Sustained gallbladder stasis promotes cholesterol gallstone formation in the ground squirrel

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 mu L; 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 pw se may lower the CSI, but its detrimental effect on the gallbladder predominates locally, and so accelerates cholesterol crystal formation in this model.