Nifedipine Induces Gingival Epithelial Hyperplasia in Rats Through Inhibition of Apoptosis

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Abstract
Nifedipine is used as a long-acting vasodilator; one of its side effects is gingival overgrowth, characterized by an accumulation of collagenous components within the gingival connective tissue and epithelial hyperplasia with elongated, branched rete pegs penetrating into the connective tissue. We investigated the effect of nifedipine on apoptosis of gingival keratinocytes of rats to elucidate the mechanism of nifedipine-induced gingival epithelial hyperplasia. Twenty-day-old rats were fed a powdered diet containing or lacking nifedipine for 8 to 30 days. The mandibular gingiva and palatal mucosa were removed on days 8, 15, or 30, and epithelial thickness was examined by light microscopy. In situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay was used to examine apoptosis of keratinocytes in the epithelium. In addition, we examined the effects of nifedipine on proliferation of keratinocytes and epithelial cell life on day 8 by 5-bromo-2'-deoxyuridine (BrdU) staining. Microscopic examination showed gingival epithelial hyperplasia in nifedipine-treated rats after day 15. Apoptosis of gingival keratinocytes was seen to be inhibited in nifedipine-treated rats on day 8 and 15. Also, nifedipine did not induce an increase of keratinocyte proliferation activity in terms of the number of cells showing positive staining with BrdU. Prolongation of cell life by nifedipine was observed on day 8 in gingival epithelium through a delay of upward cell movement compared to controls. However, epithelial hyperplasia was not detected in palatal mucosa, and there were no significant differences in apoptotic rates of keratinocytes and cell life between nifedipine-treated rats and control rats. These results suggest that nifedipine induces epithelial hyperplasia in gingival overgrowth not by an increase in keratinocyte proliferation, but by prolongation of cell life through reduction of apoptosis before epithelial hyperplasia is detectable.