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. 1990 Mar;85(3):640–646. doi: 10.1172/JCI114486

Effects of a cholecystokinin receptor antagonist on intestinal phase of pancreatic and biliary responses in man.

P Hildebrand 1, C Beglinger 1, K Gyr 1, J B Jansen 1, L C Rovati 1, M Zuercher 1, C B Lamers 1, I Setnikar 1, G A Stalder 1
PMCID: PMC296477  PMID: 2312719

Abstract

The present study was designed (a) to characterize the activity of loxiglumide as a peripheral cholecystokinin (CCK) antagonist in healthy human subjects, and (b) to determine whether CCK is a physiologic regulator of the intestinal phase of meal-stimulated exocrine pancreatic and biliary secretions in man. Intravenous loxiglumide (22 mumol/kg per h) was highly potent in antagonizing CCK8-induced pancreatic enzyme and bile acid secretion as well as pancreatic polypeptide release. The potency and selectivity of loxiglumide as an antagonist of CCK provides the tool for evaluating the role of CCK as a physiological mediator of meal-induced pancreatic and biliary responses in humans. Infusion of a liquid test meal into the duodenum evoked an immediate response of pancreatic enzyme and bilirubin outputs, respectively. Intravenous loxiglumide significantly inhibited the meal-induced pancreatic amylase output by 63% (P less than 0.05), lipase output by 43% (P less than 0.05), and bilirubin output by 59% (P less than 0.05). These data suggest that CCK is a physiological mediator of the intestinal phase of meal-stimulated pancreatic and biliary responses.

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Selected References

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  1. Adrian T. E., Besterman H. S., Bloom S. R. The importance of cholinergic tone in the release of pancreatic polypeptide by gut hormones in man. Life Sci. 1979 May 21;24(21):1989–1993. doi: 10.1016/0024-3205(79)90310-2. [DOI] [PubMed] [Google Scholar]
  2. Anagnostides A. A., Chadwick V. S., Selden A. C., Barr J., Maton P. N. Human pancreatic and biliary responses to physiological concentrations of cholecystokinin octapeptide. Clin Sci (Lond) 1985 Sep;69(3):259–263. doi: 10.1042/cs0690259. [DOI] [PubMed] [Google Scholar]
  3. Beglinger C., Fried M., Whitehouse I., Jansen J. B., Lamers C. B., Gyr K. Pancreatic enzyme response to a liquid meal and to hormonal stimulation. Correlation with plasma secretin and cholecystokinin levels. J Clin Invest. 1985 May;75(5):1471–1476. doi: 10.1172/JCI111850. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Beglinger C., Köhler E., Stalder G. A., Jansen J., Gyr K. What is the maximal effective dose of caerulein in stimulating pancreatic secretion in man? Digestion. 1986;35(2):125–128. doi: 10.1159/000199357. [DOI] [PubMed] [Google Scholar]
  5. Byrnes D. J., Henderson L., Borody T., Rehfeld J. F. Radioimmunoassay of cholecystokinin in human plasma. Clin Chim Acta. 1981 Mar 19;111(1):81–89. doi: 10.1016/0009-8981(81)90424-1. [DOI] [PubMed] [Google Scholar]
  6. Chang R. S., Lotti V. J., Monaghan R. L., Birnbaum J., Stapley E. O., Goetz M. A., Albers-Schönberg G., Patchett A. A., Liesch J. M., Hensens O. D. A potent nonpeptide cholecystokinin antagonist selective for peripheral tissues isolated from Aspergillus alliaceus. Science. 1985 Oct 11;230(4722):177–179. doi: 10.1126/science.2994227. [DOI] [PubMed] [Google Scholar]
  7. Grenner G., Deutsch G., Schmidtberger R., Dati F. Hochempfindlicher Enzymimmunoassay zur Bestimmung von Human-Pankreas-Lipase. J Clin Chem Clin Biochem. 1982 Jul;20(7):515–519. [PubMed] [Google Scholar]
  8. Hildebrand P., Beglinger C., Köhler E., Setnikar I., Gyr K. Biological effects of a proglumide derivative as cholecystokinin antagonist in conscious dogs. Regul Pept. 1987 Aug 17;18(3-4):213–220. doi: 10.1016/0167-0115(87)90009-7. [DOI] [PubMed] [Google Scholar]
  9. Hopman W. P., Kerstens P. J., Jansen J. B., Rosenbusch G., Lamers C. B. Effect of graded physiologic doses of cholecystokinin on gallbladder contraction measured by ultrasonography. Determination of threshold, dose-response relationships and comparison with intraduodenal bilirubin output. Gastroenterology. 1985 Dec;89(6):1242–1247. doi: 10.1016/0016-5085(85)90639-0. [DOI] [PubMed] [Google Scholar]
  10. Jansen J. B., Lamers C. B. Radioimmunoassay of cholecystokinin in human tissue and plasma. Clin Chim Acta. 1983 Jul 15;131(3):305–316. doi: 10.1016/0009-8981(83)90100-6. [DOI] [PubMed] [Google Scholar]
  11. Jensen R. T., Murphy R. B., Trampota M., Schneider L. H., Jones S. W., Howard J. M., Gardner J. D. Proglumide analogues: potent cholecystokinin receptor antagonists. Am J Physiol. 1985 Aug;249(2 Pt 1):G214–G220. doi: 10.1152/ajpgi.1985.249.2.G214. [DOI] [PubMed] [Google Scholar]
  12. Jensen R. T., Zhou Z. C., Murphy R. B., Jones S. W., Setnikar I., Rovati L. A., Gardner J. D. Structural features of various proglumide-related cholecystokinin receptor antagonists. Am J Physiol. 1986 Dec;251(6 Pt 1):G839–G846. doi: 10.1152/ajpgi.1986.251.6.G839. [DOI] [PubMed] [Google Scholar]
  13. Liddle R. A., Goldfine I. D., Rosen M. S., Taplitz R. A., Williams J. A. Cholecystokinin bioactivity in human plasma. Molecular forms, responses to feeding, and relationship to gallbladder contraction. J Clin Invest. 1985 Apr;75(4):1144–1152. doi: 10.1172/JCI111809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Loewe C. J., Grider J. R., Gardiner J., Vlahcevic Z. R. Selective inhibition of pentagastrin- and cholecystokinin-stimulated exocrine secretion by proglumide. Gastroenterology. 1985 Oct;89(4):746–751. doi: 10.1016/0016-5085(85)90568-2. [DOI] [PubMed] [Google Scholar]
  15. Lotti V. J., Pendleton R. G., Gould R. J., Hanson H. M., Chang R. S., Clineschmidt B. V. In vivo pharmacology of L-364,718, a new potent nonpeptide peripheral cholecystokinin antagonist. J Pharmacol Exp Ther. 1987 Apr;241(1):103–109. [PubMed] [Google Scholar]
  16. Makovec F., Bani M., Chisté R., Revel L., Rovati L. C., Rovati L. A. Differentiation of central and peripheral cholecystokinin receptors by new glutaramic acid derivatives with cholecystokinin-antagonistic activity. Arzneimittelforschung. 1986;36(1):98–102. [PubMed] [Google Scholar]
  17. Meyer B. M., Werth B. A., Beglinger C., Hildebrand P., Jansen J. B., Zach D., Rovati L. C., Stalder G. A. Role of cholecystokinin in regulation of gastrointestinal motor functions. Lancet. 1989 Jul 1;2(8653):12–15. doi: 10.1016/s0140-6736(89)90255-9. [DOI] [PubMed] [Google Scholar]
  18. Meyer F. D., Gyr K., Häcki W. H., Beglinger C., Jeker L., Varga L., Kayasseh L., Gillessen D., Stalder G. A. The release of pancreatic polypeptide by CCK-octapeptide and some analogues in the dog. Gastroenterology. 1981 Apr;80(4):742–747. [PubMed] [Google Scholar]
  19. Owyang C., May D., Louie D. S. Trypsin suppression of pancreatic enzyme secretion. Differential effect on cholecystokinin release and the enteropancreatic reflex. Gastroenterology. 1986 Sep;91(3):637–643. doi: 10.1016/0016-5085(86)90633-5. [DOI] [PubMed] [Google Scholar]
  20. Regan P. T., Go V. L., DiMagno E. P. Comparison of the effects of cholecystokinin and cholecystokinin octapeptide on pancreatic secretion, gallbladder contraction, and plasma pancreatic polypeptide in man. J Lab Clin Med. 1980 Oct;96(4):743–748. [PubMed] [Google Scholar]
  21. Setnikar I., Bani M., Cereda R., Chisté R., Makovec F., Pacini M. A., Revel L. Anticholecystokinin activities of loxiglumide. Arzneimittelforschung. 1987 Oct;37(10):1168–1171. [PubMed] [Google Scholar]
  22. Setnikar I., Chisté R., Makovec F., Rovati L. C., Warrington S. J. Pharmacokinetics of loxiglumide after single intravenous or oral doses in man. Arzneimittelforschung. 1988 May;38(5):716–720. [PubMed] [Google Scholar]
  23. Stubbs R. S., Stabile B. E. Role of cholecystokinin in pancreatic exocrine response to intraluminal amino acids and fat. Am J Physiol. 1985 Mar;248(3 Pt 1):G347–G352. doi: 10.1152/ajpgi.1985.248.3.G347. [DOI] [PubMed] [Google Scholar]
  24. TALALAY P. Enzymic analysis of steroid hormones. Methods Biochem Anal. 1960;8:119–143. doi: 10.1002/9780470110249.ch3. [DOI] [PubMed] [Google Scholar]
  25. Taylor I. L., Feldman M., Richardson C. T., Walsh J. H. Gastric and cephalic stimulation of human pancreatic polypeptide release. Gastroenterology. 1978 Sep;75(3):432–437. [PubMed] [Google Scholar]

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