A cholecystokinin receptor antagonist, loxiglumide, stimulates biliary secretion in conscious rats

The effects of the CCK receptor antagonists loxiglumide [D,L-4-(3,4-dichlorobenzoylamino)-5-(N-3-methoxy-propylpentylam ino)-5-oxo- pentanoic acid, CR 1505] and MK-329 [3S(-)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzo-diazepine-3-y l)-1H - indole-2-carboxamide, L-364,718], on bile flow were investigated in conscious rats. The bile duct of male Wistar rats was cannulated to directly collect pure bile, and the second cannula was inserted into the duodenum for reinfusion of bile. On the 4th through 7th postoperative days loxiglumide (25, 50 or 100 mg/kg body weight), MK-329 (1 mg/kg body weight) or the respective solvent (saline and 80% dimethyl sulfoxide) was injected subcutaneously. Loxiglumide caused dose-dependent increases in bile flow and bile acid output with a slight non-dose-dependent increase in bilirubin output. The integrated increments of bile flow during a 3-h period after saline and 100 mg/kg body weight loxiglumide were -14 +/- 71 and 982 +/- 61 microliters/100 g body weight, respectively, and those of bile acids were 2.5 +/- 1.4 and 23.1 +/- 4.1 mumol/100 g body weight, respectively. In contrast, MK-329 markedly decreased the bile flow (-439 +/- 76 vs. control; -32.8 +/- 76 microliters/100 g body weight/3 h, P < 0.001) and bile acids output (-16.3 +/- 6.8 vs. control; 3.4 +/- 3.8 mumol/100 g body weight/3 h, P < 0.001), while it significantly increased bilirubin output (86.4 +/- 15.6 vs. 43.5 +/- 1.1 mg/100 g body weight/3 h, P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)