A specific endothelin-1 antagonist blocks inhaled endothelin-1-induced bronchoconstriction in sheep

In this study we used conscious sheep to compare the relative potencies of inhaled endothelin- (ET) 1 and ET-3 and to determine whether a newly described selective ET-1 receptor antagonist, [diaminopropionic acid¹- Asp¹⁵]ET-1 ([Dpr¹-Asp¹⁵]ET-1, when given as an aerosol blocks ET-1- induced bronchoconstriction. Partial concentration-response curves to ET-1 and ET-3 were obtained by measuring the change in pulmonary airflow resistance (RL) after aerosol challenge. Both ET-1 (n = 6) and ET-3 (n = 4) caused concentration-dependent (10^-10-10^-7) bronchoconstriction, but ET- 3 was 400-fold less potent than ET-1. Pretreatment (30 min) with 25 breaths of 5 x 10^-8 M [Dpr¹-Asp¹⁵]ET-1 caused a 100-fold rightward shift of the ET-1 concentration-response curve. The activity of the ET-1 antagonist (25 breaths of 5 x 10^-8 M) was compared with that of various control peptides (25 breaths of 10^-8 M). ET-1 (50 breaths of 10 ⁷ M) caused an increase in RL of 133 ± 33% (SE) over baseline. [Dpr¹-Asp¹⁵]ET-1 significantly inhibited this response by 54%. No protection was seen with a monocyclic control peptide or a thrombin receptor peptide. There was, however, a small protective effect (38%, P < 0.05) seen with [Dpr¹-Asp¹⁵]ET-3, a structurally homologous ET-3 antagonist. [Dpr¹-Asp¹⁵]ET-1 had no effect on carbachol (n = 3) or leukotriene D₄-induced bronchoconstriction. Thus inhaled ET-1 and, to a lesser extent, ET-3 cause concentration-dependent bronchoconstriction in conscious sheep. The response to ET-1 can be blocked by a specific ET-1 antagonist, suggesting that this effect is mediated in part by stimulation of ET-1 receptors.