ENDOTHELIN-1 CONTRIBUTES TO ANTIGEN-INDUCED AIRWAY HYPERRESPONSIVENESS

Endothelin A (ET(A))-receptors mediate ET-1 contractions of ovine airway smooth muscle. Therefore, the ET(A)-receptor antagonist, BQ-123, was used to test the hypothesis that ET-1 contributes to antigen-induced airway responses in sheep allergic to Ascaris suum. We first established the protective effect of BQ-123 by demonstrating that BQ-123 given as an aerosol (0.3 or 1.0 mg/kg in 3 ml buffer) or by continuous intravenous infusion (100 mu g . kg(-1) . min(-1)) significantly blocked the bronchoconstriction to aerosolized ET-1 (0.2-200 mu g/ml). To determine whether ET-1 contributed to antigen-induced airway responses, BQ-123 was given either as an intravenous infusion (100 mu g . kg(-1) . min(-1)) beginning 30 min before and continuing for 8 h after antigen challenge or as an aerosol (1 mg/kg in 3 ml buffer) 30 min before and 4, 8, and 24 h after antigen challenge. Neither treatment with intravenous infusion nor aerosolized BQ-123 blocked the immediate antigen-induced bronchoconstriction, but both treatments significantly reduced the late response (similar to 50%). The treatments with aerosolized BQ-123 also blocked the antigen-induced airway hyperresponsiveness to inhaled carbachol seen 24 h after challenge. Subsequently, we found that sheep developed airway hyperresponsiveness to inhaled carbachol at 4 and 24 h after ET-1 challenge, an effect that was blocked by aerosolized BQ-123. We conclude that in allergic sheep 1) aerosolized ET-1 causes bronchoconstriction, in part, by stimulation of ET(A)-receptors, 2) ET-1 is released in the airways after antigen challenge, and 3) this peptide contributes to the severity of the allergic responses, probably by increasing airway smooth muscle responsiveness.