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PubMed1989

Effects of a novel cholecystokinin (CCK) receptor antagonist, MK-329, on gallbladder contraction and gastric emptying in humans. Implications for the physiology of CCK.

To explore the physiology of cholecystokinin (CCK) in humans, we investigated the effect on gallbladder contraction and gastric emptying of a recently developed CCK receptor antagonist, MK-329. In a double-blind, four-period crossover study eight subjects received single doses of 0.5, 2, or 10 mg MK-329, or placebo, followed by an intravenous infusion of CCK-8 (30 pmol/kg.h). In placebo-treated subjects gallbladder volumes decreased on average to 43% of initial volumes after 2 h of CCK infusion. MK-329 caused a dose-dependent inhibition of CCK-stimulated gallbladder contraction with 10 mg producing complete blockade (P less than 0.01, cf. placebo). Gallbladder contraction and gastric emptying rates after a mixed meal were then measured in a two-period crossover study. Subjects received placebo or 10 mg of MK-329 2 h before eating. Gastric emptying of both solids and liquids was measured simultaneously by gamma scintigraphy. In placebo-treated subjects plasma CCK levels increased postprandially to 2.3 pM, gallbladder volumes decreased 68.4 +/- 3.8% (SE), and the times for 50% emptying of liquids and solids from the stomach were 58 +/- 10 and 128 +/- 8 min, respectively. In MK-329-treated subjects there was a marked elevation in peak CCK levels to 13.8 pM (P less than 0.01, cf. placebo), and gallbladder contraction was completely inhibited. Solid and liquid emptying rates were unaffected. These findings demonstrate that (a) MK-329 is a potent, orally active antagonist of CCK in humans, and (b) CCK is the major regulator of postprandial gallbladder contraction. These data also support the concept of negative feedback regulation of CCK secretion and suggest that mechanisms other than CCK play a dominant role in the regulation of postprandial gastric emptying rates.

Adult↗
PubMed1997

A cholecystokinin-releasing factor mediates ethanol-induced stimulation of rat pancreatic secretion.

The mechanisms by which short-term ethanol administration alters pancreatic exocrine function are unknown. We have evaluated the effects of ethanol administration on pancreatic secretion of digestive enzymes. In our studies, anesthetized as well as conscious rats were given ethanol at a rate sufficient to cause the blood ethanol concentration to reach levels associated with clinical intoxication. Ethanol was administered over a 2-h period during which blood ethanol levels remained stably elevated. We report that intravenous administration of ethanol results in a transient increase in pancreatic amylase output and plasma cholecystokinin (CCK) levels. The ethanol-induced increase in amylase output can be completely inhibited by the CCK-A receptor antagonist L-364,718 and partially inhibited by the muscarinic cholinergic antagonist atropine. The ethanol-induced rise in amylase output can be completely prevented by instillation of trypsin into the duodenum or by lavage of the duodenum with saline during ethanol administration. Furthermore, the intraduodenal activity of a CCK-releasing factor is increased by infusion of ethanol. These studies indicate that administration of ethanol causes rat pancreatic exocrine secretion to increase. This phenomenon is mediated by a trypsin-sensitive CCK-releasing factor which is present within the duodenal lumen. These observations lead us to speculate that repeated CCK-mediated ethanol-induced stimulation of pancreatic digestive enzyme secretion may play a role in the events which link ethanol abuse to the development of pancreatic injury.

Alcoholism↗
PubMed1991

Effects of a cholecystokinin receptor antagonist on rat exocrine pancreatic response to raw soya flour.

1 Raw soya flour (RSF) in the diet induces pancreatic hypertrophy and hyperplasia in the rat, changes ascribed to production of a high circulating level of cholecystokinin (CCK) due to inhibition of trypsin in the duodenum. Prolonged ingestion results in pancreatic adenomas and carcinomas. 2 L-364, 718, a potent, highly specific CCK antagonist was used to investigate the short-term role of CCK. 3 In rats fed 50% RSF and L-364, 718 5 mg kg-1 p.o. twice daily for 4 d, there was inhibition of pancreatic hypertrophy and hyperplasia, which is further evidence that peripherally-acting CCK plays a major role in the generation of RSF-mediated changes in the pancreas.

Animals↗
PubMed1991

Endogenous cholecystokinin release responsible for pancreatic growth observed after pancreatic juice diversion.

This study was undertaken to determine whether intermittent pancreatic juice diversion (PJD) from the intestine can induce pancreatic and duodenal growth. Concomitant infusions of SMS 201-995, a somatostatin analog, and L-364,718, a cholecystokinin (CCK) receptor antagonist, were used to establish the involvement of endogenous CCK. Fed rats equipped with biliary, duodenal, and pancreatic cannulae had their pancreatic juice diverted 8 h/day for 4 days and were infused or not with either SMS 201-995 (5 micrograms/kg.h) or L-364,718 (0.5 mg/kg.h) during diversion. After 4 days, rats were killed, and their pancreas and duodenum were excised for measurements of parameters indicative of growth. In normally fed rats with pancreatic juice returned, SMS 201-995 inhibited daily pancreatic secretions of volume and protein, whereas L-364,718 inhibited only protein output. These two inhibitors had no effect on normal pancreatic and duodenal growth. PJD was associated with increased volume and protein output, increased plasma CCK level, and pancreatic growth. All of these effects were completely blocked by SMS 201-995 and L-364,718, with the exception of plasma CCK level by the CCK antagonist. None of these treatments affected duodenal growth. These results suggest that intermittent infusions of these two inhibitors had no effect on normal pancreatic and duodenal growth, but were successful in preventing pancreatic growth induced by PJD. They also indicate that endogenous CCK is involved in PJD-induced pancreatic growth.

Animals↗
PubMed1992

Effects of bombesin on pancreatic digestive enzyme gene expression.

We examined the effects of bombesin on rat pancreatic digestive enzyme gene expression using cloned complementary DNA probes for amylase, trypsinogen I, chymotrypsinogen B, and lysophospholipase. Rats were injected sc three times daily with 5 nmol/kg body wt bombesin. Pancreata were investigated after 6, 12, 24, 48, and 120 h of hormone treatment. Bombesin administration resulted in a time-dependent increase of pancreatic weight, as well as DNA and protein concentration. Cellular hypertrophy became evident after 48 h, and pancreatic hyperplasia occurred after 5 days of hormone treatment. Bombesin administration resulted in a time-dependent parallel decrease of amylase and lysophospholipase messenger RNA (mRNA) concentrations with maximal inhibition occurring after 120 h of bombesin treatment (13 +/- 1% and 14 +/- 3% of control, respectively, P less than 0.05, n = 6). In contrast, chymotrypsin and trypsin mRNA levels remained unaltered after bombesin treatment for up to 5 days. Amylase and chymotrypsin enzyme levels did not correlate with their respective mRNA concentrations. Both decreased to approximately 50% of control after 12 h and increased to 126 +/- 38% of control and 388 +/- 109% of control (P less than 0.05, n = 6), respectively, after 5 days of bombesin treatment. To test whether the bombesin regulation was mediated by the release of cholecystokinin (CCK), the specific CCK receptor antagonist L-364,718 (1 mg/kg body wt) was injected ip either alone, or 15 min before each bombesin injection for 5 days. Although the antagonist alone significantly reduced the mRNA concentrations for trypsin, chymotrypsin, and lysophospholipase to approximately 50%, it did not block the effects of bombesin on pancreatic digestive enzyme levels. These data therefore indicate that bombesin regulates pancreatic digestive enzyme mRNA and protein concentrations in a nonparallel manner; furthermore, CCK is not involved in mediating the bombesin effects on pancreatic gene expression.

Amylases↗
PubMed1998

Glucagon-like peptide-1-(7-36) amide and peptide YY mediate intraduodenal fat-induced inhibition of acid secretion in dogs.

Intraduodenal fat inhibits gastric acid secretion via the release of one or more hormonal enterogastrones thought to arise from ileocolonic mucosa. This study determined whether glucagon-like peptide-1 (GLP-1)-(7-36) amide and peptide YY (PYY), colocalized in L cells found in the ileum, mediate intraduodenal fat-induced inhibition of stimulated gastric acid, and evaluated the influence of cholecystokinin-A (CCK-A) receptor activation. Gastric acid secretion in response to duodenal perfusions of 8% peptone was measured in conscious dogs with gastric and duodenal cannulas. Intraduodenal administration of a 10% fat emulsion suppressed gastric acid secretion by 72 +/- 4% (P < 0.001) and increased plasma levels of GLP-1 and PYY by 44 +/- 5 and 46 +/- 4 fmol/ml, respectively (both P < 0.01). Pretreatment with the CCK-A receptor antagonist MK-329 completely reversed the inhibition of gastric acid by fat, suppressed rises of plasma GLP-1 (maximum change, 23 +/- 4 fmol/ml), and reduced plasma PYY responses to baseline. Intravenous infusions of 50 pmol/kg x h GLP-1 or PYY, which reproduced plasma elevations after intraduodenal fat, inhibited gastric acid secretion by 66 +/- 5% and 51 +/- 6%, respectively (both P < 0.01); coinfusions of GLP-1 and PYY abolished gastric acid secretion (P < 0.001) without influencing plasma gastrin or somatostatin. Pretreatment with 1500 pmol/kg x h of the GLP-1 antagonist exendin-(9-39) amide did not alter the magnitude of inhibition of gastric acid caused by exogenous GLP-1. These results indicate that GLP-1 and PYY released by intraduodenal fat, in part through CCK-dependent pathways, are major enterogastrones in dogs. This inhibitory action occurs independent of circulating concentrations of somatostatin and gastrin and appears to involve a GLP-1 receptor distinct from that mediating incretin effects.

Animals↗
PubMed1990

Regulation of pancreatic endocrine function by cholecystokinin: studies with MK-329, a nonpeptide cholecystokinin receptor antagonist.

A cholecystokinin (CCK) receptor antagonist, MK-329, was used to explore the physiological role of CCK in regulating pancreatic endocrine function in humans. The ability of CCK to increase plasma pancreatic polypeptide (PP) concentrations and blockade of this effect with MK-329 were evaluated in a double blind, balanced, four-period cross-over study. Eight subjects received single oral doses of 0.5, 2, or 10 mg MK-329 or placebo, followed by an iv infusion of CCK-8 (34 ng/kg.h). In placebo-treated subjects, PP increased from basal levels of 70 +/- 15 (+/- SE) to peak values of 291 +/- 58 pg/mL after CCK infusion (P less than 0.05 compared to basal). This increase in plasma PP concentration was inhibited in a dose-dependent fashion by MK-329, with 10 mg antagonizing the stimulatory effect of CCK infusion by nearly 80%. Second, the effect of MK-329 on meal-stimulated pancreatic endocrine responses was evaluated by giving placebo or 10 mg MK-329 2 h before ingestion of a mixed meal. Eight subjects were treated in a randomized two-period cross-over fashion. With placebo treatment, peak postprandial plasma insulin, glucagon, and glucose concentrations were 101 +/- 8 microU/mL, 195 +/- 15 pg/mL, and 150 +/- 10 mg/dL, respectively (all P less than 0.05). The integrated PP response following the meal was 56.3 +/- 11.1 ng/mL.minute. With MK-329 treatment, the integrated PP concentration was reduced to 33.9 +/- 2.2 ng/mL.min (P less than 0.05 compared to placebo treatment). Mean postprandial insulin, glucagon, and glucose concentrations did not differ between placebo and MK-329 treatments. We conclude that CCK receptor blockade with 10 mg MK-329 does not alter plasma insulin, glucagon, or glucose responses to a mixed meal. However, the observation that physiological concentrations of CCK increase plasma levels of PP, and the finding that CCK receptor blockade selectively attenuates the postprandial increase in plasma PP concentrations support a physiological role for CCK in regulating PP secretion.

Administration, Oral↗
PubMed1995

Loxiglumide, L-364,718 and L-365,260 prevent the inhibition of spontaneous acetylcholine release from the frontal cerebral cortex of freely moving rat peripherally administered with cholecystokinin-8S.

We examined the effect of peripheral administration of cholecystokinin (CCK)-8S on spontaneous acetylcholine (ACh) release from the frontal cortex and its prevention by loxiglumide, L-364,718 and L-365,260 in freely moving rats using intracerebral microdialysis. Subcutaneously (s.c.) administered CCK-8S at 10 and 30 micrograms/kg significantly decreased the release of ACh. The inhibitory effect of 10 micrograms/kg (s.c.) CCK-8S was prevented by loxiglumide, a mixed type of CCK-A and -B-receptor antagonist, at 1 mg/kg (intraperitoneal) and 40 micrograms/rat (intracerebroventricular, i.c.v.); L-364,718, a CCK-A-receptor antagonist, at 125 and 250 ng/rat (i.c.v.); and L-365,260, a CCK-B-receptor antagonist at 250 ng/rat (i.c.v.). These results demonstrate that peripherally administered CCK-8S inhibits spontaneous ACh release from the frontal cortex through both central CCK-A (mainly) and -B receptors.

Acetylcholine↗
PubMed1987

Physiological role of cholecystokinin in meal-induced insulin secretion in conscious rats. Studies with L 364718, a specific inhibitor of CCK-receptor binding.

It has been suggested that the gut hormone cholecystokinin (CCK), by modulating insulin output from pancreatic beta-cells, plays an important role in the enteroinsular axis. To investigate this hypothesis, eight rats were studied on two different occasions: after injection of L 364718, a specific antagonist of CCK binding to its membrane receptor, and after vehicle injection. In both studies a mixture of casein (11%) and glucose (9%) was infused through a chronic indwelling intraduodenal catheter to evoke CCK secretion. Plasma was analyzed for insulin, glucose, glucagon, and tyrosine many times during the procedure. Prior administration of the CCK antagonist significantly attenuated the increase in plasma insulin and glucagon after casein infusion. These results support the concept that cholecystokinin plays an important physiologic role in the in vivo regulation of postprandial plasma insulin and glucagon concentrations after protein ingestion.

Animals↗
PubMed1988

Stimulatory effects of cholecystokinin on isolated perifused islets inhibited by potent and specific antagonist L 364718 [corrected].

The influence of L 364718 on islet responsiveness to sulfated cholecystokinin (CCK-8S) was investigated. In islets whose inositol-containing phospholipids were prelabeled during a 2-h incubation period, subsequent exposure to L 364718 (1 nM) significantly impaired the secretion of insulin usually noted in response to 200 nM CCK-8S in the simultaneous presence of 7 mM glucose. A higher level of the antagonist (10 nM) completely abolished insulin secretion. L 364718 (1-10 nM) reduced the efflux of 3H from myo-[2-3H]-inositol prelabeled islets in parallel with the reduction in secretion. L 364718 (10 nM) significantly reduced the accumulation of 3H-containing inositol phosphates usually noted with CCK-8S addition. L 364718, at levels 10- to 100-fold greater than those necessary to attenuate CCK-8S-induced insulin secretion, had no adverse effect on the insulin secretory response of freshly isolated islets to 10 mM glucose alone, 5 mM D-glyceraldehyde, 15 mM alpha-ketoisocaproate, or 50 ng/ml gastric inhibitory polypeptide. L 364718 (1000 nM) had no adverse influence on carbamylcholine (1 mM)-induced phosphoinositide hydrolysis. These results establish L 364718 as a potent and highly selective antagonist of cholecystokinin's stimulatory actions on beta-cells. Because of its potency, selectivity, and oral effectiveness, in vivo studies with L 364718, aimed at unraveling the pleiotropic effects of CCK-8S on glucose and insulin homeostasis, seem feasible.

Animals↗
PubMed1990

Cholecystokinin is responsible for growth of the pancreas after pancreaticobiliary diversion in rats.

Pancreaticobiliary diversion (PBD) caused a more than twofold increase in pancreatic weight after 10 days, with no further increase after 15 or 20 days or 7 weeks. Although the weight gain after PBD to a minor extent (10%) reflected increased water content, the main cause was hypertrophy and hyperplasia with increased pancreatic protein and DNA content. The cholecystokinin (CCK) concentrations in plasma were increased 10-fold from the 5th postoperative day. The trophic effects on the pancreas were completely abolished by the CCK antagonist L-364,718. Further, the antagonist caused a significant reduction in pancreatic weight, protein, and DNA in otherwise untreated controls. We conclude that PBD in rats induces trophic effects on the pancreas by increasing circulating CCK concentrations and that CCK is important for normal pancreatic growth.

Anastomosis, Surgical↗
PubMed1990

Effects of cholecystokinin and cholinergic receptor blockade on guinea pig pepsinogen secretion.

Although cholecystokinin (CCK) has been reported to stimulate pepsinogen secretion, this action has been poorly characterized. To assess the ability of CCK to regulate mammalian pepsinogen secretion, guinea pig fundic mucosa was incubated in Ussing chambers with CCK-8, carbamylcholine, and pentagastrin, and with cholinergic and CCK antagonists. CCK-8 stimulated pepsinogen secretion at 10(-10) M, with an ED50 of 10(-9) M and maximally (26-fold over basal) at 10(-8) M. Carbachol stimulated pepsinogen and acid secretion with an ED50 of 3 x 10(-7) M and maximally at 10(-6) M. Pentagastrin (10(-9) M-10(-6) M) did not affect acid or pepsinogen secretion, whereas gastrin-I (10(-6) M) stimulated acid secretion slightly but did not alter pepsinogen secretion. L364, 718 (10(-5) M), a specific CCK peripheral receptor antagonist, abolished all pepsigogic effects of 3 x 10(-9) M CCK-8 without altering basal acid or pepsinogen secretion or mucosal electric characteristics. L364,718-treated tissues unresponsive to CCK-8 nevertheless secreted pepsinogen and acid in response to 3 x 10(-7) M carbachol identically to control carbachol-treated preparations. Atropine (10(-5) M) blocked the response to 3 x 10(-7) M carbachol without inhibiting 10(-9) M CCK stimulation. These results support a specific receptor-mediated role for cholecystokinin in the physiologic regulation of guinea pig pepsinogen secretion.

Animals↗
PubMed1990

Effects of endogenous and exogenous cholecystokinin and of infusion with the cholecystokinin antagonist L-364,718 on pancreatic and gastrointestinal growth.

Continuous subcutaneous infusion of cholecystokinin (CCK-8; 5 micrograms/kg/h) to rats for 7 weeks raised the plasma CCK concentration almost fivefold and increased the pancreatic weight by about 50% but was without effect on the gastrointestinal tract. Continuous subcutaneous infusion of the CCK antagonist L-364,718 (200 micrograms/kg/h) for 7 weeks reduced the weight of the pancreas by about 30% but was without effect on the gastrointestinal tract. The effect of continuous subcutaneous infusion of CCK-8 and L-364,718 in combination was very similar to that of L-364,718 alone. Pancreaticobiliary diversion (PBD) induced a nearly 10-fold increase in the plasma CCK concentration 3 and 7 weeks after the operation. The serum gastrin values were unaffected. The weight of the pancreas was more than doubled after 7 weeks. At the same time the small intestine had gained weight, but the colon was unaffected. Continuous subcutaneous infusion of L-364,718 prevented the effect of PBD on the pancreas. On the basis of the assumption that L-364,718 is a specific antagonist of CCK, we conclude that endogenous CCK has a trophic effect on the pancreas but not on the gastrointestinal tract and that it is essential for normal pancreatic growth.

Animals↗
PubMed1991

Inhibition of cholecystokinin-stimulated pancreaticobiliary output in man by the cholecystokinin receptor antagonist MK-329.

MK-329 (formerly L-364,718) is a new nonpeptide antagonist for the peripheral (type-A) cholecystokinin (CCK) receptor, which has proved effective in blocking the actions of both exogenous and endogenous CCK in several species. To evaluate the effect of MK-329 on CCK-stimulated pancreaticobiliary output in man, six normal subjects received 10 mg MK-329 or placebo orally in a randomized, crossover fashion, before a background intravenous infusion of secretin (5 pmol/kg/h) and two doses of CCK-8 (approximately 15 and 40 pmol/kg/h, each for 1 h). Gastric and duodenal juice were aspirated separately via two double-lumen tubes, with 51Cr-ethylene-diaminetetraacetic acid as a duodenal marker. After placebo treatment the background infusion of secretin produced maximum plasma concentrations of secretin similar to postprandial values, averaging about 5 pM. After placebo treatment the low dose CCK-8 infusion (15 pmol/kg/h) increased circulating CCK concentrations from basal levels of 1.8 +/- 0.2 pM to levels similar to those observed postprandially, averaging 9.2 +/- 1.3 pM, and the high dose of CCK-8 (40 pmol/kg/h) induced supraphysiologic levels of CCK, averaging 23.4 +/- 3.2 pM. Plasma concentrations of secretin and CCK were not significantly different during MK-329 treatment. As expected, infusion of CCK-8 at both doses stimulated pancreatic exocrine secretion and gallbladder contraction in placebo controls, as indicated by increases in the output of trypsin, amylase, bicarbonate, and bilirubin. Whereas MK-329 did not significantly reduce basal pancreatic secretion, the integrated incremental output of trypsin, amylase, and bicarbonate in response to stimulation with the low (physiologic) CCK dose was inhibited by 74% (p less than 0.01), 89% (NS), and 75% (p less than 0.05), respectively. Basal bilirubin output was virtually abolished after treatment with MK-329, and the response to the low dose of CCK was reduced by 98% (p less than 0.01), indicating almost complete inhibition of gallbladder contraction at physiologic circulating concentrations of CCK. It is concluded that MK-329 is an orally active antagonist of CCK-stimulated pancreaticobiliary output in man and could thus be utilized to explore the physiologic regulation of the exocrine pancreas and gallbladder by CCK.

Adult↗
PubMed1993

Hypercholecystokininemia produced by pancreaticobiliary diversion causes gastrin-like effects on enterochromaffin-like cells in the stomach of rats subjected to portacaval shunting or antrectomy.

Gastrin and possibly cholecystokinin (CCK) control the activity and growth of the histamine-containing endocrine cells, the enterochromaffin-like (ECL) cells, in the oxyntic mucosa of the rat. Portacaval shunting (PCS) is known to activate the ECL cells through as yet unknown mechanisms. PCS also exaggerates the ECL cells' response to gastrin, whereas antrectomy causes hypotrophy and hypoplasia of the ECL cells. A recent study showed that the ECL cells failed to respond to sustained hyperCCKemia caused by pancreaticobiliary diversion (PBD). In the present study we investigated whether PBD-produced hyperCCKemia influenced the effects of PCS or antrectomy on the ECL cells. The results show 1) that hyperCCKemia raised the histidine decarboxylase (HDC) activity of the ECL cells in PCS rats but not in control rats, and the CCK-A receptor blockade failed to prevent the enzyme activation; and 2) that PBD prevented the ECL cell hypoplasia and the decrease in HDC activity induced by antrectomy. The findings suggest that under special circumstances endogenous CCK may stimulate the ECL cells.

Animals↗
PubMed1994

A possible interaction between serotonin and cholecystokinin-8 in the ileo-colonic motor responses to feeding in rats.

The effects of cholecystokinin (CCK)-A, CCK-B, and 5-hydroxytryptamine-2 (5-HT2) receptor antagonists on the postprandial myoelectric activity of the ileum and the proximal and distal colon in rats were studied. After L364,718, a CCK-A receptor antagonist, or ritanserin, 5-HT2 receptor antagonist, the duration of the ileal postprandial motor pattern was reduced by 60%. In contrast, L365,260, a CCK-B receptor antagonist, had no effect. In the distal colon, the postprandial response was inhibited by CCK-A, CCK-B, and 5-HT2 receptor antagonists, whereas they were inactive in the proximal colon. CCK-8 administered at the end of the meal suppressed the inhibitory effect of ritanserin on the ileum and the distal colon. These results suggest that, in rats, CCK-8 is involved in the control of the ileal motor response to feeding through CCK-A receptors and in that of the distal colon through both CCK-A and CCK-B receptors. Serotonin seems to play a role in CCK-8 control through 5-HT2 receptors.

Animals↗
PubMed1996

Comparison of the effects of two cholecystokinin-receptor antagonists, loxiglumide and L-364,718, on the pancreatic secretory response to intraduodenal tryptophan in dogs.

BACKGROUND: The aim of the study was to compare the effects of the cholecystokinin (CCK)-receptor antagonists loxiglumide and L-364, 718 on the endogenously stimulated pancreatic exocrine secretion. METHODS: In six conscious dogs with chronic gastric and pancreatic fistulas we compared the action of different doses of loxiglumide (2.5 to 10.0 mg/kg/h) and L-364, 718 (0.025 to 0.1 mg/kg/h) on the pancreatic secretory response to intraduodenal perfusion of graded loads of tryptophan (0.37-10.0 mmol/ h), given against a background of secretin (20.5 pmol/kg/h intravenously). RESULTS: Both loxiglumide and L-364, 718 inhibited the secretin-stimulated pancreatic bicarbonate output by up to 47% and 48%, respectively. The pancreatic protein output during secretin was significantly inhibited by all doses of L-364,718 (by 65% to 82%) but not by loxiglumide. All doses of loxiglumide and L-364, 718 abolished the 180-min integrated bicarbonate response to tryptophan. The two higher doses of loxiglumide (5.0-10.0 mg/kg/h) and L-364,718 (0.05-0.1 mg/kg/h) significantly decreased the 180-min integrated response to tryptophan by 59% and 79% (loxiglumide) and by 72% and 97% (L-364, 718). The plasma CCK-like immunoreactivity basally and in response to tryptophan was not significantly altered by loxiglumide or L-364, 718. CONCLUSIONS: These findings indicate that in dogs 1) the pancreatic bicarbonate response to secretin is augmented by the hormone CCK; 2) L-364, 718 but not loxiglumide decreases pancreatic protein output during secretin; 3) endogenous released CCK is involved in the pancreatic bicarbonate response and is a major mediator of pancreatic protein response to intraduodenal tryptophan; and 4) the release of CCK by intraduodenal tryptophan is not influenced by loxiglumide and L-364, 718.

Animals↗
PubMed1995

Effects of the cholecystokinin receptor antagonist L-364,718 on pancreatitis induced by a deficient in choline and supplemented with ethionine (CDE) diet in the rat.

The role of cholecystokinin (CCK) in the development of a necrotizing acute pancreatitis induced by a diet deficient in choline and supplemented with ethionine (CDE) has been evaluated in the rat by using a potent CCK receptor antagonist L-364,718. Acute pancreatitis was induced by administration of CDE diet for 14 days. L-364,718 administration was carried out by subcutaneous injections at dose of 0.1 mg/kg/day. Pancreatic exocrine secretion (flow, protein, amylase and trypsin outputs) in resting and under infusion of 1.25 microgram/kg/h of CCK-8 were used to evaluate the pancreatic functionality. Others parameters (serum amylase, percentage fluid in pancreas, haematocrit and mortality) evaluated the severity of pancreatitis. L-364,718 slightly reduced the mortality and the increases of percentage of fluid accumulated in pancreas in CDE diet acute pancreatitis. Basal and CCK stimulated pancreatic secretion was significantly depressed 36 hours after L-364,718 treatment. A slight response to CCK was observed. Nevertheless it was lower than usually observed in control rats. Our results demonstrate that in the rat, chronic L-364,718 treatment did not completely restore pancreatic activity in acute pancreatitis induced by CDE diet. Hence CCK cannot be considered as the main factor involved in the development of this pancreatitis model.

Acute Disease↗