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PubMed1995

Cholecystokinin-GABA interactions in rat striatum.

The release of [3H]gamma-aminobutyric acid ([3H]GABA) from rat striatal slices before and during electrical field stimulation (EFS) was measured. Electrical stimulation (10 Hz) induced an increase of Ca(++)- and tetrodotoxin-sensitive [3H]GABA release from the striatal slices. In the presence of sulphated octapeptide of cholecystokinin, CCK-8S (10(-9) M, 10(-8) M and 10(-7) M) both the basal and the electrically (10 Hz)-evoked release of [3H]GABA were dose-dependently increased. These effects of CCK-8S were abolished by tetrodotoxin (10(-6) M) and were not influenced by the CCK-A receptor antagonist loxiglumide (CR1505) (10(-7) M and 10(-6) M). The stimulant effect of CCK-8S was antagonized by the newly synthesized CCK-B selective receptor antagonist PD134308 (10(-7) M and 10(-6) M). These findings suggest that CCK-8 plays a neuromodulatory role in the regulation of GABAergic neuronal activity in the striatum. The activation of CCK-B receptors located on GABAergic neurons is involved in the GABA release-potentiating effect of CCK-8S in rat striatum.

Animals↗
PubMed1993

Influence of fatty acid absorption on bidirectional release of immunoglobulin A into intestinal lumen and intestinal lymph in rats.

Effects of absorption of long and middle chain fatty acids on IgA secretion into the intestinal lumen and intestinal lymph and the factors which evoke changes in IgA secretion during the absorptive process were examined in rat small intestine. Bidirectional secretion of IgA from the intestinal mucosa into the intestinal lumen and intestinal lymph was continuously observed in the control condition. Perfusion of oleic acid (a long-chain fatty acid) micelle into the jejunal loop induced a significant increase in IgA output into the intestinal lymph. In contrast, lymphatic output of IgA was significantly decreased when oleic acid micelle was administered intraduodenally. Absorption of octanoic acid, a middle-chain fatty acid, did not produce any significant changes in IgA output into either direction. CR1505, a CCK-receptor antagonist, significantly attenuated the oleic acid-induced increase in IgA secretion into the intestinal lumen, but did not affect the oleic acid-induced decrease in lymphatic IgA secretion. Pluronic L-81, an inhibitor of chylomicron formation and secretion, significantly attenuated the decrease in IgA output into the intestinal lymph during oleic acid absorption without affecting the luminal IgA output. The rate of release of IgA into the intestinal lumen is stimulated by absorption of long-chain fatty acids possibly through the influence of locally released CCK, while the transport process of IgA into lymphatics is controlled by a different mechanism which is closely correlated with the intracellular formation and secretion of chylomicron.

Animals↗
PubMed1989

The cholecystokinin receptor antagonist CR1409 increases plasma cholecystokinin in rats.

This study was undertaken to determine whether plasma cholecystokinin (CCK) levels are affected by the administration of the CCK-receptor antagonist CR1409 to rats. Infusion of 0.19, 0.94 and 4.75 mg/kg.h CR1409 for 30 min each into 6 conscious rats increased (P less than 0.05) plasma CCK from 1.3 +/- 0.5 to 6.0 +/- 1.2, 5.4 +/- 1.2, and 5.4 +/- 1.0 pM, respectively. In a subsequent study infusion of stepwise increasing lower doses of 0.3, 1.5, 7.5, 37.5 and 187.5 micrograms/kg.h CR1409 for 30 min each into 6 other rats dose-dependently increased (P less than 0.05) plasma CCK from 1.4 +/- 0.3 to 3.1 +/- 0.6, 4.1 +/- 0.8, 5.4 +/- 1.0, 5.9 +/- 0.8 and 7.1 +/- 1.1 pM, while infusion of saline did not affect plasma CCK concentrations. We therefore conclude that the CCK-receptor antagonist CR1409 increases plasma CCK in the rat.

Animals↗
PubMed1990

Mechanism of inhibitory action of peptide YY on cholecystokinin-induced contractions of isolated dog ileum.

In isolated canine ileal longitudinal muscle preparations, cholecystokinin-octapeptide (CCK-8) produced a concentration-dependent contraction, which was suppressed by peptide YY (PYY) and was abolished by tetrodotoxin and atropine. PYY was approximately 2200-times as potent as CR1505, a CCK-receptor antagonist. PYY opposed the action of CCK-8 to a greater extent than that of nicotine and transmural electrical stimulation. Acetylcholine-induced contractions were not influenced by PYY. It seems likely that the CCK-8-induced ileal muscle contraction is associated with an activation of CCK receptors in cholinergic nerves, which generates nerve action potentials and releases acetylcholine, whereas CCK-8 acts on CCK receptors in gallbladder smooth muscle, producing contractions. It may be concluded that PYY inhibits the action of CCK-8 on ileal muscle strips, by inhibiting the release of acetylcholine from cholinergic nerve terminals. On the other hand, in the gallbladder, PYY does not appear to block cholinergic nerve function.

Animals↗
PubMed1990

Cholecystokinin is a regulator of intestinal phase-stimulated PP release.

The purpose of this study was to determine the role of CCK during the intestinal phase of pancreatic polypeptide (PP) release in man. We first compared the PP response to exogenous caerulein infusion in the presence or absence of either loxiglumide (a specific CCK antagonist) or atropine in six healthy subjects. In the second part of the study, a meal was perfused to the duodenum with and without either loxiglumide or atropine. Both loxiglumide and atropine completely abolished the PP response to exogenous or endogenous stimulation (P less than 0.05). We conclude that CCK participates in the intestinal phase of PP secretion.

Adult↗
PubMed1991

Effect of the specific cholecystokinin-receptor antagonist loxiglumide on bombesin stimulated pancreatic enzyme secretion in man.

We have investigated the effects of the specific cholecystokinin (CCK) receptor antagonist loxiglumide on basal and bombesin stimulated pancreatic enzyme secretion, bilirubin output and plasma CCK release in six healthy subjects. The data were compared with those obtained in control experiments where saline was infused instead of loxiglumide. Basal amylase output (4.7 +/- 0.8 kU/45 min), trypsin output (2.9 +/- 0.8 kU/45 min) and bilirubin output (7.7 +/- 2.8 mmol/45 min) gradually declined during infusion of loxiglumide to values of 1.3 +/- 0.3 kU/45 min, 0.5 +/- 0.1 kU/45 min and 0.4 +/- 0.0 mmol/45 min, respectively, reaching statistical significance (P less than 0.05) in the 30 to 45-min period after the start of the loxiglumide infusion. In the control experiments saline infusion failed to influence basal amylase, trypsin and bilirubin output, while bombesin stimulated amylase output from 4.7 +/- 0.8 kU/45 min to 25.1 +/- 5.1 kU/45 min (P less than 0.05), trypsin output from 2.9 +/- 0.8 kU/45 min to 11.6 +/- 2.0 kU/45 min (P less than 0.05) and bilirubin output from 7.7 +/- 2.8 mmol/45 min to 68.0 +/- 16.0 mmol/45 min (P less than 0.05). Loxiglumide failed to significantly influence bombesin stimulated amylase output (36.7 +/- 9.0 kU/45 min) and trypsin output (8.3 +/- 2.9 kU/45 min), but almost abolished bilirubin output (9.7 +/- 3.6 mmol/45 min) (P less than 0.05). Basal plasma CCK (2.4 +/- 0.1 pM) was not significantly influenced by loxiglumide (2.4 +/- 0.2 pM).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

CCK and PYY do not participate in the delayed inhibition of pancreatic secretion, after stimulation by duodenal oleic acid infusion.

The role played by CCK in the stimulation of pancreatic secretion by duodenal infusion of oleic acid in conscious rats was studied using a potent and specific CCK receptor antagonist. CR-1409 did not alter basal secretion, which does not require CCK. The three doses of CR-1409 that were used (2, 4 and 8 mg/kg/h) suppressed the protein response to duodenal infusion of oleic acid and significantly enhanced the delayed inhibition normally observed in control rats (-81%, -87% and -88% vs. -51% of basal in controls). CR-1409 dose-dependently reduced the volume of pancreatic secretion after duodenal infusion of oleic acid (0.40 +/- 0.02, 0.36 +/- 0.02, 0.34 +/- 0.03 vs. 0.48 +/- 0.04 ml/30 min for 2, 4, 8 mg/kg/h and controls, respectively) and revealed a delayed inhibition of volume and a slight reduction of bicarbonate secretion. CCK appears to be directly responsible for the protein and also water response to duodenal infusion of oleic acid, and to be indirectly involved in bicarbonate stimulation. PYY antiserum significantly augmented protein output after duodenal infusion of oleic acid (10.75 +/- 1.40, 14.10 +/- 1.60 vs. 8.60 +/- 1.20 mg/30 min, 1 microliter, 2 microliters and controls), but failed to modify the delayed inhibition: PYY modulates the response to duodenal infusion of oleic acid and is not involved in the delayed inhibition, which was shown to be also present for volume, but which is normally masked by the action of CCK.

Animals↗
PubMed1992

Role of cholecystokinin in mediating GRP-stimulated gastric, biliary and pancreatic functions in man.

To explore the mechanisms of gastrin-releasing peptide (GRP)-induced gut functions in man, we investigated the effect on gallbladder contraction, exocrine pancreatic secretion and gastric acid secretion of a recently developed CCK receptor antagonist, loxiglumide, on GRP-stimulated effects in six healthy human subjects. Intravenous infusion of graded doses of synthetic human GRP (1-27 pmol/kg per h) caused significant and dose-dependent increases in pancreatic enzyme and gastric acid secretions and in gallbladder contraction. Intravenous administration of loxiglumide (10 mg/kg per h) abolished GRP-stimulated gallbladder contraction, augmented gastric acid secretion, but did not affect exocrine pancreatic secretion. The results suggest that endogenously released CCK is (1) responsible for GRP-stimulated gallbladder contraction, and (2) involved in regulating gastric acid secretion. The results further suggest that GRP-stimulated pancreatic secretion is not mediated by CCK, but has a direct response of GRP on the exocrine pancreas.

Adult↗
PubMed1992

Direct effect of bombesin on pancreatic and gastric growth in suckling rats.

Bombesin stimulates growth of the stomach and pancreas in adult rats. Part of this effect is thought to be through the release of CCK following bombesin treatment. We studied the effect of long term administration of bombesin on the pancreas and stomach in suckling rats and examined the action of bombesin using specific CCK antagonist (CR-1409) and bombesin antagonists (GRP19-26, D-Phe19, Leu26CH2NHCOCH3 = cpd 17; L-686,095-001C002 = cpd 23). Rat pups (7-days-old) were given bombesin (20 micrograms/kg body wt. twice a day) or vehicle (1% gelatin) for 9 days. Bombesin stimulated pancreatic and gastric growth (tissue weight, total protein and DNA content all increased). Pancreatic trypsinogen concentration and content showed a 2-3-fold increase. CR-1409 at 6 mg/kg body wt., a dose that blocked the trophic action of CCK-33 when given to pups at similar ages, did not affect the bombesin-stimulated growth of the pancreas or the increase in trypsinogen level. At 2.4 mg/kg body wt., cpd 17 partially blocked and cpd 23 completely blocked the trophic effect of bombesin on the pancreas and stomach and the increase in trypsinogen level in the pancreas. RU-486, a type II glucocorticoid receptor antagonist, given at a dose sufficient to block the physiological action of glucocorticoid, had no effect on bombesin-stimulated growth of the pancreas. Thus, in vivo, bombesin acts directly on the neonatal pancreas and stomach.

Animals↗
PubMed1992

Determination of plasma cholecystokinin (CCK) concentrations by bioassay and radioimmunoassay in man. A critical evaluation.

The present investigation was designed to perform a direct comparison of a rat pancreatic acini bioassay system and a specific CCK radioimmunoassay (antiserum G-160) for the measurement of fasting and meal-stimulated plasma CCK in the presence and absence of the CCK receptor antagonist loxiglumide. The G-160 CCK antiserum is directed against the C-terminal O-sulfated tyrosine residue of the CCK molecule which is essential for full bioactivity of CCK peptides. For plasma extraction prior to bioassay measurement, hydrophobic reverse-phase chromatography on octadecylsilane cartridges was employed and resulted in simultaneous adsorption and elution of both CCK peptides and loxiglumide with recoveries of 87.5 +/- 9% and 75.0 +/- 5.9%, respectively. In the absence of loxiglumide, fasting and meal-stimulated values for CCK-like bioactivity and CCK-immunoreactivity (IR-CCK) were nearly identical (basal values: 1-2 pmol/l; meal-stimulated plateau levels: 4-6 pmol/l). After intravenous infusion of loxiglumide (30 mg/kg/h for 10 min, 10 mg/kg/h thereafter), resulting in plasma steady state levels of 200-300 mumol/l, meal-stimulated CCK-like bioactivity was undetectable, whereas IR-CCK levels were augmented 6.5-fold. In the bioassay system, standard samples containing 50 mumol/l loxiglumide produced complete inhibition of acinar lipase release in response to 50 pmol/l synthetic CCK-8. We conclude, that postprandial circulating non-CCK-like factors do not contribute significantly to the direct receptor-mediated stimulation of exocrine pancreatic secretion. The good agreement of CCK-like bioactivity and IR-CCK levels in the absence of loxiglumide confirms the sensitive and specific recognition of bioactive CCK peptides by the G-160 antiserum and suggests that this antibody exerts binding characteristics probably similar to a pancreatic acinar receptor.

Adult↗
PubMed1993

CGRP(8-37) and CGRP(32-37) contract the iris sphincter in the rabbit eye: antagonism by spantide and GR82334.

The effects of intracameral injections of CGRP(8-37) and CGRP(32-37) on pupil diameter and blood-aqueous barrier have been investigated in rabbits. The rabbits, which were pretreated with indomethacin and a muscarinic antagonist (biperiden), responded with miosis to both CGRP fragments. CGRP(8-37) was much more potent than CGRP(32-37) but one order of magnitude less potent than substance P. Nerve blockade with tetrodotoxin did not affect the response, indicating a direct effect on the iris sphincter muscle. Pre-treatment with the unselective tachykinin receptor antagonist spantide or the NK1 receptor selective antagonist GR82334 caused a rightward shift of the dose-response curves for both fragments, while the CCK receptor antagonist loxiglumide had no inhibitory effect. Neither of the fragments induced any marked leakage of Evans blue into the aqueous humor indicating that there was no agonistic interaction with CGRP receptors in the eye. We conclude that CGRP(8-37) and CGRP(32-37) are miotic agents in the rabbit eye, possibly by acting as neurokinin receptor agonists.

Animals↗
PubMed1994

Treatment with cholecystokinin receptor antagonist loxiglumide enhances insulin response to intravenous glucose stimulation in postpancreatitic rats.

Pancreatic exocrine and endocrine function in postpancreatitic rats treated with cholecystokinin (CCK) receptor antagonist loxiglumide was compared with that treated with saline and CCK octapeptide (CCK-8) or with that in normal control rats. Treatment with loxiglumide (50 mg/kg body weight), CCK-8 (2.5 micrograms/kg body weight), or saline (2.5 ml/kg body weight) was given three times a day for 6 days starting 1 day after the induction of acute pancreatitis by a 4-h subcutaneous infusion of 20 micrograms/kg body weight/h of caerulein. On day 8, pancreatic exocrine and endocrine function was simultaneously determined following an intravenous injection of a mixed solution of 0.2 g/kg body weight glucose plus 100 ng/kg body weight caerulein. Basal pancreatic juice flow was significantly increased in all of the postpancreatitic rats irrespective of the treatment, whereas the maximal juice flow in the loxiglumide- and saline-treated rats was significantly low compared with the CCK-8-treated and the control rats. Basal and the peak protein outputs in the loxiglumide-treated rats were comparable to those in saline-treated rats, but were lower than those in the control or the CCK-8-treated rats. Although serum glucose concentrations in all of the postpancreatitic rats were similar to those in the control rats, stimulated as well as basal insulin release tended to be high compared with the control rats. In particular, loxiglumide-treated rats showed the exaggerated insulin response compared with other groups of rats. These present observations indicate that administration of high dose of loxiglumide for a long period decreases pancreatic enzyme output and causes insulin resistance.

Acute Disease↗
PubMed1994

Loxiglumide inhibits cholecystokinin stimulated somatostatin secretion and simultaneously enhances gastric acid secretion in humans.

In vitro studies have demonstrated that cholecystokinin releases somatostatin from the gastric mucosa. To date, there is no information about the in vivo significance of this finding in man. Therefore, we have studied the effect of infusion of cholecystokinin resulting in plasma concentrations within the range found after meal-stimulation, on somatostatin release and on gastric acid secretion. In addition we have studied these functions during infusion of the type A cholecystokinin receptor antagonist loxiglumide. In eight healthy subjects, basal gastric acid secretion was distinctly stimulated by cholecystokinin. The effect of cholecystokinin on gastric acid secretion was markedly enhanced by loxiglumide. Cholecystokinin also significantly stimulated somatostatin output into the gastric lumen, but not into the systemic circulation. Somatostatin output into the gastric lumen during infusion of cholecystokinin was abolished by loxiglumide. The data indicate that on the one hand circulating cholecystokinin, like gastrin, stimulates gastric acid secretion probably by binding to less specific type B receptors on parietal cells that are not blocked by loxiglumide, but on the other hand that cholecystokinin, in contrast to gastrin, also inhibits gastric acid secretion probably by binding to specific type A receptors present on somatostatin producing D-cells in the gastric mucosa, that are blocked by loxiglumide.

Adult↗
PubMedDate not supplied

Cholecystokinin and cholecystokinin antagonists enhance postsynaptic excitability in the dentate gyrus.

The sulfated and unsulfated octapeptide cholecystokinin (CCK) sequences and the pancreatic CCK antagonists, CR 1409 and benzotript, were applied iontophoretically in the rat dentate gyrus granular layer while the response evoked by single pulse stimulation of the perforant path was recorded. The stimulating current was varied and the resulting relationship between the slope of the response (input) against the population spike amplitude (output) was used as a measure of excitability at the granule cell synapse. All four test compounds shifted the input/output curve to the left indicating an increase in postsynaptic excitability. These results thus imply that endogenous CCK acts at the central type of CCK receptor to modulate cortical input to granule cells by reducing the threshold for synaptic excitation.

Animals↗
PubMed1994

CCK antagonists reveal that CCK-8 and JMV-180 interact with different sites on the rat pancreatic acinar cell CCKA receptor.

The ability of CCKA antagonists to inhibit full and partial CCK agonists of the rat pancreatic acinar cell CCKA receptor has been studied. When isolated rat pancreatic acini were superfused with CCK-8 (10 pM-1 nM) or CCK-4 (1 microM), an increase in [Ca2+]i signal was initiated. Concurrent superfusion of either L-364,718 (0.1 microM) or lorglumide (10 microM), chemically distinct, specific, potent antagonists of the CCKA receptor, resulted in a rapid inhibition of the [Ca2+]i signal initiated by all concentrations of CCK-8. In contrast, Ca2+ oscillations, initiated by JMV-180 (25 nM-1 microM), a partial agonist analogue of CCK-8, were essentially unaffected by concurrent superfusion of either L-364,718 or lorglumide. When JMV-179, an analogue of JMV-180 that exhibits characteristics of a pure antagonist, was superfused concurrently with either CCK-8 or JMV-180, Ca2+ oscillations were inhibited, even in the presence of 0.1 microM L-364,718. In a similar fashion, amylase secretion stimulated by CCK-8 was markedly attenuated by L-364,718, lorglumide, and JMV-179, whereas secretion stimulated by JMV-180 was only inhibited by JMV-179. A model is proposed to reconcile this data, based on the assumption that JMV-180 and CCK-8 interact with discrete sites on the CCKA receptor, which are differentially affected by the binding of antagonists. This model may also explain how a single receptor may transduce multiple signals in response to different agonists.

Amino Acid Sequence↗
PubMed1995

Involvement of different subtypes of cholecystokinin receptors in opioid antinociception in the mouse.

Various doses of sulfated cholecystokinin octapeptide (CCK-8s) injected intracerebroventricularly (ICV) alone did not show any antinociceptive effect. CCK-8s (0.01-1 ng) pretreated ICV for 10 min dose-dependently attenuated the inhibition of the tail flick response induced by ICV-administered morphine (2 micrograms). beta-endorphin (1 microgram), and U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]benzeocetamide), 60 micrograms). However, ICV pretreatment with CCK-8s was not effective in reducing the inhibition of the tail flick response induced by [D-Pen(2)-D-Pen5]enkephalin (DPDPE; 10 micrograms) administered ICV. To determine what subtype(s) of CCK receptors are involved in antagonizing the antinociception induced by these opioids, effect of lorglumide sodium salt (a CCKA receptor antagonist) or PD135,158 N-methyl-D-glucamine salt (a CCKB receptor antagonist) on opioid-induced inhibition of the tail flick response was examined. Various doses of lorglumide sodium salt (lorglumide) or PD135,158 N-methyl-D-glucamine salt (PD135,158) injected ICV alone did not affect the basal tail flick response. The antagonistic effect of CCK-8s on morphine-, beta-endorphin-, and U50,488H-induced inhibition of the tail flick response was blocked in a dose-dependent manner by the co-ICV injection of PD135,158 (0.001-0.1 ng). The co-ICV injection of lorglumide (0.001-0.1 ng) dose-dependently blocked the antagonistic effect of CCK-8s on beta-endorphin- and U50,488H-induced, but not morphine-induced, inhibition of the tail flick response. Our results suggest that both CCKA and CCKB receptors are involved in antagonizing antinociception induced by beta-endorphin and U50,488H administered supraspinally. However, only CCKB (but not CCKA) receptors are involved in antagonizing antinociception induced by morphine administered supraspinally. CCK receptors are not involved in antagonizing the supraspinally administered DPDPE-induced antinociception.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1991

Effects of the synthetic trypsin inhibitor camostate on the development of N-nitrosobis(2-oxopropyl)amine-induced pancreatic lesions in hamsters.

Trypsin inhibitors have been shown to promote pancreatic growth as well as the development of pancreatic tumours in rats. The present study was carried out to examine the effects of the synthetic trypsin inhibitor camostate on the growth of the pancreas and on the development of pancreatic preneoplastic and neoplastic lesions in hamsters treated with N-nitrosobis(2-oxopropyl)amine. A specific cholecystokinin-receptor antagonist was administered to determine the role of cholecystokinin in camostate action. The animals were killed 19 weeks after the first injection with N-nitrosobis(2-oxopropyl)amine. Camostate caused an increase in growth of the pancreas and a decrease in the number of (pre)neoplastic ductular pancreatic lesions. Lorglumide (CR-1409) did not influence these effects of camostate. It was concluded that rats and hamsters behave differently with regard to the effect of camostate on pancreatic growth and carcinogenesis.

Animals↗
PubMed1991

Effects of bombesin on the development of N-nitrosobis(2-oxopropyl)amine-induced pancreatic lesions in hamsters.

Bombesin (BBS) has been shown to promote pancreatic growth as well as the development of pancreatic (pre)neoplasia in rats. The present study was carried out to determine the effects of bombesin on pancreatic growth and on the development of pancreatic (pre)neoplastic lesions in hamsters treated with N-nitrosobis(2-oxopropyl)amine (BOP). Bombesin caused an increase in growth of the pancreas accompanied by a decrease in the number of (pre)neoplastic ductular pancreatic lesions. Lorglumide (CR-1409) did not influence these effects of bombesin. It is concluded that in BOP-treated hamsters the effect of bombesin on the pancreas is not mediated by cholecystokinin (CCK). These data support the existence of species difference between rats and hamsters with regard to the effect of bombesin on pancreatic carcinogenesis.

Animals↗