Sepiapterin Decreases Vasorelaxation in Nitric Oxide Synthase Inhibition–Induced Hypertension

Exogenous BH4 (tetrahydrobiopterin) has been shown to improve endothelial function in cardiovascular disease; however, in the presence of elevated superoxide levels and decreased nitric oxide synthase (NOS) activity, BH4 may become autoxidized, resulting in reduced vasodilation. The authors tested the hypothesis that increasing BH4 will further reduce endothelium-dependent relaxation in aortas from rats made hypertensive by NOS inhibition. N omega-nitro-L-arginine (L-NNA, approximately 49 mg/kg/d) was administered in the rats' drinking water for 4 days. Systolic blood pressures, measured by tail-cuff technique, were significantly increased in L-NNA-treated rats. Endothelium-intact aortic segments were isolated and hung in organ chambers for the measurement of isometric force generation. Aortas from L-NNA-treated rats had decreased relaxation to acetylcholine compared with controls, and this was further decreased after incubation with sepiapterin. Superoxide dismutase (SOD) restored relaxation in aortas from L-NNA-treated rats to that of control. In addition, SOD or ascorbic acid reversed the sepiapterin-induced decrease in relaxation in aortas from L-NNA treated rats. Aortas from L-NNA-treated rats in the absence and presence of sepiapterin, and sepiapterin-treated control aortas, had increased dihydroethidium staining for superoxide compared with untreated controls. These results support the hypothesis that sepiapterin further reduces vasodilation in the presence of NOS inhibition and may be caused by BH4 autoxidation.