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PubMedDate not supplied

Effects of selective cholecystokinin antagonists L364,718 and L365,260 on food intake in rats.

The selective type A and B cholecystokinin (CCK) receptor antagonists L364,718 and L365,260 were used to identify the receptor subtype that mediates the satiety effect of endogenous CCK. Male rats (n = 12-13/group), fed ground rat chow ad lib, received L364,718 (0, 1, 10, 100, or 1000 micrograms/kg IP) or L365,260 (0, 0.1, 1, 10, 100, 1000, or 10,000 micrograms/kg IP) 2 h after lights off, and food intake was measured 1.5, 3.5, and 5.5 h later. L364,718 significantly stimulated 1.5-h food intake by more than 40% at 10 micrograms/kg and higher doses; cumulative intake at 3.5 and 5.5 h remained elevated by about 20% at 1000 and 100 micrograms/kg of L364,718, respectively. In contrast, L365,260 had no significant stimulatory effect on feeding at any dose. The potency of L365,260 for antagonizing gastrin-stimulated gastric acid secretion was examined in unanesthetized rats. Male rats (n = 14), prepared with gastric and jugular vein cannulas, received doubling doses of gastrin (G-171) (0.16-5 nmol/kg/h IV), each dose for 30 min, and gastric juice was collected for each 30-min period. G-171 stimulated gastric acid output dose dependently; the minimal effective dose was 0.16 nmol/kg/h, while maximal output (5-fold above basal) occurred at 5 nmol/kg/h. L365,260 (0, 1, 10, 100, 1000, or 10,000 micrograms/kg IV), administered 30 min before continuous infusion of G-171 (1.25 or 5 nmol/kg/h), significantly inhibited acid output only at 10,000 micrograms/kg; cumulative 60-min output was decreased by 60%. These results suggest that CCK acts at CCK-A receptors to produce satiety during the dark period in ad lib-feeding rats.

Animals↗

PubMedDate not supplied

Capsaicin-sensitive vagal afferents and CCK in inhibition of gastric motor function induced by intestinal nutrients.

The role of vagal afferent pathways and cholecystokinin (CCK) in mediating changes in gastric motor function after a meal was investigated in urethane-anesthetized rats. Proximal gastric motor function was measured manometrically, and nutrients were infused into an isolated segment of duodenum. Inhibition of gastric motility in response to duodenal infusion of protein (peptone or casein), but not carbohydrate (glucose), was significantly attenuated by administration of the CCK antagonist, L364,718. Selective ablation of vagal afferents by perineural treatment with the sensory neurotoxin, capsaicin, significantly reduced responses to both duodenal protein and glucose. These results suggest that protein in the duodenum decreases proximal gastric motor function via release of CCK and a vagal capsaicin-sensitive afferent pathway. In contrast, glucose acts via a capsaicin-sensitive vagal pathway not involving CCK. Thus separate neural and hormonal mechanisms mediate the effects of different nutrients in the duodenal feedback regulation of gastric motor function.

Afferent Pathways↗

PubMedDate not supplied

The role of cholecystokinin (CCK8) on glucose production and elimination, and on plasma insulin and glucose in rats.

The effects of the gastrointestinal hormone and neurotransmitter cholecystokinin (CCK8) are complex, since it exhibits both an insulinotropic and a glucagonotropic effect. We investigated CCK8 in vivo with respect to glucose fluxes (production and elimination) at both low (6 mM) and high plasma glucose levels (9 mM) using the primed constant D-[3-3H]glucose infusion technique. In the presence of high glucose levels there was a dose-dependent increase in glucose elimination by CCK8. No effect of CCK8 on glucose production at a high glucose infusion rate (500 mg/kg per h) was observed in contrast to a low glucose infusion rate (100 mg/kg per h); plasma glucagon levels were elevated. All effects on glucose production and elimination were specific, since they were abolished by the CCK receptor antagonist L-364,718. In summary, glucose elimination was slightly increased by CCK8 at low glucose levels but increased to a greater extent at high glucose levels; glucose production was increased by CCK8 only at low glucose levels. Thus, CCK is a regulator of glucose homeostasis.

Animals↗

PubMedDate not supplied

Peripheral factors in the mediation of cholecystokinin-induced satiety as assessed by comparative potencies of cholecystokinin antagonists.

Cholecystokinin COOH-terminal octapeptide (CCK-8) produces a satiating effect in the rat and other animals upon peripheral administration. Although it has been demonstrated that the receptors which mediate this action are located in the periphery and are of the CCK-A subtype, their anatomical location has not been firmly established. A dense population of CCK receptors in the pyloric sphincter has been suggested as a candidate. We here quantify the potency of several CCK antagonists to inhibit the contractile effect of CCK-8 on the rat pyloric sphincter in vitro. The potent and selective antagonist MK-329 has a Schild pK of 8.85; the less potent but selective antagonist lorglumide (CR-1409) a pK of 6.37; the related antagonist phenoxyacetylproglumide (phi oAc proglumide) a pK of 5.1; and the weak parent compound proglumide a pK of about 3.3. These data can be compared with the potencies of these compounds to inhibit the actions of CCK-8 to produce satiety in the rat; this comparison supports the contention that CCK receptors of the rat pyloric sphincter could in part mediate the satiety effect produced by exogenous CCK-8.

Animals↗

PubMedDate not supplied

Effects of CCK antagonists on CCK-induced suppression of locomotor activity in mice.

Sulfated cholecystokinin octapeptide (CCK-8) was administered either intraperitoneally or into the cerebral ventricle of fully conscious mice, and locomotor activity was quantified. CCK-8 administered by either route suppressed locomotor activity. Subcutaneously administered selective CCK-A receptor antagonist, L-364,718 (1 mg/kg), reversed the inhibitory effect of centrally as well as peripherally administered CCK-8, but the selective CCK-B receptor antagonist, L-365,260 (1 mg/kg), did not. These results demonstrate that centrally as well as peripherally administered CCK-8 suppresses locomotor activity in mice through an interaction with CCK-A, but not CCK-B, receptors.

Animals↗

PubMedDate not supplied

Activation of CCK-A receptors induces elevation of plasma corticosterone in rats.

Cholecystokinin octapeptide (CCK-8) and ceruletide (1 microgram/kg) produced a pronounced increment of plasma corticosterone levels at 30 min after intraperitoneal administration. The response to these peptides was suppressed by pretreatment with a selective antagonist for CCK-A receptors, (-)L-364,718, in a dose-related manner, but not with an antagonist for CCK-B receptors, (+)L-365,260. However, (-)L-364,718 itself had no effect on basal levels of plasma corticosterone. These results indicate that peripheral administration of CCK-8 and ceruletide stimulates the hypothalamo-pituitary adrenal axis through the activation of CCK-A receptors, but not CCK-B receptors.

Animals↗

PubMedDate not supplied

Mechanism of bombesin-induced pancreatic secretion in unanesthetized rats.

It is unclear whether stimulation of pancreatic enzyme secretion by intravenously administered bombesin is a direct effect on acinar cells or is mediated by release of CCK; this distinction is important for defining the potential role of bombesin-like peptides as regulators of pancreatic secretion. The role of CCK in bombesin-induced pancreatic secretion was examined in rats using CCK radioimmunoassay and the CCK receptor antagonist L-364,718. A biphasic pancreatic response occurred to sequential doubling doses of bombesin (31 to 2000 pmol/kg/h, each for 30 min; n = 9 rats); amylase secretion increased to peak at 250 pmol/kg/h (11.5 +/- 1.7 kU/30 min; 4.2 +/- 0.6 kU/30 min, basal) and then declined to basal levels at 2000 pmol/kg/h. The ED50 dose of bombesin for stimulation was 31 pmol/kg/h, and the maximal response did not differ significantly from that to exogenous CCK-8 (10.6 +/- 1.5 kU/30 min) in the same rats. When single doses of bombesin were infused for 2 h (31, 62, 125, 250 pmol/kg/h; one dose per day; order randomized; n = 8), a similar dose-response relationship was seen, both for peak amylase response and cumulative output over basal. L-364,718 (0.5 mg/kg IV) had no effect on the pancreatic response to ED50 or maximal doses of bombesin. Neither dose of bombesin altered plasma CCK levels. In contrast, other stimulants of pancreatic secretion (food ingestion, soybean trypsin inhibitor) caused marked elevations in plasma CCK levels. These results indicate that the potent stimulation of pancreatic secretion by exogenous bombesin in rats is not mediated by CCK, similar to findings in humans.

Animals↗

PubMed1994

Somatostatin is released in response to cholecystokinin by activation of type A CCK receptors.

Cholecystokinin is a principal mediator of intestinal fat-induced inhibition of gastric acid secretion, indicating that it is an important physiological enterogastrone. Cholecystokinin has been shown to inhibit acid secretion by activation of type A CCK receptors and through a mechanism involving somatostatin. In the present study, we investigated the possibility that these two mechanisms are directly related such that activation of type A CCK receptors by CCK causes the release of somatostatin. We tested this hypothesis in vivo in a study of CCK-stimulated release of somatostatin in dogs and in vitro in a study of CCK-stimulated release of somatostatin from an enriched culture of canine fundic D cells. In dogs, IV infusion of CCK (50 pmol/kg/h, IV) significantly increased circulating somatostatin concentrations above basal. Further, systemic administration of somatostatin MAb F(ab)1 fragments of a somatostatin monoclonal antibody prevented most of CCK-induced inhibition of meal-stimulated acid secretion. In canine fundic D cells in culture, CCK-stimulated somatostatin release was blocked in a dose-dependent fashion by application of a type A CCK receptor antagonist. This study indicates that CCK activates type A CCK receptors to release somatostatin from canine fundic mucosal D cells, and accounts for somatostatin-dependent CCK-induced inhibition of acid secretion.

Acids↗

PubMed1994

CCK antagonists reveal that CCK-8 and JMV-180 interact with different sites on the rat pancreatic acinar cell CCKA receptor.

The ability of CCKA antagonists to inhibit full and partial CCK agonists of the rat pancreatic acinar cell CCKA receptor has been studied. When isolated rat pancreatic acini were superfused with CCK-8 (10 pM-1 nM) or CCK-4 (1 microM), an increase in [Ca2+]i signal was initiated. Concurrent superfusion of either L-364,718 (0.1 microM) or lorglumide (10 microM), chemically distinct, specific, potent antagonists of the CCKA receptor, resulted in a rapid inhibition of the [Ca2+]i signal initiated by all concentrations of CCK-8. In contrast, Ca2+ oscillations, initiated by JMV-180 (25 nM-1 microM), a partial agonist analogue of CCK-8, were essentially unaffected by concurrent superfusion of either L-364,718 or lorglumide. When JMV-179, an analogue of JMV-180 that exhibits characteristics of a pure antagonist, was superfused concurrently with either CCK-8 or JMV-180, Ca2+ oscillations were inhibited, even in the presence of 0.1 microM L-364,718. In a similar fashion, amylase secretion stimulated by CCK-8 was markedly attenuated by L-364,718, lorglumide, and JMV-179, whereas secretion stimulated by JMV-180 was only inhibited by JMV-179. A model is proposed to reconcile this data, based on the assumption that JMV-180 and CCK-8 interact with discrete sites on the CCKA receptor, which are differentially affected by the binding of antagonists. This model may also explain how a single receptor may transduce multiple signals in response to different agonists.

Amino Acid Sequence↗

PubMed1995

Characterization of cholecystokinin receptors in canine intestinal circular muscle.

We localized and characterized the binding of [3H](+/-)-L364,718 in canine small intestine circular muscle. The highest densities of [3H]L364,718 binding were located in the fraction enriched in deep muscular plexus synaptosomal membranes. In this fraction [3H]L364,718 binding was of high density (Bmax 136.78 +/- 53.66 fmol/mg) and high affinity (Kd 1.67 +/- 0.74 nM). Kinetics studies revealed that binding was reversible and yielded a similar Kd value. L364,718, CCK-8-S, and L365,260 fully displaced [3H]L364,718 binding, but ligands at CCKB receptors, gastrin-17, and YM022 did not. Therefore, CCKA receptors in canine intestine circular muscle are located on nerve endings.

Animals↗

PubMed1996

Peripherally administered calcitonin gene-related peptide decreases food intake in mice.

Previously, calcitonin gene-related peptide (CGRP) decreased food intake when administered ICV but not when administered peripherally to rats. Amylin, which has a close structural homology to CGRP, reduced food intake administered IP at concentrations higher than those previously tested for CGRP. We examined the effects of higher doses of IP-administered CGRP on food intake. CGRP reduced food intake from 25 to 200 micrograms/kg in mice. CGRP did not reduce water intake and was not aversive in a two-bottle test. Using a lever press, CGRP was more effective at reducing milk consumption in prefed than in nonprefed mice. The effect of CGRP on food intake was not antagonized by the cholecystokinin A receptor antagonist, L364,718. These studies suggest a role for CGRP as a satiating factor.

Analysis of Variance↗

PubMed1991

Precocious alteration of digestive enzyme activities in small intestine and pancreas by chronic oral administration of protease inhibitor in suckling rats.

1. The role of endogenous CCK in the development of digestive enzyme activities in small intestine and pancreas was investigated in suckling rats. Synthetic protease inhibitor (camostat 100 micrograms/g bwt) was orally administered twice daily for 5 days from 11 days of age. 2. Pancreatic hypertrophy and hyperplasia, and alteration of pancreatic enzyme composition, especially decreases in amylase activity and increases in trypsin and chymotrypsin activities were produced by camostat treatment. These changes were completely suppressed by simultaneous administration of the potent CCK receptor antagonist L-364,718 (1 microgram/g bwt). 3. With camostat treatment, intestinal lactase activity decreased to 41%, while maltase and sucrase activities increased 3 and 2.5 times respectively. These changes in enzyme activities were not affected by the application of L-364,718. 4. The mucosal disaccharidase and pancreatic enzyme activities could not be modified by chronic subcutaneous injection of camostat. The precocious induction of maltase and sucrase activities by camostat treatment was also observed in the adrenalectomized pups. 5. These results indicate that pancreatic growth accompanied by alteration of digestive enzyme composition in the suckling rats is regulated by endogenous CCK, but the precocious induction of disaccharidase activities is not mediated by endogenous CCK released by camostat treatment.

Administration, Oral↗

PubMed1993

Evidence for autocrine growth stimulation by a gastrin/CCK-like peptide of the gastric cancer HGT-1 cell line.

Gastrin has been shown to promote the growth of some colonic tumor cell lines. To evaluate the involvement of this hormone in the proliferation of gastric tumors, we studied the effects of gastrin/CCK-receptor antagonists (L365,260 and L364,718), proglumide and C terminal-specific gastrin antibodies on the human gastric adenocarcinoma cell line HGT-1. L365,260, but not L364,718, dose-dependently inhibited cell proliferation (72% after 4 days at 10 nM) and [3H]thymidine incorporation (68% after 2 days at 10 nM) in serum-free medium. No cytotoxic effects of proglumide or L365,260 on this cell line were detected. Proglumide inhibited cell proliferation in serum-free medium (40% and 66.5% after 2 and 4 days of treatment; IC50 = 1.4 mM) and in 5% fetal calf serum (FCS)-supplemented medium (30% and 22% after 2 and 4 days of treatment; IC50 = 3.25 mM). [3H]Thymidine incorporation was also inhibited by proglumide in serum-free medium (IC50 = 2.3 mM) and 5% FCS-supplemented medium (IC50 = 3.35 mM). Gastrin did not induce cell proliferation or increase [3H]thymidine incorporation and no high-affinity gastrin binding sites were observed. However, C terminal-specific gastrin antibodies, even at low concentration, caused a dramatic decrease in both cell number (IC50 = 1:4000 antiserum dilution) and [3H]thymidine incorporation (IC50 = 1:400 antiserum dilution) in the HGT-1 cell line. In addition, immunofluorescence analysis revealed that these antibodies specifically bind HGT-1 cells and radioimmunoassay analysis confirms the presence of gastrin/CCK-like peptide in cell extracts.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗

PubMed1988

Binding sites for 125I-cholecystokinin in primate spinal cord are of the CCK-A subclass.

Cholecystokinin (CCK) receptor binding was measured in sections of human, monkey and rat spinal cord using autoradiographical techniques. In each species, high levels of specific 125I-Bolton-Hunter CCK binding were detected in the superficial layers of the dorsal horn (the substantia gelatinosa). In monkey and human but not rat spinal cord, 125I-CCK binding was dose-dependently inhibited by low concentrations of the selective CCK-A antagonist L-364,718. Binding of [3H]L-364,718, which was saturable (Bmax = 29.0 +/- 0.95 pmol/g wet wt.) and of high affinity (pKd) = 9.92 +/- 0.16) was also detected in sections of monkey spinal cord and had a similar localization to that of specific 125I-CCK binding. These data indicate that in striking contrast to CCK receptors in rat spinal cord, those in the primate cord are of the CCK-A receptor subclass.

Animals↗

PubMed1992

Selectivity of cholecystokinin (CCK) receptor antagonists, MK-329 and L-365,260, for axonally-transported CCK binding sites on the rat vagus nerve.

The ability of the cholecystokinin (CCK) receptor antagonists, MK-329 and L-365,260, to selectively inhibit 125I-Bolton-Hunter-CCK8 binding to ligated rat vagus nerve in vitro was examined at concentrations ranging from 10(-10) M to 10(-6) M. Both antagonists inhibited binding to CCK binding sites accumulating proximal to ligatures on the cervical vagus. Incubation of nerve sections in the presence of both antagonists produced an additive effect, indicating that both CCK-A and CCK-B binding sites are transported towards the periphery. In contrast, CCK binding sites accumulating distal to the ligature possessed the pharmacological characteristics of the CCK-B receptor sub-type only.

Animals↗

PubMed1992

Dual capsaicin-sensitive afferent pathways mediate inhibition of gastric emptying in rat induced by intestinal carbohydrate.

The role of the vagal and spinal afferent innervation in the inhibition of gastric emptying induced by duodenal perfusion with a disaccharide (maltose 300 mM) was investigated in awake rats fitted with gastric and duodenal cannulas. Perfusion of the duodenum with maltose inhibited gastric emptying by 44%. Maltose-induced inhibition of gastric emptying was reversed by 46% and 100% by functional ablation of the vagal or spinal capsaicin-sensitive afferent innervation, respectively. Pretreatment with the specific CCK 'A' receptor antagonist, MK329, completely abolished the effects of maltose on gastric emptying. These results suggest that disaccharides inhibit gastric emptying via activation of capsaicin-sensitive afferents in the duodenal mucosa via a mechanism involving an action of CCK at type 'A' receptors, possibly located on afferent fibers.

Afferent Pathways↗

PubMed1993

The induction and suppression of c-fos expression in the rat brain by cholecystokinin and its antagonist L364,718.

Immunohistochemical techniques were used to map c-fos expression in the rat brain after the i.p. administration of CCK-8 (8 micrograms/kg). C-fos expression was observed in the rostral and the caudal parts of the nuclei of the solitary tract (NTS), and the paraventricular nuclei (PVN) in the hypothalamus. The c-fos expression in these areas was suppressed by the administration of L364,718 (120 micrograms/kg). Since L364,718 is known to be a powerful selective antagonist to the peripheral CCK-A receptors, these data suggest that the effects produced by exogenous CCK are due to peripheral receptors that project to the NTS.

Animals↗

PubMed1993

Cholecystokinin-A but not cholecystokinin-B receptor stimulation induces endogenous opioid-dependent antinociceptive effects in the hot plate test in mice.

The effects of intracerebroventricular administration of the cholecystokinin (CCK) analogue, BDNL, and the selective CCK-B agonist, BC 264, were determined using the hot plate test in mice. BDNL (0.2 nmol and 0.5 nmol) increased the jump and the paw lick latencies. These effects were blocked by the CCK-A antagonist MK-329 (0.02 mg/kg), supporting the involvement of CCK-A receptors in CCK-induced analgesia. In contrast, the selective CCK-B agonist BC 264 produced, at one dose (2.5 nmol), a slight decrease in the lick latency that was only antagonized by the CCK-B antagonist. Naloxone, but not naltrindole, antagonized BDNL-induced analgesia. The results suggest that activation of CCK-A receptors by BDNL leads to antinociceptive responses indirectly mediated by stimulation of mu-opioid receptors by endogenous enkephalins.

Animals↗