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 pressure (PIP) induced by endothelin-1 (ET-1) administered by aerosol in ovalbumin (OA)-sensitized and challenged guinea-pigs was investigated after pretreatment or not of the animals with the neutral endopeptidase inhibitor, phosphoramidon, the cyclooxygenase inhibitor, indomethacin 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 administration of ET-1 (1 or 3 micrograms ml-1, aerosol for 2 min), whereas these doses of the peptide were only slightly active in control animals. In sensitized and unchallenged guinea-pigs, ET-1 (1 or 3 micrograms.ml-1, aerosol for 2 min) induced, as in controls, a moderate increase in PIP. In contrast, aerosol exposure of OA in sensitized guinea-pigs developed an increased PIP following ET-1 (1 and 3 micrograms.ml-1, aerosol for 2 min) administration, that was non significantly affected by pretreatment of the animals with phosphoramidon after the dose of 3 micrograms ml-1 ET-1. Guinea-pigs exposed to phorphoramidon and treated with indomethacin (10 mg kg-1, i.v.) or BN 50730 (25 mg kg-1, per os) significantly reduced the increase in PIP upon administration of ET-1 (3 micrograms.ml-1, aerosol for 2 min). No inhibitory effect of indomethacin was noted when ET-1 (3 micrograms.ml-1, aerosol for 2 min) was administered to sensitized and OA-exposed guinea-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 moderately active in reducing the increase in PIP induced by ET-1, when the animals were pretreated by phosphoramidon. These results suggest that a phosphoramidon-sensitive endopeptidase-like enzyme, present in the airway 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 metabolites, even though the participation of other mediators in this process is open.
Boichot
E
E
Institut Henri-Beaufour, Les Ulis, France.
Lagente
V
V
Mencia-Huerta
J M
JM
Braquet
P
P
D000336:Aerosols; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D016232:Endothelins / Q000494:pharmacology*; D006020:Glycopeptides / Q000494:pharmacology; D006168:Guinea Pigs; D007114:Immunization; D007213:Indomethacin / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000502:physiology; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors; D010047:Ovalbumin / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D012129:Respiratory Function Tests; D013777:Tetrazoles / Q000494:pharmacology; D058924:Thienopyridines; D013997:Time Factors; D014230:Triazoles
D000336:Aerosols; D001381:Azepines; D016232:Endothelins; D006020:Glycopeptides; D010972:Platelet Activating Factor; D013777:Tetrazoles; D058924:Thienopyridines; D014230:Triazoles; C066686:BN 50730; D010047:Ovalbumin; D011451:Prostaglandin-Endoperoxide Synthases; D015260:Neprilysin; C008890:phosphoramidon; D007213:Indomethacin