The effect of N-formyl-methionyl-leucyl-phenyl-alanine on cholinergic neurotransmission and its modulation by enkephalinase in rabbit airway smooth muscle

N-formyl-methionyl-leucyl-phenylalanine (FMLP), a synthetic analogue of bacterial chemotactic peptide, may play a role in airway hyperresponsiveness, and is cleaved by neutral endopeptidase-24.11 (enkephalinase). To determine the effect of FMLP on parasympathetic contraction of airway smooth muscle and its modulation by endogenous enkephalinase, we studied isolated rabbit tracheal ring segments under isometric conditions in vitro. FMLP did not cause muscle contraction, but it potentiated the contractile response to electrical field stimulation (EFS) in a dose-dependent fashion, with the maximal increase from the baseline response being 59.8 +/- 6.2% (mean +/- S.E.M., P less than 0.001), an effect that was abolished by t-Boc-Phe-Leu-Phe-Leu-Phe, partially inhibited by pyrilamine, but not by phentolamine or D-Pro2,D-Trp7,9]substance P. In contrast, the contractile response to administered acetylcholine was not affected by FMLP. Pretreatment of tissues with thiorphan, an enkephalinase inhibitor, further potentiated the effect of FMLP on the EFS-induced contraction. These results suggest that FMLP facilitates cholinergic neurotransmission in rabbit airway smooth muscle probably by increasing acetylcholine release, and that this effect may be modulated by enkephalinase in the airway.