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PubMed2004

Expression of cannabinoid CB1 receptors by vagal afferent neurons is inhibited by cholecystokinin.

Both inhibitory (satiety) and stimulatory (orexigenic) factors from the gastrointestinal tract regulate food intake. In the case of the satiety hormone cholecystokinin (CCK), these effects are mediated via vagal afferent neurons. We now report that vagal afferent neurons expressing the CCK-1 receptor also express cannabinoid CB1 receptors. Retrograde tracing established that these neurons project to the stomach and duodenum. The expression of CB1 receptors determined by RT-PCR, immunohistochemistry and in situ hybridization in rat nodose ganglia was increased by withdrawal of food for > or =12 hr. After refeeding of fasted rats there was a rapid loss of CB1 receptor expression identified by immunohistochemistry and in situ hybridization. These effects were blocked by administration of the CCK-1 receptor antagonist lorglumide and mimicked by administration of CCK to fasted rats. Because CCK is a satiety factor that acts via the vagus nerve and CB1 agonists stimulate food intake, the data suggest a new mechanism modulating the effect on food intake of satiety signals from the gastrointestinal tract.

Animals↗
PubMed1997

Plasma cortisol levels in captive wild felines after chemical restraint.

Eight Panthera onca (Po), 13 Felis concolor (Fc), 7 Felis yagouaroundi (Fy), 7 Felis tigrina (Ft) and 5 Felis pardalis (Fp) specimens from São Paulo State zoos were used. All animals were restrained with darts containing 10 mg/kg ketamine and 1 mg/kg xylazine. Venous blood samples were collected as soon as possible (within 15-20 min) and serum was frozen until the time for cortisol quantification. Cortisol was determined using a solid phase radioimmunoassay with an intra-assay coefficient of 8.51%. Data were analyzed statistically by the Kruskal-Wallis test, followed by Dunn's multiple comparisons test, and the one-sample t-test, with the level of significance set at P < 0.05. Data are reported as means +/- SEM. Cortisol levels differed among the captive felines: Po = 166 +/- 33a, Fc = 670 +/- 118b, Fy = 480 +/- 83b, Ft = 237 +/- 42ab, Fp = 97 +/- 12a nmol/l (values followed by different superscript letters were significantly different (P < 0.001)). Since most of the veterinary procedures on these species involve chemical restraint, these results show the necessity of preventive measures in order to minimize the effect of restraint stress on more susceptible species.

Animals↗
PubMed1988

Inhibitory effect of CR-1409, a competitive inhibitor of cholecystokinin, on pancreatic exocrine secretion in the conscious rat.

The inhibitory effect of CR-1409, a new glutaramic acid derivative and a competitive inhibitor for cholecystokinin (CCK), on the basal and CCK-stimulated pancreatic secretion was examined in the conscious rat in vivo. Rats were prepared with cannulae draining pure bile and pancreatic juice separately and with a duodenal cannula and right and left jugular vein cannulae. Plasma CCK level increased to 3.65 +/- 0.79 and 19.9 +/- 4.47 pM (mean +/- S.E.) by a 2-hr infusion of 100 and 300 pmole/kg/hr of CCK-octapeptide (CCK-8), respectively. Simultaneous infusion of 170 nmole/kg/hr of CR-1409 completely abolished pancreatic responses to 100 pmole/kg/hr of CCK-8. Infusion of CR-1409 at rate of 57 nmole/kg/hr slightly but significantly inhibited CCK-8 (100 pmole/kg/hr)-stimulated secretion. Pancreatic responses to 300 pmole/kg/hr of CCK-8 were partially inhibited but not completely abolished by the 170 nmole/kg/hr of CR-1409. Neither the basal pancreatic secretion nor the bile secretion was affected by CR-1409. We conclude that CR-1409 inhibited CCK-stimulated pancreatic secretion in vivo.

Animals↗
PubMed2004

Long-term bile diversion enhances basal and duodenal oleate-stimulated pancreatic exocrine secretion in dogs.

There have been no previous reports whether long-term bile diversion enhances pancreatic exocrine secretion. The aim of this study was to elucidate the effect of long-term bile diversion on pancreatic exocrine secretion. Four mongrel dogs were prepared for chronic gastric and pancreatic fistulas and received intraduodenal sodium oleate infusion (controls). These dogs, then underwent diversion of bile from the intestines by ligating the common bile duct and interposing a segment of jejunum between the gallbladder and the urinary bladder (total biliary diversion [TBD]). After three weeks, the dogs received an identical sodium oleate infusion. TBD augmented basal pancreatic exocrine secretion compared with controls (4.4-fold increase in basal flow volume; 9.0-fold increase in bicarbonate output; and 3.3-fold increase in protein output). Likewise, TBD augmented oleate-stimulated exocrine secretion (2.0-fold increase in cumulative flow volume; 2.6-fold increase in bicarbonate output; and 1.4-fold increase in protein output). TBD also augmented basal and oleate-stimulated plasma cholecystokinin levels. Administration of a Cholecystokinin-A receptor antagonist (loxiglumide) after TBD reduced the flow volume and bicarbonate output to the control levels, and the protein output to less than a half of the control level. Long-term bile diversion enhances basal and oleate-stimulated pancreatic exocrine secretion, at least partly via increased cholecystokinin secretion.

Animals↗
PubMed1989

The inhibitory effect of CR-1409 on amylase secretion and intracellular Ca2+ mobilization in rat pancreatic acini in vitro.

The inhibitory effects of CR-1409, a new glutaramic acid derivative developed as a cholecystokinin (CCK) receptor antagonist, on caerulein-stimulated amylase secretion and on intracellular Ca2+ ([Ca2+]i) mobilization were studied in isolated rat pancreatic acini. Pancreatic acini were prepared by collagenase digestion method and loaded with 1 microM fura-2/AM for measurement of the intracellular free Ca2+ concentration. Amylase release was examined by a perifusion method. Stimulation with 10(-10) M caerulein, 10(-5) M carbachol, or 10(-8) M gastrin-releasing peptide (GRP) led to biphasic amylase release and increase in [Ca2+]i. CR-1409 at 1 and 5 microM inhibited, by 50 and 84%, respectively, the amylase secretion and increase in [Ca2+]i induced by 10(-10) M caerulein, and 25 microM CR-1409 completely inhibited both amylase secretion and increase in [Ca2+]i induced by caerulein. However, 25 microM CR-1409 did not inhibit unstimulated secretion of amylase or the secretions induced by carbachol and GRP, which are also mediated by changes in intracellular Ca2+. We conclude that CR-1409 acts as a specific inhibitor of the CCK receptor in the pancreas, and is useful in studies on the involvement of the release and action of CCK in vitro.

Amylases↗
PubMed1990

Necessity of hyperglycemia for effects of endogenous cholecystokinin on insulin and pancreatic exocrine secretion in conscious rats.

The effects of endogenous cholecystokinin (CCK) on insulin and pancreatic exocrine secretion were examined in conscious rats. Rats with bile and pancreatic fistulae, one duodenal cannula, and two jugular vein cannulae were divided into four groups, with and without glucose infusion (0.2 g/(ml.h)), and with bile and pancreatic juice (BPJ) diversion and return. Without glucose infusion, BPJ diversion did not have any significant effect on the plasma level of insulin or glucose; but with glucose infusion, it caused a significant increase in plasma insulin concentration 1 h after the diversion. The plasma glucose concentrations in the groups with BPJ diversion and return were not significantly different, and the response of pancreatic exocrine secretion to BPJ diversion was suppressed slightly, but not significantly, by glucose infusion. The plasma CCK concentration was increased significantly by BPJ diversion, but not affected by glucose infusion. These results indicate that, as observed in in vitro experiments with exogenous CCK, in conscious rats, endogenous CCK stimulates both exocrine and endocrine secretion of the pancreas, and that hyperglycemia is necessary for these effects to become apparent.

Animals↗
PubMed1989

Age-dependent stimulation of neonatal insulin release and inositol phosphate accumulation by CCK-8 and carbachol.

Development of a robust insulin secretory response to glucose occurs during the early neonatal period. To determine if neuroendocrine agents play a role during this time, we studied the effects of selected peptides and neurotransmitters on insulin release and polyphosphoinositide metabolism in islets isolated from 1- and 3-day neonatal rats. Vasoactive intestinal peptide had no effect on glucose-stimulated release in either islet population. In contrast, sulfated cholecystokinin octapeptide (CCK-8) significantly enhanced glucose-induced insulin release in both islet groups. One-day islets were stimulated only by a concentration of 300 nM, whereas 3-day islets were responsive at 3 nM. Similar to CCK-8, there were clear differences in responses to carbachol between 1- and 3-day islets. One-day islets required a concentration of 200 microM for insulin release to be significantly greater than with glucose alone; 3-day islet insulin release was significant at 2 microM carbachol. Both agonists stimulated inositol phosphate accumulation in 3-day islets, but only CCK-8 caused a significant increase over glucose-induced levels in 1-day islets. These results indicate that islet responsiveness to CCK-8 and carbachol develops in parallel during the early neonatal period. This development may be linked to the maturation of a critical step of stimulus-secretion coupling through which these agents act.

Age Factors↗
PubMed1985

Future treatment of peptic ulcers.

Drugs which abolish acid secretion and promise improved ulcer healing rates have produced dysplasia and tumours in experimental animals given large doses for long periods. Solutions to this problem will be based on better understanding of the mechanisms involved. Healing rates might be improved by combining inhibitors of acid secretion with ulcer protectors which, unlike currently available agents, are designed to work well in the presence of diminished acid secretion. Drugs which increase mucosal defence might best be used to prevent ulceration, so the need is to develop agents which are safe for long term use.

Animals↗
PubMed1990

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.

Adult↗
PubMed1993

Cholecystokinin in the regulation of gastric acid and endocrine pancreatic secretion in humans.

In this study, a selective antagonist of cholecystokinin (CCK)-A receptors, loxiglumide, was used to evaluate the role of CCK in the control of the release of gastrin and pancreatic hormones (insulin, glucagon, pancreatic polypeptide (PP), and somatostatin) after stimulation with exogenous CCK and ingestion of a standard liquid mixed meal in healthy humans. Exogenous CCK-8, which induced a small but significant increase in gastric acid secretion, resulted in dose-dependent increments in plasma PP levels without significant changes in plasma levels of insulin, glucagon, or somatostatin. Pretreatment with loxiglumide resulted in a marked increase in CCK-induced gastric acid secretion and abolished the increments in plasma PP without alteration of plasma insulin, glucagon, or somatostatin levels. Ingestion of the liquid meal resulted in an immediate rise in intragastric pH from basal values of about 2 to pH6 lasting 90-120 min, and this was accompanied by significant increments in plasma gastrin, insulin, glucagon, PP, and somatostatin. Administration of loxiglumide (1200 mg orally) caused a reduction in the postprandial intragastric pH and the two- to three-fold increase in plasma gastrin. Plasma insulin and glucagon levels in tests with loxiglumide tended to increase, probably owing to accelerated gastric emptying, whereas plasma PP and somatostatin were significantly reduced. This study provides evidence that CCK exerts an inhibitory effect on gastric acid secretion and plasma gastrin release as well as a stimulatory influence on the release of PP and somatostatin via CCK-A receptors but does not influence directly insulin or glucagon secretion in man.

Adult↗
PubMed1994

Role of cholecystokinin in the control of gastric emptying and secretory response to a fatty meal in normal subjects and duodenal ulcer patients.

BACKGROUND: Exogenous cholecystokinin (CCK) is known to affect gastric motor and secretory activities, but its physiologic role in the control of gastric functions is unknown. METHODS: In this study involving 10 young healthy subjects and 10 duodenal ulcer (DU) patients, 500 ml of a standard meal without or with addition of 15% soybean oil was given, and the gastric emptying rate and the pH profile and plasma levels of gastrin, CCK, pancreatic polypeptide (PP), and somatostatin were determined in separate tests with placebo or with antagonism of type-A CCK receptors (loxiglumide, 1200 mg orally). RESULTS: In healthy controls and DU patients the emptying half-time was 44 and 34 min, respectively, and the addition of oil prolonged the emptying by about 50%. Pretreatment with loxiglumide significantly reduced fat-induced retardation of gastric emptying in both healthy controls and DU patients. A standard meal in healthy subjects resulted in an immediate rise in median gastric pH to about 6.0, and this was followed by gradual decrease within about 3 h to premeal values of about 2.0. After the meal, plasma gastrin rose by 57%, CCK by 177%, PP by 100%, and somatostatin by 39%. Addition of fat significantly attenuated and prolonged the pH decrease after the meal while reducing the increment in plasma gastrin and enhancing plasma CCK and PP levels. Loxiglumide significantly reduced the median postprandial pH (from control 4.8 to 2.5) and reversed the changes in the pH profile caused by the addition of fat. The increments in plasma gastrin and CCK were markedly augmented, whereas those of somatostatin and PP were significantly attenuated. DU patients showed lower postprandial pH (3.0) in tests with or without fat and higher increments in plasma gastrin. CCK antagonism failed to affect significantly the pH profile or the increments in plasma gastrin in DU patients. CONCLUSIONS: These results indicate that endogenous CCK released by a fatty meal delays gastric emptying and inhibits gastric acid and plasma gastrin responses in healthy subjects, but in DU patients the inhibitory effect of CCK is less pronounced, suggesting a defect in the action of this hormone on gastrin release and gastric acid secretion.

Adult↗
PubMed1995

Cholecystokinin in the control of gastric acid secretion and gastrin release in response to a meal at low and high pH in healthy subjects and duodenal ulcer patients.

OBJECTIVE: In healthy subjects a gastric meal at low pH inhibits gastric acid secretion, possibly by reducing gastrin release, whereas duodenal ulcer (DU) patients have been reported to show a lack of this low pH inhibition of gastric secretion. METHODS: The intragastric pH profiles were measured in seven healthy subjects and seven DU patients after meals of pH 6.5 and 3.0 without or with pretreatment with loxiglumide (1.2 g orally), a selective antagonist of type-A cholecystokinin (CCK) receptors. During all tests (30 min before and 30, 60, and 90 min after each meal) plasma gastrin, CCK, and somatostatin were determined by specific radioimmunoassays. RESULTS: In healthy subjects a standard meal at pH 6.5 and 3.0 resulted in median 3-h intragastric pH of 3.8 and 2.8, respectively. In DU patients under the same conditions the pH 6.5 meal resulted in median 3-h intragastric pH of 3.4, and the acidified meal in pH 2.2. After pretreatment with loxiglumide the median pH after both meals was significantly lower in healthy controls but not in DU patients. After the pH 6.5 meal, in healthy subjects the plasma gastrin rose by 57%, CCK by 177%, and somatostatin by 39%, and in DU patients by 152%, 367%, and 125%, respectively. Pretreatment with loxiglumide led to a marked increase in plasma gastrin response to the pH 6.5 meal only in healthy controls and not in DU subjects, and it was accompanied by a significant increase in plasma CCK and a decrease in plasma somatostatin. The pH 3.0 meal resulted in a significantly smaller rise in plasma gastrin and a higher increase in CCK and somatostatin in both groups; again, after treatment with loxiglumide only healthy controls and not DU patients showed significant increase in plasma gastrin level. CONCLUSIONS: Acidification of meals results in the reduction of plasma gastrin and increase in plasma CCK and somatostatin in both healthy subjects and DU patients. DU patients differ from healthy subjects by virtually unchanged plasma gastrin response to a meal after CCK antagonism with loxiglumide, suggesting a defect in both gastric acid and gastrin inhibition by CCK in these patients.

Adult↗
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↗
PubMed1989

Interactions between bile and pancreatic juice diversions on cholecystokinin release and pancreas in conscious rats.

Pancreatic exocrine secretion in the conscious rat is regulated by proteases secreted by the pancreas, and cholecystokinin (CCK) is known to be involved in its mechanism. It has also been reported that the absence of either pancreatic juice or bile in the duodenum could stimulate pancreatic secretion. Therefore, differences in CCK release responding to the exclusion of bile, pancreatic juice (PJ), or both bile and pancreatic juice (BPJ) from the intestine were examined by using a bioassay for cholecystokinin. Plasma CCK levels were increased by all three treatments compared with the basal value, the order of their effects being BPJ greater than PJ greater than bile diversion, and CCK concentrations produced by BPJ diversion were much greater than can be explained as simply summed effect of exclusions of bile and PJ. Pancreatic exocrine secretions were significantly increased by PJ and BPJ diversions, but the effect of bile diversion on the pancreas was not statistically significant. An additional infusion of CR-1409 (0.1 mg/rat), one of CCK receptor antagonists, inhibited exocrine function stimulated by BPJ diversion. We conclude (i) BPJ diversion is the strongest endogenous stimulant on CCK release; (ii) the potentiation between bile and PJ diversions is induced on CCK release; (iii) pancreatic protein secretion during BPJ diversion is mainly modulated by CCK.

Animals↗
PubMed2006

Cholecystokinin hyperresponsiveness in functional dyspepsia.

Functional dyspepsia (FD) is a common disorder of yet uncertain etiology. Dyspeptic symptoms are usually meal related and suggest an association to gastrointestinal (GI) sensorimotor dysfunction. Cholecystokinin (CCK) is an established brain-gut peptide that plays an important regulatory role in gastrointestinal function. It inhibits gastric motility and emptying via a capsaicin sensitive vagal pathway. The effects on emptying are via its action on the proximal stomach and pylorus. CCK is also involved in the regulation of food intake. It is released in the gut in response to a meal and acts via vagal afferents to induce satiety. Furthermore CCK has also been shown to be involved in the pathogenesis of panic disorder, anxiety and pain. Other neurotransmitters such as serotonin and noradrenaline may be implicated with CCK in the coordination of GI activity. In addition, intravenous administration of CCK has been observed to reproduce the symptoms in FD and this effect can be blocked both by atropine and loxiglumide (CCK-A antagonist). It is possible that an altered response to CCK may be responsible for the commonly observed gastric sensorimotor dysfunction, which may then be associated with the genesis of dyspeptic symptoms.

Atropine↗
PubMed1999

Recent advances in the chemistry of cholecystokinin receptor ligands (agonists and antagonists).

During the last few years, cholecystokinin (CCK) has emerged as an important hormone. This polypeptide has been located either in peripheral tissues such as the gastro-intestinal tract and the pancreas as well as in the central nervous system. High affinity CCK receptors are divided in two main subtypes: the CCK-A (A for (A for "alimentary") and the CCK-B (B for "brain") receptors. The latters are currently associated with the gastrin receptors. Since CCK is involved in many different biological processes such as gut function, digestive processes, control of feeding behaviour and neurotransmitter release, the therapeutical potential of cholecystokinin receptor ligands seems to be extremely broad and promising. Several families of CCK receptor ligands (peptides, peptidomimetics, peptoids or non-peptides) were prepared during the last twenty years. The main goal of these researches was to improve agonistic or antagonistic potency but also to find selective compounds for a specific CCK receptor subtype. This review presents the recent developments (since 1995) in the chemistry of CCK receptor ligands.

Animals↗