Tetrahydrobiopterin prevents cyclosporine-induced vasomotor dysfunction.
BACKGROUND
Cyclosporine A (CsA) is associated with negative side effects such as endothelial injury, which may lead to transplant vasculopathy. CsA can impair nitric oxide (NO) homeostasis. Therefore, tetrahydrobiopterin (BH4), a NO synthase cofactor, may limit endothelial injury by improving NO production. Our study examines the effect of CsA and BH4 exposure on endothelial function.


METHODS
Lewis rats were injected with CsA, BH4, CsA+BH4, or saline intraperitoneally daily for 2 weeks. With use of a small vessel myograph, thoracic aortic segments were assessed for endothelial-dependent (Edep) and independent relaxation after exposure to acetylcholine and sodium nitroprusside. Sensitivity to vasospasm was evaluated after exposure to endothelin (ET)-1.


RESULTS
CsA exposure resulted in impaired Edep vasorelaxation compared with control (P=0.01). BH4 attenuated the deleterious effects of CsA. Compared with control, all treatment groups demonstrated significantly increased sensitivity to ET-1. Furthermore, endothelial nitric oxide synthase expression in the thoracic aorta was reduced after CsA treatment, and this reduction was attenuated by BH4 therapy (P<0.01). ETA receptor expression in the aorta was increased after CsA treatment, but BH4 treatment prevented CsA-induced ETA over-expression (P=0.004). However, ETB receptor expression was increased by BH4 treatment compared with CsA and control (P=0.02).


CONCLUSIONS
Our findings suggest that CsA-induced vasomotor dysfunction is a result of alterations in both NO and ET-1 regulation and that BH4 may prevent the deleterious effects of CsA. However, the beneficial effects of BH4 are associated with increased sensitivity to ET-1. Therefore, a combination of BH4 and ET-1 blockade may prove to be an ideal combination for preservation of endothelial function.
Ramzy
Danny
D
Heart Transplant Program, Toronto General Hospital, University Health Network, Toronto, Ontario M5G 2C4, Canada.
Rao
Vivek
V
Tumiati
Laura C
LC
Xu
Ning
N
Miriuka
Santiago
S
Delgado
Diego
D
Ross
Heather J
HJ
D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology*; D016572:Cyclosporine / Q000009:adverse effects* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects; D019332:Endothelin-1 / Q000097:blood; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D018384:Oxidative Stress; D051381:Rats; D011917:Rats, Inbred Lew; D017466:Receptors, Endothelin / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*
D019332:Endothelin-1; D017466:Receptors, Endothelin; D001708:Biopterins; D016572:Cyclosporine; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; C003402:sapropterin