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PubMed1985

Inhibition of cholecystokinin response in the gallbladder by dibenamine and its protection by benzodiazepines.

The contractile response of the guinea-pig gallbladder to cholecystokinin (CCK) and acetylcholine (ACh) was irreversibly inhibited by 5 X 10(-5) M dibenamine, and the dibenamine-induced inhibition in the CCK response was prevented by 10(-4) M chlordiazepoxide (CDP) and diazepam (DZP), but not by 10(-2) M proglumide or 10(-6) M atropine. The dibenamine-induced inhibition in the ACh response was prevented by 10(-6) M atropine, but not by 10(-4) M CDP. These findings suggest that the binding of CCK to the CCK receptor can be inhibited by benzodiazepines.

Animals↗

PubMed1985

Inhibition of hypothermic effect of cholecystokinin by benzodiazepines and a benzodiazepine antagonist, Ro 15-1788, in mice.

Intracisternally administered cholecystokinin produced long lasting hypothermia in mice, and the hypothermic effect was significantly antagonized by benzodiazepines like chlordiazepoxide and diazepam and by a benzodiazepine antagonist, Ro 15-1788, that were administered intraperitoneally. Proglumide, a cholecystokinin antagonist, failed to prevent the hypothermia induced by cholecystokinin at a dose of 200 mg/kg. Benzodiazepines and Ro 15-1788 revealed a considerably strong hypothermic effect, but they still prevented the hypothermic effect of cholecystokinin. The precise mechanism of the antagonism between cholecystokinin and benzodiazepines remains unclear at present.

Animals↗

PubMed1988

The effect of oleate on pancreatic and bile secretion in the conscious rat.

The effects of sodium oleate infused into either the duodenum or the terminal ileum on bile and pancreatic secretion were examined in the conscious rat. Rats were prepared with cannulae draining pure bile and pancreatic juice separately, and with an ileal and two duodenal cannulae. A 40 mM taurocholate solution containing 7 mg/ml bovine trypsin was infused into the duodenum throughout the experiment to replace diverted bile-pancreatic juice to maintain the normal regulation of pancreatic secretion. The intraduodenal infusion of sodium oleate significantly increased pancreatic juice flow, protein, and bicarbonate outputs, whereas it did not affect bile secretion. Intravenous infusion of proglumide (300 mg/kg/hr) did not inhibit pancreatic secretion stimulated by intraduodenal infusion of sodium oleate. An intravenous infusion of atropine (100 micrograms/kg/hr) attenuated protein and fluid secretions but not that of bicarbonate in response to intraduodenal oleate. In contrast, the intraileal infusion of oleate had no effect on pancreatic secretion, whereas it decreased bile flow, bicarbonate, and bile salt outputs. In conclusion, sodium oleate introduced in the duodenum stimulates pancreatic secretion but oleate in the terminal ileum inhibits bile secretion.

Animals↗

PubMed2000

Effects of spinal cholecystokinin receptor antagonists on morphine antinociception in a model of visceral pain in the rat.

The objective of the present study was to determine the effects of spinal cholecystokinin (CCK) receptor antagonists on morphine antinociception in a model of visceral nociception, colorectal distension, in rats with chronic colonic inflammation and vehicle-treated controls. Three to five days after intracolonic instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS), an enhanced visceromotor response to all pressures of colorectal distension (10-80 mm Hg) was evident. The ED(50) of intrathecal morphine (0.93 microgram) in vehicle-treated rats produced significantly greater antinociception in TNBS-treated rats. Intrathecal proglumide, a nonselective CCK receptor antagonist, dose dependently enhanced the antinociceptive effect of morphine in vehicle-treated rats, but not in TNBS-treated rats. Similarly, L-365, 260, a specific CCK(B) receptor antagonist, dose dependently increased morphine's antinociceptive effects in vehicle-treated rats but had no effect in rats with TNBS-induced colonic inflammation. L-364,718, a specific CCK(A) receptor antagonist, had no effect on morphine antinociception in either vehicle-treated or TNBS-treated rats. These data indicate that CCK, acting at the CCK(B) receptor, is involved in modulating morphine antinociception following a noxious visceral stimulus. However, CCK receptor antagonists no longer enhance morphine antinociception after instillation of intracolonic TNBS, suggesting that visceral inflammation may lead to a reduction in spinal CCK release.

Analgesics↗

PubMed1992

Gastrin stimulates Ca2+ mobilization and clonal growth in small cell lung cancer cells.

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.

Benzamides↗

PubMed1992

Effects of omeprazole on the number of immunoreactive gastrin- and somatostatin-cells in the rat gastric mucosa.

The effects of omeprazole--an inhibitor of gastric acid secretion--on gastrin (G)- and somatostatin (D)-cell density in the gastric antral mucosa epithelium in rats were examined, following a 5-day treatment. It was found that omeprazole increased the density of G-cells, whereas it decreased the density of D-cells. That effect was probably independent of hypergastrinaemia, since it could not be blocked by a simultaneous treatment with proglumide--a gastrin receptor blocker. It is concluded that the observed phenomenon is a direct result of a lower gastric acidity, as a consequence of omeprazole treatment.

Animals↗

PubMed2004

Cholecystokinin octapeptide inhibits carotid sinus baroreflex in anesthetized rats.

The purpose of this study was to determine the effect of cholecystokinin octapeptide (CCK-8) on carotid sinus baroreflex in 36 anesthetized male rats by isolated carotid sinus perfusion in vivo. The results obtained are as follows. (1) By perfusion with CCK-8 (0.1, 0.5, 1.0 micromol/L), the functional curve of baroreflex was shifted to the right and upward, with a decrease in peak slope (PS) (p<0.001) and a reflex decrease (RD) in mean arterial pressure, while the threshold pressure (TP) and saturation pressure (SP) were significantly increased. Among the functional parameters of carotid sinus baroreflex, the changes in RD, PS and TP were dose-dependent. (2) Pretreatment with proglumide (100 micromol/L), a nonselective CCK receptor antagonist, the inhibitory effect of CCK-8 (0.5 micromol/L) on the baroreflex was significantly attenuated. (3) Pretreatment with L-NAME (100 micromol/L), an inhibitor of nitric oxide (NO) synthase, did not affect the inhibitory action of CCK-8 (0.5 micromol/L). (4) Preperfusion with Bay K 8644 (500 nmol/L), an agonist of calcium channel, could attenuate the effect of CCK-8 (0.5 micromol/L). It is suggested that the inhibitory action of CCK-8 on the baroreflex may be mediated by the activation of its receptors in the carotid sinus baroreceptor, leading to an inhibition of stretch-sensitive channels and a decrease in Ca(2+) influx. However, NO released from the endothelium seems not to be involved in the mechanism of this effect.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1990

Controlling gastric pH: the impact of newer agents on the critically ill patient.

The critically ill patient is at increased risk for developing erosive injury of the stomach, duodenum, and esophagus. To date, the most effective way to prevent and treat this problem is by assuring excellent intensive care support and by reducing gastric acid secretion. The histamine H2-receptor antagonists (H2RAs) are effective in both prevention and treatment of such gastric mucosal injury. Newer agents are available that have potential for use in this setting, although none have been studied as extensively in critically ill patients as have the H2RAs. These new agents include proglumide, pirenzepine, misoprostol, omeprazole, and somatostatin. To date, only the latter has been extensively studied in critically ill patients. Omeprazole, which suppresses acid very effectively, may be problematic in the critically ill, limited by its oral dosage form, acid-labile properties, and potential drug interactions.

Alprostadil↗

PubMed1990

[Cholecystokinin octapeptide (CCK-8) antagonized analgesia mediated by mu and kappa opioid receptors].

CCK-8 has been shown to antagonize the analgesia produced by morphine or endogenous opioid peptides. The present study was performed to clarify the interaction between CCK-8 and different opioid ligands. Analgesia produced by intrathecal (I.T.) injection of the specific mu receptor agonist PL017 10 ng or kappa receptor agonist NDAP 500 ng can be antagonized by I.T. injection CCK-8 at a dose as small as 4 ng. In contrast, analgesia produced by I.T. injection of the delta receptor agonist DPDPE (6.5, 13 and 26 micrograms) was not blocked by CCK-8 (4 ng or 40 ng, I.T.). The antagonistic effect of CCK-8 on PL017 and NDAP could be completely reversed by proglumide (3 micrograms, I.T.). I.T. injection of CCK-8 (4 or 40 ng single dose or cumulative dose of 0.1, 0.2, 0.5 and 1.0 microgram at 10 min intervals) produced neither analgesia nor hyperalgesia. In conclusion, CCK-8 preferentially antagonizes opioid analgesia mediated by mu and kappa receptors, and this antagonistic effect is mediated by CCK receptors.

Analgesics↗

PubMed1990

[The hormonal sensitivity of a transplantable adenocarcinoma of the large intestine].

It was found that repeated transplantation of ACATOL strain cells resulted in a loss of their sensitivity to growth-stimulating effect of pentagastrin. The effect of gastrin receptor antagonist proglumide, on ACATOL cells growth was inconstant. ACATOL tumor was sensitive to VIP and glucagon in vitro (as shown by adenylate cyclase activity assay), that makes the model promising for selecting potent hormone drugs against colorectal cancer.

Adenocarcinoma↗

PubMed1987

Asperlicin: a unique nonpeptide cholecystokinin antagonist.

The lack of a potent and specific cholecystokinin (CCK) receptor antagonist has greatly hampered studies of the role of CCK in controlling pancreatic growth, enzyme release, pancreatitis, and pancreatic carcinoma. Asperlicin, a newly described, CCK antagonist, has been shown to be a potent, competitive inhibitor of CCK-induced gallbladder and ileal muscle contraction. In this study, the effects of asperlicin on CCK- and carbachol-stimulated pancreatic enzyme release from dispersed guinea pig acini were investigated. Cholecystokinin caused a dose-dependent release of amylase and lipase. Half-maximal release of amylase (17.9% +/- 2.1%, mean +/- SEM, percent of total content) and lipase (27.3% +/- 2.1%) was seen with CCK 10(-11) mmol/L) both p less than 0.01). Asperlicin (10(-11) to 10(-4) mmol/L) caused a substantial inhibition (10(-11) mmol/L) of CCK-induced amylase release with a 50% maximal effective inhibitory dose of 10(-9) mmol/L (p less than 0.01) and maximum inhibition at 10(-6) mmol/L. Asperlicin was approximately 1000-fold more potent than proglumide (a previously described CCK receptor antagonist) which had a 50% effective inhibitory dose of 10(-6) mmol/L) and a maximal effect at 10(-4) mmol/L. Asperlicin (10(-10) to 10(-4) mmol/L) failed to alter carbachol-induced amylase release. Asperlicin is a new, potent CCK antagonist for pancreatic CCK receptors and should prove useful as an investigational tool. Such receptor antagonists may have therapeutic potential.

Amylases↗

PubMed1989

[Potentiating effect of secretin on cholecystokinin-stimulated exocrine pancreatic secretion in rats].

The potentiating effect of secretin on cholecystokinin (CCK)-stimulated exocrine pancreatic secretion was studied in anesthetized rats. Intravenous infusion of CCK-8 in three different doses of 0.03, 0.06 and 0.12 micrograms/kg-hr increased pancreatic secretion of volume, bicarbonate, amylase and trypsin outputs dose-dependently. Simultaneous infusion of CCK-8 with secretin in a dose of 0.03 CU/kg-hr produced statistically greater pancreatic secretion of volume, bicarbonate, amylase and trypsin outputs than that by CCK-8 alone, and than the sum by secretin alone and CCK-8 alone in each dose. Proglumide (600 mg/kg-hr) significantly suppressed exocrine pancreatic secretion produced by CCK-8 (0.06 micrograms/kg-hr) plus secretin (0.03 CU/kg-hr), to the level induced by secretin alone. These results indicate that CCK-8 increased pancreatic secretion dose-dependently, and secretin in a physiological dose potentiates the stimulating effect of CCK-8 on exocrine pancreatic secretion in rats.

Amylases↗

PubMed1989

[Effects of anti-tissue immune sera on the contractile response of cells isolated from smooth muscle of the pyloric antrum].

The effect of anti-tissue antisera on the contractile response of isolated smooth muscle cells from rabbit antrum has been investigated. Anti-stomach (SAE), anti-colon (SAC) and anti-diencephale (SAD) antisera induced a dose-dependent contraction is isolated cells, whereas both non-immune serum and antisera obtained by immunization with other foetal tissues were ineffective. Proglumide, the well known gastrin antagonist, similarly inhibited both gastrin- and SAE, SAC, SAD antisera-induced contraction of isolated smooth muscle cells.

Animals↗

PubMed1988

Inhibition of climbing and mossy fiber input to mouse cerebellar Purkinje cells by cholecystokinin.

Cholecystokinin (CCK)-8S was found both to decrease basal and to antagonize harmaline-dependent increases in cerebellar cyclic GMP (cGMP) in the mouse. These actions were not blocked by parenteral pretreatment with naloxone, proglumide or CR-1409, indicating a central-type CCK receptor activation with no involvement of opioid systems. These data were further confirmed by the greater potency (200x) of intraventricular relative to s.c. doses for CCK-8S. The intraventricular administration of CCK-4, t.BOC.CCK-4 and CCK-8US also resulted in decreased cerebellar cGMP levels, consistent with a central-type CCK receptor action. Direct administration of CCK-8S into the cerebellum failed to alter either basal or harmaline-stimulated cerebellar cGMP levels, indicating that the actions of this peptide on cerebellar cGMP are not directly at the level of the cerebellum. The convulsants, picrotoxin and pentylenetetrazol, elevated cerebellar cGMP with no antagonism by pretreatment with s.c. CCK-8S. In marked contrast, the increases in cerebellar cGMP induced by treatment with amphetamine, apomorphine, DN 1417, oxotremorine and harmaline were all antagonized by pretreatment with s.c. CCK-8S. These data are consistent with CCK receptor involvement in the regulation of climbing and mossy fiber input to the cerebellum. These actions apparently involve the central-type CCK receptor that resides outside of the cerebellum proper. The exact site(s) of action for CCK-8S remain(s) to be defined.

Animals↗

PubMed1987

Population response of midbrain dopaminergic neurons to neuroleptics: further studies on time course and nondopaminergic neuronal influences.

In the present study, we examined the effects of the cholecystokinin receptor antagonist, proglumide, on the depolarization-induced inactivation of A9 and A10 dopaminergic neurons produced by repeated administration of a classical antipsychotic drug (dopamine receptor antagonist). In addition, we studied the nature of the effects of acute (1-48 hr) and long-term (7 month) treatment with the butyrophenone neuroleptic haloperidol on both the basal firing rate and population response of dopamine-containing neurons in these 2 regions. Acute oral administration of haloperidol (0.5 mg/kg) results, within 1 hr of administration, in an increase in both the firing rate and number of spontaneously active dopamine neurons encountered in both A9 and A10 regions. These effects of a single treatment persist for a minimum of 6 hr and, with respect to firing rate, are not completely normalized for at least 24 hr. In contrast, 7 month continuous treatment with haloperidol reduces the number of spontaneously active DA neurons encountered in both regions in a manner similar to that observed at 21 d. This effect is inferred to be due to the induction of depolarization-induced inactivation of these neurons, since the acute administration of the normally hyperpolarizing, direct-acting dopamine receptor agonist apomorphine (64 micrograms/kg) immediately reverses this reduced number of cells per track to near control levels. This effect appears to be dependent on the continued presence of haloperidol since, when animals treated for 7 months are sampled 14 d after the cessation of drug administration, spontaneous activity is no different from that observed in age-matched controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

Behavioral effects of cholecystokinin and its related peptides in rats.

Behavioral effects of cholecystokinin (CCK) were observed in neofrontal decorticated and sham-operated rats. In the decorticated rats the cataleptic and analgesic effects of beta-endorphin were markedly enhanced. When CCK-antiserum was administered together with beta-endorphin, these effects were also enhanced. Sulfated CCK-8 decreased locomotion and rearing in open field test. Proglumide, a selective antagonist of CCK, blocked CCK-8-induced-hypomotility, but it had no influence on the actions of CCK-4. When general activity was monitored using an Automex, the activity counts markedly increased in the decorticated rats, while in the sham-operated rats such increase was not observed. Non-sulfated CCK-8 also stimulated the motility, particularly in the decorticated rats. On the other hand, CCK-4 was opposite to the results of CCK-8. In the decorticated rats rearing, sniffing and head stereotypy were increased by CCK-8, but grooming was not affected.

Animals↗

PubMed1980

Effects of antigastrin drugs on the interaction of 125I-human gastrin with rat gastric mucosa membranes.

A method for studying the interaction of 125I-human gastrin with a rat gastric mucosal membrane fraction is described, and the saturability, high affinity and reversibility of the preparations, as well as the correlation of pharmacological responses to antigastrin-drugs with the observed binding are discussed. Proglumide and other antigastrin drugs inhibit gastrin binding in a dose-dependent way, and their activities in such a system are well correlated with the "in vivo" antisecretory activities of these drugs.

Animals↗

PubMed1995

Effect of succinyl cholecystokinin heptapeptide on synaptosomal 45Ca uptake of mouse hippocampus.

AIM: To study the effect of a new peptide, succinyl cholecystokinin heptapeptide (SCH), on the uptake of 45Ca by synaptosomes from mouse hippocampus, and compare it with that of sincalide. METHODS: Protein concentration was determined by the dye method. 45Ca uptake was determined by adding 45CaCl2 into synaptosome suspending solution. Samples were incubated and terminated by filtration through glass microfiber filters and finally counted in a Beckman LS 9800 liquid scintillation spectrometer. RESULTS: SCH 0.125 - 2 mumol.L(-1) dose-dependently depressed synaptosomal 45Ca uptake, and the depressive extent was similar to that of sincalide. The suppressive effect induced by either SCH or sincalide on synaptosomal 45Ca uptake was antagonized by proglumide, which itself did not affect 45Ca uptake of synaptosomes. The inhibition of synaptosomal 45Ca uptake induced by SCH or sincalide was blocked by beta-endorphin. CONCLUSION: The replacement of the N-terminal aspartic acid residue of sincalide does not influence its effect on 45Ca uptake of hippocampal synaptosomes.

Animals↗