Effects of cholecystokinin receptor blockade on circulating concentrations of glucose, insulin, C-peptide, and pancreatic polypeptide after various meals in healthy human volunteers.

This study used a cholecystokinin (CCK) antagonist to evaluate whether CCK that is released after regular meals regulates meal-stimulated insulin secretion. Several experiments were performed in eight to 10 healthy male volunteers, each in duplicate. The subjects received different meals either with or with i.v. infusion of 5 mg/kg/h of the CCK antagonist loxiglumide (Rotta, Italy). The mixed solid-liquid meals of 600, 800, or 1,000 kcal consisting of regular German food were given orally. In addition, studies were carried out in which a liquid test meal of 750 kcal was infused into the duodenum over a 2-hour period to exclude effects of the CCK antagonist on gastric emptying. Finally, the subjects received an oral load of 100 g glucose either with or without i.v. infusion of loxiglumide. Loxiglumide at the dose used completely abolishes the actions of endogenous CCK and of exogenous CCK when given at doses that mimic postprandial circulating concentrations of this peptide at various target organs such as gallbladder, pancreas, stomach, and intestine. Loxiglumide also markedly reduced the increase in pancreatic polypeptide seen after the intraduodenal infusion of nutrients. However, loxiglumide at this dose did not alter the increase in circulating concentrations of glucose, insulin, and C-peptide after any of the various oral meals, after the intraduodenal administration of nutrients, and after the oral load of glucose. Although the present study does not rule out that in some conditions CCK may increase insulin secretion in humans, the results do rule out that CCK acts as a major physiologic incretin in healthy humans.     

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.     

Comparison of loxiglumide, a cholecystokinin receptor antagonist, and atropine on hormonal and meal-stimulated pancreatic secretion in man

The effects of loxiglumide, a potent cholecystokinin (CCK)-receptor antagonist, and atropine, a muscarinic receptor blocker, on exocrine pancreatic secretion stimulated by hormones (secretin plus CCK) and a Lundh test meal were studied in healthy young volunteers. Loxiglumide infused intravenously in gradually increasing doses (2-16 mumol/kg-h) caused a dose-dependent inhibition of pancreatic enzyme secretion induced by intravenous infusion of a constant dose of secretin (82 pmol/kg-h) plus CCK-8 (85 pmol/kg-h) but had relatively smaller influence on duodenal volume flow and bicarbonate output. Atropine (20 nmol/kg) also caused a significant reduction in pancreatic enzyme secretion but failed to affect the volume flow or bicarbonate secretion induced by secretin plus CCK, possibly owing to the high doses of secretin and CCK used in these tests. Both loxiglumide and atropine inhibited the pancreatic enzyme response to a Lundh meal, but atropine was more effective in the early phase and loxiglumide in the late phase of the postprandial secretion. Neither loxiglumide nor atropine affected the plasma gastrin and CCK levels, but both antagonists reduced plasma pancreatic polypeptide responses to the Lundh meal. We conclude that 1) loxiglumide results in a relatively stronger suppression of the pancreatic enzyme than aqueous-alkaline secretion induced by secretin plus CCK, whereas atropine inhibits only enzyme secretion; and 2) both loxiglumide and atropine suppress the pancreatic enzyme responses to the meal stimulation without affecting the postprandial plasma gastrin and CCK responses.     

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.     

Cholecystokinin's role in regulation of colonic motility in health and in irritable bowel syndrome.

Colonic motor activity and plasma concentrations of cholecystokinin (CCK) both increase after oral intake of a meal. Thus, CCK had been thought to mediate the postprandial increase in colonic motor activity, which is termed gastrocolonic response. The present study used the substance loxiglumide, which acts as a specific antagonist at the CCK-A receptor, to evaluate this hypothesis. In the first set of experiments, eight healthy subjects were studied four times on separate days. A multilumen catheter was endoscopically placed with its tip lying in the descending colon. Motor activity was recorded by a low-compliance perfusion manometry system at six locations 60-45 cm from the anus. Basal activity was recorded for at least 2 hours to achieve steady-state conditions. The order of the following four experiments was randomized: (a) intravenous infusion of the CCK analogue cerulein at increasing doses (7.5, 15, 30, and 60 ng/kg.h, each given for 30 minutes); (b) intravenous cerulein plus 5 mg/kg.h loxiglumide; (c) a 1000-kcal solid/liquid meal consisting of regular German food; and (d) a meal plus 5 mg/kg.h loxiglumide. In the second set of experiments, eight patients with irritable bowel syndrome were studied twice on two separate days, and two experiments were performed n randomized order: (a) a 1000-kcal solid/liquid meal consisting of regular German food; or (b) a meal plus 5 mg/kg.h loxiglumide. The motor index was calculated as the area under contractions by a computerized system. The 1000-kcal meal markedly increased colonic motor activity. This gastrocolonic response was significantly greater in patients with irritable bowel syndrome than in healthy volunteers. Cerulein stimulated motor activity only at pharmacological doses (30-60 ng/kg.h), which resulted in plasma CCK levels markedly exceeding postprandial values. Loxiglumide abolished the effects of cerulein even at pharmacological doses. However, loxiglumide did not inhibit the gastrocolonic response to a regular meal either in healthy volunteers or in patients with irritable bowel syndrome. Loxiglumide also failed to alter the interdigestive colonic motor activity. Therefore, effects mediated by the CCK-A receptor do not play a major physiological role in the regulation of the interdigestive and postprandial motility of the left colon.     

Effect of a cholecystokinin receptor antagonist (loxiglumide) on gallbladder contractile function in guinea pigs

We evaluated the effect of the specific cholecystokinin (CCK) receptor antagonist, loxiglumide, on gallbladder contractile function in guinea pigs. Five mg/kg body weight (BW) of loxiglumide was administered orally to guinea pigs once a day for 3 days. We then investigated gallbladder contractile function and plasma CCK concentrations in the guinea pigs. Maximal gallbladder pressure induced by cerulein was significantly depressed on the 1st and 3rd days following loxiglumide administration. On the 1st day, the plasma CCK concentration was significantly increased compared with that of the control group during fasting and 15 min after the administration of an intraduodenal test meal. These results suggest that the disturbed gallbladder contraction is due to the competitive inhibition of CCK by loxiglumide. Gallbladder contractile function in guinea pigs is depressed by loxiglumide; however, this effect is reversible after short-term loxiglumide administration.     

Role of endogenously released cholecystokinin in determining postprandial insulin levels in man: effects of loxiglumide, a specific cholecystokinin receptor antagonist.

To estimate the contribution of postprandial cholecystokinin (CCK) responses to circulating insulin concentrations and insulin secretion, a specific CCK receptor antagonist (loxiglumide; 10 mg/kg body weight/h) or saline were infused intravenously in normal volunteers, beginning 90 min before insulin secretion was stimulated on separate occasions by the intraduodenal administrations of glucose, glucose and protein, and glucose plus protein with the admixture of pancreatin. The release of CCK (radioimmunoassay) was stimulated by the protein component of the nutrients from basal 2.4 +/- 0.4 to 8.0 +/- 1.2 pmol/l. CCK plasma levels were significantly higher with loxiglumide (p < 0.05). Glucose-dependent insulinotropic polypeptide (GIP) was also released by all nutrient mixtures. Loxiglumide significantly inhibited the amount of bilirubin and pancreatic enzymes recovered from duodenal aspirates. In contrast, in none of the experiments, C-peptide increments and hence insulin secretion rates were altered by loxiglumide. With glucose and protein as intraduodenal stimulus (no pancreatin added), the plasma amino acids rose significantly less (by approximately 50% of the control experiment) and the increment in insulin (but not C-peptide) concentrations was significantly reduced by loxiglumide. This is most likely explained by a change in insulin metabolic clearance. This effect cannot be a primary action of CCK because there was no similar effect of loxiglumide with the same intraduodenal stimulus plus added pancreatin. Pancreatic enzymes reduced maldigestion secondary to loxiglumide effects on pancreatic exocrine secretion: The increment in circulating amino acid concentrations was similar with and without loxiglumide. In conclusion, CCK does not alter insulin secretion and, therefore, is not an incretin hormone in man. Blocking CCK actions on the exocrine pancreas by loxiglumide, however, can secondarily cause reductions in postprandial insulin profiles by altering insulin clearance. These changes are possibly related to reductions in circulating amino acid concentrations.     

Cholecystokinin in the inhibition of gastric secretion and gastric emptying in humans

Cholecystokinin (CCK) is known to inhibit gastric acid secretion and gastric emptying but its physiological role in the inhibition of gastric functions is not settled. In this study performed on 16 young male subjects, gastric acid secretion and emptying rate were determined after intragastric administration of 8% peptone meal alone or in combination with intravenous infusion of graded doses of CCK-8 (5-80 pmol/kg.h) or with addition of vegetable oil to meal without or with pretreatment with loxiglumide, a specific CCK antagonist. CCK-8 infusion at lower dose (5 pmol/kg.h) was ineffective but at higher doses (20-80 pmol/kg.h) it resulted in a significant reduction in acid output by 39 and 43% and a decrease in gastric emptying from 54% to 40 and 22%, respectively. Pretreatment with loxiglumide abolished almost completely the inhibition of both gastric acid and gastric emptying by CCK-8. Fat added to peptone meal reduced gastric acid secretion by 42-65% and decreased gastric emptying to 24-32%. The pretreatment with loxiglumide tended to reduce fat-induced inhibition of gastric acid secretion and gastric emptying but the difference in the inhibition of gastric functions between the tests without and with loxiglumide was not significant. This study provides evidence that exogenous CCK administered at pharmacological doses is a potent inhibitor of gastric acid secretion and gastric emptying and probably acts via specific CCK receptors. In contrast, fat induces inhibition of gastric acid secretion and gastric emptying that cannot be fully attributed to hormonally acting CCK.     

Effect of a cholecystokinin antagonist on meal-stimulated insulin and pancreatic polypeptide release in humans

A cholecystokinin (CCK) receptor antagonist, loxiglumide, was used to investigate the potential regulating role of CCK in the entero-insular axis in humans. Ingestion of a mixed liquid meal stimulated plasma CCK, insulin, and pancreatic polypeptide (PP) release in the control experiment. With iv loxiglumide (22 mumol/kg.h), mean plasma insulin and glucose levels did not differ between placebo and loxiglumide treatment. The area under the plasma concentration for PP was reduced to 6,060 +/- 1,706 (P less than 0.05) compared to that during placebo treatment (12,266 +/- 4,748). Administration of loxiglumide failed to change insulin secretion in response to perfusion of the same meal or perfusion of a 10-amino acid solution into the duodenum. However, PP secretion in response to the intraduodenal meal or amino acid mixture was abolished after loxiglumide (P less than 0.05). Intravenous administration of the 10-amino acid mixture stimulated insulin from a mean basal level of 7 +/- 3 microU/mL to a peak level of 16 +/- 4 microU/mL. Infusion of a CCK octapeptide (CCK-8) at 8.6 pmol/kg.h, which produced a plasma concentration of 3.3 pmol/L, which is within the postprandial range, augmented amino acid-stimulated insulin and PP output (P less than 0.05). When CCK-8 was infused with loxiglumide, the insulin and PP responses were similar to the values found with loxiglumide alone. We conclude that CCK receptor blockade with iv loxiglumide does not affect postprandial insulin secretion. CCK is, therefore, not a major incretin. However, it is involved in the postprandial PP response, especially during the intestinal phase stimulation. These data suggest that CCK has a role in the human enteroinsular axis.     

Cholecystokinin (CCK) in the amino acid uptake and enzyme protein secretion by the pancreas in humans

Summary Activation of type A receptors by CCK or cerulein is known to stimulate pancreatic enzyme secretion, but its role in the amino acid (AA) consumption and enzyme synthesis remains unclear. In our study, we used loxiglumide, a potent CCK-A-receptor antagonist, to investigate the role of CCK-A receptors in pancreatic consumption of circulating AAs and enzyme secretion. Five healthy male volunteers were intubated with double-lumen duodenal tube, and duodenal aspirates were collected during 60-min basal periods and then during pancreatic stimulation with iv infusion of secretin (80 pmol/kg/h) plus cerulein (50 pmol/kg/h) during three consecutive 30-min periods. The same procedure was repeated, but secretin-cerulein infusion was combined with a constant dose of loxiglumide (20 μmol/kg/h). The volume and outputs of HCO₃ ⁻, protein and enzymes (amylase and trypsin) in duodenal aspirates and gallbladder volume (by sonography) were determined at 30-min intervals. Plasma samples were drawn for total plasma AA assay by ninhydrin method to assess the pancreatic uptake of free AAs. Infusion of secretin plus cerulein caused a several-fold increase in the volume of duodenal aspirate and the outputs of HCO₃ ⁻, protein, and enzymes. During those periods, plasma AA level decreased from initially 2.20±0.3 mmol/L to 1.09±0.3 mmol/L (p<0.01) and the gallbladder volume from initially 28±8 mL to 2±0.4 mL. This increase in pancreatic secretory outputs was accompanied by significant increments in plasma insulin, glucagon, PP, and somatostain. After addition of loxiglumide to the secretin-cerulein infusion, the pancreatic volume and HCO₃ ⁻ outputs were unchanged, but the increments in protein and enzyme outputs and in plasma hormone levels decreased to preinfusion values. The total plasma AA level remained, however, unchanged after loxiglumide. Addition of loxiglumide almost completely prevented the contraction of the gallbladder. These results indicate that CCK-A receptors are involved in the secretin-cerulein-stimulated exocrine pancreatic protein enzyme secretion and islet hormone release, but do not appear to be involved in the pancreatic AA consumption.     

Effect of chronic oral administration of the CCK receptor antagonist loxiglumide on exocrine and endocrine pancreas in normal rats

Summary Conclusion In normal adult rats, administration of a low dose of loxiglumide for 7 d had no significant effect on exocrine and endocrine pancreatic function, whereas a high dose of loxiglumide decreased pancreatic enzyme output without inducing insulin resistance and diabetes mellitus. Background There is a possibility that chronic administration of cholecystokinin receptor antagonists not only inhibits the growth of the pancreas but also alters exocrine and endocrine pancreatic function. Methods Loxiglumide at a dose of 50, 100, or 200 mg/kg body weight, or the same volume of saline, was given by an orogastric tube twice daily for 7 d (13 successive times). Biochemical and functional changes were determined on d 8 at 24 h after the last administration of loxiglumide and 18 h fasting. Pancreatic exocrine and endocrine function was simultaneously determined following an intravenous injection of a mixed solution of 0.5 g/kg body weight glucose plus 100 ng/kg body weight cerulein. Results Pancreatic weight and protein content were dose-dependently decreased by loxiglumide, whereas DNA content was decreased only by the highest dose of loxiglumide. Loxiglumide caused dose-dependent decreases in pancreatic fluid and protein output. Total pancreatic insulin content in rats treated with loxiglumide was not significantly different from that in the control rats. However, insulin concentration relative to DNA content was significantly increased in rats treated with 200 mg/kg body weight loxiglumide compared with that in other groups of rats. Glucose-stimulated insulin release was significantly low in rats treated with the highest dose of loxiglumide compared with that in other groups of rats, although there was no difference of serum glucose concentrations among these four groups of rats.     

Physiological control of cholecystokinin release and pancreatic enzyme secretion by intraduodenal bile acids.

BACKGROUND: The physiological relevance of duodenal bile acids in the control of cholecystokinin release and pancreatic enzyme secretion is still unknown. AIMS: To provide a near physiological situation by perfusing a bile acid mixture mimicking the individual endogenous bile acid composition of the person under investigation. For maximal reduction of endogenous bile output the CCK-A receptor antagonist loxiglumide was infused intravenously. SUBJECTS AND METHODS: Seven healthy volunteers were studied on four different days by a duodenal marker perfusion technique. The individual bile acid composition in duodenal juice and test meal stimulated bile acid output was assessed on day 1. Bile acids were perfused at an amount of 30 or 100% as determined on day 1 in combination with the test meal in the presence or absence of loxiglumide. Pancreatic enzymes, bilirubin, and bile acid output were determined in duodenal juice. Plasma cholecystokinin (CCK) and plasma pancreatic polypeptide (PP) were measured radioimmunologically. RESULTS: Bile acid perfusion did not significantly alter stimulated pancreatic enzyme, bilirubin or bile acid output or plasma CCK. Loxiglumide did not alter basal CCK release but increased test meal stimulated CCK output fourfold (p < 0.05). The addition of bile acids to the test meal at a dose resembling 30% of bile acid output as determined on day 1 prevented this increase. Plasma PP concentration remained unchanged by bile acids and were mostly undetectable during loxiglumide infusion. CONCLUSIONS: The CCK producing cell is under constant suppression by intraduodenal bile acids which cannot be further enhanced by a physiological bile acid mixture. However, removal of duodenal bile acids by inhibition of gall bladder contraction unmasks this suppression leading to a dramatic increase in plasma CCK levels. As little as one third of postprandially released bile acids completely reverse this effect. Bile acids are the most important luminal regulator of CCK release in humans.     

Loxiglumide

D,l-4-(3,4-dichlorobenzoylamino)-5-(N-3-methoxypropyl-pentylamino)-5-oxopentanoic acid (CR 1505; loxiglumide) is a newly developed analog of proglumide. We examined the inhibitory effects of loxiglumide on pancreatic exocrine function in the isolated pancreatic acini and the isolated perfused pancreata of rats. Loxiglumide inhibited cholecystokinin octapeptide (CCK-8)-stimulated amylase release and, similarly, binding of[ ¹²⁵ I]CCK-8 to isolated rat pancreatic acini. Loxiglumide was about 3000 times more potent than the reference substance proglumide, but was about 1000 times less potent than L-364,718, another new CCK antagonist having benzodiazepine ring, in inhibiting CCK-8-stimulated amylase release. The inhibitory effect of loxiglumide displayed competitive kinetics and was specific for CCK in that the effects of other receptor secretagogues or agents bypassing receptors were not altered. The inhibitory effect of loxiglumide was fully reversible in isolated acini. However, the pancreata perfused with 10 M loxiglumide for 20 min did not respond to CCK-8 for more than 20 min even after the removal of loxiglumide infusion. In contrast, an immediate increase in pancreatic exocrine secretion was observed after proglumide removal. Loxiglumide appeared to be bound to the receptors on acinar cells in a slowly dissociating state. These results indicate that loxiglumide acts as a potent, competitive, and specific CCK antagonist on the exocrine pancreas and, because of its prolonged inhibitory action, may be useful as a therapeutic agent in pancreatic disease.This work was supported in part by a grant from the Japanese Ministry of Health and Welfare (Intractable Diseases of the Pancreas).     

Oral administration of loxiglumide (CCK antagonist) inhibits postprandial gallbladder contraction without affecting gastric emptying

The effect of a single oral dose of loxiglumide, a cholecystokinin antagonist, on postprandial gallbladder contraction and on gastric emptying was evaluated in humans. Following a 12-hr fasting period, two tablets of loxiglumide (400 mg each) or placebo was administered on different days, in random order and in a double-blind fashion to 10 healthy volunteers 15 min before the ingestion of a 1050-kcal standard meal. Gallbladder and antral volumes were measured by real-time ultrasonography in basal conditions and at fixed time intervals after the meal. Oral loxiglumide administration was followed by a total inhibition of the gallbladder contraction for 60 min after the end of the meal ingestion. Thereafter, up to the end of the study period, gallbladder volume was larger than that of the placebo study (at 300 min after the meal 2.7±1.6 ml after placebo and 8.2±3.5 ml after loxiglumide; P<0.008). No difference between placebo and loxiglumide was found in the antral volumes at any time interval (postprandial 63.5±16.5 ml after placebo and 59.4±24 ml after loxiglumide; at 300 min after the meal 20.8±13.3 ml after placebo and 18.9±9.5 ml after loxiglumide). In conclusion, a single oral dose of loxiglumide at the dose of 800 mg can inhibit postprandial gallbladder contraction without affecting gastric emptying. It would therefore appear that in man endogenous CCK, released after a solid-liquid, caloric, nutrient-balanced meal, plays a major role in the contraction of the gallbladder but does not affect gastric emptying.     

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.     

Modulation of Gallbladder Contraction by Pirenzepine in Humans

Objectives : The mechanism (s) by which cholinergic innorvatiun modulates gallbladder contraction are not fully understood. To elucidate the role of muscarinic M, receptors in the mediation of gallbladder contraction, we investigated gallbladder volume reduction, plasma cholecystokinin (CCK). and pancreatic polypeptide (I'P) responses in humans during cephalic and intestinal phases of a meal under M, muscarinic receptor blockade with pirenzepine. Methods : In eight healthy subjects, intruduodenal meal- and in seven subjects, sham feeding-induced gallbladder volume reduction was measured by real-time ultrasonography during saline or piren/-epine administration. Plasma CCK and PP were measured by radioimmunoassay. Results : Pirenzepine partially inhibited gallbladder volume reduction in response to an intraduodenal fatty meal. The integrated gallbladder volume reduction over 120 min was 4462 ± 445%.min compared with 6879 ± 279%.min in the saline control group ( p < 0.01). Integrated plasma CCK and PP responses were unchanged in the presence of pirenzepine. Pirenzepine abolished sham feeding-induced gallbladder contraction and plasma PP response. Sham feeding with either isotonic saline or pirenzepine infusion did not modify fasting plasma CCK levels. Conclusion : M, muscarinic receptors play an important role in the intestinal and cephalic phases of gallbladder contraction. Plasma CCK response to intraduodenal meal is not influenced by M, muscarinic receptor blockade with pirenzepine.     

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.     

Effect of loxiglumide and atropine on erythromycin-induced reduction in gallbladder volume in human subjects.

This study was undertaken to investigate the effect of erythromycin, a motilin agonist with prokinetic activity, on fasting gallbladder volume. To evaluate the mechanism of action of erythromycin on gallbladder motility, erythromycin (3.5 mg/kg.20 min, intravenously) was infused on three separate occasions: during cholinergic blockage with atropine (0.005 mg/kg.hr), during cholecystokinin receptor blockade with loxiglumide (10 mg/kg.hr) and during saline solution infusion (control). Atropine, loxiglumide and saline solution infusions were started 3 hr before administration of erythromycin and were continued for 3 hr thereafter. Gallbladder volumes (measured by ultrasonography), plasma cholecystokinin levels (radioimmunoassay) and plasma pancreatic polypeptide levels (radioimmunoassay) were determined at regular intervals for 6 hr in six healthy volunteers. During the 3-hr infusion before administration of erythromycin, both loxiglumide and atropine significantly increased gallbladder volumes--from 18 +/- 2 to 37 +/- 3 cm3 (p less than 0.05) and from 17 +/- 3 to 24 +/- 2 cm3 (p less than 0.05), respectively--whereas saline solution did not significantly affect gallbladder volume. During control saline solution infusion, erythromycin induced prolonged gallbladder contraction that was significant (p less than 0.05) between 60 and 180 min and reached a maximum of 45% +/- 8% at 150 min. Plasma cholecystokinin levels were not affected by erythromycin. Erythromycin induced a significant (p less than 0.05) increase in plasma pancreatic polypeptide levels, from 12 +/- 1 pmol/L to 34 +/- 3 pmol/L. Loxiglumide did not prevent the erythromycin-induced reduction in gallbladder volume. Atropine markedly reduced the effect of erythromycin, causing slight but significant (p less than 0.05) gallbladder volume reductions (18% +/- 4%) between 150 and 180 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

CCK receptor antagonist loxiglumide alters uptake of CCK in perfused liver and pancreatic acini of the rat

The aim of the present study was to analyze the effect of the specific cholecystokinin (CCK) receptor antagonist loxiglumide on hepatic and pancreatic processing of CCK-8 and the CCK analogue cerulein. Rat liver perfusion was performed in a non-recirculating system. CCK concentrations were measured by radioimmunoassay in perfusates from the inflow cannula (portal vein) and the outflow cannula (hepatic vein). In rat pancreatic acini, the effect of loxiglumide on internalization and surface-binding of radiolabelled CCK-8 was determined. Cerulein (20 nM, 2 nM) was extracted in a single pass through the liver by 29.7 and 25.4%, respectively. The hepatic uptake of CCK-8 (50 pM, 2 nM) was more than 90 and 89.9%, respectively. Loxiglumide drastically inhibited hepatic extraction of both peptides and reduced internalization of 125I-CCK-8 in pancreatic acini dose dependently by 39-93%. These results demonstrate that the potent CCK receptor antagonist loxiglumide significantly decreased CCK uptake by the liver and pancreas.     

Inhibitory effect of a new proglumide derivative, loxiglumide, on CCK action in isolated rat pancreatic acini

The effect of a new proglumide derivative, loxiglumide (DL-4-(3,4-dichloro-benzoyl-amino)-5-(N-3-methoxy-propyl-pentylamino+ ++)-5-oxo-pentanic acid; CR 1505), on binding of 125I-CCK-8 and amylase release stimulated by CCK-8 was investigated in isolated rat pancreatic acini. Loxiglumide inhibited CCK-8-stimulated amylase release and binding of 125I-CCK-8 to rat pancreatic acini in a dose-dependent manner. Loxiglumide caused a concentration-dependent rightward shift of the dose-response curve for CCK-8-stimulated amylase release without altering the maximal response. Schild plots showed a slope of 0.82 and pA2 value of 7.05. The inhibitory effect of loxiglumide on amylase release was reversible. Loxiglumide significantly inhibited amylase release in response to CCK-8, caerulein and gastrin-I. However, loxiglumide had no effect on amylase release stimulated by other receptor secretagogues (bombesin, carbamylcholine, secretion and vasoactive intestinal polypeptide) or by agents bypassing receptors (A23187 and TPA). These results indicate that loxiglumide acts as a potent, competitive and specific CCK antagonist on the pancreatic acini.