Effect of immunoneutralisation of cholecystokinin on bombesin-stimulated pancreatic enzyme secretion in the rat

Infusion of bombesin stimulates plasma cholecystokinin (CCK) and pancreatic enzyme secretion in various species, including the rat. This study was undertaken in two groups of four conscious rats with a cannulated pancreatic duct to determine the role of endogenously released CCK in mediating the effect of bombesin on pancreatic enzyme secretion. Infusion of 2 ml CCK antiserum or normal rabbit serum for 40 min was followed 10 min later by infusion of 18 pmol/kg bombesin for 30 min and after an interval of 90 min by infusion of 24 pmol/kg CCK for 30 min. After administration of control rabbit serum, pancreatic protein secretion increased by 3.2 +/- 1.0 mg/30 min during bombesin and 4.0 +/- 1.5 mg/30 min during CCK, while the plasma CCK increments were 1.7 +/- 0.5 pM and 7.0 +/- 0.9 pM for the bombesin and CCK infusions, respectively. Immunoneutralisation with the CCK antiserum did not significantly affect bombesin-stimulated pancreatic protein secretion (3.6 +/- 1.3 mg/30 min), but almost abolished the pancreatic protein response to CCK (0.5 +/- 0.2 mg/30 min). It is therefore concluded that CCK is not an important mediator of the stimulatory effect of bombesin on the pancreas in the rat.     

Effect of pancreatic enzyme supplementation on postprandial plasma cholecystokinin secretion in patients with pancreatic insufficiency

To test the hypothesis, based on studies in healthy man and dog, that patients with impaired digestion due to severe pancreatic insufficiency have impaired postprandial cholecystokinin (CCK) secretion that can be improved by the addition of pancreatic enzymes, we have studied plasma CCK responses to a test meal with and without addition of pancreatic enzymes in 10 patients with pancreatic insufficiency and steatorrhea, in 8 patients with chronic pancreatitis without steatorrhea, and in 6 healthy subjects. The patients with steatorrhea had a significantly (P less than 0.001) lower integrated plasma CCK response to the meal (177 +/- 23 pM.150 min) than the healthy subjects (468 +/- 41 pM.150 min), while patients with chronic pancreatitis without steatorrhea had an intermediate integrated postprandial CCK secretion (327 +/- 101 pM.150 min). Addition of pancreatic enzymes to the meal significantly augmented the integrated CCK response in both the patients with steatorrhea to 483 +/- 72 pM.150 min (P less than 0.01) and in those without steatorrhea to 480 +/- 85 pM.150 min (P less than 0.05). These values were not significantly different from those in the healthy subjects (521 +/- 86 pM.150 min). Integrated CCK secretion in the three groups during bombesin infusion was similar (patients with steatorrhea 134 +/- 23 pM.20 min, patients without steatorrhea 131 +/- 33 pM.20 min, and healthy subjects 146 +/- 28 pM.20 min), indicating a normal capacity to secrete CCK in response to a humoral stimulus. These data are in agreement with the suggestions from previous studies that digestion of nutrients by pancreatic enzymes plays an important role in the regulation of plasma CCK secretion after feeding.     

The effects of antagonists of receptors for gastrin, cholecystokinin and bombesin on growth of gastroduodenal mucosa and pancreas.

The effects of gastrin, cholecystokinin (CCK) and bombesin on the DNA synthesis, as a biochemical indicator of trophic action in the gastroduodenal mucosa and the pancreas have been examined in rats fasted for 48 h and in rats refed for 16 h with or without administration of specific receptor antagonists for bombesin, gastrin and CCK. Bombesin and gastrin administered three times daily for 48 h in fasted rats significantly increased the rate of DNA synthesis as measured by the incorporation of [3H] thymidine into DNA in each tissue tested. CCK significantly increased DNA synthesis in the duodenal mucosa and pancreatic tissue, but not in the gastric mucosa. The stimulation of DNA synthesis induced by bombesin in the gastroduodenal mucosa and pancreas was abolished by bombesin/GRP receptor antagonist, RC-3095. RC-3095 did not affect DNA synthesis stimulated by gastrin and CCK in these tissues. L-365,260, a receptor antagonist for gastrin suppressed the DNA synthesis induced by gastrin but not by CCK or bombesin in the gastrointestinal mucosa and pancreas. L-364,718 a specific antagonist for CCK receptors was effective only against CCK stimulated duodenal mucosa and pancreatic growth. Refeeding of 48 h fasting rats strongly enhanced the DNA synthesis in all tissues tested, and this effect was significantly reduced in the gastroduodenal mucosa by blocking only gastrin receptors (with L-365,260) and that in the duodenal mucosa and the pancreas by antagonizing of CCK receptors (with L-364,718). Antagonism of bombesin receptors (with RC-3095) did not significantly affect the stimulation of DNA synthesis induced by refeeding in all tissues tested. This study indicates that the stimulation of DNA synthesis can be achieved by exogenous gastrin, CCK and bombesin acting through separate receptor but that only gastrin and CCK play the major role in the postprandial stimulation of the growth of gastroduodenal mucosa and pancreatic tissue.     

CCK-antagonist L-364,718: influence on rat pancreatic growth induced by caerulein and bombesin-like peptides

The present study investigates the inhibitory effect of the novel potent benzodiazepine-related CCK-antagonist L-364,718 on pancreatic growth in the rat induced by chronic administration of caerulein and bombesin-like peptides. Caerulein, injected s.c. twice daily at a dose of 1 microgram/kg body weight, and bombesin (10 micrograms/kg) induced a similar increase (1.5-3-fold) in pancreatic wet weight, total protein, amylase, trypsin, putrescine and spermidine content after 14 days of treatment. Growth induced by caerulein showed a significant increase in total DNA content suggesting cellular hyperplasia, whereas bombesin-like peptides led to cellular hypertrophy. In comparison to bombesin the decapeptide neuromedin C (10 micrograms/kg) was found to be 30-50% less potent. In the same dose range, neuromedin B and the tachykinins neurokinin A and B, all structurally related to bombesin, had no significant trophic effect on the rat pancreas. Administration of the CCK-antagonist L-364,718 twice daily at a dose of 0.1 mg/kg or at 1.0 mg/kg, either s.c. or orally, led dose-dependently to a near-complete inhibition of the caerulein-induced trophic effect. In contrast, L-364,718 administered at identical dosages, did not affect pancreatic hypertrophy induced by bombesin and neuromedin C. It is concluded that both peptides mediate their effect on the rat pancreas directly and not via release of endogenous cholecystokinin. Tachykinins are not involved in the regulation of pancreatic growth. Caerulein- and bombesin-like peptides have comparable effects on the stimulation of protein and polyamine synthesis.     

The cholecystokinin receptor antagonist CR1409 increases plasma cholecystokinin in rats

This study was undertaken to determine whether plasma cholecystokinin (CCK) levels are affected by the administration of the CCK-receptor antagonist CR1409 to rats. Infusion of 0.19, 0.94 and 4.75 mg/kg.h CR1409 for 30 min each into 6 conscious rats increased (P less than 0.05) plasma CCK from 1.3 +/- 0.5 to 6.0 +/- 1.2, 5.4 +/- 1.2, and 5.4 +/- 1.0 pM, respectively. In a subsequent study infusion of stepwise increasing lower doses of 0.3, 1.5, 7.5, 37.5 and 187.5 micrograms/kg.h CR1409 for 30 min each into 6 other rats dose-dependently increased (P less than 0.05) plasma CCK from 1.4 +/- 0.3 to 3.1 +/- 0.6, 4.1 +/- 0.8, 5.4 +/- 1.0, 5.9 +/- 0.8 and 7.1 +/- 1.1 pM, while infusion of saline did not affect plasma CCK concentrations. We therefore conclude that the CCK-receptor antagonist CR1409 increases plasma CCK in the rat.     

The effect of antagonist of receptors for gastrin, cholecystokinin and bombesin on growth of gastroduodenal mucosa and pancreas.

The effects of gastrin, cholecystokinin (CCK) and bombesin on the DNA synthesis, as a biochemical indicator of trophic action in the gastroduodenal mucosa and the pancreas, have been examined in rats fasted for 48 h and in rats refed for 16 h with or without administration of specific receptor antagonists for bombesin, gastrin and CCK. Bombesin and gastrin administered three times daily for 48 h in fasted rats significantly increased the rate of DNA synthesis as measured by the incorporation of [3H] thymidine into DNA in each tissue tested. CCK significantly increased DNA synthesis in the duodenal mucosa and pancreatic tissue, but not in the gastric mucosa. The stimulation of DNA synthesis induced by bombesin in the gastroduodenal mucosa and pancreas was abolished by bombesin/GRP receptor antagonist, RC-3095. RC-3095 did not affect DNA synthesis stimulated by gastrin and CCK in these tissues. L-365,260, a receptor antagonist for gastrin suppressed the DNA synthesis induced by gastrin but not by CCK or bombesin in the gastrointestinal mucosa and pancreas. L-364,718, a specific antagonist for CCK receptors was effective only against CCK stimulated duodenal mucosa and pancreatic growth. Refeeding of 48 h fasting rats strongly enhanced the DNA synthesis in all tissues tested, and this effect was significantly reduced in the gastroduodenal mucosa by blocking only gastrin receptors (with L-365, 260) and that in the duodenal mucosa and the pancreas by antagonizing of CCK receptors (with L-364,718). Antagonism of bombesin receptors (with RC-3095) did not significantly affect the stimulation of DNA synthesis induced by refeeding in all tissues tested. This study indicates that the stimulation of DNA synthesis can be achieved by exogenous gastrin, CCK and bombesin acting through separate receptors, but that only gastrin and CCK play the major role in the postprandial stimulation of the growth of gastroduodenal mucosa and pancreatic tissue.     

Effect of the specific cholecystokinin-receptor antagonist loxiglumide on bombesin stimulated pancreatic enzyme secretion in man.

We have investigated the effects of the specific cholecystokinin (CCK) receptor antagonist loxiglumide on basal and bombesin stimulated pancreatic enzyme secretion, bilirubin output and plasma CCK release in six healthy subjects. The data were compared with those obtained in control experiments where saline was infused instead of loxiglumide. Basal amylase output (4.7 +/- 0.8 kU/45 min), trypsin output (2.9 +/- 0.8 kU/45 min) and bilirubin output (7.7 +/- 2.8 mmol/45 min) gradually declined during infusion of loxiglumide to values of 1.3 +/- 0.3 kU/45 min, 0.5 +/- 0.1 kU/45 min and 0.4 +/- 0.0 mmol/45 min, respectively, reaching statistical significance (P less than 0.05) in the 30 to 45-min period after the start of the loxiglumide infusion. In the control experiments saline infusion failed to influence basal amylase, trypsin and bilirubin output, while bombesin stimulated amylase output from 4.7 +/- 0.8 kU/45 min to 25.1 +/- 5.1 kU/45 min (P less than 0.05), trypsin output from 2.9 +/- 0.8 kU/45 min to 11.6 +/- 2.0 kU/45 min (P less than 0.05) and bilirubin output from 7.7 +/- 2.8 mmol/45 min to 68.0 +/- 16.0 mmol/45 min (P less than 0.05). Loxiglumide failed to significantly influence bombesin stimulated amylase output (36.7 +/- 9.0 kU/45 min) and trypsin output (8.3 +/- 2.9 kU/45 min), but almost abolished bilirubin output (9.7 +/- 3.6 mmol/45 min) (P less than 0.05). Basal plasma CCK (2.4 +/- 0.1 pM) was not significantly influenced by loxiglumide (2.4 +/- 0.2 pM).(ABSTRACT TRUNCATED AT 250 WORDS)     

Endogenous amylin contributes to the anorectic effects of cholecystokinin and bombesin

Previous studies indicated that amylin contributes to the anorectic effects of cholecystokinin (CCK) and bombesin (BBS), possibly by enhancing the release of pancreatic amylin or by modulating their anorectic actions within the central nervous system (CNS). To elucidate the interaction between amylin and CCK or BBS, respectively, we investigated the influence of an IP injection of CCK or BBS on feeding in amylin-deficient mice (IAPP(-/-)). The anorectic effects of CCK and BBS were nearly abolished in IAPP(-/-) mice compared to wildtype (WT) mice (e.g. 20 microg/kg CCK, 1-h food intake: WT/NaCl 0.53 +/- 0.03 g; WT/CCK 0.16 +/- 0.03 g (P < 0.001); IAPP(-/-)/NaCl 0.49 +/- 0.05 g; IAPP(-/-)/CCK 0.39 +/- 0.04 g). Acute amylin replacement restored the anorectic effect of CCK in IAPP(-/-) mice.To find out whether CCK or BBS enhance the feeding-induced release of pancreatic amylin, we injected rats with CCK-8 (0.5-50 microg/kg) or BBS (5 microg/kg) and measured plasma amylin levels after injections. Neither CCK nor BBS increased the plasma amylin level in rats. We suggest that the mediation of the anorectic effects of CCK and BBS by amylin is not dependent on a CCK- or BBS-induced release of pancreatic amylin, but may rather be due to a modulation of their effects by amylin within the CNS.     

Acid inhibition by intestinal nutrients mediated by CCK-A receptors but not plasma CCK

We examined the role of CCK-A receptors in acid inhibition by intestinal nutrients. Gastric acid and plasma CCK and gastrin levels were measured in rats with gastric and duodenal fistulas during intragastric 8% peptone and duodenal perfusion with saline, complete liquid diet (CLD; 20% carbohydrate, 6% fat, and 5% protein), and the individual components of CLD. Acid output was significantly inhibited (50-60%) by CLD, lipid, and dextrose. Plasma CCK was significantly increased by CLD (from 2.6 +/- 0.3 to 4.8 +/- 0.5 pM) and lipid (4.6 +/- 0.5 pM). CCK levels 50-fold higher (218 +/- 33 pM) were required to achieve similar acid inhibition by exogenous CCK-8 (10 nmol x kg(-1) x h(-1) iv). Intestinal soybean trypsin inhibitor elevated CCK (10.9 +/- 2.5 pM) without inhibiting acid secretion. The CCK-A antagonist MK-329 (1 mg/kg iv) reversed acid inhibition caused by CLD, lipid, and dextrose. Peptone-stimulated gastrin (21.7 +/- 1.9 pM) was significantly inhibited by CLD (14.5 +/- 3.6 pM), lipid (12.3 +/- 2.2 pM), and dextrose (11.9 +/- 1.5 pM). Lipid and carbohydrate inhibit acid secretion by activating CCK-A receptors but not by altering plasma CCK concentrations.     

Role of cholecystokinin in the intestinal fat- and acid-induced inhibition of gastric secretion.

This study was designed to determine the role of cholecystokinin (CCK) in the inhibition of gastric HCl secretion by duodenal peptone, fat and acid in dogs with chronic gastric and pancreatic fistulas. Intraduodenal instillation of 5% peptone stimulated both gastric HCl secretion and pancreatic protein secretion and caused significant increments in plasma gastrin and CCK levels. L-364,718, a selective antagonist of CCK-A receptors, caused further increase in gastric HCl and plasma gastrin responses to duodenal peptone but reduced the pancreatic protein outputs in these tests by about 75%. L-365,260, an antagonist of type B receptors, reduced gastric acid by about 25% but failed to influence pancreatic response to duodenal peptone. Addition of 10% oleate or acidification of peptone to pH 3.0 profoundly inhibited acid secretion while significantly increasing the pancreatic protein secretion and plasma CCK levels. Administration of L-364,718 reversed the fall in gastric HCl secretion and significantly attenuated pancreatic protein secretion in tests with both peptone plus oleate and peptone plus acid. Exogenous CCK infused i.v. in a dose (25 pmol/kg per h) that raised plasma CCK to the level similar to that achieved by peptone meal plus fat resulted in similar inhibition of gastric acid response to that attained with fat and this effect was completely abolished by the pretreatment with L-364,718. We conclude that CCK released by intestinal peptone meal, containing fat or acid, exerts a tonic inhibitory influence on gastric acid secretion and gastrin release through the CCK-A receptors.     

Role of gastrin and cholecystokinin in the growth-promoting action of bombesin on the gastroduodenal mucosa and the pancreas.

The effects of bombesin on the growth of the gastroduodenal mucosa and the pancreas have been examined in adult rats with intact or resected antrum and following administration of somatostatin or CCK-receptor antagonist L-364,718. The peptides were administered three times daily for 7 consecutive days, and then the animals were sacrificed and growth parameters (organ weight and RNA and DNA contents) were determined, and plasma gastrin and CCK were assayed. Compared with the control (saline) values, bombesin significantly stimulated the growth of the oxyntic and duodenal mucosa and the pancreas. These effects were partly reduced but not abolished by somatostatin, antrectomy and L-364,718, suggesting that bombesin may enhance the growth partly by releasing gastrin and CCK and partly by direct action on these tissues.     

Effect of nicotine on basal and bombesin stimulated canine plasma levels of gastrin, cholecystokinin and pancreatic polypeptide

The influence of nicotine on the basal and bombesin (BBS) stimulated plasma levels of gastrin, cholecystokinin (CCK) and pancreatic polypeptide (PP) was investigated in conscious dogs. Plasma levels of nicotine and gastrointestinal (GI) hormones were measured by employing gas liquid chromatography and specific radioimmunoassay (RIA). The basal levels of gastrin, CCK and PP were found to be in pg/ml (pmol/l) (mean +/- S.E.), 28 +/- 5 (13 +/- 3), 252 +/- 32 (66 +/- 8) and 347 +/- 136 (83 +/- 32), respectively and these values remained unchanged with nicotine. Significant increases in levels of gastrin, CCK and PP were, however, found with infusions of BBS alone or with BBS in combination with nicotine. Gastrin levels were higher whereas CCK and PP levels were lower with BBS alone than with BBS plus nicotine. The peak values for CCK and PP, but not gastrin, were less during second BBS infusion. These results indicate that nicotine, in presence of bombesin, has an inhibitory effect on the release of gastrin and a stimulatory effect on the release of PP and CCK.     

Physiological plasma concentrations of cholecystokinin stimulate pancreatic enzyme secretion and gallbladder contraction in man

The present study was undertaken to determine whether infusion of cholecystokinin (CCK) to plasma concentrations comparable to those found after a meal stimulates pancreatic enzyme secretion and gallbladder contraction. Plasma CCK concentrations were measured by radioimmunoassay using antibody T204, which binds to all carboxyl-terminal CCK-peptides containing the sulfated tyrosine region. Ingestion of a standardized test meal in 7 normal subjects induced significant increases in plasma CCK from 2.0 +/- 0.2 pmol/l to levels between 4.6 +/- 0.6 and 7.3 +/- 1.0 pmol/l (p less than 0.05-p less than 0.0005). Infusion of 2.5 pmol/kg X h CCK 33 resulted in significant increases in plasma CCK from 2.0 +/- 0.2 to 3.9 +/- 0.3 pmol/l (p less than 0.0005). This infusion of CCK induced significant increases in trypsin secretion from 0.5 +/- 0.1 to 1.4 +/- 0.2 KU/15 min (p less than 0.005) and in bilirubin output from 1.6 +/- 0.7 to 30.3 +/- 8.0 mumol/15 min (p less than 0.05). It is concluded that physiological plasma concentrations of CCK stimulate pancreatic enzyme secretion and gallbladder contraction in man.     

Healing-promoting effect of bombesin treatment on chronic gastric ulcer in rats

To evaluate whether bombesin treatment has a facilitatory effect on the healing of chronic gastric ulcer, following the induction of ulcer by serosal application of acetic acid, rats were given bombesin (30 microg/kg/day; subcutaneously) or vehicle three times a day for 7, 14 or 21 days until they were decapitated. Neither food intake nor gastric emptying rate in either vehicle-treated or bombesin-treated groups was not statistically different from control rats. Similarly, ulcer indices and gastric myeloperoxidase (MPO) activities at the first and second weeks of injury were not different among the groups. However, in the 3-week ulcer group, bombesin treatment reduced tissue MPO level significantly back to control levels. Moreover, the analysis of the surface epithelium by scanning electron and light microscopy demonstrated a significant reduction in the severity of ulcers by bombesin treatment. Pretreatment with CCK antagonists (L-364,718 or L365,260; 25 micromol/kg/day) before bombesin treatment showed that neither of the CCK antagonists had a significant effect on the bombesin-mediated healing process, suggesting that CCK receptors are not involved in the action of bombesin. In accordance with the previous studies that show its acute gastroprotective effects, bombesin is also effective in promoting the healing process of chronic gastric ulcer in rats.     

Bombesin reverses bleeding-induced hypovolemic shock, in rats

In an experimental model of bleeding-induced hypovolemic shock causing the death of all saline-treated rats within 26 +/- 4 min, the intravenous injection of bombesin (2.5, 5 or 10 micrograms/kg) dose-dependently restored blood pressure, pulse amplitude, heart rate and respiratory function, and improved survival rate as assessed at the end of the experiment (2 h). The effect on cardiovascular and respiratory functions was prompt (within 1-2 min) and sustained. The release of cholecystokinin seems to be the main mechanism of action, because the anti-shock effect of bombesin is largely prevented by the CCK-antagonist, L-364,718.     

Brain CCKA receptors mediate the colonic motor response to feeding in dogs

The influence of central vs. peripheral administration of specific type A and type B CCK receptor antagonists (L364,718 and L365,260, respectively) on colonic motor hyperactivity induced by feeding and CCK8 was investigated in dogs with strain-gauge transducers implanted on the proximal and transverse colon. Intravenous injection of L364,718 (5 and 10 micrograms/kg) reduced by 26.2% and 80.1%, respectively, the 0-4-h postprandial increase in colonic motor index; at similar doses L365,260 had no effect. Intracerebroventricular administration of L364,718, at a dose (1 microgram/kg) not active by the IV route, significantly reduced (p less than 0.01) by 67.5% the feeding-induced colonic hyperactivity. In contrast, L365,260 (1-10 micrograms/kg ICV) injected was inactive. Increase in colonic motility produced by intravenous CCK8 infusion (1 microgram/kg/h) was suppressed by previous ICV and IV administration of L364,718 at doses of 1 and 10 micrograms/kg, respectively, while L365,260 was inactive at similar doses. It is concluded that CCK8 released after a meal is responsible for the postprandial increase in colonic motility and that these effects may be mediated through activation of central CCKA receptors.     

Molecular forms of cholecystokinin in human plasma during infusion of bombesin

Bombesin is a tetradecapeptide with stimulatory actions on several gastrointestinal functions. Infusion of bombesin (60 pmol/kg. 20 min) into 7 normal subjects induced significant increases in plasma cholecystokinin (CCK) as measured with 2 sequence-specific radioimmunoassays. Employing antibody 1703, specific for carboxyl-terminal CCK-peptides containing at least 14 amino acid residues, plasma CCK concentrations rose from 0.8 +/- 0.2 pmol/l to 9.9 +/- 1.7 pmol/l (p less than 0.005), while using antibody T204, specific for the sulfated tyrosine region of CCK, plasma CCK levels increased from 2.9 +/- 0.5 pmol/l to 12.4 +/- 1.3 pmol/l (p less than 0.005). Plasma samples obtained from 3 subjects during bombesin infusion were fractionated by Sephadex column chromatography. Fractionation revealed 4 molecular forms of CCK: peak I eluted in the void volume and comprised 0-7% of CCK-like immunoreactivity, peak II eluted at 35% and comprised 8-41% of CCK-like immunoreactivity, peak III eluted at 50% and comprised 44-61% of CCK-like immunoreactivity, and peak IV eluted at 75% and comprised 15-27% of CCK-like immunoreactivity. Radioimmunoassay with a carboxyl-terminal CCK-antibody fully cross-reacting with gastrin did not reveal additional molecular forms of CCK. Since both the carboxyl-terminus and the sulfated tyrosine region are required for biological activity of CCK, it is likely that all these molecular forms of CCK possess biological activity.     

Receptor binding and biological potency of despentapeptide insulin

The receptor binding and biological potency of despentapeptide insulin (DPI) was assessed in human adipocytes, rat adipocytes and rat hepatocytes. DPI displayed a lower affinity for binding to both human adipocytes (half-maximum displacement at 0.89 +/- 0.04 and 0.20 +/- 0.02 nmol/l for DPI and insulin respectively; P less than 0.001) and rat adipocytes (half-maximum displacement at 7.12 +/- 1.06 and 1.14 +/- 0.18 nmol/l respectively, P less than 0.05). However, although DPI was less potent than unmodified insulin in stimulating glucose uptake in rat adipocytes (half-maximal stimulation at 2.0 +/- 0.67 and 0.47 +/- 0.18 nmol/l respectively; P less than 0.05), DPI was equipotent with insulin in human adipocytes (half-maximal stimulation at 0.034 +/- 0.001 and 0.027 +/- 0.001 nmol/l respectively; P greater than 0.2). In rat hepatocytes, DPI was twofold less potent in binding displacement activity (half-maximum displacement at 3.8 +/- 0.9 and 1.7 +/- 0.3 nmol/l respectively; P less than 0.01) but appeared to be equivalent in stimulating amino butyric acid uptake (half-maximum stimulation at 0.98 +/- 0.12 and 0.95 +/- 0.26 nmol/l respectively). The difference in affinity of DPI binding to rat liver membranes was less marked (1.3 fold decreased compared with insulin: 5.3 +/- 0.7 and 4.2 +/- 0.6 nmol/l respectively; P less than 0.001). Thus, the decreased receptor affinity of DPI was reflected in decreased biological potency in rat adipocytes, but not in human adipocytes nor rat hepatocytes. These data suggest differences in the binding-action linking in the cells of different tissues and different species.     

Precocious alteration of digestive enzyme activities in small intestine and pancreas by chronic oral administration of protease inhibitor in suckling rats.

1. The role of endogenous CCK in the development of digestive enzyme activities in small intestine and pancreas was investigated in suckling rats. Synthetic protease inhibitor (camostat 100 micrograms/g bwt) was orally administered twice daily for 5 days from 11 days of age. 2. Pancreatic hypertrophy and hyperplasia, and alteration of pancreatic enzyme composition, especially decreases in amylase activity and increases in trypsin and chymotrypsin activities were produced by camostat treatment. These changes were completely suppressed by simultaneous administration of the potent CCK receptor antagonist L-364,718 (1 microgram/g bwt). 3. With camostat treatment, intestinal lactase activity decreased to 41%, while maltase and sucrase activities increased 3 and 2.5 times respectively. These changes in enzyme activities were not affected by the application of L-364,718. 4. The mucosal disaccharidase and pancreatic enzyme activities could not be modified by chronic subcutaneous injection of camostat. The precocious induction of maltase and sucrase activities by camostat treatment was also observed in the adrenalectomized pups. 5. These results indicate that pancreatic growth accompanied by alteration of digestive enzyme composition in the suckling rats is regulated by endogenous CCK, but the precocious induction of disaccharidase activities is not mediated by endogenous CCK released by camostat treatment.     

Human gastrin-releasing peptide: biological potency in humans.

Gastrin-releasing peptide (GRP) was infused in graded doses (1-27 pmol/kg per h) to healthy human volunteers to study the effects on gastric, pancreatic and gallbladder functions as well as on gastrin, CCK and PP release. The results were compared to equimolar doses of synthetic bombesin. GRP significantly (P less than 0.05) stimulated gastric and pancreatic secretory responses, gallbladder contraction and gastro-enteropancreatic hormone release in a dose-dependent manner. GRP was found to be equipotent to bombesin with respect to gastric acid secretion, pancreatic enzyme output, gallbladder contraction and plasma hormone release. We conclude (a) that human GRP has similar biologic effects as synthetic bombesin; (b) as GRP is localized exclusively in nerve tissue and has potent effects on different organs, it is a likely candidate for peptidergic control of human gastric, pancreatic and gallbladder functions.