title: Xanthine derivatives inhibit the increase in intracellular Ca2+ concentration induced by acetylcholine in nasal gland acinar cells of the guinea-pig.
abstract: Intracellular calcium is considered to play a major role in secretory responses of various exocrine cell types. We examined whether xanthine derivatives can inhibit Ca2+ mobilization and entry in secretory cells in the airways. Therefore, the inhibitory effect of xanthines in the intracellular Ca2+ concentration ([Ca2+]i) in the isolated submucosal acinar cells of the guinea-pig nasal septum was investigated by means of fluorescence ratio microscopy. The inhibitory effects on Ca2+ release from stores was examined in Ca(2+)-free conditions. Effects on Ca2+ entry were estimated by two different protocols; 1) the sustained phase in a long-term application of acetylcholine (ACh) and 2) the [Ca2+]i overshoot following removal of ACh in Ca(2+)-free conditions. Xanthine derivatives, 3-isobutyl-1-methyl-xanthine (IBMX), caffeine, and theophylline, significantly inhibited the increase in [Ca2+]i evoked by ACh; both mobilization from internal Ca2+ stores and Ca2+ entry from the external space. The rank order of potency of these xanthine derivatives was IBMX > theophylline > caffeine. The addition of dibutyryl-cyclic adenosine monophosphate (cAMP) and forskolin to nasal gland acinar cells failed to inhibit the ACh-evoked increase in [Ca2+]i. Furthermore, a protein kinase A inhibitor, H-89, did not affect the inhibitory effect of the xanthine derivatives. The action of xanthines on the present acinar cells did not involve Ca(2+)-induced Ca2+ release (CICR) or an interaction with purinergic receptors. Thus, xanthines have a direct inhibitory effect both on Ca2+ release and entry in nasal gland acinar cells, and might thereby have antisecretory activity within the airways.
authors.affiliation: Pharmacological Research Laboratory, Grelan Pharmaceutical Co. Ltd, Hamura, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ishitani
authors.forename: K
authors.initials: K
authors.lastname: Ikeda
authors.forename: H
authors.initials: H
authors.lastname: Sunose
authors.forename: D
authors.initials: D
authors.lastname: Wu
authors.forename: H
authors.initials: H
authors.lastname: Honda
authors.forename: T
authors.initials: T
authors.lastname: Takasaka
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006168:Guinea Pigs; D009300:Nasal Septum / Q000166:cytology / Q000378:metabolism*; D013997:Time Factors; D014970:Xanthines / Q000494:pharmacology*
chemical_list: D014970:Xanthines; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000109:Acetylcholine; D002118:Calcium