title: Lafutidine-induced increase in intracellular ca(2+) concentrations in PC12 and endothelial cells.
abstract: Lafutidine, a histamine H(2) receptor antagonist, exerts gastroprotective effects in addition to gastric antisecretory activity. The gastrointestinal protective effects of lafutidine are mediated by capsaicin-sensitive neurons, where capsaicin excites neurons by opening a member of the transient receptor potential channel family (TRPV1). Since the effect of lafutidine on the intracellular Ca(2+) concentration ([Ca(2+)](i)) in cells has not been elucidated, we investigated the lafutidine response to [Ca(2+)](i) in rat pheochromocytoma PC12 and human endothelial cells. Lafutidine at pharmacological concentrations greater than 1 mM induced a sustained increase in [Ca(2+)](i) in the presence of extracellular CaCl(2) in PC12 cells, while capsaicin showed dual effects on [Ca(2+)](i) in PC12 cells, where it activated TRPV1 and inhibited store-operated Ca(2+) entry. The thapsigargin (an activator of store-operated Ca(2+) entry)-induced increase in [Ca(2+)](i) in PC12 cells was inhibited by capsaicin and SKF96365, an inhibitor of store-operated Ca(2+) entry, and the lafutidine response was inhibited by capsaicin but not by SKF96365. In endothelial cells, lafutidine induced an increase in [Ca(2+)](i) in a SKF96365-insensitive manner. These results suggest that lafutidine stimulates Ca(2+) entry via the capsaicin-sensitive pathway but not the SKF96365-sensitive pathway. The possible role of store-operated Ca(2+) entry induced by lafutidine on gastrointestinal function is also discussed.
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Kunieda
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Someya
authors.forename: Syunji
authors.initials: S
authors.lastname: Horie
authors.forename: Hirofusa
authors.initials: H
authors.lastname: Ajioka
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Murayama
mesh_terms: D000081:Acetamides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000737:chemistry* / Q000378:metabolism; D002122:Calcium Chloride / Q000494:pharmacology; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015151:Immunoblotting / Q000379:methods; D007424:Intracellular Fluid / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D010880:Piperidines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D019284:Thapsigargin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000081:Acetamides; D007093:Imidazoles; D010880:Piperidines; D011725:Pyridines; C076948:lafutidine; D019284:Thapsigargin; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; C071423:capsazepine; D002122:Calcium Chloride; D002211:Capsaicin; D002118:Calcium