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At least 685 records · Page 38Linked to original sources
PubMed1991

Studies of three non-peptide cholecystokinin antagonists (devazepide, lorglumide and loxiglumide) in human isolated alimentary muscle and guinea-pig ileum.

1. Three recently described non-peptide cholecystokinin (CCK) antagonists (devazepide, lorglumide, loxiglumide) have been studied for their antagonism of the contraction to cholecystokinin-octapeptide (CCK-OP) in human alimentary muscle and guinea-pig intestine. 2. Each antagonist caused a concentration-dependent inhibition of the contraction induced by CCK-OP, regardless of regional and species differences. 3. The potencies of each drug, estimated by use of an adaptation of the Cheng & Prusoff equation, were similar in the different regions of human alimentary tract (weighted mean apparent pKB, +/- s.e. mean: devazepide, 5.76 +/- 0.08, n = 20; lorglumide, 5.82 +/- 0.04, n = 25; loxiglumide, 5.87 +/- 0.07, n = 24). 4. In contrast, the potencies differed markedly in the guinea-pig ileum. Apparent pKB values obtained by the same method as with human tissues were, mean +/- s.e.mean: devazepide, 10.61 +/- 0.61; lorglumide, 7.43 +/- 0.20; loxiglumide, 6.67 +/- 0.12. pKB values obtained from classical competition experiments were: devazepide, 10.09 +/- 0.09; lorglumide 7.70 +/- 0.12; loxiglumide 6.08 +/- 0.22. 5. The CCK receptors in human gut muscle from different regions seem to be similar, but there appear to be species differences.

Animals↗
PubMed1992

Combined dose-ratio analysis of cholecystokinin receptor antagonists, devazepide, lorglumide and loxiglumide in the guinea-pig gall bladder.

1. Interactions between cholecystokinin octapeptide (CCK-8) and CCKA-receptor antagonists derived from benzodiazepines (devazepide) and glutamic acid (lorglumide and loxiglumide) have been examined in an improved bioassay using the guinea-pig, isolated, gall bladder preparation. 2. The presence of CCKB-receptors in the assay was provisionally-ruled out on the basis of the low potency of pentagastrin in the assay. By applying analyses of both agonism and antagonism, pentagastrin was shown to behave as a partial agonist at the CCKA-receptor. 3. Devazepide, lorglumide and loxiglumide behaved as simple competitive antagonists of CCKA-receptors and pKB values of 9.98, 7.59 and 7.07 were estimated, respectively. 4. Application of a combined dose-ratio analysis to the interactions between CCK-8 and combinations of devazepide/lorglumide and devazepide/loxiglumide indicated that these molecules behave as syntopic, competitive, antagonists at the CCKA-receptor. 5. We conclude that the guinea-pig gall bladder assay contains a homogeneous population of CCKA-receptors and offer an explanation for the differences between our results and those obtained recently by Maubach et al. (1991) which were taken as preliminary evidence for CCKA-receptor heterogeneity.

Analysis of Variance↗
PubMed1995

Characterization of the receptors and mechanisms involved in the cardiovascular actions of sCCK-8 in the pithed rat.

1. The cardiovascular actions of cholecystokinin and related peptides were investigated in the pithed rat. The receptors and the mechanisms involved in these experiments were characterized. 2. Sulphated cholecystokinin octapeptide (sCCK-8, 0.1-100 nmol kg-1, i.v.) elicited a dose-dependent bradycardia and increase in mean arterial blood pressure. Neither gastrin-17 nor pentagastrin had any effect at concentrations up to 100 nmol kg-1. 3. Both the pressor response and bradycardia elicited by sCCK-8 were reduced by the selective CCKA receptor antagonists, devazepide (0.5-50 nmol kg-1) and lorglumide (1-7 mumol kg-1). The selective CCKB receptor antagonists, CI-988 (1 mumol kg-1) and L-365,260 (15 mumol kg-1) did not inhibit the effects of sCCK-8. 4. The pressor response induced with sCCK-8 was reduced by treatment with either phentolamine (3 mumol kg-1) or guanethidine (2 mumol kg-1) and was unaffected by treatment with propranolol, atropine or hexamethonium. The pressor response also persisted following bilateral adrenalectomy. 5. The bradycardia induced with sCCK-8 was unaffected by treatment with phentolamine, propranolol, guanethidine, atropine, hexamethonium or bilateral adrenalectomy. 6. The tetrapeptide of cholecystokinin (CCK-4) elicited a dose-dependent pressor response but did not induce bradycardia. The pressor response was unaffected by devazepide (50 nmol kg-1), L-365260 (15 mumol kg-1) or phentolamine (3 mumol kg-1). 7. In the pithed rat, sCCK-8 acted via CCKA receptors to increase arterial blood pressure indirectly, at least in part, through activation of alpha-adrenoceptors. The observed bradycardia was also mediated byCCKA receptors but possibly through a direct action on the heart.

Adrenalectomy↗
PubMed1996

Pharmacological profile of TP-680, a new cholecystokininA receptor antagonist.

1. The pharmacological characteristics of a newly developed serine derivative (R)-1-[3-(3-carboxypyridine-2-yl) thio-2-(indol-2-yl)carbonylamino]propionyl-4-diphenylmethyl- piperazine (TP-680), a cholecystokinin type A (CCKA) receptor antagonist, were studied and compared with those of MK-329 and loxiglumide. 2. TP-680 showed approximately 2 and 22 times greater selectivity for peripheral CCKA receptors relative to brain CCK (CCKB) receptors than MK-329 and loxiglumide, respectively, when IC50 values for inhibition of [125I]-CCK-8 binding in isolated acini and cerebral cortex were compared. 3. TP-680 was approximately 17 times less potent than MK-329, but was 106 times more potent than loxiglumide in inhibiting 100 pM CCK-8-stimulated amylase release from rat pancreatic acini. The antagonism produced by TP-680 was specific for CCK in that the effects of other receptor secretagogues or agents bypassing receptors were not altered. 4. TP-680 caused a parallel rightward shift of the dose-response curve for CCK-8-stimulated amylase release as did MK-329 and loxiglumide. However, in contrast to MK-329 and loxiglumide, TP-680 suppressed the maximal responses of CCK-8-induced amylase release in a concentration-dependent fashion, indicating that TP-680 is an unsurmountable antagonist. 5. Repeated washing of acini after a 30 min treatment with TP-680 restored the responsiveness but not the sensitivity, causing a residual inhibition on the action of CCK-8. 6. The addition of loxiglumide prior to or together with application of TP-680 protected CCK receptors from unsurmountable and irreversible antagonism by TP-680. 7. Our results indicate that TP-680 is a potent and the most selective CCKA receptor antagonist for the pancreas reported to date.

Amylases↗
PubMed1998

Involvement of cholecystokininA receptors in transient lower esophageal sphincter relaxations triggered by gastric distension.

OBJECTIVE: Transient lower esophageal sphincter relaxations (TLESRs) are the main mechanism underlying gastroesophageal reflux. In the present study we evaluated the effect of loxiglumide, a specific cholecystokininA (CCKA)-receptor antagonist, on the occurrence of TLESRs evoked by gastric distension. METHODS: Eight healthy subjects underwent esophageal manometry using a 10-lumen sleeve assembly during placebo or loxiglumide (10 mg/kg/h) in a randomized double-blind order. Gastric distension was induced by inflation of 400 ml of air. RESULTS: Basal lower esophageal pressure (LESP) and swallow-induced relaxation were not affected by loxiglumide. Loxiglumide significantly reduced the number of TLESRs, from 11.5 (5.8-18.3) to 6.0 (3.3-14.3) during the total recording period of 1 h, and from 5.5 (4.25-7.5) to 2.0 (0.5-6.8) during the first 15 min. The number of common cavities was significantly decreased by loxiglumide, from 8.0 (4.0-20.0) to 5.0 (2.0-7.8). TLESRs represented the main mechanism (60% during placebo, 74% during loxiglumide) underlying common cavities, followed by swallow-induced relaxation. CONCLUSIONS: Loxiglumide significantly reduces the number of TLESRs triggered by gastric distension without interfering with swallow-related relaxation of the lower esophageal sphincter, suggesting the involvement of CCKA receptors in the reflex pathway mediating TLESRs.

Adult↗
PubMed1998

Physiological role of cholecystokinin in gastroprotection in humans.

OBJECTIVE: Cholecystokinin (CCK) is able to protect gastric mucosa against acute injury in experimental animals but little is known about the role of this hormone in maintaining mucosal integrity in humans. This double-blind, placebo controlled study was performed in 16 healthy volunteers. It describes the effects of CCK-8 infused intravenously (i.v.) at physiological doses and endogenous CCK released by intraduodenal (i.d.) oleate on gastric mucosal damage, as brought about by ethanol without or with pretreatment with loxiglumide, a selective CCK-A receptor antagonist. METHODS: CCK-8 was infused i.v. 30 min before and throughout the study or i.d. oleate was instilled through a separate duodenal tube. Thirty minutes after the start of i.v. infusion of CCK or i.d. oleate instillation, 100 ml of 50% ethanol spray was applied to the gastric mucosa using an endoscope. Gastroscopy was performed and mucosal lesions were quantified using modified Lanza score. Gastric biopsies were taken from oxyntic mucosa for histological evaluation and gastric content was aspirated for radioimmunoassay of somatostatin. RESULTS: In placebo-treated subjects ethanol caused endoscopic damage, with an average score of 2.8+/-0.2. Histologically, a widespread disruption of surface epithelium and deep hemorrhagic necrotic lesions were observed. Pretreatment with CCK or i.d. oleate markedly reduced the endoscopic lesion score to 0.7+/-0.1 and 0.3+/-0.1, respectively, and in both cases this reduction was accompanied by a significant rise in plasma CCK. Histologically, surface epithelium was still disrupted but deep necrotic lesions were absent. Gastric content collected before and after CCK or oleate showed a several-fold increase of luminally released somatostatin. CONCLUSIONS: Pretreatment with loxiglumide abolished the protective effects of i.v. CCK-8 and i.d. oleate on mucosal lesions induced by ethanol and prevented the rise in intragastric somatostatin, but failed to affect the increments in plasma CCK. Endogenous CCK plays a physiological role in the maintenance of mucosal integrity. This occurs through activation of CCK-A receptors and is associated with an increased gastric luminal release of somatostatin.

Adult↗
PubMed1990

Cholecystokinin causes contraction of the pupillary sphincter in monkeys but not in cats, rabbits, rats and guinea-pigs: antagonism by lorglumide.

The effects of intracameral injections of cholecystokinin (CCK) on the pupil size were determined in monkeys, cats, rabbits, rats and guinea-pigs. In animals under muscarinic cholinergic blockade, CCK caused miosis in monkeys but not in the other species investigated. In monkeys CCK-8 was more potent than CCK-33, which was, however, much more potent than non-sulphated CCK-8. These observations indicate that peripheral type A receptors mediated the miotic response. The effect of CCK-8 was not appreciably influenced by pretreatment with indomethacin, 3 mg kg-1 body wt, indicating that prostaglandins were not involved in the response. Nerve blockade with 0.9 micrograms tetrodotoxin intracamerally had no clear effect on the dose-response relationship for CCK-8. The effect of the peptide thus seems to be directly on receptors on the pupillary sphincter muscle. Pretreatment with lorglumide caused a dose-dependent rightward shift of the dose-response curve, indicating competitive antagonism. The results indicate that in monkeys, but not in rabbit, cats, rats and guinea-pigs, CCK is a potent miotic with a direct effect on the pupillary sphincter mediated by type A CCK receptors on the muscle.

Animals↗
PubMed1994

Effects of CCK on pancreatic function and morphology.

This report reviews the effects of CCK on the pancreas and in particular analyzes recent studies in which CCK antagonists were used to evaluate the physiological role of CCK in modulating pancreatic function and morphology. CCK is released from endocrine cells of the small intestine in response to a meal. In various animal species there are CCK receptors on pancreatic acinar cells with two sites; occupation of the high affinity site is thought to mediate pancreatic secretion and growth, whereas occupation of the low affinity site by high CCK concentrations is thought to be responsible for supramaximal inhibition of secretion and pancreatitis. Recently, CCK receptors were also found on postganglionic cholinergic neurons in the gastrointestinal tract. Administration of CCK agonists stimulates pancreatic secretion and growth. Although in some previous studies CCK was given at doses that mimic its postprandial increase in plasma, these studies did not prove that the actions of exogenous CCK were physiologically important. In addition, it was unclear if CCK primarily acts as a true hormone or as a neurotransmitter. The development of specific CCK receptor antagonists made it possible to better evaluate the physiological role of CCK. In humans, CCK-A antagonists like loxiglumide or L-364,718 at doses that completely inhibited the action of supraphysiological doses of exogenous CCK reduced meal-stimulated pancreatic enzyme secretion only by approximately 50%. On the other hand, atropine abolished the postprandial increase in pancreatic secretion and in addition markedly reduced the increase in pancreatic secretion due to infusion of "physiological" doses of CCK (i.e., CCK doses that mimic its postprandial increase in plasma). The increase in pancreatic bicarbonate secretion was only slightly reduced by CCK blockade. CCK antagonists failed to reduce the postprandial increase in plasma insulin, but markedly reduced the postprandial PP release. CCK-A antagonists caused slight hypotrophy and hypoplasia of the exocrine pancreas. However, even after 9 months of effective blockade of the CCK-A-receptor, mice had normal body weight and an almost normal pancreas. CCK antagonists were unable to alter short-term changes in pancreatic growth due to feeding and fasting. In some species, CCK agonists induced development of pancreatic nodules and increased the growth of malignant tumors. Studies about the effects of CCK antagonists on induction and growth of pancreatic tumors showed controversial results. In conclusion, CCK may act on the pancreas by three pathways: (1) At low doses it serves as a neurotransmitter by acting on cholinergic neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Effect of cholecystokinin on gastric motility in humans.

Gastric emptying after food ingestion is regulated by neural and hormonal factors. However, the relative contributions of each pathway is not yet clearly defined. The classic gut hormone CCK seems to be involved in the regulation of gastric emptying in humans. Experimental evidence is best for gastric emptying of liquid meals that release CCK from the duodenum: (1) CCK infused at postprandial plasma concentrations inhibits gastric emptying of a liquid and a semisolid meal. (2) Administration of the CCK antagonist loxiglumide significantly accelerated gastric emptying of a liquid mixed meal and a glucose meal. Discrepant results with the antagonist MK329 are difficult to explain considering the marked acceleration of gastric emptying rates by the specific and potent antagonist MK329 shown in several animal studies. Taken together, current information favors the conclusion, however, that CCK mainly controls gastric emptying of the liquid but not the solid components. Thus, CCK is involved in the physiologic regulation of gastric emptying and gastric motility in man. Blocking CCK-A receptors accelerates gastric emptying of liquid meals and abolishes the gastrocolonic reflex. Therefore, CCK may play a role as a common regulator of postprandial gallbladder contraction and pancreatic enzyme secretion as well as of gastric emptying rates under certain conditions. Such common control would optimize the nutrient-to-digestive juices concentration ratio. The importance of endogenous CCK on gastric emptying of solid meals, however, is poorly understood and remains to be defined. Only very limited information is available on gastric motility. Much more work has to be done before a clear concept can be developed.

Benzodiazepinones↗