NO: a molecule with two masks of 'NO' theatre.

Abstract

Nitric oxide (NO), a potent vasodilator as well as a retrograde neurotransmitter, is involved in multiple functions such as modification of skeletal muscle contractile force and development, control of total body sodium content and body fluid homeostasis, male sexual performance and development of the gastric pyloric sphincter. Under physiological conditions, NO is believed to always be present fluctuating or spiking at quite low levels (∼ nM). It is produced by constitutively expressed neuronal and endothelial type of NO synthase (NOS-I and NOS-III, respectively), widely present in the whole body. High NO levels achieved by hyper-activation of NOS-I are involved in disorders such as ischemia reperfusion injury and glutamatergic neurodegenerative processes in the central nervous system. Under inflammatory conditions, high levels of NO are temporally produced by an inducible type of NO synthase (NOS-II), which is absent under normal conditions. High amounts of NO may be a double-edged weapon. On the one hand, NO may exert beneficial effects for the body, acting as an antibacterial, -parasital, -viral agent as well as an tumoricidal agent. On the other hand, NO, if not adequately controlled, will be detrimental to the body itself because NO may react with concomitantly produced superoxide anion, thereby generating highly toxic compounds such as peroxynitrite and hydroxyl radical. Obviously, the body carefully controls NOS-II expression through a number of endogenous and exogenous molecules. These compounds act either as inducers of the expression of NOS-II, e.g., bacterial lipopolysaccharides (LPS) and immune cytokines, such as interferon-γ (IFNγ), tumour necrosis factor-α (TNFα), interleukin-1β (IL-1β), or as suppressors like corticosteroids, estrogens, transforming growth factor-β (TGFβ), interleukin-4 (IL-4), interleukin-8 (IL-8), interleukin-10 (IL-10), calcium ionophores and glutamate. Due to the co-ordinated action among some of these molecules, the temporally and spatially correct NOS-II expression is normally warranted during inflammation [1]. An increasing body of evidence indicates that low physiological amounts of NO suppress the transcription of the NOS-II gene in a variety of cell types [2]. The inhibitory effect of NO on NOS-II gene expression has been attributed to the NO-mediated inactivation of the transcriptional factor NF-κB by two distinct mechanisms: 1) suppression of NF-κB activation, and induction and stabilization of the