Tetrahydrobiopterin Reverses the Impairment of Acetylcholine-induced Vasodilatation in Diabetic Ocular Microvasculature

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Abstract
The purpose of this study is to test whether tetrahydrobiopterin, an essential cofactor in nitric oxide synthesis, can reverse endothelium dysfunction in diabetic ocular circulation. Using the streptozotocin-induced diabetic rat model and the isolated perfusion eye technique, the response to the acetylcholine (an endothelium-dependent vasodilator mediated by stimulated nitric oxide release) induced vasodilatation of the diabetic ocular vasculature before and after tetrahydrobiopterin administration was compared. Age matched normal rats were used for reference response. Six streptozotocin-induced diabetic rats and eleven control rats at 21.5 ± 0.2 weeks and 21.2 ± 2.1 weeks postinduction, respectively, were used. The dose response curve from the diabetic eyes was found to be significantly different from that of the control eyes (p < 0.001) with significantly reduced responses to 10-4M acetylcholine. After 30 min of administration of tetrahydrobiopterin to the diabetic eyes, however, the acetylcholine-induced vasodilatation response was significantly (p < 0.001) increased compared with the response prior to tetrahydrobiopterin administration. The vasodilatory response in the diabetic eyes after tetrahydrobiopterin administration was at a level that was comparable with the control response (p = 0.742). We have shown that acute administration of tetrahydrobiopterin is effective in reversing to control level the impaired acetylcholine-induced vasodilatory response at 21.5 ± 0.2 weeks postinduction. Our result suggests that a decreased level of tetrahydrobiopterin in the eyes of the streptozotocin-induced diabetic rats may be responsible for the ocular vascular endothelium dysfunction.