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The inability of CCK to block (or CCK antagonists to substitute for) the stimulus effects of chlordiazepoxide.

To further examine the relationship between cholecystokinin (CCK) and GABA, the present study assessed the ability of the CCK-A antagonist devazepide and the CCK-B antagonist L-365,260 to substitute for the stimulus effects of chlordiazepoxide (CDP), as well as the ability of CCK-8s to block these effects, in female Long-Evans rats within the conditioned taste aversion baseline of drug discrimination learning. Both devazepide and L-365,260 failed to substitute for the discriminative stimulus properties of CDP, and CCK-8s failed to block its stimulus effects. The benzodiazepine diazepam did substitute for, and the benzodiazepine antagonist flumazenil did block, the stimulus effects of CDP. This suggests that the lack of substitution for, or antagonism of, CDP by the CCK antagonists and CCK-8s, respectively, was not due to the inability of the present design to assess such effects. Possible bases for the current findings, e.g., necessity of an anxiogenic baseline, drug and receptor specificity, as well as the dose-response nature of the interaction, were discussed. Given that a relationship between CCK and GABA has been reported in other designs, the present results suggest that such a relationship may be preparation specific.

Animals↗
PubMed2000

Release of distal gut peptide YY (PYY) by fat in proximal gut depends on CCK.

We tested the hypothesis that the release of PYY by fat confined to the proximal small intestine is dependent on CCK. Using a multi-fistulated model, plasma PYY levels were compared in 6 dogs after 60 mM oleate was perfused into the proximal one-half of the small intestine following i.v. administration of saline or devazepide, a CCK-A antagonist. Plasma PYY increased with fat (P < 0. 05), but plasma PYY level was lower following devazepide at 60 min and 90 min (P < 0.05). We conclude that CCK serves as a foregut signal linking fat in the proximal gut with the release of distal gut PYY.

Animals↗
PubMed1998

Cholecystokinin modulates the aversive component of morphine withdrawal syndrome in rats.

The conditioned place aversion paradigm was used to investigate the role of cholecystokinin in the aversive/dysphoric component of morphine abstinence. Several cholecystokinin ligands were chronically administered during the development of morphine dependence: the CCKA antagonist devazepide, the CCKB antagonists PD-134,308 and L-365,260, and the CCKB agonist BC 264. The CCK-B antagonists L-365,260 and PD-134,308 decreased and completely blocked (respectively) the place aversion induced by naloxone in morphine dependent animals whereas BC 264 and devazepide were inactive in this model. No effect was observed in non-dependent animals after chronic administration of these CCK-ligands. These results show a distinct role for CCK receptors in the regulation of the motivational component of morphine abstinence, probably related to their differential effects in the regulation of limbic dopaminergic neurons.

Animals↗
PubMed1999

Postprandial normal saline intake delays gastric emptying of solids in conscious dogs: partial involvement of CCK in its mechanism.

Although it is known that a caloric liquid meal given after food intake delays solid gastric emptying, the effect of a noncaloric liquid is not known. The aims of this study were to determine the effect of normal saline given at 3 hr after feeding on gastric antral motor activity and gastric emptying and to evaluate the role of endogenous cholecystokinin in the changes in gastric function induced by postprandial saline intake in conscious dogs. Two cannulas were implanted in each of five mongrel dogs for infusion of phenolsulfonphthalein into the proximal duodenum and for aspiration of luminal samples from the distal duodenum. Gastric contractile and emptying activity were measured by the force transducer method and a freeze-drying method newly developed by our group, respectively. Postprandial pancreaticobiliary secretion was assessed from amylase and bile acid outputs into the duodenum. One hundred grams of freeze-dried dog food was given as a solid meal after mixing it with 100 ml of normal saline. The dogs were given 100 ml of normal saline per os at 3 hr after feeding. In another study, intravenous administration of devazepide, a specific cholecystokinin-A receptor antagonist, at a dose of 0.1 mg/kg/hr was begun 15 min before postprandial saline intake and continued for 1 hr. Gastric antral motility was significantly (P < 0.01) inhibited for 30 min after the dogs had drunk saline at 3 hr after feeding. The mean fractional emptying rate of gastric solids in percentage per 30 min after postprandial saline intake was significantly (P < 0.05) slower than that in the control study without saline intake at 3 hr after feeding. Amylase output into the duodenum after postprandial saline intake showed a gradual increase lasting for about 1 hr, whereas that of bile acid increased transiently but markedly 15 min after saline intake, in comparison with the control study. Pretreatment with devazepide partially ameliorated the suppression of gastric antral motility. Postprandial intake of saline inhibited gastric motor activity and delayed solid gastric emptying, whereas it increased the outputs of amylase and bile acid. Endogenous cholecystokinin may be partially involved in these phenomena caused by saline intake at 3 hr after feeding.

Administration, Oral↗
PubMed1997

The influence of 5-HT2 and 5-HT4 receptor antagonists to modify drug induced disinhibitory effects in the mouse light/dark test.

1. The ability of 5-HT2 and 5-HT4 receptor antagonists to modify the disinhibitory profile of diazepam and other agents was investigated in male BKW mice in the light/dark test box. 2. The 5-HT2A/2B/2C receptor antagonists ritanserin, MDL11939 and RP62203 and also methysergide, which failed to modify mouse behaviour when administered alone, caused dose-related enhancements (4 to 8 fold) in the potency of diazepam to disinhibit behavioural responding to the aversive situation of the test box. 3. Ritanserin was shown to enhance the disinhibitory potency of other benzodiazepines, chlordiazepoxide (4 fold), temazepam (10 fold) and lorazepam (10 fold), the 5-HT1A receptor ligands, 8-OH-DPAT (25 fold), buspirone (100 fold) and lesopitron (500 fold), the 5-HT3 receptor antagonists, ondansetron (100 fold) R(+)-zacopride (100 fold) and S(-)-zacopride (greater than a 1000 fold), the substituted benzamides, sulpiride (10 fold) and tiapride (5 to 10 fold) and the cholecystokinin (CCK)A receptor antagonist, devazepide (100 fold). It also reduced the onset of action of disinhibition following treatment with the 5-HT synthesis inhibitor parachlorophenylalanine. Ritanserin failed to enhance the disinhibitory effects of the CCKB receptor antagonist CI-988, the angiotensin AT1 receptor antagonist losarten or the angiotensin converting enzyme inhibitor ceranapril. 4. The 5-HT4 receptor antagonists SDZ205-557, GR113808 and SB204070 caused dose-related reductions in the disinhibitory effect of diazepam, returning values to those shown in vehicle treated controls. The antagonists failed to modify mouse behaviour when administered alone. 5. GR113808 was also shown to cause a dose-related antagonism of the disinhibitory effects of chlordiazepoxide, lorazepam, 8-OH-DPAT, buspirone, lesopitron, ondansetron, R(+)-zacopride, sulpiride, tiapride, devazepide, CI-988, losarten, ceranapril and parachlorophenylalanine. 6. It was concluded that in BKW mice (a) the failure of 5-HT2 and 5-HT4 receptor antagonists when administered alone to modify behaviour in the light/dark test indicates an absence of an endogenous 5-HT tone at the 5-HT2 and 5-HT4 receptors and (b) the enhancement by the 5-HT2 receptor antagonists and attenuation by the 5-HT4 receptor antagonists of drug-induced disinhibition indicates a plurality of 5-HT receptor involvement in the mediation of drug-induced disinhibitory profiles in the mouse.

Animals↗
PubMed1997

Synergistic interaction between leptin and cholecystokinin to reduce short-term food intake in lean mice.

Leptin is a circulating protein involved in the long-term regulation of food intake and body weight. Cholecystokinin (CCK) is released postprandially and elicits satiety signals. We investigated the interaction between leptin and CCK-8 in the short-term regulation of food intake induced by 24-hr fasting in lean mice. Leptin, injected intraperitoneally (i.p.) at low doses (4-120 microg/kg), which did not influence feeding behavior for the first 3 hr postinjection, decreased food intake dose dependently by 47-83% during the first hour when coinjected with a subthreshold dose of CCK. Such an interaction was not observed between leptin and bombesin. The food-reducing effect of leptin injected with CCK was not associated with alterations in gastric emptying or locomotor behavior. Leptin-CCK action was blocked by systemic capsaicin at a dose inducing functional ablation of sensory afferent fibers and by devazepide, a CCK-A receptor antagonist but not by the CCK-B receptor antagonist, L-365,260. The decrease in food intake which occurs 5 hr after i.p. injection of leptin alone was also blunted by devazepide. Coinjection of leptin and CCK enhanced the number of Fos-positive cells in the hypothalamic paraventricular nucleus by 60%, whereas leptin or CCK alone did not modify Fos expression. These results indicate the existence of a functional synergistic interaction between leptin and CCK leading to early suppression of food intake which involves CCK-A receptors and capsaicin-sensitive afferent fibers.

Animals↗
PubMed1992

CCK antagonists and CCK-monoamine interactions in the control of satiety.

The introduction of potent cholecystokinin (CCK) receptor antagonists, selective for either the CCK-A or the CCK-B subtype, has provided a great impetus to the study of activity of endogenous CCK in relation to the control of feeding. This paper reviews experiments in which devazepide (a selective CCK-A receptor antagonist) and L-365,260 (a selective CCK-B-gastrin receptor antagonist) have been used. Both compounds increase food consumption (under certain conditions) and postpone the onset of satiety. L-365,260 is the more potent, suggesting a role for central CCK-B type receptors in satiety. In addition, use of CCK antagonists permits the study of important functional interactions between CCK and other neurochemical factors that serve to control feeding. Thus, devazepide, but not L-365,260, blocked the anorectic effect of either d-fenfluramine or serotonin. Hence, CCK-A type receptors appear to be involved in the anorectic effect of these drugs. This result serves as an example to illustrate a principle of cooperativity in the satiety-inducing effects of diverse neurochemical signals.

Animals↗
PubMed1990

Modulatory role for CCK-B antagonists in Parkinson's disease.

We examined the ability of selective CCK-A and CCK-B receptor antagonists to induce or modulate the locomotor stimulant effects of dopamine agonists in MPTP-treated squirrel monkeys. Administration of 1-100 micrograms/kg i.p. of either the selective CCK-A receptor antagonist devazepide (MK-329) or the CCK-B receptor antagonist L-365,260 alone failed to stimulate a locomotor response in parkinsonian monkeys. In contrast, treatment with L-365,260 caused a 50-60% potentiation of the locomotor stimulatory effects of L-DOPA or (+)-PHNO. No such modulatory effects were observed following pretreatment with devazepide. We suggest that CCK-B receptor antagonists may be useful adjuncts to existing dopamine replacement therapy for improved management of Parkinson's disease.

Animals↗
PubMed1995

The ratio between anionic and cationic trypsin in rat pancreas varies with CCK stimulation.

The effects of long-term hyperstimulation with cholecystokinin (CCK) on the pancreatic contents of anionic and cationic trypsin(ogen) and amylase were studied in the rat. Endogenous hyperCCKemia was evoked in rats by pancreaticobiliary diversion (PBD), and exogenous hyperCCKemia by continuous subcutaneous CCK infusion. In addition, the effect of continuous subcutaneous infusion of the CCK A receptor antagonist devazepide was studied. After 4 weeks blood samples were obtained for the determination of plasma CCK concentrations and the animals were sacrificed. The pancreatic glands were harvested, weighted, and extracted. The extracts were analyzed for anionic and cationic trypsin and amylase. Enzyme contents showed a large interindividual variation. The most consistent change in enzyme pattern was an increase in the ratio between anionic and cationic trypsin in animals with hyperCCKemia (PBD operated or CCK infused). Furthermore, this ratio decreased significantly in animals treated with devazepide. In conclusion, stimulation of the CCK receptor changed the ratio between anionic and cationic trypsin in the pancreatic gland, while it was reversed during blockade of the receptor.

Amylases↗
PubMed2004

A non-invasive method for measurement of gastric emptying in mice: effects of altering fat content and CCK A receptor blockade.

The ability to make repetitive non-invasive measurements of gastric emptying of nutritive solids in awake, unstressed mice is highly desirable. The aim of the present study was to develop such a technique using nuclear scintigraphy and diets differing in triglyceride content. Awake mice were accustomed to light restraint and to feeding cooked, egg white (0.00 g fat g(-1)), whole egg (0.10 g fat g(-1)), or egg yolk (0.31 g fat g(-1)). Gastric emptying of each diet was measured by labelling the test meals with Technetium(99m) Mebrofenin and using a conventional gamma camera equipped with a high resolution, parallel hole collimator. Gastric emptying of cooked whole egg was also determined following administration of either vehicle or CCK A receptor antagonist, devazepide. The half-emptying time (t(1/2)) significantly increased with increasing triglyceride content from 14 +/- 5 min to 51 +/- 6 min and 82 +/- 4 min for egg white, whole egg and egg yolk, respectively. Administration of devazepide significantly decreased t(1/2) of whole egg to 28 +/- 2 min. These results demonstrate the sensitivity and predictability of this technique in mice and importantly, provide an opportunity to alter the macronutrient or caloric content of the meal to determine effects on gastric emptying.

Animals↗
PubMed1991

The behavioural properties of CI-988, a selective cholecystokininB receptor antagonist.

1. The behavioural effects of a selective cholecystokininB (CCKB) receptor antagonist CI-988 were investigated in rodents. 2. In three rodent tests of anxiety (rat elevated X-maze, rat social interaction test and mouse light/dark box) CI-988 over the dose range 0.001-10.0 mg kg-1, (i.p.) produced an anxiolytic-like action. The magnitude of this effect was similar to that of chlordiazepoxide (CDP). In contrast, the selective CCKA receptor antagonist, devazepide, was inactive. CI-988 also showed anxiolytic-like action in the rat conflict test but the magnitude of this effect was about 2.5 fold less than that of CDP. 3. Central but not peripheral administration of the selective CCKB receptor agonist, pentagastrin, like FG 7142, produced an anxiogenic-like action. 4. The pentagastrin-induced anxiety was dose-dependently antagonized by CI-988, whereas devazepide was inactive. However, ten times higher doses of CI-988 were required to block a similar action of FG 7142. 5. In contrast to CDP, CI-988 up to 3000 fold higher doses than those inducing anxiolysis was inactive in tests measuring sedation and ataxia. It also failed to antagonize pentylenetetrazol-induced tonic seizures. Furthermore, CI-988 did not interact with alcohol or barbiturates. Thus, CI-988 appears to be an anxioselective compound. 6. The anxiolytic-like action of CDP in the rat elevated X-maze was dose-dependently antagonized by flumazenil. In contrast, the benzodiazepine receptor antagonist failed to block a similar effect of CI-988. 7. Thus, CI-988 shows anxiolytic-like activity in several animal models of anxiety. The anxiolytic-like effect of CI-988 involves a novel mechanism of action, that is likely to be mediated by selective antagonism of the brain CCKB receptor. It is suggested that CI-988 should have a better side-effect profile in man than the benzodiazepines.

Animals↗
PubMed1995

The use of receptor desensitization to analyse CCKA and CCKB/gastrin receptors coupled to contraction in guinea-pig stomach muscle.

1. The results of previous studies have been in conflict with respect to the involvement of specific cholecystokinin (CCKA) and CCKB/gastrin receptors in guinea-pig gastric muscle. Here, in an in vitro, guinea-pig gastric muscle assay, pentagastrin (PG) and tetragastrin (TG) behaved as high potency agonists and produced symmetrical concentration-effect curves. In contrast, cholecystokinin-octapeptide (CCK-8), while also behaving as a high potency agonist, produced flat asymmetrical curves. Unlike recent data reported using this tissue (Boyle et al., 1993), the CCKA receptor-selective antagonist, devazepide (3, 10, 30 nM) produced a rightward shift of the upper region of the CCK-8 curve rendering it biphasic. The lower phase was abolished by the CCKB/gastrin receptor-selective antagonist, L-365260 (300 nM) indicating that the contractile effects of CCK-8 in this tissue are mediated by both receptor types. 2. L-365260 produced a concentration-dependent, parallel rightward displacement of PG concentration-effect curves. However, a flat Schild plot slope parameter (0.77 +/- 0.06) was obtained. Therefore, an empirical pA2 value of 8.64 +/- 0.21 was estimated from the smallest dose ratio. This value is consistent with published values characteristic of an interaction at CCKB/gastrin receptors. 3. TG (1 microM) was used to densensitize selectively the CCKB/gastrin receptors in the gastric muscle assay and thereby expose a population of receptors capable of responding to subsequent stimulation by CCK-8 but not by PG. The selectivity of TG for CCKB/gastrin- over CCKA receptors was demonstrated by its low efficacy compared to CCK-8 in the guinea-pig gallbladder assay, a tissue shown previously to contain a homogeneous population of CCKA receptors. In TG-desensitized gastric muscle, CCK-8 concentration-effect curves were symmetrical and could be displaced in a simple parallel fashion by devazepide at nanomolar concentrations consistent with an interaction at CCKA receptors (pKB approximately 10). 4. These results indicate that the guinea-pig gastric muscle contains both CCKA- and CCKB/gastrin receptors and the effects of CCK-8 are mediated via both of these receptors. Notwithstanding the complexity of the behaviour of L-365260, it was possible to obtain a reasonable description of the system using a simple 2-receptor model in which the effects of individual receptor activation were assumed to be additive. The absence of a simple competitive interaction of PG with L-365260 may indicate, for example, non-homogeneity of CCKB/gastrin receptors or lack of concentration equilibrium between the bath and the receptor biophase.

Animals↗
PubMed1995

Characterization of the receptors and mechanisms involved in the cardiovascular actions of sCCK-8 in the pithed rat.

1. The cardiovascular actions of cholecystokinin and related peptides were investigated in the pithed rat. The receptors and the mechanisms involved in these experiments were characterized. 2. Sulphated cholecystokinin octapeptide (sCCK-8, 0.1-100 nmol kg-1, i.v.) elicited a dose-dependent bradycardia and increase in mean arterial blood pressure. Neither gastrin-17 nor pentagastrin had any effect at concentrations up to 100 nmol kg-1. 3. Both the pressor response and bradycardia elicited by sCCK-8 were reduced by the selective CCKA receptor antagonists, devazepide (0.5-50 nmol kg-1) and lorglumide (1-7 mumol kg-1). The selective CCKB receptor antagonists, CI-988 (1 mumol kg-1) and L-365,260 (15 mumol kg-1) did not inhibit the effects of sCCK-8. 4. The pressor response induced with sCCK-8 was reduced by treatment with either phentolamine (3 mumol kg-1) or guanethidine (2 mumol kg-1) and was unaffected by treatment with propranolol, atropine or hexamethonium. The pressor response also persisted following bilateral adrenalectomy. 5. The bradycardia induced with sCCK-8 was unaffected by treatment with phentolamine, propranolol, guanethidine, atropine, hexamethonium or bilateral adrenalectomy. 6. The tetrapeptide of cholecystokinin (CCK-4) elicited a dose-dependent pressor response but did not induce bradycardia. The pressor response was unaffected by devazepide (50 nmol kg-1), L-365260 (15 mumol kg-1) or phentolamine (3 mumol kg-1). 7. In the pithed rat, sCCK-8 acted via CCKA receptors to increase arterial blood pressure indirectly, at least in part, through activation of alpha-adrenoceptors. The observed bradycardia was also mediated byCCKA receptors but possibly through a direct action on the heart.

Adrenalectomy↗
PubMed1994

Gastrointestinal effects of diazepam-withdrawal are linked to activation of central cholecystokinin-ergic pathways in rats.

The influence of flumazenil-precipitated diazepam withdrawal on intestinal myoelectric activity and colonic transit was evaluated, in diazepam-dependent rats. Administered intraperitoneally, flumazenil (15 mg kg-1) induced a strong stimulation of the duodenal spiking activity lasting 197 +/- 20 min, and accelerated colonic transit corresponding to a significantly (P < 0.05) increased value of the geometric centre (3.52 +/- 0.23 vs 2.44 +/- 0.1 for the control). Both devazepide and L365260 administered intracerebroventricularly at a dose of 10 micrograms kg-1 abolished the flumazenil-induced withdrawal effect on the duodenum, whereas at a lower dose (1 microgram kg-1) only L365260 was able to antagonize this effect. In the same way, devazepide, loxiglumide and L365260 suppressed the effect of precipitated withdrawal on colonic transit when administered intracerebroventricularly at a dose of 10 micrograms kg-1, whereas similar blockade was obtained at a dose of 5 micrograms kg-1 with L365260, and 10 ng kg-1 with PD135-158. It is concluded that in rats precipitated diazepam-withdrawal altered intestinal motility and colonic transit and that these effects are mediated by central release of cholecystokinin (CCK) or activation of CCK-ergic neurons.

Animals↗
PubMed1996

Sensitivity of vagal mucosal afferents to cholecystokinin and its role in afferent signal transduction in the rat.

1. Extracellular recordings from rat mesenteric paravascular nerve bundles were made in order to characterize the responses of different populations of afferents supplying the small intestine to intravenous cholecystokinin (CCK; in the form of sulphated CCK8). 2. Approximately 70% of mesenteric nerve bundles contained CCK-sensitive afferent fibres. Responsive afferents had low spontaneous discharge (1.6 +/- 0.3 impulses s-1) and showed a 14-fold increase in firing at the peak of the response to 50 pmol CCK with the overall response lasting several minutes. The onset of the response occurred after a latency of (3.9 +/- 0.1 s) following i.v. administration of CCK, which corresponds largely to the circulation delay in these animals. The threshold dose of CCK was < 5 pmol. 3. The response to 100 pmol CCK was completely abolished by devazepide (0.5 mg kg-1) and by chronic subdiaphragmatic vagotomy performed 10-14 days prior to experimentation, indicating that CCK sensitivity was via CCKA receptors and exclusively mediated via vagal afferents rather than splanchnic or enteric afferents. 4. Evidence that CCK-sensitive afferents had mucosal receptive fields was indicated by the lack of any response to luminal distension and the sensitivity of the CCK response to luminal anaesthesia. Furthermore, CCK-sensitive afferents responded to luminal hydrochloric acid (50 mM) in a slowly adapting manner. The response to acid was significantly reduced (P < 0.005), but not abolished, by devazepide at a time when the response to exogenous CCK had been completely eliminated. 5. The exquisite sensitivity of some vagal mucosal afferents to CCK suggests that they may play a physiological role in the reflex and behavioural consequences of CCK release from the small intestine, possibly acting in a paracrine fashion. However, this sensitivity to CCK represents only one aspect of the broad chemosensitivity of these mucosal afferents and is not an obligatory component of the signal transduction pathway.

Afferent Pathways↗
PubMed2003

Chylomicron components activate duodenal vagal afferents via a cholecystokinin A receptor-mediated pathway to inhibit gastric motor function in the rat.

Nutrients in the intestine initiate changes in secretory and motor function of the gastrointestinal (GI) tract. The nature of the 'sensors' in the intestinal wall is not well characterized. Intestinal lipid stimulates the release of cholecystokinin (CCK) from mucosal entero-endocrine cells, and it is proposed that CCK activates CCK A receptors on vagal afferent nerve terminals. There is evidence that chylomicron components are involved in this lipid transduction pathway. The aim of the present study was to determine (1) the pathway mediating reflex inhibition of gastric motility and (2) activation of duodenal vagal afferents in response to chylomicrons. Mesenteric lymph was obtained from awake rats fitted with lymph fistulas during intestinal perfusion of lipid (Intralipid, 170 micromol h(-1), chylous lymph) or a dextrose and/or electrolyte solution (control lymph). Inhibition of gastric motility was measured manometrically in urethane-anaesthetized recipient rats in response to intra-arterial injection of lymph close to the upper GI tract. Chylous lymph was significantly more potent than control lymph in inhibiting gastric motility. Functional vagal deafferentation by perineural capsaicin or CCK A receptor antagonist (devazepide, 1 mg kg(-1), i.v.) significantly reduced chylous lymph-induced inhibition of gastric motility. The discharge of duodenal vagal afferent fibres was recorded from the dorsal abdominal vagus nerve in an in vitro preparation of the duodenum. Duodenal vagal afferent nerve fibre discharge was significantly increased by close-arterial injection of CCK (1-100 pmol) in 43 of 83 units tested. The discharge of 88% of CCK-responsive fibres was increased by close-arterial injection of chylous lymph; devazepide (100 microg, i.a.) abolished the afferent response to chylous lymph in 83% of these units. These data suggest that in the intestinal mucosa, chylomicrons or their products release endogenous CCK which activates CCK A receptors on vagal afferent nerve fibre terminals, which in turn initiate a vago-vagal reflex inhibition of gastric motor function.

Animals↗
PubMed1994

Intestinal lipid inhibits gastric emptying via CCK and a vagal capsaicin-sensitive afferent pathway in rats.

The mechanism by which lipid in the duodenum inhibits gastric emptying was investigated in awake rats fitted with chronic gastric and duodenal cannulas. Perfusion of the duodenum with lipid (Intralipid, 5 and 10%; total amount 50 and 100 mg) caused a significant inhibition (26 and 78%, respectively) of gastric emptying of a nonnutrient liquid (0.9% saline). Functional ablation of the capsaicin-sensitive vagal, but not the spinal, sensory innervation to the upper gastrointestinal tract significantly attenuated by 57% lipid-induced inhibition of gastric emptying. In intact rats, administration of a specific cholecystokinin (CCK)-A receptor antagonist, devazepide, significantly attenuated by 66% the response to lipid. Administration of devazepide in perivagal capsaicin-treated rats did not further reduce the response to lipid. These results suggest that lipid in the duodenum inhibits gastric emptying via a mechanism involving an action of CCK at type A receptors and capsaicin-sensitive vagal afferents.

Afferent Pathways↗
PubMed2000

Luminal dietary protein, not amino acids, induces pancreatic protease via CCK in pancreaticobiliary-diverted rats.

We determined whether pancreatic adaptation to a high-protein diet depends on ingested protein in the intestinal lumen and whether such adaptation depends on a CCK or capsaicin-sensitive vagal afferent pathway in pancreaticobiliary-diverted (PBD) rats. Feeding a high-casein (60%) diet but not a high-amino acid diet to PBD rats increased pancreatic trypsin and chymotrypsin activities compared with those after feeding a 25% casein diet. In contrast, feeding both the high-nitrogen diets induced pancreatic hypertrophy in PBD rats. These pancreatic changes by the diets were abolished by treatment with devazepide, a CCK-A receptor antagonist. Protease zymogen mRNA abundance in the PBD rat was not increased by feeding the high-casein diet and was decreased by devazepide. Perivagal capsaicin treatment did not influence the values of any pancreatic variables in PBD rats fed the normal or high-casein diet. We concluded that luminal protein or peptides were responsible for the bile pancreatic juice-independent induction of pancreatic proteases on feeding a high-protein diet. The induction was found to be dependent on the direct action of CCK on the pancreas. Pancreatic growth induced by high-protein feeding in PBD rats may depend at least partly on absorbed amino acids.

Adaptation, Physiological↗