Early development of experimental biliary pancreatitis and its amelioration by CCK-receptor blockade.

BACKGROUND/AIMS: Development of pancreatitis has extensively been studied in models using CDE-diet and cerulein. This study analyzes early alterations and effects of CCK-receptor blockade in a model of biliary pancreatitis which better reflects the pathogenesis of human pancreatitis. MATERIAL AND METHODS: The common part of the bile and pancreatic duct was surgically ligated in fed rats which were allowed to recover. The CCK-antagonist CR1409 at 10 mg/kg or 0.9% NaCl was s.c. given every 6 hours. Morphological alterations were quantified by histological grading. Biochemical evidence of pancreatitis was assessed by determination of amylase concentrations in serum and ascites. A bioassay was used to determine plasma cholecystokinin. RESULTS: Ligation of the common bile and pancreatic duct caused an increase in serum amylase, development of ascites with high amylase concentrations, and morphological evidence of pancreatitis without major mortality. Electron microscopy showed early loss of microvilli and defects in basal lamina representing initial stages of duct ruptures. Early ultrastructural damage to acini included multiple vacuoles, peripheral loss of density of ("targetoid") zymogen granules and dilatation of RER. Acinar vacuolization, edema, hemorrhage and necrosis mainly occurred in areas neighboring the ducts. Duct ligation was associated with a significant increase in plasma CCK. The CCK-antagonist significantly reduced the biochemical and morphological severity of obstructive pancreatitis. CONCLUSIONS: Obstruction of the common channel of the bile and pancreatic ducts results in transient mild to moderate acute pancreatitis and in an increase in plasma CCK. Since CCK-receptor blockade ameliorated the severity of pancreatitis it is likely that increased plasma CCK plays a contributory or permissive role in pancreatitis caused by duct obstruction.

Influence of ductal pressure and infusates on activity and subcellular distribution of lysosomal enzymes in the rat pancreas.

BACKGROUND & AIMS: Subcellular redistribution of lysosomal enzymes into the zymogen-enriched fraction (cosedimentation) in pancreatic homogenates occurs after different pancreatic injuries and has been proposed to be the trigger event for acute pancreatitis. This phenomenon is now studied in models of biliary pancreatitis. METHODS: The bile-pancreatic duct in rats was either obstructed or retrogradely infused at different degrees of pressure and with solutions of various injurious potential. Controls were untreated or sham operated. Six hours later, the pancreas was analyzed for the total activity of cathepsin B and beta-galactosidase and their distribution among subcellular fractions. RESULTS: In control animals, 17% and 29%, respectively, of these lysosomal enzymes were found in the zymogen fraction. Redistribution occurred after all duct manipulations, including obstruction. In contrast to sham operation and duct obstruction, all modes of duct infusion resulted in marked increases in the total activity of lysosomal enzymes. CONCLUSIONS: Increased lysosomal activity in models of biliary pancreatitis might contribute to acinar injury or represent a cellular repair mechanism. Cosedimentation at a certain extent is a physiological event. Redistribution reflects a uniform response to a range of perturbations, some of which do not cause pancreatitis. Thus, it seems unlikely that redistribution is the trigger event for acute pancreatitis.

Effect of hypergastrinemia and blockade of gastrin-receptors on pancreatic growth in the mouse.

BACKGROUND/AIM: The present study evaluates whether endogenous gastrin regulates pancreatic growth in the mouse. MATERIALS AND METHODS: Male NMRI mice weighing 12-15 g were assigned to six groups (10 mice/group) which were treated with different combinations of 0.9% NaCl, omeprazole, a CCK-A antagonist, a CCK-B antagonist, loxiglumide, and L365, 260 for 10 days each according to different protocols. RESULTS: Omeprazole caused a marked, 10-fold increase in serum gastrin which was not affected by the gastrin antagonist, but markedly reduced by the CCK-A antagonist. The marked increase in endogenous gastrin caused by omeprazole did not promote pancreatic growth in any way. Similarly, the gastrin antagonist did not inhibit pancreatic growth. In contrast, the CCK-A antagonist significantly decreased pancreatic weight and protein content. CONCLUSIONS: The present results strongly suggest that endogenous gastrin--in contrast to CCK--does not regulate pancreatic growth in the mouse. The inhibitory effect of loxiglumide on omeprazole-induced increase in serum gastrin might be explained by recent findings which showed that CCK-A antagonists can stimulate gastric acid secretion probably due to a reduction of the inhibitory effect of basal CCK on the D-cell and its somatostatin release. Probably such a slight stimulation of gastric acid secretion caused by the CCK-A antagonist might reduce the gastrin increase caused by omeprazole's abolishment of acid secretion.

Effects of C1-esterase inhibitor in three models of acute pancreatitis.

The present studies were done to evaluate the therapeutic potential of C1-esterase inhibitor in three different models of acute pancreatitis: (1) Edematous pancreatitis with acinar cell necrosis was induced by 7-h ip injections of 50 micrograms/kg cerulein in mice; (2) Hemorrhagic pancreatitis was induced by feeding a choline-deficient, ethionine-supplemented (CDE) diet in mice; and (3) Hemorrhagic pancreatitis was induced by retrograde infusion of 0.6 mL 5% sodium-taurocholate into the pancreatic duct in rats. C1-esterase inhibitor was given at 100 mg/kg iv before the onset of pancreatitis and at certain intervals thereafter. The severity of pancreatitis was assessed at various times after its onset by determination of serum amylase, by grading of histological alterations, and by determination of survival (survival determined only in models of hemorrhagic pancreatitis). In some of the models, C1-esterase inhibitor slightly ameliorated the degree of histological alterations; the increase in serum amylase was reduced by C1-esterase inhibitor only in CDE diet-induced pancreatitis. In all three models, C1-esterase inhibitor, however, failed to cause major beneficial effects and also failed to improve survival in taurocholate- and diet-induced pancreatitis. Additional studies in 12 patients with acute pancreatitis showed that C1-esterase inhibitor activity was markedly increased in serum of all patients during the first 9 d of the disease, suggesting that C1-esterase inhibitor behaves like an acute phase protein. Taken together the results from the animal and the human studies, C1-esterase inhibitor appears to only have a limited potential for treatment of acute pancreatitis.

[How many patients with chronic viral hepatitis qualify for interferon therapy? Prospective analysis of university ambulatory care]. / Wie viele Patienten mit chronischer Virushepatitis kommen für eine Interferontherapie in Betracht? Prospektive Analyse einer Universitätsambulanz.

How many patients with chronic viral hepatitis are suitable for interferon therapy? A prospective analysis of a university out-patient department. The present study prospectively analyzes 273 consecutive patients admitted to the outpatient-hepatology clinic for interferon therapy of chronic viral hepatitis from 1989 to 1991. 149/273 (54.6%) patients suffered from hepatitis-B viral infection (HBV). Of the 107 patients with NANB-hepatitis (39.2%) 103 patients finally proved to have hepatitis-C viral infection (HCV) (96.3%). In 17/273 patients (6.2%) the outside diagnosis of viral hepatitis was wrong. The percentage of men versus women was significantly greater in HBV (71.8% vs. 28.2%) than in HCV infection (52.4% vs. 47.5%) (p < 0.01; c2-test). The admittance of patients increased from 68 patients in 1989 to 88 patients in 1990 and 117 patients in 1991. The percentage of HCV-patients increased from 26.4% in 1989 to 38.6% in 1990 and 43.6% in 1991. The number of patients with HCV-infection admitted by non-university hospitals versus practitioners and internists was significantly greater in HCV-infection (48.5% vs. 51.5%) compared to HBV-infection (hospitals: 36.9%; practitioners: 63.1%) (p < 0.05). Interferon therapy was initiated in 131/252 patients (52%) with HBV- or HCV-infection. HCV-patients were treated with interferon significantly more frequently (59.2%) compared with HBV-patients (46.9%) (p = 0.05). Since interferon therapy was initiated in only about 50% of HBV- and HCV-patients, the selection criteria for such treatment need to be publicized more effectively. The marked increase in patients with HCV-infection suggests that recent improvements in serology of viral hepatitis are widely and appropriately used in clinical practice.

Prospective randomized controlled trial of sequential treatment with corticoids and alpha-interferon versus treatment with interferon alone in patients with chronic active hepatitis B.

OBJECTIVES: A randomized controlled trial was conducted to prospectively compare the efficacy of sequential treatment with corticoids and alpha-interferon versus treatment with interferon (IFN) alone in patients with chronic hepatitis B. METHODS: Sixty patients with chronic active hepatitis B and positive serum HBV-DNA were randomized into two treatment groups (n = 20, respectively) and one control group (no treatment; n = 20). In one treatment group, patients received first an oral corticoid (2 weeks 40 mg/day and further 2 weeks 20 mg/die prednisolone); thereafter interferon-alpha (Intron A, Essex) was given as three subcutaneous injections of 2 million units per week for 3 months. In patients in whom therapy did not eliminate HBe-Ag and HBV-DNA two months after its end, a similar sequential treatment was given with the same corticoid dose but a higher IFN dose of 5 MU. In the other treatment group patients were given three subcutaneous injections of 5 MU IFN per week for 4 months. The sequential corticoid/IFN treatment at a dose of 3 x 2 MU IFN resulted in seroconversion of HBe-Ag in only 4 of 20 patients (20%). Of the remaining 16 patients 14 subjects received a repetitive corticoid/IFN therapy with the same corticoid dose but with a 3 x 5 MU dose of IFN. RESULTS: With the higher IFN dose, 6 of 14 patients had a seroconversion of HBe-Ag. Therapy with 3 x 5 MU IFN without prior corticoids resulted in a seroconversion in 8 of 20 patients (40%). Calculated for both doses, the sequential corticoid/IFN therapy eliminated HBe-Ag and HBV-DNA in 10/20 patients (50%); therapy with IFN alone was almost as effective (40% seroconversion) (p > 0.05 for comparison of seroconversion rates by chi 2-test). Seroconversion of HBe-Ag and elimination of HBV-DNA occurred in parallel and were associated with a decrease of serum transaminases and a regression of inflammatory activity on rebiopsy. In the control group there was no spontaneous seroconversion of HBs-Ag, HBe-Ag or HBV-DNA. CONCLUSIONS: The present results show that in many patients who failed to respond to a sequential therapy with corticoids and 2 MU IFN, the higher IFN dose of 5 MU effectively eliminated HBe-Ag and HBV-DNA. Sequential corticoid/IFN therapy and therapy with IFN alone eliminated HBe-Ag and HBV-DNA in a similar percentage of patients. Further statistical analysis showed that, in particular, patients with low transaminases benefit from prior corticoid treatment. In all groups, patients with low serum HBV-DNA and a short history of infection had the best treatment results.

Effects of cholecystokinin receptor blockade on circulating concentrations of glucose, insulin, C-peptide, and pancreatic polypeptide after various meals in healthy human volunteers.

This study used a cholecystokinin (CCK) antagonist to evaluate whether CCK that is released after regular meals regulates meal-stimulated insulin secretion. Several experiments were performed in eight to 10 healthy male volunteers, each in duplicate. The subjects received different meals either with or with i.v. infusion of 5 mg/kg/h of the CCK antagonist loxiglumide (Rotta, Italy). The mixed solid-liquid meals of 600, 800, or 1,000 kcal consisting of regular German food were given orally. In addition, studies were carried out in which a liquid test meal of 750 kcal was infused into the duodenum over a 2-hour period to exclude effects of the CCK antagonist on gastric emptying. Finally, the subjects received an oral load of 100 g glucose either with or without i.v. infusion of loxiglumide. Loxiglumide at the dose used completely abolishes the actions of endogenous CCK and of exogenous CCK when given at doses that mimic postprandial circulating concentrations of this peptide at various target organs such as gallbladder, pancreas, stomach, and intestine. Loxiglumide also markedly reduced the increase in pancreatic polypeptide seen after the intraduodenal infusion of nutrients. However, loxiglumide at this dose did not alter the increase in circulating concentrations of glucose, insulin, and C-peptide after any of the various oral meals, after the intraduodenal administration of nutrients, and after the oral load of glucose. Although the present study does not rule out that in some conditions CCK may increase insulin secretion in humans, the results do rule out that CCK acts as a major physiologic incretin in healthy humans.

Effects of antioxidants and free radical scavengers in three different models of acute pancreatitis.

The present studies were done to evaluate the therapeutic potential of several antioxidants and free radical scavengers in three different models of acute pancreatitis. (a) Edematous pancreatitis with acinar cells necrosis was induced by seven hourly intraperitoneal injections of 50 micrograms of caerulein per kg in mice. (b) Hemorrhagic pancreatitis was induced by feeding a choline-deficient, ethionine-supplemented (CDE) diet in mice. (c) Hemorrhagic pancreatitis was induced by retrograde infusion of 0.6 ml of 5% sodium taurocholate into the pancreatic duct in rats. The following antioxidants and free radical scavengers were given at various doses intravenously, subcutaneously, or intraperitoneally before the onset of pancreatitis: Ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one], superoxide dismutase, catalase, deferoxamine (Desferal), dimethyl sulfoxide, or allopurinol. The severity of pancreatitis was assessed at various times after its onset by determination of serum amylase and pancreatic weight (edema), by grading of histological alterations, and by determination of survival (survival determined in models of hemorrhagic pancreatitis). In general, free radical scavengers and antioxidants ameliorated edema and inflammation to a greater degree than necrosis and the increase in serum amylase. Superoxide dismutase (as did Ebselen in previous studies) exerted beneficial effects on survival in diet-induced pancreatitis in the absence of marked effects on pancreatic necrosis, suggesting that these beneficial effects are due to amelioration of extrapancreatic complications that often contribute to mortality in acute pancreatitis. None of the antioxidants had major beneficial effects in taurocholate-induced hemorrhagic pancreatitis. Thus, formation of free radicals may be important for progression and outcome in diet-induced and, to a lesser degree, in caerulein-induced pancreatitis but not at all in taurocholate-induced pancreatitis. Different models of pancreatitis may, therefore, involve different degrees and mechanisms of free radical formation. Despite the amelioration of edema and the beneficial effects on mortality seen for some antioxidants in some of the models, antioxidants and free radical scavengers appear to have only a limited potential for treatment of acute pancreatitis.

Acute experimental hemorrhagic-necrotizing pancreatitis induced by feeding a choline-deficient, ethionine-supplemented diet. Methodology and standards.

The present work evaluates the methodology and standards of acute hemorrhagic-necrotizing pancreatitis induced by feeding a choline-deficient, ethionine-supplemented (CDE) diet to mice. The diet model appears to be a good approximation of severe necrotizing human pancreatitis. Both the gross and histological appearance of the pancreatic and peripancreatic inflammation as well as the clinical and biochemical course of diet-induced pancreatitis resemble human disease. By limiting the period of feeding the diet, one can control the mortality at any desired level between 0 and 100%. Ascites, acidosis, hypoxia and hypovolemia occur in this model as well as in human pancreatitis. The time course of the morphological and biochemical alterations have extensively been studied and are, thus, well defined in this model. Despite the differences in pathogenesis of pancreatitis induced in this model versus human disease, the experimental pancreatitis and clinical pancreatitis share several pathophysiologic features. Therefore, the model is suitable to study pathophysiologic aspects of this disease. The diet model is particularly well suitable to study the potential for new therapeutic substances. The small size of the animals used, however, is a limitation for the evaluation of surgical procedures and of new diagnostic tools. Several pitfalls and problems have to be considered in order to obtain valuable data. The amount of injury produced by the CDE diet depends critically on sex, age and weight of the mice. Special care has to be taken to guarantee that the intake of the CDE diet is identical between different experimental groups. Therefore, each set of experiments needs to include a separate control group of mice which receive the CDE diet without any other special treatment. The potential benefit of an experimental therapy can be assessed by measuring survival, various biochemical and histological features, and alterations in hematocrit, pH and blood gases.

Effects of cholecystokinin-receptor blockade on pancreatic and biliary function in healthy volunteers.

This study used the specific cholecystokinin (CCK)-receptor antagonist loxiglumide to evaluate whether endogenous CCK, which is released after a meal, regulates pancreatic and biliary functions. Eight healthy volunteers were studied twice on separate days. The subjects received a continuous intraduodenal infusion of a 750-kcal liquid test meal for 2 hours either with or without IV infusion of 5 mg.kg-1.h-1 of loxiglumide. Loxiglumide at this dose abolishes the actions of CCK at various target organs including gallbladder and pancreas, when given at doses that mimic postprandial plasma concentrations of CCK. Loxiglumide markedly decreased the meal-stimulated outputs of amylase, trypsin, and chymotrypsin by 55%-70% of control values but only slightly decreased duodenal volume (25% inhibition of mean integrated secretion). Loxiglumide abolished gallbladder emptying induced by infusion of nutrients and even increased gallbladder volumes when compared with prior fasting values. Correspondingly, loxiglumide almost abolished the output of bilirubin after infusion of nutrients. However, loxiglumide failed to alter the increase in circulating concentrations of glucose, insulin, and C peptide after infusion of nutrients. The present results show that CCK is one of several factors that regulate pancreatic protein secretion after absorption of nutrients. However, CCK is probably not involved in regulation of pancreatic secretion of fluid. In contrast, gallbladder function is mainly regulated by CCK, both in terms of its emptying after intestinal absorption of nutrients and in terms of maintenance of its fasting volume. Cholecystokinin does not play a major physiological role as an insulinotropic factor.

Effects of the seleno-organic substance Ebselen in two different models of acute pancreatitis.

This study evaluated the effects of the seleno-organic substance Ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one] in two models of acute hemorrhagic and acute edematous pancreatitis. Ebselen is known to catalyze glutathione peroxidase-like reactions and to inhibit lipid peroxidation. Hemorrhagic pancreatitis was induced by feeding a choline-deficient, ethionine-supplemented (CDE) diet to mice for 66 h. Edematous pancreatitis was induced by 7-h subcutaneous injections of 50 micrograms/kg of cerulein in mice. Ebselen was given from the beginning of the CDE diet either as a subcutaneous injection of 100 mg/kg at 6-h intervals or was mixed in with the CDE diet to yield a daily dose of 100 mg/kg of Ebselen. In further experiments, Ebselen was given at various time intervals after the beginning of the CDE diet as subcutaneous injections of 100 mg/kg at 6-h intervals. In the cerulein model, Ebselen was given 5 min prior to each cerulein injection at doses from 10-500 mg/kg. Prophylactic administration of Ebselen given orally or subcutaneously significantly improved survival from 38.5% in the control group of saline-injected CDE-fed mice to 61.9 and 65.0%, respectively. Ebselen also reduced increases in serum amylase and pancreatic weight in the diet model. Therapeutic administration of Ebselen significantly increased survival only when injections were started 20 h after the beginning of the CDE diet (64%), but not when started after 40 h (44%). Similarly, increases in serum amylase and pancreatic weight due to the CDE diet were significantly reduced by Ebselen only when injections were started after 20 h but not when started after 40 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Pancreatic exocrine secretion in acute experimental pancreatitis.

Little is known about exocrine pancreatic secretory function in patients with acute pancreatitis, in particular during the early phase of the disease. Therefore, this study evaluates basal and stimulated pancreatic secretion in vivo and in vitro in four different models of acute pancreatitis which reflect its clinical spectrum of severity: (a) edematous pancreatitis induced in the rat by seven IP injections of 50 micrograms/kg cerulein at hourly intervals; (b) edematous pancreatitis with cellular necrosis induced in the mouse by seven IP injections of 50 micrograms/kg cerulein at hourly intervals; (c) hemorrhagic pancreatitis induced in the mouse by feeding an ethionine-supplemented, choline-deficient diet for 66 hours; and (d) hemorrhagic pancreatitis induced in the rat by retrograde infusion of 0.6 mL 5% sodium taurocholate into the pancreatic duct. Secretory studies were performed in vivo and in vitro at various times after onset of pancreatitis. The results show that the exocrine pancreas gradually became resistant to cholecystokinin stimulation after the onset of acute pancreatitis in all four animal models. Cholecystokinin-stimulated secretion was almost abolished in vivo and in vitro at the time of maximal histological damage. In vivo basal secretion was also reduced. In vitro there was an increase in basal release of amylase from isolated acini that was not caused by an increase in luminal secretion but by enzyme release from damaged cells. The time course of improvement of secretory function after acute experimental pancreatitis depended on the severity of the pancreatitis. Recovery of secretory capacity took longer after severe necrotizing pancreatitis than after edematous pancreatitis. However, the ultimate resolution of secretory function was remarkable, in particular after severe hemorrhagic pancreatitis. In all four models, secretory capacity became indistinguishable from normal before the morphological alterations had completely resolved. The present experimental data suggest that pancreatic secretion, and particularly pancreatic secretory response to cholecystokinin, may also be reduced in patients early after the onset of acute pancreatitis.

Effects of long-term CCK stimulation and CCK blockade on pancreatic and intestinal growth, morphology, and function.

This study evaluated the effects of long-term cholecystokinin (CCK) stimulation and blockade on pancreatic and intestinal growth, function, and morphology. CCK release was induced by feeding of the protease inhibitor camostate and CCK blockade by feeding of the CCK antagonist CR 1409. Four groups of NMRI-mice received the following diets for 9 months (each group consisting of 36 mice): (1) chow (control); (2) chow + 100 mg/kg/day camostate; (3) chow + 50 mg/kg/day CR 1409; (4) chow + 100 mg/kg/day camostate + 50 mg/kg/day CR 1409. Long-term feeding of camostate greatly increased pancreatic weight by induction of marked hypertrophy (increase in protein content) and moderate hyperplasia (increase in DNA content). Camostate feeding also increased secretory capacity of the exocrine pancreas. Despite camostate-induced growth neither hyperplastic nor neoplastic nodules developed. The CCK-antagonist CR 1409 markedly inhibited the effects of camostate which are therefore mainly mediated by CCK. Neither long-term CCK stimulation nor CCK blockade altered morphology or composition of duodenal mucosa. Feeding of CR 1409 alone (i.e., without camostate) slightly but significantly decreased pancreatic content of protein and secretory capacity of enzymes when compared to the chow-fed control; pancreatic weight and DNA content remained unchanged after long-term administration of CR 1409. Thus, long-term, continuous and effective blockade of the CCK-receptor only slightly inhibited pancreatic growth and secretory capacity. CCK is, therefore, not an essential growth factor for the pancreas, although increases of endogenous CCK stimulate pancreatic growth and secretory capacity.

Does acute consumption of large alcohol amounts lead to pancreatic injury? A prospective study of serum pancreatic enzymes in 300 drunken drivers.

Blood samples of 300 consecutive subjects suspected for drunken driving were prospectively analyzed for concentrations of pancreatic and hepatic enzymes. Mean alcohol concentration was 1.5 +/- 0.8 0/00 (+/- SD; range 0-3.7 0/00). Increased enzyme concentrations were found in 25/300 subjects for amylase, in 43/300 for trypsin, in 49/300 for gamma-glutamyl transferase and in 82/300 for glutamic oxaloacetic transaminase. Subjects with alcohol concentrations greater than 1 0/00 had abnormal pancreatic and hepatic enzymes more frequently than subjects with alcohol concentrations smaller than 1 0/00. However, pancreatic enzyme levels were higher than twice the upper normal limit only in 3/300 subjects, whereas hepatic enzyme levels exceeded twice the upper normal limit in 31/300 subjects. Therefore, other factors in addition to alcohol are necessary to initiate acute pancreatitis. The liver is more susceptible to acute injury by alcohol than the pancreas.

Comparative effects of CCK receptor antagonists on rat pancreatic secretion in vivo.

The present experiments evaluate in vivo effects of recently described cholecystokinin (CCK) receptor antagonists on rat pancreatic secretion. Pancreaticobiliary secretion was studied after bile duct cannulation in anesthetized rats. After two basal 10-min fractions were selected, secretion was stimulated by intravenous caerulein (0.1-30.0 micrograms/kg) or secretin, and collected for seven further 10-min fractions. Peptide antagonists (CR 1409, CR 1392, and CR 1505) and nonpeptide antagonists (asperlicin and L364,718) were given intravenously 10 min before agonists. Increasing doses of antagonists gradually reduced secretion of protein and enzymes stimulated by submaximal and maximal doses of caerulein. The antagonists did not alter nonstimulated or secretin-stimulated secretion, indicating their specificity for the CCK receptor. Except for proglumide and asperlicin, all antagonists were able to abolish caerulein-stimulated pancreatic secretion, as evaluated by the mean integrated 1-h response to a near-maximal dose of caerulein. The caerulein dose-response curve was gradually shifted to the right by increasing doses of CR 1409, indicating competitive-like kinetics. Inhibition of secretion due to supramaximal doses of caerulein, however, could be reversed by doses of CR 1409 smaller than expected from extrapolating truely competitive kinetics from an in vitro situation to the in vivo situation. The rank order of potency of the compounds to antagonize caerulein-stimulated secretion in vivo agreed with their relative potencies to antagonize caerulein-stimulated amylase secretion from pancreatic acini in vitro as well as with their affinity to bind to peripheral CCK receptors in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

New proglumide-analogue CCK receptor antagonists: very potent and selective for peripheral tissues.

The present study evaluates the ability of two recently synthesized analogues of proglumide, both 4-benzamido-N,N-di-alkyl-glutaramic acid derivatives, to act as cholecystokinin receptor antagonists. Both new antagonists inhibited cholecystokinin-stimulated amylase release and, similarly, binding of 125I-cholecystokinin to isolated rat pancreatic acini. These effects displayed competitive kinetics; both antagonists showed no agonist activity and were specific in that only those secretagogues were inhibited that interact with the cholecystokinin receptor. Both antagonists also inhibited binding of 125I-cholecystokinin to mouse pancreatic membrane particles similarly to results with rat pancreatic acini. With the more potent of the two new antagonists, half-maximal inhibition of action and binding of cholecystokinin was observed with low concentrations of approximately 10(-7) M; compared with proglumide, the new antagonists were as much as 4,000 times more potent. Unlike proglumide, which inhibits binding of cholecystokinin to pancreas and brain tissue similarly, both antagonists inhibited binding of cholecystokinin to the pancreas at much lower concentrations compared with brain. The more potent of the inhibitors was 300 times more potent in inhibiting binding of cholecystokinin to pancreatic tissues compared with brain.