Effects of substance P on human colonic mucosa in vitro.
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.
Riegler
M
M
Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Castagliuolo
I
I
So
P T
PT
Lotz
M
M
Wang
C
C
Wlk
M
M
Sogukoglu
T
T
Cosentini
E
E
Bischof
G
G
Hamilton
G
G
Teleky
B
B
Wenzl
E
E
Matthews
J B
JB
Pothoulakis
C
C
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D003106:Colon / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D017097:Electric Impedance; D004594:Electrophysiology; D019833:Genistein / Q000494:pharmacology; D006632:Histamine / Q000502:physiology; D006636:Histamine Release / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D007477:Ions; D008407:Mast Cells / Q000502:physiology; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013373:Substance P / Q000494:pharmacology*; D013779:Tetrodotoxin / Q000494:pharmacology; D014018:Tissue Distribution / Q000502:physiology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007477:Ions; D018040:Receptors, Neurokinin-1; D013373:Substance P; D013779:Tetrodotoxin; D006632:Histamine; D019833:Genistein; D007213:Indomethacin