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Nitric Oxide: A Physiologic Messenger

Charles J. Lowenstein, MD; Jay L. Dinerman, MD; and Solomon H. Snyder, MD
[+] Article and Author Information

From The Johns Hopkins University School of Medicine, Baltimore, Maryland. Requests for Reprints: Solomon H. Snyder, MD, Departments of Neuroscience, Pharmacology, and Molecular Sciences, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205. Grant Support: By the National Institutes of Health through grants PSA K1102451 (Dr. Lowenstein), MH18501, DA00266, and Research Scientist Award DA-00074; and a grant from the W.M. Keck Foundation (Dr. Snyder).

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1994;120(3):227-237. doi:10.7326/0003-4819-120-3-199402010-00009
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Purpose: To review the physiologic role of nitric oxide, an unusual messenger molecule that mediates blood vessel relaxation, neurotransmission, and pathogen suppression.

Data Sources: A MEDLINE search of articles published from 1987 to 1993 that addressed nitric oxide and the enzyme that synthesizes it, nitric oxide synthase.

Study Selection: Animal and human studies were selected from 3044 articles to analyze the clinical importance of nitric oxide. Descriptions of the structure and function of nitric oxide synthase were selected to show how nitric oxide acts as a biological messenger molecule.

Data Extraction: Biochemical and physiologic studies were analyzed if the same results were found by three or more independent observers.

Data Synthesis: Two major classes of nitric oxide synthase enzymes produce nitric oxide. The constitutive isoforms found in endothelial cells and neurons release small amounts of nitric oxide for brief periods to signal adjacent cells, whereas the inducible isoform found in macrophages releases large amounts of nitric oxide continuously to eliminate bacteria and parasites. By diffusing into adjacent cells and binding to enzymes that contain iron, nitric oxide plays many important physiologic roles. It regulates blood pressure, transmits signals between neurons, and suppresses pathogens. Excess amounts, however, can damage host cells, causing neurotoxicity during strokes and causing the hypotension associated with sepsis.

Conclusions: Nitric oxide is a simple molecule with many physiologic roles in the cardiovascular, neurologic, and immune systems. Although the general principles of nitric oxide synthesis are known, further research is necessary to determine what role it plays in causing disease.


nitric oxide


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Figure 1.
Diagrammatic representation of the structure of cloned forms of nitric oxide synthase with sites for cofactor binding.P

CAL = binding site for calmodulin; FMN = flavin mononucleotide; FAD = flavin adenine dinucleotide; NADPH = reduced form of nicotinamide adenine dinucleotide phosphate;  = site for phosphorylation by cyclic adenosine monophosphate-dependent protein kinase. The sites for heme, arginine, and tetrahydrobiopterin binding are unknown.

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Figure 2.
Nitric oxide arterial smooth muscle.

A messenger molecule such as acetylcholine binds to the acetylcholine receptor on an endothelial cell, activating inward calcium currents. Calcium binds to calmodulin and activates endothelial cell nitric oxide synthase, which converts arginine plus oxygen into citrulline and nitric oxide. Nitric oxide diffuses out of the endothelial cell into an adjacent smooth muscle cell and activates guanylate cyclase by binding to the iron in its heme group. The increase in cyclic guanosine monophosphate (cGMP) causes smooth muscle relaxation, and thus vasodilation. GTP = guanosine triphosphate.

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Figure 3.
Induction of nitric oxide synthase in macrophages.

Lipopolysaccharide (LPS) is released from the wall of infecting bacteria, causing host cells to release tumor necrosis factor-α (TNF-α). Tumor necrosis factor-α binds to macrophages and activates intracellular proteins such as nuclear factor-κ B (NF- κ B), which induce the transcription of nitric oxide synthase. Once synthesized, macrophage nitric oxide synthase continuously makes nitric oxide, which can kill bacteria. MAC-NOS = macrophage nitric oxide synthase.

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