CCK-RECEPTOR ANTAGONISTS PROGLUMIDE AND LOXIGLUMIDE STIMULATE BILE-FLOW AND BILIARY GLUTATHIONE EXCRETION

The mechanism for the choleresis induced by CCK-receptor antagonists, proglumide, loxiglumide, and CR 1409, was examined in anesthetized rat s and compared to the effects of CCK itself. These agents were infused intravenously over a 2-hr period, and bile flow, and biliary excretio n of bicarbonate, total bile acids, and glutathione were measured in 3 0-min intervals. All three antagonists produced a dose-dependent chole resis, but a significant decrease in bile acid excretion, indicating t hat they stimulate bile flow via a bile acid-independent mechanism. Th e increase in bile flow was associated with a parallel increase in bil iary glutathione and bicarbonate output in rats treated with proglumid e and loxiglumide. In animals pretreated with acivicin to inhibit gamm a-glutamyltransferase activity, proglumide was shown to stimulate bili ary excretion of reduced glutathione (GSH), but not glutathione disulf ide (GSSG), indicating the absence of oxidative stress in the liver. G SH output was increased by only 0.5-0.9 mu mol/30 min after infusion o f proglumide at a dose of 75 mg/kg/hr, whereas bile volume was increas ed 0.2-0.4 ml/30 min, indicating that this increased biliary GSH excre tion can account for only a small fraction of the increased bile volum e, given an osmotic efficiency for GSH of 34 mu l/mu mol. In contrast to CCK receptor antagonists, CCK itself had no effect on bile flow and outputs of bicarbonate, GSH, and bile acids, suggesting that the effe cts of the antagonists are not related to their interaction with CCK r eceptors. These findings demonstrate that proglumide and loxiglumide s timulate a bile acid-independent bile flow that is only partially expl ained by an increase in GSH excretion.