Cholecystokinin (
CCK) receptor antagonists are shown to have therapeutic as well as preventive effects in some types of
acute pancreatitis. However, there is a possibility that administration of
CCK receptor antagonists with a high inhibitory potency on the endocrine pancreas to patients with
acute pancreatitis exacerbates the associated
glucose intolerance. In the present study we simultaneously examined the effects of the newly developed
benzodiazepine derivative
FK480 and
proglumide-related antagonist
KSG-504 on CCK octapeptide (CCK-8)-stimulated exocrine and endocrine function in the isolated perfused rat pancreas.
FK480 and
KSG-504 inhibited CCK-8-stimulated pancreatic juice flow,
protein output, and
insulin release in a dose-dependent manner.
FK480 was approximately 10 times more potent than
KSG-504 in inhibiting exocrine and endocrine secretion. Both antagonists inhibited CCK-8-stimulated
insulin release more potently than exocrine secretion.
FK480 caused a dose-dependent residual inhibition of exocrine secretion after its removal from the perfusate, whereas
insulin release was only slightly impaired even at the highest dose. In contrast, termination of
KSG-504 infusion resulted in an immediate increase in both exocrine and
insulin responses without causing any residual inhibition. With regard to the residual inhibition, therefore,
KSG-504 had no significant influences on exocrine and
insulin release, whereas
FK480 inhibited exocrine secretion more potently than
insulin response. These results suggest that
FK480 might become a useful therapeutic agent for
pancreatitis with respect to its long-duration inhibitory effect on exocrine secretion and short-duration inhibitory effect on
insulin release.