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


RESULTS
The average doses of PGF2(alpha) required to attain 50% of the maximal contraction to KCl was significantly lower (P < .001) in the cyclosporine group (8.6 +/- 1.94 x 10(-6) mol/L) compared to the control group (24.8 +/- 5.2 x 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.
El-Hamamsy
I
I
Research Center, Montreal Heart Institute, 5000 Belanger Street East, Montreal, Quebec H1T 1C8, Canada.
Grant
M
M
Stevens
L M
LM
Malo
O
O
Carrier
M
M
Perrault
L P
LP
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology; D003331:Coronary Vessels; D016572:Cyclosporine / Q000633:toxicity*; D015237:Dinoprost / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology*; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D013552:Swine
D000975:Antioxidants; D001708:Biopterins; D016572:Cyclosporine; D015237:Dinoprost; C003402:sapropterin