Phenytoin-Induced Elevation of the Intracellular Calcium Concentration by Stimulation of Calcium-Sensing Receptors in Gingival Fibroblasts
- 1 Department of Dental Pharmacology, Matsumoto Dental University, Shiojiri, Japan
- 2 Hard Tissue Pathology Unit, Institute of Oral Science, Matsumoto Dental University, Shiojiri, Japan.
- 3 Hard Tissue Pathology Unit, Institute of Oral Science, Matsumoto Dental University, Shiojiri, Japan.
Abstract
Background: The mechanism concerning gingival overgrowth as a side effect of phenytoin, a therapeutic drug for epilepsy has been still unclear. As one of mechanisms, by measuring the intracellular calcium concentration ( [Ca 2+ ]i) of the gingival fibroblasts, it has been advocated that there is relationship between gingival overgrowth and phenytoin-induced alterations in the [Ca 2+ ]i in gingival fibroblasts. To confirm that phenytoin elevates the [Ca 2+ ]i, and if so, to find out its mode of action. Methods: The [Ca 2+ ]i was measured with the Ca 2+ -sensitive fluorescent dye fura-2/AM. Cells were soaked in a flexiperm chamber and perfused by a saline. Drugs at appropriate concentrations were added to the per fusate. Results: Phenytoin concentration-dependently elevated the [Ca 2+ ]i. NPS 2390, a calcium-sensing receptor (CaSR) blocker, significantly suppressed the phenytoin-induced [Ca 2+ ]i elevation. U73122, a phospholipase C (PLC) inhibitor, inihibited the phenytoin-induced [Ca 2+ ]i elevation. TMB-8, a blocker of inositol triphophate (IP 3 ) receptors in ER, sig nificantly depressed the phenytoin-induced [Ca 2+ ]i elevation. m -3M3FBS, a PLC activator, enhanced the pheny toin-induced [Ca 2+ ]i elevation. From the findings obtained, it is disc ussed as follows: The Ca 2+ -free saline and NPS2390, a CaSR antagonist, inhibited the phenytoin-induced [Ca 2+ ]i rise; These results indicate that CaSRs exist in gingival fi broblasts and that CaSRs are involved in the phenytoin-induced [Ca 2+ ]i rise; U73122 and TMB-8 depressed the pheny toin-induced [Ca 2+ ]i elevation and furthermore, m -3M3FBS enhanced the phenytoin-induced [Ca 2+ ]i elevation, showing that the Ca 2+ release from the ER is involved in the phenytoin-induced [Ca 2+ ]i elevation. Conclusion: We have con cluded that phenytoin elevates the [Ca 2+ ]i by activating CaSRs and enhancing the Ca 2+ release from the Ca 2+ stores in gingival fibroblasts.
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