The dual personality of NO

doi:10.1016/S0165-6147(00)01499-1

Trends in Pharmacological Sciences

Volume 21, Issue 7, 1 July 2000, Pages 249-252

https://doi.org/10.1016/S0165-6147(00)01499-1 Get rights and content

Abstract

In the body, nitric oxide (NO) is an important physiological regulator of functions such as vasodilatation and neurotransmission. Under pathological conditions, high concentrations of NO can either be beneficial (e.g. anti-bacterial, anti-parasitic and anti-viral) or detrimental; NO can therefore be considered a double-edged sword. When manipulating NO levels clinically, attention should be paid to minimize the negative effects and maximize the beneficial effects of NO. This article highlights recent evidence that supports the complexity of the regulatory mechanisms that lead to sophisticated endogenous NO production.

Section snippets

Paradoxical induction of iNOS expression

The above-mentioned findings, although intriguing, have created a puzzle that is difficult to solve: when physiological levels of NO are present in the body, the induction of iNOS expression is supposed to be a very rare phenomenon. Clearly, this is not the case.

This dilemma can be resolved assuming that, before or at the early phase of iNOS induction, NO levels decrease beneath the putative threshold value that maintains an inhibitory effect on iNOS activity. This decrease in the concentration

Inverse regulation of constitutive and inducible NOS isoforms

If a sharp decline in constitutively produced NO can, as it appears, be a key event in modulating the induction of iNOS expression, what can happen under circumstances in which constitutive NO levels are upregulated? Might moderately elevated constitutive NO levels (e.g. between normal and potentially harmful) be involved in those conditions in which the induction of iNOS expression does not occur easily? If so, might the same factors that upregulate constitutive NOS activity inhibit iNOS

Concluding remarks

In the early 1990s, a simple and general view for the biological role of NO was established: low levels of NO, as synthesized by constitutive NO synthase (nNOS or eNOS), are involved in physiological events, whereas high levels of NO, as produced by iNOS, have a role in pathological processes. Consistently, NO has been claimed to be a molecule with a dual distinct character (Jekyll and Hyde, or with a double-faced Janus). This simplified view faced a severe problem when NO (or more precisely

Acknowledgements

We give special thanks to A. Merante for skilful help in preparing the figures, and to L. Mattace for editorial assistance. The authors’ research is supported by research grants from the MURST and CNR (single project and Targeted Project on Biotechnology).

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Trends in Pharmacological Sciences

ViewpointThe dual personality of NO

Abstract

Section snippets

Paradoxical induction of iNOS expression

Inverse regulation of constitutive and inducible NOS isoforms

Concluding remarks

Acknowledgements

International Union of Pharmacology Nomenclature in nitric oxide research

Pharmacol. Rev.

Inducible nitric oxide synthase from a rat alveolar macrophage cell line is inhibited by nitric oxide

J. Immunol.

Inhibition by sodium nitroprusside of the expression of inducible nitric oxide synthase in rat neutrophils

Br. J. Pharmacol.

Induction of nitric oxide synthase mRNA expression. Suppression by exogenous nitric oxide

J. Biol. Chem.

Nitric oxide regulates nitric oxide synthase-2 gene expression by inhibiting NF-κB binding to DNA

Biochem. J.

Neuronal (type I) nitric oxide synthase regulates nuclear factor κB activity and immunologic (type II) nitric oxide synthase expression

Proc. Natl. Acad. Sci. U. S. A.

NO inhibits cytokine-induced iNOS expression and NF-κB activation by interfering with phosphorylation and degradation of IκB-α

Arterioscler. Thromb. Vasc. Biol.

Basal nitric oxide limits immune, nervous and cardiovascular excitationhuman endothelia express a mu opiate receptor

Prog. Neurobiol.

Induction and stabilization of IκBα by nitric oxide mediates inhibition of NF-κB

J. Biol. Chem.

Inhibition of NF-κB DNA binding by nitric oxide

Nucleic Acids Res.

Viewpoint
The dual personality of NO