Effects of substance P on human colonic mucosa in vitro

Previous studies indicated that the peptide substance P (SP) causes Cl--dep endent secretion in animal colonic mucosa. We investigated the effects of S P in human colonic mucosa mounted in Ussing chamber. Drugs for pharmacologi cal characterization of SP-induced responses were applied 30 min before SP. Serosal, but not luminal, administration of SP (10(-8) to 10(-6) M) induce d a rapid, monophasic concentration and Cl--dependent, bumetanide-sensitive short-circuit current (I-sc) increase, which was inhibited by the SP neuro kinin 1 (NK1)-receptor antagonist CP-96345, the neuronal blocker TTX, the m ast cell stabilizer lodoxamide, the histamine 1-receptor antagonist pyrilam ine, and the PG synthesis inhibitor indomethacin. SP caused TTX- and lodoxa mide-sensitive histamine release from colonic mucosa. Two-photon microscopy revealed NK1 (SP)-receptor immunoreactivity on nerve cells. The tyrosine k inase inhibitor genistein concentration dependently blocked SP-induced I-sc increase without impairing forskolin- and carbachol-mediated I-sc increase . We conclude that SP stimulates Cl--dependent secretion in human colon by a pathway(s) involving mucosal nerves, mast cells, and the mast cell produc t histamine. Our results also indicate that tyrosine kinases may be involve d in this SP-induced response.