Effect of active sensitization on the bronchopulmonary responses to tachykinins in the guinea pig. Modulation by peptidase inhibitors.
The i.v. administration of substance P (SP, 0.25-16 micrograms/kg) or of the selective metabolic stable NK-1 agonist, [Glp6,Pro9]SP-(6-11) (septide, 0.03-0.25 microgram) to atropine-treated guinea pigs or to isolated perfused lungs triggered a dose-dependent bronchoconstriction, which was enhanced in animals actively sensitized to ovalbumin. In vivo, bronchial hyper-responsiveness was restricted to SP and to septide, inasmuch as neurokinin A (0.06-1 microgram/kg)- or capsaicin (0.5-32 micrograms/kg)-induced bronchoconstriction were not modified. In contrast, isolated lungs from sensitized guinea pigs exhibited an increased bronchoconstriction also in response to capsaicin (0.01-10 micrograms), which was inhibited by atropine in the medium. Pretreatment of actively sensitized guinea pigs either with indomethacin plus mepyramine, the lipoxygenase inhibitor BW A4C or with the platelet-activating factor antagonist SR 27417, did not modify bronchial hyper-reactivity to SP. Captopril (5 mg/kg i.v.), but not thiorphan (0.8 mg/kg i.v.), increased the SP-induced bronchoconstriction in actively sensitized animals, whereas both inhibitors were equally effective in nonsensitized guinea pigs. Thiorphan, however, did not modify the in vivo response to septide. Our results demonstrate that guinea pigs sensitized to ovalbumin exhibit bronchial hyperreactivity to SP, but not to neurokinin A, as compared to nonsensitized animals, suggesting a decrease in the neutral endopeptidase activity in the airways brought by the immunization. However, the results obtained by using septide indicate that other mechanisms may be involved in the bronchial hyper-reactivity to SP.
Capaz
F R
FR
Unité de Pharmacologie Cellulaire, Institut National de la Santé et de la Recherche Médicale No. 285, Paris, France.
Ruffié
C
C
Lefort
J
J
Manzini
S
S
Vargaftig
B B
BB
Pretolani
M
M
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects*; D006168:Guinea Pigs; D007114:Immunization; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010477:Perfusion; D011480:Protease Inhibitors / Q000494:pharmacology*; D015320:Tachykinins / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000378:metabolism
D011480:Protease Inhibitors; D015320:Tachykinins; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha