L-Arginine regulates neuronal nitric oxide synthase production of superoxide and hydrogen peroxide

Tetrahydrobiopterin (H₄B) in the absence of l-arginine has been shown to be an important factor in promoting the direct formation of hydrogen peroxide (H₂O₂) at the expense of superoxide (O ₂^.-) by neuronal nitric oxide synthase (NOS1) [Rosen GM, Tsai P, Weaver J, Porasuphatana S, Roman LJ, Starkov AA, et al. Role of tetrahydrobiopterin in the regulation of neuronal nitric-oxide synthase-generated superoxide. J Biol Chem 2002;277:40275-80]. Based on these findings, it is hypothesized that l-arginine also shifts the equilibrium between O₂^.- and H₂O₂. Experiments were designed to test this theory. As the concentration of l-arginine and N ^ω-hydroxyl-l-arginine increases, the rate of NADPH consumption for H₄B-bound NOS1 decreased resulting in lower rates of both O ₂^.- and H₂O₂ generation, while increasing the rate of nitric oxide (^.NO) production. At saturating concentrations of l-arginine or N^ω-hydroxyl-l-arginine (50 μM), NOS1 still produced O₂^.- and H₂O ₂. Both L-arginine and N^ω-hydroxyl-L-arginine have greater impact on the rate of generation of O₂^.- than on H₂O₂.