Endothelin-1 contributes to antigen-induced airway hyperresponsiveness. Noguchi, K., K. Ishikawa, M. Yano, A. Ahmed, A. Cortes, and W. M. Abraham. New Drug Discovery Research Laboratories, Tsukuba Research Institute, Banyu Pharmaceutical CO, Okubo 3, Tsukuba 300-33, Japan and Pulmonary Division, University of Miami at Mount Sinai Medical Center, Miami Beach, FL 33140 USA
APStracts 2:0157A, 1995.
In this study, the endothelin (ET)A receptor antagonist, BQ-123, was used to formally test the hypothesis that ET-1 contributes to antigen-induced airway responses in sheep allergic to Ascaris suum. BQ-123 was used because ETA receptors mediate ET-1 induced contractions of ovine airway smooth muscle. We first established the protective effect of BQ-123 aerosol (0.3 or 1.0 mg/kg in 3 ml buffer) or continuous IV infusion (100 [mu]g/kg/min) on ET-1 induced bronchoconstriction. Concentration response curves to aerosol ET-1 (0.2-200 [mu]g/ml) were obtained by measuring the change in pulmonary airflow resistance (RL) after each administration of ET-1 and determining the ET-1 concentration that increased RL by 50% (PC50). ET-1 challenges were performed 30 min after appropriate vehicle controls and after treatment with aerosol and IV BQ-123 or indomethacin (2 mg/kg, iv). PC50 (geometric mean) for aerosol and IV controls were 1.02 and 0.72 [mu]g/ml (P=NS). PC50 for 0.3 and 1.0 mg/kg BQ-123 aerosol and IV BQ-123 were 2.82, 63.6 and 69.8 [mu]g/ml, respectively (all P<0.05 vs control). Indomethacin had no effect (PC50 = 1.21 [mu]g/ml). To determine if ET-1 contributed to antigen -induced airway responses, BQ-123 was given either as an IV infusion (100 [mu]g/kg/min) 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, 4 h, 8h and 24 h after antigen challenge. Airway responsiveness to inhaled carbachol was determined before and 24 h after antigen challenge. Neither treatment with IV nor aerosol BQ-123 blocked the immediate antigen induced bronchoconstriction, but both treatments significantly reduced the late response (50%). The additional treatments with aerosol BQ-123 also blocked the antigen -induced airway hyperresponsiveness 24h after challenge. Subsequently, we found that sheep developed airway hyperresponsiveness to inhaled carbachol at 4 h and 24 h after ET-1 challenge. This effect was blocked by aerosol BQ-123. These results indicate that in allergic sheep: a) aerosolized ET-1 causes bronchoconstriction, in part, by stimulation of ETA receptors, b) ET-1 is released in the airways after antigen challenge, and c) this peptide contributes to the severity of the allergic responses, probably by increasing airway smooth muscle responsiveness. 

Received 30 January 1995; accepted in final form 4 April 1995.
APS Manuscript Number A110-5.
Article publication pending Journal of Applied Physiology.
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 19 April 1995.