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PubMed2000

Inhibition by CCK of ascending contraction elicited by mucosal stimulation in the duodenum of the rat.

CCK released by intraluminal stimuli modifies duodenal activity contributing to a decrease in gastric emptying. However, the neural mechanisms by which CCK controls motility are not well known. The aim of this study was to investigate the interaction between CCK and the enteric nervous system through the study of the effects of CCK-8 on ascending excitation. Anaesthetized Sprague-Dawley rats were prepared with a strain-gauge sutured to the duodenum wall. An electrode holder was placed in the duodenum lumen to elicit ascending contraction. Electrical field stimulation of the duodenal mucosa (4 Hz, 0.6 ms, 30 V) induced an ascending excitation which was blocked by hexamethonium (10 mg kg-1; n=5) and atropine (0.3 mg kg-1; n=5), but enlarged by L-NNA (10(-5) mol kg-1; n=5). CCK-8 (3 ¿ 10(-9) mol kg-1 10 min-1) blocked ascending excitation and an inhibition of the induced phasic activity was observed instead (n=18). Individually, none of the CCK receptor antagonists (L-364 718 and L-365 260) (3 ¿ 10(-7) mol kg-1; n=6 each) blocked the inhibition of ascending excitation induced by CCK-8. However, simultaneous infusion of both antagonists abolished CCK-8 effect on electrical stimulation (n=5). Similarly, none of the CCK-8 agonists (A-71623, A-71378, gastrin) modified the ascending excitation. In contrast, the simultaneous infusion of A-71623 and CCK-4 (n=4) induced an effect similar to CCK-8. In conclusion, CCK-8 blocked ascending contraction elicited by electrical field stimulation of duodenal mucosa by means of simultaneous activation of CCK-A and CCK-B receptors.

Adrenergic beta-Antagonists↗
PubMed1997

Dual modulation of dopamine release from anterior nucleus accumbens through cholecystokinin-B receptor subsites.

Previous binding studies have suggested the existence of two affinity states for cholecystokinin-B (CCK-B) receptor. One study, using BC 197 and BC 264, two highly selective CCK-B agonists, has shown that BC 197 is selective for one subsite, B1, and that BC 264 has the same affinity for the two subsites, B1 and B2. Therefore, the possible involvement of CCK-B subsites in the modulation of endogenous dopamine (DA) release from slices of the anterior part of the nucleus accumbens was investigated with these two agonists in order to associate a functional response with activation of each subsite. The selective B1 agonist BC 197 produced a dose-dependent increase of 35 mM K(+)-stimulated DA release. In contrast, at a low concentration (20 nM), BC 264 inhibited the K(+)-evoked DA release, whereas at a higher concentration (1 microM), it stimulated the DA release. These two opposing effects were suppressed by the CCK-B antagonist PD-134,308, but not by the CCK-A antagonist L-364,718 and were not prevented by tetrodotoxin, a Na(+)-channel blocker. Moreover, BC 264 at 20 nM, in the presence of PD-134,308 at a concentration that would block the B2 subsites (0.1 nM), increased the evoked DA release. All together, these results support further the existence of distinct CCK-B subsites and suggest that, in the anterior nucleus accumbens, their stimulation mediates opposite effects on K(+)-stimulated DA release via a presynaptic mechanism.

Animals↗
PubMed2004

Melatonin and its precursor, L-tryptophan: influence on pancreatic amylase secretion in vivo and in vitro.

Melatonin, considered as a main pineal product, may be also synthetized in the gastrointestinal tract from L-tryptophan. Melatonin has been recently shown to affect insulin release and its receptors have been characterized in the pancreas however, the effects of melatonin on the pancreatic enzyme secretion have not been examined. The aim of this study was to investigate the effects of melatonin or L-tryptophan on amylase secretion in vivo in anaesthetized rats with pancreato-biliary fistulas, and in vitro using isolated pancreatic acini. Melatonin (1, 5 or 25 mg/kg) or L-tryptophan (10, 50 or 250 mg/kg) given to the rats as a intraperitoneal (i.p.) bolus injection produced significant and dose-dependent increases in pancreatic amylase secretion under basal conditions or following stimulation of enzyme secretion by diversion of bile-pancreatic juice. This was accompanied by a dose-dependent rise in melatonin plasma level. Stimulation of pancreatic enzyme secretion caused by melatonin or L-tryptophan was completely abolished by vagotomy, deactivation of sensory nerves with capsaicin or pretreatment with CCK1 receptor antagonists (tarazepide or L-364,718). Pretreatment with luzindole, an antagonist of melatonin MT(2) receptor failed to affect melatonin- or L-tryptophan-induced amylase secretion. Administration of melatonin (1, 5 or 25 mg/kg i.p.) or L-tryptophan (10, 50 or 250 mg/kg i.p.) to the rats resulted in the dose-dependent increase of cholecystokinin (CCK) plasma immunoreactivity. Enzyme secretion from isolated pancreatic acini was not significantly affected by melatonin or L-tryptophan used at doses of 10(-8) -10(-5) M. We conclude that exogenous melatonin, as well as that produced endogenously from L-tryptophan, stimulates pancreatic enzyme secretion in vivo while increasing CCK release. Stimulatory effect of melatonin or L-tryptophan on the exocrine pancreas involves vagal sensory nerves and the CCK release by these substances.

Amylases↗
PubMed2001

Mitogenic effect of gastrin and expression of gastrin receptors in duct-like cells of rat pancreas.

BACKGROUND & AIMS: Ductular metaplastic cells are observed during pancreas injury. Growth control by gastrin and expression of gastrin/cholecystokinin (CCK) B receptors were evaluated in these cells. METHODS: Acinoductal transdifferentiation was induced in vitro by culturing of acinar cells, and ductular metaplasia was obtained in vivo by ligation of the pancreatic ducts. Mitogenic effects of gastrin I on ductal complexes in vivo and of tetragastrin, pentagastrin, and gastrin I and II, with or without the CCK-B receptor antagonist L-365,260, on duct-like cells in vitro were analyzed by 5-bromo-2'-deoxyuridine labeling. Immunocytochemistry, Western blotting, and reverse-transcription polymerase chain reaction were applied for detection of the CCK-B receptor. RESULTS: Gastrin analogues induced a mitogenic stimulus in the duct-like cells in vitro and in ductal complexes in duct-ligated rat pancreas. Immunocytochemistry showed expression of CCK-B receptors in these models and in fetal but not normal adult exocrine pancreas. Additionally, up-regulation of CCK-B receptors during ductular metaplasia was shown by Western blotting and reverse-transcription polymerase chain reaction. CONCLUSIONS: Duct-like pancreatic epithelial cells in vitro and ductal complexes in vivo express gastrin/CCK-B receptors and proliferate in response to gastrin.

Animals↗
PubMed2003

Effects of early decompression and cholecystokinin inhibition in rats with acute pancreatitis induced by bile-pancreatic-duct obstruction.

Biologic data related to pancreatic regeneration and acinar-cell homeostasis after ductal decompression would be useful in clinical settings to elucidate the time at which obstructions in human biliary acute pancreatitis (AP) should be removed. Our aim was to evaluate the outcome of AP after early removal of bile-pancreatic-duct obstruction (BPDO) and to ascertain whether cholecystokinin (CCK) blockade accelerates recovery from the disease. We conducted analysis of apoptosis and cell cycle, as well as measurements of enzyme and calcium load, in acinar cells using flow cytometry to ascertain the capability of the pancreas to regain its function after AP. Male Wistar rats were subjected to AP by means of BPDO for 6 hours and 24 hours. In other groups, the BPDO was opened 24 hours after induction; 3 days and 7 days later they were killed. Half of the rats in which the BPDO was opened were administered L364,718, a CCK-receptor antagonist (0.1 mg/kg/12 hours), 30 minutes before the induction of BPDO. Plasma amylase activity, hematocrit, and pancreatic weight returned to control values after BPDO opening. The highest degree of oxidative stress was found in the pancreases of rats subjected to BPDO for 6 hours, as indicated by the decrease in pancreatic glutathione content, but it was not restored 7 days after BPDO opening. Cell-cycle distribution, as measured with propidium iodide DNA staining, showed increases in the proportion of acinar cells in S-phase from 3 days after BPDO opening in L364,718-treated and nontreated rats. Annexin V-fluorescein isothiocyanate labeling revealed deletion of acinar cells by way of apoptosis 3 days after BPDO opening. However, it may be compensated 7 days after BPDO opening because regardless of whether rats were treated with L364,718, significant increases in synthesis and mitosis were detected. Accumulation of digestive enzymes and calcium in acinar cells was found during BPDO, but this appeared to have normalized 3 days after BPDO opening and onward in both L364,718-treated and nontreated rats. In conclusion, early removal of obstruction allowed rapid cell proliferation and prevented the progression of severe alterations within acinar cells induced by BPDO. CCK blockade does not accelerate pancreatic recovery after BPDO opening.

Acute Disease↗
PubMed1986

Biochemical and pharmacological characterization of an extremely potent and selective nonpeptide cholecystokinin antagonist.

3S(-)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4- benzodiazepine-3-yl)-1H-indole-2-carboxamide (L-364,718) interacted in a competitive manner with rat pancreatic cholecystokinin (CCK) receptors as determined by Scatchard analysis of the specific binding of 125I-labeled CCK. The affinity of L-364,718 for both pancreatic (IC50, 81 pM) and gallbladder (IC50, 45 pM) CCK receptors in radioligand binding assays greatly exceeded that of other reported nonpeptide CCK antagonists and was similar to that of CCK itself. In vitro functional studies utilizing CCK-induced contractions of the isolated guinea pig ileum and colon further demonstrated that L-364,718 acts as a competitive CCK antagonist, which lacks agonist activity and has a similar high affinity in these tissues (pA2, 9.9). L-364,718 exhibited a very high selectivity for peripheral CCK receptors relative to brain CCK, gastrin, and various other peptide and nonpeptide receptors in both in vitro radioligand and isolated tissue assays. In vivo, low intravenous doses of L-364,718 (0.1 mg/kg) markedly antagonized the contractions of the guinea pig gallbladder produced by intravenous administration of CCK for at least 2 hr. Administered orally, L-364,718 (ED50, 0.04 mg/kg) was highly effective as an antagonist of CCK-induced inhibition of gastric emptying in mice. The biochemical and pharmacological properties of L-364,718--namely, very high affinity and selectivity for peripheral CCK receptors, long-lasting in vivo efficacy, and oral bioavailability--makes this compound a powerful tool for investigating the physiological and pharmacological actions of CCK, and possibly its role in gastrointestinal disorders.

Animals↗
PubMed1989

Cholecystokinin evokes secretion of oxytocin and vasopressin from rat neural lobe independent of external calcium.

Cholecystokinin (CCK) and its receptors are abundantly represented in the central nervous system. However, a specific role or mechanism of action for CCK in this context has not been established. CCK coexists with oxytocin in magnocellular neurons of the hypothalamic-neurohypophysial system, sharing common neurosecretory vesicles with oxytocin in the neural lobe of the pituitary. The neural lobe, which consists primarily of oxytocin- and vasopressin-containing axons and nerve terminals and their surrounding glia, provides a relatively simple model system allowing for the study of the regulation of neurosecretion at the nerve terminal level, free from the complex array of synaptic effects present throughout the rest of the central nervous system. In this paper, we demonstrate the presence of high-affinity CCK binding sites in the rat neural lobe and show that activation of these receptors by the sulfated octapeptide, CCK-8, and related peptides causes potent secretion of oxytocin and vasopressin from the isolated nerve terminals. The secretagogue action of CCK-8, which is blocked by a CCK receptor antagonist (L-364,718), is independent of electrical stimulation and extracellular calcium and is blocked by an inhibitor of protein kinase C. Thus, the action of CCK on the neural lobe provides an example of peptide ligand-induced neurosecretion apparently mediated by second messengers rather than depolarization-induced calcium influx.

Alkaloids↗
PubMed1991

Evidence for an involvement of the brain cholecystokinin B receptor in anxiety.

The effect of neuropeptide cholecystokinin (CCK) receptor agonists and antagonists was examined in the rat elevated X-maze model of anxiety. The selective CCK-B receptor antagonists CI-988 (PD 134308) and L-365,260 produced anxiolytic-like effects, whereas MK-329, a CCK-A receptor antagonist, was respectively less potent by factors of 313 and 200. The intracerebroventricular administration of the nonselective CCK receptor agonist caerulein or the selective CCK-B receptor agonist pentagastrin increased dose dependently the level of anxiety. CI-988 dose dependently antagonized the anxiogenic response to pentagastrin but not that induced by pentylenetetrazol. These results strongly suggest that activation of the brain CCK-B receptor induces anxiety and that selective antagonists of this receptor represent a separate class of anxiolytic agents.

Animals↗
PubMed1994

Direct demonstration of three different states of the pancreatic cholecystokinin receptor.

We used rat pancreatic acini as well as COS-7 cells transfected with the cloned pancreatic cholecystokinin (CCK) receptor and measured the abilities of CCK octapeptide (CCK-8) and L-364,718 (a CCK receptor antagonist) to inhibit binding of 125I-labeled CCK-8 (125I-CCK-8) and [3H]L-364,718. With pancreatic acini 125I-CCK-8 bound to two different states of the CCK receptor. The high-affinity state (1% of the receptors) had a Kd for CCK-8 of 985 pM and the low-affinity state (19% of the receptors) had a Kd for CCK-8 of 30 nM. [3H]L-364,718 bound to low-affinity receptors and to a previously unrecognized very-low-affinity state (80% of the receptors) having a Kd for CCK-8 of 13 microM. L-364,718 had the same affinity (Kd 3 nM) for each of the three different states of the CCK receptor. Similar measurements using transfected COS cells also identified three different states of the CCK receptor, with the very-low-affinity state being the most abundant. Thus, the ability of the CCK receptor to exist in three different states is an intrinsic property of the CCK receptor molecule itself.

Animals↗
PubMed1995

Modulation of cholecystokinin activity by albumin.

We found that a variety of cholecystokinin (CCK) receptor ligands bind to bovine serum albumin (BSA). This binding was rapid, fully reversible, temperature independent, of low affinity, and specific for BSA; it depended on the concentration of BSA, the chemical structure of the ligand, and the chemical composition of the incubation medium. BSA also decreased the binding of 125I-labeled CCK octapeptide (125I-CCK-8) to CCK receptors on pancreatic acini and membranes but increased the potency with which CCK-8 inhibited binding of 125I-CCK-8. These counterintuitive findings appeared to result from BSA altering the affinities of CCK-8 for different affinity states of the pancreatic CCK receptor. An alternate hypothesis is that BSA increased the efficacy of CCK-8 such that it bound to receptors and also caused biochemical changes in other receptors that reduced their ability to bind 125I-CCK-8. BSA enhanced the ability of CCK-8 to stimulate amylase secretion from pancreatic acini and to cause contraction of dispersed gastric smooth muscle cells. Thus, CCK can bind to BSA, and the BSA-CCK complex has substantially different activities from the free, uncomplexed hormone.

Animals↗
PubMed1996

Purification and characterization of a luminal cholecystokinin-releasing factor from rat intestinal secretion.

Cholecystokinin (CCK) secretion in rats and humans is inhibited by pancreatic proteases and bile acids in the intestine. It has been hypothesized that the inhibition of CCK release caused by pancreatic proteases is due to proteolytic inactivation of a CCK-releasing peptide present in intestinal secretion. To purify the putative luminal CCK-releasing factor (LCRF), intestinal secretions were collected by perfusing a modified Thiry-Vella fistula of jejunum in conscious rats. From these secretions, the peptide was concentrated by ultrafiltration followed by low-pressure reverse-phase chromatography and purified by reverse-phase high-pressure liquid chromatography. Purity was confirmed by high-performance capillary electrophoresis. Fractions were assayed for CCK-releasing activity by their ability to stimulate pancreatic protein secretion when infused into the proximal small intestine of conscious rats. Partially purified fractions strongly stimulated both pancreatic secretion and CCK release while CCK receptor blockade abolished the pancreatic response. Amino acid analysis and mass spectral analysis showed that the purified peptide is composed of 70-75 amino acid residues and has a mass of 8136 Da. Microsequence analysis of LCRF yielded an amino acid sequence for 41 residues as follows: STFWAYQPDGDNDPTDYQKYEHTSSPSQLLAPGDYPCVIEV. When infused intraduodenally, the purified peptide stimulated pancreatic protein and fluid secretion in a dose-related manner in conscious rats and significantly elevated plasma CCK levels. Immunoaffinity chromatography using antisera raised to synthetic LCRF-(1-6) abolished the CCK releasing activity of intestinal secretions. These studies demonstrate, to our knowledge, the first chemical characterization of a luminally secreted enteric peptide functioning as an intraluminal regulator of intestinal hormone release.

Amino Acid Sequence↗
PubMed1995

Agonist-stimulated cyclic ADP ribose. Endogenous modulator of Ca(2+)-induced Ca2+ release in intestinal longitudinal muscle.

We have previously shown that agonist-induced Ca2+ mobilization in intestinal longitudinal muscle is mediated by ryanodine-sensitive, inositol 1,4,5-trisphosphate-insensitive sacroplasmic Ca2+ channels. Ca2+ release via these channels is triggered by agonist-stimulated Ca2+ influx and results in Ca(2+)-induced Ca2+ release. The present study examined whether cyclic ADP-ribose (cADPR) is synthesized in response to stimulation of longitudinal muscle by agonists and modulates the activity of Ca2+ release channels. Cyclic ADPR bound with high affinity to dispersed longitudinal muscle cells (IC50 1.9nM) and induced Ca2+ release (EC50 3.8 nM), increase in [Ca2+]i (EC50 2.0 nM), and contraction (EC50 1.1 nM); cADPR had no effect on circular muscle cells. The effects of cADPR were blocked by ruthenium red, dantrolene, and the specific antagonist, 8-amino-cADPR, and were augmented by caffeine but not affected by heparin. The binding of cADPR and its ability to stimulate Ca2+ release were dependent on the concentration of Ca2+. Cyclic ADPR was capable of stimulating Ca2+ release at subthreshold Ca2+ concentrations (25-100 nM) and of enhancing Ca(2+)-induced Ca2+ release. Longitudinal muscle extracts incubated with beta-NAD+ produced a time-dependent increase in Ca(2+)-mobilizing activity identified as authentic cADPR by blockade of Ca2+ release with 8-amino-cADPR and ruthenium red. Ca2+ mobilizing activity was increased by cholecystokinin octapeptide (CCK-8) in a concentration-dependent fashion. The increase induced by CCK-8 was suppressed by the CCK-A antagonist, L364,718, nifedipine, and guanyl-5'-yl thiophosphate. The study shows that ADP-ribosyl cyclase can be stimulated by agonists and that cADPR can act as an endogenous modulator of Ca(2+)-induced Ca2+ release.

Adenosine Diphosphate Ribose↗
PubMed2005

Cross-interactions of two p38 mitogen-activated protein (MAP) kinase inhibitors and two cholecystokinin (CCK) receptor antagonists with the CCK1 receptor and p38 MAP kinase.

Although SB202190 and SB203580 are described as specific p38 MAP kinase inhibitors, several reports have indicated that other enzymes are also sensitive to SB203580. Using a pharmacological approach, we report for the first time that compounds SB202190 and SB203580 were able to directly and selectively interact with a G-protein-coupled receptor, namely the cholecystokinin receptor subtype CCK1, but not with the CCK2 receptor. We demonstrated that these compounds were non-competitive antagonists of the CCK1 receptor at concentrations typically used to inhibit protein kinases. By chimeric construction of the CCK2 receptor, we determined the involvement of two CCK1 receptor intracellular loops in the binding of SB202190 and SB203580. We also showed that two CCK antagonists, L364,718 and L365,260, were able to regulate p38 mitogen-activated protein (MAP) kinase activity. Using a reporter gene strategy and immunoblotting experiments, we demonstrated that both CCK antagonists inhibited selectively the enzymatic activity of p38 MAP kinase. Kinase assays suggested that this inhibition resulted from a direct interaction with both CCK antagonists. Molecular modeling simulations suggested that this interaction occurs in the ATP binding pocket of p38 MAP kinase. These results suggest that SB202190 and SB203580 bind to the CCK1 receptor and, as such, these compounds should be used with caution in models that express this receptor. We also found that L364,718 and L365,260, two CCK receptor antagonists, directly interacted with p38 MAP kinase and inhibited its activity. These findings suggest that the CCK1 receptor shares structural analogies with the p38 MAP kinase ATP binding site. They open the way to potential design of either a new family of MAP kinase inhibitors from CCK1 receptor ligand structures or new CCK1 receptor ligands based on p38 MAP kinase inhibitor structures.

Adenosine Triphosphate↗
PubMed1998

Elevation of feed intake in parasite-infected lambs by central administration of a cholecystokinin receptor antagonist.

The role of cholecystokinin (CCK) in modulating feed intake depression in parasite-infected lambs was investigated using CCK receptor antagonists (L364-718 and loxiglumide). Four experiments were carried out using ewe lambs infected with 4000 Trichostrongylus colubriformis larvae/d or non-infected controls (n8, live weight 25 kg). Animals were fed daily on a nutritionally complete pelleted diet and had free access to water. In the first experiment, infected and non-infected animals were injected subcutaneously with CCK antagonist (100 micrograms L364-718) or carrier alone as a single dose. In the second experiment, CCK antagonist (loxiglumide: 0, 5, 10 or 20 mg/kg live weight) was injected into a jugular vein immediately before feeding. In the third experiment, animals were infused continuously with the CCK antagonist (loxiglumide; 10 mg/kg per h) for 10 min before feeding and for the first 2 h of feeding. In the final experiment, lambs were fitted with an indwelling cerebral ventricular cannula and infused with a CCK antagonist (loxiglumide, 162 micrograms/min), CCK agonist (CCK-8, 2.5 pmol/min), loxiglumide plus CCK-8 or sterile saline solution alone via the cannula for 30 min before feeding and for the first 60 min of feeding. In all the experiments short-term feed intake was recorded at 10 and 15 min intervals for the first and second hours of feeding respectively, then at hourly intervals for the remainder of the 8 h recording period. Peripheral injection with L364-718 or loxiglumide did not elevate feed intake in either the infected or non-infected animals. However, feed intake was increased (P < 0.05) in the short term by central infusion of loxiglumide, this effect being greater in the infected animals and apparently due to an elevation in intake during the second hour of feeding. CCK-8 depressed short term feed intake only in the infected animals (P < 0.05). Total daily feed consumption was not influenced by any of the pharmacological agents. The results indicate an involvement of central CCK receptors in regulation of feed intake depression following gastrointestinal parasitism of sheep and the possibility of a similar role in non-infected sheep. They do not support the singular importance of a peripheral action of CCK in determining satiety.

Animals↗
PubMed1993

Effects of high fat diet and cholecystokinin receptor blockade on pancreatic growth and tumor initiation in the hamster.

The mechanism by which high-fat diet potentiates pancreatic cancer is not known, but trophic hormones may be involved. In preliminary growth studies, hamsters fed a high fat diet (17.5% lard, 17.5% corn oil) for 14 days showed a 16.3% increase (P < 0.01) in pancreatic weight compared to controls on low fat diet (2.5% lard, 2.5% corn oil). A significant increase was also seen at 28 days. Similar increases were seen in pancreatic DNA (29%, P < 0.01) and pancreatic RNA (22%, P < 0.05) at 14 days. Plasma cholecystokinin (CCK) levels at 14 days were 2.5 fold higher in the animals fed high fat (P < 0.01). Infusion of the CCK antagonist MK329 (25 nmol/kg/h) completely abolished the increase in pancreatic weight, pancreatic DNA and pancreatic RNA. The effect of CCK receptor blockade during the initiation period of carcinogenesis was investigated in hamsters fed the same diets used in the growth studies. One hundred animals received a single injection of N-nitrosobis(2-oxopropyl)amine, (BOP, 20 mg/kg). Half of the hamsters in each diet group received a 2 week infusion of MK329 (25 nmol/kg/h), beginning 8 days before carcinogen administration. At the time of death, 55 weeks after carcinogen administration, non-fasting plasma CCK levels were 31% higher in the high fat fed hamsters than in the low fat fed animals (P < 0.01). The high-fat diet group had a 3-fold increase in total cancer incidence and a 5-fold increase in advanced lesions (adenocarcinomas). Tumor incidence and yield were not changed in either diet group by CCK-receptor blockade during the initiation period. Cholecystokinin appears to mediate the short-term trophic effect that high-fat feeding has on the pancreas. However, potentiation of pancreatic cancer by high-fat diet in the hamster cancer model does not appear to be influenced by endogenous cholecystokinin at the time of tumor induction.

Animals↗
PubMed1995

Induction of pancreatic growth and proteases by feeding a high amino acid diet does not depend on cholecystokinin in rats.

We examined differences in pancreatic growth, enzyme content and enzyme concentration between rats fed diets containing normal (2.49 g nitrogen/kg diet) or high (7.46 g nitrogen/kg diet) levels of an amino acid mixture and those in rats fed diets containing normal and high levels of casein for 11 d. Rats fed these diets were injected with a potent cholecystokinin antagonist, MK-329 (2.5 mg/kg body wt.d) or with vehicle only. Pancreatic contents (units in pancreas per 100 g body wt) of protein, trypsinogen and chymotrypsinogen were greater in rats fed a high amino acid diet compared with those in rats fed a normal amino acid diet. Proportionate increases in protein and the serine proteases in pancreata of the high amino acid group relative to those of the normal amino acid group were comparable to those of the high casein group relative to the normal casein group. The pancreatic protease concentrations (units/g pancreas) of rats fed the high casein diet and treated with MK-329 were lower than in rats fed high casein but not treated with MK-329. This difference was not observed in rats fed the high amino acid diet. These results demonstrate that pancreatic growth and proteases are induced by dietary amino acids in rats, and the stimulatory effects of amino acids on exocrine pancreas do not depend on cholecystokinin.

Amino Acids↗
PubMed2003

The soybean beta-conglycinin beta 51-63 fragment suppresses appetite by stimulating cholecystokinin release in rats.

We previously demonstrated that soybean beta-conglycinin peptone suppresses food intake and gastric emptying by direct action on rat small intestinal mucosal cells to stimulate cholecystokinin (CCK) release. The aim of the present study was to define the active fragment in beta-conglycinin by using synthetic peptides chosen from the sequence of three beta-conglycinin subunits. We selected the fragments that had multiple nonadjacent arginine residues, and investigated their ability to bind to components of the rat intestinal brush border membrane as well as to stimulate CCK release and appetite suppression. The fragment from 51 to 63 of the beta subunit (beta 51-63) had the strongest binding activity. Intraduodenal infusion of beta 51-63 inhibited food intake and markedly increased portal CCK concentration. The threshold concentration of beta 51-63 to affect food intake was 3 micro mol/L. The CCK-A receptor antagonist abolished the beta 51-63-induced suppression of food intake. Three types of smaller fragments of beta 51-63 (beta 51-59, beta 53-63 and beta 53-59) and two types of fragments similar to beta 51-63 in the beta-conglycinin alpha and alpha' subunits (alpha 212-224 and alpha' 230-240) had less binding ability than did beta 51-63. Model peptides constructed with arginine (R) and glycine (G), such as GRGRGRG, had strong binding affinity, but peptides containing a single R or RR did not. These results indicate that the beta-conglycinin beta 51-63 fragment is the bioactive appetite suppressant in beta-conglycinin, and multiple arginine residues in the fragment may be involved in this effect.

Animals↗
PubMed1996

Influence of gastrin on human astrocytic tumor cell proliferation.

BACKGROUND: Gastrin and cholecystokinin (CCK) mediate their effects through at least two types of receptors (CCK receptors A and B). While it has been hypothesized that gastrin, a stimulator of gastric acid secretion, is also a neurotransmitter and a stimulator of cell proliferation in various normal and neoplastic tissues, its effect on astrocytic brain tumors has not been actively investigated. PURPOSE: Our goal was to determine the effects of gastrin and gastin and/or CCK antagonists on the proliferation in vitro of astrocytic tumor cells by use of both established cell lines and primary cell cultures of tumor tissue. METHODS: Ten established astrocytic tumor cell lines, SW1088, SW1783, Hs683, H4, U87, U118, U138, U373, T98G, and A172, were studied. The effects of added gastrin (at 0.01, 0.1, and microM) and the gastrin/CCK antagonists L-365,260, CI-988, L-364,718, and JMV 234 (each at 0.01, 0.1, and 1 microM) on the cellular proliferation rates of the 10 cell lines were indirectly measured by use of the colorimetric tetrazolium assay. The influence of gastrin (at 0.01 microM) on the cellular proliferation of primary cultures from nine freshly explanted astrocytic tumors was assessed by means of tritiated thymidine uptake and autoradiography. RESULTS: At specific concentrations, added gastrin increased the cellular proliferation of three established astrocytic cell lines (A172, Hs683, and SW1088), decreased it in two (U373 and T98G), and was without effect on the remaining five. Gastrin decreased cellular proliferation in one primary astrocytic tumor cell culture, stimulated it in five, and had no apparent effect in the remaining three. L-365,260, a CCK receptor B antagonist used at 0.01 microM, increased cellular proliferation in seven cell lines (A172, H4, Hs683, SW1783, T98G, U118, and U138), decreased it in one (U87), and had no effect in the remaining two. CI-988, another CCK receptor B antagonist used at 0.01 microM, inhibited cellular proliferation in five cell lines (A172, H4, SW1783, U373, and U87), stimulated it in two (T98G and U138), and had no effect in three. The CCK receptor A antagonists L-364,718 and JMV 234, both used at 0.01 microM, affected the cellular proliferation of only three of the 10 cell lines. CONCLUSIONS: These results suggest that gastrin (and perhaps CCK that belongs to the same peptide family) may play a role in the growth of a substantial proportion of human astrocytic tumors.

Amino Acid Sequence↗