Cyclosporine-Induced Coronary Endothelial Dysfunction: Is Tetrahydrobiopterin the Solution?

Abstract

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 (BH 4) is a potent antioxidant and an essential cofactor of nitric oxide biosynthesis. The purpose of this study was to investigate whether BH 4 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 (MH 4 [0.1 mol/L], a BH 4 analog) to assess its effect on the cylcosporine-induced endothelial dysfunction. Results The average doses of PGF2 α 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) (% E max [5HT]: 77% ± 4%; P < .05). Addition of MH 4 significantly reversed this impaired response (% E max [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 BH 4 on coronary endothelial function following exposure to cyclosporine, which could reduce the incidence of endothelial dysfunction and cardiac allograft vasculopathy following cardiac transplantation.