BLOCKADE OF MAST-CELL HISTAMINE-SECRETION IN RESPONSE TO NEUROTENSIN BY SR-48692, A NONPEPTIDE ANTAGONIST OF THE NEUROTENSIN BRAIN RECEPTOR

1 Pretreatment of rat isolated mast cells with SR 48692, a nonpeptide antagonist of the neurotensin (NT) receptor, prevented histamine secre tion in response to NT. 2 This inhibition was rapid in onset (similar to 1 min) and dependent upon the concentration of SR 48692 (IC50 simil ar to 1-10 nM). 3 SR 48692 (1-1000 nM) did not inhibit histamine secre tion elicited by substance P, bradykinin or compound 48/80, or by anti -IgE stimulation of sensitized mast cells. 4 When SR 48692 was injecte d intradermally (5 pmol in 50 mu l) into anaesthetized rats, 15 min be fore the intradermal injection of NT, it reduced the effect of NT on v ascular permeability. 5 When injected intravenously, SR 48692 attenuat ed 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 demo nstrated specific interaction of SR 48692 with receptors for NT in bra in, our results suggest the presence of specific NT receptors on mast cells.