title: Role of CCK in regulation of pancreaticobiliary functions and GI motility in humans: effects of loxiglumide.
abstract: To evaluate the physiological role of cholecystokinin (CCK) in humans, we studied the influence of the specific CCK receptor antagonist loxiglumide (CR 1505) on gallbladder contraction, pancreatic enzyme output, plasma CCK concentrations, mouth-to-cecum transit time (MCTT), stool weight, and fecal fat excretion. Infusion of CCK-8, producing CCK plasma levels of 10-12 pmol/l, decreased gallbladder volume to 21% of the initial volume (P less than 0.01) and increased bilirubin output 8- to 10-fold and pancreatic enzyme secretion 2- to 4-fold. Infusion of loxiglumide (10 mg.kg-1.h-1 iv) abolished CCK-8-stimulated enzyme and bilirubin output. Basal gallbladder volume increased 68% during loxiglumide infusion (P less than 0.001) and 137% (P less than 0.001) after 7 days of oral loxiglumide treatment (3 x 1.6 g/day). Gallbladder contraction and bilirubin output in response to the intraduodenal instillation of a liquid meal (382 kcal) was completely inhibited by loxiglumide; gallbladder volume even increased 45% postprandially during loxiglumide infusion (P less than 0.02) and 145% after long-term loxiglumide treatment (P less than 0.001). Meal-stimulated pancreatic enzyme output was diminished 46-53% after acute and 25-29% after chronic administration of loxiglumide. Meal-stimulated integrated plasma CCK-immunoreactive (CCK-ir) concentrations, determined by RIA, were 3.2-fold higher during loxiglumide infusion (P less than 0.02); plateau CCK levels were markedly elevated (10.1 +/- 1.4 vs. 3.7 +/- 0.5 pM). Plasma CCK-like bioactivity, measured by a sensitive bioassay, was identical to CCK-ir levels in the absence of loxiglumide; in the presence of loxiglumide, no circulating CCK-like bioactivity was detectable, indicating complete inhibition of plasma CCK. MCTT was augmented 24% (P less than 0.05). Oral treatment with loxiglumide increased stool weight 72% (P less than 0.01) and fecal fat excretion 186% (P less than 0.001). In conclusion, 1) meal-induced gallbladder contraction and fasting tone are primarily controlled by CCK; 2) the contribution of CCK to the intestinal phase of postprandial pancreatic enzyme secretion is 40-50%; 3) GI motility and absorption are partially controlled by CCK; and 4) postprandial CCK secretion is substantially augmented by loxiglumide via an unknown mechanism.
authors.affiliation: Department of Medicine, Georg-August-University of Göttingen, Federal Republic of Germany.
authors.forename: W E
authors.initials: WE
authors.lastname: Schmidt
authors.forename: W
authors.initials: W
authors.lastname: Creutzfeldt
authors.forename: A
authors.initials: A
authors.lastname: Schleser
authors.forename: A R
authors.initials: AR
authors.lastname: Choudhury
authors.forename: R
authors.initials: R
authors.lastname: Nustede
authors.forename: M
authors.initials: M
authors.lastname: Höcker
authors.forename: R
authors.initials: R
authors.lastname: Nitsche
authors.forename: H
authors.initials: H
authors.lastname: Sostmann
authors.forename: L C
authors.initials: LC
authors.lastname: Rovati
authors.forename: U R
authors.initials: UR
authors.lastname: Fölsch
mesh_terms: D000328:Adult; D001663:Bilirubin / Q000097:blood; D002766:Cholecystokinin / Q000037:antagonists & inhibitors / Q000097:blood / Q000502:physiology*; D004435:Eating; D005243:Feces; D005704:Gallbladder / Q000187:drug effects / Q000502:physiology*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006801:Humans; D008049:Lipase / Q000097:blood / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010179:Pancreas / Q000187:drug effects / Q000502:physiology*; D010189:Pancreatic Juice / Q000187:drug effects / Q000378:metabolism; D011377:Proglumide / Q000031:analogs & derivatives* / Q000494:pharmacology; D012016:Reference Values; D014357:Trypsin / Q000097:blood / Q000378:metabolism
chemical_list: C053737:loxiglumide; D002766:Cholecystokinin; D008049:Lipase; D014357:Trypsin; D011377:Proglumide; D001663:Bilirubin