Electrical physiological evidence for highand low-affinity vagal CCK-A receptors

1999 ◽  
Vol 277 (2) ◽  
pp. G469-G477 ◽  
Author(s):  
Ying Li ◽  
Jinxia Zhu ◽  
Chung Owyang
Keyword(s):  
Receptor Antagonist ◽  
Receptor Field ◽  
Cck Receptors ◽  
Physiological Conditions ◽  
Nodose Ganglia ◽  
Afferent Fibers ◽  
Electrophysiological Studies ◽  
Vagal Afferent ◽  
Cck Receptor Antagonist ◽  
Afferent Response

We have demonstrated that under physiological conditions CCK acts through vagal high-affinity CCK-A receptors to mediate pancreatic secretion. In this study, we evaluated the vagal afferent response to endogenous CCK in rats and defined the CCK-receptor affinity states and the vagal-receptive field responsive to CCK stimulation using electrophysiological studies. Experiments were performed on anesthetized rats prepared with bile-pancreatic fistula. Plasma CCK levels were elevated by diverting bile-pancreatic juice (BPJ). The single-unit discharge of sensory neurons supplying the gastrointestinal tract was recorded from the nodose ganglia. All units studied were either silent or they had a very low resting discharge frequency. Thirty-two single units were studied extensively; seven were shown to be stimulated by diversion of BPJ (2.6 ± 2 impulses/min at basal to 40 ± 12 impulses/min after diversion). Acute subdiaphragmatic vagotomy or perivagal capsaicin treatment abolished the response. The CCK-A-receptor antagonist CR-1409, but not the CCK-B antagonist L-365260, blocked the vagal response to endogenous CCK stimulation. Infusion of the low-affinity CCK-receptor antagonist CCK-JMV-180 completely blocked the vagal afferent response to the diversion of BPJ in three of seven rats tested but had no effect on the response in the remaining four. In a separate study, we demonstrated that gastric, celiac, or hepatic branch vagotomy abolished the response in different subgroups of neurons. In conclusion, under physiological conditions, CCK acts on both high- and low-affinity CCK-A receptors present on distinct vagal afferent fibers. The vagal CCK-receptor field includes the regions innervated by the gastric, celiac, and hepatic vagal branches. This study provides electrophysiological evidence that vagal CCK receptors are present on the vagal gastric, celiac, and hepatic branches and may occur in high- and low-affinity states.

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

1994 ◽  
Vol 267 (1) ◽  
pp. R303-R308 ◽  
Author(s):  
G. J. Schwartz ◽  
P. R. McHugh ◽  
T. H. Moran
Keyword(s):  
Receptor Antagonist ◽  
Atropine Sulfate ◽  
Vagal Afferents ◽  
Cholinergic Blockade ◽  
Transduction Mechanisms ◽  
Vagal Afferent ◽  
Cck Antagonists ◽  
Cck Receptor Antagonist ◽  
Afferent Response

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.

Secretin activates vagal primary afferent neurons in the rat: evidence from electrophysiological and immunohistochemical studies

2005 ◽  
Vol 289 (4) ◽  
pp. G745-G752 ◽  
Author(s):  
Ying Li ◽  
Xiaoyin Wu ◽  
Harry Yao ◽  
Chung Owyang
Keyword(s):  
Sensory Neurons ◽  
Neuronal Response ◽  
Afferent Pathways ◽  
Nodose Ganglia ◽  
Afferent Fibers ◽  
Intestinal Distension ◽  
Vagal Afferent ◽  
Immunohistochemical Studies ◽  
Afferent Response ◽  
First Time

In this study, we evaluated the vagal afferent response to secretin at physiological concentrations and localized the site of secretin's action on vagal afferent pathways in the rat. The discharge of sensory neurons supplying the gastrointestinal tract was recorded from nodose ganglia. Of 91 neurons activated by electrical vagal stimulation, 19 neurons showed an increase in firing rate in response to intestinal perfusion of 5-HT (from 1.5 ± 0.2 to 25 ± 4 impulses/20 s) but no response to intestinal distension. A close intra-arterial injection of secretin (2.5 and 5.0 pmol) elicited responses in 15 of these 19 neurons (from 1.5 ± 0.2 impulses/20 s at basal to 21 ± 4 and 43 ± 5 impulses/20 s, respectively). Subdiaphragmatic vagotomy and perivagal application of capsaicin, but not supranodose vagotomy, completely abolished the secretin-elicited vagal nodose neuronal response. In a separate study, 9 tension receptor afferents among 91 neurons responded positively to intestinal distension but failed to respond to luminal 5-HT. These nine neurons also showed no response to administration of secretin. As expected, immunohistochemical studies showed that secretin administration significantly increased the number of Fos-positive neurons in vagal nodose ganglia. In conclusion, we demonstrated for the first time that vagal sensory neurons are activated by secretin at physiological concentrations. A subpopulation of secretin-sensitive vagal afferent fibers is located in the intestinal mucosa, many of which are responsive to luminal 5-HT.

scholarly journals Leptin inhibits gastric emptying in rats: role of CCK receptors and vagal afferent fibers

2007 ◽  
pp. 315-322 ◽  
Author(s):  
B Çakır ◽  
Ö Kasımay ◽  
E Devseren ◽  
BÇ Yeğen
Keyword(s):  
Gastric Emptying ◽  
Food Intake ◽  
Receptor Blocker ◽  
Adrenergic Blockade ◽  
Phenol Red ◽  
Gastric Emptying Rate ◽  
Cck Receptors ◽  
Afferent Fibers ◽  
Cephalic Phase ◽  
Vagal Afferent

Leptin regulates energy homeostasis and body weight by balancing energy intake and expenditure. It was recently reported that leptin, released into the gut lumen during the cephalic phase of gastric secretion, is capable of initiating intestinal nutrient absorption. Vagal afferent neurons also express receptors for both CCK and leptin, which are believed to interact in controlling food intake. The present study was undertaken to investigate the central and peripheral effects of leptin on gastric emptying rate. Under anesthesia, male Sprague-Dawley rats (250-300 g) were fitted with gastric Gregory cannulas (n=12) and some had additional cerebroventricular cannulas inserted into their right lateral ventricles. Following recovery, the rate of gastric emptying of saline (300 mOsm/kg H(2)O) was determined after instillation into the gastric fistula (3 ml, 37 degrees C, containing phenol red, 60 mg/l as a non-absorbable dilution marker). Gastric emptying rate was determined from the volume and phenol red concentrations recovered after 5 min. Leptin, injected intraperitoneally (i.p.; 10, 30, 60, 100 microg/kg) or intracerebroventricularly (i.c.v.; 5, 15 microg/rat) 15 min before the emptying, delayed gastric emptying rate of saline at the dose of 30 microg/kg or 15 microg/rat (p<0.001). When CCK(1) receptor blocker L-364,718 (1 mg/kg, i.p.), CCK(2) receptor blocker L-365,260 (1 mg/kg, ip) or adrenergic ganglion blocker bretylium tosylate (15 mg/kg, i.p.) was administered 15 min before ip leptin (30 microg/kg) injections, leptin-induced delay in gastric emptying was abolished only by the CCK(1) receptor blocker (p<0.001). However, the inhibitory effect of central leptin on gastric emptying was reversed by adrenergic blockade, but not by either CCK antagonists. Our results demonstrated that leptin delays gastric emptying. The peripheral effect of leptin on gastric motility appears to be mediated by CCK(1) receptors, suggesting the release of CCK and the involvement of vagal afferent fibers. On the other hand, the central effect of leptin on gastric emptying is likely to be mediated by adrenergic neurons. These results indicate the existence of a functional interaction between leptin and CCK receptors leading to inhibition of gastric emptying and short-term suppression of food intake, providing an additional feedback control in producing satiety.

Abstract 20340: Defect of Ca 2+ -activated Cl - Channel in Intestinal Nodose Neurons Contributes to Impaired Satiety Signal in High-Fat Diet Induced Obesity

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Runping Wang ◽  
Yongjun Lu ◽  
Michael Z Cicha ◽  
Kamal Rahmouni ◽  
Mark W Chapleau ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Vagal Afferents ◽  
High Fat ◽  
Altered Expression ◽  
Cck Receptors ◽  
Whole Cell Patch Clamp ◽  
Nodose Ganglia ◽  
Maximum Current ◽  
Vagal Afferent ◽  
High Level

High fat diet inhibits the cholecystokinin (CCK) induced satiety signal in vagal afferents, which may contribute to the associated increased food intake. We hypothesized that a defect of Ca 2+ -activated chloride channel (CaCC) in high fat (HFD) fed mice leads to the reduction of CCK responses in intestinal vagal afferent nodose neurons. By using the whole cell patch-clamp in cultured nodose ganglia neurons isolated from C57BL/6 mice, we found that CCK (10nM) induced large inward chloride (Cl - ) currents (36.0±11pA/pF) that were eliminated with the fast Ca 2+ chelator BAPTA (1.0±0.5pA/pF, n=7), and reduced significantly by the CaCC channel inhibitor niflumic acid (100 μM, 13.6±2.0pA/pF, p<0.05, n=8). The response to CCK in DiI-labeled proximal intestinal nodose neurons from obese mice fed a 60% HFD for 10 weeks was reduced significantly (6.1±2.9pA/pF, n=7, p<0.01) relative to control lean mice (24.8±4.9pA/pF, n=7). The underlying molecular mechanism of the reduced CCK response in mice fed a HFD did not involve altered expression of CCK receptors in nodose neurons. We found that the relative mRNA (qPCR) of CCK receptor B was not significantly changed (1.01±0.13 in control vs. 1.18±0.31 in HFD nodose ganglia, n=4, p>0.05) and the mRNA of CCK receptor A was even increased from 1.06±0.37 in control to 1.54±0.41 in HFD ganglia (n=4, p<0.05). In contrast, the CaCC channel mRNA (Ano I) was decreased to 0.61±0.09 relative to 1.01±0.20 (n=4, p<0.001), and Ano II mRNA was decreased to 0.31±0.07 relative to 1.02±0.22 (n=4, p<0.001) in nodose ganglia from HFD fed vs. control lean mice. Since the maximum current induced by a saturation level of ligand reflects the level of protein expressed on the cytoplasmic membrane, we tested the CaCC current induced by a high level of intracellular Ca 2+ (20μM). We found that the maximum current was smaller in DiI labeled intestinal nodose neurons from HFD fed mice (13.7±2.9 pA/pF vs. 26.9±3.6 pA/pF in control mice, n=10, p<0.05). Our results indicate that CCK-activated currents recorded from intestinal vagal afferent nodose neurons are reduced in mice fed a HFD, and are associated with reduced expression of a CCK-activated Ca 2+ -dependent Cl - channel. This mechanism may contribute significantly to HFD-induced suppression of the satiety reflex.

scholarly journals 4119 Cholecystokinin (CCK) Receptor Antagonist Reverses Nonalcoholic Steatohepatitis (NASH) by Reducing Hepatic Macrophages and Inflammatory Cytokines

2020 ◽  
Vol 4 (s1) ◽  
pp. 93-94
Author(s):  
Martha Gay ◽  
Anita Safronenka ◽  
Hong Cao ◽  
Robin Tucker ◽  
Narayan Shivapurkar ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Receptor Antagonist ◽  
Inflammatory Cytokines ◽  
Receptor Expression ◽  
Receptor Blockade ◽  
High Fat ◽  
Cck Receptors ◽  
Cytokines And Chemokines ◽  
Hepatic Macrophages ◽  
Cck Receptor Antagonist

OBJECTIVES/GOALS: NASH increases the risk of cirrhosis and liver cancer. High-fat diets increase CCK levels and CCK receptors have been identified on fibroblasts and immune cells. We hypothesized that CCK receptor blockade could prevent NASH by altering the hepatic microenvironment and macrophage activation. METHODS/STUDY POPULATION: Female mice were fed a Choline Deficient Ethionine supplemented (CDE) saturated fat diet or control high-fat diet for 18 weeks. Mice in each group were treated with a CCK receptor antagonist, proglumide (0.1 mg/ml) in the drinking water or regular water. Resected livers were stained for H&E for features of NASH and F4/80 for macrophages analysis. Liver RNA was evaluated for the expression of cytokines and chemokines using an 84-gene Profiler array (Qiagen). Oxidative stress was analyzed by qRT-PCR for heat shock proteins (HSPs) 27, 60, 70 and 90 and for glutathione by a fluorometric assay. Differences in CDE fed and CDE/proglumide-treated mouse livers were evaluated. RESULTS/ANTICIPATED RESULTS: Livers from mice on the CDE diet displayed histologic features of NASH that were prevented by proglumide. Cytokines and chemokines expression, especially CCL20 and CCL2, were increased in the CDE fed mice and these levels were reduced greater than 20-fold with proglumide. Infiltration of F4/80+ macrophages was markedly increased in the CDE livers and these were reduced by > 50% (p < 0.0001) with proglumide. RNA expression of HSP70 (p = 0.006) and HSP27 (p = 0.011) were reduced with proglumide. Hepatic glutathione concentration more than doubled in the CDE/proglumide treated mice compared to CDE mice. CCK-B receptor expression increased in the CDE-fed mouse livers compared to controls. DISCUSSION/SIGNIFICANCE OF IMPACT: CCK receptor blockade decreases NASH by reducing hepatic macrophages, oxidative stress, and blocking inflammatory cytokines and chemokines. This data supports our novel hypothesis that CCK receptors play a role in NASH and proglumide may provide an innovative treatment for this condition.

scholarly journals Effect of Extracellular Calcium on Excitability of Guinea Pig Airway Vagal Afferent Nerves

2003 ◽  
Vol 89 (3) ◽  
pp. 1196-1204 ◽  
Author(s):  
Bradley J. Undem ◽  
Eun Joo Oh ◽  
Eric Lancaster ◽  
Daniel Weinreich
Keyword(s):  
Guinea Pig ◽  
Action Potential ◽  
Extracellular Calcium ◽  
C Fibers ◽  
Afferent Nerves ◽  
Nodose Ganglia ◽  
Cation Conductance ◽  
Afferent Fibers ◽  
Low Threshold ◽  
Vagal Afferent

The effect of reducing extracellular calcium concentration ([Ca2+]o) on vagal afferent excitability was analyzed in a guinea pig isolated vagally innervated trachea-bronchus preparation. Afferent fibers were characterized as either having low-threshold, rapidly adapting mechanosensors (Aδ fibers) or nociceptive-like phenotypes (Aδ and C fibers). The nociceptors were derived from neurons within the jugular ganglia, whereas the low-threshold mechanosensors were derived from neurons within the nodose ganglia. Reducing [Ca2+]o did not affect the excitability of the low-threshold mechanosensors in the airway. By contrast, reducing [Ca2+]o selectively increased the excitability of airway nociceptors as manifested by a substantive increase in action potential discharge in response to mechanical stimulation, and in a subset of fibers, by overtly evoking action potential discharge. This increase in the excitability of nociceptors was not mimicked by a combination of ω-conotoxin and nifedipine or tetraethylammonium. Whole cell patch recordings from airway-labeled and unlabeled neurons in the vagal jugular ganglia support the hypothesis that [Ca2+]o inhibits a nonselective cation conductance in vagal nociceptors that may serve to regulate excitability of the nerve terminals within the airways.

Gastric loads and cholecystokinin synergistically stimulate rat gastric vagal afferents

1993 ◽  
Vol 265 (4) ◽  
pp. R872-R876 ◽  
Author(s):  
G. J. Schwartz ◽  
P. R. McHugh ◽  
T. H. Moran
Keyword(s):  
Food Intake ◽  
Vagal Afferents ◽  
Sufficient Information ◽  
Afferent Activity ◽  
Combined Load ◽  
Synergistic Inhibition ◽  
Afferent Fibers ◽  
Inhibit Food Intake ◽  
Vagal Afferent ◽  
Afferent Response

Both gastric preloads and exogenous cholecystokinin (CCK) administration inhibit food intake, and combinations of preloads and CCK suppress feeding to a greater degree than either stimulus delivered alone. A role for the vagus nerve in mediating CCK's inhibition of food intake has been proposed, and gastric vagal afferent fibers respond to both gastric loads and local CCK infusions. To examine whether combined load and CCK stimuli may synergistically augment gastric neural afferent activity at the level of the peripheral vagus, we have examined the gastric vagal afferent responses (n = 8) to a range of gastric saline loads (1, 2, and 3 ml) and exogenous close celiac arterial CCK (10 and 100 pmol) when administered alone or in combination. Gastric loads ineffective in eliciting a significant increase in vagal afferent activity when administered alone became effective when combined with doses of CCK that were subthreshold for the production of a vagal afferent response. Gastric loads that alone were effective in producing a significant vagal afferent response yielded an even greater response when administered in combination with both subthreshold and suprathreshold doses of CCK. These data demonstrate that, in rats, signals produced by combined gastric load and exogenous CCK administration are integrated peripherally and interact synergistically. These results suggest that signals arising from the vagus may provide sufficient information for the synergistic inhibition of food intake produced by combinations of gastric loads and exogenous CCK.

Blockade of type A, but not type B, CCK receptors postpones satiety in rhesus monkeys

1993 ◽  
Vol 265 (3) ◽  
pp. R620-R624 ◽  
Author(s):  
T. H. Moran ◽  
P. J. Ameglio ◽  
H. J. Peyton ◽  
G. J. Schwartz ◽  
P. R. McHugh
Keyword(s):  
Food Intake ◽  
Receptor Antagonist ◽  
Rhesus Monkeys ◽  
Type A ◽  
Intragastric Administration ◽  
Maximal Effect ◽  
Type B ◽  
Cck Receptors ◽  
Total Food Intake ◽  
Cck Receptor Antagonist

The exogenous administration of the brain/gut peptide cholecystokinin (CCK) inhibits food intake in a variety of species, including subhuman primates and humans. To determine the role of endogenously released CCK in the control of food intake in rhesus monkeys, we examined the ability of the selective type A and type B CCK antagonists devazepide and L-365260 to affect total daily food intake and various meal patterns. Various doses of the antagonists were administered intragastrically 30 min before a daily 4-h feeding period. One-gram food pellets were delivered in response to lever pulls, and intake was computer monitored. Intragastric administration of the type A CCK receptor antagonist devazepide (10-320 micrograms/kg) significantly increased food intake in a dose-related fashion. The threshold for increasing intake was 32 micrograms/kg, and a maximal effect was obtained at a dose of 100 micrograms/kg that increased total 4-h food intake by 47%. The effect of devazepide on food intake was mediated by significant increases in the size and duration of the initial meal, lengthening of the subsequent intermeal interval, and a decrease in the satiety ratio (intermeal interval/1st meal size). In contrast, intragastric administration of the type B CCK receptor antagonist L-365260 (3.2-320 micrograms/kg) did not significantly affect total food intake or any of the meal parameters. These data demonstrate that endogenously released CCK acting through type A CCK receptors plays a role in regulating food intake in rhesus monkeys.

CCK is involved in both peripheral and central mechanisms controlling food intake in chickens

1997 ◽  
Vol 272 (1) ◽  
pp. R334-R340 ◽  
Author(s):  
A. Rodriguez-Sinovas ◽  
E. Fernandez ◽  
X. Manteca ◽  
A. G. Fernandez ◽  
E. Gonalons
Keyword(s):  
Food Intake ◽  
Receptor Antagonist ◽  
Receptor Type ◽  
Receptor Antagonists ◽  
Cck Receptors ◽  
High Affinity ◽  
Increase Food Intake ◽  
Cck Receptor Antagonist ◽  
Cck Receptor Antagonists ◽  
Voluntary Food Intake

The aim of this work was to study the involvement of cholecystokinin (CCK) in the control of food intake in chickens. The following aspects were studied: 1) the effects of intravenous and intracerebroventricular sulfated octapeptide of CCK (CCK-8s) on voluntary food intake; 2) the effects of two CCK-receptor antagonists. L-365,260 and L-364,718, on food intake; and 3) the ability of such drugs to block the effects of CCK-8s on food intake in the chicken. Intravenous and intracerebroventricular CCK-8s caused a decrease in food intake. Intraperitoneal L-365,260, a CCK-receptor antagonist with low affinity for the two CCK receptors described in the chicken, increases food intake. Intracerebroventricular L-364,718, a drug that has high affinity for the chicken central CCK-receptor type, increased food intake. The effect of intravenous CCK-8s on food intake was not blocked by L-364,718 or L-365,260, whereas that of intracerebroventricular CCK-8s was blocked by intracerebroventricular L-364,718. It is concluded that central endogenous CCK plays a role in the control of food intake, which is dependent on central CCK-receptor type; nevertheless, peripheral CCK also decreases food intake acting on the peripheral CCK-receptor type. The fact that intracerebroventricular L-364,718 is able to increase food intake is related to its high affinity for the central CCK-receptor type of this species. Finally, three different speculations that might explain the fact that intraperitoneal L-365,260 increases food intake are discussed.

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