Effects Of Cholecystokinin Octapeptide Research Articles

Facilitating effect of CCK on nicotinic neurotransmission in cat pancreatic ganglion.

Previous studies have demonstrated the presence of cholecystokinin (CCK)-like peptides in nerve terminals surrounding ganglion neurons of the cat pancreas. The present study was undertaken to determine the effect of cholecystokinin octapeptide (CCK-8) on ganglionic transmission. Recordings were made intracellularly in vitro from ganglion neurons in isolated pieces of the pancreas. Sulfated CCK-8 (S-CCK-8) and nonsulfated CCK-8 initiated or increased ongoing fast excitatory postsynaptic potential (fEPSP) activity, an effect antagonized by hexamethonium. Superfusion of S-CCK-8 in concentrations ranging from 10(-11) to 10(-8) M significantly augmented the amplitude of nerve-evoked subthreshold fEPSPs without a significant change in either membrane potential or membrane input resistance. S-CCK-8 (10(-8)M) also increased the quantal content and quantal size of nerve-evoked fEPSPs and increased the response to exogenously applied acetylcholine (ACh). Concentrations of S-CCK-8 higher than 10(-8)M caused depolarization and an increase in membrane input resistance, an effect unaltered by a low-Ca+, high-Mg2+ solution. It was concluded that S-CCK-8 potentiated nicotinic transmission by facilitating release of ACh from preganglionic nerve terminals and by increasing the postsynaptic membrane sensitivity to ACh.

Cholecystokinin depolarizes neurons of cat pancreatic ganglion

The effect of cholecystokinin octapeptide (CCK-8) on membrane potential and conductance of cat pancreatic ganglion neurons was studied in vitro by means of intracellular microelectrode recording methods. Microejection of S-CCK-8 and NS-CCK-8 evoked, by direct action, a slow, reversible membrane depolarization. The majority of neurons tested were more sensitive to S-CCK-8. The depolarizing response to S-CCK-8 and NS-CCK-8 was accompanied in different neurons by a variable change in membrane permeability to Na+ and/or K+. The effects of S-CCK-8 and NS-CCK-8 were mediated by the CCKB receptor. The results suggest that S-CCK-8 and NS-CCK-8 increase the excitability of pancreatic ganglion neurons by acting on postsynaptic CCKB receptors.

Interaction between CCK and opioids in the modulation of the rectocolonic inhibitory reflex in rats.

The effects of cholecystokinin octapeptide (CCK-8) as well as the involvement of opioid system were evaluated in rectal distension (RD)-induced colonic motor inhibition in rats. Rats were surgically prepared with electrodes implanted on the proximal colon, and a catheter was implanted in lateral ventricle of the brain. RD was performed by inflation (0.0-1.6 ml) of a balloon rectally inserted. RD 1.6 ml of induced an inhibition of the colonic spike bursts (3.1 +/- 0.5 per 5 min vs. 8.1 +/- 0.4 before RD). Intracerebroventricular but not intravenous injection of CCK-8 and A-71623 (50 and 100 ng/kg) reduced the RD-induced colonic motor inhibition, whereas A-63387 was ineffective. PD-135,158 (10 micrograms/kg icv) suppressed the inhibitory reflex caused by RD. Devazepide (100 micrograms/kg icv) had no effect in this reflex function. Devazepide (1 microgram/kg), naloxone (0.1 mg/kg), and nor-binaltorphimine (nor-BNI; 10 mg/kg) reversed the blocking effect of CCK-8, whereas PD-135,158 (0.1 microgram/kg) and naltrindole (1 mg/kg) have no effect. In conclusion, CCK-8 acts on central alimentary cholecystokinin receptors to modulate the RD-induced inhibition of colonic motility through pathways involving activation of endogenous kappa-receptors.

Effect of cholecystokinin octapeptide and atropine on human colonic motility, tone and transit: [formula omitted], G.M. Thomforde, R.B. Hanson, M. Camilleri. Gastroenterology Research Unit, Mayo Clinic, Rochester, MN

Effect of cholecystokinin octapeptide and atropine on human colonic motility, tone and transit: [formula omitted], G.M. Thomforde, R.B. Hanson, M. Camilleri. Gastroenterology Research Unit, Mayo Clinic, Rochester, MN

The transfer of rats from a familiar to a novel environment prolongs the increase of extracellular dopamine efflux induced by CCK8 in the posterior nucleus accumbens

The effects of cholecystokinin octapeptide (CCK8) on extracellular dopamine (DA) and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, were measured in the nucleus accumbens (N. Acc.). The experiments were carried out using in vivo microdialysis in awake rats submitted, or not, to a novel environment, the four-hole box. The exploratory behavior of the animals was studied concurrently in these boxes and in the elevated plus maze. Without CCK8 treatment, the transfer of animals from their home cages to the four-hole box induced a transient increase in DA efflux and also tended to increase its metabolites in the posterior N. Acc. In rats placed in a familiar environment, the administration of 25 pmol of CCK8 in this region immediately enhanced DA release, with levels rapidly returning to normal at the end of the perfusion. In contrast, this treatment produced a longer effect in rats transferred to the four-hole box, since the DA efflux was still increased 80 min after the removal of CCK8. The intra-accumbal administration of CCK8 induced a hypoexploration in the four-hole box. Moreover, an anxiogenic-like effect of CCK8 was found in the elevated plus maze, only in rats submitted to a novel environment (four-hole box). These data show that (1) the postero-accumbens DA neurons can be activated by environmental changes and (2) that the intensity of the CCK8 effects on extracellular DA levels and on anxiety-like responses seems to depend on the activity of these neurons previous to CCK8 treatment. The prolonged DA release induced by CCK8 in animals placed in a new situation could correspond to a biochemical anticipation preparing them to react when faced by another stimulus.

Cholecystokinin is a potent protective agent against alcohol-induced gastric injury in the rat. Role of endogenous prostaglandins.

Cholecystokinin is a gastrointestinal hormone known to physiologically regulate pancreatic protein secretion and gallbladder contractility. Some evidence suggests that cholecystokinin is also involved in the maintenance of gastrointestinal mucosal integrity. This study was undertaken to ascertain whether cholecystokinin could prevent the gastric mucosal injury induced by acidified ethanol and what role prostaglandins, and type A and type B cholecystokinin receptors might play in this process. Conscious, fasted rats were given subcutaneous saline or cholecystokinin octapeptide (10-100 micrograms/kg) 30 min before a 1-ml oral gastric bolus of acidified ethanol (150 mM HCl/50% ethanol). Five minutes later, rats were sacrificed and the total area of macroscopic injury quantitated (square millimeters). In additional experiments using a similar protocol, 1 ml of either the cyclooxygenase inhibitor, indomethacin (5 mg/kg), a type A cholecystokinin receptor antagonist, L-364,718 (0.01-1 mg/kg), or the type B cholecystokinin receptor antagonist, L-365,260 (12.5-25 mg/kg) was given intraperitoneally 30 min prior to pretreatment with cholecystokinin octapeptide. Cholecystokinin octapeptide dose-dependently prevented mucosal injury from acidified ethanol (corroborated by histology). The protective effect of cholecystokinin octapeptide was completely negated by L-364,718 and partially reversed by indomethacin, while L-365,260 had no discernible effect in this process. In a further study, cholecystokinin was unable to prevent the damaging effects of aspirin and the inhibition of endogenous prostaglandins. This, it appears that cholecystokinin is able to maintain mucosal integrity in the face of a damaging insult by activation of type A cholecystokinin receptors, an effect mediated, at least in part, through the release of endogenous prostaglandins.

The effect of cholecystokinin-octapeptide on the hepatobiliary dysfunction caused by total parenteral nutrition

Purpose: Patients on total parenteral nutrition (TPN) commonly have hepatobiliary dysfunction. Interruption of the enterohepatic circulation (EHC) and gallbladder stasis are part of the pathogenesis. Cholecystokinin-octapeptide (CCK-OP), by emptying the gallbaldder, stimulates the EHC. This study was performed to determine whether daily CCK-OP infusions can ameliorate the hepatobiliary dysfunction caused by TPN. Methods: Rabbits maintained on a standard TPN for 12 days were divided into two groups. One group (n = 6) received daily intravenous doses of CCK-OP, and the other (n = 13) received TPN only. A lab-chow-fed (LCF) group (n = 8) served as controls. The authors studied bile flow and bile acid secretion rates, sulfobromophthalein (BSP) secretion, gallbladder emptying in response to CCK-OP, and liver histology. Results: The LCF group had a bile flow of 82.3 μL/kg/min; that for the TPN-only group was 45.7 μL/kg/min ( P < .001). The daily CCK-OP group did not improve more than the TPN-only group, with a bile flow of 45.8 μL/kg/min ( P = NS). Bile acid secretion was 0.64 μmol/kg/min for the LCF group, 0.46 for the TPN-only group ( P = NS), and 0.46 for the daily CCK-OP group ( P = NS). TPN impaired the ability of the gallbladder to empty, and this was restored with daily CCK-OP. In the LCF group, the mean BSP secretion was 81.7% of a 5-mg/kg bolus within 60 minutes, compared with 72.5% in the daily CCK-OP group ( P = NS) and 63.5% in the TPN-only group ( P < .01). Histological examination of the liver showed that daily CCK-OP produced less periportal inflammation and fibrosis, although all TPN groups had hepatocyte damage in the centrilobular area. Conclusion: Stimulation of the EHC with daily CCK-OP infusions during TPN decreased periportal inflammation and fibrosis, maintained gallbladder emptying capacity, and improved organic anion (BSP) secretion, although bile flow and bile acid secretion were not improved, and hepatocyte damage persisted.

CCKB-Receptor Activation Augments the Long-Term Potentiation in Guinea Pig Hippocampal Slices

Effects of cholecystokinin octapeptide (CCK-8) on long-term potentiation (LTP) of CA1 synaptic transmission induced by tetanic stimulation of the input fibers were examined in guinea pig hippocampal slices. CCK-8 and a selective agonist for the CCKB receptor, non-sulfated CCK-8, dose-dependently augmented the magnitude of LTP. Concomitant application of a selective antagonist for the CCKB-receptor subtype, L-365,260 (3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-methylphenyl)urea), completely blocked the augmentation of LTP induced by CCK-8, whereas a selective CCKA-receptor antagonist, L-364,718 (3S(—)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine)), had little effect. Thus, enhancement of LTP by CCK appears to be mediated by CCKB receptors. Furthermore, CCK-8 enhanced paired-pulse facilitation at a concentration of 10−7 M without affecting the amplitude of the population spike induced by single stimulation. This effect was mimicked by a low dose of tetraethylammonium (TEA), a K+ channel blocker. Moreover, both CCK-8 and TEA reduced the late component of evoked field potentials. This late evoked potential was diminished by increasing the extracellular K+ concentration. It is suggested that CCK-8 reduces the K+ conductance in CA1 pyramidal neurons. This reduction in the K+ conductance might be related to enhancement of the LTP.

Effects of cholecystokinin octapeptide and BC 264, a potent and selective CCK-B agonist on aspartate and glutamate release from rat hippocampal slices

In rat hippocampal slices, BC 264 (0.1–1 μM), a highly potent and selective CCK-B agonist, was found to increase basal release of endogenous glutamate and aspartate but not that of GABA. The natural peptide, cholecystokinin octapeptide (CCK 8) at 1 μM, induced the same effect. The selective CCK-B receptor antagonist, L-365,260, completely reversed these responses, confirming that they are related to CCK-B receptor activation. In the absence of extracellular Ca 2+, the increase in excitatory amino acid release was completely abolished. In contrast to the basal release, the potassium evoked release of aspartate and glutamate was not modified by BC 264.

Effects of cholecystokinin octapeptide on potassium currents in cultured sympathetic neurons.

Effects of cholecystokinin octapeptide on potassium currents in cultured sympathetic neurons.

Effects of cholecystokinin octapeptide and somatostatin on the motility and release of [3H]acetylcholine in canine colon

1. The longitudinal and circular muscle layers of canine colon showed a different pattern of mechanical activity: regular rhythmic phasic contractions in the circular strips and irregular rhythmic prolonged contractions in the longitudinal strips. 2. The spontaneous motility of both layers was suppressed by atropine (1 microM) or hexamethonium (1 microM), suggesting the involvement of ACh. 3. Somatostatin (1 nM-1 microM) decreased, while CCK8 (1-10 nM) increased the spontaneous and electrically-induced contractions of the colonic muscles, the circular layer being more sensitive as compared to the longitudinal layer. 4. CCK8 enhanced both resting and electrically-induced [3H]ACh release, while SOM inhibited the electrically-stimulated [3H]ACh release.

The Antagonistic Effect of Cholecystokinin Octapeptide (CCK-8) on Opioid Effects in Cardiovascular Activities Was Mediated by CCK-B Receptor

Previous studies have shown that CCK-8 has distinct antiopioid effect in the central sites related with pain control and blood pressure control. The aim of this study was to explore the receptor mechanism by which CCK-8 antagonized the depressor effect of u-and k-opioid agonists, and to observe whether CCK-8 could antagonize the depressor effect induced by muscimol, a nonopioid substance. The results showed that (ⅰ) The antagonistic effect of CCK-8 on opioid-induced hypotension could be blocked by intrathecal (i.t.) administration of CCK-B antagonist L-365, 260 at nanogram doses, or by CCK-A antagonist devazepide at doses 20—40 times higher than L-365, 260, indicating that it was the CCK-B receptor which mediates the antiopioid effect. (ⅱ) The depressor effect induced by intrathecal muscimol, a GABA agonist, was blocked neither by naloxone nor by CCK-8, supporting the notion that CCK-8 is an endogenous opioid antagonist rather thana universal anti-hypotension agent.

The antagonistic effect of cholecystokinin octapeptide (CCK-8) on opioid effects in cardiovascular activities was mediated by CCK-B receptor.

Previous studies have shown that CCK-8 has distinct antiopioid effect in the central sites related with pain control and blood pressure control. The aim of this study was to explore the receptor mechanism by which CCK-8 antagonized the depressor effect of u- and k-opioid agonists, and to observe whether CCK-8 could antagonize the depressor effect induced by muscimol, a nonopioid substance. The results showed that (i) The antagonistic effect of CCK-8 on opioid-induced hypotension could be blocked by intrathecal (i. t.) administration of CCK-B antagonist L-365, 260 at nanogram doses, or by CCK-A antagonist devazepide at doses 20-40 times higher than L-365, 260, indicating that it was the CCK-B receptor which mediates the antiopioid effect. (ii) The depressor effect induced by intrathecal muscimol, a GABA agonist, was blocked neither by naloxone nor by CCK-8, supporting the notion that CCK-8 is an endogenous opioid antagonist rather than a universal anti-hypotension agent.

Relationship between amino acid transport and protein synthesis in rat isolated pancreatic acini under stimulation with cholecystokinin.

The effects of cholecystokinin octapeptide (CCK8) on amino acid transport and protein synthesis in the pancreatic acini were determined. The question of whether those effects differed between amino acid transport systems A and L was also investigated. The influx of alpha-[3H]aminoisobutyric acid (AIB, system A) and [14C]cycloleucine (system L) into isolated rat pancreatic acini and the incorporation of [14C]alanine (system A) and [3H]leucine (system L) into trichloroacetic acid (TCA)-precipitable protein in pancreatic acini were studied in the presence of various concentrations of CCK8. CCK inhibited the amino acid transport across the basolateral membrane of pancreatic acini. This effect was mediated by Ca2+, and was more responsive to amino acid transport system L than to A. CCK also inhibited protein synthesis in pancreatic acini in a dose-dependent manner. The inhibition of protein synthesis by CCK was thought to be mainly due to the inhibition of amino acid transport by CCK. Therefore, the predominant utilization of extracellular amino acids in protein synthesis was suggested.

Pancreatic acini possess endothelin receptors whose internalization is regulated by PLC-activating agents

Endothelin-1 (ET-1) and ET-3 mRNA have been found in the pancreas. We investigated the ability of ET-1, ET-2, and ET-3 to interact with and alter dispersed rat pancreatic acinar cell function. Radiolabeled ETs bound in a time- and temperature-dependent fashion, which was specific and saturable. Analysis demonstrated two classes of receptors, one class (ETA receptor) had a high affinity for ET-1 but a low affinity for ET-3, and the other class (ETB receptor) had equally high affinities for ET-1 and ET-3. No specific receptor for ET-2 was identified. Pancreatic secretagogues that activate phospholipase C (PLC) inhibited binding of 125I-labeled ET-1 (125I-ET-1) or 125I-ET-3, whereas agents that act through adenosine 3',5'-cyclic monophosphate (cAMP) did not. A23187 had no effect on 125I-ET-1 or 125I-ET-3 binding, whereas the phorbol ester 12-O-tetradecanoylphorbol 13-acetate reduced binding. The effect of cholecystokinin octapeptide (CCK-8) was mediated through its own receptor. Stripping of surface bound ligand studies demonstrated that both 125I-labeled ET-1 and 125I-labeled ET-3 were rapidly internalized. CCK-8 decreased the internalization but did not change the amount of surface bound ligand. Endothelins neither stimulate nor alter changes in enzyme secretion, intracellular calcium, cAMP, or [3H]inositol trisphosphate (IP3). This study demonstrates the presence of ETA and ETB receptors on rat pancreatic acini; occupation of both receptors resulted in rapid internalization, which is regulated by PLC-activating secretagogues. Occupation of either ET receptor did not alter intracellular calcium, cAMP, IP3, or stimulate amylase release.

Effect of cholecystokinin octapeptide and somatostatin on the mechanical and electrical activity of the colon of conscious dogs

AbstractIntraluminal pressure and electrical activity of the colon of conscious dogs were recorded using silver bipolar electrodes and a pressure transducer. Two phases in the mechanogram of the transverse colon were observed: a quiescent phase (lack of contractions) lasting 12.05 ± 0.54 min and a contractile phase lasting 14.46 ± 0.88 min. The electrical activity was characterized by a quiescent phase (only slow waves in the electrogram) with a duration of 13.55 ± 1.73 min. Groups of spike potentials bursting in the rhythm of the slow waves appeared during the activity phase lasting 15.60 ± 2.02 min. Cholecystokinin octapeptide (CCK8) (10–20 ng/kg i.v.) significantly increased the duration of 1–3 active phases and shortened the duration of the quiescent phases. The percentage of slow waves with spike potentials during the active phase in the electro‐gram increased. Colonic contractions also increased, i.e. CCK8 evoked an enhanced motility of the colon. Somatostatin (1–2 μg/kg i.v.) increased by two to three times the duration of the quiescent phases. Atropine (50–100 μg/kg i.v.) or somatostatin (1–2 μg/kg i.v.) inhibited both the spontaneous and the CCK8‐induced colonic motility. It is suggested that the inhibitory effect of somatostatin on spontaneous and CCAV induced colonic activity in conscious dogs is mediated by a decrease in cholinergic neurotransmission.

CCK A receptors mediate slow depolarizations in cultured mammalian sympathetic neurons

The effect of cholecystokinin octapeptide (CCK-8) was examined in guinea-pig celiac ganglion (CG) neurons in primary culture using standard intracellular recording techniques. Sulfated CCK-8 (CCK-8S; 1 μM) evoked slow depolarizing responses in 94% of CG neurons tested. In contrast, membrane potential was not affected by nonsulfated CCK-8 (CCK-8NS; 1 μM), CCK tetrapeptide (CCK-4; 1 μM), or gastrin (1 μM). The selective CCK A receptor antagonist L 364,718 potently inhibited CCK-8S-induced slow depolarizations(IC 50 2.9 pM). In contrast, the selective CCK B receptor antagonist L 365,260 was a weak inhibitor of CCK-8S-induced slow depolarizations (IC 50 1.3 μM). The depolarizing responses to CCK-8S were associated with an average increase in cell input resistance of 61%. Single electrode voltage clamp experiments indicated that CCK-8S-induced depolarizations were associated with a slow inward shift in holding current. Thus, the present findings indicate that guinea-pig cultured CG neurons are endowed with excitatory CCK A receptors the activation of which elicits a decrease in membrane conductance, thereby resulting in slow depolarizations.

Effects of cholecystokinin octapeptide on the hypothalamic-pituitary-adrenal axis function and on vasopressin, prolactin and growth hormone release in humans.

Cholecystokinin (CCK), a gastrointestinal (GI) hormone, is also present in structures of the central nervous system such as cortex, hippocampus, amygdala, olfactory tubercle and in regions involved in the regulation of the pituitary function. Although a number of studies have evaluated the effects of CCK on hypothalamic-pituitary-adrenal (HPA) axis function and on arginine vasopressin (AVP), prolactin (PRL) and growth hormone (GH) plasma levels in the laboratory animal, its role in humans has not been explored. Hence, we examined the effects of the exogenous administration of this GI hormone on corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), cortisol, AVP, PRL and GH plasma levels in humans. To accomplish this, graded doses (0, 50, 140 and 420 ng/kg) of sulfated CCK octapeptide (CCK-8), the full biologically active peptide, were infused intravenously to healthy men in 30 min. Blood samples were collected 30 min and immediately before the infusion was started (baseline) and 15, 30, 45, 60 and 90 min thereafter. CRH, ACTH, and AVP were extracted from plasma proteins using cartridges of SepPak C18. These hormones and cortisol were measured by radioimmunoassay whereas PRL and GH were measured by immunoradiometric assay. CCK-8 increased plasma ACTH and cortisol levels only at the dose of 420 ng/kg, whereas it had no detectable effect on plasma CRH levels. It increased also plasma AVP levels at the doses of 140 and 420 ng/kg. However, this effect reached the statistical significance only at the highest dose tested. CCK-8 stimulated PRL and GH release in a dose-dependent fashion. The lowest stimulatory dose was 140 ng/kg for both hormones.(ABSTRACT TRUNCATED AT 250 WORDS)

Cholecystokinin octapeptide stimulates phasic and tonic pyloric motility in healthy humans.

Stimulation of localised pyloric contractions may be an important mechanism in the slowing of gastric emptying by cholecystokinin infusion. The effect of cholecystokinin octapeptide on fasting pyloric motility was investigated in 14 healthy volunteers. Antral, pyloric, and duodenal pressure responses to normal saline and graded injections of cholecystokinin octapeptide (5, 10, and 20 ng/kg) were measured. Injections were given double blind and in randomised order. All doses of cholecystokinin octapeptide initially stimulated (p < 0.05 cf saline) phasic pressure waves localised to the pylorus--the median number of pyloric pressure waves in the 5 minutes after injection being 0, 3.5, 6, and 7 for the saline and the 5, 10, 20 ng/kg cholecystokinin octapeptide injections respectively. The phasic pyloric motor response to 20 ng/kg cholecystokinin octapeptide injection was greater than that to 5 ng/kg (p < 0.05). Basal pyloric pressure increased after 20 ng/kg (1.0 v 0.2 mm Hg, p < 0.05 cf saline). Antral and duodenal pressure waves were suppressed initially by all doses of cholecystokinin (p < 0.05 cf saline). Subsequently, 20 of the 42 cholecystokinin octapeptide, injections but none of the saline injections, were followed by antropyloric pressure waves. Atropine, 15 micrograms/kg iv as a bolus, and then 4 micrograms/kg/hour iv as an infusion, had no effect on the stimulation of localised phasic pyloric pressure waves by cholecystokinin octapeptide 10 ng/kg. It is concluded that stimulation of pyloric contractions and suppression of antral and proximal duodenal motility may contribute to the slowing of gastric emptying produced by cholecystokinin.

S2-5 Effect of cholecystokinin octapeptide on learning and memory in rats

S2-5 Effect of cholecystokinin octapeptide on learning and memory in rats