title: Sustained gallbladder stasis promotes cholesterol gallstone formation in the ground squirrel.
abstract: Although gallbladder stasis exists in most patients with cholesterol gallstones, it is unknown whether stasis is a causative factor of gallstone disease or merely a consequence of it. We studied the impact of sustained gallbladder stasis induced by a cholecystokinin (CCK)-A receptor antagonist (MK-329) on gallstone formation in ground squirrels fed either a trace or a high-cholesterol diet. MK-329 markedly inhibited gallbladder contraction in vitro in response to CCK (at EC100, control: 3.6 +/- 0.5 vs. MK-329: 1.1 +/- 0.3 g; P < .05) and increased gallbladder fasting volume in vivo (control: 462 +/- 66 vs. MK-329: 1,004 +/- 121 microL; P < .05). Whereas the high-cholesterol diet alone (1%-cholesterol diet + placebo) increased the cholesterol saturation index (CSI) in control animals (trace-cholesterol diet + placebo), MK-329 significantly (P < .05) decreased the CSI in both hepatic and gallbladder bile in animals on the trace-(trace-cholesterol diet + MK-329) as well as on the high-cholesterol diets (1%-cholesterol diet + MK-329). The mucin content of the mucus layer on the epithelial surface of the gallbladder wall more than doubled (P < .05) with the high-cholesterol diet; adding MK-329 to the latter group produced a further 82% increase (P < .05). The cholesterol diet + MK-329 group had the highest (100%) incidence of cholesterol crystals that were evident in fresh gallbladder bile, coincident with a shortened nucleation time (2.5 +/- 0.6 days; P < .05 vs. the cholesterol diet + placebo group, 5.8 +/- 1.0 days or the other 2 groups, >21 days). Bile from animals on the trace-cholesterol diet, whether or not receiving MK-329, lacked crystals in bile and exhibited a normal nucleation time (>21 days). Thus, stasis per se may lower the CSI, but its detrimental effect on the gallbladder predominates locally, and so accelerates cholesterol crystal formation in this model.
authors.affiliation: Department of Medicine, Faculty of Medicine, University of Calgary, Alberta, Canada.
authors.forename: Q W
authors.initials: QW
authors.lastname: Xu
authors.forename: M
authors.initials: M
authors.lastname: Mantle
authors.forename: J G
authors.initials: JG
authors.lastname: Pauletzki
authors.forename: E A
authors.initials: EA
authors.lastname: Shaffer
mesh_terms: D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D002769:Cholelithiasis / Q000209:etiology*; D002784:Cholesterol / Q000378:metabolism*; D020109:Devazepide; D009077:Mucins / Q000502:physiology; D012589:Sciuridae
chemical_list: D001570:Benzodiazepinones; D009077:Mucins; D002784:Cholesterol; D020109:Devazepide