Inhibition by nifedipine of adherence- and activated macrophage-induced death of human gingival fibroblasts

The effects of nifedipine on the death and proliferation of gingival fibrob lasts were investigated to elucidate the mechanism of gingival overgrowth t hat is associated with chronic administration of Ca2+ channel blockers. The number of adhered viable and dead fibroblasts obtained from healthy human gingiva increased after confluence, whereas cell death was inhibited by nif edipine in a concentration-dependent manner. A similar inhibition was also observed in the presence of other calcium channel blockers, such as nicardi pine, diltiazem, and verapamil. When gingival fibroblasts were co-cultured with RAW264 (macrophage-like) cells, lipopolysaccharide (LPS) caused the co ncentration-dependent death of fibroblasts. Nifedipine significantly inhibi ted the LPS-induced cell death. Although neither LPS nor N-ethyl-2-(1-ethyl -2-hydroxy-2-nitroso-hydrazino)-ethanamine, a nitric oxide donor, directly caused fibroblast death, 3-morpholino-sydnonimine (SIN-1). a peroxynitrite donor, induced fibroblast death, regardless of the presence of RAW cells. T he cell death induced by SIN-1 was not affected by nifedipine treatment. LP S stimulation caused an increase in the immunoreactivity of inducible nitri c oxide synthase (iNOS) and in the nitrite concentration in the incubation medium of RAW cells. The induction of iNOS was completely prevented by the incubation with nifedipine. The inhibition by nifedipine of nitrite product ion in RAW cells was also observed after treatment with nicardipine, but no t with either diltiazem or verapamil. Therefore, the inhibition by nifedipi ne of both adherence- and LPS-stimulated macrophage-induced death of fibrob lasts may be the mechanism of gingival overgrowth seen during chronic treat ment with Ca2+ channel blockers. (C) 2001 Published by Elsevier Science B.V .