Nitric Oxide Synthesis: An Overview

// Corey Schuler, MS, DC, LN, CNS


Endothelium-derived relaxing factor (EDRF) was discovered in 1980 by Furchgott and Zawadzki.1 In 1987, it was determined that EDRF was actually nitric oxide (NO).2 Further clarification found that NO was the primary EDRF but other molecules play a role as well.3 NO is an inorganic molecule that naturally occurs in mammalian biology and has been widely studied for health effects in the body.4 NO bioactivity may support coronary artery dilation and may support normal endothelial repair.5 Excess NO may result in free radical production.6 Optimal levels of NO supports healthy endothelial cells and vessel health.7

NO is synthesized by the enzyme NOS which has three major isoforms: neuronal (nNOS), inducible (iNOS), and endothelial (eNOS). nNOS is expressed in neurons and regulates the release of catecholamines in the heart. iNOS is found primarily in macrophages and participates in the early immune defense response. Platelets express the endothelial form of the nitric oxide synthase (eNOS) and generate NO. eNOS also promotes diastolic relaxation and decreases oxygen consumption in cardiac muscle through paracrinally produced NO. All forms of NOSs produce NO from L-arginine.8 The below figure shows a general overview of NOS.9

Diagram of NO Synthesis Process

In endothelial cells, eNOS catalyzes the oxidation of L-arginine to NO and L-citrulline, with the assistance of tetrahydrobiopterin (BH4), oxygen, and NADPH cofactors.10 Increased intercellular Ca2+ in response to stressors displaces the inhibitor caveolin from calmodulin (CaM), activating eNOS. NO diffuses to vascular smooth muscle and causes relaxation by activating guanylate cyclase (GC), thereby increasing intracellular cyclic guanosine monophosphate (cGMP). The graphic below shows how this comes together.11

Process of increasing intracellular cyclic guanosine monophosphate (cGMP)

As understanding of NO continues, contributors to its production, function, and metabolism also improves. We are now almost 35 years out from the discovery of EDRF and new information about medications that attenuate or stimulate NO production, foods that interfere or contribute to its function, and how certain lifestyle behaviors influence metabolism of NO continue to be published.

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2. Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9265-9.
3. Fleming I, Busse R. J Mol Cell Cardiol. 1999 Jan;31(1):5-14.
4. Ziolo MT, Katoh H, Bers DM. Am J Physiol Heart Circ Physiol. 2001 Dec;281(6):H2295-303.
5. Cannon RO 3rd. Clin Chem. 1998 Aug;44(8 Pt 2):1809-19.
6. Brady AJ, Poole-Wilson PA. Br Heart J. Aug 1993;70(2):103-105.
7. Massion PB, Feron O, Dessy C, Balligand JL. Circ Res. 2003 Sep 5;93(5):38-98.
8. Balligand JL, Cannon PJ. Arterioscler Throb Vasc Biol. 1997 Oct;17(10):1846-58.
9. Leiper J, Nandi M. Nat Rev Drug Discov. 2011 Apr;10(4):277-91.
10. Stuehr, DJ.  J Nutr. 2004 Oct;134(10):2748S-2751S.
11. Behrendt D, Ganz P. Am J Cardiol. 2002 Nov 21;90(10C):40L-48L.


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