[Cholecystokinin and its antagonists: effects on digestive motility].
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Benzodiazepinones↗
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Role of cholecystokinin in postprandial and vagally stimulated duodenal and gallbladder motility in dogs.
This study was designed to determine the role of cholecystokinin (CCK) in postprandial motility pattern of the duodenum and gallbladder (GB) in conscious dogs provided with chronic duodenal electrodes for recording of myoelectric activity and GB fistulas for measurement of intraluminal pressure and volume of GB and to calculate the GB motility index (MI) and GB emptying rate. During naturally occurring activity front (phase III MMC) in the duodenum there was significant increase in the MI of GB accompanied by about 20-30% reduction in the GB volume. These changes in duodenal and GB motility pattern could be duplicated by i.v. motilin. Feeding abolished the appearance of spontaneous activity front in the duodenum and greatly increased motility of GB while reducing its volume. Administration of CCK receptor antagonists in fed dogs failed to affect the motility changes induced by meal in the duodenum but abolished these of the GB. Vagal cholinergic stimulation with insulin, 2DG or urecholine caused similar effects to that induced by food i.e. increased duodenal spike activity, abolished phase III of the MMC, decreased GB volume and increased GB motility. Pretreatment with CCK antagonists did not affect significantly duodenal spike activity or GB motility but significantly increased the GB volume. Atropine 125 micrograms/kg) blocked almost completely spontaneous activity front in the duodenum and accompanying alterations in the motility and volume of GB. We conclude that CCK contributes to the MMC related alterations in the GB motor activity and is essential in cholinergic stimulation induced of the GB emptying but not in vagally induced duodenal and GB motility.
Animals↗
Cholecystokinin is not a major determinant for the changes in beta-cell function seen after pancreatico-biliary diversion in rats.
The influence of longterm increase in the plasma CCK levels on beta-cell function in rats was studied by using the pancreatico-biliary diversion (PBD) model. An intravenous glucose load (800 mg glucose/kg) was performed three weeks after the PBD operation. Additionally a group of PBD operated animals as well as an unoperated group received the CCK receptor antagonist L364,718 continuously during the three week study period. The proliferation rate of endocrine pancreatic cells was studied by means of 3H-thymidine administration. PBD caused a decrease in basal levels of insulin and glucose and an augmented insulin secretory response after glucose injection. There was no appreciable influence on the glucose elimination rate. When PBD animals were given the CCK receptor antagonist no differences were observed with regard to insulin and glucose compared to PBD animals without antagonist. The CCK-antagonist did not influence the beta-cell function in unoperated animals. Further, the proliferation rate of the endocrine pancreatic cells was not significantly changed in the PBD rats. The results suggest that PBD is accompanied by significant changes in basal and stimulated insulin secretion. These changes are probably not a direct consequence of the increased plasma CCK levels that follows PBD. Moreover, the insulin secretory response to glucose in normal rats was not influenced by longterm administration of the CCK receptor antagonist. Our observations should encourage further studies on the complex entero-insular interactions following pancreaticobiliary diversion.
Animals↗
Effects of protein binding and experimental disease states on brain uptake of benzodiazepines in rats.
The brain uptake of a number of benzodiazepines with different lipophilic and protein binding characteristics was investigated in male Sprague-Dawley rats using the rapid intracarotid artery injection technique. When the compounds were administered as a solution in Ringer's buffer, pH 7.4, the uptake was in the order of [14C]diazepam greater than [14C]L-663,581 (anxiolytic agent) greater than [3H]L-364,718 (morphine analgesia potentiator) greater than [14C]L-365,260 (anxiolytic agent) and their extraction ratio values were 71.0 +/- 6.8, 65.0 +/- 12.0, 42.0 +/- 5.0 and 6.0 +/- 2.0%, respectively. The respective permeability-surface product values were 0.755 +/- 0.152, 0.647 +/- 0.180, 0.329 +/- 0.05 and 0.035 +/- 0.011 ml/min/g. The rank order of brain extraction did not correlate well with the drugs' lipophilicity determined by octanol-buffer partition coefficient. For example, L-365,260 had the highest octanol/buffer partition coefficient, but the lowest brain extraction. Plasma protein binding significantly decreased the uptake by the brain but to a lesser extent than that predicted from the unbound drug fraction in vitro, suggesting that drug binding to plasma protein did not limit the transport of drug through the blood-brain barrier. For one compound, L-364,718, the extraction ratio and permeability-surface product values were increased markedly in CC1(4)-induced hepatic injury. Other disease states, uranyl nitrate-induced renal failure and streptozotocin-induced diabetes, had no apparent effect on the uptake of the compounds tested. The effect of disease state on the brain uptake of drug appeared to be dependent on the type of disease and the type of drug studied.
Animals↗
Effects of MK-329 on gastric emptying of solids in cats.
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Animals↗
Cerulein-induced pancreatitis in the ex vivo isolated perfused canine pancreas.
Infusion of supramaximal doses of the cholecystokinin analog cerulein is well established as an in vivo technique for inducing experimental pancreatitis in small animals. An attempt was made to simulate this model and initiate pancreatitis in the ex vivo isolated perfused canine pancreas. Control preparations gained minimal weight (mean 8.3 +/- 5.1 gm), demonstrated no edema accumulation, and did not develop hyperamylasemia (mean 1342 +/- 790 units) after 4 hours of perfusion. Electron microscopy after 4 hours of perfusion remained normal. Intraarterial cerulein infusion produced significant weight gain (mean 27.6 +/- 12.3 gm; p less than 0.001), edema formation, and marked hyperamylasemia (mean 26,838 +/- 21,341 units; p less than 0.001) after 4 hours of perfusion. During the 4-hour perfusion, electron microscopy of cerulein preparations demonstrated depletion of zymogen granules, condensing vacuole formation, and basolateral exocytosis. Pretreatment of cerulein preparations with the free radical scavengers superoxide dismutase and catalase and the iron chelator deferoxamine did not modify the pancreatitis. Continuous infusion of the nonpeptide cholecystokinin antagonist L364,718 reduced cerulein-induced weight gain (4.3 +/- 3.4 gm; p less than 0.001) and hyperamylasemia (9392 +/- 6718 units; p less than 0.05). We conclude that cerulein pancreatitis in the ex vivo isolated perfused canine pancreatic preparation is identical physiologically, biochemically, and morphologically with that seen in intact animals.
Acid-Base Equilibrium↗
Down-regulation and recycling of high affinity cholecystokinin receptors on pancreatic acinar cells.
First incubating dispersed acini from rat pancreas with monensin, a cation ionophore that can inhibit recycling of receptors, inhibited binding of 125I-cholecystokinin 8 (125I-CCK-8) measured during a second incubation by as much as 50%. A maximal effect of monensin required 90 min of first incubation. Detectable inhibition of binding of 125I-CCK-8 occurred with 300 nM monensin, and inhibition increased progressively with concentrations of monensin up to 25 microM. Pancreatic acini possess two classes of receptors that bind 125I-CCK-8. One class has a high affinity (Kd = 461 pM) and a low capacity for CCK (512 fmol/mg DNA); the other class has a low affinity (Kd = 47 nM) and a high capacity for CCK (18 pmol/mg DNA). First incubating acini with monensin caused an 84% decrease in the number of high affinity CCK receptors with no change in the number of low affinity CCK receptors or the values of Kd for either class of receptors indicating that there is recycling of high affinity CCK receptors but not low affinity CCK receptors. First incubating acini with monensin did not alter CCK-stimulated amylase secretion indicating that in contrast to previous conclusions, occupation of low affinity CCK receptors mediates CCK-stimulated enzyme secretion. Moreover, the biphasic dose-response curve for CCK-stimulated enzyme secretion from monensin-treated acini suggests that pancreatic acini also possess a third, previously unrecognized class of very low affinity CCK receptors.
Animals↗
Centrally administered cholecystokinin suppresses feeding through a peripheral-type receptor mechanism.
Agonists and antagonists selective for the brain-type [cholecystokinin (CCK)-B] and the peripheral-type (CCK-A) CCK receptor were used to localize the site(s) of action at which CCK inhibits food consumption. BC 264, a highly selective CCK-B receptor agonist, did not decrease consumption of a palatable meal when administered either i.p. or into the lateral ventricles of the brain, whereas CCK decreased feeding when administered i.p. at the same doses. CCK decreased feeding when administered i.v.t. at a high dose, 5 micrograms. L-364,718, an antagonist selective for the CCK-A receptor, blocked completely the action of centrally administered CCK, whereas L-365,260, a selective CCK-B receptor antagonist, had no effect on the ability of centrally administered CCK to inhibit feeding. To estimate the quantity of i.v.t. administered CCK which reached the periphery, a tracer of radiolabeled [3H]p-CCK8 ([3H]CCK octapeptide sulfate), combined with unlabeled pCCK8 (5 micrograms) was administered i.c.t. Thirty minutes after administration, intact radiolabeled pCCK8 was extracted from the plasma and measured in the blood in nanomolar concentrations, exceeding the amounts of CCK octapeptide sulfate reported previously to be present in the plasma after a meal. Intraventricularly administered CCK thus appears to reduce feeding in the rat through a mechanism involving a CCK-A receptor subtype in the periphery.
Animals↗
A model of gastric emptying in cats shows solid emptying is promoted by MK-329: a CCK antagonist.
The effect of MK-329, a potent, orally active, nonpeptidal cholecystokinin (CCK) antagonist, was measured on the gastric emptying rate of a solid meal in cats. External scintigraphy of cats that had been fed a meal of technetium-99m-(99mTc) labeled rabbit liver and light cream allowed the measurement of the emptying rates of either the liquid or solid portion of a meal under physiologic conditions. In cats, liquids emptied 2.6 times faster than solids [163 +/- 11 min vs. 62 +/- 3 min (mean +/- s.e.)]. At 3 or 10 mg/kg p.o., MK-329 gastric emptying was significantly accelerated, with the mean half-time of emptying being decreased by 34 +/- 11% (mean +/- s.e.) of the control half-times (p less than 0.02). Using only responders (five of six animals), mean half-time was decreased by 55 +/- 4% of the control half-times. CCK is important in regulating the emptying of solid food from the stomach because the CCK antagonist MK-329 accelerates that emptying.
Animals↗
Role of cholecystokinin in gastric emptying of liquid and solid meals in dogs.
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Animals↗
Autoradiographical detection of cholecystokinin-A receptors in primate brain using 125I-Bolton Hunter CCK-8 and 3H-MK-329.
In vitro autoradiography was performed in order to visualize cholecystokinin-A (CCK-A) receptors in sections of Cynomolgus monkey brain. CCK-A receptors were defined as those which displayed high affinity for the selective non-peptide antagonist MK-329 (L-364,718) and were detected in several regions by selective inhibition of 125I-Bolton Hunter CCK using MK-329 or direct labeling with 3H-MK-329. In the caudal medulla, high densities of CCK-A sites were present in the nucleus tractus solitarius, especially the caudal and medial aspects, and also the dorsal motor nucleus of the vagus. CCK-A sites were localized to a number of hypothalamic nuclei such as the supraoptic and paraventricular nuclei, the dorsomedial and infundibular nuclei as well as the neurohypophysis. The mammillary bodies and supramammillary nuclei also contained CCK-A receptor sites. High concentrations of CCK-A receptors were present in the substantia nigra zona compacta and also the ventral tegmental area and may be associated with dopamine cell bodies. Binding of 3H-MK-329 was also detected in parts of the caudate nucleus and ventral putamen. The detection, by autoradiographical means, of CCK-A receptors throughout the Cynomolgus monkey brain contrasts with similar studies performed using rodents and suggests differences in the density and, perhaps, the importance of CCK-A receptors in the primate as opposed to the rodent. The data suggest the possibility that CCK-A receptors may be involved in a number of important brain functions as diverse as the processing of sensory information from the gut, the regulation of hormone secretion, and the activity of dopamine cell activity.
Animals↗
In vivo pharmacology of L-364,718, a new potent nonpeptide peripheral cholecystokinin antagonist.
The in vivo pharmacological activity of L-364,718, a new, potent peripheral cholecystokinin (CCK) antagonist, was characterized in several species using assay systems that measure various well known actions of CCK upon the gastrointestinal system. Administered p.o., L-364,178 was highly potent in antagonizing cholecystokinin octapeptide (CCK-8)-induced inhibition of gastric emptying in mice (ED50 = 38 micrograms/kg), rats (ED50 = 140 micrograms/kg) and dogs (ED50 = 91 micrograms/kg) as well as CCK-8-induced reduction in food consumption in rats (ED50 = 321 micrograms/kg). Administered i.v., L-364,718 effectively antagonized the contractile effects of CCK on the colon in rabbits (ED50 = 34 micrograms/kg) and the gallbladder in cats (ED50 = 210 micrograms/kg). Secretion of pancreatic protein and amylase elicited by CCK in cats was also antagonized by L-364,718 (ED50 less than 1.0 mg/kg i.v.). The CCK antagonism produced by L-364,718 in all species persisted for at least 2 to 5 hr. In the absence of exogenously administered CCK-8, L-364,718 per se had no effect in any of the assay systems studied, indicating a lack of CCK-like agonist properties. Specificity for CCK was demonstrated by the inability of L-364,718 (1.0-5.0 mg/kg) to antagonize either amino acid- or atropine-induced inhibition of gastric emptying in rats and dogs, respectively. L-364,718 also did not antagonize motilin-induced gallbladder contractions or secretin-induced pancreatic secretion in cats.(ABSTRACT TRUNCATED AT 250 WORDS)
Amylases↗
Roles of endogenous cholecystokinin in biliary, pancreatic and gastric function: studies with L-364,718, a specific cholecystokinin receptor antagonist.
A new, highly potent antagonist of gut cholecystokinin (CCK) receptors has been examined for effects upon postprandial biliary and exocrine pancreatic secretion in conscious dogs with chronic duodenal pouches. This drug (L-364,718) markedly inhibited the postprandial increases in biliary volume, bile acid and bilirubin secretion. However, even at high p.o. doses relative to its ability to antagonize the effects of exogenous CCK, no effects were observed upon the pancreatic secretion of either fluid volume or amylase and lipase under similar conditions. In additional studies, pretreatment with L-364,718 did not significantly reverse the inhibitory effects of a fatty acid salt (sodium oleate) upon gastric emptying in gastric fistula dogs. Moreover, pretreatment with L-364,718 had no significant effects upon postprandial acid and pepsin secretion in lesser curvature (vagally innervated) pouch dogs or did it affect basal (interdigestive) gastric secretion in rats. These results suggest that endogenous CCK plays a critical physiological role in regulating postprandial biliary outflow, but not pancreatic enzyme secretion or the gastric emptying of at least liquid fatty substances. The latter two findings stand in contrast with classical views regarding the physiological function(s) of this hormone.
Amylases↗
Distinct requirements for activation at CCK-A and CCK-B/gastrin receptors: studies with a C-terminal hydrazide analogue of cholecystokinin tetrapeptide (30-33).
We describe here the properties of tert-butyloxycarbonyl-Trp-Leu-Asp-Phe-NHNH2 (A-57696), a C-terminal hydrazide analogue of tert-butyloxycarbonyl-CCK4 (Boc-Trp-Met-Asp-Phe-NH2), at four cholecystokinin (CCK) receptor-bearing tissues, the guinea pig pancreas and gall bladder (Type A), guinea pig cortex (Type B), and NCI-H345 cells, a human small cell lung cancer cell line that expresses CCK-B/gastrin receptors. Using 125I-Bolton-Hunter-cholecystokinin octapeptide (26-33) (125I-Bolton-Hunter-CCK8) as the radioligand, A-57696 was found to be selective for cortical CCK-B receptors (IC50 = 25 nM), compared with pancreatic CCK-A receptors (IC50 = 15 microM). A-57696 behaved as a competitive antagonist in reversing CCK8-stimulated pancreatic amylase secretion and phosphoinositide breakdown. By Schild analysis, its Kd was determined to be 4.7 and 6.8 microM in amylase and phosphoinositide assays, respectively. A-57696 (100 microM) did not elicit gall bladder contraction, and it inhibited contractions induced by CCK8. The Kd of A-57696 at gall bladder CCK-A receptors was 19 microM. In contrast, A-57696 behaved as a partial agonist (80% of maximal CCK8 response) in stimulating calcium mobilization at CCK-B/gastrin receptors on NCI-H345 cells. A-57696 and CCK8 inhibited each other in calcium mobilization experiments utilizing the fluorescent dye Indo-1. Stimulatory actions of CCK8 and A-57696 were reversed by the CCK-B-selective (R)-L-365,260 (100 nM), whereas at the same concentration, the CCK-A-selective (S)-L-365,260 was ineffective. Binding studies using 125I-Bolton-Hunter-CCK8 and 125I-gastrin indicated that binding sites labeled by these two ligands displayed similar affinities for CCK8, desulfated CCK8, gastrin, A-57696, and both enantiomers of L-365,260. A-57696 represents a new class of CCK-A peptide antagonist at guinea pig pancreas a new class of CCK-A peptide antagonist at guinea pig pancreas and gall bladder. Its contrasting functional activities at guinea pig CCK-A and CCK-B/gastrin receptors in a human tumor cell demonstrate that, in addition to the previously described differences in binding specificity for selective agonists and antagonists, CCK-A receptors and CCK-B/gastrin receptors have different requirements for activation.
Amino Acid Sequence↗
Type-A cholecystokinin binding sites in cow brain: characterization using (-)-[3H]L364718 membrane binding assays.
(-)-[3H]L364718 membrane binding assays were employed to localize and characterize cholecystokinin (CCK)-A binding sites in rat and cow brain. Specific binding was detected in all brain areas tested, but in all areas of rat brain and most areas of cow brain the level was too low to allow characterization of the ligand binding specificity of these sites. Membranes prepared from cow nucleus accumbens and striatum contained higher levels of (-)-[3H]L364718 specific binding which represented 55-70% of total binding. Characterization of the ligand binding properties of (-)-[3H]L364718 binding sites in cow nucleus accumbens revealed that these sites are similar to CCK-A sites found in pancreatic membranes. Binding of (-)-[3H]L364718 was saturable and had high affinity (Kd = 45 pm). Sites labeled by (-)-[3H]L364718 displayed stereospecificity for the stereoisomers of CR1409. The competition curve for CCK8 was shallow and was steepened and shifted to the right by the presence of the stable GTP analog guanosine 5'-(beta,delta-imido)triphosphate. The potency of CCK8, but not (-)-L36478, was also affected by the buffer in which the assay was conducted. Future use of (-)-[3H]L364718 membrane binding assays using cow nucleus accumbens and/or striatum will help explore the possibility of differences in ligand recognition among CCK-A sites found in brain and peripheral tissues.
Animals↗
Characterization of the binding of [3H]-(+/-)-L-364,718: a new potent, nonpeptide cholecystokinin antagonist radioligand selective for peripheral receptors.
[3H]-(+/-)-L-364,718 a new, potent and selective nonpeptide peripheral cholecystokinin (CCK) antagonist bound saturably and reversibly to rat pancreatic membranes. The radioligand recognized a single class of binding sites with a high affinity (Kd = 0.23 nM). The binding of [3H]-(+/-)-L-364,718 was stereospecific in that the more biologically active (-)-enantiomer demonstrated greater potency than the (+)-enantiomer. The rank order of potency of various CCK agonists and antagonists in displacing [3H]-(+/-)-L-364,718 correlated with their ability to displace [125I]CCK-8 and their known pharmacological activities in peripheral tissues. However, the absolute potencies of agonists were greater in displacing [125I]CCK-8 than [3H]-(+/-)-L-364,718. As described for other physiologically relevant receptor systems, the potency for displacement of [3H]-(+/-)-L-364,718 binding by CCK agonists, but not antagonists, was reduced by guanosine 5'-(beta, gamma-imido)triphosphate and NaCl and enhanced by MgCl2. [3H]-(+/-)-L-364,718 also demonstrated specific binding to bovine gall bladder tissue but not guinea pig brain or gastric glands, consistent with its selectivity as a peripheral CCK antagonist. [3H]-(+/-)-L-364,718 binding to pancreatic membranes was not affected by various pharmacological agents known to interact with other common peptide and nonpeptide receptor systems. These data indicate that [3H]-(+/-)-L-364,718 represents a new potent nonpeptide antagonist radioligand for the study of peripheral CCK receptors which may allow differentiation of agonist and antagonist interactions.
Animals↗
Autoradiographic localization and biochemical characterization of peripheral type CCK receptors in rat CNS using highly selective nonpeptide CCK antagonists.
Two potent and highly selective nonpeptide antagonists, L-365,031 [1-methyl-3-(4-bromobenzoyl)amino-5-phenyl-3H-1,4 benzodiazepin-2-one] and 3H-L-364,718 [1-methyl-3-(2-indoloyl)amino-5-phenyl-3H-1,4 benzodiazepin-2-one] were used to localize "peripheral" CCK receptors in rat brain. In autoradiographic experiments, L-365,031 displaced 125I-Bolton Hunter CCK-8 binding from the interpeduncular nucleus (IPN) (IC50 = 7 X 10(-8) M), the area postrema (AP), and the nucleus tractus solitarius (NTS) without influencing specific binding to other areas, such as the cerebral cortex or the spinal tract of the trigeminal nerve. Desulfated CCK preferentially inhibited 125I-CCK binding to cerebral cortex (IC50 = 7 X 10(-8) M) rather than IPN (IC50 greater than 1 X 10(-6) M) or AP-NTS. In the medulla the localization of 3H-L-364,718 binding was similar to L-365,031-sensitive 125I-CCK-8 binding and was found in the AP and medial, but not lateral, aspects of the NTS. In membranes prepared from IPN, NTS, and AP, 3H-364,718 binding was of high affinity (Kd = 0.14 nM), saturable (Bmax = 20 fmol/mg protein), and inhibited by compounds previously shown to act at pancreatic CCK receptors. The receptors labeled by 3H-364,718 were modulated by guanyl nucleotide, which reduced agonist affinity 10-fold without affecting antagonist binding. The localization and high density of CCK receptors in AP and NTS suggest that these receptors may play an important role in processing sensory afferent information.
Animals↗
Peripheral and central cholecystokinin receptors regulate postprandial intestinal motility in the rat.
Postprandial cholecystokinin (CCK) has been suggested as an important mediator of disruption of migrating myoelectric complexes (MMC) after a meal. However, the role of CCK in regulating small intestinal motility in rats and the participation of central and/or peripheral CCK-A and B receptors in CCK actions, are still unclear. For this study, Sprague-Dawley rats were prepared with electrodes in the small intestine, a catheter in the jugular vein and an intracerebroventricular (i.c.v.) cannula. Postprandial disruption of the MMC was blocked by the i.v. infusion of the CCK-B antagonist L-365,260 (2 x 10(-7) mol/kg), but not by the infusion of the CCK-A antagonist L-364,718. When administered i.c.v., L-364,718 (2.25 x 10(-9) mol), but not L-365,260, restored the MMC pattern. The i.v. infusion of CCK-8 (1-3 x 10(-9) mol/kg) or CCK-4 (10(-7) mol/kg) disrupted the MMC pattern. CCK-8 effects where prevented by the i.v. infusion of either L-364,718 or L-365,260. Administered i.c.v., only the antagonist L-364,718 prevented CCK-8 disruption of the MMC. These results suggest that CCK-mediated motor changes after a meal are due to stimulation of peripheral CCK-B receptors. CCK also induces a release of central CCK that through CCK-A receptors participates on MMC disruption.
Animals↗