DIFFERENTIAL-EFFECTS OF PHOSPHORAMIDON ON NEUROKININ-A-INDUCED AND SUBSTANCE-P-INDUCED AIR-FLOW OBSTRUCTION AND AIRWAY MICROVASCULAR LEAKAGE IN GUINEA-PIG

1 The effects of the inhaled neuropeptides, neurokinin A (NKA) and substance P (SP) on lung resistance (R(L)) and airway microvascular permeability were studied in anaesthetized guinea-pigs. 2 Single doses of inhaled NKA (3 x 10(-5), 1 x 10(-4), 3 x 10(-4) M; 45 breaths) and SP (1 x 10(-4), 3 x 10(-4), 1 x 10(-3); 45 breaths) caused a dose-dependent increase in both R(L) and airway microvascular leakage, assessed as extravasation of the albumin marker, Evans blue dye. 3 NKA at 1 x 10(-4) and 3 x 10(-4)M resulted in a significantly higher increase in R(L) than SP at the same doses. 4 Inhaled SP (3 x 10(-4) M; 45 breaths) caused significantly higher Evans blue dye extravasation in main bronchi and proximal intrapulmonary airways compared to the same dose of NKA. 5 Pretreatment with the specific inhibitor of neural endopeptidase (NEP24.11), phosphoramidon, caused an approximately 100 fold leftward shift of the R(L) responses to inhaled NKA and SP. 6 Phosphoramidon significantly potentiated both NKA- and SP-induced airway microvascular leakage at proximal intrapulmonary airways, but not at any other airway level. 7 Inhibition of NEP24.11 potentiate both the SP- or NKA-induced airflow obstruction to a larger extent than the induced airway microvascular leakage, suggesting that NEP24.11 is more important in the modulation of the airflow obstruction observed after these mediators.