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Pharmacological modulation of the effects of N ‐formyl‐L‐methionyl‐L‐leucyl‐L‐phenylalanine in guinea‐pigs: involvement of the arachidonic acid cascade
Author(s) -
Boukili M. Abdelhakim,
Bureau Michel,
Lagente Vincent,
Lefort Jean,
LellouchTubiana Arielle,
Malanchère Evelyne,
Vargaftig B. Boris
Publication year - 1986
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1986.tb10267.x
Subject(s) - bronchoconstriction , mepyramine , chemistry , leukotriene , leukotriene d4 , cyclooxygenase , antagonist , thromboxane a2 , arachidonic acid , endocrinology , medicine , leukotriene b4 , pharmacology , platelet activating factor , biochemistry , receptor , inflammation , enzyme , asthma
1 The intravenous administration of the chemotactic and secretagogue peptide N ‐formyl‐L‐methionyl‐L‐leucyl‐L‐phenylalanine (FMLP; 0.3–30 μg 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 111 In‐labelled platelets in the thoracic region at the height of bronchoconstriction was noted. 2 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 H 1 ‐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. 3 FMLP‐induced dose‐dependent contraction of parenchymal lung strips was accompanied by the formation of immuno‐reactive thromboxane B 2 in amounts markedly less than those formed from exogenous arachidonic acid at concentrations equieffective in inducing contractions. 4 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. 5 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.