1. Pretreatment of rat isolated mast cells with SR 48692, a nonpeptide antagonist of the neurotensin (NT) receptor, prevented histamine secretion in response to NT. 2. This inhibition was rapid in onset (approximately 1 min) and dependent upon the concentration of SR 48692 (IC50 approximately 1-10 nM). 3. SR 48692 (1-1000 nM) did not inhibit histamine secretion elicited by substance P, bradykinin or compound 48/80, or by anti-IgE stimulation of sensitized mast cells. 4. When SR 48692 was injected intradermally (5 pmol in 50 microliters) into anaesthetized rats, 15 min before the intradermal injection of NT, it reduced the effect of NT on vascular permeability. 5. When injected intravenously, SR 48692 attenuated the effects of NT on haematocrit and blood stasis. 6. These results demonstrate that SR 48692 selectively antagonizes the actions of NT on rat isolated mast cells as well as mast cells in vivo. Given the demonstrated specific interaction of SR 48692 with receptors for NT in brain, our results suggest the presence of specific NT receptors on mast cells.