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 rats and compared to the effects of CCK itself. These agents were infused intravenously over a 2-hr period, and bile flow, and biliary excretion of bicarbonate, total bile acids, and glutathione were measured in 30-min intervals. All three antagonists produced a dose-dependent choleresis, but a significant decrease in bile acid excretion, indicating that they stimulate bile flow via a bile acid-independent mechanism. The increase in bile flow was associated with a parallel increase in biliary glutathione and bicarbonate output in rats treated with proglumide and loxiglumide. In animals pretreated with acivicin to inhibit gamma-glutamyltransferase activity, proglumide was shown to stimulate biliary excretion of reduced glutathione (GSH), but not glutathione disulfide (GSSG), indicating the absence of oxidative stress in the liver. GSH output was increased by only 0.5-0.9 mumol/30 min after infusion of proglumide at a dose of 75 mg/kg/hr, whereas bile volume was increased 0.2-0.4 ml/30 min, indicating that this increased biliary GSH excretion can account for only a small fraction of the increased bile volume, given an osmotic efficiency for GSH of 34 microliters/mumol. 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 effects of the antagonists are not related to their interaction with CCK receptors. These findings demonstrate that proglumide and loxiglumide stimulate a bile acid-independent bile flow that is only partially explained by an increase in GSH excretion.