Luminal sequestration of bile salts with cholestyramine and the oral administration of bile salts represent current forms of therapy for some diseases. We have recently reported that secretion of these salts exerts negative feedback control on the release of cholecystokinin (CCK). The purpose of this study was to examine the effects of long-term alterations of luminal concentrations of bile salts on CCK target organs, the pancreas and gallbladder. The bile salt pool in adult guinea pigs was either enriched by feeding 0.5 percent sodium taurocholate or depleted by feeding 2 percent cholestyramine. Pancreatic growth, gallbladder contractility, the concentration of cholecystokinin receptors in the gallbladder muscle, and meal-stimulated plasma levels of cholecystokinin were significantly stimulated by feeding the bile salt sequestrant cholestyramine to guinea pigs. Administration of the bile salt taurocholate produced the opposite effects. Inhibition of CCK release by bile salts and up-regulation of CCK receptors by CCK may be the mechanisms responsible for the actions of bile salts on CCK target organs.