Cholecystokinin-JMV-180 and pilocarpine are potent inhibitors of cholecystokinin and carbachol actions on guinea pig pancreatic acinar cells

The release of amylase and the elevation of cytoplasmic Ca2+ concentration ([Ca2+]i) in response to cholecystokinin-octapeptide (CCK-8), the cholecystokinin analogue JMV-180, the stable choline ester carbamylcholine (carbachol) and the muscarinic agonist pilocarpine were studied in guinea-pig pancreatic acinar cells. The maximal amylase and [Ca2+]i responses to JMV-180 and pilocarpine were 12-15% of the corresponding responses to CCK-8 and carbachol. The amylase and [Ca2+]i responses to maximal concentrations of CCK-8 and carbachol were inhibited in concentration-dependent manners by JMV-180 and pilocarpine, respectively. In individual acinar cells, JMV-180 and pilocarpine like low concentrations of CCK-8 and carbachol caused oscillations of [Ca2+]i. The sustained [Ca2+]i responses to maximal concentrations of CCK-8 and carbachol were transformed into oscillatory responses during simultaneous exposure to JMV-180 and pilocarpine, respectively. Maximal concentrations of JMV-180 and pilocarpine did not cause homologous or heterologous desensitization of the [Ca2+]i responses but inhibited desensitization evoked by maximal concentrations of CCK-8 or carbachol. JMV-180 and pilocarpine acted as weak, partial agonists exhibiting effective inhibition of the acinar cell responses to full agonists. The effects appeared to be best explained by interactions with two forms of the respective receptor with JMV-180 and pilocarpine acting as partial agonists for one state of the receptor and as antagonist for the second state.