The characteristics of mast cell heterogeneity include differences in mast cell staining, cellular structure, content of proteoglycans and vasoactive amines, and in vitro responses to secretagogues. We have found that the anesthetic agent, droperidol-fentanyl, significantly decreased rat synovial vascular permeability after selective synovial mast cell degranulation. In contrast, there was no effect on skin mast cell-induced vascular permeability. To address the possibility that this difference in response represents mast cell heterogeneity and uniqueness of synovial mast cells, we investigated the effects of three different anesthetic agents on synovial mast cells. In these studies we examined whether (1) the drugs affect synovial mast cells and (2) whether the drugs affect synovial mast cells differently from mast cells in skin. Our data indicate that, compared to inhaled methoxyflurane and ethyl ether, subcutaneous droperidol-fentanyl had a significant inhibitory effect on synovial, but not skin, mast cell-mediated vascular permeability, which was associated with a significant inhibition of synovial mast cell histamine release. Thus, the permeability differences were not due only to effects on histamine receptors. Our data suggest the possibility that there are significant functional differences between synovial and skin mast cells, a phenomenon that may have important therapeutic implications for treatment of mast cell-mediated synovial inflammation.