Intravenous Infusion Of CCK-8 Research Articles

Role of capsaicin-sensitive peripheral sensory neurons in anorexic responses to intravenous infusions of cholecystokinin, peptide YY-(3-36), and glucagon-like peptide-1 in rats.

Cholecystokinin (CCK)-induced suppression of feeding is mediated by vagal sensory neurons that are destroyed by the neurotoxin capsaicin (CAP). Here we determined whether CAP-sensitive neurons mediate anorexic responses to intravenous infusions of gut hormones peptide YY-(3-36) [PYY-(3-36)] and glucagon-like peptide-1 (GLP-1). Rats received three intraperitoneal injections of CAP or vehicle (VEH) in 24 h. After recovery, non-food-deprived rats received at dark onset a 3-h intravenous infusion of CCK-8 (5, 17 pmol·kg⁻¹·min⁻¹), PYY-(3-36) (5, 17, 50 pmol·kg⁻¹·min⁻¹), or GLP-1 (17, 50 pmol·kg⁻¹·min⁻¹). CCK-8 was much less effective in reducing food intake in CAP vs. VEH rats. CCK-8 at 5 and 17 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 39 and 71% in VEH rats and 7 and 18% in CAP rats. In contrast, PYY-(3-36) and GLP-1 were similarly effective in reducing food intake in VEH and CAP rats. PYY-(3-36) at 5, 17, and 50 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 15, 33, and 70% in VEH rats and 13, 30, and 33% in CAP rats. GLP-1 at 17 and 50 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 48 and 60% in VEH rats and 30 and 52% in CAP rats. These results suggest that anorexic responses to PYY-(3-36) and GLP-1 are not primarily mediated by the CAP-sensitive peripheral sensory neurons (presumably vagal) that mediate CCK-8-induced anorexia.

Exogenous cholecystokinin-8 reduces vagal efferent nerve activity in rats through CCK(A) receptors.

It has been proposed that the vagus nerve plays a role in mediating cholecystokinin-8 (CCK-8) effect on such gastric functions as motility, emptying and gastric acid secretion. To examine the contribution of the efferent pathways in realizing these effects, efferent mass activity in the ventral gastric vagal nerve in Sprague-Dawley rats was recorded. Intravenous infusion of CCK-8 (0.1-1 nmol) suppressed the efferent activity. The effect of CCK-8 was significantly reduced in animals with total subdiaphragmatic vagotomy in comparison to those with partial vagotomy. Intravenous infusion of CCK(A) receptor antagonist L-364,718 (1-100x10(-6) g) blocked the response of vagal efferent activity to 0.1 nmol CCK-8, but the CCK(B) receptor antagonist L-365,260 (1-100x10(-6) g) did not in the conditions of either partial or total vagotomy. Intracisternal infusion of L-364,718 (1x10(-6) g) blocked the response of vagal efferent activity to 0.1 nmol CCK-8 i.v. Infusion of exogenous CCK-8 did not affect the activity of supradiaphragmatic vagal afferents. The results suggest that the effect of systemically administered CCK-8 on vagal efferent activity is mediated by both peripherally (subdiaphragmatically) and centrally localized CCK(A) receptors.

Effects of proglumide on cholecystokinin-8-induced exocrine and endocrine pancreatic responses in conscious sheep

The effects of cholecystokinin (CCK)-8, either alone or together with the CCK antagonist, proglumide on both exocrine and endocrine pancreatic responses were examined in conscious sheep. Intravenous infusions of CCK-8 (120 pmol/kg/min for 40 min) with vehicle (0 μmol/kg/min proglumide) significantly increased both amylase output in pancreatic juice and plasma insulin concentrations ( P < 0.05). Concomitant infusions of proglumide (5–40 μmol/kg/min for 50 min) inhibited both amylase and insulin secretory responses induced by CCK-8 infusion. The antagonistic effects of proglumide occurred in a dose-dependent manner, and proglumide infusion at dose of 20 μmol/kg/min or above simultaneously inhibited CCK-8-induced amylase and insulin responses. In conclusion, although the type of receptor involved is not characterized at present, exogenously infused CCK-8 acts on B cells via a CCK-receptor-mediated mechanism and induces insulin secretion in sheep.

Defect in pancreatic exocrine and endocrine response to CCK in genetically diabetic OLETF rats.

Clinical as well as experimental studies in insulinopenic diabetes mellitus have demonstrated abnormal pancreatic exocrine responses to cholecystokinin (CCK). In the present study, we examined pancreatic exocrine and endocrine function in the recently developed genetically diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats and compared them with those in the control Long-Evans Tokushima Otsuka (LETO) rats of the same age. Stepwise increasing doses of CCK octapeptide (CCK-8; 0.027-7.0 nmol.kg-1.h-1) evoked a characteristic biphasic dose-response curve for pancreatic juice and protein output in the LETO rats, whereas the OLETF rats were totally insensitive to CCK-8 stimulation. However, the responsiveness and the sensitivity to both carbamylcholine and secretin were similar in the two groups. Intraduodenal infusion of casein (500 mg/h) failed to stimulate pancreatic exocrine secretion in the OLETF rats despite a greater CCK response than in the LETO rats (peak response: 8.43 +/- 0.97 vs 5.12 +/- 0.30 pmol/l in LETO, P < 0.01). Intravenous infusion of CCK-8 (4.4 nmol.kg-1.20 min-1) caused a significant increase in serum insulin concentrations and a concomitant decrease in glucose levels in the LETO rats but not in the OLETF rats. On the other hand, an intravenous bolus injection of 1.1 mmol/kg glucose caused a greater insulin release in the OLETF rats than in the LETO rats. In contrast, gastric acid secretion in the OLETF rats was significantly high in basal and in response to intravenous infusion of CCK-8 compared with that in the LETO rats. Four subcutaneous injections of 20 micrograms/kg caerulein at hourly intervals over 3 h induced acute pancreatitis in the LETO rats but did not elicit any significant increase in serum amylase or lipase activities and pancreatic wet weight or histological evidence of acute pancreatitis in the OLETF rats. These results indicate that the exocrine and endocrine pancreas of the recently developed genetically diabetic OLETF rats are totally and specifically insensitive to exogenous and endogenous CCK stimulation, whereas parietal cells in these rats are sensitive to CCK stimulation.

Effects of KSG-504, a New Cholecystokinin-A-Receptor Antagonist, on Pancreatic Exocrine and Endocrine Secretions in Rats

The effects of KSG-504 ((S)-arginium (R)-4-[N-(3-methoxypropyl)-N-pentylcarbamoyl]-5-(2-naphthylsulf onyl) pentanoate monohydrate), a new cholecystokinin (CCK)-A-receptor antagonist, on pancreatic exocrine secretion in anesthetized rats and endocrine secretion in conscious rats were studied. Intravenous injection of KSG-504 inhibited the pancreatic amylase output stimulated by intravenous infusion of CCK-8 in a dose-dependent manner (ED50: 18 micrograms/kg/min). Moreover, KSG-504 significantly reduced the CCK-8-stimulated increases in pancreatic juice volume and outputs of protein, trypsin and lipase. Intraduodenal infusion of casein increased the plasma CCK concentration and the pancreatic amylase output. KSG-504 significantly inhibited the pancreatic amylase output stimulated by casein. Pancreatic juice volume and bicarbonate output were significantly stimulated by intravenous infusion of secretin, but were not changed by KSG-504. When pancreatic exocrine secretion was stimulated by secretin plus CCK-8, KSG-504 suppressed the increases in juice volume and bicarbonate output to the level stimulated by secretin alone. Basal pancreatic amylase output was decreased by KSG-504. KSG-504 decreased the level of plasma immunoreactive insulin (IRI) stimulated by glucose plus CCK-8, but had no effect on IRI stimulated by glucose alone and the basal IRI. These in vivo studies suggest that KSG-504 has significant inhibitory effects both on the pancreatic exocrine and endocrine secretion stimulated by CCK, but has no effect on the exocrine secretion stimulated by secretin.

Mediation by CCKB receptors of the CCK‐evoked hyperaemia in rat gastric mucosa

1. Cholecystokinin octapeptide (CCK-8) and gastrin-17 augment gastric mucosal blood flow in the rat. The present study examined whether the gastric vasodilator effect of these peptides is mediated by CCKA or CCKB receptors. 2. Intravenous injection of CAM-1481 (1 mg kg-1), a dipeptoid antagonist of CCKA receptors, or CAM-1028, a dipeptoid CCKB receptor antagonist (1 mg kg-1), had no effect on basal gastric mucosal blood flow as determined by the clearance of hydrogen in urethane-anaesthetized rats. 3. Intravenous infusion of CCK-8 or gastrin-17 (8-200 pmol min-1) increased gastric mucosal blood flow in a dose-dependent fashion. The CCKB receptor antagonist, CAM-1028, significantly attenuated the hyperaemic response to CCK-8 and gastrin-17 whereas the CCKA receptor antagonist, CAM-1481, did not antagonize CCK-8 but caused a slight attenuation of the vasodilator response to gastrin-17. 4. The selectivity of the two antagonists was proved by the findings that CAM-1028, but not CAM-1481, inhibited gastric acid secretion evoked by CCK-8 or gastrin-17 (CCKB receptor assay) while CAM-1481, but not CAM-1028, inhibited the CCK-8-induced contraction of guinea-pig isolated gall bladder strips (CCKA receptor assay). 5. These data show that the actions of CCK-8 and gastrin-17 to increase mucosal blood flow in the rat stomach are primarily mediated by CCKB receptors.

Cholecystokinin does not act on the efferent pathway of cholinergic and adrenergic nerves to inhibit ruminal contractions in sheep (Ovis aries).

The effect of exogenous cholecystokinin-octapeptide (CCK-8) on ruminal contractions and the role of efferent pathways of cholinergic and adrenergic nerves on the effect were studied in sheep. Intravenous infusion of CCK-8 at 11.4 and 45.6 pmol/kg/min significantly inhibited the frequency and amplitude of ruminal contractions in conscious sheep. After bilateral cervical vagotomy, intravenous infusion of CCK-8 at 45.6 mol/kg/min had no detectable effect on amplitude of ruminal contractions induced by electric stimulation to the cervical vagus nerve (1 msec, 20 Hz, 5 mA, for 10 sec at 1-min intervals) in anesthetized sheep. The amplitude of contractile responses of ovine ruminal muscle strips to acetylcholine at 5 x 10(-5) M was not inhibited by CCK-8 applied simultaneously at 1 x 10(-9) M. Intravenous infusion of phentolamine at 53.0 nmol/kg/min, propranolol at 101.4 nmol/kg/min, or their combined infusion did not alter the inhibitory action of CCK-8 at either dose on ruminal contractions in conscious sheep. These results suggest that CCK-8, which does not act on the efferent pathway of cholinergic and adrenergic nerves, may reflexively inhibit reticuloruminal contractions via vagal afferent fibers in sheep.

Effects of intravenous infusions of cholecystokinin (CCK)-8 on exocrine and endocrine pancreatic secretion in conscious sheep.

The effects of cholecystokinin (CCK)-8 on both exocrine and endocrine pancreatic functions were examined simultaneously in five conscious sheep. Intravenous infusions of CCK-8 (0, 5, 10, 20, 30, 60, 120 and 240 pmol/kg/min for 40 min) induced dose-dependent increases in flow rate, and in protein and amylase outputs in pancreatic juice. The same CCK-8 infusions induced dose-dependent increases in plasma insulin, but no change in plasma glucagon concentrations. The threshold dose (10-30 pmol/kg/min) of CCK-8 infusion for stimulating insulin secretion was similar to that for stimulating amylase output. In conclusion, using amylase output as an indicator of physiological action, CCK is one of the potential candidates as a physiological regulator of insulin, but not glucagon secretion in sheep.

Effect of a Novel Cholecystokinin Receptor Antagonist, FK480, Administered Intraduodenally, on Pancreatic Secretion in Rats

The effect of a new cholecystokinin (CCK)-A receptor antagonist, FK480, developed in Japan, on pancreatic exocrine secretion stimulated by exogenous CCK and intraduodenal casein was investigated in vivo when administered to anesthetized rats intraduodenally, and its CCK antagonistic activity was compared with that of CR 1505. Intraduodenal administration of FK480 at graded doses of 0.0016-1.0 mg/kg-h produced dose-dependent inhibition of pancreatic juice volume and amylase output stimulated by intravenous infusion of CCK-8 at a dose of 0.06 micrograms/kg-h. The half-maximal inhibitory dose (ID50) of FK480 for CCK-8-stimulated amylase secretion was 0.025 mg/kg-h, whereas the ID50 of CR 1505 was 5.2 mg/kg-h, indicating that FK480 is 208 times more potent than CR 1505. Moreover, intraduodenal FK480 (0.2 mg/kg-h) significantly suppressed pancreatic juice volume and amylase output augmented by intraduodenal infusion of casein (400 mg/h). It is concluded that FK480 administered intraduodenally has a significant, potent inhibitory action on the exocrine pancreas stimulated by exogenous CCK and intraduodenal casein.

Physiological role of cholecystokinin on gastric emptying and acid output in dogs

We investigated the physiological role of cholecystokinin (CCK) on gastric emptying and acid secretion in seven conscious dogs with gastric cannulae. Two hundred milliliters of a 4% amino acid meal was given via the cannula, and both gastric emptying and acid output were measured concurrently using a dye-dilution technique. Gastric emptying of the liquid amino acid meal was exponential, and the acid output and plasma concentrations of CCK, gastrin, and somatostatin peaked within 30 min after the meal. Intravenous infusion of CCK-8 at 28 and 56 pmol/kg/hr but not 14 pmol/kg/hr increased plasma levels of the peptide and inhibited gastric emptying as well as acid output. Plasma gastrin was not affected significantly by the CCK infusion, whereas plasma somatostatin increased significantly in response to 56 pmol/kg/hr of CCK-8. Loxiglumide, 22 mumol/kg/hr, significantly enhanced gastric emptying and augmented acid output, as well as plasma gastrin response, whereas it abolished the postprandial rise in plasma somatostatin. We concluded that in dogs, CCK plays an important role in the physiologic regulation of postprandial gastric emptying of a liquid caloric meal and acid output. Its inhibitory effect on gastric acid secretion appears to be mediated, at least in part, by somatostatin.

A New CCK-A Antagonist, KSG-504, Administered Intraduodenally, Inhibits Pancreatic Secretion in Rats

We studied the effect in anesthetized rats of a new cholecystokinin (CCK) receptor antagonist developed in Japan, KSG-504, administered intraduodenally, on pancreatic exocrine secretion stimulated by exogenous CCK and intraduodenal casein. Intraduodenal administration of KSG-504 in graded doses of 2.5-50 mg/kg/h produced dose-dependent inhibition of pancreatic juice volume and amylase output stimulated by intravenous infusion of CCK-8 in a dose of 0.06 micrograms/kg/h. The ID50 (half-maximal inhibition dose) of KSG-504 for CCK-8-stimulated amylase secretion was 3.4 mg/kg/h. Moreover, intraduodenal KSG-504 (5 and 25 mg/kg/h) dose dependently suppressed pancreatic juice volume, and amylase output increased with intraduodenal infusion of casein (400 mg/h). It is concluded that KSG-504 administered intraduodenally has a significant, potent inhibitory action on the exocrine pancreas stimulated by exogenous CCK and intraduodenal casein.

Effects of CCK‐8 on ingestive behaviors of suckling and weanling rats

The present series of experiments was designed to determine the dose-response characteristics of the cholecystokinin suppression effect on rat pups ingesting through suckling and adult modes. Pups at 10-22 days of age were deprived of their dam and food for 6 hr. At test time, the subjects received intraperitoneal injections or intravenous infusions of CCK-8 at 2, 4, 8, or 16 micrograms/kg in saline, or the saline vehicle alone. The pups were permitted to ingest for 30 min immediately after the injection or during the infusion. Ingestion included taking milk from the dam by suckling or feeding from the substrate. Regardless of the route of administration, CCK-8 elicited a low level of suppression across all doses and all ages when pups ingested within the natural suckling situation. In marked contrast, pups ingesting from the substrate in the adult mode suppressed their intake of bovine light cream or chow pellets in a dose-related manner following injections of the peptide. The blockade of the CCK dose-related suppression effect during suckling indicates that a different set of mechanisms governs intake of milk from the mother. The results may be related to the level of arousal required to sustain motivated behaviors while pups engage in the different modes of ingestion.

Potentiating Effect of CCK and Secretin on Rat Exocrine Pancreas and its Cholinergic Dependence

We investigated whether physiological doses of cholecystokinin (CCK) potentiate the stimulating effect of a physiological dose of secretin on exocrine pancreatic secretion, and the effect of atropine on this potentiating action in rats. Pure pancreatic juice was collected from anesthetized rats prepared by pancreatic duct and bile duct cannulation. Intravenous infusion of CCK-8 in three different doses, 0.03, 0.06, and 0.12 micrograms/kg/h, significantly increased pancreatic juice volume and amylase output, dose-dependently. Simultaneous infusion of CCK-8 in graded doses with secretin in a dose of 0.03 CU/kg/h, produced a dose-related increase in pancreatic secretory response significantly greater than the response to CCK-8 alone (p less than 0.05) and greater than the sum of the response to secretin alone and CCK-8 alone. The incremental pancreatic secretion, including juice volume and amylase output, in response to intravenous infusion of CCK-8 with secretin, was significantly suppressed by intravenous administration of atropine in a dose of 100 micrograms/kg/h (p less than 0.01). Thus, it is concluded that CCK-8 and secretin in physiological doses potentiate each other's stimulatory action on exocrine pancreatic secretion and this potentiating action appears to be cholinergic-dependent.

Effects of CCK on Gene Expression of Endocrine Pancreatic Hormones

Regulation of endocrine pancreatic hormone gene expression by cholecystokinin (CCK) was examined in the rat using cloned cDNA probes to quantify changes in specific mRNAs (insulin, glucagon, pancreatic polypeptide and somatostatin). Plasma CCK levels were raised to concentrations comparable to physiologic postprandial values either by including soybean trypsin inhibitor (SBTI) in the intraduodenal perfusate of an elemental diet (6.9 +/- 1.0 pM, n = 6), or by intravenous infusion of CCK-8 (6.0 +/- 0.9 pM, n = 6). SBTI infusion for 48 h resulted in a three- to fourfold increase in procarboxypeptidase B and kallikrein mRNA levels. Similar increases were observed when CCK was infused intravenously for 24 h. In contrast, neither SBTI intraduodenally, nor intravenous CCK had any effects on mRNA levels of insulin, glucagon, PP or somatostatin. These data therefore indicate that CCK at physiologic postprandial plasma concentrations stimulates pancreatic protease gene expression but has no effects on gene expression of endocrine pancreatic hormones.

Effect of CCK antagonists CR 1409 and CR 1505 on rat pancreatic exocrine secretion in vivo.

The action of cholecystokinin (CCK) antagonists CR 1409 and CR 1505 on pancreatic exocrine secretion stimulated by exogenous and endogenous CCK was studied in vivo in anesthetized rats, and compared with proglumide. Intravenous administration of CR 1409 and CR 1505 in graded doses between 0.04 and 25 mg/kg/h resulted in a dose-dependent inhibition in pancreatic juice volume and amylase output stimulated by intravenous infusion of CCK-8 in a dose of 0.06 microgram/kg/h. CR 1409 is 1,000 times and CR 1505 is 267 times more potent than proglumide, based on the ED50 (effective dose for half-maximal inhibition) for CCK-8-stimulated amylase secretion. Intraduodenal administration of casein in a dose of 400 mg/h caused significant increases in plasma CCK concentration and pancreatic secretion of juice volume and outputs of amylase and trypsin. Both CR 1409 and CR 1505 in a dose of 5 mg/kg/h suppressed the increases in pancreatic juice volume and both amylase and trypsin outputs induced by casein given intraduodenally. These results indicate that CCK antagonists including CR 1409, CR 1505, and proglumide inhibit pancreatic exocrine secretion stimulated by not only exogenous, but also endogenous CCK in rats.

Effects of cholecystokinin on pancreatic ornithine decarboxylase gene expression.

The effects of cholecystokinin (CCK) on pancreatic ornithine decarboxylase (ODC) gene expression were studied in the rat. Plasma CCK concentrations were raised to levels comparable to postprandial values either by intravenous infusion of CCK octapeptide (CCK-8) or by intraduodenal perfusion of soybean trypsin inhibitor (SBTI). ODC mRNA levels were quantified using a cloned cDNA probe. ODC mRNA increased to 166 +/- 34% (n = 4) of control after 1 h, peaked at 254 +/- 39% (n = 4) of control after 24 h, and remained significantly elevated for up to 48 h of SBTI infusion. Intravenous infusion of CCK-8 for 24 h increased ODC mRNA levels to the same extent observed with SBTI infusion. The CCK receptor antagonist L364,718 by itself had no effect on ODC mRNA levels but totally abolished the induction of ODC mRNA by both intravenous CCK infusion and intraduodenal infusion of SBTI. These data therefore indicate that CCK plasma concentrations comparable to postprandial values regulate pancreatic ODC at a pretranslational level and that SBTI exerts its effects on pancreatic ODC via an increase in plasma CCK.

Action of the cholecystokinin antagonist L364,718 on gastric emptying in the rat.

Cholecystokinin (CCK) is a potent inhibitor of gastric emptying. We have examined the effects of a novel potent peripheral CCK receptor antagonist (L364,718) on the action of endogenous and exogenous CCK octapeptide (CCK-8) on gastric emptying in the rat. In conscious gastric fistula rats, the recovery of liquid test meals of 3.0 ml (containing phenol red as a dilution marker) was determined over periods up to 8 min. Compared with saline, gastric emptying of solutions of peptone (4.5%), 50 mM HCl, and hyperosmolal saline was significantly delayed. The emptying of saline was also delayed by intravenous infusion of CCK-8 (400 pmol.kg-1.h-1). The CCK antagonist L364,718 reversed the effect of peptone in a dose-dependent manner and inhibited the response to exogenous CCK, but the emptying of physiological saline, 50 mM HCl, or hyperosmolal saline remained unchanged. A protease inhibitor (FOY-305) that is thought to release endogenous CCK by inhibiting negative feedback control by luminal proteases also delayed emptying, and this response was inhibited by L364,718. We conclude that CCK has a physiological role in the mediation of the effect of proteins on gastric emptying in the rat.

In vivo action of bombesin on exocrine pancreatic secretion in the rat: independent of cholecystokinin and cholinergic mediation.

This study evaluates the effect of bombesin on pancreatic enzyme secretion in the rat and determines whether the stimulatory action of bombesin is mediated through the release of cholecystokinin (CCK) or via a cholinergic pathway. We performed in vivo experiments on conscious rats prepared with cannulae inserted in the pancreatic duct, in the external jugular vein, and in the duodenum. Intravenous infusion of bombesin stimulated pancreatic protein output in a dose-dependent fashion. Bombesin infused at 5 micrograms/kg/h stimulated pancreatic protein secretion from a basal of 12 +/- 5 to 42 +/- 10 mg/h. Infusion of proglumide (400 mg/kg/h) did not affect the stimulatory effect of bombesin on pancreatic protein secretion (38 +/- 5 mg/h). In contrast, infusion of proglumide abolished the pancreatic protein output elicited by intravenous infusion of CCK8 (500 ng/kg/h). This suggests that bombesin does not act through CCK to mediate exocrine pancreatic secretion. In separate studies we intravenously infused rats with atropine (100 micrograms/kg/h) prior to infusion with bombesin. Administration of atropine slightly decreased secretory volume but did not affect the action of bombesin. Combined administration of atropine and proglumide also did not affect pancreatic protein output stimulated by bombesin. Since infusion of neither proglumide nor atropine inhibited the stimulatory action of bombesin, the action of bombesin in the rat is probably direct and not through the release of CCK or via a cholinergic pathway.

Receptor-mediated internalization and secretion of cholecystokinin into rat pancreatic duct fluid.

We measured cholecystokinin (CCK) in pancreatic duct secretions (PDS) after infusion of different amounts of CCK-8 (the C-terminal octapeptide of cholecystokinin) into rats. Injection of 23, 46, and 92 ng of CCK-8 increased immunoreactive cholecystokinin in PDS by 3-, 13-, and 28-fold above basal levels within 30 min. Continuous intravenous infusion of CCK-8 (50 ng/min) into rats for 30 min, followed by a 30-min rest period, and then a final infusion of peptide for another 30 min increased CCK in PDS only during the final period by 12-fold to 500 pg/30 min. Neither gastrin nor oxidized CCK-8 were detected in PDS after intravenous infusion of each peptide. Administration of proglumide (ip), a CCK receptor antagonist, during continuous CCK infusion significantly reduced immunoreactive CCK levels in PDS to 2% of the control group (P less than or equal to 0.01). CCK was also rapidly internalized into dispersed pancreatic acinar cells in a temperature-dependent fashion, and this process was inhibited by proglumide. The above data suggest that CCK in PDS reflects a peptide-specific process that is receptor mediated. We propose that circulating cholecystokinin binds to specific receptors on pancreatic acinar cells, is internalized, and is then secreted into pancreatic duct fluid.

An intragastric meal releases the putative satiety factor cholecystokinin from hypothalamic neurons in cats

The release of cholecystokinin-like immunoreactivity (CCK-LI) from feline hypothalamus was studied in relation to a meal by use of the push-pull perfusion technique. While levels of CCK-LI in the perfusate of overnight-fasted anesthetized cats were below assay sensitivity (<7pg/30min), intragastric administration of a carbohydrate-amino acid meal elicited a 3-fold increase in CCK-LI, identified by high-performance liquid chromatography as the C-terminal octapeptide of CCK (CCK-8). Examination of an extrahypothalamic site showed no comparable release in CCK-LI. Intravenous infusions of CCK-8 at doses imitating physiological blood levels up to 400 times higher than those seen after physiological stimulation demonstrated the existence of a CCK blood-brain barrier in the lateral hypothalamus. These observations provide support that CCK may play a physiological role in termination of feeding behavior.