Endothelin-1 contributes to antigen-induced airway hyperresponsiveness.
Endothelin A (ETA)-receptors mediate ET-1 contractions of ovine airway smooth muscle. Therefore, the ETA-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 micrograms.kg-1.min-1) significantly blocked the bronchoconstriction to aerosolized ET-1 (0.2-200 micrograms/ml). To determine whether ET-1 contributed to antigen-induced airway responses, BQ-123 was given either as an intravenous infusion (100 micrograms.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 (approximately 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 ETA-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.
Noguchi
K
K
New Drug Discovery Research Laboratories, Tsukuba Research Institute, Banyu Pharmaceutical, Japan.
Ishikawa
K
K
Yano
M
M
Ahmed
A
A
Cortes
A
A
Abraham
W M
WM
D000280:Administration, Inhalation; D000818:Animals; D000947:Antigens, Helminth / Q000276:immunology*; D017165:Ascaris suum; D016535:Bronchial Hyperreactivity / Q000276:immunology* / Q000517:prevention & control; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000502:physiology*; D007262:Infusions, Intravenous; D010456:Peptides, Cyclic / Q000008:administration & dosage; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000502:physiology; D012756:Sheep
D000947:Antigens, Helminth; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; C072247:cyclo(Trp-Asp-Pro-Val-Leu)