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). CONCLUSION: 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.