BRONCHOPULMONARY RESPONSES TO ENDOTHELIN-1 IN SENSITIZED AND CHALLENGED GUINEA-PIGS - ROLE OF CYCLOOXYGENASE METABOLITES AND PLATELET-ACTIVATING-FACTOR

The effect of phosphoramidon on the increase in pulmonary inflation pr essure (PIP) induced by endotlielin-1 (ET-1) administered by aerosol i n ovalbumin (OA)-sensitized and challenged guinea-pigs was investigate d after pretreatment or not of the animals with the neutral endopeptid ase inhibitor, phosphoramidon, the cyclooxygenase inhibitor, indometha cin or the platelet activating factor (PAF) antagonist, BN 50730. When guinea-pigs were pretreated by phosphoramidon (0.1 mM, aerosol for 15 min), a significant enhancement of PIP was observed after administrat ion of ET-1 (1 or 3 mug ml-1, aerosol for 2 min), whereas these doses of the peptide were only slightly active in control animals. In sensit ized and unchallenged guinea-pigs, ET-1 (1 or 3 mug.ml-1, aerosol for 2 min) induced, as in controls, a moderate increase in PIP. In contras t, aerosol exposure of OA in sensitized guinea-pigs developed an incre ased PIP following ET-1 (1 and 3 mug.ml-1, aerosol for 2 min) administ ration, that was non significantly affected by pretreatment of the ani mals with phosphoramidon after the dose of 3 mug ml-1 ET-1. Guinea-pig s exposed to phorphoramidon and treated with indomethacin (10 mg kg-1, iv) or BN 50730 (25 mg kg-1, per os) significantly reduced the increa se in PIP upon administration of ET-1 (3 mug.ml-1, aerosol for 2 min). No inhibitory effect of indomethacin was noted when ET-1 (3 mug.ml-1, aerosol for 2 min) was administered to sensitized and OA-exposed guin ea-pigs, pretreated or not with phosphoramidon. In contrast, BN 50730 significantly reduced the increase in PIP induced by ET-1 observed in sensitized and OA-exposed guinea-pigs. Moreover, this drug was moderat ely active in reducing the increase in PIP induced by ET-1, when the a nimals were pretreated by phosphoramidon. These results suggest that a phosphoramidon-sensitive endopeptidase-like enzyme, present in the ai rway tissue modulates the effect of ET-1. Furthermore, the increase in PIP to ET-1 observed in aerosol-sensitized and antigen-exposed guinea -pigs appears to be mediated by PAF rather than cyclooxygenase metabol ites, even though the participation of other mediators in this process is open.