title: Caffeine inhibits a low affinity but not a high affinity mechanism for cholecystokinin-evoked Ca2+ signalling and amylase release from guinea pig pancreatic acini.
abstract: Caffeine has been found to inhibit the formation and action of Ca2+-mobilizing inositol 1,4,5-trisphosphate (IP3) in pancreatic acinar cells. The aim of the present study was to investigate the effects of caffeine on cytoplasmic Ca2+ concentrations ([Ca2+]i) and amylase release in response to different agonists. [Ca2+]i was determined by cytofluorometry using fura-2 as indicator and amylase release with a substrate reagent. Stimulation with low concentrations of carbachol or cholecystokinin octapeptide (CCK-8) induces [Ca2+]i oscillations whereas higher concentrations cause sustained elevation of [Ca2+]i. The less efficacious agonists pilocarpine and CCK-JMV-180 evoke oscillations only. Caffeine inhibited carbachol-induced elevation of [Ca2+]i and amylase responses in a competitive manner, abolishing the responses to low and incompletely inhibiting the responses to high concentrations of the agonist. Also, the [Ca2+]i elevations by pilocarpine were abolished by caffeine. The effects on CCK-8-induced elevation of [Ca2+]i and amylase secretion were paradoxical, the caffeine inhibition being more pronounced at high than at low concentrations of CCK-8. This enigma was further emphasized by moderate effects of caffeine on the responses to CCK-JMV-180. The results indicate that carbachol, pilocarpine and high concentrations of CCK-8 elicit IP3-mediated responses and that CCK-JMV-180 and low concentrations of CCK-8 elevate [Ca2+]i and stimulate amylase release by another signal transduction mechanism.
authors.affiliation: Pharmacological Division, Medical Products Agency, Uppsala, Sweden. lars.sjodin@fysiologi.uu.se
authors.forename: L
authors.initials: L
authors.lastname: Sjödin
authors.forename: E
authors.initials: E
authors.lastname: Gylfe
mesh_terms: D000681:Amylases / Q000378:metabolism*; D000818:Animals; D002110:Caffeine / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects*; D002217:Carbachol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism; D012844:Sincalide / Q000494:pharmacology*
chemical_list: D002110:Caffeine; D002217:Carbachol; D000681:Amylases; D012844:Sincalide