinin mediation of colonic absorption via peptide YY: foregut-hindgut axis.

Peptide YY (PYY), a 36-amino-acid polypeptide, is found in abundance in the colon, a region where its physiologic roles are unknown. Previous studies have revealed a substantial increase in plasma PYY after cholecystokinin (CCK) administration. PYY is released from the hindgut in response to a meal and inhibits CCK release. In this study we evaluated the effects of CCK and PYY on intestinal absorption of water and electrolytes. Colonic, ileal, or jejunal Thiry-Vella fistulas (TVFs) were created in 12 dogs, and intestinal continuity was reestablished. The TVFs were perfused with an isotonic buffer solution containing [14C] PEG as a volume marker. Electrolyte and water transport were measured every 15 minutes, and plasma PYY and CCK levels were measured by radioimmunoassay. Group 1 dogs received an intravenous bolus of MK329, a specific CCK receptor antagonist, at 20 nmol/kg after a standard mixed meal; group 2 colonic TVF dogs received a meal and an intravenous bolus of PYY polyclonal antibody at 1 mg/kg. Postprandially, all three regions of the bowel became significantly proabsorptive for water, sodium, and chloride. In the colon postprandial absorption was abolished by MK329 starting 60 minutes after a meal, whereas specific CCK receptor blockade blunted ileal absorption. CCK receptor blockade did not affect postprandial absorption in the jejunum. Postprandial PYY levels did not rise in MK329-treated animals. PYY antibody reduced colonic absorption during the postprandial phase. Reduction of meal-induced colonic absorption and PYY release by MK329 in awake dogs suggests an important foregut-hindgut hormonal feedback loop. Foregut-derived CCK stimulates hindgut PYY release, which in turn stimulates colonic absorption while inhibiting further CCK release.

Animals↗