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Investigation of the Endothelin System in Experimental Heart Failure

  • Gillian A. Gray
  • Lorcan Sherry
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Part of the Methods in Molecular Biology™ book series (MIMB, volume 206)

Abstract

The first evidence that endothelin-1 (ET-1) was implicated in the pathophysiology of chronic heart failure (CHF) came from studies demonstrating elevated plasma concentrations of the mature peptide in patients with CHF (1) Subsequent studies showed that plasma levels of ET-1 and particularly of its precursor big ET-1 correlated with the severity of CHF (2) and were able to predict the necessity for heart transplant (3). The ET system has since been studied in CHF patients using acute administration of inhibitors of ET formation, ET receptor agonists and ET receptor antagonists either locally into the forearm or hand vein (4,5, see  Chapter 14) or systemically (6,7). These hemodynamic studies provided an indication that blockade of the ET system might be of therapeutic benefit in CHF. However, these types of studies are unable to answer questions relating to tissue expression of the ET-1 synthesizing pathway or ET receptors and how these might be altered during disease progression. These questions can be best addressed initially using experimental models, which also permit detailed histological and molecular analysis of the pathways modified by ET system blockade and can be followed through to a mortality endpoint. Studies in experimental animals provided the first evidence that ET receptor antagonists might improve survival in heart failure (8) and these observations are now being followed through into clinical trials in CHF patients (9).

Keywords

Chronic Heart Failure Infarct Size Chronic Heart Failure Patient Ventricular Free Wall Coronary Artery Ligation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    McMurray J. J., Ray S. G. Abdullah I., Dargie H. J., and Morton J. J. (1992) Plasma endothelin in chronic heart failure. Circulation 85, 1374–1379.PubMedGoogle Scholar
  2. 2.
    Wei C. M., Lerman A. Rodehoffer R. J., and Burnett J. J. (1994) Endothelin in human congestive heart failure. Circulation 89, 1580–1586.PubMedGoogle Scholar
  3. 3.
    Pacher R., Stanek B., and Hulsmann M. (1996) Prognostic impact of bigendothelin-1 plasma concentrations compared with invasive hemodynamic evaluation in severe heart failure. J. Am. Coll. Cardiol. 27, 633–641.PubMedCrossRefGoogle Scholar
  4. 4.
    Love M. P., Haynes W. G., Gray G. A., Webb D. J., and McMurray J. J. V. (1996) Endothelin in chronic heart failure: the therapeutic potential of converting enzyme inhibition and receptor blockade. Circulation. 94, 2131–2137.PubMedGoogle Scholar
  5. 5.
    Love M. P., Haynes W. G., Webb D. J., and McMurray J. J. V. (2000) Venous endothelin receptor function in patients with chronic heart failure. Clin. Sci. 98, 65–70.PubMedCrossRefGoogle Scholar
  6. 6.
    Kiowski W., Sutsch G., and Hunziker P. (1995) Evidence for endothelin-1 mediated vasoconstriction in severe chronic heart failure. Lancet 346, 732–736.PubMedCrossRefGoogle Scholar
  7. 7.
    Cowburn P. J., Cleland J. G. F., McArthur J. D., MacLean M. R., McMurray J. J. V., Dargie H. J., and Morton J. J. (1999) Endothelin(B) receptors are functionally important in mediating vasoconstriction in the systemic circulation in patients with left ventricular systolic dysfunction. J. Am. Coll. Cardiol. 33, 932–938.PubMedCrossRefGoogle Scholar
  8. 8.
    Sakai S., Miyauchi T., and Sakurai Y. (1996) Inhibition of myocardial endothelin pathway improves long-term survival in heart failure. Nature 384, 353–355.PubMedCrossRefGoogle Scholar
  9. 9.
    Mylona P. and Cleland J. G. F. (1999) Update of REACH-1 and MERIT-HF clinical trials in heart failure. Eur. J. Heart Failure 1, 197–200.CrossRefGoogle Scholar
  10. 10.
    Schaper W., ed. (1998) Spotlight on Animal Models and Human Cardiovascular Disease. Cardiovasc. Res. 39, 1–260.Google Scholar
  11. 11.
    Arnolda L. F., Llewellyn-Smith I. J., and Minson J. B. (1999) Animal models of heart failure. Aust. New Zealand J. Med. 29, 403–409.CrossRefGoogle Scholar
  12. 12.
    Sakai S., Miyauchi T., and Yamaguchi I. (2000) Long-term endothelin receptor antagonist administration improves alterations in expression of various cardiac genes in failing myocardium of rats with heart failure. Circulation 101, 2849–2853.PubMedGoogle Scholar
  13. 13.
    Gray G. A., Mickley E. J., Webb D. J., and McEwan P. E. (2000) Localisation and function of ET-1 and ET receptors in small arteries post-myocardial infarction: Upregulation of smooth muscle ETB receptors that modulate contraction. Br. J. Pharmacol. 130, 1735–1744.PubMedCrossRefGoogle Scholar
  14. 14.
    Smith P. J. W., Ornatsky O., Stewart D. J., Picard P., Dawood F., Wen W. H., et al. (2000) Effects of estrogen replacement on infarct size, cardiac remodelling, and the endothelin system after myocardial infarction in ovariectomized rats. Circulation 102, 2983–2989.PubMedGoogle Scholar
  15. 15.
    Mulder P., Richard V., Derumeaux G., Hogie M., Henry J. P., Lallemand F., et al. (1997) Role of endogenous endothelin in chronic heart failure-Effect of long-term treatment with an endothelin antagonist on survival, hemodynamics, and cardiac remodelling. Circulation 96, 1976–1982.PubMedGoogle Scholar
  16. 16.
    Mulder P., Boujedaini H., Richard V., Derumeaux G., Henry J. P., Renet S., et al. (2000) Selective endothelin-A versus combined endothelin-A/endothelin-B receptor blockade in rat chronic heart failure. Circulation 102, 491–493.PubMedGoogle Scholar
  17. 17.
    Docherty C. C. and MacLean M. R. (1998) Endothelin (B) receptors in rabbit pulmonary resistance arteries: Effect of left ventricular dysfunction. J. Pharmacol. Exp. Therap. 284, 895–903.Google Scholar
  18. 18.
    Cannan C. R., Burnett J. C., and Lerman A. (1996) Enhanced coronary vasoconstriction to endothelin-B-receptor activation in experimental congestive heart failure. Circulation 93, 646–651.PubMedGoogle Scholar
  19. 19.
    Arai M., Yoguchi A., Iso T., Takahashi T., Imai S., and Suzuki T. (1995) Endothelin and its binding sites are upregulated in pressure-overload cardiac hypertrophy. Am. J. Physiol. 37, H2084–H2091.Google Scholar
  20. 20.
    Iwanaga Y., Kihara Y., Hasegawa K., Inagaki K., Yoneda T., Kaburagi S., et al. (1998) Cardiac endothelin-1 plays a critical role in the functional deterioration of left ventricles during the transition from compensatory hypertrophy to congestive heart failure in salt-sensitive hypertensive rats. Circulation 98, 2065–2073.PubMedGoogle Scholar
  21. 21.
    Bolger G. T., Berry R., Liard F., Garneau M., and Jaramillo J. (1992) Cardiac responses and binding sites for endothelin in normal and cardiomyopathic hamsters. J. Pharmacol. Exp. Therap. 260, 1314–1322.Google Scholar
  22. 22.
    Friedrich E. B., Muders F., Luchner A., Dietl O., Riegger G. A. J., and Elsner D. (1999) Contribution of the endothelin system to the renal hypoperfusion associated with experimental congestive heart failure. J. Cardiovasc. Pharmacol. 34, 612–617.PubMedCrossRefGoogle Scholar
  23. 23.
    Tojo T., Tsunoda Y., Nakada S., and Tomoike H. (2000) Effects of long-term treatment with nonselective endothelin receptor antagonist, TAK-044, on remodelling of cardiovascular system with sustained volume overload. J. Cardiovasc. Pharmacol. 35, 777–785.PubMedCrossRefGoogle Scholar
  24. 24.
    Seta Y., Kanda T., Yokoyama T., Arai M., Sekiguchi K., Tanaka T., et al. (2000) Therapy with the nonpeptide endothelin receptor antagonist 97–139 in a murine model of congestive heart failure-Reduction of cardiac mass and myofiber hypertrophy. Jap. Heart J. 41, 79–85.PubMedCrossRefGoogle Scholar
  25. 25.
    Miyauchi T. and Masaki T. (1999) Pathophysiology of endothelin in the cardiovascular system. Ann. Rev. Physiol. 61, 391–415.CrossRefGoogle Scholar
  26. 26.
    Selye H., Oemar B. S., and Siebenmann R. (1960) Simple technique for the surgical occlusion of coronary vessels in rats. Angiology 11, 398–407.PubMedCrossRefGoogle Scholar
  27. 27.
    Pfeffer M. A., Pfeffer J. M., and Fishbein M. C. (1979) Myocardial infarct size and ventricular function in rats. Circ. Res. 44, 503–512.PubMedGoogle Scholar
  28. 28.
    Pfeffer M. A., Lamas G. A., Vaughan D. E., Parisi A. F., and Braunwald E. (1988) Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. New Engl. J. Med. 68, 525–533.Google Scholar
  29. 29.
    McEwan P. E., Valdenaire O., Sutherland L., Webb D. J., and Gray G. A. (1998) A non-radioactive method for localisation of ET receptor mRNA in situ. J. Cardiovasc. Pharmacol. 31, S443–S447.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2002

Authors and Affiliations

  • Gillian A. Gray
    • 1
  • Lorcan Sherry
    • 2
  1. 1.Endothelial Cell Biology and Molecular Cardiology Group, Centre for Cardiovascular Sciences, Division of Biomedical and Clinical Laboratory SciencesUniversity of EdinburghEdinburghUK
  2. 2.Research and DevelopmentOrganon Laboratories Ltd.NewhouseUK

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