Whether specific binding sites for endothelin-1 and endothelin-3 exist in mouse bone marrow-derived mast cells (BMMC) and if these endothelins are capable of stimulating chemical mediator release from the cells was investigated. A single component of binding sites for endothelin-1 was found in the cells, but no binding sites for endothelin-3 were observed. Endothelin-1 at 1–100 nM concentration dependently induced release of histamine and immunoreactive leukotriene C₄ from BMMC, while endothelin-3 at up to 100 nM did not stimulate the release of either mediator. Time course experiments revealed that the release of histamine and immunoreactive leukotriene C₄ induced by endothelin-1 occurred rapidly, reaching near maximal levels within 20 s and 2 min, respectively, after the stimulation, while histamine release induced by antigen, at the concentration which induced an extent of release similar to that induced by 100 nM endothelin-1, required comparatively prolonged incubation (approximately 10 min for submaximal levels). Cyclo(D-Asp-Pro-D-Val-Leu-D-Trp) (BQ-123), a selective antagonist of endothelin ET_A receptors, not only dissociated [¹²⁵I] endothelin-1 specifically bound to BMMC but also inhibited the release of both mediators from endothelin-1-induced cells. These results suggested strongly that BMMC have endothelin ET_A receptors on their cell membrane, stimulation of which leads to chemical mediator release, probably via a mechanism different from that involved in the antigen-induced release.