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At least 505 records · Page 28Linked to original sources
PubMed2001

Cholecystokinin-8 (CCK-8) has no effect on heart rate in rats lacking CCK-A receptors.

Heart rate responses to i.v. administration of cholecystokinin-8 (CCK-8) were investigated in Otsuka Long-Evans Tokushima Fatty (OLETF) rats lacking CCK-A receptors and control Long-Evans Tokushima Otsuka (LETO) rats. The heart rate decreased after i.v. administration of 3 nmol.kg(-)(1) of CCK-8 in LETO rats, but not in OLETF rats. Bradycardia in the LETO rats disappeared after treatment with MK-329, but not after treatment with L-365,260. The expression of CCK-A receptor precursor mRNA was found exclusively in the atrium in LETO rats. These results suggest that CCK-8 decreases heart rate via CCK-A receptors located in the atrium of the rats.

Animals↗
PubMed2002

Cholecystokinin-8 induces intracellular calcium signaling in cultured myenteric neurons from neonatal guinea pigs.

The responsiveness of cultured myenteric neurons to cholecystokinin (CCK-8) was examined using fura-2-based digital microfluorimetric measurement of intracellular calcium ([Ca(2+)](i)). CCK-8 (10(-10)-10(-6)M) evoked concentration-dependent increases in percentage of neurons responding (8-52%) and delta[Ca(2+)](i) (76-169 nM). Gastrin (1 microM) also induced an increase in [Ca(2+)](i) in 29+/-6% of neurons (delta[Ca(2+)](i): 71+/-3 nM). L-364,718, an antagonist for the CCK-A receptor, blocked [Ca(2+)](i) response to CCK-8. Removal of extracellular calcium eliminated CCK-induced [Ca(2+)](i) increments, as did the addition of the calcium channel inhibitors nickel (1mM) and lanthanum (5mM). Nifedipine (1-50 microM) dose-dependently attenuated CCK-caused [Ca(2+)](i) responses. CCK evokes [Ca(2+)](i) signaling in myenteric neurons by the influx of extracellular calcium, likely through L-type calcium channels.

Animals↗
PubMed2003

Effect of long-term CCK blockade on the pancreatic acinar cell renewal in rats with acute pancreatitis.

This study determines the effect of 7-day pretreatment with L364,718 (a potent cholecystokinin (CCK) receptor antagonist) on pancreatic cell turnover during the course of acute pancreatitis (AP) induced in the rat by bile-pancreatic duct obstruction (BPDO). Cell cycle distribution and apoptosis were analyzed by flow cytometry using propidium iodide (PI) and Annexin V staining. Besides altering the pancreatic redox status, long-term CCK blockade inhibited the normal proliferation of acinar cells as indicated by the significant increase in G(0)/G(1)-phase cells and the decrease in G(2)/M-cells found in control rats treated with L364,718 for 7 days. A progressive depletion in pancreatic GSH was found from 3 to 24h after BPDO with similar values in L364,718-pretreated and non-treated rats, which led to a maximum peak in malondialdehyde (MDA) levels 6h after BPDO. However, plasma amylase activity and ascites volume indicated higher severity of AP in L364,718-pretreated rats. CCK blockade enhanced the alterations that appear in cell cycle distribution of acinar cells during AP demonstrated by the significantly higher increase in G(0)/G(1)-cells and decrease in S-cells found in L364,718-treated rats 48h after BPDO. Our results indicate that the renewal of acinar cells deleted by apoptosis 48h after BPDO worsens if CCK is blocked before inducing AP.

Acute Disease↗
PubMed1997

Relationship between gallbladder bile concentration and motility in conscious dogs: role of cholecystokinin.

The relationship between gallbladder (GB) bile concentration and motility was studied in conscious dogs. The 12-h GB bile concentrations between meals could be divided into three periods: diluting, minimum, and concentrating periods. During the diluting period, inhibition of GB contractions by a CCKA receptor antagonist, atropine or hexamethonium, resulted in concentration of GB bile, whereas during the concentrating period, CCK-8 shifted the concentration process back to dilution. The GB appears to absorb water continuously from GB bile, which is not regulated by cholinergic or CCKA receptors. The postprandial progressive dilution of GB bile is brought about by GB pumping controlled by cholecystokinin (CCK).

Animals↗
PubMed1997

Full and partial agonist activity of C-terminal cholecystokinin peptides at the cloned human CCK-A receptor expressed in Chinese hamster ovary cells.

The agonist activities of the C-terminal cholecystokinin peptides sulfated cholecystokinin octapeptide (CCK-8S), non-sulfated cholecystokinin octapeptide (CCK-8NS), pentagastrin and CCK-4 at the cloned human CCK-A receptor expressed in Chinese hamster ovary cells were evaluated in two functional assays of receptor activation. [125I]-CCK-8S displacement studies employing membranes derived from these cells revealed the expected rank order of affinity for a number of CCK receptor ligands. CCK-8S was a potent agonist in (i) stimulating the mobilization of intracellular free Ca2+, measured with the Ca2+ sensitive fluorescent indicator FURA-2, and (ii) stimulating increases in extracellular acidification rates, measured by microphysiometry. Consistent with their lower affinities for CCK-A receptors, CCK-8NS, pentagastrin and CCK-4 were weaker agonists in both functional assays. In addition, these peptides exhibited partial agonist activity relative to the maximum response observed with CCK-8S in both assays. These results demonstrate that CCK-8S represents the minimum ligand requirement for both high affinity and full agonist activity at the human CCK-A receptor subtype.

Animals↗
PubMed1997

Effect of L364.718 during suckling on the sensitivity to the hypophagic effect of cholecystokinin in adult rats.

1. In the present study it was investigated whether drugs acting at the cholecystokinin (CCK)-A receptor given to rat pups may result in long-lasting changes in body weight or regulation of food intake controlled by CCK. 2. From day 3 to day 10 of life, male and female Wistar rat pups were treated with the CCK-A receptor antagonist L-364.718 and the CCK-A + B agonist CCK-8S. 3. In adult rats, treated with L364.718 during suckling, the sensitivity to the acute hypophagic action of CCK-8S was weaker or abolished compared to adults treated with saline during suckling. In adult rats given CCK-8S during suckling acute treatment with CCK-8S reduced food intake to the same extent as in the group treated with saline postnatally. 4. These data show that early postnatal treatment with the CCK-A receptor antagonist L364.718 has an impact on the hypophagic response to CCK-8S in later life.

Animals↗
PubMed1997

Evidence for a role of cholecystokinin as neurotransmitter in the guinea-pig enteric nervous system.

Intracellular recordings were made of neurons in the myenteric plexus of the guinea-pig distal ileum. Slow excitatory postsynaptic potentials (sEPSPs) were evoked by electrical stimulation of an interganglionic fibre tract. The effect of cholecystokinin (CCK) receptor antagonists on the sEPSPs was investigated in 11 neurons. Application of the CCK receptor antagonists L-364,718 and L-365,260 (each 250 nM) markedly attenuated the sEPSPs in five of 11 neurons. The amplitude of the sEPSP reduced from 15 +/- 3 to 7 +/- 2 mV and the change in membrane resistance during the sEPSP was reduced from 28 +/- 9 to 11 +/- 8 MS. In six of 11 neurons the CCK antagonists had no effect on the sEPSPs. The results provide evidence that neurally released CCK is involved in the mediation of sEPSPs in some enteric neurons.

Animals↗
PubMed1999

Anti-analgesia and reduced antinociception from supraspinally administered beta-endorphin in stressed rats: dependence on spinal cholecystokinin via cholecystokinin B receptors.

Rats exposed to the stress of repeated exposure to a noxious heat source (52.5 degrees C, hot plate) exhibit stress-induced analgesia, but reduced antinociception (detected using the tail-flick test) to the administration of beta-endorphin into the periaqueductal gray region of the brain. This is accompanied by an anti-analgesic response (reduction in the stress-induced increase of tail flick latency) to doses of beta-endorphin (0.03 nmol) lower than those usually associated with antinociception. These alterations are prevented and antinociceptive potency is maintained when rats are treated with cholecystokinin (CCK) antagonists intrathecally. The potency of L-365,260 and L-364,718, selective CCK(B) and CCK(A) receptor antagonists, respectively, correlated with their apparent affinities for CCK(B) receptors, suggesting that the altered sensitivity to beta-endorphin is mediated via CCK(B) receptors.

Analgesia↗
PubMed1997

Caerulein may potentiate morphine-induced antinociception by cholecystokinin-A and/or cholecystokinin-B receptor mechanisms.

1. The effects of a cholecystokinin agonist and antagonist on morphine antinociception in the tail-flick test have been evaluated. 2. The administration of different doses of caerulein (0.01, 0.05 and 0.1 mg/kg) 30 min prior to morphine (1.5, 3 and 6 mg/kg) increased the antinociception induced by morphine in mice. 3. In animals pretreated with cholecystokinin antagonists MK-329 (0.125 and 0.25 mg/kg) and L-365,260 (0.125 and 0.25 mg/kg), the antinociceptive effect of morphine was not changed. However, high doses (0.5 mg/kg) of each antagonist potentiated the morphine response. 4. Low doses of cholecystokinin antagonists (0.125 and 0.25 mg/kg), that did not cause antinociception, when employed in combination with caerulein (0.05 mg/kg) decreased the response of morphine plus caerulein. 5. It is concluded that the cholecystokinin agonist caerulein potentiated the morphine response by stimulation of cholecystokinin-A and/or cholecystokinin-B receptors.

Analgesics, Opioid↗
PubMed1997

Cholecystokinin and neurotensin inversely modulate excitatory synaptic transmission in the parabrachial nucleus in vitro.

Cholecystokinin and neurotensin are present in fibres innervating the parabrachial nucleus and have previously been shown to modulate the flow of visceral afferent information through the parabrachial nucleus to the cortex in the rat. This study examined the effects of cholecystokinin and neurotensin on synaptic transmission in the parabrachial nucleus using a pontine slice preparation and the nystatin perforated-patch recording technique. Stimulation of the ventral, external lateral portion of the parabrachial nucleus elicited glutamate-mediated, excitatory postsynaptic currents in cells recorded in the parabrachial nucleus. Bath application of neurotensin dose-dependently and reversibly enhanced, while cholecystokinin attenuated, the evoked excitatory postsynaptic current. In addition, the frequency of spontaneous, miniature excitatory postsynaptic currents recorded in parabrachial nucleus cells was significantly increased by neurotensin and decreased by cholecystokinin application. Paired-pulse depression was also enhanced and decreased by neurotensin and cholecystokinin, respectively. These synaptic changes induced by neurotensin and cholecystokinin were not accompanied by changes in input resistance of parabrachial nucleus cells over a wide voltage range (although neurotensin reduced an outwardly rectifying conductance at potentials positive to -20 mV), nor did these peptides alter the inward current induced by a brief bath application of the glutamate agonist, alpha-amino-3-hydroxy-methylisoxazole-4-propionate. The neurotensin antagonist, SR48692 (100 microM), completely and reversibly blocked the neurotensin-induced enhancement of the excitatory postsynaptic current. The non-selective cholecystokinin receptor antagonist, proglumide (100 microM), completely and reversibly blocked the cholecystokinin-induced attenuation of the excitatory postsynaptic current. In addition, the selective cholecystokinin-A receptor antagonist, L-364,718 (10 microM), but not the selective cholecystokinin-B receptor antagonist, L-365,260 (100 microM), blocked the effect of cholecystokinin on synaptic transmission. These results suggest that neurotensin and cholecystokinin act at presynaptic neurotensin and cholecystokinin-A receptors, respectively, to modulate excitatory synaptic transmission in the parabrachial nucleus.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2000

Cholecystokinin mediates depression of feed intake in dairy cattle fed high fat diets.

Two experiments were conducted to investigate the effects of 1) different concentrations of dietary fat and 2) i.v. administration of a cholecystokinin receptor antagonist (MK-329) on feed intake and plasma concentrations of hormones and metabolites in dairy cattle. In Experiment 1, 4 lactating Holstein cows were used in a 4 x 4 Latin square design. Treatments were diets with 1) no fat added, 2) 30 g fat/kg feed (calcium salts of long-chain fatty acids as fat supplement), 3) 60 g fat/kg, and 4) 90 g fat/kg added. Cows were fed once daily a diet of concentrate, corn silage, alfalfa haylage, and alfalfa pellets. Dry matter intake decreased linearly with increasing concentrations of dietary fat (P < 0.0001). Overall plasma concentrations of nonesterified fatty acids (P < 0.0001), triacylglycerol (P < 0.0006), and cholecystokinin (P < 0.02), increased linearly with each level of dietary fat, but there was a linear decrease in plasma insulin (P < 0.0008). In Experiment 2, 4 nonpregnant and nonlactating Holstein heifers were used in a cross-over design in a 2 x 2 factorial arrangement of treatments. Treatments were diet (fatty acids, 27 g/kg vs 103 g/kg diet dry matter) and i.v. injections (MK-329 vs vehicle). Heifers were fed once daily a total mixed ration of corn silage, cracked corn and soybean meal with or without fat supplement. Diets were switched by period and either MK-329 (70 microg/kg body weight) or its vehicle was injected i.v. at 2 hr postfeeding. Daily dry matter intake was decreased by feeding the high fat diet (P < 0.02) but was not affected by injections. Injection of MK-329, however, increased dry matter intake by 92% in heifers fed the high fat diet during the first 2 hr postinjection compared to vehicle injection. Plasma pancreatic polypeptide concentration was increased by the high fat diet at 2 hr postfeeding (P < 0.02) but was lowered by MK-329 at 1 hr postinjection (P < 0.001). Plasma insulin was lowered by the high fat diet (P < 0.01) but was not affected by injections. The elevated plasma cholecystokinin concentration may have mediated depressed feed intake of dairy cattle fed the high fat diets.

Animals↗
PubMed2003

Cholecystokinin reduces ethanol consumption in golden hamsters.

In experimental conditions, golden hamsters (Mesocricetus auratus) avidly consume ethanol solutions. However, they are relatively resistant to the deleterious effects of ethanol even after months of continuous consumption, apparently because they metabolize ethanol rapidly and efficiently. Male hamsters with ad libitum access to food and water were presented with isocaloric solutions [weight/weight (wt./wt.)] of 10% ethanol and 17.75% glucose for 40-min periods on alternate days. When hamsters were injected with 0.9% saline before solution presentation the mean intake of ethanol solution (0.55 g) was about half that of glucose solution (1.08 g). Hamsters derived a mean of 0.36 g/kg/40 min of absolute ethanol from the ethanol solution, an amount that does not seem to exceed their metabolic capacity for ethanol. An intraperitoneal injection of a 2.0-microg/kg dose of the C-terminal octapeptide of cholecystokinin (CCK-8) reduced intakes of both solutions by >50% if administered 5 min before solution presentation, but it was ineffectual if administered 45 min before presentation. When citric acid (2.5 g/l) was added to the glucose solution the baseline intakes of the two solutions were virtually equivalent, and when CCK-8 was administered over a range of doses (0.5-2.0 microg/kg) the intakes of the solutions did not differ significantly at any dose, supporting the suggestion that the pharmacological properties of ethanol play little or no role in mediating the consumption-inhibiting effect of exogenously administered cholecystokinin (CCK). Prior administration of lorglumide, a selective CCK type A receptor antagonist, completely attenuated the inhibitory effect of CCK-8. Findings are consistent with the notion that endogenous CCK plays a key role in the short-term control of ethanol intake in hamsters.

Alcohol Drinking↗
PubMedDate not supplied

Spontaneous preference for ethanol in naive rats is influenced by cholecystokinin A receptor antagonism.

Naive adult male Wistar rats free to choose between water or 10% ethanol (v/v) spontaneously became water-preferring (WP) rats, as they drank mainly water (approximately 35 ml per day), or alcohol-drinking (ED) rats, as they also drank a significant amount of ethanol (approximately 14 ml per day). The selective CCKA receptor antagonist L-364,718 at doses selective for the CCKA receptor (5 micrograms/kg, IP) halved the consumption of alcohol of the ED rats without modifying their total liquid in-take. In contrast, the CCKB antagonists L-365,260 or GV150013 were without effect when used at doses selective for the CCKB receptor. These data indicate that the CCK system could be involved in the modulation of alcohol intake. In particular, they suggest that CCKA receptors could play a role in the ethanol preference.

Alcohol Drinking↗
PubMed2003

Alteration of CCK-induced satiety in post-Nippostrongylus brasiliensis-infected rats.

In rats, the nematode Nippostrongylus brasiliensis induces an intestinal inflammation, but after the inflammation had resolved and the worm burden eliminated, morphological alterations of the intestinal wall, mainly consisting of mast cell hyperplasia and enteric nerve remodeling, persist for several weeks. Intestinal signals reaching the brain through the vagus nerve and involving neuropeptides such as CCK, play a role in the control of food intake. Our hypothesis was that neuroimmune alterations of the intestine may alter this control. This work was aimed to evaluate whether post-infection alterations of the intestinal wall may affect the satiety effects of CCK and further, the role of mast cells and their mediators, histamine and serotonin, in post-N. brasiliensis-infected rats. In basal conditions, food intake was not different in control and post-infected groups of rats. Post-infected rats were characterized by prolonged satiety effects of both CCK and histamine but not serotonin. The prolonged effect of CCK was reduced when mast cells were previously stabilized by ketotifen, which had no effect per se on food intake. No difference was observed in the increase of food intake induced by CCK-A and CCK-B receptor antagonists in both control and post-infected rats. Mast cell degranulation with compound 48/80 induced severe anorectic effects that lasted for less than 24h in post-infected rats and as long as 6 days in controls. Thus, in our experimental conditions, i.e., within 30-50 days post-N. brasiliensis infection, we observed an enhancement of the anorectic effect of exogenous CCK involving mast cell degranulation and histamine.

Animals↗
PubMed1999

Quantitative structure-activity relationship study on some nonpeptidal cholecystokinin antagonists.

A quantitative structure-activity relationship (QSAR) analysis has been performed on a series of 1,4-benzodiazepine derivatives, which were found to act as antagonists of cholecystokinin (CCK), a gastrointestinal peptide hormone. The CCK acts with three different receptor subtypes termed as CCK-A, CCK-B, and gastrin receptor, which can be found in peripheral system, brain, and stomach, respectively. With all the three subtypes, the binding of the compounds is found to significantly depend on the lipophilicity of the compounds and their ability to form the hydrogen bonds with the receptor. However, the binding sites in CCK-A receptor seem to be slightly rigid as compared to those in CCK-B or gastrin receptor. The latter two appear to have similar binding features.

Animals↗
PubMed1993

Development of 1,4-benzodiazepine cholecystokinin type B antagonists.

A series of 3-(arylureido)-5-phenyl-1,4-benzodiazepines, nonpeptidal antagonists of the peptide hormone cholecystokinin (CCK), are described. Derived by reasoned modification of the CCK-A selective 3-carboxamido-1,4-benzodiazepine, MK-329, this paper chronicles the development of potent, orally effective compounds in which selectivity for the CCK-B receptor subtype was achieved. The principal lead structure that emerged from these studied is L-365,260, a compound which has been submitted for clinical evaluation. Details of the ability to modulate the receptor interactions of these benzodiazepines by appropriate structure modifications are discussed which imply the possibility of further refining the CCK-B receptor affinity and selectivity of this class of compounds.

Animals↗
PubMed1992

Hybrid cholecystokinin-A antagonists based on molecular modeling of lorglumide and L-364,718.

A series of novel nonpeptide cholecystokinin-A (CCK-A) antagonists have been synthesized. Designed on the basis of the structural homology between lorglumide and L-364,718, as investigated with molecular modeling, these compounds constitute a link between the N-acylglutamic acid and 3-amino-5-phenyl-1,4-benzodiazepin-2-one derived antagonists. The prepared compounds were tested in vitro as antagonists of the binding of [3H]-(+/-)-L-364,718 and [3H]-CCK-8(S) to rat pancreas and guinea pig brain membranes, respectively. All compounds proved to be selective for the (peripheral) CCK-A receptor, the most potent analogue, 6, having a Ki value of 90 nM. The structure-activity profile of the series of hybrid compounds relates closest to that of the N-acylglutamic acid derived antagonists.

Animals↗