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 (O2−) 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 Nω-hydroxyl-l-arginine increases, the rate of NADPH consumption for H4B-bound NOS1 decreased resulting in lower rates of both O2− and H2O2 generation, while increasing the rate of nitric oxide (NO) production. At saturating concentrations of l-arginine or Nω-hydroxyl-l-arginine (50 μM), NOS1 still produced O2− and H2O2. Both l-arginine and Nω-hydroxyl-l-arginine have greater impact on the rate of generation of O2− than on H2O2.