title: The effect of the cholecystokinin receptor antagonist MK-329 on meal-stimulated pancreaticobiliary output in humans.
abstract: To determine the physiological role of circulating cholecystokinin (CCK), the effect of the CCK receptor antagonist MK-329 on upper digestive processes was investigated in six normal volunteers after a mixed meal. In a double-blind, two-period, randomized crossover design, the subjects received either 10 mg MK-329 or placebo orally 3 hours 15 minutes before the meal, which contained 51CrCl3 as food marker. A five-lumen tube with the tip in the distal duodenum allowed continuous marker infusion (57Co-B12) and duodenal aspiration as well as recordings of antral and duodenal motility patterns via three pressure sensors. Postprandially, MK-329 caused a significant reduction of 30%-60% (P less than 0.05) in pancreatic trypsin output during the initial three 15-minute periods; thereafter, the output was virtually the same than after placebo. Thus, the integrated enzyme response was only reduced by 15% (NS) during the 3-hour period beginning 15 minutes after the meal. In contrast, gallbladder contraction, determined by total bile acid excretion, was inhibited by 77% (P less than 0.05), indicating a crucial role of CCK in regulating gallbladder motility. Except for the initial 30 minutes postprandially, MK-329 also induced a significant reduction in duodenal pH with mean values ranging from 3.5 +/- 0.2 to 4.1 +/- 0.3 compared with 4.5 +/- 0.3 to 5.0 +/- 0.4 after placebo (P less than 0.05), probably because of lowered secretion of pancreatic bicarbonate. Gastric emptying rate was significantly accelerated by MK-329 during the initial 75 minutes after the meal, but the time for 50% emptying did not differ from placebo [127.5 +/- 7.7 vs. 140.0 +/- 9.0 minutes (NS)]. No changes were observed in the motility pattern of the proximal duodenum after feeding. Whereas MK-329 only caused a slight increase of the basal plasma CCK concentrations, the postprandial levels were markedly enhanced. Peak concentrations were 10.0 +/- 1.3 vs. 4.0 +/- 0.5 pmol/L after placebo (P less than 0.001), and the integrated response exceeded the control value by 175% (P less than 0.01). The results suggest that circulating CCK is not an essential mediator of the postprandial pancreatic enzyme secretion in humans, whereas it plays a critical role in gallbladder emptying.
authors.affiliation: Department of Clinical Chemistry and Surgical Gastroenterology C, Rigshospitalet, Copenhagen, Denmark.
authors.forename: P
authors.initials: P
authors.lastname: Cantor
authors.forename: P E
authors.initials: PE
authors.lastname: Mortensen
authors.forename: J
authors.initials: J
authors.lastname: Myhre
authors.forename: I
authors.initials: I
authors.lastname: Gjorup
authors.forename: H
authors.initials: H
authors.lastname: Worning
authors.forename: E
authors.initials: E
authors.lastname: Stahl
authors.forename: T T
authors.initials: TT
authors.lastname: Survill
mesh_terms: D000328:Adult; D001570:Benzodiazepinones / Q000494:pharmacology*; D001647:Bile Acids and Salts / Q000378:metabolism; D002766:Cholecystokinin / Q000097:blood; D020109:Devazepide; D004386:Duodenum / Q000378:metabolism; D005246:Feedback; D005502:Food; D005704:Gallbladder / Q000187:drug effects* / Q000502:physiology; D005746:Gastric Emptying / Q000187:drug effects; D005769:Gastrointestinal Motility; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D014357:Trypsin / Q000378:metabolism
chemical_list: D001570:Benzodiazepinones; D001647:Bile Acids and Salts; D011949:Receptors, Cholecystokinin; D002766:Cholecystokinin; D014357:Trypsin; D020109:Devazepide