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. 1994 May;112(1):207–213. doi: 10.1111/j.1476-5381.1994.tb13053.x

Reversal of established responses to endothelin-1 in vivo and in vitro by the endothelin receptor antagonists, BQ-123 and PD 145065.

T D Warner 1, G H Allcock 1, J R Vane 1
PMCID: PMC1910322  PMID: 8032643

Abstract

1. Endothelin-1 binds almost irreversibly to its receptors and causes prolonged vasoconstrictions. Here we have studied the reversal of established responses to ET-1 in vivo and in vitro by BQ-123, an ETA receptor-selective antagonist, and/or PD 145065, an ETA/ETB receptor non-selective antagonist. 2. In anaesthetized rats pretreated with hexamethonium, infusion of ET-1 (10(-11) mol kg-1 min-1) increased the mean arterial pressure (MAP) from 93 +/- 1.5 mmHg to 137 +/- 2.4 mmHg after 70 min (n = 29). While the ET-1 infusion was continued an additional infusion of BQ-123 caused a gradual dose-dependent reduction in the pressor effect of ET-1. For instance, after a 60 min infusion of BQ-123 (10(-8) mol kg-1 min-1) the MAP was decreased by 29.3 +/- 4.3 mmHg (n = 4). 3. PD 145065 was a much weaker antagonist of the established pressor effects of ET-1. At 10(-8) mol kg-1 min-1 it had no significant effect and even at 10(-7) mol kg-1 min-1 the elevated blood pressure was only reduced by 11.8 +/- 8.0 mmHg (n = 5) after 60 min. Co-infusion of BQ-123 and PD 145065 caused smaller reductions in the established response to ET-1 than infusion of BQ-123 alone. 4. Sustained contractions of rat aortic rings induced by ET-1 (3 x 10(-9) M) and mediated by ETA receptors were slowly reversed by addition of BQ-123 (10(-5) M) or PD 145065 (10(-5) M).(ABSTRACT TRUNCATED AT 250 WORDS)

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Selected References

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  1. Anggård E., Galton S., Rae G., Thomas R., McLoughlin L., de Nucci G., Vane J. R. The fate of radioiodinated endothelin-1 and endothelin-3 in the rat. J Cardiovasc Pharmacol. 1989;13 (Suppl 5):S46–S74. doi: 10.1097/00005344-198900135-00012. [DOI] [PubMed] [Google Scholar]
  2. Arai H., Hori S., Aramori I., Ohkubo H., Nakanishi S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature. 1990 Dec 20;348(6303):730–732. doi: 10.1038/348730a0. [DOI] [PubMed] [Google Scholar]
  3. Bazil M. K., Lappe R. W., Webb R. L. Pharmacologic characterization of an endothelinA (ETA) receptor antagonist in conscious rats. J Cardiovasc Pharmacol. 1992 Dec;20(6):940–948. doi: 10.1097/00005344-199212000-00014. [DOI] [PubMed] [Google Scholar]
  4. Clozel M., Gray G. A., Breu V., Löffler B. M., Osterwalder R. The endothelin ETB receptor mediates both vasodilation and vasoconstriction in vivo. Biochem Biophys Res Commun. 1992 Jul 31;186(2):867–873. doi: 10.1016/0006-291x(92)90826-7. [DOI] [PubMed] [Google Scholar]
  5. Cristol J. P., Warner T. D., Thiemermann C., Vane J. R. Mediation via different receptors of the vasoconstrictor effects of endothelins and sarafotoxins in the systemic circulation and renal vasculature of the anaesthetized rat. Br J Pharmacol. 1993 Mar;108(3):776–779. doi: 10.1111/j.1476-5381.1993.tb12877.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Doherty A. M., Cody W. L., He J. X., DePue P. L., Cheng X. M., Welch K. M., Flynn M. A., Reynolds E. E., LaDouceur D. M., Davis L. S. In vitro and in vivo studies with a series of hexapeptide endothelin antagonists. J Cardiovasc Pharmacol. 1993;22 (Suppl 8):S98–102. doi: 10.1097/00005344-199322008-00027. [DOI] [PubMed] [Google Scholar]
  7. Harrison V. J., Randriantsoa A., Schoeffter P. Heterogeneity of endothelin-sarafotoxin receptors mediating contraction of pig coronary artery. Br J Pharmacol. 1992 Mar;105(3):511–513. doi: 10.1111/j.1476-5381.1992.tb09009.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hay D. W. Pharmacological evidence for distinct endothelin receptors in guinea-pig bronchus and aorta. Br J Pharmacol. 1992 Aug;106(4):759–761. doi: 10.1111/j.1476-5381.1992.tb14407.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hirata Y., Yoshimi H., Takata S., Watanabe T. X., Kumagai S., Nakajima K., Sakakibara S. Cellular mechanism of action by a novel vasoconstrictor endothelin in cultured rat vascular smooth muscle cells. Biochem Biophys Res Commun. 1988 Aug 15;154(3):868–875. doi: 10.1016/0006-291x(88)90220-3. [DOI] [PubMed] [Google Scholar]
  10. Ihara M., Noguchi K., Saeki T., Fukuroda T., Tsuchida S., Kimura S., Fukami T., Ishikawa K., Nishikibe M., Yano M. Biological profiles of highly potent novel endothelin antagonists selective for the ETA receptor. Life Sci. 1992;50(4):247–255. doi: 10.1016/0024-3205(92)90331-i. [DOI] [PubMed] [Google Scholar]
  11. Inoue A., Yanagisawa M., Kimura S., Kasuya Y., Miyauchi T., Goto K., Masaki T. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci U S A. 1989 Apr;86(8):2863–2867. doi: 10.1073/pnas.86.8.2863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kon V., Yoshioka T., Fogo A., Ichikawa I. Glomerular actions of endothelin in vivo. J Clin Invest. 1989 May;83(5):1762–1767. doi: 10.1172/JCI114079. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Maggi C. A., Giuliani S., Patacchini R., Rovero P., Giachetti A., Meli A. The activity of peptides of the endothelin family in various mammalian smooth muscle preparations. Eur J Pharmacol. 1989 Dec 12;174(1):23–31. doi: 10.1016/0014-2999(89)90869-8. [DOI] [PubMed] [Google Scholar]
  14. Marsault R., Feolde E., Frelin C. Receptor externalization determines sustained contractile responses to endothelin-1 in the rat aorta. Am J Physiol. 1993 Mar;264(3 Pt 1):C687–C693. doi: 10.1152/ajpcell.1993.264.3.C687. [DOI] [PubMed] [Google Scholar]
  15. McMurdo L., Corder R., Thiemermann C., Vane J. R. Incomplete inhibition of the pressor effects of endothelin-1 and related peptides in the anaesthetized rat with BQ-123 provides evidence for more than one vasoconstrictor receptor. Br J Pharmacol. 1993 Feb;108(2):557–561. doi: 10.1111/j.1476-5381.1993.tb12840.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Moreland S., McMullen D. M., Delaney C. L., Lee V. G., Hunt J. T. Venous smooth muscle contains vasoconstrictor ETB-like receptors. Biochem Biophys Res Commun. 1992 Apr 15;184(1):100–106. doi: 10.1016/0006-291x(92)91163-k. [DOI] [PubMed] [Google Scholar]
  17. Sakurai T., Yanagisawa M., Takuwa Y., Miyazaki H., Kimura S., Goto K., Masaki T. Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor. Nature. 1990 Dec 20;348(6303):732–735. doi: 10.1038/348732a0. [DOI] [PubMed] [Google Scholar]
  18. Skolovsky M., Galron R., Kloog Y., Bdolah A., Indig F. E., Blumberg S., Fleminger G. Endothelins are more sensitive than sarafotoxins to neutral endopeptidase: possible physiological significance. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4702–4706. doi: 10.1073/pnas.87.12.4702. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Sumner M. J., Cannon T. R., Mundin J. W., White D. G., Watts I. S. Endothelin ETA and ETB receptors mediate vascular smooth muscle contraction. Br J Pharmacol. 1992 Nov;107(3):858–860. doi: 10.1111/j.1476-5381.1992.tb14537.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Takayanagi R., Kitazumi K., Takasaki C., Ohnaka K., Aimoto S., Tasaka K., Ohashi M., Nawata H. Presence of non-selective type of endothelin receptor on vascular endothelium and its linkage to vasodilation. FEBS Lett. 1991 Apr 22;282(1):103–106. doi: 10.1016/0014-5793(91)80454-b. [DOI] [PubMed] [Google Scholar]
  21. Waggoner W. G., Genova S. L., Rash V. A. Kinetic analyses demonstrate that the equilibrium assumption does not apply to [125I]endothelin-1 binding data. Life Sci. 1992;51(24):1869–1876. doi: 10.1016/0024-3205(92)90038-q. [DOI] [PubMed] [Google Scholar]
  22. Warner T. D., Allcock G. H., Corder R., Vane J. R. Use of the endothelin antagonists BQ-123 and PD 142893 to reveal three endothelin receptors mediating smooth muscle contraction and the release of EDRF. Br J Pharmacol. 1993 Oct;110(2):777–782. doi: 10.1111/j.1476-5381.1993.tb13879.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Warner T. D., Allcock G. H., Mickley E. J., Vane J. R. Characterization of endothelin receptors mediating the effects of the endothelin/sarafotoxin peptides on autonomic neurotransmission in the rat vas deferens and guinea-pig ileum. Br J Pharmacol. 1993 Oct;110(2):783–789. doi: 10.1111/j.1476-5381.1993.tb13880.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Warner T. D., Battistini B., Allcock G. H., Vane J. R. Endothelin ETA and ETB receptors mediate vasoconstriction and prostanoid release in the isolated kidney of the rat. Eur J Pharmacol. 1993 Dec 21;250(3):447–453. doi: 10.1016/0014-2999(93)90032-d. [DOI] [PubMed] [Google Scholar]
  25. Warner T. D., Mitchell J. A., de Nucci G., Vane J. R. Endothelin-1 and endothelin-3 release EDRF from isolated perfused arterial vessels of the rat and rabbit. J Cardiovasc Pharmacol. 1989;13 (Suppl 5):S85–S102. doi: 10.1097/00005344-198900135-00021. [DOI] [PubMed] [Google Scholar]
  26. Watanabe T., Suzuki N., Shimamoto N., Fujino M., Imada A. Endothelin in myocardial infarction. Nature. 1990 Mar 8;344(6262):114–114. doi: 10.1038/344114a0. [DOI] [PubMed] [Google Scholar]
  27. Whittle B. J., Lopez-Belmonte J., Rees D. D. Modulation of the vasodepressor actions of acetylcholine, bradykinin, substance P and endothelin in the rat by a specific inhibitor of nitric oxide formation. Br J Pharmacol. 1989 Oct;98(2):646–652. doi: 10.1111/j.1476-5381.1989.tb12639.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Yanagisawa M., Kurihara H., Kimura S., Tomobe Y., Kobayashi M., Mitsui Y., Yazaki Y., Goto K., Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988 Mar 31;332(6163):411–415. doi: 10.1038/332411a0. [DOI] [PubMed] [Google Scholar]
  29. de Nucci G., Thomas R., D'Orleans-Juste P., Antunes E., Walder C., Warner T. D., Vane J. R. Pressor effects of circulating endothelin are limited by its removal in the pulmonary circulation and by the release of prostacyclin and endothelium-derived relaxing factor. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9797–9800. doi: 10.1073/pnas.85.24.9797. [DOI] [PMC free article] [PubMed] [Google Scholar]

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