Substance P causes a chloride-dependent short-circuit current response in rabbit colonic mucosa in vitro

Background: The neuropeptide substance P (SP) induces secretion in animals. The effect of SP on rabbit colon is not known. We: therefore investigated the effect of SP on rabbit colonic mucosa mounted in Ussing chambers. Methods: Colonic mucosae were incubated with SP in Cl--containing or Cl--free buffer. Drugs for pharmacologic characterization of SP-induced electrophysiologic changes were applied to the serosal bath 30 min before SP administration. Results: Serosal, but not luminal, administration of SP (10(-8)-10(-6) M) induced a rapid, transient, bumetanide-sensitive, dose- and chloride-dependent short-circuit current (I-sc) increase (P < 0.001), which was inhibited by 85%, 80%, 82%, 90%, and 70% after serosal preincubation with the neurokinin-1 (NK-1) receptor antagonist CP-96,345, the neuronal blocker tetrodotoxin (10(-6) M), the mast cell stabilizer lodoxamide (10(-6) M), the H1-receptor antagonist pyrilamine (10(-6) M), or the prostaglandin synthesis inhibitor indomethacin (10(-6) M), respectively (P < 0.001). Conclusions: SP stimulates a chloride-dependent I-sc increase in the rabbit colon which is mediated by nerves and mast cells and the mast cell product histamine.