Immunologically induced histamine release from rat peritoneal mast cells is enhanced by low levels of substance P

Although direct activation of mast cells by high concentrations (> 10(-6) M ) of substance P is well established, the effect of sub-micromolar concentr ations of the neuropeptide on mast cell activation has not been reported. W e hence investigated if substance P would modulate immunologic activation o f mast cells by studying the effect of the neuropeptide on anti-rat immunol oglobulin E antibody (anti-IgE)-induced histamine release from purified rat peritoneal mast cells. We observed that substance P could dose-dependently potentiate anti-IgE-induced histamine release from rat peritoneal mast cel ls at concentrations (3 x 10(-9) M to 3 x 10(-7) M) which alone induced ins ignificant or low level of histamine release. While the potentiating effect of substance P was not suppressed by any of the non-peptide tachykinin rec eptor antagonists CP99994 ((2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperid ine), SR48968 ((S)-N-methyl-N-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dic hlorophenyl) butyl-benzamide) and SR142801 ((S)-(N)-(1-[3-(1-benzoyl-3(3,4- dichlorophenyl)piperidine-4-yl)propyl]-4-phenylpiperidin-4-yl)-N-methyl-ace tamide), it was mimicked by compound 48/80 and suppressed by benzalkonium c hloride. Hence, substance P enhanced anti-IgE-induced histamine release thr ough a similar receptor-independent mechanism as the direct mast cell activ ating action of polybasic compounds. Since high concentrations of substance P required for directly activating mast cells may not be achievable physio logically, the enhancing actions of the neuropeptide on the immunologic act ivation of mast cells may be more clinically relevant in the pathogenesis o f various inflammatory conditions. (C) 2001 Elsevier Science B.V. All right s reserved.