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PubMed1996

The increased satiating potency of CCK-8 by estradiol is not mediated by upregulation of NTS CCK receptors.

Estradiol benzoate (EB) increases the satiating effect of CCK-8 in ovariectomized rats. It is possible that this effect of EB is due to upregulation of CCKA receptors in the terminals of vagal afferent fibers because these receptors have been implicated in the mediation of the satiating effect of intraperitoneally injected CCK-8. To test this hypothesis, we used in vitro quantitative autoradiography to measure the effects of EB on the binding characteristics of CCK receptors in the nucleus tractus solitarius (NTS), a region that contains central terminal projections of abdominal vagal afferent fibers. As additional measures of EB's effects on CCK receptors, we also characterized EB's effects on CCK.8 binding in the area postrema (AP), a brain region rich in CCKA receptors, the ventromedial hypothalamus (VMH), a region rich in CCKB receptors, and in the pancreas, a gland rich in CCKA receptors. Saturation binding experiments were run using [125I]CCK-8 (approximately 40 pM, 2200 Ci/mmol) and 0.1-100 nM unlabelled CCK-8. EB did not change the number (Bmax) or affinity (Kd) of CCK receptors in the NTS. Furthermore, competition experiments with 500 nM of the selective CCKA receptor antagonist devazepide or the selective CCKB antagonist L365,260 demonstrated that EB failed to affect CCK receptor subtype number in the medial and lateral divisions of the NTS. EB also did not affect binding in the AP or VMH. These results do not confirm our hypothesis. The lack of effect of EB on vagal CCKA receptors in the NTS was not due to inappropriate conditions of tissue sampling or autoradiographic technique because EB increased the number, but not the affinity, of CCKA receptors in the pancreas significantly.

Animals↗
PubMed1991

Evidence that CCKB receptors mediate the regulation of exploratory behaviour in the rat.

Peripheral administration of cholecystokinin tetrapeptide (CCK-4) at non-sedative doses (25-50 micrograms/kg) decreased the exploratory activity of rats in an elevated plus-maze. This effect was antagonized by treatment with CCK receptor antagonists proglumide (1 and 10 mg/kg), lorglumide (0.1 and 1 mg/kg), L 365,260 (10 micrograms/kg) and devazepide (1 mg/kg). The results suggest that the exploratory behaviour of rats can be altered by pharmacological manipulations at CCK-B receptors.

Animals↗
PubMed1993

Comparative involvement of 5-HT1, 5-HT2 and 5-HT3 receptors in stress-induced colonic motor alterations in rats.

The role of 5-HT1, 5-HT2 and 5-HT3 receptors in the genesis of colonic motor alterations induced by emotional stress was evaluated in rats equipped with implanted nickel/chrome electrodes on the proximal colon and a catheter into the lateral ventricle of the brain. In control rats the frequency of colonic spike bursts increased from 7.6 +/- 1.3 to 16.8 +/- 1.3 per 10 min when the rats were placed in a test cage in which they had previously received electric footshocks. I.p. injection of methysergide (0.1 mg/kg) reduced by 54% the emotional stress-induced increase of colonic spike burst frequency, while a higher dosage (1 mg/kg) of methysergide had no effect. The i.p. injection of ketanserin (a 5-HT2 receptor antagonist, 0.1 and 1 mg/kg) or granisetron (a 5-HT3 receptor antagonist, 0.1 and 1 mg/kg) had no effect on emotional stress-induced colonic hyperkinesia. The i.p. injection of the 5-HT1A receptor agonists, buspirone (1 mg/kg) or 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino(tetralin) (0.05 and 0.1 mg/kg) or benzodiazepine (clonazepam, 1 mg/kg) significantly reduced or suppressed the emotional stress-induced increase of colonic spike bursts. Injected i.c.v., buspirone, but not 8-OH-DPAT, also reduced the emotional stress-induced hyperkinesia. Pretreatment with devazepide receptor (1 microgram/kg) antagonized the inhibitory effects of buspirone and 8-OH-DPAT injected i.p. on emotional stress-induced colonic hyperkinesia but did not alter the effects of clonazepam (1 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1995

Mechanisms mediating NG-nitro-L-arginine methyl ester-induced hypophagia in mice.

NG-Nitro-L-arginine methyl ester (50 mg/kg s.c.), an inhibitor of nitric oxide (NO) synthase, has been reported to increase brain serotonin (5-hhydroxytryptamine, 5-HT) metabolism and induce hypophagia. Conversely, enhanced NO synthase activity is found to be accompanied by a decrease in 5-HT level. This negative correlation between NO and 5-HT in the regulation of food intake was further studied in mice. 5-HT depletion by p-chlorophenylalanine (250 mg/kg i.p., twice daily for 2 days) failed to antagonize the hypophagic effect of NG-nitro-L-arginine methyl ester. Similarly, treatment with the NO synthesis precursor, L-arginine (1000 mg/kg s.c.), did not reverse the anorexia induced by fenfluramine (10 mg/kg s.c.), a 5-HT releaser/uptake inhibitor. Pretreatment with (-)-pindolol, methylsergide and ritanserin had no effect on the hypophagic action of NG-nitro-L-arginine methyl ester, suggesting the lack of involvement of 5-HT1 and 5-HT2 receptors. The selective neuronal NO synthase inhibitor, 7-nitroindazole (12.5-50.0 mg/kg i.p.), however, did not exhibit any hypophagic effect whilst NG-nitro-L-arginine methyl ester increased gastric retention, which may subsequently induce satiety. Moreover, the hypophagic effect of NG-nitro-L-arginine methyl ester, which was unassociated with changes in water intake and malaise induction, was also unattenuated by cholecystokinin (CCK) receptor antagonists, devazepide (10 mg/kg i.p.) and PD 135,158 ([1S-[1 alpha,2 beta[S*(S*)],4 alpha ]]-4-[[2-[[3-(1 H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7- trimethylbicyclo[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino] -1-phenylethyl] amino]-4-oxo-butanoic acid N-methyl-D-glucamine salt; 1 mg/kg i.p.).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Effects of a new sigma ligand, JO 1784, on cysteamine ulcers and duodenal alkaline secretion in rats.

BACKGROUND: The ulceroprotective effects of JO 1784 [(+)-N-cyclopropyl-methyl-N-methyl-1,4-diphenyl-1-ethyl-but-3-en-1-yl amine, hydrochloride], a new specific and highly selective sigma ligand, were examined in rats. METHODS: Different models of gastric ulcers (4-hour restraint stress, aspirin, ethanol, and taurocholate) and cysteamine-induced duodenal ulcers were used. The gastric acid secretion (4-hour Shay rat preparation) and the duodenal bicarbonate secretion were also studied. RESULTS: JO 1784 elicited a potent protection against duodenal ulcers but had a weaker protective effect on any of the gastric ulceration models tested. It displayed no gastric antisecretory activity but induced a dose-dependent stimulation of duodenal bicarbonate secretion. Haloperidol, hexamethonium, tetrodotoxin, bivagotomy (but not atropine), and the intravenous but not intracerebroventricular administration of devazepide, a cholecystokinin A antagonist, inhibited the stimulatory effect of JO 1784. CONCLUSION: These results show that JO 1784, a selective sigma ligand, is a potent protector of the duodenal mucosa. This activity may be related to its stimulating effect on bicarbonate secretion, which is driven through a complex nervous mechanism involving muscarinic synapses, vagal afferent fibers, and peripheral cholecystokinin receptors. This drug might open a new specific way in the treatment of duodenal ulcers.

Animals↗
PubMed1991

Increased food intake after type A but not type B cholecystokinin receptor blockade.

To assess the role of cholecystokinin (CCK) receptors in mediating the satiating effect of an oral preload, overnight food-deprived rats (n = 7) were given access to a high-carbohydrate liquid diet for 40 min. At the end of 40 min, food was removed and rats were injected subcutaneously (SC) with devazepide (DVZ; 1 ng/kg-1 mg/kg), an antagonist selective for the CCK-A receptor, or its vehicle, 0.5% carboxymethylcellulose (CMC). Thirty min after injection, rats were given access to the same liquid food for 60 min. DVZ increased food intake significantly. Furthermore, the effectiveness of a very low dose of DVZ (10 ng/kg) is strong evidence that the effect of DVZ was specific for CCK-A receptors. Three of the rats that increased food intake after DVZ were also tested with L-365,260, an antagonist selective for the CCK-B receptor (10 ng/kg-100 micrograms/kg). L365,260 did not increase food intake significantly. These results confirm and extend previous reports that CCK-A receptor blockade increases food intake after an oral preload. They do not, however, demonstrate a role for the CCK-B receptor in mediating the satiating effect of ingested food under the same experimental conditions.

Animals↗
PubMed1992

Feeding behavior in rats fed diets containing medium chain triglyceride.

The effect of dietary medium chain triglyceride (MCT) on short-term food intake was compared with the effect of long chain triglyceride (LCT) in rats. Corn oil and glyceryl tricaprylate were used as LCT and MCT sources, respectively. Rats were given diets containing 200 g MCT/kg diet (MCT diet), 100 g MCT + 100 g LCT/kg diet (ML diet), or 200 g LCT/kg diet (LCT diet) in Experiment 1. Cumulative food intake was determined every h for the first 12 h, then at 2-h intervals thereafter during the subsequent 12 h. As early as 1 h after feeding, cumulative food intake significantly decreased in MCT-fed animals in a dose-dependent fashion. In Experiment 2, rats were given a choice between MCT and LCT diets for 1 h to confirm whether or not the palatability of diets was influenced by dietary fat sources. There was no difference in food intake between the two diets. In Experiment 3, the responsibility of endogenous cholecystokinin (CCK) for the difference in food intake between the two diets was investigated for 6 h by using a CCK-A receptor antagonist, Devazepide (DVZ, 1 mg/kg b. wt.). Food intake in the MCT diet and also in the LCT diet was improved by DVZ. It is concluded that the satiety, but not the palatability, is affected by carbon chain length in dietary triglyceride sources, although the responsibility of endogenous CCK is very small.

Animals↗
PubMed1995

Odor-induced inhibition of intake after pairing of odor and CCK-8 in neonatal rats.

This study determined whether an odor that was paired with injections of CCK octapeptide would later come to inhibit independent feeding in neonatal rats. An odor so paired in rats that were not food or maternally deprived later reduced feeding during the infants' first independent feeding experience. Devazepide, the CCKA receptor antagonist, blocked the reduced intake when injected prior to the feeding test. These studies demonstrate that CCK is an effective unconditioned stimulus even when the animal is not eating during the conditioning process. Furthermore, the conditioned stimulus (the odor) causes behavioral change either by sensitizing a system that includes the CCKA receptor, by causing the release of endogenous CCK, or by changing some non-CCK system that enhances the processing of CCKA receptor-mediated information.

Animals↗
PubMed1994

Central administration of Tyr-MIF-1 stimulates gastrointestinal motility in rats: evidence for the involvement of dopamine, sigma and CCK receptors.

The effect of central administration of the endogenous peptide Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) on the gastrointestinal myoelectric activity and its mechanism of action were studied in rats. Tyr-MIF-1 (40 & 80 micrograms/kg i.c.v.) stimulated antral and duodenal myoelectric activity in a multiphasic manner. On the antrum it induced a primary increase of the frequency of antral spike bursts followed by a consecutive return to control value and a second rise of the frequency. Likewise duodenal migrating myoelectric complexes (MMCs) were initially disrupted and replaced by an irregular spiking activity followed by a reaparition of the phase III of the MMCs with increased amplitude and frequency. Haloperidol (1 mg/kg i.p.) blocked all the effects of Tyr-MIF-1 whereas sulpiride (5 mg/kg s.c.) blocked only the duodenal stimulation without affecting that on the antrum. Similarly BMY-14802 (0.5 mg/kg s.c.) antagonized selectively the primary antral stimulation and the initial disruption of duodenal MMC induced by Tyr-MIF-1. L365 260 (10 micrograms/kg i.c.v.) has also antagonized only the initial disruption of duodenal MMCs. DTG and JO 1784 (100 micrograms/kg i.c.v. each) reproduced fully the effect of Tyr-MIF-1 on the duodenum but not that on the antrum. Domperidone, (+)SCH 23390, devazepide, PK 11-195 and flumazenil did not have effect on the action of Tyr-MIF-1. It is concluded that Tyr-MIF-1 stimulates the antrum involving haloperidol sensitive but nondopamine, dopamine, probably sigma receptors, and the duodenum via a pathway where central D2 dopamine, sigma and CCKB receptors are implied.

Action Potentials↗
PubMedDate not supplied

Activation of CCK-B receptors elevates cytosolic Ca2+ levels in a pituitary cell line.

Cytosolic Ca2+ levels ([Ca2+]i) in GH3 cells, a rat anterior pituitary tumor cell line, were monitored with fura-2 by fluorescence measurements. Cholecystokinin octapeptide (CCK-8) produced a transient elevation of [Ca2+]i. The elevation of [Ca2+]i by CCK-8 was inhibited by L-365,260, but not by devazepide. It was still observed when extracellular Ca2+ was eliminated, indicating that CCK-8 mobilizes Ca2+ from intracellular storage sites after interaction with CCK-B receptors. Cholecystokinin octapeptide increased the turnover of phosphatidylinositol, but it did not affect cyclic AMP levels. A possible involvement of phosphatidylinositol breakdown and calcium mobilization in the transduction system of CCK-B receptors in GH3 cells is suggested.

Animals↗
PubMedDate not supplied

GH3 cells, an anterior pituitary cell line, express CCK-B receptors.

We found that GH3 cells, a rat anterior pituitary tumor cell line, expressed a single class of high-affinity binding sites for radiolabeled cholecystokinin octapeptide (CCK-8) with a Kd of 48 pM. The binding sites had high affinity for CCK-8, CCK-4, gastrin I, and L-365,260 (CCK-B antagonist), and had low affinity for devazepide (CCK-A antagonist), indicating that the binding sites are CCK-B receptors. GTP and its stable analogues inhibited radiolabeled CCK-8 binding to GH3 cell membranes, suggesting a coupling of CCK-B receptors to a G-protein.

Animals↗
PubMed1996

Modulation of neurotransmitter release by cholecystokinin in the neostriatum and substantia nigra of the rat: regional and receptor specificity.

The effect of cholecystokinin peptides on the release of dynorphin B, aspartate, glutamate, dopamine and GABA in the neostriatum and substantia nigra of the rat was investigated using in vivo microdialysis. Sulphated cholecystokinin-8S in the dialysis perfusate (1-100 microM) induced a concentration-dependent increase in extracellular dynorphin B and aspartate levels, both in the neostriatum and substantia nigra. Striatal dopamine levels were only increased by 100 microM of cholecystokinin-8S, while in the substantia nigra they were increased by 10-100 microM of cholecystokinin-8S. Extracellular GABA and glutamate levels were increased following 100 microM of cholecystokinin-8S only. Striatal cholecystokinin-8S administration also produced a significant increase in nigral dynorphin B levels. Local cholecystokinin-4 (100 microM) produced a moderate, but significant, increase of extracellular dynorphin B and aspartate levels in the neostriatum and substantia nigra. No effect was observed on the other neurotransmitters investigated. A 6-hydroxydopamine lesion of the nigrostriatal dopamine pathway did not affect the increases in dynorphin B and aspartate levels produced by local administration of cholecystokinin-8S. Basal extracellular GABA levels were increased significantly in both the neostriatum and substantia nigra ipsilateral to the lesion. Nigral glutamate and aspartate levels were also increased in the lesioned substantia nigra, but in the lesioned neostriatum aspartate levels were decreased. The cholecystokinin-B antagonist L-365,260 (20 mg/kg, s.c.), but not the cholecystokinin-A antagonist L-364,718 (devazepide; 20 mg/kg, s.c.), significantly inhibited the effect of cholecystokinin-8S on striatal dynorphin B and aspartate levels. In the substantia nigra, however, the effect of cholecystokinin-8S on dynorphin B and aspartate levels was inhibited to a similar extent by both L-365,260 and L-364,718. Pretreatment with L-364,718, but not with L-365.260, prevented the increase in nigral dopamine levels produced by nigral cholecystokinin-8S administration. Taken together, these results suggest that cholecystokinin-8S modulates dynorphin B and aspartate release in the neostriatum and substantia nigra of the rat via different receptor mechanisms. In the neostriatum, the effect of cholecystokinin-8S on dynorphin B and aspartate release is mediated via the cholecystokinin-B receptor subtype, while in the substantia nigra, cholecystokinin-8S modulates dynorphin B and aspartate release via both cholecystokinin-A and cholecystokinin-B receptor subtypes. Cholecystokinin-8S modulates dopamine release mainly in the substantia nigra, via the cholecystokinin-A receptor subtype.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2005

A novel, quantitative bio-assay for cholecystokinin type-1 receptor activity in the anaesthetised rat.

INTRODUCTION: Cholecystokinin type-1 (CCK(1)) receptors mediate many of the physiological functions of CCK including delay of gastric emptying, pancreatic enzyme secretion, intestinal motility and gallbladder contractility. Existing in-vivo assays for the quantitative measurement of CCK(1) receptor mediated function are generally variable, limited in precision and require a relatively large number of animals to obtain statistically meaningful data. We found that they did not provide robust pharmacokinetic-pharmacodynamic data for profiling compounds acting at these receptors. Accordingly, here we describe a novel rat duodenal contractility assay that addresses these problems. METHODS: Rats were anaesthetised and a saline-filled balloon was inserted through the body of the stomach and secured in the duodenum approximately 1 cm from the pyloric sphincter for measurement of intra-lumenal pressure. Studies were performed to determine a dose, rate and frequency of administration of CCK8S that produced a readily quantifiable response. RESULTS: Initial experiments revealed that sustained exposure to CCK8S resulted in the rapid development of tachyphylaxis. After investigating different dosing paradigms, it was found that pulsatile delivery of CCK8S (intravenous infusion for 1 min every 10 min) produced a readily quantifiable contractile response that did not exhibit tachyphylaxis. The assay response output was defined as the number of contractions >5 mm Hg over baseline. The contractions were blocked in a dose-dependent manner by intravenous bolus injections of the CCK(1) receptor antagonists, dexloxiglumide (2 and 20 micromol/kg), and devazepide (3-100 nmol/kg) but not by the CCK(2) receptor antagonist gastrazole (10 micromol/kg). CONCLUSION: A novel, simple, high quality assay for the quantification of the in-vivo activity of CCK(1) receptor ligands is described. CCK8S delivered by pulsatile intravenous infusion to anesthetized rats produced a burst of contractile activity of the duodenum mediated by CCK(1) receptors. This activity was highly reproducible and sustained for more than 3 h providing an assay that circumvents problems associated with agonist-induced tachyphylaxis.

Anesthesia↗
PubMed1997

Evidence for CCK(A) receptor involvement in the acquisition of conditioned activity produced by cocaine in rats.

Cholecystokinin (CCK) is co-localized with dopamine (DA) in the nucleus accumbens (NAC) where evidence suggests that CCK(B) receptor-mediated mechanisms inhibit, while CCK(A) receptor-mediated mechanisms facilitate, DA function. As DA has been implicated in the acquisition of conditioned activity, the present experiments investigated the effects of CCK(A) and CCK(B) receptor selective antagonists on the acquisition and expression of conditioned activity produced by cocaine. Paired rats received four cocaine-environment pairings whereas Unpaired rats received the two stimuli explicitly unpaired, in that they received cocaine in the home cage. Using this procedure, cocaine (10 mg/kg, i.p.) reliably produced conditioned activity such that the Paired group showed a higher level of locomotion than the Unpaired group on a subsequent drug-free test day. Systemic administration of devazepide, a CCK(A) receptor antagonist, but not L-365,260, a CCK(B) receptor antagonist, blocked the acquisition of conditioned activity. Microinjection of the CCK(A) antagonist PD-140548 into the NAC similarly impaired the acquisition of conditioned activity. However, systemic administration of neither the CCK(A) nor CCK(B) receptor antagonist modified the expression of cocaine-induced conditioned activity once established. These studies suggest that CCK(A), but not CCK(B), receptor mediated mechanisms in the NAC play a key role in the acquisition of conditioned activity.

Animals↗
PubMed1998

Fos expression in the brain induced by peripheral injection of CCK or leptin plus CCK in fasted lean mice.

We previously reported a synergistic interaction between leptin and cholecystokinin (CCK) to reduce food intake through CCK-A receptors in lean mice fasted for 24 h. To identify the activated neuronal pathways, we investigated changes in Fos expression in brain nuclei 2 h after single or combined intraperitoneal (i.p.) injections of leptin (120 microg/kg) and sulfated CCK-8 (3.5 microg/kg) in male lean mice (C57BL/6) fasted for 24 h using immunohistochemistry for Fos, the protein product of the early gene, c-fos. Leptin did not increase Fos expression in the brain compared with vehicle-treated mice. CCK increased the numbers of Fos-positive neurons in the nucleus of the solitary tract (NTS)/area postrema (AP), central nucleus of the amygdala (CeA) and, to a smaller extent, in the paraventricular nucleus of the hypothalamus (PVN) (5.2-, 2.3- and 0. 3-fold respectively). Injections of leptin-CCK further enhanced Fos expression by 40% in the PVN compared with that induced by CCK alone, but not in the other nuclei. Devazepide (a CCK-A receptor antagonist, 1 mg/kg, i.p.) prevented the increase in Fos expression induced by leptin-CCK in the PVN and by CCK alone in the PVN, CeA and NTS/AP. These results indicate that in fasted mice, i.p. injection of CCK increases Fos expression in specific brain nuclei through CCK-A receptors while leptin alone had no effect. Leptin in conjunction with CCK selectively enhanced Fos expression in the PVN. The PVN may be an important site mediating the synergistic effect of leptin-CCK to regulate food intake.

Adipose Tissue↗
PubMed1996

Investigation of 5-HT3 receptor-mediated contraction in guinea-pig distal colon.

We investigated the participation of cholinergic and tachykininergic mechanisms in 5-hydroxytryptamine (5-HT)-induced contraction via 5-HT3 receptors in longitudinal and circular muscle of guinea-pig isolated distal colon. 5-HT produced concentration-dependent contractile responses in longitudinal and circular muscle. The 5-HT3 receptor antagonists ramosetron (YM060) ((R)-5-[(1-methyl-3-indolyl) carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride), YM114 (KAE-393) ((R)-5-[(2,3-dihydro-1-indolyl)carbonyl]-4,5,6,7-tetrahydro-1 H-benzimidazole hydrochloride), ondansetron and granisetron produced a concentration-dependent shift to the right of the 5-HT concentration-response curves in both muscle. However, methysergide and GR113808 had no effect on 5-HT-induced contraction. In the longitudinal muscle, atropine concentration-dependently inhibited 5-HT-induced contraction, and tetrodotoxin abolished it. (+/-)-CP96,345 attenuated the contractile response to 5-HT, but (+/-)-SR48,968 had no effect on it. In the presence of atropine, (+/-)-CP96,345 completely blocked 5-HT-induced contraction. In the circular muscle, atropine had no effect on the contractile response to 5-HT, whereas tetrodotoxin completely suppressed it. The contractile response elicited by 5-HT in the circular muscle was not inhibited by either (+/-)-CP96,345, (+/-)-SR48,968, devazepide, L-365,260 or indomethacin. It is suggested that 5-HT acts via 5-HT3 receptors to release acetylcholine and substance P, which in turn are responsible for contraction of the longitudinal muscle. In the circular muscle, as in the longitudinal muscle, 5-HT-induced contraction is mediated by the 5-HT3 receptor. Unlike the case in longitudinal muscle, however, this contraction involves neither cholinergic nor tachykininergic transmission. It is also suggested that neither cholecystokinin (CCK) nor prostaglandins participate in 5-HT3 receptor-mediated contraction in circular muscle.

Animals↗
PubMed1997

Neural modulation of the antisecretory effect of peptide YY in the rat jejunum.

The endocrine and neural peptide, peptide YY, inhibits intestinal secretion of water and electrolytes in several animal species and in man. Peptide YY receptors have been evidenced on isolated rat jejunal crypt cells, but neural receptors are also likely to participate in the antisecretory effect of peptide YY in vivo. The aim of the present study was to investigate the mechanisms of the peptide YY effect on vasoactive intestinal peptide (VIP)-stimulated jejunal net water flux in the rat. Antagonist experiments using several drugs affecting neurally mediated processes were done for the purpose. A small peptide YY dose (10 pmol/kg) inhibited significantly (P < 0.005) the jejunal net water flux produced by 30 microg/kg per h of VIP. The inhibitory effect of peptide YY was suppressed, or strongly and significantly reduced, by tetrodotoxin, hexamethonium, lidocaine, idazoxan and BMY14,802 (51-(4-fluorophenyl)-4-(-4-(5-fluoro-2pyrimidinyl)-1-piperazinyl)- 1-butanol), whereas devazepide and L-NAME (L-omega-N-arginine methyl ester) had no effect. These results suggest that peptide YY inhibits VIP-stimulated jejunal net water flux in vivo through a neural mechanism implicating the participation of nicotinic synapses, alpha2-adrenoceptors and sigma receptors.

Animals↗
PubMed2003

Endogenous CCK depresses contractile activity within the ascending myenteric reflex pathway of rat ileum.

The ascending excitatory reflex is an important part of the myenteric reflex. In order to study the ascending neural pathways, isolated segments of rat ileum were stimulated by electrical stimulation of the gut wall (20 V, 3 pulses per second, 1 ms) using platinum electrodes. The excitatory contractile response was recorded using perfused manometric side-hole tubing located 2 and 4 cm orally to the stimulation site. The contractile response to electrical stimulation was abolished by atropine (10(-6) M) or hexamethonium (10(-4) M). The excitatory response increased after administration of the cholecystokinin A (CCK(A)) receptor antagonists lorglumide (3x10(-6) M: +44.1%), devazepide (10(-8) M: +19.4%; 10(-7) M: +30.0%) and SR-27897 (10(-10) M: +21.8%, 10(-8) M: +47.0%, P<0.05, n=8). However, the CCK(B) receptor antagonist L-365,260 also caused a significant increase in the oral excitation (10(-6) M: +27.4%). sCCK-8 caused a significant reduction in the ascending response (10(-8) M: -11.5%) and induced spontaneously occurring contractions at doses ranging from 10(-10)-10(-6) M. CCK-9 significantly increased the ascending response (10(-7) M: +10.9%, P<0.05). However, caerulein (10(-10) M: -25.9%, 10(-8) M: -26.8%; P<0.01) and pentagastrin (10(-10) M: -20.2%, P<0.05; 10(-8) M: -23.7%, P<0.01; 10(-6) M: -28.3%, P<0.001) reduced the ascending contractile response significantly. These data, obtained with potent and highly specific CCK receptor antagonists, demonstrate an inhibitory role of endogenously released CCK within the ascending neural pathway. The data further suggest that exogenously applied CCK-related peptides have different effects on the myenteric reflex which might be due to excitation of the different involved neurons (short and long ascending inter- and motorneurons) in an unphysiological order. Thus in experiments investigating more complex neuronal circuits, experiments with antagonists should be regarded as more specific.

Animals↗