Agonist-dependent modulation of arterial endothelinA receptor function

M. G. Compeer, M. J. P. M. T. Meens, T. M. Hackeng, W. A. Neugebauer, C. Hoeltke, J. G. R. De Mey*

*Corresponding author for this work

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BACKGROUND AND PURPOSE Endothelin-1 (ET-1) causes long-lasting vasoconstrictions. These can be prevented by ETA receptor antagonists but are only poorly reversed by these drugs. We tested the hypothesis that endothelin ETA receptors are susceptible to allosteric modulation by endogenous agonists and exogenous ligands. EXPERIMENTAL APPROACH Rat isolated mesenteric resistance arteries were pretreated with capsaicin and studied in wire myographs, in the presence of L-NAME and indomethacin to concentrate on arterial smooth muscle responses. KEY RESULTS Endothelins caused contractions with equal maximum but differing potency (ET-1 = ET-2 > ET-3). ET-1115 neither mimicked nor antagonized these effects in the absence and presence of ET1621. 4AlaET-1 (ETB agonist) and BQ788 (ETB antagonist) were without effects. BQ123 (peptide ETA antagonist) reduced the sensitivity and relaxed the contractile responses to endothelins. Both effects depended on the agonist (pKB: ET-3 = ET-1 > ET-2; % relaxation: ET-3 = ET-2 > ET-1). Also, with PD156707 (non-peptide ETA antagonist) agonist-dependence and a discrepancy between preventive and inhibitory effects were observed. The latter was even more marked with bulky analogues of BQ123 and PD156707. CONCLUSIONS AND IMPLICATIONS These findings indicate allosteric modulation of arterial smooth muscle ETA receptor function by endogenous agonists and by exogenous endothelin receptor antagonists. This may have consequences for the diagnosis and pharmacotherapy of diseases involving endothelins.
Original languageEnglish
Pages (from-to)1833-1845
JournalBritish Journal of Pharmacology
Issue number6
Publication statusPublished - Jul 2012


  • endothelin-1
  • ETA receptors
  • agonist-dependence
  • allosteric modulation

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