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PubMed1993

C-terminal calcitonin gene-related peptide fragments and vasopressin but not somatostatin-28 induce miosis in monkeys.

The miotic effects of C-terminal calcitonin gene-related peptide (CGRP) fragments, somatostatin-28 and vasopressin have been evaluated with special attention being paid to possible interactions with cholecystokinin (CCK)A receptors. The peptides were injected intracamerally to anesthetized monkeys pretreated with indomethacin and atropine. CGRP-(32-37) induced a miosis with a potency 1000 times lower than that previously found with sulphated CCK-8. Two other fragments, CGRP-(30-37) and CGRP-(31-37), also had miotic properties. The CGRP-(32-37)-induced miosis was antagonized by the CCKA receptor antagonist loxiglumide. No contractile effect was elicited by 67 pmol-7.4 nmol somatostatin-28. Vasopressin (360 pmol) caused a small reduction in pupil size. Loxiglumide pretreatment did not affect the reduction in pupil size but a vasopressin receptor antagonist partly inhibited the response. The results indicate that CGRP-(32-37) is a miotic with low potency but high efficacy in the monkey eye, probably interacting with CCKA receptors, and that vasopressin is a mitotic with low potency and efficacy, probably acting via vasopressin receptors.

Analysis of Variance↗
PubMed1995

Exogenous and endogenous cholecystokinin protects gastric mucosa against the damage caused by ethanol in rats.

Cholecystokinin (CCK) shows a potent influence on gastric secretion and motility but its role in gastric mucosal integrity has been little examined. In this study we found that exogenous CCK octapeptide protected gastric mucosa against ethanol-induced gastric injury but was ineffective against aspirin-induced damage. The protective effects of CCK were dose-dependent and almost completely reversed by pretreatment with the specific CCKA receptor antagonist, loxiglumide, while the CCKB receptor antagonist, L-365,260, was not effective. The CCK-induced protection against ethanol injury was accompanied by a significant increase in gastric blood flow. The inhibition of nitric oxide (NO) synthase by NG-nitro-L-arginine methyl ester attenuated the gastroprotection and gastric hyperemia induced by CCK while the concurrent treatment with L-arginine, but not D-arginine restored the protective activity of CCK and the accompanying increase in gastric blood flow. Endogenous CCK released by intraduodenal instillation of oleate prevented the formation of acute gastric lesions induced by both ethanol and aspirin and the protective effects were abolished by pretreatment with loxiglumide. We conclude that CCK exerts protective activity against ethanol-induced damage and that this effect is mediated through specific CCKA receptors and hyperemia involving NO.

Amino Acid Oxidoreductases↗
PubMed1994

A cholecystokinin receptor antagonist, loxiglumide, stimulates biliary secretion in conscious rats.

The effects of the CCK receptor antagonists loxiglumide [D,L-4-(3,4-dichlorobenzoylamino)-5-(N-3-methoxy-propylpentylam ino)-5-oxo- pentanoic acid, CR 1505] and MK-329 [3S(-)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzo-diazepine-3-y l)-1H - indole-2-carboxamide, L-364,718], on bile flow were investigated in conscious rats. The bile duct of male Wistar rats was cannulated to directly collect pure bile, and the second cannula was inserted into the duodenum for reinfusion of bile. On the 4th through 7th postoperative days loxiglumide (25, 50 or 100 mg/kg body weight), MK-329 (1 mg/kg body weight) or the respective solvent (saline and 80% dimethyl sulfoxide) was injected subcutaneously. Loxiglumide caused dose-dependent increases in bile flow and bile acid output with a slight non-dose-dependent increase in bilirubin output. The integrated increments of bile flow during a 3-h period after saline and 100 mg/kg body weight loxiglumide were -14 +/- 71 and 982 +/- 61 microliters/100 g body weight, respectively, and those of bile acids were 2.5 +/- 1.4 and 23.1 +/- 4.1 mumol/100 g body weight, respectively. In contrast, MK-329 markedly decreased the bile flow (-439 +/- 76 vs. control; -32.8 +/- 76 microliters/100 g body weight/3 h, P < 0.001) and bile acids output (-16.3 +/- 6.8 vs. control; 3.4 +/- 3.8 mumol/100 g body weight/3 h, P < 0.001), while it significantly increased bilirubin output (86.4 +/- 15.6 vs. 43.5 +/- 1.1 mg/100 g body weight/3 h, P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1996

Effect of the selective CCKB receptor antagonist LY288513 on conditioned fear stress in rats.

In order to investigate the involvement of cholecystokinin (CCK) in the regulation of anxiety, the effect of the selective non-peptide CCKB receptor antagonist LY288513 ((4S, 5R)-N-(4-bromophenyl)-3-oxo-4,5-diphenyl-1-1-pyrazolidinecarboxamide+ ++) on freezing behavior induced by conditioned fear stress was examined using a time-sampling procedure. Rats were individually subjected to 5 min of inescapable electric footshock in a shock chamber. Twenty-four hours after the footshock, the rats were again placed in the shock chamber and observed for 5 min without shocks: this procedure is termed conditioned fear stress. Subcutaneous administration of LY288513 30 min before footshock (0.3 mg/kg) and 30 min before conditioned fear stress (0.03 mg/kg) reduced conditioned freezing. This indicates that LY288513 blocked both the acquisition and expression of conditioned fear. The relatively selective non-peptide CCKA receptor antagonist, lorglumide (D, L-4-(3,4-dichlorobenzoylamino)-5-(diphentylamino)-5-oxo-pent anoic acid), blocked the expression of conditioned fear, though only at a high dose (1.0 mg/kg). The peripheral non-peptide CCKA/B receptor antagonist, loxiglumide (D, L-4-(3,4-dichlorobenzoylamino)-5- (N-3-methoxypropyl-pentylamino)-5-oxo-pentanoic acid), failed to do so. These results suggest that brain CCKB receptors are involved in the regulation of anxiety.

Animals↗
PubMed1996

Synergistic interactions between human transfected adenosine A1 receptors and endogenous cholecystokinin receptors in CHO cells.

The effect of Gi coupled receptor activation (adenosine A1 and 5-HT1B receptors) on cholecystokinin receptor-stimulated inositol phosphate accumulation has been investigated in Chinese hamster ovary cells transfected with the human adenosine A1 receptor cDNA (CHO-A1). CHO cells constitutively express the 5-HT1B receptor [Berg, Clarke, Sailstad, Saltzman and Maayani (1994) Mol. Pharmacol. 46, 477-484]. Our previous studies using CHO-A1 cells have revealed that both the adenosine A1 and 5-HT1B receptor are negatively coupled to adenylyl cyclase activity and stimulate increases in [Ca2+]i, through a pertussis toxin-sensitive pathway. In the present study the selective adenosine A1 receptor agonist N6-cyclopentyladenosine stimulated a pertussis toxin-sensitive increase in total [3H]inositol phosphate accumulation. The sulphated C-terminal octapeptide of cholecystokinin (CCK-8) stimulated a robust and pertussis toxin-insensitive increase in [3H]inositol phosphate accumulation through the activation of CCKA receptors. Co-stimulation of CHO-A1 cells with N6-cyclopentyladenosine and CCK-8 produced a synergistic increase in [3H]inositol phosphate accumulation. The synergistic interaction between N6-cyclopentyladenosine and CCK-8 was abolished in pertussis toxin-treated cells. Synergy between N6-cyclopentyladenosine and CCK-8 still occurred in the absence of extracellular calcium. The 5-HT1B receptor agonist 5-carboxyamidotryptamine did not stimulate a measurable increase in [3H]inositol phosphate accumulation. Furthermore, 5-carboxyamidotryptamine had no significant effect on CCK-8 mediated [3H]inositol phosphate production. Activation of endogenous P2U receptors (Gq/Gll coupled) with ATP gamma S produced a significant increase in [3H]inositol phosphate accumulation. Co-stimulation of CHO-A1 cells with ATP gamma S and CCK-8 produced additive increases in [3H]inositol phosphate accumulation. These data indicate that CHO-A1 cells may prove a useful model system in which to investigate further the mechanisms underlying the intracellular 'cross-talk' between phospholipase C coupled receptors (Gq/Gll linked) and Gi/Go coupled receptors.

Adenosine↗
PubMed1996

Pharmacological profile of T-0632, a novel potent and selective CCKA receptor antagonist, in vitro.

The pharmacological profile of a new CCKA receptor antagonist, T-0632 [sodium (S)-3-[1-(2-fluorophenyl)-2,3-dihydro-3-[(3-isoquinolinyl)-carbonyl] amino-6-methoxy-2-oxo-1-H-indole]propanoate], was examined in in vitro studies and compared with those of L-364,718 [3S(-)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1, 4-benzodiazepine-3-yl)-1H-indole-2-carboxamide] and loxiglumide [D,L-4-(3,4-dichlorobenzoylamino)-5-(N-3-methoxypropyl-pentylam ino)-5- oxopentanoic acid]. T-0632 inhibited the specific binding of [125I]CCK-8 to rat pancreatic CCKA receptor in a concentration-dependent and competitive manner. The Ki value of T-0632 for the CCKA receptor was estimated to be 0.24 nM, which was 23 000-fold less than the Ki value (5600 nM) for guinea pig CCKB receptor. L-364,718 and loxiglumide were 1500- and 64-fold selective for CCKA over CCKB receptor, respectively. T-0632, L-364,718 and loxiglumide inhibited CCK-8 (100 pM)-stimulated amylase release from rat pancreatic acini in a concentration-dependent manner with IC50 values of 5.0 nM, 5.0 nM and 3.0 microM, respectively. In the isolated rabbit gallbladder smooth muscle, T-0632 and loxiglumide competitively inhibited CCK-8-induced contraction with pA2 values of 8.5 and 7.0, respectively. However, L-364,718 showed an apparent non-competitive antagonism. The IC50 values of T-0632, L-364,718 and loxiglumide for CCK-8 (30 nM)-induced contraction were 31 nM, 4.9 nM and 1300 nM, respectively. The inhibitory effects of T-0632 and loxiglumide in gallbladder smooth muscle were readily reversible, but L-364,718 showed a long-lasting inhibition. These results suggest that T-0632 is a potent, reversible and more selective CCKA receptor antagonist compared with L-364,718 and loxiglumide.

Amylases↗
PubMed1996

Pharmacological profile of T-0632, a novel potent and selective CCKA receptor antagonist, in vivo.

The pharmacological profile of a new CCKA receptor antagonist, T-0632 [sodium (S)-1-(2-fluorophenyl)-2,3-dihydro-3-[(3-isoquinolinylcarbonyl) amino]-6-methoxy-2-oxo-1H-indole-3-propanoate], was examined in in vivo studies and compared with those of L-364, 718 [3S(-)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1, 4-benzodiazepine-3-yl)-1 H-indole-2-carboxamide] and loxiglumide [D.L-4-(3,4-dichlorobenzoylamino)-5-(N-3-methoxypropyl-pentylam ino)-5- oxopentanoic acid]. In rats, intravenously administered T-0632, L-364,718 and loxiglumide dose dependently inhibited cholecystokinin octapeptide (CCK-8)-stimulated pancreatic exocrine secretion with estimated ED50 values of 0.025, 0.016 and 1.8 mg/kg, respectively. The ED50 values for intraduodenal administration of these compounds were 0.040, 0.26 and 3.0 mg/kg, respectively. In mice, orally administered T-0632 prevented caerulein-induced pancreatitis, CCK-8-induced inhibition of gastric emptying and CCK-8-induced gallbladder emptying in dose-dependent manners with ED50 values of 0.028, 0.04, and 0.12 mg/kg, respectively. The effect of T-0632 for caerulein-induced pancreatitis was 4-fold more potent than that for gallbladder emptying. In contrast, the effects of L-364,718 and loxiglumide for caerulein-induced pancreatitis were 2-4-fold weaker than those for gallbladder emptying. In dogs, T-0632 and loxiglumide maximally inhibited CCK-8-stimulated pancreatic amylase secretion at doses of 0.01 and 10 mg/kg, respectively. At these doses, the effect of T-0632 on CCK-8-induced increase in the gallbladder intraluminal pressure was weaker than that of loxiglumide. These results suggest that T-0632 has a potent antagonistic action on CCKA receptors in several animal species and the effects of T-0632 are more selective for the pancreas over the gallbladder compared with L-364,718 and loxiglumide.

Animals↗
PubMed1992

Monitor peptide gene expression is increased by exogenous CCK in the rat pancreas and in a rat pancreatic acinar cell line (AR4-2J).

Monitor peptide (CCK-releasing peptide) mRNA increased on the administration of CCK in rat pancreas and the AR4-2J pancreatic cell line. Subcutaneous injection of CCK into rats at 8 h intervals increased the level of monitor peptide mRNA in the pancreas. Concomitant injection of CCK antagonist CR-1409 strongly decreased it. The monitor peptide mRNA was also increased by CCK in AR4-2J cells and was decreased by the antagonist. These findings suggest that the plasma CCK induced by prolonged intake of a high protein diet may be responsible for the adaptative increase in the monitor peptide as well as exocrine proteases in the pancreas.

Amylases↗
PubMed1996

Cholecystokinin receptor antagonist, loxiglumide, inhibits invasiveness of human pancreatic cancer cell lines.

Recently, cholecystokinin has been reported to be important in regulating the growth of pancreatic cancer. We investigated the effect of loxiglumide (LXG), a cholecystokinin receptor antagonist, on the invasiveness of two human pancreatic cancer cell lines. Cells were treated with LXG for 24 h, and examined in the invasion assay. The expression and activity of MMP-9 in supernatants from cancer cells were analyzed by Western blotting and zymogram. Interestingly, the invasiveness of cancer cells and expression of MMP-9 were decreased by LXG in a dose-dependent manner. LXG may be a useful therapeutic agent against pancreatic cancer.

Blotting, Western↗
PubMed1988

Effect of cholecystokinin receptor antagonist on pancreatic responses to exogenous gastrin and cholecystokinin and to meal stimuli.

Exocrine pancreatic response to food is believed to result from the interaction of neural and hormonal factors, but their contribution in the net postprandial secretion is unknown. Recent description of a highly specific and potent cholecystokinin (CCK)-receptor antagonist permitted the evaluation of the physiologic role of CCK in postprandial pancreatic secretion. In dogs with chronic pancreatic fistula, CCK antagonism caused little alteration in sham feeding- or urecholine-induced pancreatic protein secretion, but reduced by approximately 60% the pancreatic protein response to a gastrointestinal meal and virtually abolished the pancreatic responses to duodenal perfusion with amino acids or oleate and to exogenous CCK, but not to secretin or neurotensin. The pancreatic protein responses, particularly to lower doses of gastrin, were also reduced by CCK-receptor antagonist, but no changes in the responses to secretin or neurotensin were detected. Cholecystokinin antagonism also significantly reduced the pancreatic polypeptide responses to CCK, gastrin, and the gastrointestinal meal, possibly due to removal of the CCK-mediated release of pancreatic polypeptide. We conclude that CCK plays a crucial role in the mediation of the gastrointestinal phase, but not the cephalic phase, of pancreatic secretion.

Animals↗
PubMed1989

Influence of cholecystokinin antagonist on the effects of cholecystokinin and bombesin on azaserine-induced lesions in rat pancreas.

Both cholecystokinin and bombesin have been shown to promote pancreatic carcinogenesis in the azaserine-rat model. The present study was undertaken to discriminate between the effects of cholecystokinin and bombesin and to establish the modulating properties of the specific cholecystokinin receptor antagonist CR-1409 on pancreatic carcinogenesis. After initiation with 30 mg/kg of azaserine, six groups of 15 Wistar rats were treated for 16 wk with cholecystokinin, bombesin, or gelatin (control), some in combination with CR-1409. Doses of cholecystokinin (2.5 micrograms/kg) and bombesin (10 micrograms/kg) were chosen that rendered approximately equal plasma cholecystokinin levels. Both cholecystokinin and bombesin were found to stimulate pancreatic growth, whereas CR-1409 only inhibited the growth-promoting effect of cholecystokinin significantly. Furthermore, both peptides stimulated the development of putative preneoplastic lesions, whereas CR-1409 only inhibited the effect of cholecystokinin significantly. It is concluded that (a) CR-1409 inhibits the promoting effect of cholecystokinin on pancreatic growth and azaserine-induced early pancreatic lesions and (b) the effects of bombesin cannot be fully ascribed to stimulation of the secretion of endogenous cholecystokinin.

Animals↗
PubMed1989

Differential effects of atropine and a cholecystokinin receptor antagonist on pancreatic secretion.

The present study evaluates the effect of atropine and of the cholecystokinin receptor antagonist loxiglumide on feedback regulation of basal pancreatic secretion in 6 healthy volunteers. The intraduodenal instillation of the protease inhibitor camostate reduced enzymatic activities of trypsin and chymotrypsin by 80%. This was accompanied by a strong increase in amylase and lipase output. The intravenous infusion of atropine (5 micrograms/kg.h) completely abolished the stimulatory effect of camostate on enzyme output. The infusion of loxiglumide (10 mg/kg.h) caused no changes in camostate-induced stimulation of enzyme output. Plasma levels of cholecystokinin were not altered after intraduodenal instillation of camostate whether atropine, loxiglumide, or saline were infused. We suggest that the protease inhibitor camostate, by inhibition of the enzymatic activity of trypsin and chymotrypsin, interferes with feedback regulation of basal pancreatic secretion in humans, and this mechanism is predominantly mediated by the cholinergic system.

Adult↗
PubMed1989

Effects of loxiglumide on gallbladder emptying in healthy volunteers.

This study evaluates the effects of the specific cholecystokinin receptor antagonist loxiglumide on gall-bladder emptying after a meal or after intravenous infusion of caerulein in humans. Ten healthy male volunteers were studied five times on separate days. The following five studies were performed in randomized order: (a) caerulein was intravenously infused at doses increasing from 7.5 to 120 ng/kg.h without the antagonist; (b) in addition to increasing doses of caerulein, loxiglumide was given intravenously at doses of 0.2, 1.0, or 5.0 mg/kg.h; (c) a solid-liquid 800-kcal meal was given without loxiglumide; (d) the 800-kcal meal was given with simultaneous infusion of 1 or 5 mg/kg.h loxiglumide; and (e) loxiglumide (5 mg/kg.h) was given. without caerulein or the test meal. Gallbladder volume was measured by ultrasound. Loxiglumide dose-dependently inhibited gallbladder emptying induced by caerulein or the meal. High doses of the antagonist did not only abolish meal-induced gallbladder emptying but increased gallbladder volume after administration of caerulein or the meal when compared with prior fasting values. The antagonist given alone markedly increased gallbladder volumes compared with prior fasting values. In conclusion, given alone markedly increased gallbladder volumes compared with prior fasting values. In conclusion, cholecystokinin is the hormone primarily and mainly responsible for mediation of gallbladder emptying after a regular meal. Cholecystokinin might also play a physiologic role in the regulation of the fasting tone of the gallbladder.

Adult↗
PubMed1990

Effect of loxiglumide on gallbladder contractile response to cerulein and food in humans.

The present study investigated the effect of loxiglumide, a new selective cholecystokinin-receptor antagonist, on the gallbladder contractile responses to caerulein and to food in humans. In 6 healthy men, the gallbladder emptying driven by intravenous infusion of stepwise increasing doses of cerulein (10-80 ng/kg . h) and that induced by a 550-cal standard meal were monitored by ultrasonography. In both sets of experiments, the effect of loxiglumide was tested at various infusional rates against a control infusion of saline. An infusional rate of 2.5 mg/kg . h of loxiglumide abolished the gallbladder response even to maximal doses of cerulein, whereas a rate of 1.0 mg/kg . h counteracted the cholecystokinetic activity of cerulein up to the dose of 20 ng/kg . h. In postprandial experiments, the cholecystokinin antagonist dose-dependently inhibited the physiologic gallbladder contraction. The maximal gallbladder emptying, which always occurred 85 min after the meal, was 71.1% +/- 3.3% of basal volume in control studies, 39.2% +/- 1.8% during infusion of 2.5 mg/kg . h of loxiglumide, and 17.3% +/- 5.9% when 5.0 mg/kg . h were infused. A dose of 7.5 mg/kg . h of loxiglumide was able to prevent any postprandial emptying of the gallbladder. The present study shows that a selective cholecystokinin receptorial blockade competitively antagonizes cerulein-induced gallbladder contraction and dose-dependently inhibits postprandial gallbladder emptying.

Adult↗
PubMed1990

Effect of loxiglumide, a cholecystokinin antagonist, on pancreatic polypeptide release in humans.

The purpose of this study was to determine the role of cholecystokinin in the regulation of postprandial pancreatic polypeptide secretion in humans. The pancreatic polypeptide responses to modified sham feeding and gastric instillation of a test meal were first compared with the response to oral ingestion of the same meal. The experiments were repeated under cholinergic (atropine) and cholecystokinin (loxiglumide) blockade. Atropine completely abolished the pancreatic polypeptide response to sham feeding and caused significant reductions after gastric and oral food intake. Loxiglumide, on the other hand, significantly reduced pancreatic polypeptide release to oral food (51% inhibition) without affecting the response to sham feeding. In separate experiments using a duodenal perfusion system, the effects of atropine and loxiglumide on intestinal phase-stimulated pancreatic polypeptide release were examined, and both cholinergic and cholecystokinin blockade induced complete suppression. It was concluded (a) that cholecystokinin is involved in postprandial pancreatic polypeptide response, especially during the intestinal phase stimulation, and (b) that the cholinergic system is crucial and superimposed on cholecystokinin in stimulating pancreatic polypeptide release.

Adult↗
PubMed1991

Role of cholecystokinin in the regulation of gastric emptying and pancreatic enzyme secretion in humans. Studies with the cholecystokinin-receptor antagonist loxiglumide.

The role of cholecystokinin (CCK) in the regulation of gastric emptying and pancreatic enzyme secretion was evaluated by infusing the CCK-receptor antagonist loxiglumide. Gastric emptying rates and pancreatic secretory outputs were measured in five healthy volunteers by the double-indicator perfusion technique using a multiple-lumen tube in the duodenum. Placebo or loxiglumide (22 mumol.kg-1.h-1) was infused throughout each experiment. Five hundred-milliliter liquid intragastric meals of (a) fat, protein, and glucose (Ensure; Abbott, Chicago, IL); (b) glucose, 20 g/dL; and (c) guar gum, 1.1 g/dL, were given in random order. In addition, the effect of a physiologic CCK-8 dose (20 pmol.kg-1.h-1) after an intragastric 500-mL saline meal (0.154 mol/L) was tested. Intravenous CCK-8 induced a marked retardation of the gastric emptying rate of the saline solution (P less than 0.05) while stimulating pancreatic secretory outputs; both effects were completely abolished by the infusion of loxiglumide. Loxiglumide markedly accelerated the gastric emptying rates (by approximately 40%) and simultaneously diminished lipase (by approximately 75%) and trypsin (by approximately 50%) outputs of both the mixed meal (P less than 0.01) and the pure glucose meal (P less than 0.05). Additional experiments using gamma camera scintigraphy confirmed the accelerating effect of loxiglumide on gastric emptying of the mixed meal (P less than 0.01). The gastric emptying rate of the guar meal, which did not release CCK, was not influenced by the infusion of loxiglumide. Loxiglumide distinctly augmented plasma CCK levels after the mixed (2.6 times) and the pure glucose (2.1 times) meals while markedly reducing (approximately 76%) pancreatic polypeptide release (P less than 0.02). It is concluded that endogeneous CCK exerts a major role in the regulation of both gastric liquid emptying and pancreatic secretion in humans.

Adult↗
PubMed1991

Interaction of the cholinergic system and cholecystokinin in the regulation of endogenous and exogenous stimulation of pancreatic secretion in humans.

Pancreatic enzyme secretion is regulated in humans by the cholinergic system and by cholecystokinin (CCK). The interaction between both regulatory systems in response to exogenous and endogenous stimulation was analyzed in the present study using the cholinergic antagonist atropine and the CCK antagonist loxiglumide. A dose-dependent stimulation of pancreatic enzyme output was achieved either by duodenal perfusion of graded caloric loads or by IV infusion of increasing doses of cerulein. Prestimulated pancreatic secretion was inhibited by atropine and loxiglumide. Atropine furthermore almost completely blocked meal-stimulated pancreatic secretion, whereas loxiglumide caused 60% inhibition. The enzyme response to graded doses of exogenous CCK was significantly inhibited by atropine and loxiglumide. Plasma levels of CCK were not altered by atropine but increased with infusion of loxiglumide. This study supports the concept that pancreatic enzyme secretion is predominantly dependent on a cholinergic tone and that CCK modulates the enzyme-secretory response.

Adult↗
PubMed1991

Effects of cholecystokinin-receptor blockade on pancreatic and biliary function in healthy volunteers.

This study used the specific cholecystokinin (CCK)-receptor antagonist loxiglumide to evaluate whether endogenous CCK, which is released after a meal, regulates pancreatic and biliary functions. Eight healthy volunteers were studied twice on separate days. The subjects received a continuous intraduodenal infusion of a 750-kcal liquid test meal for 2 hours either with or without IV infusion of 5 mg.kg-1.h-1 of loxiglumide. Loxiglumide at this dose abolishes the actions of CCK at various target organs including gallbladder and pancreas, when given at doses that mimic postprandial plasma concentrations of CCK. Loxiglumide markedly decreased the meal-stimulated outputs of amylase, trypsin, and chymotrypsin by 55%-70% of control values but only slightly decreased duodenal volume (25% inhibition of mean integrated secretion). Loxiglumide abolished gallbladder emptying induced by infusion of nutrients and even increased gallbladder volumes when compared with prior fasting values. Correspondingly, loxiglumide almost abolished the output of bilirubin after infusion of nutrients. However, loxiglumide failed to alter the increase in circulating concentrations of glucose, insulin, and C peptide after infusion of nutrients. The present results show that CCK is one of several factors that regulate pancreatic protein secretion after absorption of nutrients. However, CCK is probably not involved in regulation of pancreatic secretion of fluid. In contrast, gallbladder function is mainly regulated by CCK, both in terms of its emptying after intestinal absorption of nutrients and in terms of maintenance of its fasting volume. Cholecystokinin does not play a major physiological role as an insulinotropic factor.

Adult↗