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PubMed1985

Structure-activity relationships of C-terminal tri- and tetrapeptide fragments that inhibit gastrin activity.

A series of tri- and tetrapeptide derivatives, analogues of the gastrin C-terminal region with no phenylalanine residue, were synthesized. These peptides were tested for their ability to inhibit gastrin-stimulated acid secretion in vivo as well as binding of [125I]-(Nle11)-HG-13 to gastric mucosal cell receptors in vitro. Most of the peptides tested exhibited gastrin antagonist activity in vivo and in vitro. Most active derivatives were 20-30 times more potent than the well-known gastrin antagonist derivatives proglumide and benzotript and had 20-200 times more binding affinity. The smallest fragment exhibiting antagonist activity was the tripeptide Boc-L-tryptophyl-L-methionyl-L-aspartic acid amide.

Animals↗
PubMed1999

Somatic electrical nerve stimulation regulates the motility of sphincter of Oddi in rabbits and cats: evidence for a somatovisceral reflex mediated by cholecystokinin.

Cholecystokinin (CCK) plays an important role in regulating the biliary motility in herbivorous and carnivorous animals. Little is known about how the motility of the sphincter of Oddi (SO) is regulated through a somatic stimulation. It was our aim to test the hypothesis that somatic electrical nerve stimulation (SENS) affects SO motility in animals with different types of SO through CCK-related mechanisms. The activity of SO in anesthetized rabbits and cats was measured by using a continuously perfused open-tip manometric method. SENS was brought about by applying an electric current (2/15 Hz alternatively, 20 min) to two needles positioned near spinal nerves in the 6th and 7th intercostal space in the right midclavicular line. The SO motility before and X min after the start of SENS, designated as pre-SENS and SENS-X respectively, were recorded and saved in a computer equipped with off-line analysis software. The SO activity in rabbits, in terms of phasic contraction pressure and duration of summation peak during SENS were significantly higher than that before SENS. The phasic contraction pressure of pre-SENS, SENS-10, and SENS-16 were 6.83 +/- 0.39 mm Hg, 9.23 +/- 0.83 mm Hg and 10.46 +/- 0.81 mm Hg, respectively (P < 0.03, N = 13). The duration of summation peak in pre-SENS, SENS-10, and SENS-16 were 7.26 +/- 0.41 sec, 10.22 +/- 0.46 sec, and 13.49 +/- 2.31 sec, respectively (P < 0.05, N = 13). The SENS-induced SO hyperactivity was not inhibited by pretreatment with atropine, propranolol, phentolamine, or naloxone, but was blocked by pretreatment with the CCK receptor antagonist, proglumide, and by injection of anti-CCK-8 antibody during SENS in a dose-dependent manner. In contrast, SENS induced an inhibitory SO response in cats. However, in both circumstances, an obvious elevation of plasma CCK level determined by radioimmunoassay was noted after SENS. We conclude that SENS causes secretion of CCK, which in turn affects biliary tract motility in animals with different types of SO. This provides an easily applicable method for those patients who have hyperactive SO function.

Animals↗
PubMed2002

Opioidergic effects of nonopioid analgesics on the central nervous system.

1. The analgesic effect of nonsteroidal anti-inflammatory drugs (NSAIDs) is partly due to the fact that they act upon the periaqueductal gray matter (PAG) and the rostral ventromedial medulla of the brain stem and thus activate the descending pain-control system, which inhibits nociceptive transmission at the spinal dorsal horn. 2. The analgesic action of dipyrone (metamizol) and of lysine-acetylsalicylate (LASA), two well-known NSAIDs. whether microinjected into the PAG or given systemically, can be reverted by naloxone. Repeated administration of dipyrone or LASA induces tolerance to their antinociceptive effect, with cross-tolerance to morphine, and a withdrawal syndrome upon naloxone administration. Dipyrone tolerance can be reverted by proglumide, a cholecystokinin antagonist. 3. These findings reveal a close association between the central action of NSAIDs and endogenous opioids.

Analgesics, Non-Narcotic↗
PubMed1985

Effects of putative satiety peptides on feeding and drinking behavior in golden hamsters (Mesocricetus auratus).

A series of experiments was conducted to characterize the effects of putative satiety peptides on feeding in the Syrian hamster, a species known to have physiological feeding controls different from those of other animals. Peripheral injections of cholecystokinin octapeptide (CCK-8) reduced feeding in hamsters in a dose-related fashion. CCK-8 was equally effective in reducing food intake in female hamsters tested during the light and dark portions of the illumination cycle but was ineffective in males tested during the light portion. Systemic injections of proglumide, a putative CCK receptor antagonist, did not alter spontaneous food intake and did not reverse the suppression of feeding resulting from peripheral CCK-8 injections. Systemic injections of bombesin (BBS), thyrotropin releasing hormone (TRH), and calcitonin (CT) produced a dose-related suppression of food intake. BBS appeared to do so specifically. In contrast, TRH appeared to reduce feeding by temporarily debilitating the animals; CT, by evoking behavior (increased locomotor activity) incompatible with feeding. Intracerebroventricular (icv) injections of CCK-8, BBS, and CT produced dose-related inhibition of feeding, but only CCK-8 appeared to affect feeding behavior selectively. Reduced feeding after icv BBS was associated with excessive grooming, and icv CT, like systemic CT, increased locomotor behavior. These findings in the hamster are discussed in relation to peptidergic control of feeding in other species.

Animals↗
PubMed1992

Autocrine stimulation of growth of AR4-2J rat pancreatic tumour cells by gastrin.

The control of cell proliferation by gastrin has been investigated in a rat pancreatic tumour cell line, AR4-2J. Exogenous gastrin, 10(-12) to 10(-8) M, stimulated cell growth of thymidine-synchronised AR4-2J cells cultured over 48 h in serum-free medium. Cell lysates of AR4-2J cells contained an average of 4.5 and 3.5 pg gastrin per 10(6) cells, when grown in serum-supplemented or serum-free media, respectively, as revealed by radioimmunoassay. In serum-free medium, AR4-2J secrete 34 ng 1(-1) 10(-6) cells of gastrin over 48 h. Addition of an anti-gastrin immunoglobulin preparation, but not control immunoglobulins, caused a maximum 52% reduction in cell growth. These data are consistent with an autocrine role for gastrin in the control of AR4-2J cell growth. These results were supported by studies with gastrin/CCK receptor antagonists. Six non-peptide gastrin/CCK receptor antagonists inhibited AR4-2J cell growth in a concentration-related manner. The concentration required for 50% inhibition (IC50) of cell growth by the amino acid-derived antagonists proglumide (3.5 x 10(-3) M), benzotript (1.8 x 10(-3) M), loxiglumide (1.1 x 10(-4) M) and lorglumide (6.7 x 10(-5) M) were of the same order and significantly correlated with their IC50 for inhibition of 125I-gastrin binding to AR4-2J cells. Inhibition of cell growth by these antagonists was partially reversed by the addition of exogenous gastrin. In contrast, the IC50 for inhibition of cell growth with two benzodiazepine-derived antagonists, the CCK-B receptor antagonist L-365,260 (4.6 x 10(-5) M) and the CCK-A receptor antagonist devazepide (1.7 x 10(-5) M) were two-three orders of magnitude greater than those required to inhibit gastrin binding (10(-8)-10(-7) M). The growth inhibitory effects of L-365,260 and devazepide were not reversed by exogenous gastrin suggesting these benzodiazepine-derived antagonists do not inhibit cell growth by interaction with gastrin receptors. The results are consistent with gastrin being an autocrine growth factor in AR4-2J cells, and that stimulation of cell growth is due to stimulation of the gastrin, rather than CCK-B, receptor sub-type. This study highlights that gastrin receptor antagonists warrant further investigation as agents to control growth of tumours, such as those from the gastrointestinal tract, which express gastrin receptors.

Animals↗
PubMed2001

Binding sites for progastrin-derived peptides in colonic crypts.

BACKGROUND AND AIMS: Gastrin17gly acts as a growth factor for the colonic mucosa. Studies on the binding properties of the receptor involved in transducing the proliferative effects have generally been confined to colorectal carcinoma cell lines, and no investigation of gastrin17gly receptors on normal colonocytes has yet been reported. The aim of this study was to investigate the binding of 125I-[Met15]-gastrin17gly to normal colonic crypts. METHODS: Crypts were released from normal rat and rabbit colonic mucosa by treatment with EDTA and isolated by centrifugation. The binding of 125I-[Met15]-gastrin17gly was measured in displacement experiments with increasing concentrations of either gastrin17gly, gastrin17 or gastrin receptor antagonists. The concentrations required for 50% inhibition were determined by the use of curve fitting. RESULTS: 125I-[Met15]-Gastrin17gly bound to both rat and rabbit crypts, and displacement experiments with unlabeled gastrin17gly revealed that the IC50 values were 1.0 +/- 0.6 and 0.6 +/- 0.2 micromol/L, respectively. Binding was also competed by gastrin17, with IC50 values of 2.4 +/- 1.7 and 2.4 +/- 0.7 micromol/L, respectively. Binding was inhibited by the non-selective gastrin/CCK receptor antagonists proglumide and benzotript, but not by the cholecystokinin (CCK)-A receptor antagonist L364 718, or the gastrin/CCK-B receptor antagonist L365 260. CONCLUSION: We conclude that the gastrin17gly binding site on normal colonic crypts has properties consistent with the gastrin/CCK-C receptor.

Animals↗
PubMed1986

Cholecystokinin antagonists.

The three classes of CCK antagonists illustrate the various factors governing affinity of the antagonists for the CCK receptor. The major influence in determining potency of the cyclic nucleotide derivatives, amino acid derivatives and C-terminal fragments of CCK, are hydrophobic forces. In contrast, structural requirements are the major influences in determining potency of the N-terminal fragments of CCK-26-33. The most potent CCK antagonist in each of the three classes is illustrated in Fig. 11. CBZ-CCK-27-32-NH2 is 30 times more potent than N-CBZ-cystine, which is, in turn, slightly more potent than Bt2 cGMP. All these CCK antagonists, however, are relatively weak. For example, CBZ-CCK-27-32-NH2 inhibits binding of 125I-CCK by 50% at a concentration of approximately 5 microM. In contrast, the agonist CCK-26-33 inhibits binding of 125I-CCK by 50% at a concentration of approximately 1 nM. The antagonists remain useful for analyzing those responses that are caused by CCK, though the relatively low potencies of the antagonists may limit their usefulness as antagonists of CCK in vivo systems. This limitation, however, may be only theoretical. For example, proglumide, which requires an in vitro concentration of 0.3 mM to cause half-maximal inhibition of binding of 125I-CCK, can inhibit the actions of CCK and gastrin in animals (Hutchison and Dockray 1980; Stubbs and Stabile 1985) and of gastrin in man (Lamers and Jansen 1983). Nevertheless, the identification of CCK antagonists with greater potency than those hitherto described will facilitate studies of the actions of CCK.

Amino Acids↗
PubMed1984

Cytosolic calcium regulates epidermal growth factor endocytosis in rat pancreas and cultured fibroblasts.

Cholecystokinin octapeptide (CCK8), the COOH-terminal moiety of cholecystokinin (CCK), exerted a rapid inhibitory effect on total cell-associated 125I-labeled epidermal growth factor (125I-EGF) binding by decreasing the rate of EGF internalization in isolated rat pancreatic acini. Removal of CCK8 from incubation medium followed by extensive washing of acini did not abolish its inhibitory effect, indicating that its action was not readily reversible. Proglumide, a competitive antagonist of CCK8, blocked the inhibitory action of the secretagogue. Addition of CCK8 to cells previously exposed to 125I-EGF did not enhance the release of cell-associated 125I activity. CCK8 did not inhibit the binding of 125I-labeled insulin to pancreatic acini. Other pancreatic secretagogues that enhance digestive-enzyme release through Ca2+, including caerulein, bombesin, carbachol, gastrin, and the Ca2+ ionophore A23187, also inhibited cell-associated 125I-EGF radioactivity. Further, at 37 degrees C the ionophore A23187 inhibited specific 125I-EGF binding in human A-431 carcinoma cells, Swiss 3T3 cells, and Rat-1 fibroblasts, and this effect was abolished when 125I-EGF internalization was reduced by incubating cells at 4 degrees C. It is concluded that alterations in cellular Ca2+ in the pancreas and other cells lead to inhibition of EGF endocytosis.

Animals↗
PubMed2006

Gastrin induces leukocyte-endothelial cell interactions in vivo and contributes to the inflammation caused by Helicobacter pylori.

Gastric mucosal inflammation causes hypergastrinemia, and gastrin receptors have been detected in several leukocyte types. We have analyzed whether gastrin affects the leukocyte-endothelial cell interactions in vivo by monitoring leukocyte rolling, adhesion, and emigration in rat mesenteric venules using intravital microscopy. Mesenteric superfusion with exogenous gastrin increased these processes in a concentration- and time-dependent manner, effects prevented by the cholecystokinin (CCK)-2 receptor antagonists (proglumide, L-365,260) but not by the CCK-1 receptor antagonist devazepide. A similar response was induced by exogenous CCK or endogenously released gastrin. CCK-2 receptors were localized in mesenteric macrophages and polymorphonuclear leukocytes. This effect of gastrin is not modulated by somatostatin and is independent of the endogenous release of histamine. To analyze whether hypergastrinemia elicited by Helicobacter pylori (HP) modulates the inflammation induced by the germ, rats were chronically administered with an extract of a CagA+/VacA+ strain of HP. This protocol increased gastrinemia and induced an inflammatory response in the rat mesentery. Blockade of CCK-2 receptors attenuated this response and induced a qualitative change in the leukocyte infiltrate suggestive of a receding inflammatory process. Our results reveal a new proinflammatory role of gastrin that seems to contribute to the maintenance of the inflammation elicited by HP components.

Animals↗
PubMed1988

Asperlicin, a nonpeptidal cholecystokinin receptor antagonist, attenuates sodium taurocholate-induced acute pancreatitis in rats.

Asperlicin (ASP), a new, nonpeptidal cholecystokinin (CCK) receptor antagonist isolated from the fungus Aspergillus alliaceus, has an affinity that is 300-400 times greater than that of proglumide for gallbladder, ileal, and pancreatic CCK receptors. The long in vivo half-life and high selectivity for peripheral CCK receptors make ASP suitable for investigations on the physiological and pharmacological actions of CCK. Endogenous CCK has been postulated to participate in the pathogenesis of acute hemorrhagic pancreatitis (AHP) in rats and mice. We examined the effects of ASP in rats on the early course (6 h) of AHP induced by a retrograde infusion of sodium taurocholate (NaTC) into the common bile-pancreatic duct. An i.v. bolus injection of ASP (either 10 mg/kg or 30 mg/kg) in dimethyl sulfoxide (DMSO) given 1 h prior to AHP induction failed to significantly alter pancreas weights, serum amylase concentrations, or pancreatic histopathology when compared with AHP control rats treated with vehicle alone. However, rats given 2 i.p. injections of ASP (either 20 mg/kg/injection or 40 mg/kg/injection) in DMSO: olive oil 1 h before and 2 h after induction of AHP exhibited significantly reduced serum amylase concentrations. Additionally, rats given the high dose i.p. injections of ASP also had significantly reduced pancreas weights and less severe pancreas histopathology compared with AHP control animals. These data indicate that endogenous CCK participates in the pathogenesis of NaTC-induced AHP in the rat.

Acute Disease↗
PubMed1989

Failure of a potent cholecystokinin antagonist to protect against diet-induced pancreatitis in mice.

The effects of a potent cholecystokinin (CCK) receptor antagonist, L-364,718, on two forms of experimental acute pancreatitis in mice were evaluated. The antagonist prevented the hyperamylasemia, pancreatic edema, and acinar cell vacuolization that followed administration of a supramaximally stimulating dose of the cholecystokinin analogue cerulein. In contrast, the same dose of L-364,718 (1 mg/kg/6 h) and an even higher dose (10 mg/kg/6 h) failed to prevent the hyperamylasemia, acinar cell necrosis, and mortality that followed administration of a choline-deficient ethionine-supplemented diet. These observations are at variance with those previously reported to follow administration of the relatively weak cholecystokinin antagonist proglumide (Niederau C et al. J Clin Invest 1986;78:1056-63). The observations reported in this communication suggest that cholecystokinin does not play an important role in diet-induced pancreatitis and that CCK receptor antagonists are unlikely to be of benefit in the treatment of clinical acute pancreatitis.

Animals↗
PubMed1995

Different inhibitory effects of the newly developed CCK receptor antagonists FK480 and KSG-504 on pancreatic exocrine and endocrine secretion in the isolated perfused rat pancreas.

Cholecystokinin (CCK) receptor antagonists are shown to have therapeutic as well as preventive effects in some types of acute pancreatitis. However, there is a possibility that administration of CCK receptor antagonists with a high inhibitory potency on the endocrine pancreas to patients with acute pancreatitis exacerbates the associated glucose intolerance. In the present study we simultaneously examined the effects of the newly developed benzodiazepine derivative FK480 and proglumide-related antagonist KSG-504 on CCK octapeptide (CCK-8)-stimulated exocrine and endocrine function in the isolated perfused rat pancreas. FK480 and KSG-504 inhibited CCK-8-stimulated pancreatic juice flow, protein output, and insulin release in a dose-dependent manner. FK480 was approximately 10 times more potent than KSG-504 in inhibiting exocrine and endocrine secretion. Both antagonists inhibited CCK-8-stimulated insulin release more potently than exocrine secretion. FK480 caused a dose-dependent residual inhibition of exocrine secretion after its removal from the perfusate, whereas insulin release was only slightly impaired even at the highest dose. In contrast, termination of KSG-504 infusion resulted in an immediate increase in both exocrine and insulin responses without causing any residual inhibition. With regard to the residual inhibition, therefore, KSG-504 had no significant influences on exocrine and insulin release, whereas FK480 inhibited exocrine secretion more potently than insulin response. These results suggest that FK480 might become a useful therapeutic agent for pancreatitis with respect to its long-duration inhibitory effect on exocrine secretion and short-duration inhibitory effect on insulin release.

Animals↗
PubMed1987

Cholecystokinin stimulates dopamine synthesis in synaptosomes by a cyclic AMP-dependent mechanism.

The effects of different fragments of cholecystokinin (CCK) on dopamine synthesis were studied in synaptosomal preparations from the striatum, substantia nigra, and frontal cortex. In striatal synaptosomes, dopamine synthesis rate measured by dopamine accumulation was 12.5% lower than that measured by 3,4-dihydroxyphenylalanine (DOPA) accumulation; however, K+-accelerated synthesis was the same for both methods. Synthesis rate was independent of exogenous tyrosine levels. In the three regions studied, the combined stimulatory effects of 8-Br-cyclic AMP and high K+ were additive. CCK-5, CCK-3, CCK-27-33, and CCK-8 (sulphated) enhanced synthesis, CCK-5 being the most potent fragment. The nonsulphated octapeptide had no effect. In all three regions, CCK-5 and high K+ had an additive effect on dopamine synthesis; CCK-5 and 8-Br-cyclic AMP together produced the same enhancement of synthesis as CCK-5 alone. CCK-5 produced similar dose-dependent increases in dopamine synthesis and cyclic AMP accumulation in striatal synaptosomes, and both effects were blocked by the CCK antagonist proglumide.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1990

Modification by cholecystokinin octapeptide of the binding of mu-, delta-, and kappa-opioid receptors.

Previous study has shown that cholecystokinin (CCK) octapeptide (CCK-8) suppressed the binding of opioid receptors to the universal opioid agonist [3H]etorphine. In the present study, highly selective tritium-labeled agonists for the mu-[(tryrosyl-3,5-3H][D-Ala2,MePhe4,Gly-ol5]enkephalin ([3H]DAGO], delta- ([tyrosyl-3,5-3H][D-Pen2,5]enkephalin ([3H]DPDPE], and kappa- ([3H]U69,593) opioid receptors were used to clarify which type(s) of opioid receptor in rat brain homogenates is suppressed by CCK-8. In the competition experiments, CCK-8 suppressed the binding of [3H]DAGO and [3H]U69,593 but not that of [3H]DPDPE to the respective opioid receptor. This effect was blocked by the CCK antagonist proglumide at 1 mumol/L. In the saturation experiments, CCK-8 at concentrations of 0.1 nmol/L to 1 mumol/L decreased the Bmax of [3H]DAGO binding sites without affecting the KD; on the other hand, CCK-8 increased the KD of [3H]U69,593 binding without changing the Bmax. The results suggest that CCK-8 inhibits the binding of mu- and kappa-opioid receptors via the activation of CCK receptors.

Animals↗
PubMed1985

A potent nonpeptide cholecystokinin antagonist selective for peripheral tissues isolated from Aspergillus alliaceus.

A new, competitive, nonpeptide cholecystokinin (CCK) antagonist, asperlicin, was isolated from the fungus Aspergillus alliaceus. The compound has 300 to 400 times the affinity for pancreatic, ileal, and gallbladder CCK receptors than proglumide, a standard agent of this class. Moreover, asperlicin is highly selective for peripheral CCK receptors relative to brain CCK and gastrin receptors. Since asperlicin also exhibits long-lasting CCK antagonist activity in vivo, it should provide a valuable tool for investigating the physiological and pharmacological actions of CCK.

Animals↗
PubMed1985

The distension stimulus to gastric acid secretion in the isolated mouse stomach.

Distension of the isolated mouse stomach stimulated gastric acid secretion. Atropine, cimetidine, or proglumide antagonized the actions of cholinomimetics, histamine, and gastrin, respectively. However, these antagonists and the nerve blocking agent, tetrodotoxin, were without effect on basal secretion or distension-stimulated secretion. It is concluded that in the isolated mouse stomach neither basal secretion nor secretion evoked by distension involve the release of any of the established "physiological" secretagogues or the activation of intramural nerves.

Animals↗
PubMed1988

Isolation from porcine intestinal extracts of a cholecystokinin-like peptide and a peptide with homology to cytochrome oxidase polypeptide VII and chymodenin.

A number of different forms of cholecystokinin (CCK) exist in the brain and intestine. Gel permeation and ion exchange chromatography and high performance liquid chromatography have been used to isolate a peptide from partially purified porcine intestinal extracts with N-terminal homology to porcine brain CCK-58. This peptide contracted both the guinea pig ileum longitudinal muscle and gallbladder muscle and these responses were inhibited by dibutyryl cyclic GMP or proglumide. The potency was approximately 1/100 of that of CCK-8. The reason for this low potency is unclear, but it is possible that a critical part of the biologically active region is modified or that it is a truncated form of CCK-58. A further peptide was isolated with a sequence homologous to cytochrome oxidase polypeptide VII and chymodenin.

Amino Acid Sequence↗
PubMed1982

Receptors on smooth muscle cells: characterization by contraction and specific antagonists.

Smooth muscle cells were isolated from the stomach of the guinea pig, and the kinetics, stoichiometry, and specificity of contraction in response to the C-terminal octapeptides of cholecystokinin (CCK-OP), gastrin-17, and acetylcholine were examined. All three agonists elicited dose-dependent peak contraction that did not depend on the presence of extra-cellular calcium. The potencies of CCK-OP and gastrin-17 were equal (D50, 10(-11) M) and 10 times greater than the potency of acetylcholine (D50, 10(-10) M). A combination of low doses of acetylcholine and CCK-OP was synergistic; however, its effect did not exceed the maximal responses to either agonists alone or to high extracellular concentrations of calcium. The specificity of the receptors was established by the use of atropine and the two CCK-receptor antagonists dibutyryl cGMP and proglumide. The span of the dose-response curves was wide, suggesting the existence of receptor heterogeneity. It is concluded that gastric smooth muscle cells of the guinea pig possess distinct, high-affinity receptors for CCK-gastrin and acetylcholine; the receptors mediate contraction that is not immediately dependent on the presence of extracellular calcium.

Animals↗