Acute Amelioration of Diabetic Endothelial Dysfunction with a Derivative of the Nitric Oxide Synthase Cofactor, Tetrahydrobiopterin

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Abstract
Tetrahydrobiopterin is a cofactor for nitric oxide synthase. In low concentrations of this cofactor, nitric oxide synthase is known to produce less nitric oxide and, correspondingly, enhanced quantities of the oxidant species, hydrogen peroxide. In this study, we tested the hypothesis that an exogenous tetrahydrobiopterin derivative might improve endothelial nitric oxide synthase activity in diabetic endothelium. Diabetes was induced in Sprague-Dawley rats with intravenous injections of streptozotocin. After 8 weeks, endothelium-dependent relaxation was assessed in aortic rings by using acetylcholine, whereas endothelium-independent relaxation was assessed by using nitroglycerin. Acetylcholine-induced relaxation was impaired in diabetic rings, whereas nitroglycerin-induced relaxation was unimpaired. Exposure of rings for 30 min with 100 microM of the pteridine derivative, 6-methyl-5,6,7,8-tetrahydropterin (in the presence of diethylenetriaminepentaacetic acid to inhibit oxidation), followed by washing and equilibration in control media, augmented relaxation induced by acetylcholine in diabetic rings but had no effect on relaxation in control rings. Pteridine exposure did not alter relaxation or sensitivity to nitroglycerin in control rings either with or without endothelium. In diabetic rings, pteridine exposure augmented maximal relaxation to nitroglycerin in rings with or without endothelium while increasing the sensitivity only in rings with endothelium but not in rings without endothelium. In contrast, there was no effect of pteridine exposure on relaxation or sensitivity to nitroglycerin in diabetic rings (with or without endothelium) that are pretreated with L-nitroarginine. In summary, tetrahydrobiopterin availability can play a key role in the regulation of nitric oxide production by diabetic endothelium.