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

W. M. Abraham, A. Ahmed, A. Cortes, M. J. Spinella, A. B. Malik, T. T. Andersen

Research output: Contribution to journalArticle

19 Scopus citations

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 languageEnglish (US)
Pages (from-to)2537-2542
Number of pages6
JournalJournal of applied physiology
Volume74
Issue number5
DOIs
StatePublished - 1993

Keywords

  • airway pharmacology
  • asthma
  • receptors

ASJC Scopus subject areas

  • Endocrinology
  • Physiology
  • Orthopedics and Sports Medicine
  • Physical Therapy, Sports Therapy and Rehabilitation

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    Abraham, W. M., Ahmed, A., Cortes, A., Spinella, M. J., Malik, A. B., & Andersen, T. T. (1993). A specific endothelin-1 antagonist blocks inhaled endothelin-1-induced bronchoconstriction in sheep. Journal of applied physiology, 74(5), 2537-2542. https://doi.org/10.1152/jappl.1993.74.5.2537