The oesophago-gastric junction functions as an anti-reflux barrier preventing increased exposure of the oesophageal mucosa to gastric contents. Failure of this anti-reflux barrier results in gastro-oesophageal reflux disease, and may lead to complications such as oesophagitis, Barrett's oesophagus and eventually oesophageal carcinoma. Recent studies have suggested that transient lower oesophageal sphincter relaxation is the main mechanism underlying gastro-oesophageal reflux. It involves a prolonged relaxation of the lower oesophageal sphincter, mediated by a vago-vagal neural pathway, synapsing in the brainstem. Several drugs, such as atropine, baclofen and loxiglumide, have been shown to reduce the rate of transient lower oesophageal sphincter relaxations and concomitantly the number of reflux episodes. These findings illustrate that transient lower oesophageal sphincter relaxations may represent a potential new target for the pharmacological treatment of gastro-oesophageal reflux disease. It is possible that the reduction in the number of transient lower oesophageal sphincter relaxations may also contribute to the beneficial effect of fundoplication and new endoscopic anti-reflux procedures. It should be emphasized, however, that other factors, such as low lower oesophageal sphincter pressure, the presence of a hiatal hernia and impaired oesophageal peristalsis, are also of great importance. Therefore, whether the targeting of transient lower oesophageal sphincter relaxations is the 'golden bullet' in anti-reflux therapy remains to be proven, as evidence of an effective control of gastro-oesophageal reflux in reflux patients is still lacking. (+info)
Role of cholecystokinin-8 in nerve growth factor and nerve growth factor mRNA expression in carrageenan-induced joint inflammation in adult rats.
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OBJECTIVES: The aim of our study was to investigate the role of cholecystokinin-8 (CCK-8), which is able to induce the synthesis of nerve growth factor (NGF), in the joint inflammation of carrageenan-injected rats. METHODS: Adult rats were injected in the ankle joint with carrageenan, with or without CCK-8 or a CCK receptor antagonist (proglumide), and tissue swelling, NGF levels and NGF mRNA expression were assessed. RESULTS: Expression of NGF and NGF mRNA increased transiently after carrageenan injection. This effect was not altered by CCK-8 injection but was inhibited by the CCK receptor antagonist. The decrease in NGF level after treatment with the antagonist was concurrent with an increase in paw swelling. CONCLUSIONS: The results demonstrate that, whereas CCK-8 has no anti-inflammatory action in carrageenan-injected animals, proglumide induces a worsening of inflammation and reduces the expression of both NGF and NGF mRNA in inflamed ankle joints. Our data point to a regulatory action of CCK-8 on NGF synthesis during acute synovitis and suggest a role for NGF in the healing phase of inflammation. (+info)
Role for the cholecystokinin-A receptor in fever: a study of a mutant rat strain and a pharmacological analysis.
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The involvement of the cholecystokinin (CCK)-A receptor in fever was studied. The polyphasic febrile responses to lipopolysaccharide (LPS; 10 microg kg-1, I.V.) were compared between wild-type Long-Evans (LE) rats and the CCK-A-receptor-deficient Otsuka LE Tokushima Fatty (OLETF) rats. The response of the wild-type rats was biphasic, which is typical for LE rats. Phases 1 and 2 of the response of the OLETF rats were similar to those of the LE rats, but the OLETF rats also developed a robust phase 3. This late enhancement of the febrile response could reflect either the absence of the A receptor per se or a secondary trait of the mutant strain. To distinguish between these possibilities, we conducted a pharmacological analysis. We studied whether the normally low phase 3 of LE rats can be enhanced by a CCK-A-receptor antagonist, sodium lorglumide (4.3 microg kg-1 min-1, 120 min, I.V.), and whether the normally high phase 3 of Wistar rats can be attenuated by a CCK-A receptor agonist, sulphated CCK-8 (up to 0.17 microg kg-1 min-1, 120 min, I.V.). The dose of sodium lorglumide used was sufficient to increase food intake (to block satiety), but it did not affect the fever response. In both febrile and afebrile rats, CCK-8 induced dose-dependent skin vasodilatation and decreased body temperature, but it failed to produce any effects specific for phase 3. We conclude that the exaggeration of phase 3 in OLETF rats reflects a secondary trait of this strain and not the lack of the CCK-A receptor per se. None of the three known phases of the febrile response of rats to LPS requires the CCK-A receptor. (+info)
Differential mechanism and site of action of CCK on the pancreatic secretion and growth in rats.
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Recent studies demonstrated that cholecystokinin (CCK) at physiological levels stimulates pancreatic enzyme secretion via a capsaicin-sensitive afferent vagal pathway. This study examined whether chemical ablation of afferent vagal fibers influences pancreatic growth and secretion in rats. Bilateral subdiaphragmatic vagal trunks were exposed, and capsaicin solution was applied. Pancreatic wet weight and pancreatic secretion and growth in response to endogenous and exogenous CCK were examined 7 days after capsaicin treatment. Perivagal application of capsaicin increased plasma CCK levels and significantly increased pancreatic wet weight compared with those in the control rats. Oral administration of CCK-1 receptor antagonist loxiglumide prevented the increase in pancreatic wet weight after capsaicin treatment. In addition, continuous intraduodenal infusion of trypsin prevented the increase in plasma CCK levels and pancreatic wet weight after capsaicin treatment. There were no significant differences in the expression levels of CCK-1 receptor mRNA and protein in the pancreas in capsaicin-treated and control rats. Intraduodenal administration of camostat or intravenous infusion of CCK-8 stimulated pancreatic secretion in control rats but not in capsaicin-treated rats. In contrast, repeated oral administrations of camostat or intraperitoneal injections of CCK-8 significantly increased pancreatic wet weight in both capsaicin-treated and control rats. Present results suggest that perivagal application of capsaicin stimulates pancreatic growth via an increase in endogenous CCK and that exogenous and endogenous CCK stimulate pancreatic growth not via vagal afferent fibers but directly in rats. (+info)
CCK-1 receptor blockade for treatment of biliary colic: a pilot study.
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BACKGROUND: Loxiglumide is a potent and selective cholecystokinin-1 (CCK-1) receptor antagonist able to inhibit gall-bladder contraction. AIM: To assess the effect of CCK-1 receptor blockade on the pain of patients with biliary colic. PATIENTS AND METHODS: Fourteen patients with biliary colic but no suspicion for acute cholecystitis, were randomly and blindly assigned to loxiglumide (50 mg i.v.) or hyoscine-N-butyl bromide (20 mg i.v.) treatment. Pain intensity was monitored by a Visual Analogue Scale. Patients with less than 80% response at 30 min, were retreated with a second injection of the same compound. RESULTS: Reduction in pain score (mean +/- S.E.M.) was faster and significantly greater in patients treated with loxiglumide (n = 7) than in controls (n = 7): 88 +/- 7% vs. 47 +/- 12% after 20 min, P < 0.05; 92 +/- 6% vs. 49 +/- 13%, after 30 min, P < 0.05. Only one of seven patients treated with loxiglumide needed a second injection at 30 min (vs. six of seven controls, P < 0.05). No adverse effect was observed after either treatment. CONCLUSIONS: Loxiglumide is highly effective in obtaining pain relief in patients with biliary colic. The analgesic effect of CCK-1 receptor blockade is superior to that of a conventional anticholinergic treatment. (+info)
Gastrin stimulates Ca2+ mobilization and clonal growth in small cell lung cancer cells.
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Gastrin has been postulated to be a physiological growth factor, but compelling in vitro evidence of this has been difficult to obtain. In the present study we investigated whether small cell lung carcinoma cell lines could provide a useful model system to study the effects of gastrin on signal transduction and cell proliferation in vitro. We found that the addition of gastrin to small cell lung cancer cells loaded with the fluorescent Ca2+ indicator fura 2-tetraacetoxymethylester causes a rapid and transient increase in the intracellular concentration of Ca2+ ([Ca2+]i) followed by homologous desensitization. The [Ca2+]i response was especially prominent in the small cell lung carcinoma cell line H510. In this cell line, gastrin I, gastrin II, cholecystokinin residues 26-33 (CCK-8), and unsulfated CCK-8 increased [Ca2+]i in a concentration-dependent fashion with half-maximum effects at 7, 2.5, 3, and 5 nM, respectively. The Ca(2+)-mobilizing effects of gastrin and CCK-8 were prevented by proglumide, benzotript, and the specific gastrin/CCKB receptor antagonist L365260. Gastrin stimulated the clonal growth of H510 cells in semisolid (agarose-containing) medium, increasing both the number and the size of the colonies. Gastrin and CCK agonists were equally effective in promoting clonal growth. The broad-spectrum neuropeptide antagonists [D-Arg1,D-Phe5,D-Trp7,9,Leu11] substance P and [Arg6,D-Trp7,9,MePhe8] substance P (6-11) markedly inhibited gastrin-stimulated Ca2+ mobilization and clonal growth. These results show that gastrin acts as a direct growth factor through gastrin/CCKB receptors and demonstrate, for the first time, that these peptides can stimulate the proliferation of cells outside the gastrointestinal tract. (+info)
Receptor strategies in pancreatitis.
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A variety of receptors on pancreatic acinar and duct cells regulate both pancreatic exocrine secretion and intracellular processes. These receptors are potential sites of action for therapeutic agents in the treatment of pancreatitis. Cholecystokinin (CCK) receptor antagonists, which may reduce the level of metabolic "stress" on acinar cells, have been shown to mitigate the severity of acute pancreatitis in a number of models. Not all studies have shown a benefit, however, and differences may exist between different structural classes of antagonists. Because increased pancreatic stimulation due to loss of feedback inhibition of CCK has been proposed to contribute to the pain of some patients with chronic pancreatitis, CCK receptor antagonists could also be of benefit in this setting. Somatostatin and its analogs diminish pancreatic secretion of water and electrolytes and have been effective in treating pancreatic fistulas and pseudocysts. These agents are also being evaluated for their ability to reduce pain in chronic pancreatitis (perhaps by reducing ductal pressure by diminishing secretory volume) and mitigating the severity of acute pancreatitis (possibly by reducing the metabolic load on acinar cells). Recently described secretin receptor antagonists may also have therapeutic value as a means of selectively inhibiting pancreatic secretion of water and electrolytes. (+info)
Monitor peptide gene expression is increased by exogenous CCK in the rat pancreas and in a rat pancreatic acinar cell line (AR4-2J).
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Monitor peptide (CCK-releasing peptide) mRNA increased on the administration of CCK in rat pancreas and the AR4-2J pancreatic cell line. Subcutaneous injection of CCK into rats at 8 h intervals increased the level of monitor peptide mRNA in the pancreas. Concomitant injection of CCK antagonist CR-1409 strongly decreased it. The monitor peptide mRNA was also increased by CCK in AR4-2J cells and was decreased by the antagonist. These findings suggest that the plasma CCK induced by prolonged intake of a high protein diet may be responsible for the adaptative increase in the monitor peptide as well as exocrine proteases in the pancreas. (+info)