devazepide and camostat

It has been shown in the rat that endogenous cholecystokinin (CCK), released in response to the non-nutrient trypsin inhibitor camostat, reduces food intake at meals and increases Fos-like immunoreactivity (Fos-LI; a marker for neuronal activation) in the dorsal vagal complex (DVC) of the hindbrain but not the myenteric plexus of the duodenum and jejunum. Experiment 1: We examined Fos-LI in the myenteric and the submucosal plexuses of the gut in response to orogastric gavage of camostat in rats. As we reported previously, camostat failed to increase Fos-LI in the myenteric plexus. We show here that camostat increased Fos-LI in the submucosal plexus of the duodenum and jejunum. Camostat also increased Fos-LI in the DVC. Experiment 2: Pretreatment with devazepide, a specific CCK(1) receptor antagonist abolished camostat-induced Fos-LI in the submucosal plexus and the DVC. Experiment 3: Bilateral subdiaphragmatic vagotomy reduced camostat-induced Fos-LI in the submucosal plexus approximately 40% and abolished it in the DVC.. Activation of the submucosal plexus by cholecystokinin at the CCK(1) receptor accompanies stimulation of the dorsal vagal complex of the hindbrain and inhibition of food intake. Unlike the submucosal plexus, activation of the myenteric plexus is not necessary for cholecystokinin's influence on the dorsal vagal complex and food intake. The lack of activation in the myenteric plexus after camostat stimulation, in contrast to nutrient releasers of CCK such as oleate, suggests that intestinal stimulants can either release different amounts of CCK or cause release of CCK from I cells with different molecular forms of CCK. This would suggest that CCK-8 is released by camostat and is not able to travel to the myenteric plexus while a more stable form of CCK such as CCK-58 can travel to this site that is further away from the I cell.

Topics: Animals; Cholecystokinin; Devazepide; Eating; Esters; Gabexate; Gastrointestinal Tract; Guanidines; Hormone Antagonists; Models, Biological; Myenteric Plexus; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Cholecystokinin; Solitary Nucleus; Submucous Plexus; Vagus Nerve

The effect of camostate, a potent releaser of endogenous cholecystokinin (CCK), and of caerulein, an amphibian peptide mimicking the biological actions of CCK, as well as of selective CCK receptor antagonists on gastric emptying of liquids was studied in the rat. Oral administration of camostate (200 mg/kg with the liquid test meal preceded by the same dose 10 min before the meal) significantly delayed gastric emptying of saline, an effect which was completely blocked by previous administration of the CCKA receptor antagonist, devazepide, at a dose (1 mg/kg i.v.) unable to modify the emptying rate when administered alone. Caerulein (0.03-30 nmol/kg i.v.) also delayed the emptying rate in a dose-dependent manner, with an ID50 of 3.94 nmol/kg. The effect of the peptide was also inhibited by devazepide. The CCKB receptor antagonist, L365,260 (3R-(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1, 4-benzodiazepine-3-yl)-N'-(3-methylphenyl)-urea; 3 mg/kg i.v.), was completely unable to modify the CCK (both endogenous and exogenous)-induced delay in gastric emptying. Repeated (7 days) camostate administration did not modify the gastric motor response to endogenous CCK, thus, suggesting that adaptation did not take place. These results demonstrate that endogenous and exogenous CCK delays gastric emptying of liquids through stimulation of CCKA receptors and suggest that adaptation of the gastric motor response to CCK does not occur.

Topics: Analysis of Variance; Animals; Benzodiazepinones; Ceruletide; Devazepide; Dose-Response Relationship, Drug; Esters; Gabexate; Gastric Emptying; Gastrointestinal Agents; Guanidines; Hormone Antagonists; Male; Phenylurea Compounds; Protease Inhibitors; Rats; Rats, Sprague-Dawley; Receptors, Cholecystokinin

Our results suggest that the cholecystokinin (CCK) receptor antagonist L-364,718 has a protective effect on taurocholate-induced pancreatitis, and thus, it is inferred that CCK may have a significant pathophysiological role in the early phase of pancreatitis.. Conflicting results have been obtained from studies designed to determine the role of CCK in the initial stages of pancreatitis.. We evaluated the protective effect of the CCK receptor antagonist L-364,718 (devazepide) and of the trypsin inhibitor camostat, on taurocholate-induced pancreatitis in rats. L-364,718 (1 mg/kg) or camostat (200 mg/kg) was administered intragastrically 30 min before the induction of pancreatitis.. Infusion of sodium taurocholate (50 mg/kg) into the pancreaticobiliary duct caused severe pancreatitis with marked hyperamylasemia and reduction of tissue enzyme content at 12 h postinfusion. Pretreatment with L-364,718, but not with camostat, caused significant improvement in signs of experimental pancreatitis based on tissue enzyme content and morphology. Compared with untreated pancreatitis, there was relatively well-preserved lobular architecture, less edema, less infiltration of inflammatory cells, and more zymogen granules after L-364,718 pretreatment. Moreover, the reduction of enzyme content owing to pancreatitis was ameliorated by L-364,718 pretreatment.

Topics: Amylases; Animals; Benzodiazepinones; Cholagogues and Choleretics; Devazepide; Esters; Gabexate; Guanidines; Histocytochemistry; Hormone Antagonists; Male; Pancreas; Pancreatitis; Rats; Rats, Sprague-Dawley; Receptors, Cholecystokinin; Sincalide; Taurocholic Acid; Trypsin Inhibitors

This study examined the effects of endogenous cholecystokinin (CCK) released by bombesin and FOY-305 (a synthetic inhibitor of trypsin on pancreatic regeneration in rats).. Trophic gut hormones (CCK and bombesin) stimulate the growth of the normal rat pancreas. However, the influence of endogenous gut hormones on pancreatic regeneration is unclear.. Male Fisher rats (n = 6 to 8 per group) were fed a protein-free diet and given ethionine (700 mg/kg intraperitoneally daily) for 8 to 9 days to induce degeneration of the pancreas. Regeneration was stimulated by giving the rats a regular chow diet. The effects of bombesin (10 micrograms/kg three times a day for 7 days) or FOY-305 (200 mg/kg daily for 8 days) on the process of regeneration were examined.. At the end of the degeneration phase, there was near-total destruction of pancreatic acinar cells. Both bombesin and FOY-305 stimulated pancreatic regeneration. Growth measurements (weight and total content of DNA and protein) were significantly increased (p < 0.05) in the bombesin- and FOY-305-treated rats compared with controls. Histologic examination revealed widespread repopulation of the pancreas with acinar cells in the bombesin- and FOY-305-treated groups. The stimulating effects of both bombesin and FOY-305 on pancreatic regeneration were blocked completely by the CCK-receptor antagonist L-364,718. Growth measurements were not significantly increased in the groups of control rats or rats given L-364,718 alone.. These results show that bombesin and FOY-305 significantly stimulated pancreatic regeneration. Because the stimulating effects of bombesin and FOY-305 on regeneration were blocked by the specific CCK-receptor antagonist L-364,718, it was concluded that this effect was mediated by endogenous CCK.

Topics: Animals; Benzodiazepinones; Bombesin; Cholecystokinin; Devazepide; Esters; Gabexate; Guanidines; Male; Pancreas; Rats; Rats, Inbred F344; Regeneration; Time Factors; Trypsin Inhibitors

Pancreatic secretion in rats is regulated by feedback inhibition of cholecystokinin (CCK) release by proteases in the gut lumen, but little is known about the role of gastric acid in this regulation. This study, carried out on conscious rats with large gastric fistulas (GF) and pancreatic fistulas, shows that diversion of pancreatic juice results in the progressive stimulation of pancreatic secretion only in rats with the GF closed. When the GF was kept open, the diversion resulted in only small increment in pancreatic secretion and this was accompanied by progressive increase in gastric acid outputs. Similar amounts of HCl instilled into the duodenum in rats with the GF open fully reproduced the increase in pancreatic secretion observed after the diversion of pancreatic juice. Pretreatment with omeprazole (15 mumol/kg) to suppress gastric acid secretion or with L-364,718 (5 mumol/kg) to antagonize CCK receptors in the diverted state, resulted in the decline in pancreatic secretion similar to that observed after opening the GF. CCK given s.c. (20-320 pmol/kg) failed to cause any significant rise in the post-diversion pancreatic secretion in rats with the GF closed, but stimulated this secretion dose-dependently when the GF was open. Camostate (6-200 mg/kg) in rats with pancreatic juice returned to the duodenum caused dose-dependent increase in pancreatic secretion, but after opening the GF or after omeprazole this increase was reduced by about 75%. This study provides evidence that gastric acid plays a crucial role in the pancreatic response to diversion of pancreatic juice or inhibition of luminal proteases, and that factors that eliminate gastric acid secretion reduce this response.

Topics: Animals; Benzodiazepinones; Cholecystokinin; Devazepide; Esters; Feedback; Gabexate; Gastric Acid; Gastric Fistula; Guanidines; Male; Omeprazole; Pancreas; Pancreatic Fistula; Protease Inhibitors; Rats; Rats, Wistar

We investigated a hormonal mechanism in a trypsin inhibitor-induced pancreatic hypersecretion in rats. Intraduodenal administration of a synthetic trypsin inhibitor, camostat, resulted in significant increases in plasma concentration of both secretin and cholecystokinin in a dose-related manner that paralleled a significant increase in exocrine pancreatic secretion. To eliminate the effect of circulating secretin in rats, a rabbit antisecretin serum was given IV that resulted in a 77% reduction in bicarbonate secretion stimulated by intraduodenal camostat. A cholecystokinin receptor antagonist, MK-329, also inhibited significantly the camostat-induced increase in pancreatic secretion; volume and bicarbonate output were reduced by 35% each and amylase output by 73%. The combined administration of antisecretin serum and MK-329 completely abolished the pancreatic exocrine secretion stimulated by camostat. These observations indicate that the camostat-stimulated pancreatic exocrine secretion is mediated by the increased release of both secretin and cholecystokinin in rats.

Topics: Analysis of Variance; Animals; Benzodiazepinones; Cholecystokinin; Devazepide; Dose-Response Relationship, Drug; Esters; Gabexate; Guanidines; Immune Sera; Least-Squares Analysis; Male; Pancreas; Rabbits; Rats; Rats, Inbred Strains; Secretin; Trypsin Inhibitors

1. The role of endogenous CCK in the development of digestive enzyme activities in small intestine and pancreas was investigated in suckling rats. Synthetic protease inhibitor (camostat 100 micrograms/g bwt) was orally administered twice daily for 5 days from 11 days of age. 2. Pancreatic hypertrophy and hyperplasia, and alteration of pancreatic enzyme composition, especially decreases in amylase activity and increases in trypsin and chymotrypsin activities were produced by camostat treatment. These changes were completely suppressed by simultaneous administration of the potent CCK receptor antagonist L-364,718 (1 microgram/g bwt). 3. With camostat treatment, intestinal lactase activity decreased to 41%, while maltase and sucrase activities increased 3 and 2.5 times respectively. These changes in enzyme activities were not affected by the application of L-364,718. 4. The mucosal disaccharidase and pancreatic enzyme activities could not be modified by chronic subcutaneous injection of camostat. The precocious induction of maltase and sucrase activities by camostat treatment was also observed in the adrenalectomized pups. 5. These results indicate that pancreatic growth accompanied by alteration of digestive enzyme composition in the suckling rats is regulated by endogenous CCK, but the precocious induction of disaccharidase activities is not mediated by endogenous CCK released by camostat treatment.

Topics: Administration, Oral; Adrenalectomy; Animals; Animals, Newborn; Benzodiazepinones; Cholecystokinin; Devazepide; Digestion; Esters; Gabexate; Guanidines; Injections, Subcutaneous; Intestine, Small; Pancreas; Protease Inhibitors; Rats; Rats, Inbred Strains; Receptors, Cholecystokinin

Previous studies demonstrated that pancreatic enzyme secretion in rats is stimulated by the diversion of pancreatic juice from the duodenum or by the inhibition of pancreatic proteinases in the intestinal lumen but little attention has been paid to the role of gastric secretion in this stimulation. This study, carried out on conscious rats with large gastric (GF) and pancreatic fistulas, confirms that diversion of pancreatic juice in rats with the GF closed results in the progressive stimulation of pancreatic secretion reaching the maximum similar to that induced by exogenous CCK. When the GF was kept open, the diversion resulted in only small increment in pancreatic secretion and this was accompanied by progressive increase in gastric acid outputs. Similar amounts of HCl (25-400 mumol/h) instilled intraduodenally (i.d.) in rats with the GF open fully reproduced the increase in pancreatic secretion observed after the diversion of pancreatic juice and this effect was completely abolished by the pretreatment with L-364,718, a specific CCK receptor antagonist. Pretreatment with omeprazole to suppress completely gastric acid secretion in the diverted state resulted in a decline in pancreatic secretion similar to that observed after opening the GF. Camostate given in graded doses (6-200 mg/kg) either i.d. or s.c. in rats with pancreatic juice returned to the duodenum caused a dose-dependent increase in pancreatic secretion, but after opening the GF or after omeprazole this increase was reduced by about 50% while after L-364,718 it was abolished. This study provides evidence that gastric secretion plays an important role in the pancreatic response to diversion of pancreatic juice or inhibition of luminal proteinases (but not to feeding) and the elimination of gastric acid reduces this response.

Topics: Animals; Benzodiazepinones; Devazepide; Duodenum; Eating; Esters; Fistula; Gabexate; Gastric Juice; Guanidines; Hydrochloric Acid; Male; Omeprazole; Pancreas; Pancreatic Juice; Protease Inhibitors; Rats; Rats, Inbred Strains; Receptors, Cholecystokinin

This study was an investigation of the role of cholecystokinin (CCK) in the stimulatory action of cholestyramine on rat exocrine pancreas. Postprandial CCK release was significantly enhanced by acute administration of cholestyramine (12.7 +/- 1.8 vs 3.7 +/- 0.5 pmol/L in controls). Over four weeks, rats were fed either regular diet or diet containing 6% cholestyramine, and were treated with the specific CCK receptor antagonist L-364,718 (2 x 0.5 mg/kg body weight/day s.c.) or DMSO (vehicle for the antagonist). Cholestyramine significantly increased pancreatic weight and trypsin and chymotrypsin contents. L-364,718 abolished these effects. Concomitant administration of antagonist and cholestyramine elevated amylase content, compared to controls. CCK levels in fasted animals did not differ between the four groups. The effect of the same dose of L-364,718 on pancreatic enzyme depletion, induced by the protease inhibitor camostate, was studied in a control experiment. A single dose of camostate (200 mg/kg) caused a 44-68% decrease in enzyme content. L-364,718 reversed this effect for all enzymes. We conclude that CCK is the mediator of cholestyramine-induced pancreatic hypertrophy and increase in content of proteases. After long-term administration, the CCK receptor antagonist, in combination with cholestyramine revealed an agonistic effect on individual, pancreatic enzyme content.

Topics: Administration, Oral; Animals; Benzodiazepinones; Cholecystokinin; Cholestyramine Resin; Chymotrypsin; Devazepide; Dimethyl Sulfoxide; DNA; Dose-Response Relationship, Drug; Esters; Gabexate; Guanidines; Hypertrophy; Male; Organ Size; Pancreas; Rats; Rats, Inbred Strains; Receptors, Cholecystokinin; Time Factors; Trypsin; Trypsin Inhibitors

Since endogenous cholecystokinin (CCK) is released after oral administration of camostate, it has been suggested that camostate-induced pancreatic growth is mediated via circulating CCK. To test this concept, we investigated the effects of three potentially inhibitory substances on rat pancreatic hypertrophy caused by feeding of camostate over 2 weeks: (1) L-364,718, the novel specific highly potent nonpeptide CCK receptor antagonist, (2) octreotide (SMS 201-995), a potent long-lasting somatostatin analogue and (3) pancreastatin (33-49), the biologically active C-terminal fragment of the novel gastrointestinal peptide pancreastatin. Camostate feeding (200 mg/kg) once daily for 14 days induced a significant increase in pancreatic weight, total protein, trypsinogen and polyamine levels, whereas total amylase content was substantially diminished. Simultaneous oral or subcutaneous treatment with L-364,718 (0.3 mg/kg twice daily) completely suppressed all trophic effects of camostate. Octreotide (25 micrograms/kg twice daily s.c.) and pancreastatin (33-49) (10 micrograms/kg twice daily s.c.) did not change any trophic parameter. In case of octreotide it could be shown that two daily injections only partially suppressed elevated CCK levels. Pancreatic DNA and putrescine levels were slightly reduced in rats receiving the CCK antagonist alone. These results demonstrate that camostate-induced pancreatic hypertrophy in rats is caused by the release of endogenous CCK which may contribute to the maintenance of normal pancreatic DNA and putrescine concentrations.

Topics: Animals; Benzodiazepinones; Cholecystokinin; Chromogranin A; Devazepide; Esters; Gabexate; Guanidines; Hypertrophy; Male; Octreotide; Pancreas; Pancreatic Hormones; Protease Inhibitors; Rats; Rats, Inbred Strains

1. Graded doses of bombesin infused I.V. into conscious rats with chronic pancreatic fistulae induced a dose-dependent stimulation of protein secretion, similar to that obtained with caerulein. This stimulation does not appear to be mediated by cholecystokinin (CCK) receptors because peptidergic (CR-1409) and non-peptidergic (L-364718) CCK antagonists failed to affect protein secretion at a dose range which caused almost complete suppression of caerulein-induced pancreatic secretion. 2. Studies in vitro on isolated rat pancreatic acini revealed that caerulein, pentagastrin and bombesin all showed the same efficacy in their ability to stimulate amylase release. In contrast, CCK antagonists competitively inhibited amylase release induced by caerulein and pentagastrin but not by bombesin or urecholine, indicating that the latter two agents act directly on acinar cells via receptors which are separate from those involved in stimulation induced by caerulein and pentagastrin. 3. DNA synthesis, measured by the incorporation of [3H]thymidine into DNA, was significantly stimulated by caerulein, soybean trypsin inhibitor (FOY 305), pentagastrin and by bombesin in a dose-dependent manner. CCK receptor antagonists prevented stimulation of DNA synthesis induced by caerulein, FOY 305 and pentagastrin but not by bombesin. 4. This study indicates that bombesin strongly stimulates pancreatic enzyme secretion, with an efficacy similar to that of caerulein, and also exerts a potent growth-promoting action on the pancreas, both effects appearing to be mediated by mechanisms independent of the CCK receptors.

Topics: Animals; Benzodiazepinones; Bombesin; Ceruletide; Cholecystokinin; Devazepide; DNA; Esters; Gabexate; Glutamine; Guanidines; Pancreas; Pentagastrin; Proglumide; Protease Inhibitors; Proteins; Rats; Receptors, Cholecystokinin

Cholecystokinin (CCK) is a potent inhibitor of gastric emptying. We have examined the effects of a novel potent peripheral CCK receptor antagonist (L364,718) on the action of endogenous and exogenous CCK octapeptide (CCK-8) on gastric emptying in the rat. In conscious gastric fistula rats, the recovery of liquid test meals of 3.0 ml (containing phenol red as a dilution marker) was determined over periods up to 8 min. Compared with saline, gastric emptying of solutions of peptone (4.5%), 50 mM HCl, and hyperosmolal saline was significantly delayed. The emptying of saline was also delayed by intravenous infusion of CCK-8 (400 pmol.kg-1.h-1). The CCK antagonist L364,718 reversed the effect of peptone in a dose-dependent manner and inhibited the response to exogenous CCK, but the emptying of physiological saline, 50 mM HCl, or hyperosmolal saline remained unchanged. A protease inhibitor (FOY-305) that is thought to release endogenous CCK by inhibiting negative feedback control by luminal proteases also delayed emptying, and this response was inhibited by L364,718. We conclude that CCK has a physiological role in the mediation of the effect of proteins on gastric emptying in the rat.

Topics: Animals; Benzodiazepinones; Cholecystokinin; Devazepide; Esters; Gabexate; Gastric Emptying; Guanidines; Male; Peptide Hydrolases; Peptones; Rats; Rats, Inbred Strains; Sincalide

Chronic feeding of rats with camostate results in pancreatic hypertrophy or hyperplasia, or both. Previous studies suggest that this effect of camostate occurs via an increase in endogenous cholecystokinin due to an enteral feedback mechanism involving the inhibition of trypsin in the duodenum. Studies employing proglumide, a weak and relatively nonspecific cholecystokinin antagonist, have failed to fully abolish camostate-induced pancreas growth. We examined the effects of L-364,718, a new and highly potent cholecystokinin receptor antagonist, on camostate-induced pancreas growth in rats. The pancreas weights and the concentrations of ribonucleic acid, protein, and chymotrypsinogen in the pancreas of rats treated with camostate alone were significantly elevated over those of controls. These effects of camostate were completely abolished in rats treated with camostate + L-364,718. The pancreas weights and the concentrations of deoxyribonucleic acid and ribonucleic acid in the pancreas of rats treated with L-364,718 alone were significantly lower than values in control rats. These data indicate that camostate-induced pancreas growth in rats appears to be dependent on the actions of endogenous cholecystokinin and that cholecystokinin may play a role in the maintenance of pancreatic growth in normal rats.

Topics: Animals; Benzodiazepinones; Cholecystokinin; Devazepide; Esters; Gabexate; Guanidines; Hypertrophy; Male; Organ Size; Pancreas; Protease Inhibitors; Rats; Rats, Inbred Strains