TY - JOUR
T1 - Cyclosporine-induced coronary endothelial dysfunction
T2 - Is tetrahydrobiopterin the solution?
AU - El-Hamamsy, I.
AU - Grant, M.
AU - Stevens, L. M.
AU - Malo, O.
AU - Carrier, M.
AU - Perrault, L. P.
N1 - Funding Information:
Supported through grants from the “Fonds de recherche de l’Institut de Cardiologie de Montréal” (FRICM), the Department of Surgery of the “Université de Montréal”. Dr. Louis P. Perrault is a scholar of the “Fonds de la recherche en santé du Québec” (FRSQ).
Funding Information:
Anesthesia was induced with intramuscular mixture injection of ketamine (20 mg/kg; Rogarsetic, Montreal, Quebec, Canada) and Xylazine (2 mg/kg; Rompun, Toronto, Ontario, Canada). Swine were artificially ventilated with an O 2 /air mixture (3:2). Light anesthesia was supported by halothane 1% v/v (Halocarbon Laboratories, River Edge, NJ). Sacrifice was achieved by exsanguination under anesthesia. No cardioplegia was used. The heart was explanted and the left anterior descending, the circumflex, and the right coronary arteries were removed from the myocardium and dissected free from adventitial tissue.
PY - 2005/6
Y1 - 2005/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=21844448863&partnerID=8YFLogxK
U2 - 10.1016/j.transproceed.2005.03.021
DO - 10.1016/j.transproceed.2005.03.021
M3 - Article
C2 - 15964417
AN - SCOPUS:21844448863
SN - 0041-1345
VL - 37
SP - 2365
EP - 2370
JO - Transplantation Proceedings
JF - Transplantation Proceedings
IS - 5
ER -