Nitric Oxide: Synthesis and Action

Abstract Nitric oxide (NO) is a diatomic radical implicated in a variety of pathways including vascular homeostasis, neurotransmission and immune defence. NO is produced endogenously by three nitric oxide synthases (NOS) and can also be formed from nitrates and nitrites. Several mechanisms regulate NOS function, including protein–protein interactions, posttranslational modifications, cell localization, calcium levels, substrate availability, and the cell redox status. Picomolar NO concentrations activate guanylyl cyclase to increase cGMP levels and lead to vasodilation and memory formation. Excess NO concentrations cause posttranslational modifications of cellular components and formation of peroxynitrite leading to inflammation and cell death. Due to its involvement in multiple pathways and high reactivity with a myriad of downstream targets, tight regulation of NO production is crucial to maintain cellular function. Major advancements in understanding NO chemistry, production and downstream signalling have provided new avenues to target this pathway for the treatment of cardiovascular, neurodegenerative and autoimmune diseases. Key Concepts Nitric oxide is produced endogenously by three nitric oxide synthase (NOS) isozymes. Low NO levels mediate cell signalling, while high NO levels mediate the immune response and defence against pathogens. A tight regulation of NO production is necessary to maintain cellular function. The guanylyl cyclase enzyme (GC1) is the primary receptor of NO in smooth muscle cells and mediates vasorelaxation. Better understanding of NO/GC1 signalling will lead to novel drugs targeting this pathway for improved cardiovascular health. Nitrite, a product of nitrate reduction via oral bacteria, is a biologically relevant source of NO under hypoxic and acidic conditions. Dysfunction in NO synthesis due to oxidative damage leads to NOS uncoupling and increased output of ROS, a well‐known trait of cardiovascular disease (CVD).