Does vitamin C enhance nitric oxide bioavailability in a tetrahydrobiopterin-dependent manner? In vitro, in vivo and clinical studies

Ascorbate (Asc) has been shown to increase nitric oxide (NO) bioavailability and thereby improve endothelial function in patients showing signs of endothelial dysfunction. Tetrahydrobiopterin (BH4) is a co-factor of endothelial nitric oxide synthase (eNOS) which may easily become oxidized to the inactive form dihydrobiopterin (BH2). Asc may increase NO bioavailability by a number of mechanisms involving BH4 and eNOS. Asc increases BH4 bioavailability by either reducing oxidized BH4 or preventing BH4 from becoming oxidized in the first place. Asc could also increase NO bioavailability in a BH4-independent manner by increasing eNOS activity by changing its phosphorylation and S-nitrosylation status or by upregulating eNOS expression. In this review, we discuss the putative mechanisms by which Asc may increase NO bioavailability through its interactions with BH4 and eNOS.