The
intravenous administration of the chemotactic and
secretagogue peptide N-formyl-L-methionyl-L-leucyl-
L-phenylalanine (FMLP; 0.3-30 micrograms kg-1) to the guinea-pig induces bronchoconstriction and dose-dependent
leukopenia accompanied by mild
thrombocytopenia. No electron microscopic evidence of platelet aggregation in lungs or significant accumulation of 111In-labelled platelets in the thoracic region at the height of bronchoconstriction was noted. Bronchoconstriction and
leukopenia induced by FMLP were not affected by
prostacyclin, by platelet depletion, by the
platelet-activating factor (
Paf-acether) antagonist
BN 52021 or by the
histamine H1-antagonist
mepyramine. Bronchoconstriction, but not
leukopenia, was inhibited by
aspirin, whereas the peptido-
leukotriene antagonist compound
FPL 55712 and the
cyclo-oxygenase lipoxygenase inhibitor indomethacin reduced bronchoconstriction to a limited extent only. The mixed
cyclo-oxygenase/
lipoxygenase inhibitor compound
BW 755C was very effective in blocking bronchoconstriction by the highest dose of FMLP used, but failed to interfere with
leukopenia. FMLP-induced dose-dependent contraction of parenchymal lung strips was accompanied by the formation of immuno-reactive
thromboxane B2 in amounts markedly less than those formed from exogenous
arachidonic acid at concentrations equieffective in inducing contractions. FMLP-induced contractions of the guinea-pig lung strip were not modified by
mepyramine nor by
FPL 55712. They were reduced by
indomethacin and
aspirin and an even greater reduction was obtained with
aspirin used in combination with
FPL 55712.
BW 755C suppressed the effects of all the concentrations of FMLP tested, whereas tert-butyloxy-carbonyl-L-methionyl-L-leucyl-
L-phenylalanine, a chemical analogue of FMLP, displaced the concentration-response curve to the right, without reducing the maximal contraction obtained. The present results indicate that: (a) bronchoconstriction by FMLP is not due to platelet activation, to
cyclo-oxygenase-dependent mechanisms or to peptido-
leukotriene formation. The inhibitory effect of
aspirin and
BW 755C involves a property other than
cyclo-oxygenase inhibition, which is not shared by
indomethacin. (b) The contractile effects of FMLP on parenchymal lung strips follow an interaction with specific receptor sites, as shown by the effectiveness of tert-butyloxy-carbonyl-L-methionyl-L-leucyl-
L-phenylalanine, and involves the combined effects of
cyclo-oxygenase and
lipoxygenase metabolites.