EFFECT OF 2 NEW CHOLECYSTOKININ ANTAGONISTS ON GALLBLADDER EMPTYING IN OPOSSUMS

In this investigation we evaluated the effect of two new cholecystokinin (CCK) antagonists, CR 1409 and L364,718, on gallbladder emptying in the opossum. Gallbladder emptying was elicited by both exogenous and endogenous CCK. The three test challenges were 1) intravenous infusion of CCK octapeptide (OP) (10 ng.kg-1.min-1), 2) feeding, and 3) intraduodenal infusion of Isocal (0.4 ml/min), a fat-containing nutrient. During control conditions each test challenge elicited approximately 60% gallbladder emptying within 30 min and 70% emptying by 60 min. At given doses both CR 1409 and L364,718 substantially antagonized or abolished the gallbladder emptying elicited by each of the test challenges. The antagonism for postprandial gallbladder emptying was diminished between 30 and 50 min compared with that for CCK-OP infusion and intraduodenal infusion of Isocal. Unexpectedly, the gallbladder emptying induced by infusion of motilin (5-mu-g.kg-1.h-1) was antagonized by either CR 1409 or L364,718. In anesthetized animals, gallbladder contraction was induced by a variety of agonists, such as bethanechol, histamine phosphate, 5-hydroxytryptamine, and phenylephrine. In this later model CR 1409 and L364,718 functioned solely as selective antagonists. We conclude that for the oposum gallbladder 1) the CCK antagonists CR 1409 and L364,718 antagonize or abolish gallbladder emptying induced by exogenous or endogenous CCK;2) the pattern of CCK antagonism after feeding suggests that the early phase of postprandial gallbladder emptying is mediated by a mechanism other than endogenous CCK, whereas late postprandial emptying is mediated by release of endogenous CCK; and 3) CR 1409 and L364,718 are not totally specific antagonists for gallbladder CCK receptors alone but also antagonize gallbladder contraction induced by motilin. The mechanism of this latter effect remains to be determined, but it is not due to a release of CCK by motilin infusion.