Nitric Oxide: Role in Human Disease

Nitric oxide regulates a variety of physiological processes, including smooth muscle contractility, platelet reactivity, neurotransmission and the cytotoxic activity of immune cells. A number of diseases have been linked to the inappropriate release of nitric oxide, including hypertension, atherosclerosis, septic shock, neurodegeneration, arthritis and asthma.

Keywords: nitric oxide; hypertension; atherosclerosis; neurodegeneration; inflammation

Figure 1. Mean arterial blood pressure (MABP) in conscious endothelial nitric oxide synthase (eNOS) mutant and wild-type mice. Blood pressure in the eNOS mutant animals was higher than that in their wild-type counterparts; this difference was more marked in male than in female animals. From Rees et al. (2000), with permission.
Figure 2. Effect of NG-monomethyl-l-arginine (L-NMMA) on mean arterial pressure in a patient with septic shock. Arrows show bolus injections of L-NMMA (1, 0.3 mg kg– 1; 2, 0.3 mg kg– 1; 3, 1 mg kg– 1). Hatching indicates noradrenaline infusions (g kg– 1 min– 1), as shown. From Petros et al. (1991), with permission.
Figure 3. Immunohistochemical demonstration of nitrergic degeneration in the corpus cavernosum of streptozotocin-induced diabetic rats. Neuronal nitric oxide synthase (nNOS) immunostaining in (a) a control rat, (b) a 4-week diabetic rat (note the varicosity formation and breakage in the nerve fibres), (c) an 8-week diabetic rat (note that the nitrergic nerves have become very sparse), (d) an 8-week diabetic rat treated with the NOS inhibitor NG-nitro-l-arginine methyl ester (L-NAME) (note that the structure and number of nitrergic nerve fibres are preserved during diabetes) and (e) a rat treated with L-NAME for 8 weeks (note that the structure and number of nerve fibres are not different from those in (a)). Bar, 33 m for (c), 43 m for others. The results are typical of those observed in 6–12 animals in each. From Cellek et al. (1999), with permission.
Figure 4. Nitrite concentration (determined by chemiluminescence) in synovial fluid (SF) and serum samples from patients with rheumatoid arthritis (RA) and osteoarthritis (OA), and in serum samples from controls matched for age and sex. From Farrell et al. (1992), with permission.
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 References
    Cellek S, Rodrigo J, Lobos E et al. (1999) Selective nitrergic neurodegeneration in diabetes mellitus – a nitric oxide-dependent phenomenon. British Journal of Pharmacology 128: 1804–1812.
    Farrell AJ, Blake D, Palmer RMJ and Moncada S (1992) Increased concentrations of nitrite in synovial fluid and serum samples suggest increased nitric oxide synthesis in rheumatic diseases. Annals of Rheumatic Diseases 51: 1219–1222.
    Furchgott RF and Zawadzki JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 333: 373–376.
    Petros A, Bennett D and Vallance P (1991) Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock. Lancet 338: 1557–1558.
    book Rees DD, Higgs EA and Moncada S (2000) "Nitric oxide and the vessel wall". In: Colman RW, Hirsh J, Marder VJ, Clowes AW and George NJ (eds) Hemostasis and Thrombosis: Basic Principles and Clinical Practice, 4th edn, pp. 673–682. Philadelphia: Lippincott-Raven.
 Further Reading
    Barnes PJ and Liew FY (1995) Nitric oxide and asthmatic inflammation. Immunology Today 16: 128–130.
    Brown GC and Cooper CE (1994) Nanomolar concentrations of nitric oxide reversibly inhibit synaptosomal respiration by competing with oxygen at cytochrome oxidase. FEBS Letters 356: 295–298.
    Burnett AL (1995) Nitric oxide control of lower genitourinary tract functions: a review. Urology 45: 1071–1083.
    proceedings Clementi E, Brown GC, Feelisch M and Moncada S (1998) Persistent inhibition of cell respiration by nitric oxide: crucial role of S-nitrosylation of mitochondrial complex I and protective action of glutathione. Proceedings of the National Academy of Sciences of the USA 95: 7631–7636.
    Cooke JP and Dzau VJ (1997) Nitric oxide synthase: role in the genesis of vascular disease. Annual Review of Medicine 48: 489–509.
    Garthwaite J (2000) The physiological roles of NO in the central nervous system. Handbook of Experimental Pharmacology 143: 259–275.
    Huang PL and Fishman MC (1996) Genetic analysis of nitric oxide synthase isoforms: targeted mutation in mice. Journal of Molecular Medicine 74: 415–421.
    Ignarro LJ, Ross G and Tillisch J (1991) Pharmacology of endothelium-derived nitric oxide and nitrovasodilators. Western Journal of Medicine 154: 51–62.
    McDonald LJ and Murad F (1996) Nitric oxide and cyclic GMP signalling. Proceedings of the Society for Experimental Biology and Medicine 211: 1–6.
    Mac Micking J, Xie Q and Nathan C (1997) Nitric oxide and macrophage function. Annual Review of Immunology 15: 323–350.
    book Moilanen E, Whittle BJR and Moncada S (1999) "Nitric oxide as a factor in inflammation". In: Gallin JI and Snyderman R (eds). Inflammation: Basic Principles and Clinical Correlates, pp. 787–800. Philadelphia: Lippincott Williams and Wilkins.
    Moncada S and Higgs EA (1995) Molecular mechanisms and therapeutic strategies related to nitric oxide. FASEB Journal 9: 1319–1330.
    Moncada S, Palmer RM and Higgs EA (1991) Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacological Reviews 43: 109–142.
    Nathan CF and Hibbs JB Jr (1991) Role of nitric oxide synthesis in macrophage antimicrobial activity. Current Opinion in Immunology 3: 65–70.
    Radomski MW, Zakar T and Salas E (1996) Nitric oxide in platelets. Methods in Enzymology 269: 88–107.
    book Sanders KM and Keef KD (2000) "The role of nitric oxide as a neurotransmitter in the gastrointestinal tract". In: Toda N, Moncada S, Furchgott R and Higgs EA (eds). Nitric Oxide and the Peripheral Nervous System, pp. 115–130. London: Portland Press.
    Stuehr DJ (1999) Mammalian nitric oxide synthases. Biochimica et Biophysica Acta 1411: 217–230.
    Toda N and Okamura T (1998) Cerebral vasodilators. Japanese Journal of Pharmacology 76: 349–367.
    Zamora R, Vodovotz Y and Billiar TR (2000) Inducible nitric oxide synthase and inflammatory diseases. Molecular Medicine 6: 347–373.
    Zhang J and Snyder SH (1995) Nitric oxide in the nervous system. Annual Review of Pharmacology and Toxicology 35: 213–233.
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Moncada, Salvador, and Higgs, Annie(Jan 2003) Nitric Oxide: Role in Human Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0003390]