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Am J Physiol Gastrointest Liver Physiol 276: G1473-G1483, 1999;
0193-1857/99 $5.00
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Vol. 276, Issue 6, G1473-G1483, June 1999

Effects of substance P on human colonic mucosa in vitro

Martin Riegler1,3, Ignazio Castagliuolo1, Peter T. C. So2, Margaret Lotz1, Chi Wang1, Michael Wlk3, Tacettin Sogukoglu3, Enrico Cosentini3, Georg Bischof3, Gerhard Hamilton3, Bela Teleky3, Etienne Wenzl3, Jeffrey B. Matthews4, and Charalabos Pothoulakis1

1 Division of Gastroenterology and 4 Department of Surgery, Beth Israel Deaconess Medical Center, Boston 02215; 2 Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02141; and 3 University Clinic of Surgery, Vienna General Hospital, A-1090 Vienna, Austria

Previous studies indicated that the peptide substance P (SP) causes Cl--dependent secretion in animal colonic mucosa. We investigated the effects of SP in human colonic mucosa mounted in Ussing chamber. Drugs for pharmacological characterization of SP-induced responses were applied 30 min before SP. Serosal, but not luminal, administration of SP (10-8 to 10-6 M) induced a rapid, monophasic concentration and Cl--dependent, bumetanide-sensitive short-circuit current (Isc) increase, which was inhibited by the SP neurokinin 1 (NK1)-receptor antagonist CP-96345, the neuronal blocker TTX, the mast cell stabilizer lodoxamide, the histamine 1-receptor antagonist pyrilamine, and the PG synthesis inhibitor indomethacin. SP caused TTX- and lodoxamide-sensitive histamine release from colonic mucosa. Two-photon microscopy revealed NK1 (SP)-receptor immunoreactivity on nerve cells. The tyrosine kinase inhibitor genistein concentration dependently blocked SP-induced Isc increase without impairing forskolin- and carbachol-mediated Isc 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 product histamine. Our results also indicate that tyrosine kinases may be involved in this SP-induced response.

genistein; histamine; short-circuit current; neurokinin 1 receptor


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