Nitric Oxide in Human Health and Disease


Nitric oxide (NO) is a free radical, actively produced in human body. NO exerts crucial roles in vascular and neuronal signal transduction, smooth muscle contractility, bioenergetics, platelet adhesion and aggregation, immunity, and cell death regulation. The evidence accumulated over the last 25 years suggests that a defective control of the NO levels causes pathologies, such as hypertension, cardiovascular dysfunctions, neurodegeneration, arthritis, asthma and septic shock. Despite dealing with NO, the boundary between health and disease is still blurry, although the feeling is that pulses of NO in the low concentration range (piconanomolar) are by and large physiological, whereas cell persistence in the high concentration range (micromolar) may turn to pathological. Evidence is growing that the dark side of NO resides on its concentration levels and on the production of peroxynitrite and other reactive oxygen and nitrogen species; last but not least, the type of biomolecule reacting with NO and, when present, the cell bioenergetic changes induced strongly contribute to physiological or pathological outcomes.

Key Concepts:

  • Nitric oxide shares with O2 and towards biomolecules, high reactivity and duality of effects, both beneficial and detrimental.

  • In the human body, a variety of metabolic effects are induced by NO, owing to the widespread nitrergic signalling and bioenergetic chemistry.

  • It is time to verify whether the S‐nitrosation of proteins and enzymes is as important as their phosphorylation.

  • The NO chemistry in the human body appears tightly integrated with the chemistry of H2S and CO.

  • The intracellular NO and O2−• concentration, both absolute and relative, are vital to cell redox homoeostasis: it is their imbalance that triggers pathological responses.

  • Sometimes, the NO released by one isoform antagonises the effects of NO produced by another isoform. During cerebral ischaemia, for instance, the nNOS appears involved in tissue injury, whereas the eNOS preserves blood flow and tissue oxygenation.

  • The mechanism of macromolecular damage by peroxynirite is still poorly understood.

  • Feeling is growing that besides the oxidative stress, a reductive stress should be also considered.

  • For how long should a cell Ca++ transient lasts to stimulate cNOS? Moreover, is amplitude and duration of such a stimulus different in physiology and pathology?

Keywords: radical chemistry; nitrosative stress; bioenergetics; nitrergic transmission; neurodegeneration; mitochondria; haem proteins pathophysiology; warburg effect; melatonin; molecular mechanisms

Figure 1.

Cell targets of NO and reactive nitrogen–oxygen species. Top pathway: reactions leading, predominantly, to physiological outcomes, contrary to bottom pathway where pathological effects are induced particularly by an early formation of RONS and ONOO. The affinity of NO for the targets decreases from left to right. sGC, soluble guanylate cyclase; CcOX, cytochrome c oxidase; Nht, nonheme targets; RONS, reactive oxygen and nitrogen species; Prt, proteins; Lip, lipids; Nac, nucleic acids and FeS centres. Modified by permission of Hill et al. © The American Society for Biochemistry and Molecular Biology.

Figure 2.

Nitrergic signal transmission within the neuroeffector junction and at the endothelium smooth muscle cell interface. The NO released from a nerve terminal and an endothelial cell stimulates the production of cGMP, with activation of PKG. Simplified schematic representation of the smooth muscle cell relaxation sequence of reactions.

Figure 3.

Heart disease deaths by sex: age distribution and eNOS expression. (a) Ratios calculated according to the California Department of Public Health on the Heart Disease Mortality Data Trends (California 2000–2008), available online at: (b) eNOS expression (western blot analysis) in the endothelial cells from the internal mammal artery of postmenopausal women versus aged man (*P<.001). Modified by permission of Mannacio et al. © Elsevier.

Figure 4.

Nitric oxide and the penile erection. Following sexual stimulus, NO is released in nonadrenergic noncholinergic (NANC) fibres as well as from endothelial eNOS at the level of pudendal arteries and cavernosal smooth muscle cells. Arteries relaxation and veins compression (against tunica albuginea) result in a greater inflow of blood relative to outflow. As a consequence, the intracavernosal blood pressure rises and erection occurs. Reproduced with permission from Jeremy et al. © Nature Publishing Group.

Figure 5.

Nitric oxide in the synaptic signal transmission. At synaptic level, the presynaptic stimulus induces depolarisation of postsynaptic terminal (ΔΨ), the process requiring the mobility of small cations (K +and Na+); concomitantly, glutamate is released, inducing the N‐methyl‐D‐aspartate receptors (NMDAr) to release Mg++ and allow [Ca2+]i to rise. This causes neuronal nitric oxide synthase (nNOS) to synthesise NO; the back diffusion of NO induces the sGC activation with further glutamate release and potentiation of the signal.

Figure 6.

Nitric oxide and mitochondrial oxygen reactive species. According to Moncada and Erusalimsky (), a temporary inhibition of cytochrome c oxidase by NO may lead to enhancement of superoxide anion (O2) and thereby of H2O2 acting as a signalling molecule (top panel). When inhibition by NO persists, the concentration of cell detrimental ONOO rises (bottom). Modified by permission of Brunori et al. © Elsevier.

Figure 7.

Expression of iNOS in chronic active human multiple sclerosis (MS) plaques. (a) Active periventricular lesion showing iNOS expression (green) along the ventricle (lower border) and around a blood vessel (V). The arrow indicates a region of normal white matter close to lesion. Single * indicates the area magnified in (b) and (**) the border of the plaque, with some green fluorescence, and including inflammatory cells (red) are also seen nearby the lesion. (V) indicates the vessel (4x). (b) Cellular inflammatory infiltration of the MS plaque, A * area. iNOS (green) cell surface macrophage/microglia marker CD64 (red) (magnification 60x). (c) Perivascular iNOS expression near a plaque (40x). (d) Periventricular section of a chronic active lesion showing ependymal cells, marked in red (perinuclear glial fibrillar acid protein, GFAP), with diffuse intracellular iNOS expression (100x). (Cell nucleus=blue); (Lipofuscin=white). Modified by permission of Hill et al. © Elsevier.

Figure 8.

NO oxidation products in synovial fluids of humans and experimental animals. (Top) Nitrite and nitrate levels in synovial exudates of zymosan‐induced arthritis of the rat temporomadibular joint. Modified with permission from Chaves et al. © Helliada Vasconcelos Chaves. (Bottom) Nitrite concentration in synovial fluid (SF) and serum (SR) samples of patients with rheumatoid arthritis (RA) and osteo arthritis (OA). Modified by permission of Farrell et al. © BMJ publishing group.



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Further Reading

Antonopoulos AS, Margaritis M, Lee R, Channon K and Antoniades C (2012) Statins as anti‐inflammatory agents in atherogenesis: molecular mechanisms and lessons from the recent clinical trials. Current Pharmaceutical Design 18(11): 1519–1530.

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Paolo, Sarti(Apr 2013) Nitric Oxide in Human Health and Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0003390.pub2]