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Background: The role of nitric oxide (NO) on bone metabolism is controversial, since it can either stimulate bone formation or resorption. We investigated the effect of local administration of the NO donor isosorbide in an experimental periodontal disease model. Methods: Wistar rats were subjected to a ligature placement around the cervix of the right second upper molar and were sacrificed after 11 days. Alveolar bone loss was measured in one quadrant as the sum of the distances between the cuspid tip and the alveolar bone along the axis of each molar root, which was subtracted from the contralateral side, used as unligated control. The semiquantitative histopathological scale of the periodontium was based on cell infiltration and alveolar bone and cementum integrity. Groups were treated with a gel containing 1% or 5% isosorbide applied to the vestibular side of the molar gingiva 1 hour before the placement of the ligature and then twice daily until sacrifice. Controls included one group subjected to periodontitis and no treatment (MT) and another that received the gel containing just the vehicle (V). Results: The application of the vehicle gel produced an increase of the alveolar bone resorption, without altering the inflammatory changes, compared to the NT group. The 5% isosorbide produced a significant reduction of the alveolar bone resorption, compared to V and NT. This reduction was confirmed by histological analysis, showing less inflammatory cell infiltration and preservation of the cementum and the alveolar process. Conclusion: Local application of isosorbide reduces alveolar bone resorption in experimental periodontal disease in rats, suggesting a local anti-inflammatory effect of isosorbide. [ABSTRACT FROM AUTHOR]