EXOCRINE EFFECTS OF THE CCK ANTAGONIST L-364,718 IN CANINE PANCREATICAUTOGRAFTS

This study evaluated the effect of the cholecystokinin antagonist L364 ,718 on exocrine secretion in canine pancreatic autografts with pancre aticocystostomies. Urinary (autograft) amylase (U/min) and bicarbonate (mmole/min) secretion, over a 6 hr interval, were determined in the b asal state (Group A), after a bolus injection of 20 nmoles/kg of L-364 ,718 (Group B), during a continuous cholecystokinin octapeptide (OP-CC K) infusion at 125 ng/kg/hr either alone (Group C), with a bolus injec tion of 20 nmoles/kg (Group D), or 30 nmoles/kg (Group E), of L-364,71 8 1 hr before initiating OP-CCK, or 20 nmoles/kg of L-364,718 1 hr aft er initiating OP-CCK (Group F). L-364,718 had no effect on basal or OP -CCK-stimulated secretion of bicarbonate. Basal amylase secretion was decreased 1 hr after L-364,718 and remained significantly lower than c ontrols throughout the study interval. When compared to Group C (280.3 +/- 48.6), OP-CCK-stimulated amylase secretion was significantly lowe r for the first hour after L-364,718 in both Group D (157 +/- 46.7) an d Group E (31.9 +/- 11.6). In Group E, 2, 3, and 4 hr post-L-364,718 a mylase releases were 60.2 +/- 19.7, 77.7 +/- 25.1, and 87.2 +/- 28.3 c ompared to 335.5 +/- 85.9, 291.0 + 21.8, and 289.9 +/- 45.7 in Group C indicating a sustained significant inhibition of stimulated autograft amylase secretion with the higher L-364,718 dosage. In Group F, no si gnificant change in amylase secretion was demonstrated, indicating tha t L-364,718 must be administered prior to CCK stimulation to be effect ive. These studies demonstrate that L-364,718 has a dose dependent, in hibitory effect on basal, and OP-CCK-stimulated amylase secretion in a denervated autograft model. The therapeutic potential of L-364,718 an d other CCK receptor antagonists in pancreatic transplantation warrant s further study. (C) 1996 Academic Press, lnc.