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

Nitric oxide (NO center dot) is a gaseous free radical molecule with a short half-life (similar to 1 s), which can gain or lose an electron into three interchangeable redox-dependent forms, the radical (NO center dot), the nitrosonium cation (NO+), and nitroxyl anion (HNO). NO center dot acts as an intra and extracellular signaling molecule regulating a wide range of functions in the cardiovascular, immune, and nervous system. NO center dot donors are collectively known by their ability to release NO center dot in vitro and in vivo, being proposed as therapeutic pharmacological tools for the treatment of several pathologies, such as cardiovascular disease. The highly reactive NO center dot molecule is easily oxidized under physiological conditions to N-oxides, nitrate/nitrite and nitrogen dioxide. Different cellular responses are triggered depending on: 1) NO center dot 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 center dot 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 center dot 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 center dot 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 center dot donors to use, since different outcomes are to be expected. This article will comment recent findings regarding physiological responses involving NO center dot species and their pharmacological modulation with donor drugs, especially in the context of the photic transduction pathways at the hypothalamic circadian clock.