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PubMed2003

Intravenous glucose infusion decreases intracisternal thyrotropin-releasing hormone induced vagal stimulation of gastric acid secretion in anesthetized rats.

Gastroparesis is a common complication of diabetes attributed to autonomic neuropathy. This study investigated whether acute hyperglycemia influences central thyrotropin-releasing hormone (TRH), a well-established brain medullary vagal stimulus, induced gastric acid secretion in overnight fasted, urethane-anesthetized rats. Intravenous infusion of D-glucose (20%, 30% and 40%) dose dependently reduced intracisternal TRH-induced gastric acid secretion (71+/-28 micromol/90 min) by 39%, 90% and 100% respectively. Pretreatment with cholecystokinin(A) (CCK(A)) receptor antagonist devazepide (1 mg/kg) did not influence the inhibitory effect of intravenous glucose (30%). These results indicate that hyperglycemia may have a central effect to antagonize medullary TRH stimulation of vagal outflow to the stomach.

Anesthetics, Intravenous↗
PubMed1997

Cholecystokinin, dopamine D2 and N-methyl-D-aspartate binding sites in the nucleus of the solitary tract of the rat: possible relationship to ingestive behavior.

Receptor autoradiography was used to investigate the distribution of brainstem binding sites for cholecystokinin, dopamine and N-methyl-D-aspartate with particular reference to the nucleus of the solitary tract of the rat, an area involved in the control of ingestive behavior. Binding sites for the A and B subtypes of the cholecystokinin receptor, labeled with [(125)I]cholecystokinin octapeptide sulfate in the presence or absence of antagonists for the devazepide (A) or L-365,260 (B) receptor, were present throughout the caudal rostral extent of the nucleus of the solitary tract, the A type predominating in the commissural, medial and gelatinous part and the B type in the lateral part. In the most rostral part of the medial nucleus of the solitary tract, both A and B receptors were present. Dopamine D2 receptors, labeled with [(125)I]NCQ-298, were found in all parts of the nucleus of the solitary tract. No binding to the dopamine D1 receptor, labeled with [(125)I]SCH-23982, was found in the brainstem. N-Methyl-D-aspartate receptors, labeled with [(3)H]dizocilpine maleate, were also present in the entire caudorostral extent of the nucleus of the solitary tract. Binding to cholecystokinin A receptors was co-distributed with [(125)I]NCQ-298 and [(3)H]dizocilpine maleate binding in the caudal and rostral parts of the nucleus of the solitary tract, and binding to cholecystokinin B receptors overlapped with [(125)I]NCQ-298 and [(3)H]dizocilpine maleate binding in the rostral nucleus of the solitary tract. These results are consistent with the hypothesis that cholecystokinin, dopamine and glutamate interact in the nucleus of the solitary tract in the control of ingestive behavior.

Animals↗
PubMed1997

Characterization of cholecystokininA and cholecystokininB receptors expressed by vagal afferent neurons.

The cholecystokinin receptors expressed by vagal afferent neurons mediate the effect of cholecystokinin in inhibiting food intake and gastric emptying. We have determined the relative abundance of cholecystokininA, gastrin-cholecystokininB and gastrin-cholecystokininC receptor populations in the rat vagus by autoradiography using [125I]Bolton Hunter-cholecystokinin-8, [125I]Bolton Hunter-heptadecapeptide gastrin and [125I]Leu(15)2-17Glycine-extended heptadecapeptide gastrin, together with the selective antagonists devazepide and L-740093. The results indicate approximately three-fold higher abundance of cholecystokininA compared with gastrin-cholecystokininB receptors, and no significant representation of gastrin-cholecystokininC receptors. Topical capsaicin applied to the vagal nerve trunk abolished the accumulation of sites binding both [125I]Bolton Hunter-labelled cholecystokinin-8 and heptadecapeptide gastrin indicating that both cholecystokininA and gastrin-cholecystokininB receptor populations were present on afferent fibres. The molecular identity of the receptors expressed by rat and human nodose ganglia was examined using the reverse transcription polymerase chain reaction. Products of the predicted size for the cholecystokininA and gastrin-cholecystokininB receptors were identified. The human and rat cholecystokininA receptor products were cloned and the sequences were found to be 99% homologous to those published for receptors expressed by rat pancreas and human gall bladder. We conclude that cholecystokininA and gastrin-colecystokininB receptors are synthesized by nodose ganglion cells, and that the receptor proteins are transported to the periphery along afferent fibres. While there is a clear role for vagal cholecystokininA receptors, the function of vagal afferent gastrin-cholecystokininB receptors remains to be determined.

Afferent Pathways↗
PubMed1999

Antipsychotic potential of CCK-based treatments: an assessment using the prepulse inhibition model of psychosis.

Systemic injections of cholecystokinin (CCK), a "gut-brain" peptide, have been shown to modulate brain dopamine function and produce neuroleptic-like effects on such dopamine-regulated behaviors as locomotor activity. However, clinical trials of CCK agonists in schizophrenia patients showed mixed results. To re-examine the antipsychotic potential of CCK-based treatments, we examined systemic injections of CCK analogs in an animal model with strong face and construct validity for sensorimotor-gating deficits seen in schizophrenia patients and with strong predictive validity for antipsychotic drug activity. Prepulse inhibition (PPI) occurs when a weak acoustic lead stimulus ("prepulse") inhibits the startle response to a sudden loud sound ("pulse"). PPI is significantly reduced in schizophrenia patients and rats treated with dopamine agonists. Antipsychotics reverse decreased PPI in rats to a degree highly correlated with their clinical efficacy. Subcutaneous (s.c.) injections of caerulein (10 micrograms/kg) a mixed CCKA/B agonist, partially reversed amphetamine-induced reduction of PPI; whereas, s.c. haloperidol (0.5 mg/kg) totally reversed amphetamine-induced disruption of PPI. Caerulein's effect on PPI was blocked by pretreatment with a CCKA antagonist (devazepide) but not a CCKB antagonist (L-365,260). CCK-4, a preferential CCKB agonist, had no significant effect on PPI. These results suggest that caerulein produces a weak neuroleptic-like effect on PPI that is mediated by stimulation of CCKA receptors. Possible circuities in this effect are discussed. In a separate experiment, s.c. caerulein produced to a more potent neuroleptic-like profile on amphetamine-induced hyperlocomotion, suggesting that selection of preclinical paradigms may be important in evaluating the antipsychotic potential of CCK-based treatments.

Animals↗
PubMedDate not supplied

Diverse effects of phytohaemagglutinin on gastrointestinal secretions in rats.

Kidney bean lectin phytohaemagglutinin (PHA) is known for its binding capacity to the small intestinal surface inducing marked hyperplasia and hypertrophy and an increased pancreatic function. Recent observations indicate that PHA is able to attach to gastric mucosal and parietal cells. Therefore, we compared the effects of PHA on gastric acid secretion, and pancreatic amylase secretion in rats. To study gastric secretion in conscious animals, rats were surgically prepared with chronic stainless steel gastric cannula and with indwelling polyethylene jugular vein catheter. Acid secretion was determined by titration of the collected gastric juice to pH 7.0. Similar studies were performed to investigate the effect of PHA on pancreatic enzyme secretion in conscious rats supplied with pancreatic cannula. Pancreatic enzyme secretion was also studied in rats anesthetized with either halothane or urethane. In conscious rats PHA significantly inhibited basal acid secretion when compared to vehicle-treated controls. The effect was dose-dependent and reversible. On the other hand, given in the same doses as in the acid-secretory studies, PHA stimulated pancreatic amylase secretion in rats prepared with chronic pancreatic cannula. This effect was blocked by devazepide, a CCK-A receptor antagonist. In halothane-anesthetized rats PHA administration increased pancreatic amylase secretion, too. During urethane anesthesia, however, the stimulatory effect of PHA was not observed. These results provide evidence that intragastric PHA treatment induces opposite effects on gastric acid secretion and pancreatic enzyme secretion: it is a potent inhibitor of acid output, and a stimulator of pancreatic enzyme discharge. Our data also show that the stimulatory effect of PHA on pancreatic enzyme secretion can be blocked by urethane, an anaesthetic that is known to turn off the negative pancreatic feedback control of pancreatic function in rats.

Amylases↗
PubMed1994

Role of cholecystokinin in the motivational control of instrumental action in rats.

In 4 experiments, the role of cholecystokinin (CCK) in the motivational control of instrumental performance in rats was assessed. Following instrumental training with food rewards, injections of CCK (either 2 micrograms/kg or 4 micrograms/kg) had no effect on instrumental performance in extinction, even when the opportunity was given to learn about the incentive value of the food outcome under CCK. These results contrasted markedly with the effects of shifts in food deprivation. Rewarded instrumental performance was, however, reduced by both doses of CCK, suggesting that CCK may mediate deprivation-related shifts in incentive value. Tests of this hypothesis found that the alimentary CCK antagonist devazepide (MK329) attenuated the devaluation of a food outcome produced by exposure to the outcome in a nondeprived state. These data are interpreted as suggesting that CCK may act as a satiety-specific incentive signal.

Animals↗
PubMed2003

Roles for CCK1 and 5-HT3 receptors in the effects of CCK on presympathetic vasomotor neuronal discharge in the rat.

1 The role of peripheral 5-hydroxytryptamine (5-HT(3)) receptors and cholecystokinin type 1 (CCK(1)) receptors in the inhibitory effects of phenylbiguanide (PBG) and CCK on arterial blood pressure, heart rate and the discharge of presympathetic vasomotor neurones of the rostral ventrolateral medulla (RVLM) was studied in alpha-chloralose-anaesthetized rats. 2 CCK (1 and 4 micro g kg(-1), i.v.) and PBG (2 and 10 micro g kg(-1), i.v.) reduced arterial blood pressure and heart rate, and inhibited the discharge of single RVLM presympathetic vasomotor neurones in a dose-related manner. 3 Devazepide (0.5 mg kg(-1), i.v.), a selective CCK(1) receptor antagonist, blocked the effects of CCK on arterial blood pressure, heart rate and neuronal discharge but did not significantly alter these responses to PBG. MDL72222 (0.1 mg kg(-1), i.v.), a selective 5-HT(3) receptor antagonist, blocked the effects of PBG on arterial blood pressure, heart rate and presympathetic neuronal discharge. MDL72222 attenuated the effects of CCK on arterial blood pressure, heart rate and RVLM presympathetic neuronal discharge. Vehicle did not significantly alter any of the responses to CCK or PBG. 4 These experiments suggest that systemically administered CCK acts directly through CCK(1) receptors to modulate sympathetic vasomotor function. In addition, the actions of CCK also are partly dependent on activation of 5-HT(3) receptors. CCK may release 5-HT which then acts at 5-HT(3) receptors to produce sympathetic vasomotor inhibition. In contrast, the actions of PBG are entirely dependent on 5-HT(3) receptors and are independent of any actions at the CCK(1) receptor.

Animals↗
PubMed2001

Enhanced intestinal motor response to cholecystokinin in post-Nippostrongylus brasiliensis-infected rats: modulation by CCK receptors and the vagus nerve.

The jejunal inflammation induced in rats by the nematode Nippostrongylus brasiliensis is followed by intestinal neuroimmune alterations including mast cell hyperplasia and nerve remodelling. On the other hand, cholecystokinin (CCK) plays a pivotal role in the regulation of intestinal motility. The aim of this study was to determine whether the intestinal motor response to CCK is altered 30 days after infection by N. brasiliensis. Thus, CCK-8 (50 microg kg(-1) intraperitoneally) disrupted the pattern of jejunal migrating myoelectric complexes for a longer time in postinfected rats (95.5 +/- 3.5 min) than in controls (48.1 +/- 5.1 min). This enhanced jejunal response was also found after oral administration of the potent releaser of endogenous CCK, soybean trypsin inhibitor. In contrast, no alteration of the inhibition of colonic motility by CCK administration was observed. The increased responsiveness of jejunal motility to CCK persisted after mast cell stabilisation or depletion but was prevented by atropine, devazepide and L-365260 (CCK-A and CCK-B receptor antagonists, respectively) and vagotomy. These results indicate that neuroimmune alterations after N. brasiliensis infection lead to an increased intestinal motility response to CCK that involves a cholinergic mediation, a vagal pathway and alterations in intestinal CCK-A and CCK-B receptors.

Animals↗
PubMed2006

Gastrin induces leukocyte-endothelial cell interactions in vivo and contributes to the inflammation caused by Helicobacter pylori.

Gastric mucosal inflammation causes hypergastrinemia, and gastrin receptors have been detected in several leukocyte types. We have analyzed whether gastrin affects the leukocyte-endothelial cell interactions in vivo by monitoring leukocyte rolling, adhesion, and emigration in rat mesenteric venules using intravital microscopy. Mesenteric superfusion with exogenous gastrin increased these processes in a concentration- and time-dependent manner, effects prevented by the cholecystokinin (CCK)-2 receptor antagonists (proglumide, L-365,260) but not by the CCK-1 receptor antagonist devazepide. A similar response was induced by exogenous CCK or endogenously released gastrin. CCK-2 receptors were localized in mesenteric macrophages and polymorphonuclear leukocytes. This effect of gastrin is not modulated by somatostatin and is independent of the endogenous release of histamine. To analyze whether hypergastrinemia elicited by Helicobacter pylori (HP) modulates the inflammation induced by the germ, rats were chronically administered with an extract of a CagA+/VacA+ strain of HP. This protocol increased gastrinemia and induced an inflammatory response in the rat mesentery. Blockade of CCK-2 receptors attenuated this response and induced a qualitative change in the leukocyte infiltrate suggestive of a receding inflammatory process. Our results reveal a new proinflammatory role of gastrin that seems to contribute to the maintenance of the inflammation elicited by HP components.

Animals↗
PubMed2001

Bicarbonate and fluid secretion evoked by cholecystokinin, bombesin and acetylcholine in isolated guinea-pig pancreatic ducts.

1. HCO3- secretion was investigated in interlobular duct segments isolated from guinea-pig pancreas using a semi-quantitative fluorometric method. Secretagogue-induced decreases in intracellular pH, following blockade of basolateral HCO3- uptake with a combination of amiloride and DIDS, were measured using the pH-sensitive fluoroprobe BCECF. Apparent secretory HCO3- fluxes were calculated from the initial rate of intracellular acidification. 2. In the presence of HCO3-, stimulation with secretin (10 nM) or forskolin (5 microM) more than doubled the rate of intracellular acidification. This effect was abolished in the absence of HCO3-. It was also abolished in the presence of HCO3- when DIDS and NPPB were applied to the luminal membrane by microperfusion. We therefore conclude that the increase in acidification rate is a useful index of secretagogue-induced HCO3- secretion across the luminal membrane. 3. Secretin, cholecystokinin (CCK) and bombesin each stimulated HCO3- secretion in a dose-dependent fashion. They evoked comparable maximal responses at about 10 nM and the EC50 values were 0.5 nM for secretin, 0.2 nM for CCK and 30 pM for bombesin. Acetylcholine (ACh) was also effective, with a maximum effect at 10 microM. 4. The stimulatory effect of CCK was blocked completely by the CCK1 receptor antagonist devazepide but not by the CCK2 receptor antagonist L365,260. The CCK analogue JMV-180 (Boc-Tyr(SO3H)-Nle-Gly-Trp-Nle-Asp-phenylethyl ester), which is an agonist of the high-affinity CCK1 receptor but an antagonist of the low-affinity receptor, also stimulated HCO3- secretion but with a smaller maximal effect than CCK. JMV-180 partially inhibited the response to a high concentration of CCK but not to a lower concentration, suggesting that both high- and low-affinity states of the CCK1 receptor evoke HCO3- secretion. 5. The stimulatory effect of bombesin was blocked completely by the gastrin-releasing peptide (GRP) receptor antagonist D-Phe6-bombesin(6-13)-methyl ester (BME) but not by the neuromedin B (NMB) receptor antagonist D-Nal-cyclo[Cys-Tyr-D-Trp-Orn-Val-Cys]-Nal-NH2 (BIM-23127). 6. Secretagogue-evoked fluid secretion was also examined using video microscopy to measure the rate of swelling of ducts whose ends had sealed during overnight culture. Secretin, CCK, bombesin and ACh all evoked fluid secretion with maximal rates of approximately 0.6 nl x min(-1) x mm(-2), and with concentration dependences similar to those obtained for HCO3- secretion. 7. We conclude that CCK, bombesin and ACh stimulate the secretion of a HCO3--rich fluid by direct actions on the interlobular ducts of the guinea-pig pancreas and that these responses are mediated by CCK1 receptors, GRP receptors and muscarinic cholinoceptors, respectively.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1991

The effect of CCKB/gastrin antagonists on stimulated gastric acid secretion in the anaesthetized rat.

1. The urethane-anaesthetized, vagotomised rat preparation was used to investigate the effects of the histamine H2-antagonist ranitidine, the proton pump inhibitor omeprazole and the CCKB/gastrin antagonists CI-988, PD 136450 and L-365,260 on pentagastrin-, histamine- and bethanechol-induced gastric acid secretion. 2. The novel CCKB/gastrin antagonists CI-988 and PD 136450, and L-365,260 dose-dependently inhibited pentagastrin-induced secretion. The ED50 value for PD 136450 was 0.05 mumol kg-1, the same following intravenous or subcutaneous administration. 3. CI-988 and PD 136450 administered subcutaneously at dose levels highly effective for antagonism of pentagastrin responses had no effect on basal acid secretion. 4. Ranitidine inhibited pentagastrin-, bethanechol-, and histamine-induced acid secretion, whereas the CCKB/gastrin antagonists inhibited only the secretory response to pentagastrin. 5. The selective CCKA antagonist, devazepide, was inactive at up to 300 mumol kg-1 i.p. against the three stimulants of acid secretion. 6. CI-988 and PD 136450 will be useful research tools with which to investigate the role of CCKB/gastrin receptors in gastric acid secretion and the trophic activities of gastrin and cholecystokinin (CCK) on the gastrointestinal tract.

Animals↗
PubMed1993

2-Naphthalenesulphonyl L-aspartyl-(2-phenethyl)amide (2-NAP)--a selective cholecystokinin CCKA-receptor antagonist.

1. The in vitro pharmacological characterization of the sodium salt of 2-naphthalenesulphonyl 1-aspartyl-(2-phenethyl)amide [2-NAP], a hydrophilic compound derived from the C-terminal aspartate-phenylalanine dipeptide of cholecystokinin (CCK), is described. 2. 2-NAP behaved as a competitive antagonist of sulphated cholecystokinin octapeptide (CCK-8) at CCKA-receptors in both intact tissue bioassays (guinea-pig gall bladder, pancreas and ileum, human and rabbit gall bladder) and a radioligand displacement assay (guinea-pig pancreatic cells). The mean pKB, over assays, was 6.5. 3. Compared to the other assays, the rabbit gall bladder assay gave a significantly higher pKB estimate [7.0] for 2-NAP and a significantly lower estimate [8.9] for devazepide (formerly L-364,718 and MK-329), a well-characterized CCKA-receptor antagonist; these anomalous results suggest that a different class of CCKA-receptors may be involved. 4. 2-NAP, was found to be highly selective, having at least 300 fold greater affinity for CCKA-receptors than for 50 other pharmacological loci, including gastrin/CCKB, as estimated by bioassay or radioligand displacement.

Aged↗
PubMed1996

Evaluation of the specificity and potency of a series of cholecystokinin-B/gastrin receptor antagonists in vivo.

The potency and specificity of five proposed cholecystokinin-B receptor antagonists, YM022, RP73870, L-740,093, L-365,260 and LY288513, were studied in rats and mice. Gastrin activates rat stomach histidine decarboxylase via cholecystokinin-B/gastrin receptors. To examine cholecystokinin-B receptor-mediated effects of the five drugs, they were infused intravenously to fasted rats and the histidine decarboxylase activity in the oxyntic mucosa was determined. While YM022, RP73870, L-740,093 and L-365,260 failed to activate histidine decarboxylase, they dose-dependently antagonized the gastrin-induced histidine decarboxylase activation. LY288513 had no effect in the doses tested. The maximal inhibitory effect of L-365,260, L-740,093, RP73870 and YM022 on histidine decarboxylase, activated by the intravenous infusion of an ED50 does of gastrin (0.4 nmoles/kg/hr), was seen at doses of 3, 0.3, 0.1 and 0.1 mumoles/kg/hr, respectively; the corresponding ID50 values were 0.4, 0.02, 0.007 and 0.004 mumoles/kg/h. In a follow-up study, YM022 and RP73870 were found to produce a rightward shift of the gastrin dose-response curve, which is consistent with competitive inhibition. The effect of the five drugs on a cholecystokinin-A receptor-mediated response was examined by studying gastric emptying in mice. Cholecystokinin-8s, given by a subcutaneous bolus injection, dose-dependently inhibits gastric emptying. The specific cholecystokinin-A receptor antagonist devazepide (given intravenously as a bolus injection) antagonized the effect of cholecystokinin-8s in a dose-dependent manner, with an ID50 value of 28 nmoles/kg. None of the drugs inhibited the gastric emptying or prevented the cholecystokinin-8s-induced effect at the doses tested. The results indicate that YM022, RP73870, L-740,093 and L-365,260 act as cholecystokinin-B receptor antagonists in vivo, being without measurable agonistic activity. Furthermore, they do not interact with cholecystokinin-A receptors at te doses tested. Among the cholecystokinin-B receptor antagonists studied YM022 and RP73870 are superior, the rank order of potency being YM022 > or = RP73870 > L-740,093 > L-365,260.

Analysis of Variance↗
PubMed2000

Effect of CCK pretreatment on the CCK sensitivity of rat polymodal gastric vagal afferent in vitro.

To prevent the blood-borne interference and reflex actions via neighboring organs and the central nervous system, the study was conducted in an in vitro isolated stomach-gastric vagus nerve preparation obtained from overnight-fasted, urethan-anesthetized rats. Afferent unit action potentials were recorded from the gastric branch of the vagus nerve. The left gastric artery was catheterized for intra-arterial injection. In vitro we found that 1) 55/70 gastric vagal afferents (GVAs) were polymodal, responding to CCK-8 and mechanical stimuli, 13 were mechanoreceptive, and 2 were CCK-responsive; 2) sequential or randomized intra-arterial injections of CCK-8 (0.1-200 pmol) dose-dependently increased firing rate and reached the peak rate at 100 pmol; 3) the action was suppressed by CCK-A (Devazepide) but not by CCK-B (L-365,260) receptor antagonist; 4) neither antagonist blocked the mechanosensitivity of GVA fibers. These results are consistent with corresponding in vivo well-documented findings. Histological data indicate that the layered structure of the stomach wall was preserved in vitro for 6-8 h. Based on these results, it seems reasonable to use the in vitro preparation for conducting a study that is usually difficult to be performed in vivo. For instance, because there was no blood supply in vitro, the composition of the interstitial fluid, i.e., the ambient nerve terminals, can be better controlled and influenced by intra-arterial injection of a defined solution. Here we report that acutely changing the ambient CCK level by a conditioning stimulus (a preceding intra-arterial injection of increasing doses of CCK-8) reduced the CCK sensitivity of GVA terminals to a subsequent test stimulus (a constant dose of CCK-8 intra-arterial injection).

Action Potentials↗
PubMed2006

Endogenous cholecystokinin reduces food intake and increases Fos-like immunoreactivity in the dorsal vagal complex but not in the myenteric plexus by CCK1 receptor in the adult rat.

We hypothesized that endogenous CCK reduces food intake by activating the dorsal vagal complex (DVC) and the myenteric neurons of the gut. To test this hypothesis, adult rats were given camostat mesilate; a nonnutrient releaser of endogenous CCK, by orogastric gavage, and Fos-like immunoreactivity (Fos-LI) was quantified in the DVC and the myenteric plexus. The results for endogenous CCK were compared with those for exogenous CCK-8. Exogenous CCK-8 reduced food intake and stimulated Fos-LI in the DVC and in myenteric neurons of the duodenum and jejunum. In comparison, endogenous CCK reduced food intake and increased DVC Fos-LI but did not increase Fos-LI in the myenteric plexus. Similar to CCK-8, devazepide, a specific CCK(1) receptor antagonist, and not L365,260, a specific CCK(2) receptor antagonist, attenuated the reduction of food intake by camostat. In addition, Fos-LI in the DVC in response to both exogenous CCK-8 and camostat administration was significantly attenuated by vagotomy, as well as by blocking CCK(1) receptors. These results demonstrate for the first time that reduction of food intake in adult rats by endogenous CCK released by a nonnutrient mechanism requires CCK(1) receptors, the vagus nerve, and activation of the DVC, but not the myenteric plexus.

Animals↗
PubMed2005

An enteric signal regulates putative gastrointestinal presympathetic vasomotor neurons in rats.

Ingestion of a meal results in gastrointestinal (GI) hyperemia and is associated with systemic and paracrine release of a number of peptide hormones, including cholecystokinin (CCK) and 5-hydroxytryptamine (5-HT). Systemic administration of CCK octapeptide inhibits a subset of presympathetic neurons of the rostroventrolateral medulla (RVLM) that may be responsible for driving the sympathetic vasomotor tone to the GI viscera. The aim of this study was to determine whether endogenous release of CCK and/or 5-HT also inhibits CCK-sensitive RVLM neurons. The effects of intraduodenal administration of the secretagogues sodium oleate (SO) and soybean trypsin inhibitor (SBTI) on circulating levels of CCK and 5-HT were examined. In separate experiments, the discharge rates of barosensitive, medullospinal, CCK-sensitive RVLM presympathetic vasomotor neurons were recorded after rapid intraduodenal infusion of SO-SBTI or water. Alternatively, animals were pretreated with the CCK1 receptor antagonists devazepide and lorglumide or the 5-HT3 antagonist MDL-72222 before SO-SBTI administration. Secretagogue infusion significantly increased the level of circulating CCK, but not 5-HT. SO-SBTI significantly decreased (58%) the neuronal firing rate of CCK-sensitive RVLM neurons compared with water (5%). CCK1 receptor antagonists did not reverse SO-SBTI-induced neuronal inhibition (58%), whereas the 5-HT3 antagonist significantly attenuated the effect (22%). This study demonstrates a functional relation between a subset of RVLM presympathetic vasomotor neurons and meal-related signals arising from the GI tract. It is likely that endogenously released 5-HT acts in a paracrine fashion on GI 5-HT3 receptors to initiate reflex inhibition of these neurons, resulting in GI vasodilatation by withdrawal of sympathetic tone.

Animals↗
PubMed1994

Pharmacological dissociation of responses to CCK and gastric loads in rat mechanosensitive vagal afferents.

To identify the transduction mechanisms underlying gastric vagal afferent responses to gastric loads and cholecystokinin (CCK), we investigated the ability of specific CCK antagonists, acute pylorectomy, and cholinergic blockade to effect these vagal afferent responses. The CCK-B antagonist L-365,260 (10 pmol-1 nmol) failed to block the gastric vagal afferent response to gastric loads or 100 pmol CCK, while the CCK-A antagonist devazepide (100 pmol-100 nmol) competitively and dose dependently attenuated the response to CCK but not to gastric loads. Application of 100 nmol of the low-affinity CCK receptor antagonist CCK-JMV-180 also completely blocked the gastric vagal afferent response to 100 pmol CCK. Acute pylorectomy failed to block the gastric vagal afferent response to 100 pmol CCK or 2-ml gastric loads. Atropine sulfate administration (15 mg/rat) failed to block the gastric vagal afferent response to 100 pmol CCK or 2-ml gastric loads. These data suggest that 1) the vagal afferent response to CCK is mediated through CCK's interactions with vagal, rather than pyloric, CCK-A receptors, and 2) the vagal afferent responses to CCK and to gastric loads are mediated by dissociable, possibly independent, transduction mechanisms.

Animals↗
PubMed1999

Cholecystokinin and serotonin receptors in the regulation of fat-induced satiety in rats.

The present study investigated the relationship between endogenous CCK and serotonin (5-HT) in fat-induced satiety. Male Wistar rats with duodenal cannulas were adapted to eating 6 h/day along with receiving an infusion of saline or one of two isocaloric solutions (10 ml, 1 kcal/ml, 0.45 ml/min) varying in fat and carbohydrate content (20 or 80% energy from fat). Rats were infused 10 min after food presentation. The satiation/satiety response was determined from measures of meal size (MS), intermeal interval (IMI), and total food intake (TFI). Infusion with either fat solution reduced MS compared with saline; however, the 80% fat infusate reduced TFI and lengthened the IMI compared with saline and the 20% fat infusate. CCK and 5-HT involvement in fat-induced satiety was investigated by preceding the 80% fat infusate with CCK and/or 5-HT3 receptor antagonists Devazepide (Dev) and Tropisetron (Trop). A CCK releaser, trypsin inhibitor (TI), was added to the 20% fat infusate to enhance satiety. Pretreatment with Dev or Trop alone attenuated the inhibitory effects of the 80% solution on IMI, whereas reversal of the inhibitory effects on MS and TFI were sensitive only to Dev at the doses provided. Both antagonists together completely blocked the satiating effects of the 80% fat infusate on all feeding variables measured. Addition of TI to the 20% fat infusate lengthened the IMI but did not affect MS or TFI. These results provide evidence for the participation of both endogenous CCK and 5-HT in the satiety response to fat in the intestine.

Animals↗