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Cyclosporine-induced coronary endothelial dysfunction: is tetrahydrobiopterin the solution?

I El-Hamamsy1, M Grant, L M Stevens

  • 1Research Center, Montreal Heart Institute, 5000 Belanger Street East, Montreal, Quebec H1T 1C8, Canada.

Transplantation Proceedings
|June 21, 2005
PubMed

Insights

Tetrahydrobiopterin (BH(4)) can reverse cyclosporine-induced coronary endothelial dysfunction. This finding suggests BH(4) may protect against cardiac allograft vasculopathy after heart transplantation.

Area of Science:

  • Cardiovascular Research
  • Transplantation Immunology
  • Pharmacology

Background:

  • Coronary endothelial dysfunction post-heart transplant predicts cardiac allograft vasculopathy.
  • Cyclosporine, an immunosuppressant, may directly cause this endothelial dysfunction.
  • Tetrahydrobiopterin (BH(4)) is an antioxidant and nitric oxide synthesis cofactor.

Purpose of the Study:

  • To investigate if BH(4) can reverse cyclosporine-induced endothelial dysfunction.
  • To assess the protective role of BH(4) against cyclosporine's effects on coronary arteries.

Main Methods:

  • Utilized an in vitro model with porcine epicardial coronary arteries.
  • Incubated arteries with cyclosporine (10(-4) mol/L) alone or with a BH(4) analog (MH(4)).
  • Performed organ chamber experiments to assess coronary endothelial function.

Main Results:

  • Cyclosporine significantly reduced endothelium-dependent relaxations to serotonin.
  • Addition of MH(4) (a BH(4) analog) significantly reversed this impairment.
  • Endothelium-independent relaxations and bradykinin responses remained unaffected.

Conclusions:

  • BH(4) demonstrates a significant protective effect on coronary endothelial function against cyclosporine.
  • BH(4) may reduce the incidence of endothelial dysfunction and cardiac allograft vasculopathy.
  • BH(4) represents a potential therapeutic strategy in heart transplantation.
Abstract

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