G. Varga et al., EFFECT OF A NEW CCK-A RECEPTOR ANTAGONIST, DEXLOXIGLUMIDE, ON THE EXOCRINE PANCREAS IN THE RAT, J PHYSL-PAR, 91(3-5), 1997, pp. 257-264
The effect of dexloxiglumide, a new potent cholecystokinin (CCK) antag
onist, on pancreatic enzyme secretion and growth was studied in the ra
t. Pancreatic exocrine secretion was studied both in vitro (isolated a
nd perfused pancreatic segments) and in vivo (anaesthetized animals wi
th cannulation of the common bile duct) whereas the trophic effect was
investigated after short-term (7 days) administration of the CCK-agon
ist, caerulein, or camostate (a potent trypsin inhibitor), with or wit
hout dexloxiglumide. CCK-8 stimulated amylase release from in vitro pa
ncreatic segments in a concentration-dependent manner. Dexloxiglumide
displaced the concentration response curves to CCK-8 to the right with
out affecting the maximum response, suggesting a competitive antagonis
m. The Schild plot analysis of data gave a straight line with a slope
(0.90 +/- 0.36) not significantly different from unity. The calculated
pA(2) for dexloxiglumide was 6.41 +/- 0.38. In vivo experiments confi
rmed results from irt vitro studies since intravenous dexloxiglumide r
educed pancreatic exocrine secretion induced by submaximal CCK-8 stimu
lation (0.5 nmol/kg/h) in a dose-dependent manner, the ID50 being 0.64
mg/kg. Both exogenous and endogenous (released by camostate) CCK incr
eased the weight of the pancreas, the total pancreatic protein and DNA
, trypsin and amylase content. Dexloxiglumide (25 mg/kg), administered
together with caerulein (1 mu g/kg), reduced the peptide-induced incr
ease in pancreatic weight, protein and enzyme content. Similarly when
dexloxiglumide was given together with camostate (200 mg/kg), all the
observed changes were reduced by concomitant administration of the ant
agonist. These results demonstrate the ability of dexloxiglumide to an
tagonize the effects of CCK on pancreatic secretion and growth, sugges
ting that this compound is a potent and selective antagonist of CCK-A-
receptors in the pancreas.