Gallbladder stasis probably procedes cholesterol gallstone formation, and studies suggest that treatments aimed at preventing stasis diminish the incidence of gallstones. These observations suggest that biliary motor dysfunction plays a significant role in cholesterol gallstone pathogenesis, but the mechanism by which stasis occurs remains obscure, and the potential therapeutic significance of these observations has not yet been realized. Preliminary findings suggest that alterations in biliary prostaglandin systhesis may be a critical pathogenic event, occurring quite early in the course of pathogenesis. The objectives of this study are to precisely define abnormalities of gallbladder and cystic duct motility and establish their temporal relationship to cholesterol cholelithiasis. In addition, the possibility that these abnormalities are prostaglandin mediated will be specifically explored. Cholesterol gallstones will be induced in prairie dogs and baboons by a) supplementation of dietary cholesterol and b) depletion of the bile salt pool with cholestyramine. In the prairie dog both in vitro and in vivo studies will assess gallblader and cystic duct motility 1,2,4, and 6 weeks after initiating stone pathogenesis. Results will be correlated with physiologic assessments of gallbladder emptying function measured at corresponding time intervals. Additional studies will measure changes in prostaglandin synthetic rate in the gallbladder and cystic duct during the course of stone formation, using highly specific radioimmunoassays. The effects of prostaglandin synthesis inhibitors on biliary motor function, gallbladder mucus secretion and gallstone incidence will also be determined. Studies in the baboon initially will be limited to non-invasive assessment of gallbladder emptying using serial ultrasonography. However, these studies have been designed to permit correlation of the results in these two species and, thus, may suggest mechanisms of gallstone formation which are relevant to primates.
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