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PubMed1986

Beneficial effects of cholecystokinin-receptor blockade and inhibition of proteolytic enzyme activity in experimental acute hemorrhagic pancreatitis in mice. Evidence for cholecystokinin as a major factor in the development of acute pancreatitis.

The effects of the cholecystokinin (CCK)-receptor antagonist proglumide, the protease inhibitor gabexate, and the hormones secretin and cholecystokinin-octapeptide (CCK-8) were studied in a model of acute hemorrhagic pancreatitis induced by feeding mice a choline-deficient, ethionine-supplemented (CDE) diet. Injections of gabexate and proglumide from initiation of CDE diet (before induction of pancreatitis) increased survival from 37% (diet alone) to 85 and 75%, respectively, and also ameliorated histological alterations and increases in serum amylase concentration and pancreatic activated trypsin. Secretin had no major beneficial effect. When proglumide or gabexate were given after induction of pancreatitis, proglumide still increased survival to 75%, whereas gabexate no longer did. Injection of nontoxic doses of CCK-8 before proglumide or gabexate injections completely abolished all beneficial effects and also increased the severity of pancreatitis due to CDE diet alone. Blockade of CCK receptors and early inhibition of protease activity may be beneficial in severe acute pancreatitis. Cholecystokinin appears to play a contributory role in the development of pancreatitis.

Acute Disease↗
PubMed1988

Antiproliferative effects of gastrin receptor antagonists and antibodies to gastrin on human colon carcinoma cell lines.

The gastrointestinal hormone gastrin has been shown to stimulate the growth of normal colonic mucosa. To examine for a possible role of gastrin in the proliferation of cultured colon tumor cells, we have studied the effects of two gastrin receptor antagonists, proglumide and benzotript, and of antibodies to gastrin. We find that proglumide (50% effective concentration, 2 to 5 mM) and benzotript (50% effective concentration, 0.4 to 0.8 mM) inhibit the monolayer growth of six human colon cancer cell lines. Addition of exogenous gastrin abrogated the growth-inhibitory effect of proglumide. The anchorage-independent growth of colon carcinoma cells was also inhibited by the two gastrin antagonists. Also, a dose-dependent increase in carcinoembryonic antigen secretion was observed upon treatment with proglumide and benzotript in three cell lines examined. Half-maximal inhibition of labeled gastrin binding was observed at concentrations of 0.4 mM benzotript and 8.6 mM proglumide. In addition, antigastrin antiserum added to HCT 116 cells adapted to growth in serum-free medium resulted in a concentration-dependent inhibition of cellular proliferation. These data suggest that gastrin may function as an autocrine growth factor in colon carcinoma.

Antibodies↗
PubMed1994

Characterization of the effect of cholecystokinin (CCK) on neurons in the periaqueductal gray of the rat: immunocytochemical and in vivo and in vitro electrophysiological studies.

The periaqueductal gray (PAG) is an important integration site for pain, autonomic functions, vocalization, fear and anxiety. Cholecystokinin (CCK) is a major neurotransmitter in the PAG and CCK receptors are heterogeneously distributed within the PAG. Since CCK antagonists are anxiolytic and potentiate morphine analgesia, it is possible that these effects of CCK are mediated through alteration of neuronal activities in the PAG. The goals of this study were to examine the anatomical and physiological properties of the PAG CCK containing systems. The distribution of CCK-containing axons and boutons in PAG was examined using immunohistochemical procedures. These studies show that CCK-like immunoreactive (CCK-LIR) fibers and terminals are present throughout PAG, but are particularly heavily concentrated in a focal column that runs longitudinally throughout the rostrocaudal axis of dorsolateral PAG and in nucleus cuneiformis which represents a caudolateral extension of PAG. The physiological effects of CCK on PAG neurons were examined in both in vivo and in vitro preparations. In the in vivo experiments multibarreled electrodes were used to record from PAG neurons and to apply CCK and the CCK antagonists, CR1409 and proglumide. Of 37 neurons recorded in vivo, CCK caused excitation in 25 cells, inhibited 7 cells and had no effect on 5 cells. The excitatory effect was blocked by CR1409 in 11/11 cells tested. Proglumide blocked the excitatory response of CCK in 12/14 cells. Proglumide blocked the inhibitory effect in 2 of 7 cells, but CR1409 had no effect on CCK-evoked inhibition in 7 cells tested. Extracellular, conventional intracellular and whole cell patch clamping procedures were used to study CCK actions in the in vitro slice preparation. In the extracellular recording experiments, responses of PAG cells to CCK were measured in slices that were maintained at 22 degrees C (room temperature) and at 32 degrees C. CCK excited 40/56, inhibited 7/56 and had no effect on 9/56 cells; excitatory responses were blocked by CR1409 in 32/36 cells and by proglumide in 25/27 cells tested. Inhibitory responses to CCK were unaffected by CR1409, but were blocked in 3/7 cells by proglumide. Conventional intracellular recordings were made from 13 cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1980

The activity of N-acetylglucosamine kinase in rat gastric mucosa.

The activity of N-acetylglucosamine kinase in the rat glandular stomach was studied to elucidate its participation in aspirin-induced ulcers, and the effect of proglumide, an anti-ulcer agent which was found to increase gastric mucosal hexosamine, on this enzymatic activity was also studied. N-Acetylglucosamine kinase activity was found to be significantly higher in the antrum than in the corpus, the antrum being 1.3--1.9 times as active as the corpus. The mucosal layer itself was about 1.8--2.0 times as active as the whole tissue of the glandular stomach. This enzymatic activity in the glandular stomach was found to decrease slightly after fasting and to further decrease after intragastric administration of aspirin (100 mg/kg). The pylorus-ligated rats showed a significant decline of this enzymatic activity following the administration of aspirin. Acceleration of N-acetylglucosamine kinase activity with proglumide was demonstrated in vivo and in vitro experiments. Prior treatment with proglumide prevented aspirin-induced ulcers and correspondingly stimulated this enzymatic activity. These results suggest that the activity of N-acetylglucosamine kinase in the rat glandular stomach closely parallels the distribution and localization of gastric hexosamine, glycosaminoglycans, and glycoproteins. A decrease of this enzymatic activity correlates with the production of ulcers by aspirin. The mechanism by which proglumide increases gastric hexosamine is at least partly attributed to the activation of N-acetylglucosamine kinase in the glandular stomach.

Animals↗
PubMedDate not supplied

Inhibition of satiety by a cholecystokinin antagonist is independent of gastric emptying.

The ability of a cholecystokinin antagonist Proglumide to inhibit satiety induced by intraperitoneal injections of cholecystokinin octapeptide (CCK-OP) and bombesin was examined in rats equipped with chronic gastric cannulae. Both CCK-OP and bombesin significantly suppressed sham feeding. Proglumide administered alone did not alter sham feeding but it abolished the suppression of feeding induced by CCK-OP. In contrast, Proglumide did not inhibit the effect of a low dose of bombesin, but partially inhibited satiety induced by a high dose of bombesin, thus confirming our previous findings. These results indicate that the effect of Proglumide is independent of its recently described effects on gastric emptying in rat.

Animals↗
PubMedDate not supplied

Preventive effect of cholecystokinin octapeptide on experimental amnesia in rats.

The effect of intracerebroventricular (ICV) administration of cholecystokinin octapeptide (CCK-8) on electroconvulsive shock (ECS)-induced amnesia in passive avoidance response was studied in rats. In normal rats, CCK-8 in doses from 1 ng to 1 microgram had no effect on the response when injected before the training trials, immediately after foot shock or before the first retention test. However, proglumide, a CCK-8 receptor blocker, induced marked amnesia when injected in doses from 0.1 to 10 micrograms before the training trials and in doses of 1 and 10 micrograms before the first retention test, though not subsequent to foot shock. ECS given immediately after the foot shock caused amnesia in the 24 hr and 48 hr retention tests, which could have been prevented by CCK-8 injected in doses of 10 ng to 1 microgram prior to the training trials, of 10 ng to 1 microgram following ECS and of 0.1 and 1 microgram before the first retention test. In addition, the effects of CCK-8 and proglumide became pronounced following chronic ICV infusion, using an osmotic minipump, for 7 days at a dose of 1 ng/day and 10 ng/day, respectively. The amnesia induced by proglumide was not affected by arginine vasopressin (AVP), while AVP in doses of 10 ng and 100 ng given 30 min before the training trials prevented ECS-induced amnesia. The antiamnesic effect of AVP was abolished by simultaneous administration of proglumide. On the other hand, AVP-antiserum produced marked amnesia which could be antagonized by CCK-8. However, the antiamnesic effect of CCK-8 was not suppressed by AVP-antiserum.(ABSTRACT TRUNCATED AT 250 WORDS)

Amnesia↗
PubMedDate not supplied

Pentagastrin-stimulated DNA synthesis in mouse gut is influenced by the circadian system.

Gastrin is trophic for rodent gut mucosa. Proglumide, a competitive inhibitor of gastrin, can exert an antitrophic effect and can block pentagastrin-stimulated DNA synthesis. We have examined the influence of the circadian system on pentagastrin-stimulated DNA synthesis in the murine stomach (glandular and nonglandular stomach) and colon. We studied 224 male CD2F1 mice divided into four groups. Group A was ad lib fed (controls). Groups B, C, and D received 6-9 intraperitoneal injections of either NaCl, pentagastrin or pentagastrin + proglumide, at 8-h intervals prior to sacrifice. Mice from each group (A-D) were killed (by cervical dislocation) at 3-h intervals for 24 h. Incorporation of tritiated thymidine (DNA synthesis) was measured, and significant (p less than 0.001) circadian rhythms were found, which were not eliminated after treatment with either pentagastrin or pentagastrin + proglumide. DNA synthesis in the glandular stomach increased significantly after treatment with pentagastrin , but only during the span of time when DNA synthesis was increasing also in control mice; it had no effect at other times. Proglumide blocked the effect of pentagastrin only during the time of increasing DNA synthesis; it had no effect at other times. The identical regimen given at different times in the circadian cycle yielded significantly different results. In the intact animal, studies on the effects of various stimulators or inhibitors of DNA synthesis should be time-qualified.

Animals↗
PubMed1993

Evidence for autocrine growth stimulation by a gastrin/CCK-like peptide of the gastric cancer HGT-1 cell line.

Gastrin has been shown to promote the growth of some colonic tumor cell lines. To evaluate the involvement of this hormone in the proliferation of gastric tumors, we studied the effects of gastrin/CCK-receptor antagonists (L365,260 and L364,718), proglumide and C terminal-specific gastrin antibodies on the human gastric adenocarcinoma cell line HGT-1. L365,260, but not L364,718, dose-dependently inhibited cell proliferation (72% after 4 days at 10 nM) and [3H]thymidine incorporation (68% after 2 days at 10 nM) in serum-free medium. No cytotoxic effects of proglumide or L365,260 on this cell line were detected. Proglumide inhibited cell proliferation in serum-free medium (40% and 66.5% after 2 and 4 days of treatment; IC50 = 1.4 mM) and in 5% fetal calf serum (FCS)-supplemented medium (30% and 22% after 2 and 4 days of treatment; IC50 = 3.25 mM). [3H]Thymidine incorporation was also inhibited by proglumide in serum-free medium (IC50 = 2.3 mM) and 5% FCS-supplemented medium (IC50 = 3.35 mM). Gastrin did not induce cell proliferation or increase [3H]thymidine incorporation and no high-affinity gastrin binding sites were observed. However, C terminal-specific gastrin antibodies, even at low concentration, caused a dramatic decrease in both cell number (IC50 = 1:4000 antiserum dilution) and [3H]thymidine incorporation (IC50 = 1:400 antiserum dilution) in the HGT-1 cell line. In addition, immunofluorescence analysis revealed that these antibodies specifically bind HGT-1 cells and radioimmunoassay analysis confirms the presence of gastrin/CCK-like peptide in cell extracts.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗
PubMed1991

Spinal co-administration of cholecystokinin antagonists with morphine prevents the development of opioid tolerance.

The effects of intrathecal (i.t.) co-administration of the cholecystokinin (CCK) antagonists lorglumide or proglumide with a "low" (1 microgram) and "high" (10 micrograms) dose of i.t. morphine on the development of opioid tolerance were determined using the rat tail-flick assay. Although co-injection of 7 ng lorglumide or 20 ng proglumide (doses which have been demonstrated to acutely enhance 1 microgram morphine, i.t.) were without effect, co-administration of 70 ng lorglumide or 64 ng proglumide with 1 microgram morphine for 6 days inhibited development of tolerance to this dose of opioid. Higher doses of CCK antagonists (1400 ng lorglumide and 1280 ng proglumide) were required to prevent the tolerance induced by 10 micrograms morphine. These findings provide further evidence that CCK mediates, at least partially, tolerance which develops to the analgesic effect of opioids and indicate the involvement of CCK pathways in the spinal cord. The results are also consistent with a mechanism in which the level of activation of compensatory, anti-opioid CCK circuitry is increased in proportion to the functional level of opioid pathways.

Analysis of Variance↗
PubMed2006

Peripheral participation of cholecystokinin in the morphine-induced peripheral antinociceptive effect in non-diabetic and diabetic rats.

The effects of cholecystokinin (CCK-8) and the CCK receptor antagonist proglumide, on antinociception induced by local peripheral (subcutaneous) injected morphine in non-diabetic (ND) and streptozotocin-induced diabetic (D) rats, were examined by means of the formalin test. Morphine induced dose-dependent antinociception both in ND and D rats. However, in D rats, antinociceptive morphine potency was about twofold less than in ND rats. Pre-treatment with CCK-8 abolished the antinociceptive effect of morphine in a dose-dependent manner in both groups of rats. Additionally, proglumide enhanced the antinociceptive effect induced by all doses of morphine tested. Both CCK-8 and proglumide had no effect on flinching behaviour when given alone to ND rats. Unlike ND rats, in D rats proglumide produced dose-dependent antinociception and CCK-8 enhanced formalin-evoked flinches, as observed during the second phase of the test. In conclusion, our data show a decrease in peripheral antinociceptive potency of morphine when diabetes was present. Additionally, peripheral CCK plays an antagonic role to the peripheral antinociceptive effect of morphine, additional to the well known CCK/morphine interaction at spinal and supraspinal level.

Animals↗
PubMed1997

The somatostatin receptor-adenylate cyclase system in rat pancreatic acinar membranes after temporary pancreaticobiliary duct ligation.

The mechanism whereby somatostatin (SS) produces beneficial effects in established pancreatitis induced by pancreaticobiliary duct ligation (PBDL) is still not clear. The aim of the work was to evaluate the possibility of a direct action of SS on pancreatic acinar cells from rats with acute pancreatitis. For this purpose, we studied the SS-receptor-adenylate cyclase system in pancreatic acinar membranes from both, control rats and rats with experimentally induced acute pancreatitis. On the other hand, it has been reported that cholecystokinin (CCK) diminishes the number of SS receptors in pancreatic acinar cells. Proglumide, a CCK receptor antagonist reduces the severity of acute pancreatitis in the rat. Therefore, we have also examined the effect of proglumide on the somatostatinergic system in controls and rats with acute pancreatitis. Fourteen hours after PBDL, the SS receptors, the capacity of the SS analogue SMS 201-995 to inhibit forskolin-stimulated adenylate cyclase activity and PTX-catalyzed [32P] ADP-ribosylation of the alpha1 subunits of Gi proteins could not be detected in pancreatic acinar membranes. One month after reopening the closed pancreaticobiliary duct (PBD), the pancreas showed regeneration of acinar cells, and the above-mentioned parameters were significantly lower than in the control group. Two months after reopening the closed PBD, all these parameters had returned to control values. The administration of proglumide (20 mg/kg i.p.), a cholecystokinin receptor antagonist, accelerated pancreatic regeneration and approached all these parameters to control values one month after reopening the closed PBD. The present study suggests that the beneficial effects of SS on established pancreatitis induced by PBDL may not be due to a direct action of the peptide on pancreatic acinar cells at least at 14 hours after PBDL. In addition, these findings suggest that in established pancreatitis the effect of proglumide on the SS receptor-adenylate cyclase system could be due to its action on pancreatic regeneration.

Adenylyl Cyclases↗
PubMed1983

The effect of a gastrin-receptor antagonist on gastric acid secretion and serum gastrin in the Zollinger-Ellison syndrome.

We studied the effect of intravenous administration of a gastrin-receptor antagonist (proglumide) on gastric acid secretion and serum gastrin in three patients with Zollinger-Ellison syndrome. Proglumide administered as a bolus injection (50 mg/kg) or as an infusion (50 mg/kg hour and 100 mg/kg hour) or as a combination of bolus injection and infusion (50 mg/kg I.V. followed by 50 mg/kg hour) inhibited gastric acid secretion by 13-62%. Cimetidine (2 mg/kg I.V. followed by 2 mg/kg hour) inhibited gastric acid secretion by 83-86%. Neither proglumide nor cimetidine significantly influenced serum gastrin concentrations. We conclude that proglumide is a relatively weak inhibitor of gastric acid secretion in patients with the Zollinger-Ellison syndrome.

Adult↗
PubMed1988

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

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

Animals↗
PubMed2005

Selective CCK-A but not CCK-B receptor antagonists inhibit HT-29 cell proliferation: synergism with pharmacological levels of melatonin.

Some data suggest that cholecystokinin (CCK) receptor agonists stimulate the growth of colon cancer. Melatonin, an endogenous indoleamine with strong antioxidant properties, displays antiproliferative and proapoptotic properties both in vivo or in vitro in several types of tumors. We used HT-29 human colon cancer cells, expressing CCK receptors, to test the antiproliferative effects of several antagonists of CCK-A and/or CCK-B and their possible synergism with melatonin. HT-29 cells were cultured in RPMI 1640 medium supplemented with fetal bovine serum at 37 degrees C. Cell proliferation was assessed by the incorporation of [3H]-thymidine into DNA. Annexin V-FITC plus propidium iodine were used for flow cytometry apoptosis/necrosis evaluation. The following drugs were tested: gastrin (CCK-B agonist); CCK-8s (CCK-A agonist); proglumide (CCK-A plus CCK-B antagonist); lorglumide (CCK-A antagonist); PD 135,158 (CCK-B antagonist and weak CCK-A agonist); devazepide or L 364,718 (CCK-A antagonist); L 365,260 (CCK-B antagonist), and melatonin. The results shown a lack of effects of gastrin on HT-29 cell proliferation, whereas CCK-8s induced proliferation at high doses. The order of the antiproliferative effect of the other drugs was devazepide > lorglumide > proglumide. These drugs produce cell death mainly inducing apoptosis. Melatonin showed strong antiproliferative effect at millimolar concentrations, and it induced apoptotic cell death. Melatonin generally enhanced the antiproliferative effects of devazepide, lorglumide and proglumide and increased the proglumide-induced apoptosis. These results suggest that melatonin and CCK-A antagonists are useful for controlling human colon cancer cell growth in culture and in combined therapy significantly increases their efficiency.

Antineoplastic Agents↗
PubMed1989

Effects of three different cholecystokinin receptor antagonists on basal and stimulated insulin and glucagon secretion in mice.

Cholecystokinin (CCK) receptor antagonists may be valuable tools for investigating the physiological role of CCK in islet function. In this study, the effects of the three different CCK receptor antagonists, proglumide, CR 1409 and L-364,718, on basal and stimulated insulin and glucagon secretion were investigated in vivo in the mouse. Each of the CCK antagonists was injected intravenously, either alone or together with one of the secretagogues CCK-8 (5.3 nmol kg-1), carbachol (0.16 mumol kg-1) or glucose (2.8 mmol kg-1). At a low dose level, proglumide (28 mumol kg-1) inhibited selectively CCK-8-induced insulin and glucagon secretion. However, at a higher dose level (280 mumol kg-1), proglumide inhibited also carbachol- and glucose-induced insulin secretion. Furthermore, proglumide elevated basal plasma levels of both glucagon and glucose. CR 1409 inhibited CCK-8-induced insulin secretion at a high (21 mumol kg-1) but not at a low (0.21 mumol kg-1) dose level. In contrast, CCK-8-induced glucagon secretion was not affected by CR 1409. L-364,718 (2.4 mumol kg-1) inhibited both CCK-8-induced insulin and glucagon secretion. In contrast, L-364,718 did not affect basal plasma levels of insulin, glucagon or glucose or those levels after stimulation with carbachol or glucose. We conclude that, of these three CCK antagonists, L-364,718 is the most specific CCK receptor antagonist for studies of both insulin and glucagon secretion in the mouse.

Animals↗
PubMed1988

Characterization of a new CCK antagonist, L364,718: in vitro and in vivo studies.

In this study we examined a novel, orally effective, nonpeptidal cholecystokinin (CCK) antagonist, 3S(-)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl) -1H-indole-2-carboxamide (L364,718) on CCK-induced amylase release. We used isolated rat pancreatic acini and incubated them with CCK-8 with or without various CCK receptor antagonists. L364,718 (3-100 nM), proglumide (1-10 mM), and the proglumide derivative CR1409 (1-30 microM) each caused a progressive rightward shift in the CCK-8 dose-response curve without a change in maximal amylase secretion. Plotting the data according to the method of Schild indicated competitive inhibition. The Kis for L364,718, CR1409, and proglumide were 0.25 nM, 0.15 microM, and 0.5 mM, respectively. Thus L364,718 was 600-fold more potent than CR1409 and 2,000,000-fold more potent than proglumide in inhibiting CCK-8-induced amylase release. Inhibition of 125I-Bolton-Hunter-CCK-8 binding to acini by these receptor antagonists had a similar rank potency. L364,718 was tested against other pancreatic exocrine secretagogues and was effective against agonists that only act through the CCK receptor. In rats, diversion of pancreatic juice from the duodenum stimulated pancreatic amylase output and elevated plasma CCK levels. The stimulated amylase secretion was blocked by intravenous administration of L364,718. Furthermore, extracted plasma CCK from rats with diversion of pancreatic juice from the duodenum stimulated amylase release from pancreatic acini, and this stimulation was blocked by addition of L364,718.(ABSTRACT TRUNCATED AT 250 WORDS)

Amylases↗
PubMed1985

Endogenous cholecystokinin and intestinal satiety.

The role of endogenous cholecystokinin (CCK) as a mediator of intestinal satiety is examined. We used rats equipped with a chronic gastric fistula and an indwelling duodenal catheter to assess the effects of direct duodenal stimulation on sham feeding. To evaluate the contribution of endogenous CCK to intestinal satiety we used a specific competitive antagonist of the satiety action of CCK, proglumide. Intraduodenal infusion of 11 or 5 ml liquid diet suppressed sham feeding. Administration of proglumide caused a partial reversal of the suppression of feeding produced by the 11-ml, but not the 5-ml, intraduodenal infusion. Administration of proglumide alone did not influence sham feeding but completely abolished the suppression of sham feeding induced by a maximal dose of exogenous CCK. These results indicate that CCK contributes to intestinal satiety under specific test conditions only. Moreover, since that component of suppression reversed by proglumide was small in comparison with the overall inhibition of eating, these results indicate that factors other than CCK are important in intestinal satiety.

Analysis of Variance↗
PubMed1989

[Inhibitory effect of CR 1409 (cholecystokinin antagonist) on pancreatic exocrine secretion in rats].

New cholecystokinin (CCK) receptor antagonist, CR 1409 (lorglumide), was evaluated for anti-CCK activity on pancreatic exocrine secretion in anesthetized rats in vivo, compared with proglumide. Both CR 1409 in a dose range of 0.04-25 mg/kg-hr and proglumide in a dose range of 30-600 mg/kg-hr given intravenously, showed significant inhibitory effect on pancreatic secretion in terms of juice volume and amylase output stimulated by intravenous CCK-8 (0.06 micrograms/kg-hr), in a dose-related manner. CR 1409 is about 1000 times more potent than proglumide, based on ED 50. Furthermore, intravenous administration of either CR 1409 (5 mg/kg-hr) or proglumide (600 mg/kg-hr) resulted in significant suppression on pancreatic secretion stimulated by intraduodenal casein in a dose of 400 mg/hr. Thus, very potent CCK receptor antagonist, CR 1409, inhibited pancreatic exocrine secretion stimulated by not only exogenous CCK, but also intraduodenal casein in rats.

Amylases↗