Fig. 1

NO biosynthesis and eNOS uncoupling. Endogenous NO is produced by NOS by the oxidation of l-arginine to l-citrulline + NO (NADPH and BH4-dependent reaction). NO is one of the end-products of the reaction. Most of the effects of NO in the cardiovascular system are mediated by the activation of sGC, which catalyzes the formation of the second messenger cGMP from GTP. The activation of GMP‐dependent PKG leads to vascular relaxation (A). Several circumstances may alter eNOS activity causing the reduction of NO levels and triggering the production of superoxide instead of NO, a process defined as “eNOS uncoupling”. For example, the depletion of eNOS cofactor BH4, l-arginine deficiency, and increase in endogenous eNOS inhibitor ADMA lead to eNOS uncoupling. This process is largely deleterious and has been linked to endothelial dysfunction, ROS increase and other vascular pathologies. Moreover, NO bioavailability is reduced by free oxy-Hb. B NO: nitric oxide; NOS: nitric oxide synthase; sGC: soluble guanylate cyclase; cGMP: cyclic guanosine monophosphate; GTP: guanosine-5′-triphosphate; PKG: Protein Kinase G; BH4: tetrahydrobiopterin; ADMA: asymmetric dimethylarginine; oxy-Hb: oxyhemoglobin