thapsigargin and lafutidine

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.

Topics: Acetamides; Animals; Calcium; Calcium Chloride; Capsaicin; Dose-Response Relationship, Drug; Endothelial Cells; Humans; Imidazoles; Immunoblotting; Intracellular Fluid; PC12 Cells; Piperidines; Pyridines; Rats; Thapsigargin; Time Factors