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PubMed1990

Effects of CCK-receptor antagonists on CCK-stimulated pepsinogen secretion and calcium increase in isolated guinea pig gastric chief cells.

The effects of CCK-receptor antagonists such as dibutyryl cyclic GMP (dbcGMP), L-364,718, and CR1409 on COOH-terminal octapeptide of CCK (CCK-8)-stimulated chief cell responses were examined using isolated guinea pig gastric chief cells. L-364,718 and CR1409 inhibited CCK-8-stimulated pepsinogen secretion over the same concentration range as they inhibited CCK-8-stimulated increases in intracellular Ca2+ concentration ([Ca2+]i), respectively. Schild analysis of the CCK dose-response curve indicates that L-364,718 and CR1409 exert their inhibitory effects on CCK-8-stimulated chief cell responses in a competitive manner. By contrast, dbcGMP inhibited not only CCK-8- but also carbachol-stimulated pepsinogen secretion. Furthermore, dbcGMP inhibited CCK-8-stimulated pepsinogen secretion more potently than the increases in [Ca2+]i. These results suggest that L-364,718 and CR1409 act as CCK-receptor antagonists, but dbcGMP has another inhibitory effect on pepsinogen secretion in addition to the effect as a CCK-receptor antagonist in guinea pig gastric chief cells.

Animals↗
PubMed1990

Oral administration of loxiglumide (CCK antagonist) inhibits postprandial gallbladder contraction without affecting gastric emptying.

The effect of a single oral dose of loxiglumide, a cholecystokinin antagonist, on postprandial gallbladder contraction and on gastric emptying was evaluated in humans. Following a 12-hr fasting period, two tablets of loxiglumide (400 mg each) or placebo was administered on different days, in random order and in a double-blind fashion to 10 healthy volunteers 15 min before the ingestion of a 1050-kcal standard meal. Gallbladder and antral volumes were measured by real-time ultrasonography in basal conditions and at fixed time intervals after the meal. Oral loxiglumide administration was followed by a total inhibition of the gallbladder contraction for 60 min after the end of the meal ingestion. Thereafter, up to the end of the study period, gallbladder volume was larger than that of the placebo study (at 300 min after the meal 2.7 +/- 1.6 ml after placebo and 8.2 +/- 3.5 ml after loxiglumide; P less than 0.008). No difference between placebo and loxiglumide was found in the antral volumes at any time interval (postprandial 63.5 +/- 16.5 ml after placebo and 59.4 +/- 24 ml after loxiglumide; at 300 min after the meal 20.8 +/- 13.3 ml after placebo and 18.9 +/- 9.5 ml after loxiglumide). In conclusion, a single oral dose of loxiglumide at the dose of 800 mg can inhibit postprandial gallbladder contraction without affecting gastric emptying. It would therefore appear that in man endogenous CCK, released after a solid-liquid, caloric, nutrient-balanced meal, plays a major role in the contraction of the gallbladder but does not affect gastric emptying.

Administration, Oral↗
PubMed1990

Role of cholecystokinin in bombesin- and meal-stimulated pancreatic polypeptide secretion in dogs.

This study was undertaken to delineate the role of cholecystokinin (CCK) in bombesin- and meal-stimulated pancreatic polypeptide (PP) secretion in seven conscious dogs by studying: (1) the stimulatory effect of similar plasma levels of CCK induced by a meal and infusions of bombesin and the synthetic CCK analog cerulein on plasma PP, and (2) the inhibition of PP secretion by the CCK-receptor antagonist CR-1409 during these three stimuli. The stimulation of PP secretion during bombesin (11.0 +/- 1.6 nM/hr) and after the meal (8.9 +/- 2.0 nM/hr) were significantly (P less than 0.05) greater than during infusion of the CCK analog cerulein (2.7 +/- 0.4 nM/hr). CR-1409 significantly inhibited the bombesin- and meal-stimulated PP secretion to 2.0 +/- 0.4 nM/hr (81%; P less than 0.05) and 3.1 +/- 1.2 nM/hr (47%; P less than 0.05), respectively, while the cerulein-stimulated PP release was almost abolished to 0.2 +/- 0.1 nM/hr (93%; P less than 0.05) by the drug. These findings point to an important role for CCK in the regulation of bombesin- and meal-stimulated PP secretion.

Animals↗
PubMed1995

Effect of endogenous cholecystokinin on postprandial gallbladder refilling. Ultrasonographic study in healthy subjects and in gallstone patients.

The postprandial release of cholecystokinin (CCK) regulates gallbladder (GB) contraction but little is known about the role, if any, of the still-elevated CCK blood levels on subsequent GB refilling. To assess the role of CCK in GB refilling, a CCK-receptor antagonist, loxiglumide, or saline were infused intravenously in a random double-blind fashion after the ingestion of a liquid test meal in 16 healthy subjects. An identical study protocol was performed in 10 GB "contractor" patient with radiolucent stones to ascertain whether the reported reduced CCK effect on GB emptying also affects GB refilling. GB volumes were assessed ultrasonographically in the fasting state and for 150 min at 15-min intervals after meal ingestion. GB volumes during postprandial refilling were significantly greater during loxiglumide than placebo infusion (P < 0.01), but they did not differ between gallstone and control subjects. In conclusion, postprandial endogenous CCK has a relevant role in delaying GB refilling, and this effect is not altered in patients with radiolucent gallstones.

Adult↗
PubMed1994

Physiological role of cholecystokinin on gastric emptying and acid output in dogs.

We investigated the physiological role of cholecystokinin (CCK) on gastric emptying and acid secretion in seven conscious dogs with gastric cannulae. Two hundred milliliters of a 4% amino acid meal was given via the cannula, and both gastric emptying and acid output were measured concurrently using a dye-dilution technique. Gastric emptying of the liquid amino acid meal was exponential, and the acid output and plasma concentrations of CCK, gastrin, and somatostatin peaked within 30 min after the meal. Intravenous infusion of CCK-8 at 28 and 56 pmol/kg/hr but not 14 pmol/kg/hr increased plasma levels of the peptide and inhibited gastric emptying as well as acid output. Plasma gastrin was not affected significantly by the CCK infusion, whereas plasma somatostatin increased significantly in response to 56 pmol/kg/hr of CCK-8. Loxiglumide, 22 mumol/kg/hr, significantly enhanced gastric emptying and augmented acid output, as well as plasma gastrin response, whereas it abolished the postprandial rise in plasma somatostatin. We concluded that in dogs, CCK plays an important role in the physiologic regulation of postprandial gastric emptying of a liquid caloric meal and acid output. Its inhibitory effect on gastric acid secretion appears to be mediated, at least in part, by somatostatin.

Animals↗
PubMed1996

Effects of cholecystokinin and carbachol on membrane fluidity in pancreatic acini.

The effects of pancreatic secretagogues on the membrane fluidity of pancreatic acini were investigated using 1-[4-(trimethylammonium)phenyl]-6-phenyl-1,3,5-hexatriene iodide as a probe. Two kinds of pancreatic secretagogues, one category of which induces acute pancreatitis (cholecystokinin and carbachol) and another which does not induce acute pancreatitis (bombesin, CCK-JMV-180, and secretin), as well as lecithin were used to investigate the effect of changes in membrane fluidity of acini. Our study revealed that the membrane fluidity of the pancreatic acini was unaffected by a physiological dose (10(-11) M) of cholecystokinin. However, stimulation with a supramaximal dose of cholecystokinin (10(-8) M) increased membrane fluidity markedly within 20 min. Membrane fluidity increased dose-dependently with increasing CCK stimulation. A supramaximal dose of cholecystokinin also induced bleb formation and increased LDH release. These phenomena were blocked by simultaneous incubation with CR1505 (Loxiglumide), a potent antagonist of peripheral cholecystokinin receptors. A supramaximal dose of carbachol (10(-3) M) also induced increases in the membrane fluidity. Pancreatic secretagogues that do not induce acute pancreatitis did not induce alterations in membrane fluidity. Lecithin increased both membrane fluidity and LDH release. These observations suggest that this increase in membrane fluidity of the pancreatic acini may be related to membrane alteration and to functional damage of the acini. These observations [correction of observation] can serve as a window to detect the development of acute pancreatitis at an early stage.

Animals↗
PubMed1995

Effect of gastrin-releasing peptide (GRP) on guinea pig gallbladder contraction in vitro.

Few studies have reported the effects of gastrin-releasing peptide (GRP)/bombesin on the guinea pig gallbladder, and the results are contradictory. Because such contradictory results may, in part, be due to technical factors, we investigated the effect of GRP on guinea pig gallbladder smooth muscle, using an improved horizontal organ bath. The guinea pigs were killed and the gallbladder was removed. Four longitudinal muscle strips (2 x 12 mm) were suspended in Krebs-Ringer solution at 37 degrees C and aerated with 95% O2 and 5% CO2. The mechanical activity of the strips was recorded isotonically by displacement-voltage transducers, via L-arms, to which a piezoelectric element with a frequency of 100 Hz and movement of 50 microns was applied. GRP contracted gallbladder muscle strips dose dependently, but the calculated maximal response was 22.4% and 20.1% of the acetylcholine- and cholecystokinin octapeptide (CCK8)-induced responses, respectively. The GRP-induced contraction was unaffected by the muscarinic blocker, atropine, or by the CCK receptor antagonist, loxiglumide. It is concluded that GRP weakly, but apparently directly, stimulates guinea pig gallbladder contraction.

Acetylcholine↗
PubMed1996

Role of endogenous platelet-activating factor in the regulation of pancreatic blood flow during caerulein stimulation.

The role of endogenous platelet-activating factor (PAF) in the control of pancreatic blood flow during caerulein stimulation was investigated. Pancreatic blood flow in anesthetized rats was measured continuously by laser Doppler flowmetry for 2 h during the intravenous infusion of caerulein (0.25 micrograms/kg per h). Pancreatic blood flow showed a gradual, consistent, and significant increase, reaching 114.2 +/- 2.3% of the basal value after 120 min. Changes in pancreatic blood flow induced by caerulein were completely inhibited by a cholecystokinin (CCK) antagonist (loxiglumide, 5 mg/ kg per h, i.v.) and by a specific PAF antagonist (CV-6209, 1 mg/kg, i.v.-bolus). Systemic blood pressure remained stable in all groups. These results suggest an important role of endogenously yielded PAF in regulating pancreatic blood flow during caerulein stimulation to the pancreas.

Animals↗
PubMed1996

Effect of a cholecystokinin receptor antagonist (loxiglumide) on gallbladder contractile function in guinea pigs.

We evaluated the effect of the specific cholecystokinin (CCK) receptor antagonist, loxiglumide, on gallbladder contractile function in guinea pigs. Five mg/kg body weight (BW) of loxiglumide was administered orally to guinea pigs once a day for 3 days. We then investigated gallbladder contractile function and plasma CCK concentrations in the guinea pigs. Maximal gallbladder pressure induced by cerulein was significantly depressed on the 1st and 3rd days following loxiglumide administration. On the 1st day, the plasma CCK concentration was significantly increased compared with that of the control group during fasting and 15 min after the administration of an intraduodenal test meal. These results suggest that the disturbed gallbladder contraction is due to the competitive inhibition of CCK by loxiglumide. Gallbladder contractile function in guinea pigs is depressed by loxiglumide; however, this effect is reversible after short-term loxiglumide administration.

Animals↗
PubMed1995

Effects of intraduodenal administration of a low dose of cholecystokinin (CCK) antagonist (CR-1505) on plasma CCK concentration, intestinal CCK content, and levels of CCK mRNA.

The effects of the intraduodenal administration of a low dose of CR-1505 for 3-7 days on the gene expression of cholecystokinin (CCK), plasma CCK concentration, and CCK content in the intestinal mucosa were examined in rats. The simultaneous changes of protein and enzyme content in the pancreas were also determined. CR-1505 was infused continuously into the duodenum at a dose of 3 mg/kg per day, calculated to correspond to a dose of 150-200 mg/day in humans. Seven days after the administration of CR-1505, a liquid meal (4.5 kcal/3 ml) was introduced into the stomach and changes in the intestinal CCK content and plasma CCK concentration were examined. The level of CCK mRNA in the intestine was significantly higher in rats treated with CR-1505 than in control rats. The plasma CCK concentration, the CCK content of the intestinal mucosa, and the composition of pancreatic enzymes did not significantly differ in rats treated with CR-1505 and the untreated controls. In control rats, the administration of the liquid meal increased the plasma CCK concentration and significantly decreased the intestinal CCK content in water extracts, but did not affect the amount extracts in acid whereas the ingestion of the meal did not cause any significant changes in rats treated with CR-1505. These findings indicate that a low dose of CR-1505 stimulates the gene expression of CCK without enhancing CCK release or exerting an effect on the pancreas.

Animals↗
PubMed1996

Duration of anti-cholecystokinin (CCK) action on the rat exocrine pancreas of new CCK receptor antagonist FK480 administered orally.

We assessed the duration of the anti-cholecystokinin (CCK) action of FK480, a new non-peptide CCK-A receptor antagonist developed in Japan, in an in vivo study in rats, comparing it with CR 1505. Pancreatic exocrine secretion stimulated by intravenous infusion of CCK-8 (0.06 microgram/kg per h) was measured at intervals of 0-24 h after the oral administration of FK480 (1.5 mg/kg) and CR 1505 (30 mg/kg). FK480 significantly inhibited both CCK-stimulated pancreatic juice volume flow and amylase output 0, 4, 8, and 12 h after oral administration, whereas the inhibitory effect of CR 1505 had completely disappeared by 8 h after oral administration. It was concluded that orally administered FK480 has a prolonged anti-CCK action.

Administration, Oral↗
PubMed1990

Growth-promoting effects of gastrin on mouse colon cancer cells in vitro: absence of autocrine effects.

We have previously demonstrated trophic effects of gastrin on mouse colon cancer (MC-26) cells, in vivo, and demonstrated the presence of gastrin receptors (GR) on these cells. The cellular and intracellular mechanism by which gastrin expresses trophic effects on colon cancer cells is, however, as yet unknown. For us to start investigating the possible mechanisms involved, it was important that we first develop an in vitro model, in which gastrin expresses its trophic effects directly on the MC-26 cells. The growth-promoting effects of gastrin on the MC-26 cells were examined in various in vitro culture models, in terms of [3H]thymidine incorporation and cell number. A significant trophic effect of gastrin could be demonstrated on quiescent cells in culture, in the absence of serum. The optimal cell-culture conditions for observing trophic effects of gastrin were defined and included a 24-h period of rapid growth of MC-26 cells in serum-supplemented normal growth medium, followed by a 24-h period of culture in serum-free medium containing an optimal dose (1.0 mM) of thymidine, to achieve growth-arrest of the cells. Addition of gastrin (0.5 to 25 nM) to the quiescent, growth-arrested cells resulted in significant dose-dependent increases in both the incorporation of [3H]thymidine uptake by the cells, and a significant increase in cell number. The concentration of GR on the growth-arrested quiescent MC-26 cells in culture was significantly increased compared to the GR concentration on the control, asynchronized cells. The increased presence of GR on the growth-arrested, synchronized MC-26 cells may have allowed us to observe a significant trophic effect of gastrin on the MC-26 cells, in vitro itself. To determine if gastrin was functioning as an autocrine growth factor for MC-26 cells, we examined the effect of gastrin antibodies on the growth of MC-26 cells; no significant effect of the antigastrin IgG on the growth of MC-26 cells was observed.

Animals↗
PubMed1992

Growth inhibition of human pancreatic cancer cells by cholecystokinin receptor antagonist in tissue culture and in nude mice.

The Human pancreatic carcinoma cell line KP-1N and its clone KP-1NL which has a high rate of liver metastasis were established. Ki-ras DNA point mutation on the codon 12 was found. The growth of KP-1N was stimulated by a physiological range of concentration (10(-11)-10(-10) M) of cholecystokinin and the increase was inhibited by the addition of a cholecystokinin receptor antagonist (CR 1505). Daily injections of CR 1505 (35 mg/kg) diminished the number of tumor colonies in the liver that were formed after an intrasplenic injection of the highly liver metastatic KP-1NL cells. These results suggest that cholecystokinin antagonists may be useful as growth inhibitors for some pancreatic cancer.

Adenocarcinoma↗
PubMed1988

Effects of cisapride on the pancreatic exocrine secretion in rats.

Exocrine pancreatic secretion to intravenous injections of a new stimulant of gastrointestinal motility, R51,619 (cisapride) was studied in conscious rats, and in the isolated pancreatic acini in vitro. The injection of cisapride (2 mg/kg) significantly increased fluid, bicarbonate and protein output in vivo. Atropine completely abolished the pancreatic responses to cisapride, and CR 1409, a new glutaramic acid derivative and a competitive cholecystokinin (CCK) inhibitor, tended to decrease the cisapride-induced pancreatic exocrine secretion. However, amylase release and Ca2+ efflux from the isolated pancreatic acini were not stimulated. These results suggest that cisapride indirectly affects the pancreatic exocrine secretion primarily by releasing acethycholine from the intrapancreatic nerve endings and in part by releasing CCK from the duodenum, but has no direct action on the pancreas.

Acetylcholine↗
PubMed1991

Bioactivity of synthetic human cholecystokinin (CCK)-33 in vitro and in vivo.

The relative potencies of synthetic human cholecystokinin (h-CCK)-33, porcine CCK-33 (p-CCK-33) and CCK-8 were examined by measuring pancreatic secretion in the conscious rat (in vivo) and amylase release from rat pancreatic acini using a perifusion study (in vitro). The increments of protein output during an 1-hr infusion of 100 pmol/kg/hr of h-CCK-33, p-CCK-33 and CCK-8 were 27.0 +/- 2.9 mg/hr (M +/- SE), 19.3 +/- 2.8 and 14.0 +/- 1.8 mg/hr, respectively. H-CCK-33 and p-CCK-33 showed significantly higher responses of protein output than CCK-8 in a same molar ratio, in vivo. In vitro, the stimulation with 10(-10) M h-CCK-33, p-CCK-33 and CCK-8 led to a similar biphasic amylase release in a perifusion study. Twenty-five microM CR-1409, an antagonist for CCK receptor, completely inhibited the 10(-10) M h-CCK-33-stimulated amylase release. Although it was found that h-CCK-33 and p-CCK-33 were more potent than CCK-8 in vivo, 10(-10) M CCK-8, h-CCK-33 and p-CCK-33 were equipotent on rat pancreatic acini in vitro. It is suggested that the discrepancy in potencies of the large molecular form and small molecular form of CCK in vivo and in vitro may be attributed to the delay of degradation of the large molecular form of CCK in vivo.

Amylases↗
PubMed1990

Role of secretin and cholecystokinin in oleic acid-stimulated pancreatic secretion in rats.

We investigated the possible role of endogenous secretin and cholecystokinin (CCK) on oleic acid-stimulated pancreatic exocrine secretion in anesthetized rats. Intraduodenal infusion of oleic acid (pH 6.5) in three different doses (0.06, 0.25 and 1 mmole/hr) resulted in dose-related increases in pancreatic juice volume, bicarbonate and amylase outputs (r = 0.665, 0.736 and 0.517, respectively) (P less than 0.001). Plasma secretin and CCK concentrations also elevated significantly in response to oleic acid, in a dose-related manner (r = 0.721 and 0.546, respectively) (P less than 0.001). There were statistically significant correlations between plasma secretin concentrations and bicarbonate outputs, and between plasma CCK concentrations and amylase outputs in response to oleic acid (P less than 0.01). Potent CCK antagonist, CR 1409 (5 mg/kg.hr) administered intravenously suppressed completely increase in amylase output induced by oleic acid, and partially in juice volume and bicarbonate output. It is concluded that both endogenous secretin and CCK play important roles on oleic acid-induced pancreatic secretion in rats.

Amylases↗
PubMed1993

Duration and potency of anticholecystokinin action of subcutaneous and oral loxiglumide on cerulein-stimulated pancreatic exocrine secretion.

The duration and the potency of the antiCCK activities of loxiglumide given by sc and oral routes were examined in rats. Pancreatic juice flow and protein output in response to an iv bolus injection of cerulein (100 ng/kg body wt) were measured at specified time intervals from 1-12 h after loxiglumide administration. Subcutaneous loxiglumide (10 g/kg body wt) effectively suppressed cerulein-stimulated protein output for 4 h and pancreatic juice volume for 6 h, when total outputs during a 60-min period after cerulein stimulation were compared with the control value without loxiglumide pretreatment. Oral dose of loxiglumide exerted longer-term anti-CCK activity (protein output: 6 h, pancreatic juice: 8 h) than the same sc dose. In addition, oral loxiglumide showed more potent suppression of protein output than the same sc dose at the corresponding time interval. Higher oral dose of loxiglumide (50 mg/kg body wt) caused longer inhibition on both protein (8 h) and pancreatic juice secretion (12 h). These results suggest that the half-life of loxiglumide given by oral route is longer than that by sc route or that the bioavailability of oral loxiglumide is higher than that of sc dose. The present study demonstrates that loxiglumide, given either by sc or by oral route, has long duration of action in antagonizing responses to exogenously administered cerulein.

Administration, Oral↗
PubMed1995

Cholecystokinin (CCK) in the amino acid uptake and enzyme protein secretion by the pancreas in humans.

Activation of type A receptors by CCK or cerulein is known to stimulate pancreatic enzyme secretion, but its role in the amino acid (AA) consumption and enzyme synthesis remains unclear. In our study, we used loxiglumide, a potent CCK-A-receptor antagonist, to investigate the role of CCK-A receptors in pancreatic consumption of circulating AAs and enzyme secretion. Five healthy male volunteers were intubated with double-lumen duodenal tube, and duodenal aspirates were collected during 60-min basal periods and then during pancreatic stimulation with iv infusion of secretion (80 pmol/kg/h) plus cerulein (50 pmol/kg/h) during three consecutive 30-min periods. The same procedure was repeated, but secretin-cerulein infusion was combined with a constant dose of loxiglumide (20 mumol/kg/h). The volume and outputs of HCO3-, protein and enzymes (amylase and trypsin) in duodenal aspirates and gallbladder volume (by sonography) were determined at 30-min intervals. Plasma samples were drawn for total plasma AA assay by ninhydrin method to assess the pancreatic uptake of free AAs. Infusion of secretin plus cerulein caused a several-fold increase in the volume of duodenal aspirate and the outputs of HCO3-, protein, and enzymes. During those periods, plasma AA level decreased from initially 2.20 +/- 0.3 mmol/L to 1.09 +/- 0.3 mmol/L (p < 0.01) and the gallbladder volume from initially 28 +/- 8 mL to 2 +/- 0.4 mL. This increase in pancreatic secretory outputs was accompanied by significant increments in plasma insulin, glucagon, PP, and somatostatin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗