Sustained gallbladder stasis promotes cholesterol gallstone formation in the ground squirrel

Abstract

Although gallbladder stasis exists in most patients with quence of it. [1][2][3][4][5] Identifying events in a chronological fashion is particularly difficult in humans before gallstone formation. 5 cholesterol gallstones, it is unknown whether stasis is a causative factor of gallstone disease or merely a consequence of Defective gallbladder emptying likely occurs before stone formation, followed by the appearance of cholesterol crysit. We studied the impact of sustained gallbladder stasis induced by a cholecystokinin (CCK)-A receptor antagonist (MK-tals. 1,6,7 In one report on patients with cholesterol crystals alone (without gallstones), gallbladder emptying was im-329) on gallstone formation in ground squirrels fed either a trace or a high-cholesterol diet. MK-329 markedly inhibited paired. 6 Unfortunately, all the patients in this study had chronic cholecystitis, a confounding factor, which in itself gallbladder contraction in vitro in response to CCK (at EC 100 , control: 3.6 { 0.5 vs. MK-329: 1.1 { 0.3 g; P õ .05) and could have adversely affected gallbladder motor function. 1,5,8 Ground squirrels fed a high-cholesterol diet form cholesincreased gallbladder fasting volume in vivo (control: 462 { 66 vs. MK-329: 1,004 { 121 mL; P õ .05). Whereas the terol crystals and/or gallstones within a reasonably short period. [9][10][11][12][13] Defective gallbladder contractility develops very high-cholesterol diet alone (1%-cholesterol diet / placebo) increased the cholesterol saturation index (CSI) in control early in these animals, concurrent with a rise in cholesterol saturation of bile and the appearance of cholesterol crystals, animals (trace-cholesterol diet / placebo), MK-329 significantly (P õ .05) decreased the CSI in both hepatic and gall-but before stone formation. A major limitation in this model is the inability to assess directly the primary role of gallbladbladder bile in animals on the trace-(trace-cholesterol diet / MK-329) as well as on the high-cholesterol diets (1%-choles-der hypomotility in the process of gallstone formation because of the concurrent changes in both hepatic bile formaterol diet / MK-329). The mucin content of the mucus layer on the epithelial surface of the gallbladder wall more than tion and gallbladder motility.13-14 Our previous study in the same animal model showed that a cholecystokinin (CCK)-A doubled (P õ .05) with the high-cholesterol diet; adding MK-329 to the latter group produced a further 82% increase (P receptor antagonist (MK-329) suppressed gallbladder emptying, but reduced the cholesterol saturation in both hepatic õ .05). The cholesterol diet / MK-329 group had the highest (100%) incidence of cholesterol crystals that were evident in and gallbladder bile.14 This apparent paradox challenges the traditional concept that gallbladder stasis is a primary fresh gallbladder bile, coincident with a shortened nucleation time (2.5 { 0.6 days; P õ .05 vs. the cholesterol diet / and/or contributing factor in cholesterol gallstone formation. [1][2][3][15][16][17][18] placebo ...

Effect of the prokinetic agent, erythromycin, in the richardson ground squirrel model of cholesterol gallstone disease

“…[31][32][33] Ground squirrels on this high-cholesterol diet have elevated mucin both in the bulk phase of gallbladder bile and at the mucosal surface of the gallbladder wall. 49 Because mucin hypersecretion is largely mediated by the excess cholesterol present in bile and/or in gallbladder mucosa, it is not surprising that erythromycin not only markedly reduced the CSI, but also significantly prolonged the nucleation time, perhaps by removing the stimulus for mucin production and/or secretion. 10,31 Thus, erythromycin treatment significantly reduced the number of animals on the high-cholesterol diet who developed solid cholesterol crystals.…”

“…38 Because both erythromycin and motilin have little direct effect on gallbladder smooth muscle, [46][47][48] it is most likely that the enhanced gallbladder contractility measured here in vitro is secondary to a much-improved CSI. The reduction in cholesterol saturation should alleviate the smooth muscle defect, which results when excess cholesterol in bile absorbs into the gallbladder wall 10,49 and disrupts signalling across the membrane. 10,17,18,29,30 Nucleation, the process of de novo crystal formation in bile, is much more rapid in gallbladder bile from patients with cholesterol gallstones than that from normal subjects.…”

Identification And Replication Of Six Loci Associated With Gallstone Disease

“…(22) Finally, an increased elastase activity in the liver of carriers of p.Glu366Lys may cause breakdown of elastic fibers in the bile ducts and gallbladder, leading to bile stasis, a risk factor for the development of gallstones. (23) Rs1800961 causes a change in HNF4A amino acid residue 139 from threonine to isoleucine (p.Thr139Ile). HNF4A encodes hepatocyte nuclear factor 4 alpha, a transcription factor that is expressed in the liver and pancreas.…”

Strategies for Design of Non Peptide CCK1R Agonist/Antagonist Ligands

“…Thus, in the case of CCK1R agonists, the study of the 1,5-benzodiazepine GI181771X (32a) and the thiazole SR-146131, which had reached Phase II for obesity, was discontinued [9], probably due to development of tolerance in long term treatments [105]. Respecting the CCK1R antagonists, the Phase II study of devazepide for gastric motility disorders was discontinued in 2001, due to stasis induced cholesterol cholelythiasis [10,106]. However, according to the New Molecular Entities Data Base of Prous Science, devazepide continues in Phase II studies as an opiod analgesia enhancer, for the treatment of chronic and neuropathic pain.…”