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

I. El-Hamamsy, M. Grant, L. M. Stevens, O. Malo, M. Carrier, L. P. Perrault

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Background. Coronary endothelial dysfunction after heart transplantation is predictive of cardiac allograft vasculopathy. Immunosuppressive drugs, particularly cyclosporine may contribute to this dysfunction by a direct effect. Tetrahydrobiopterin (BH4) is a potent antioxidant and an essential cofactor of nitric oxide biosynthesis. The purpose of this study was to investigate whether BH4 could reverse the endothelial dysfunction induced by cyclosporine. Methods. A previously described in vitro model of drug incubation in Krebs-bicarbonate solution (4°C, 48 hours) of porcine epicardial coronary arteries was used. Coronary endothelial function studies were performed in organ chamber experiments after incubation with cyclosporine (10-4 mol/L) in the presence or absence of 6-methyltetrahydropterin (MH4 [0.1 mol/L], a BH4 analog) to assess its effect on the cylcosporine-induced endothelial dysfunction. Results. The average doses of PGF2α required to attain 50% of the maximal contraction to KCl was significantly lower (P < .001) in the cyclosporine group (8.6 ± 1.94 × 10-6 mol/L) compared to the control group (24.8 ± 5.2 × 10-6 mol/L). Exposure to cyclosporine induced a significant decrease in endothelium-dependent relaxations to serotonin (5HT) (% Emax [5HT]: 77% ± 4%; P < .05). Addition of MH4 significantly reversed this impaired response (% Emax [5HT]: 62% ± 4%; P < .05). No alterations of relaxation were observed with bradykinin in both groups. Endothelium-independent relaxations to sodium nitroprussiate were fully preserved. Conclusions. These results suggest a significant protective role of BH4 on coronary endothelial function following exposure to cyclosporine, which could reduce the incidence of endothelial dysfunction and cardiac allograft vasculopathy following cardiac transplantation.

Original languageEnglish
Pages (from-to)2365-2370
Number of pages6
JournalTransplantation Proceedings
Issue number5
StatePublished - Jun 2005
Externally publishedYes


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