Don't just say no: Differential pathways and pharmacological responses to diverse nitric oxide donors

Nitric oxide (NO) is a gaseous free radical molecule with a short half-life (∼1 s), which can gain or lose an electron into three interchangeable redox-dependent forms, the radical (NO), the nitrosonium cation (NO⁺), and nitroxyl anion (HNO). NO acts as an intra and extracellular signaling molecule regulating a wide range of functions in the cardiovascular, immune, and nervous system. NO donors are collectively known by their ability to release NOin vitro and in vivo, being proposed as therapeutic pharmacological tools for the treatment of several pathologies, such as cardiovascular disease. The highly reactive NO molecule is easily oxidized under physiological conditions to N-oxides, nitrate/nitrite and nitrogen dioxide. Different cellular responses are triggered depending on: 1) NO concentration [e.g., nanomolar for heme coordination in the allosteric site of guanylate cyclase (sGC) enzyme]; 2) the type of chemical bound to the nitrosated group (i.e., bound to nitrogen, N-nitro, or bound to sulphur atom, S-nitro) determining post-translational cysteine nitrosation; 3) the time-dependent availability of molecular targets. Classic NO donors are: organic nitrates (e.g., nitroglycerin, or glyceryl trinitrate, GTN; isosorbide mononitrate, ISMN), diazeniumdiolates having a diolate group [or NONOates, e.g., 2-(N,N-diethylamino)-diazenolate-2-oxide], S-nitrosothiols (e.g., S-nitroso glutathione, GSNO; S-nitroso-N-acetylpenicillamine, SNAP) or the organic salt sodium nitroprusside (SNP). In addition, nitroxyl (HNO) donors such as Piloty's acid and Angeli's salt can also be considered. The specific NO form released, as well as its differential reactivity to thiols, could act on different molecular targets and should be discussed in the context of: a) the type and amount of NO species determining the sensitivity of molecular targets (e.g., heme coordination, or S-nitrosation); b) the cellular redox state that could gate different effects. Experimental designs should take special care when choosing which NO donors to use, since different outcomes are to be expected. This article will comment recent findings regarding physiological responses involving NO species and their pharmacological modulation with donor drugs, especially in the context of the photic transduction pathways at the hypothalamic circadian clock.