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PubMed2003

Cholecystokinin-A receptors are involved in food intake suppression in rats after intake of all fats and carbohydrates tested.

The hypothesis of these studies was that all fats and carbohydrates suppress food intake, at least in part, via cholecystokinin-A receptors (CCKAR). Fat (coconut oil, beef tallow, olive and safflower oil) and carbohydrate (cornstarch, sucrose, glucose and fructose) preloads were given intragastrically (1 g/4 mL) 30 min before feeding. Devazepide (0.25 mg/kg), a CCKAR antagonist, was given intraperitoneally at 60 or 30 min before or with each of the macronutrient preloads. Devazepide reversed food intake suppression caused by all fat and carbohydrate sources, but the effect was not consistently related to the time of devazepide administration or to any specific feeding interval. Among the fats, coconut and olive oil were most responsive to devazepide. The effect of all carbohydrates on food intake was decreased by devazepide. We conclude that CCKAR play a role in food intake suppression caused by all fats and carbohydrates, but their role is dependent upon the composition of the fat or carbohydrate.

Animals↗
PubMed1999

Pharmacologic profile of TS-941, a new benzodiazepine derivative cholecystokinin-receptor antagonist, in in vitro isolated rat pancreatic acini.

We investigated the pharmacologic characteristics of a newly developed benzodiazepine derivative (S)-(-)-N-[2,3-dihydro-2-oxo-5-phenyl-1-[(1H-tetrazol-5-yl)methyl] -1H-1,4-benzodiazepine-3-yl]-2-indolecarboxamide (TS-941), a cholecystokinin type A (CCK-A)-receptor antagonist, in the isolated rat pancreatic acini and compared with those of well-known CCK-A-receptor antagonists, devazepide and loxiglumide. TS-941 inhibited CCK-8-stimulated amylase release concentration dependently, as did devazepide and loxiglumide, with a half-maximal inhibition (IC50) at 78.6 +/- 10.3 nM. TS-941 was approximately 23 times less potent than devazepide (IC50, 3.4 +/- 0.3 nM), but was 50 times more potent than loxiglumide (IC50, 3,966 +/- 544 nM) in inhibiting 100 pM CCK-8-stimulated amylase release from rat pancreatic acini. TS-941 had a fivefold lower selectivity than devazepide for pancreatic CCK (CCK-A) over brain CCK (CCK-B) receptors but fourfold greater than loxiglumide when IC50 values for inhibition of [125I]CCK-8 binding in isolated acini and cerebral cortex were compared. The antagonism produced by TS-941 was specific for CCK in that the effects of other receptor secretagogues or agents bypassing receptors were not altered. TS-941 caused a parallel rightward shift of the entire dose-response curve for CCK-8-stimulated amylase release without altering the maximal increase, as did devazepide and loxiglumide. TS-941, whether added at the beginning or 20 min after the CCK-8 stimulation, inhibited amylase release. TS-941 caused a concentration-dependent residual inhibition of the action of CCK-8. The acini, once incubated with a high concentration of TS-941 (10 microM; 127 times IC50) for 30 min, was 10-fold less sensitive to CCK-8 than the acini preincubated without TS-941, whereas the sensitivity and the responsiveness to CCK-8 stimulation of those incubated with a low concentration of TS-941 (1.0 microM) were similar to the control acini. These results indicate that TS-941 is a potent, competitive, and selective CCK-A receptor antagonist for the pancreas.

Amylases↗
PubMed1993

Reciprocal interaction of 5-hydroxytryptamine and cholecystokinin in the control of feeding patterns in rats.

1. The effect of the CCKA receptor antagonist, devazepide (100 mg kg-1) on meal parameters during the initial phase of the dark period was studied in free-feeding rats by use of a procedure for continuously monitoring feeding patterns. 2. In a second experiment, the effect of devazepide on the reduction in meal parameters induced by the 5-hydroxytryptamine (5-HT) releaser and uptake inhibitor, (+)-fenfluramine (1.5 mg kg-1) in 4 h food-deprived rats was examined. 3. The hypophagic effect of an intraperitoneal injection of cholecystokinin (CCK-8, 4 micrograms kg-1) was studied in rats treated with the 5-HT receptor antagonist, metergoline (1 and 2 mg kg-1). 4. Devazepide increased the size of the first meal in free-feeding, but not in 4 h food-deprived rats and partially antagonized the effect of (+)-fenfluramine on the size and duration of the first meal. The reduction in eating rate induced by (+)-fenfluramine was not modified by devazepide. No changes in (+)-fenfluramine or (+)-norfenfluramine levels were found in the brain of rats treated with devazepide. 5. The effect of CCK-8 on meal size was completely antagonized by 2 mg kg-1 metergoline. A significant interaction was also found between 2 mg kg-1 metergoline and CCK-8 as regards their effect on the inter-meal interval. 6. The results suggest a reciprocal interaction between 5-HT and CCK-8 in enhancing the satiating effect of food in rats.

Animals↗
PubMed2004

Pharmacological study of IQM-97,423, a potent and selective CCK1 receptor antagonist with protective effect in experimental acute pancreatitis.

The pharmacological profile of the new CCK1 receptor antagonist IQM-97,423, (4aS,5R)-2-benzyl-5-(tert-butylaminocarbonyl-tryptophyl)amino-1,3-dioxoperhydropyrido-[1,2-c]pyrimidine, was examined in in vitro and in vivo studies and compared with typical CCK1 antagonists such as devazepide and lorglumide. IQM-97,423 showed a high affinity at [3H]-pCCK8-labeled rat pancreatic CCK1 receptors, and was virtually devoid of affinity at brain CCK2 receptors. IQM-97,423 antagonized CCK8S-stimulated alpha-amylase release from rat pancreatic acini with a potency similar to devazepide and much higher than lorglumide. In the guinea pig isolated longitudinal muscle-myenteric plexus preparation, IQM-97,423 produced a full antagonism of the contractile response elicited by CCK8S and a weaker effect on the contraction elicited by CCK4, suggesting a selective antagonism at CCK1 receptors. The protective effect of IQM-97,423 and devazepide was tested in two models of acute pancreatitis in rats, induced by injection of cerulein or by combined bile and pancreatic duct obstruction. The new compound fully prevented the cerulein-induced increase in plasma pancreatic enzymes and in pancreas weight with a potency similar to devazepide. In common bile-pancreatic duct ligature-induced acute pancreatitis, IQM-97,423 partially prevented, like devazepide, the increase in plasma pancreatic enzyme activity and in pancreas weight. Consequently, the pyridopyrimidine derivative IQM-97,423 is a potent and highly selective CCK1 receptor antagonist with preventive effects in two experimental models of acute pancreatitis and a potential therapeutic interest.

Acute Disease↗
PubMed1993

[Potentiation of morphine- and ohmefentanyl-induced analgesia by cholecystokinin receptor antagonists in rat].

It has been reported that intrathecal (i.t.) injection of CCK-8 showed a marked antagonism to analgesic effects mediated by mu-opioid receptors in rat. The present study was performed to ascertain whether the blockade of endogenously released CCK-8 by potent and selective CCK-A antagonist devazepide and CCK-B antagonist L-365260 would affect opioid analgesia at the spinal cord level. A marked potentiation of the analgesic effect induced by morphine (4 mg/kg, sc) was produced by i.t. injection of 100 ng devazepide or 2.5 ng L-365260. Dose-response curves for the enhancement of the two drugs on morphine analgesia were bell-shaped. Intrathecal injection of 66 ng devazepide or 1.25 ng L-365260 was also shown to potentiate the analgesic effect induced by the selective mu-opioid agonist ohmefentanyl (OMF) (32 ng, i.t.). The dose-response curves were also bell-shaped. Devazepide or L-365260 per se produced no significant changes in rat tail flick latency (TFL). The above results are interpreted to mean that endogenously released CCK-8 in the spinal cord plays an antagonistic role to opioid analgesia, and it is the CCK-B receptors that mediate the anti-opioid effect since the dose of devazepide is 40-50 times higher than that of L-365260.

Analgesics↗
PubMed1993

Neurobehavioural effects of SR 27897, a selective cholecystokinin type A (CCK-A) receptor antagonist.

The activity of SR 27897, a potent and selective CCK-A vs CCK-B receptor antagonist (Ki = 0.2 nM on guinea-pig pancreas vs 2000 nM on rat brain) was studied on behavioural, electrophysiological and biochemical effects induced by peripheral or central injection of CCK-8S. For comparative purposes, devazepide, a reference CCK-A receptor antagonist, was investigated in these same models. CCK-induced hypophagia and CCK-induced hypolocomotion in rats, two behavioural changes associated with the stimulation of peripheral CCK-A receptors, were dose-dependently antagonized by SR 27897 (ED50 = 0.003 and 0.002 mg/kg i.p., respectively) and devazepide (ED50 = 0.02 and 0.1 mg/kg i.p., respectively). CCK-induced decrease of cerebellar cGMP levels in mice was also reduced by SR 27897 (ED50 = 0.013 mg/kg) and by devazepide (0.084 mg/kg). The CCK-induced turning behaviour after intrastriatal injection in mice, and the potentiation of the rate suppressant activity of apomorphine on rat DA neurons, were blocked by higher doses of SR 27897 and devazepide, consistent with the probable central origin of these effects. The respective ED50s were 0.2 mg/kg i.p. for SR 27897 and 4.9 mg/kg i.p. for devazepide in the former model, while the respective minimal effective doses were 1.25 and 5 mg/kg i.p. in the latter test. In most tests the i.p./p.o. ratio for SR 27897 was near unity, suggesting a high oral bioavailability of the compound. Taken together, these findings support the notion that SR 27897 behaves as a potent CCK-A antagonist able to cross the blood brain barrier.

Animals↗
PubMed1994

Opposite effects mediated by CCKA and CCKB receptors in behavioural and hormonal studies in rats.

We compared the influence of two cholecystokinin (CCK) antagonists, devazepide and L-365,260 [3R-(+)-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3y l)-N'-(3-methyl-phenyl)urea], upon two distinct phenomena, behavioural and hormonal effects of caerulein (5 micrograms/kg s.c.), and unselective CCK agonist, in rats. Behavioural effects were assessed in the elevated plus-maze and open field tests. In separate experiments, effects on thyrotropin (TSH), prolactin (PRL) and growth hormone (GH) levels in serum of male rats were studied. Caerulein inhibited the exploratory behaviour in the plus-maze. Time spent in the open part, the number of line crossings and closed arm entries were significantly decreased, whereas the ratio of failed attempts/closed arm entries was increased. The anti-exploratory effect of caerulein was antagonized by the pretreatment with L-365,260 (10 micrograms/kg), a preferential antagonist at CCKB receptors, but was increased by devazepide (1-100 micrograms/kg), a preferential CCKA antagonist. L-365,260 (1-100 micrograms/kg) and devazepide (1-100 micrograms/kg) given alone did not change the behaviour of rats in the plus-maze test. Caerulein (5 micrograms/kg) itself did not modify the locomotor activity of rats in open field. However, the concomitant administration of caerulein with devazepide (1-10 micrograms/kg) reduced the frequency of line crossings and rearings. In the hormonal studies caerulein significantly decreased the cold-induced increase of TSH levels in serum. GH and PRL levels were not markedly affected by caerulein.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Time-course of the pancreatic changes following long-term stimulation or inhibition of the CCK-A receptor.

Cholecystokinin (CCK) reportedly induces both hyperplastic and hypertrophic changes in the pancreas. Blockade of the CCK receptor results in decreased pancreatic secretion and atrophy. The aim of this study was to evaluate the time-course of the effects of stimulation and inhibition of the CCK-A receptor in the rat exocrine pancreas. Male rats had infusion of sulfated CCK-8, the CCK-A receptor antagonist devazepide, or sodium chloride by osmotic minipumps. After 36 h, 3, 7, or 28 d the rats had ip injections of thymidine, and 1 h later they were sacrificed. The pancreas was excised, weighed, and its content of protein, DNA, water, and enzymes was analyzed. Histologic samples were prepared for autoradiography. Pancreatic weight, protein, and DNA were increased at 36 h after the start of CCK infusion and throughout the study period. CCK stimulation also increased the content of trypsin at days 3 and 28. The labeling index of pancreatic acinar cells was increased at 36 h. Blockade of endogenous CCK by the receptor antagonist devazepide led to decreased pancreatic weight from the third day of infusion, whereas the protein content was decreased from the seventh day. At day 28, the DNA content was decreased by devazepide. However, the labeling index of acinar cells decreased transiently already at 36 h. Neither CCK nor devazepide caused any changes of protein content:DNA content ratio during the study. Continuous infusion of CCK caused pancreatic hyperplasia already after 36 h. Stimulation up to 28 d did not cause any further effects. The adverse changes found after blockade of the CCK-A receptor showed much of the same time-course.

Animals↗
PubMed1996

The changes in the rat parotid glands following total parenteral nutrition and pancreatico-biliary diversion are not mediated by cholecystokinin.

CONCLUSIONS: The results of the present study suggest that the pancreas and parotid glands both respond with hypoplasia during absence of food in the digestive tract and with hyperplasia following pancreatico-biliary diversion (PBD). Factors other than cholecystokinin (CCK) are, however, involved in the effects on the parotid glands, since infusion of CCK-8S and devazepide was without influence. BACKGROUND AND AIM: Total parenteral nutrition (TPN) causes reduced pancreatic weight, whereas PBD evokes hyperCCKemia and enlargement of the rat pancreas. The pancreas and parotid glands have in part similar morphology and function. Therefore, we studied the possible presence of alterations also in the parotid glands during TPN, after PBD and during infusion of sulfated cholecystokinin (CCK-8S) and the CCK-A receptor antagonist devazepide, respectively. MATERIALS AND RESULTS: Rats either received TPN for 7 d, or were kept under otherwise identical conditions with free access to food and water. TPN markedly reduced both pancreatic and parotid wet weight and thereby also the protein and amylase contents, and pancreatic DNA content was decreased. There was a significant correlation between the pancreas and parotid glands when comparing these parameters. The concentration of plasma CCK was unaffected by TPN. PBD caused a sevenfold increase in plasma CCK and a three fold increase in the pancreatic weight compared to control rats 28 d after the operation. The protein and DNA contents in the pancreas were found to be increased. The parotid glands increased twofold in weight, but their protein and amylase contents were not affected. There was a significant correlation between the pancreas and parotid glands when comparing weight, and protein and amylase concentrations. Infusion of CCK-8S during 28 d caused a marked increase in pancreatic wet wt and protein and DNA contents. The CCK-A receptor antagonist devazepide induced a reduction in protein and DNA contents in the pancreas. The parotid glands were not affected by either treatment. No effect on the labeling index of serous and ductal cells of the parotid gland was seen at 36 h, 3, 7, and 28 d of infusion with CCK-8S or devazepide.

Amylases↗
PubMed2006

CCK2 receptors mediate inhibitory effects of cholecystokinin on the motor activity of guinea-pig distal colon.

Cholecystokinin and related peptides are involved in the control of intestinal motility and cholecystokinin receptor ligands might represent new pharmacological tools for the treatment of symptoms associated with functional bowel disorders. However, the respective roles played by cholecystokinin receptor subtypes and the mechanisms underlying these regulatory actions remain undetermined. This study was designed to examine the influence of cholecystokinin receptor subtypes on the motor activity of guinea-pig distal colon. The effects of drugs acting on CCK1 and CCK2 receptors were assessed in vitro on the contractile activity of longitudinal smooth muscle, both under basal conditions and in the presence of transmural electrical stimulation or KCl-induced contractions. The application of cholecystokinin octapeptide sulphate (cholecystokinin-8S) to colonic preparations induced concentration-dependent contractions which were prevented by devazepide (CCK1 receptor antagonist), enhanced by GV150013 (CCK2 receptor antagonist) or N(omega)-nitro-L-arginine methylester (L-NAME, nitric oxide synthase inhibitor), and unaffected by tetrodotoxin. The application of gastrin-17 to colonic preparations resulted in relaxant responses which were insensitive to devazepide, and prevented by GV150013, L-NAME or tetrodotoxin. L-NAME, N(omega)-propyl-L-arginine (NPA, neuronal nitric oxide synthase inhibitor) or GV150013 enhanced electrically evoked contractile responses, whereas devazepide did not. When tested in the presence of L-NAME or NPA the enhancing effect of GV150013 on electrically induced contractions no longer occurred. In the presence of KCl-induced pre-contractions, cholecystokinin-8S or gastrin-17 evoked concentration-dependent relaxations, which were unaffected by devazepide and were counteracted by GV150013, L-NAME, NPA or tetrodotoxin. In conclusion, the present results indicate that, at level of distal colon, CCK1 receptors mediate direct contractile effects on smooth muscle, whereas CCK2 receptors on enteric neurons mediate relaxant responses via nitric oxide release.

Adamantane↗
PubMed1999

CCK1 and CCK2 receptors regulate gastric pepsinogen secretion.

The present study investigated (1) the pharmacological profile of cholecystokinin (CCK) receptor subtypes involved in the regulation of gastric pepsinogen secretion, (2) the influence of gastric acidity on peptic responses induced by CCK-8-sulfate (CCK-8S) or gastrin-I; and (3) the mechanisms accounting for the effects of CCK-like peptides on pepsinogen secretion. In anaesthetized rats, i.v. injection of CCK-8S or gastrin-I increased both pepsinogen and acid secretion. The pepsigogue effect of CCK-8S was higher than that of gastrin-I, whereas acid hypersecretion after CCK-8S was lower than that induced by gastrin-I. Peptic output following CCK-8S was partly blocked by i.v. injection of the CCK1 receptor antagonist, devazepide (-75.3%), or the CCK2 receptor antagonist, L-365,260 [3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3 yl)-N'-(3-methyl-phenyl)urea; -27.9%], but was fully prevented by combined administration of devazepide and L-365,260. The gastric acid hypersecretory effect of CCK-8S was enhanced by devazepide (+84.5%) and blocked by L-365,260. In contrast, the gastric secretory actions of gastrin-I were insensitive to devazepide, but abolished by L-365,260. Excitatory effects of CCK-8S and gastrin-I were not modified by vagotomy or atropine, whereas cimetidine or alpha-fluoromethylhistidine (irreversible blocker of histidine decarboxylase) partly prevented acid hypersecretion induced by both peptides without affecting their pepsigogue effects. After pretreatment with omeprazole, both CCK-8S and gastrin-I failed to stimulate acid secretion, while they increased pepsinogen output. In rats with gastric perfusion of acid solutions, CCK-8S or gastrin-I increased peptic output in a pH-independent manner either with or without pretreatment with omeprazole. Ablation of capsaicin-sensitive sensory nerves as well as application of lidocaine to the gastric mucosa failed to modify the excitatory effects of CCK-8S or gastrin-I on pepsinogen and acid secretion. Blockade of the nitric oxide (NO) synthase pathway by N(G)-nitro-L-arginine-methyl ester prevented the pepsigogue actions of both CCK-8S and gastrin-I (-61.8% and -71.7%, respectively), without affecting the concomitant increase in acid output. In addition, both these peptides significantly increased the release of NO breakdown products into the gastric lumen. The present results suggest that: (1) both CCK1 and CCK2 receptors mediate the peptic secretory responses induced by CCK-like peptides; (2) the excitatory inputs of CCK-8S and gastrin-I to chief cells are not driven through acid-dependent mechanisms or capsaicin-sensitive afferent sensory nerves; and (3) under in vivo conditions, the stimulant actions of CCK-like peptides on pepsinogen secretion are mediated, at least in part, by an increase in NO generation.

Acids↗
PubMed1998

A CCK(A)-receptor antagonist administered to the neonate alters mother-infant interactions in the rat.

The importance of the infant's cholecystokinin (CCK) system for eliciting optimal maternal care was examined in 6-9-day-old Sprague-Dawley rats. After administration of either vehicle, CCK-8 (1 or 8 microg/kg) or devazepide (1 mg/kg; a selective CCK(A) receptor antagonist), pups were either individually isolated (Experiment 1) or individually reunited with their dam (Experiment 2) and the rats' behavior was observed. When isolated, pups that received devazepide displayed significantly more head-lifting and wall-climbing attempts than vehicle-treated controls, suggesting that endogenous CCK dampens activity. Devazepide-treated rats were found more frequently in proximity with their mothers when reunited with them, and they emitted more ultrasonic vocalizations compared to vehicle controls. Pups treated with 1 microg/kg CCK received less body licking than vehicle controls. In addition, dams hovered and crouched over devazepide-treated pups more than over pups treated with 1 microg/kg CCK. The results suggest that endogenous CCK has a calming, quieting effect in the neonatal pup and that this, in turn, results in less infant-mother attractivity and reduced levels of maternal care.

Animals↗
PubMed2001

Examining the role of cholecystokinin in appetitive learning in the infant rat.

The role of Cholecystokinin (CCK), a gut hormone and neuropeptide, in early learning was examined. Pairing a novel odor (presented away from the nest) with exogenously administered CCK (0.25 & 0.5 microg/kg IP) has been shown to produce a conditioned-odor preference in infant rats (Weller, A.; Blass, E.M. Behav. Neurosci. 104:199-206; 1990). This suggests that CCK can act as a positive unconditioned stimulus (UCS). In the present study the possibility that CCK mediates learning was examined in 12-day-old rats, using rewards that represent aspects of the dam and the nest. In Experiments 1 and 2, pups received the selective CCK1 receptor antagonist devazepide (600 microg/kg), the selective CCK2 receptor antagonist L365,260 (600 microg/kg), or vehicle. In a series of training trials, choosing a particular floor texture was rewarded by 20 sec. on a rug texture (experiment 1) or with maternal (feces) odor (experiment 2). In experiment 3, after administering devazepide (0, 600, or 1000 microg/kg) a novel odor was paired once with reunion of the pup with its dam. The dependent measure in all studies was the pup's relative preference toward the (tactile or olfactory) conditioned stimulus (CS), determined in preference tests. Conditioned preferences were evident in all experiments. The CCK receptor antagonists did not increase conditioned preference levels. L365, 260 (experiment 2) and devazepide (experiment 1) clearly blocked the appearance of the conditioned effect in one of the experiments. In addition, devazepide treatment eliminated the conditioned effect in the two other experiments, by increasing preference levels in the control groups. In summary, the results suggest that endogenous CCK mediates some aspects of the infant's acquisition of new associations. The role of the two receptor-subtypes appears to be different, depending on the context and the nature of the rewarding stimulus.

Animals↗
PubMed1993

Endogenous cholecystokinin reduces vocalization in isolated 10-day-old rats.

Devazepide, the cholecystokinin (CCK) A receptor blocker, markedly and specifically affected the behavior of 10-day-old rats isolated from their mother and siblings. Whereas intraoral infusions of milk or fat, which cause CCK release, calmed infants, that is, reduced levels of ultrasonic vocalization, devazepide fully blocked this reduction. Devazepide did not affect calming caused by sucrose infusions, which do not release CCK. Moreover, devazepide did not reduce the elevated pain limen caused by milk or fat infusions. These data parallel earlier findings obtained with administration of exogenous CCK and implicate endogenous CCK in the maintenance of infant steady state and calm. The possibility that CCK contributes to the normal development of mother-infant affectional systems is discussed.

Animals↗
PubMed2003

Effects of peripheral CCK receptor blockade on food intake in rats.

Type A cholecystokinin receptor (CCKAR) antagonists differing in blood-brain barrier permeability were used to test the hypothesis that satiety is mediated, in part, by CCK action at CCKARs located peripheral to the blood-brain barrier. At dark onset, non-food-deprived rats received a bolus injection of devazepide (2.5 micromol/kg iv), a 3-h infusion of A-70104 (1 or 3 micromol x kg-1 x h-1 iv), or vehicle either alone or coadministered with a 3-h infusion of CCK-8 (10 nmol x kg-1 x h-1 iv) or a 2-h intragastric infusion of peptone (1 g/h). Food intake was determined from continuous computer recordings of changes in food bowl weight. Devazepide penetrates the blood-brain barrier; A-70104, the dicyclohexylammonium salt of Nalpha-3-quinolinoyl-d-Glu-N,N-dipentylamide (A-65186), does not. CCK-8 inhibited 3-h food intake by more than 50% and both A-70104 and devazepide abolished this response. A-70104 and devazepide stimulated food intake and similarly attenuated the anorexic response to intragastric infusion of peptone. Thus endogenous CCK appears to act, in part, at CCKARs peripheral to the blood-brain barrier to inhibit food intake.

Animals↗
PubMed2002

Effects of peripheral CCK receptor blockade on gastric emptying in rats.

Type A CCK receptor (CCKAR) antagonists differing in blood-brain barrier permeability [devazepide penetrates; the dicyclohexylammonium salt of Nalpha-3-quinolinoyl-d-Glu-N,N-dipentylamide (A-70104) does not] were used to test the hypothesis that duodenal nutrient-induced inhibition of gastric emptying is mediated by CCKARs located peripheral to the blood-brain barrier. Rats received A-70104 (700 or 3,000 nmol. kg(-1). h(-1) iv) or devazepide (2.5 micromol/kg iv) and either a 15-min intravenous infusion of CCK-8 (3 nmol. kg(-1). h(-1)) or duodenal infusion of casein, peptone, Intralipid, or maltose. Gastric emptying of saline was measured during the last 5 min of each infusion. A-70104 and devazepide abolished the gastric emptying response to a maximal inhibitory dose of CCK-8. Each of the macronutrients inhibited gastric emptying. A-70104 and devazepide attenuated inhibitory responses to each macronutrient. Intravenous injection of a CCK antibody to immunoneutralize circulating CCK had no effect on peptone or Intralipid-induced responses. Thus endogenous CCK appears to act in part by a paracrine or neurocrine mechanism at CCKARs peripheral to the blood-brain barrier to inhibit gastric emptying.

Animals↗
PubMed2002

Effects of peripheral CCK receptor blockade on feeding responses to duodenal nutrient infusions in rats.

Type A cholecystokinin receptor (CCKAR) antagonists differing in blood-brain barrier permeability were used to test the hypothesis that duodenal delivery of protein, carbohydrate, and fat produces satiety in part by an essential CCK action at CCKARs located peripheral to the blood-brain barrier. Fasted rats with open gastric fistulas received devazepide (1 mg/kg iv) or A-70104 (700 nmol. kg(-1). h(-1) iv) and either a 30-min intravenous infusion of CCK-8 (10 nmol. kg(-1). h(-1)) or duodenal infusion of peptone, maltose, or Intralipid beginning 10 min before 30-min access to 15% sucrose. Devazepide penetrates the blood-brain barrier; A-70104, the dicyclohexylammonium salt of Nalpha-3-quinolinoyl-d-Glu-N,N-dipentylamide, does not. CCK-8 inhibited sham feeding by approximately 50%, and both A-70104 and devazepide abolished this response. Duodenal infusion of each of the macronutrients dose dependently inhibited sham feeding. A-70104 and devazepide attenuated inhibitory responses to each macronutrient. Thus endogenous CCK appears to act in part at CCKARs peripheral to the blood-brain barrier to inhibit food intake.

Animals↗
PubMed1996

Role of cholecystokinin in the anorexia produced by duodenal delivery of glucose in rats.

We used the type A cholecystokinin receptor (CCK-AR) antagonist devazepide to assess the importance of CCK in mediating the anorexia produced by 2-h duodenal infusions of glucose (9.2, 11.0, and 18.3 mmol.kg-1.h-1) and the glucose dimer maltose (4.5, 6.7, and 8.5 mmol.kg-1.h-1) at the start of the dark period in nonfasted rats with free access to food. Glucose and maltose appeared to inhibit 2- to 3-h food intakes dose dependently from 19 to 91%. The highest doses of glucose and maltose administered suppressed feeding similarly by increasing first meal latency and decreasing meal frequency; lower doses produced less reliable effects on meal patterns. Devazepide appeared to completely reverse the cumulative intake responses and some of the meal pattern responses to the 9.2-mmol.kg-1.h-1 dose of glucose and to partially attenuate responses to the two higher glucose doses and to the minimal effective dose of maltose (6.7 mmol.kg-1.h-1). The magnitudes of these devazepide effects were not statistically different from those produced by devazepide when vehicle was infused duodenally. These results suggest that CCK may play a significant necessary role in mediating the satiety response to duodenal delivery of small but not large loads of glucose.

Animals↗