Stimulation of chloride secretion by N-formyl-methionylleucylphenylalanine (FMLP) in rabbit ileal mucosa.

1. Formyl-methionyl peptides are potent neutrophil chemoattractants which may be involved in inflammatory responses in the intestine. Effects of formyl-methionylleucylphenylalanine (FMLP) on electrical properties and Cl- fluxes were examined with the Ussing chamber technique employing stripped segments of rabbit ileal mucosa. 2. Serosal but not mucosal addition of FMLP elicited a transient (peak effect within 2 min), concentration-dependent (maximal effect at 30 nM and half-maximal effect at 3 nM) increase in short-circuit current (Isc) which was not inhibited by pretreatment of the tissue with mepyramine (10 microM), tetrodotoxin (0.1 microM) or atropine (10 microM). The related peptides FMLP-benzylamide (FMLP-benz) and methionyl-leucylphenylalanine (MLP) produced concentration-dependent increases in Isc which were qualitatively similar to FMLP. The order of potencies of these peptides was FMLP-benz greater than FMLP greater than MLP. 3. The lack of an effect of mucosal FMLP (300 nM) on Isc does not appear to be due to metabolism since addition of an aliquot of this bathing solution to the serosal bathing solution of a naive tissue increased Isc as expected. Addition of FMLP (30 nM) to the serosal bathing solution of a tissue pre-stimulated with serosal FMLP (30 nM) failed to elicit a response. 4. The increase in Isc produced by FMLP (30 nM) was inhibited by removal of Ca2+ from the serosal bathing solution and by removal of Cl- from both bathing solutions. FMLP (30 nM) increased the serosal-to-mucosal flux of Cl- and decreased the transepithelial conductance (Gt). 5. The cyclo-oxygenase inhibitors indomethacin (1 microM), mefenamate (10 microM) or piroxicam (30 microM) added to both the serosal and mucosal bathing solutions inhibited the increase in Isc elicited by FMLP (30 nM). 6. Measurement of release of immunoreactive thromboxane B2, 6-keto-PGF1 alpha and PGE2 revealed that FMLP (30 nM) selectively increased PGE2 release by an indomethacin-sensitive pathway. 7. Thus, in addition to being potent chemoattractants, formyl-methionyl peptides stimulate electrogenic Cl- secretion and also increase prostaglandin production.