Characterization of a persistent inhibitory action of L-364,718 on cholecystokinin-stimulated enzyme secretion in pancreatic acini.
Examining the actions of L-364,718 on rat pancreatic acini, we found that L-364,718 causes persistent inhibition of cholecystokinin (CCK)-8-stimulated enzyme secretion in acini that were first incubated with L-364,718, washed repeatedly, and then reincubated with CCK-8. This inhibition is maximal after as little as 5 s of first incubation with L-364,718, is unaltered by reducing the temperature of the first incubation from 37 to 4 degrees C and is specific for CCK-8 in that carbachol-stimulated enzyme secretion is unaltered. The inhibitory potency of L-364,718 added to the first incubation followed by washing and reincubation with CCK-8 is nearly the same as when L-364,718 is added together with CCK-8 in the same incubation. The persistent inhibitory action of L-364,718 is not attributable to residual free L-364,718 in the bulk phase of the second incubation medium. In addition, L-364,718 does not cause persistent inhibition by binding irreversibly to CCK receptors because the binding reaction is completely reversible and the persistent inhibition can be surmounted with appropriate concentrations of CCK-8. When acini are first incubated with L-364,718 and washed repeatedly, approximately 0.2% of the original L-364,718 remains trapped in a microenvironment within the acini. This trapping presumably results in a sufficiently high concentration of L-364,718 to produce its persistent, albeit surmountable inhibition.
Bhat
S T
ST
Department of Internal Medicine, St. Louis University Medical Center, Missouri 63104.
Talkad
V D
VD
Pollo
D A
DA
Gardner
J D
JD
D000681:Amylases / Q000378:metabolism*; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001570:Benzodiazepinones / Q000378:metabolism / Q000494:pharmacology*; D002217:Carbachol / Q000494:pharmacology; D002766:Cholecystokinin / Q000037:antagonists & inhibitors*; D020109:Devazepide; D007700:Kinetics; D008297:Male; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011949:Receptors, Cholecystokinin / Q000378:metabolism; D012844:Sincalide / Q000494:pharmacology*
D001570:Benzodiazepinones; D011949:Receptors, Cholecystokinin; D001285:Atropine; D002217:Carbachol; D002766:Cholecystokinin; D000681:Amylases; D020109:Devazepide; D012844:Sincalide