Fig. 1.

Uncoupling eNOS initiates a vicious cycle of nitrosative stress. Oxidation of its cofactor, tetrahydrobiopterin (BH₄), uncouples the endothelial isoform of nitric oxide synthase (eNOS), which then generates the superoxide anion (O₂ ⁻). Superoxide then combines with nitric oxide (NO) produced by adjacent, still-coupled eNOS to form the powerful oxidant peroxynitrite (ONOO⁻), which in turn upregulates nuclear factor kappa B (NFκB). NFκB activates expression of the inducible nitric oxide synthase (iNOS), which produces massive amounts of NO that combine with eNOS-generated O₂ ⁻ to intensify ONOO⁻ formation.