Abstract
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.
Original language | English (US) |
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Pages (from-to) | 2537-2542 |
Number of pages | 6 |
Journal | Journal of Applied Physiology |
Volume | 74 |
Issue number | 5 |
DOIs | |
State | Published - 1993 |
Externally published | Yes |
Keywords
- airway pharmacology
- asthma
- receptors
ASJC Scopus subject areas
- Physiology
- Physiology (medical)