1. Introduction sponsible for a dysfunction of nitric oxide synthase leading to a shift in the balance between the production of Nitric oxide (NO) plays a crucial role in the regulation protective NO and deleterious oxygen-derived free radicals of vascular tone and maintenance of vascular integrity(Fig. 1). Tetrahydrobiopterin is known to be a cofactor of [1–3]. Indeed, nitric oxide reduces vascular tone, inhibits aromatic amino acid monooxygenases, which are regarded leucocytes adhesion to the endothelium, platelet-vessel as key enzymes in the biosynthesis of several neurowall interaction, as well as vascular smooth muscle cell transmitters, including catecholamines and serotonin [23]. proliferation and migration. Accordingly, major risk fac- It is indeed well established that inborn errors of tetrahytors for atherosclerotic vascular disease such as hyper- drobiopterin metabolism lead to cofactor deficiency, hycholesterolemia, diabetes, hypertension and smoking, have perphenylalaninemia, and neurological impairment [24]. In been associated with impaired nitric oxide activity [4–11]. contrast, an important role of tetrahydrobiopterin in car-In vivo the activity of the L-arginine-NO pathway is a diovascular system has been recognized only recently. The balance between the synthesis and breakdown of NO. first step of tetrahydrobiopterin biosynthesis involves Although, there are several reasons to believe that NO activation of guanosine triphosphate (GTP)-cyclohydrolase synthesis could be impaired [12–14], reduced NO activity I, which catalyzes the conversion of GTP to dihydroneopcould be caused by enhanced catabolism. Indeed, the in terin triphospahte [25]. Intracellular levels of tetrahydrovivo half-life of NO is determined mainly by its reaction biopterin can also be increased by treating cells or animals with oxyhemoglobin and superoxide anion [15]. Superox- with sepiapterin, which is converted to tetrahydrobiopterin