We have previously demonstrated the release of histamine and leukotriene B 4 (LTB 4 ) induced by substance P (SP) from guinea pig skin in vitro. To investigate the mechanisms of SP-induced mediator release, the patterens of SP-induced mediator release were compared with those of antigen-induced mediator release in guinea pig skin in vitro. SP (10 - 4 M) caused a rapid release of histamine which was evident at 1min after challenge reaching the maximum (25.6%) at 5min. This release was partially dependent on extracellular calcium. In contrast, antigen challenge caused a relatively slow release of histamine which was evident at 3min after challenge reaching the maximum at 15min. This release was completely dependent on extracellular calcium.These results suggested that SP caused mediator release from cutaneous mast cells by the different mechanism from antigen-induced reaction.