Skip to main content
SpringerLink
Log in

Influence of acute selective endothelin-receptor-A blockade on renal hemodynamics in a rat model of chronic allograft rejection

  • Original Article
  • Published:
Transplant International

Abstract

We have recently demonstrated up-regulation of renal endothelin (ET) synthesis in a rat model of chronic renal allograft rejection. Treatment with a selective ET-A receptor antagonist improved survival and reduced functional and morphological kidney damage. However, the underlying mechanisms have not yet been elucidated, as ET exhibits both hemodynamic and inflammatory properties. Therefore, in the present study we investigated acute hemodynamic effects of the selective ET-A receptor antagonist LU 302146 (LU) on chronic renal allograft rejection in rats. Experiments were performed in the Fisher-to-Lewis model of chronic renal allograft rejection. Lewis-to-Lewis isografts served as controls. After 2, 12, and 24 weeks, hemodynamic measurements were performed on anesthetized animals. Measurement of mean arterial pressure (MAP) was performed via a catheter in the femoral artery. Renal blood flow (RBF) was measured by an ultrasonic flow probe placed around the renal transplant artery. Medulla blood flow (MBF) and cortex blood flow (CBF) were determined with laser Doppler probes. Hemodynamic response upon intravenous bolus injection of LU (50 mg/kg) was investigated. The application of LU was followed by a decline in MAP that reached statistical significance only in isografts (ISOs) after 12 weeks and allografts (ALLOs) after 24 weeks. RBF slightly decreased in all groups; however, without reaching statistical significance. MBF showed a small increase in ALLO12 and ALLO24 whereas CBF slightly decreased in all groups. Acute ET-A receptor blockade does not induce important hemodynamic effects in kidneys undergoing chronic rejection. The lack of response to ET-A receptor blockade suggests that the beneficial effect of ET receptor antagonists in this model is likely to be due to improvement of renal morphology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1a–c.

Similar content being viewed by others

References

  1. Amuchastegui SC, Azzollini N, Mister M, Pezzotta A, Perico N, Remuzzi G (1998) Chronic allograft nephropathy in the rat is improved by angiotensin II receptor blockade but not by calcium channel antagonism. J Am Soc Nephrol 9:1948–1955

    CAS  PubMed  Google Scholar 

  2. Azuma H, Binder J, Heemann U (1995) Effects of RS61443 on functional and morphological changes in chronically rejecting rat kidney allografts. Transplantation 59:460–466

    CAS  PubMed  Google Scholar 

  3. Azuma H, Nadeau KC, Ishibashi M, Tilney NL (1995) Prevention of functional, structural, and molecular changes of chronic rejection of rat renal allografts by a specific macrophage inhibitor. Transplantation 60:1577–1582

    CAS  PubMed  Google Scholar 

  4. Azuma H, Nadeau K, Takada M, Mackenzie HS, Tilney NL (1997) Cellular and molecular predictors of chronic renal dysfunction after initial ischemia/reperfusion injury of a single kidney. Transplantation 64:190–197

    CAS  PubMed  Google Scholar 

  5. Bauersachs J, Braun C, Fraccarollo D, Widder J, Ertl G, Schilling L, Kirchengast M, Rohmeiss P (2000) Improvement of renal dysfunction in rats with chronic heart failure after myocardial infarction by treatment with the endothelin-A receptor antagonist, LU 135252. J Hypertens 18:1507–1514

    CAS  PubMed  Google Scholar 

  6. Benigni A (2000) Endothelin antagonists in renal disease. Kidney Int 57:1778–1794

    Article  CAS  PubMed  Google Scholar 

  7. Benigni A, Remuzzi G (2001) How renal cytokines and growth factors contribute to renal disease progression. Am J Kidney Dis 37 [Suppl 2]:S21–S24

    Google Scholar 

  8. Berger R, Stanek B, Hulsmann M, Frey B, Heher S, Pacher R, Neunteufl T (2001) Effects of endothelin-A receptor blockade on endothelial function in patients with chronic heart failure. Circulation 103:981–986

    CAS  PubMed  Google Scholar 

  9. Birck R, Knoll T, Braun C, Kirchengast M, Munter K, Woude FJ van der, Rohmeiss P (1998) Improvement of postischemic acute renal failure with the novel orally active endothelin-A receptor antagonist LU 135252 in the rat. J Cardiovasc Pharmacol 32:80–86

    Article  CAS  PubMed  Google Scholar 

  10. Braun C, Ade M, Unger T, Woude FJ van der, Rohmeiss P (1997) Effects of bradykinin and icatibant on renal hemodynamics in conscious spontaneously hypertensive and normotensive rats. J Cardiovasc Pharmacol 30:446–454

    Article  CAS  PubMed  Google Scholar 

  11. Braun C, Lang C, Hocher B, Gretz N, Woude FJ van der, Rohmeiss P (1997) Influence of the renal endothelin system on the autoregulation of renal blood flow in spontaneously hypertensive rats. Kidney Blood Press Res 20:6–10

    CAS  PubMed  Google Scholar 

  12. Braun C, Conzelmann T, Vetter S, Schaub M, Back WE, Kirchengast M, Yard B, Schnuelle P, Woude FJ van der, Rohmeiss P (1999) Improvement of chronic renal allograft rejection in rats with the oral endothelin-A receptor antagonist LU 135252. Transplantation 68:739–746

    CAS  PubMed  Google Scholar 

  13. Braun C, Vetter S, Conzelmann T, Schaub M, Back WE, Kirchengast M, Tullius SG, Schnuelle P, Woude FJ van der, Rohmeiss P (2000) Treatment with a combined endothelin-A/B receptor antagonist does not prevent chronic renal allograft rejection in rats. J Cardiovasc Pharmacol 36:428–437

    Article  CAS  PubMed  Google Scholar 

  14. Braun C, Vetter S, Conzelmann T, Schaub M, Kirchengast M, Woude FJ van der, Rohmeiss P (2000) Improved recovery following posttransplant acute renal failure in rat renal isografts with an oral endothelin-A receptor antagonist. Exp Nephrol 8:283–290

    Article  CAS  PubMed  Google Scholar 

  15. Deng DX, Jiang J, Garcia B, Zhong R, Chakrabarti S (2000) Endothelin-1, endothelin-3 and their receptors (endothelin-A and endothelin-B) in chronic renal transplant rejection in rats. Transpl Int 13:175–182

    Article  CAS  PubMed  Google Scholar 

  16. Diamond JR, Tilney NL, Frye J (1992) Progressive albuminuria and glomerulosclerosis in a rat model of chronic renal allograft rejection. Transplantation 54:710–716

    CAS  PubMed  Google Scholar 

  17. Dorst CJ (1978) Vessel diameter-independent volume flow measurements using ultrasound. Proc San Diego Biomed Symp 17:299–302

    Google Scholar 

  18. Ehrenreich H, Schilling L (1995) New developments in the understanding of cerebral vasoregulation and vasospasm: the endothelin–nitric oxide network. Cleve Clin J Med 62:105–116

    CAS  PubMed  Google Scholar 

  19. Gellai M, Jugus M, Fletcher T, DeWolf R, Nambi P (1994) Reversal of postischemic acute renal failure with a selective endothelin-A receptor antagonist in the rat. J Clin Invest 93:900–906

    CAS  PubMed  Google Scholar 

  20. Hansell P (1992) Evaluation of methods for estimating renal medullary blood flow. Ren Physiol Biochem 15:217–230

    CAS  PubMed  Google Scholar 

  21. Häyry P, Isoniemi H, Yilmaz S (1993) Chronic allograft rejection. Immunol Rev 134:33–81

    PubMed  Google Scholar 

  22. Herrero I, Torras J, Riera M (1999) Prevention of cold ischaemia-reperfusion injury by an endothelin receptor antagonist in experimental renal transplantation. Nephrol Dial Transplant 14:872–880

    Article  CAS  PubMed  Google Scholar 

  23. Hocher B, Thone-Reineke C, Rohmeiss P, Schmager F, Slowinski T, Burst V, Siegmund F, Quertermous T, Bauer C, Neumayer HH, Schleuning WD, Theuring F (1997) Endothelin-1 transgenic mice develop glomerulosclerosis, interstitial fibrosis, and renal cysts but not hypertension. J Clin Invest 99:1380–1389

    CAS  PubMed  Google Scholar 

  24. Hostetter TH (1994) Chronic transplant rejection. Kidney Int 46:266–279

    CAS  PubMed  Google Scholar 

  25. Kohan DE (1993) Endothelins in the kidney: physiology and pathophysiology. Am J Kidney Dis 22:493–510

    CAS  PubMed  Google Scholar 

  26. Lee S (1967) An improved technique of renal transplantation in the rat. Surgery 61:771–773

    CAS  PubMed  Google Scholar 

  27. Lucas M, Jasmin JF, Dupuis J (2001) Effect of ET-A receptor antagonist on pulmonary hypertension and vascular reactivity in rats with congestive heart failure. Pulm Pharmacol Ther 14:307–314

    Article  CAS  PubMed  Google Scholar 

  28. Orth SR, Odoni G, Amann K, Strzelczyk P, Raschack M, Ritz E (1999) The ET-A receptor blocker LU 135252 prevents chronic transplant nephropathy in the "Fisher to Lewis" model. J Am Soc Nephrol 10:387–391

    CAS  PubMed  Google Scholar 

  29. Rohmeiss P, Birck R, Braun C, Münter K, Woude FJ van der, Kirchengast M (1998) Pharmacology of the endothelin-A receptor antagonist: LU 135252. Cardiovasc Drug Rev 16:391–412

    CAS  Google Scholar 

  30. Simonson MS (1993) Endothelin: multifunctional renal peptides. Physiol Rev 73:375–410

    CAS  PubMed  Google Scholar 

  31. Tullius SG, Tilney LN (1995) Both alloantigen-dependent and -independent factors influence chronic allograft rejection. Transplantation 59:313–318

    CAS  PubMed  Google Scholar 

  32. Welch WJ, Deng X, Snellen H, Wilcox CS (1995) Validation of miniature ultrasonic transit-time flow probes for measurement of renal blood flow in rats. Am J Physiol 31:F175–F178

    Google Scholar 

  33. Wilhelm SM, Stowe NT, Robinson AV, Schulak JA (2001) The use of the endothelin receptor antagonist, tezosentan, before or after renal ischemia protects renal function. Transplantation 71:211–216

    CAS  PubMed  Google Scholar 

  34. Wolf SC, Gaschler F, Brehm S, Klaussner M, Amann K, Risler T, Brehm BR (2000) Endothelin-receptor antagonists in uremic cardiomyopathy. J Cardiovasc Pharmacol 36 [5 Suppl 1]:S348–S350

    Google Scholar 

  35. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T (1988) A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332:411–415

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by a grant to Thomas Knoll from the "Graduiertenkolleg Experimentelle Nieren- und Kreislaufforschung", Deutsche Forschungsgemeinschaft, University of Heidelberg.

Author information

Authors and Affiliations

  1. Department of Urology, Faculty of Clinical Medicine of the University of Heidelberg, University Hospital of Mannheim, Theodor-Kutzer-Ufer 1–3, 68135, Mannheim, Germany

    Thomas Knoll & Maurice Stephan Michel

  2. V. Department of Medicine, Faculty of Clinical Medicine of the University of Heidelberg, University Hospital of Mannheim, Mannheim, Germany

    Jens Oltersdorf, Uwe Göttmann, Meike Schaub, Fokko J. van der Woude, Peter Rohmeiss & Claude Braun

  3. Knoll AG, Ludwigshafen, Germany

    Michael Kirchengast

Authors
  1. Thomas Knoll
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jens Oltersdorf
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Uwe Göttmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Meike Schaub
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maurice Stephan Michel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael Kirchengast
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Fokko J. van der Woude
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Peter Rohmeiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Claude Braun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas Knoll.

About this article

Cite this article

Knoll, T., Oltersdorf, J., Göttmann, U. et al. Influence of acute selective endothelin-receptor-A blockade on renal hemodynamics in a rat model of chronic allograft rejection. Transpl Int 16, 425–429 (2003). https://doi.org/10.1007/s00147-003-0574-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00147-003-0574-6

Keywords

Search

Navigation