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

Abstract Ascorbate (Asc) has been shown to increase nitric oxide (NO) bioavailability and thereby improve endothelial function in patients showing signs of endothelial dysfunction. Tetrahydrobiopterin (BH 4 ) is a co-factor of endothelial nitric oxide synthase (eNOS) which may easily become oxidized to the inactive form dihydrobiopterin (BH 2 ). Asc may increase NO bioavailability by a number of mechanisms involving BH 4 and eNOS. Asc increases BH 4 bioavailability by either reducing oxidized BH 4 or preventing BH 4 from becoming oxidized in the first place. Asc could also increase NO bioavailability in a BH 4 -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 BH 4 and eNOS.