Abstract
We investigated the interaction of KSG-504 with CCK-8 or pentagastrin-induced gallbladder and gastrointestinal responses in vitro and in vivo. KSG-504 (10-7-10-4 M) inhibited CCK-8-induced contractions of both isolated guinea pig gallbladder and rabbit terminal cavity of the bile duct in a concentration-dependent manner. Furthermore, intravenous administration of KSG-504 also dose-dependently inhibited CCK-8-induced gallbladder contraction in anesthetized guinea pigs with an IC50 value of 0.23 mg/kg. In conscious mice, KSG-504 inhibited both CCK-8 and egg yolkstimulated gallbladder emptying in a dose-dependent manner (IC50 : 13.3 and 9.6 mg/kg, respectively). The CCK-8-induced delay of gastric emptying in conscious rats was also antagonized by KSG-504 with an IC50 value of 3.78 mg/kg, i.v., whereas pentagastrin-stimulated gastric acid secretion in anesthetized rats was not affected by KSG-504 at all. KSG-504 (1 mg/kg, i.v.) also inhibited CCK-8-induced duodenal and jejunal contractions in anesthetized rabbits. These results indicate that KSG-504 exerts an antagonistic effect on CCK-A receptors in the gastrointestinal tract, but not on gastrin receptors in the stomach.
