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Monroe Community College
Rochester, New York


CME FOR THE PRACTICING PARAMEDIC

Nitric Oxide
It Just Won't Go Away, What Is It?

Bob Breese, EMT-P
 

Since its publicized "discovery" in 1987, Nitric Oxide (NO) has become the focus of major research in control of many cellular functions, including circulation of the blood, regulating activities in the brain, lungs, liver, kidneys, stomach, gut, genitals and other organs.  This research has spawned over 3000 scientific papers dedicated to NO and has even given rise the NO society, with such watch phrases as Just Say NO! It was even voted the "Molecule of the Year" in 1992.

Nitric Oxide is considered a free-radical-- a group of chemicals that when bonded, do not share two electrons, rather they have one free electron.  This makes free-radicals very reactive as the compounds seek another electron to complete the bond.  Oxygen is a common reactant in free-radical processes, having a propensity to take part in single-electron transfer or free radical addition reactions in which electrons become paired.  NO, a common gaseous chemical, is now recognized to play a vital role in vascular and neuronal physiology.

Nitric Oxide was first 'discovered' when Furchgott and Zawadski showed that vessels that had been stripped of their endothelial layers could not relax after stimulation.  This led them to conclude that there must be a factor that is released from endothelial cells that causes smooth muscle relaxation.  Curiosity caused researchers to look to the many known amines, peptides and lipids for this allusive Endothelial-derived Relaxing Factor (EDRF).  In 1987, Salvador Moncada published a paper stating that NO is produced to control the relaxation of muscles of blood vessels.  Previously, NO was regarded as an environmental pollutant, at best a nuisance, at worst a poison

Nitric Oxide is produced in endothelial cells from L-arginine, an amino acid.  When blood vessels contract, they do so because of an increase in intracellular Ca++  This increased calcium activates an enzyme called NO synthase (NOS) which cause the release of NO.  NO rapidly diffuses into vascular smooth muscle where it activates guanylate cyclase.  This, in turn, reduces intracellular Ca++ levels.  So in essence, increased intracellular calcium causes vessels to constrict, which causes increased shear stress (stretch) leading to the release of NO, which causes vessels to relax in a classic autocrine or paracrine function. This is thought to be the mechanism for flow-induced vasodilitation.   Figure 1 shows this pathway.  Medications such as nitroglycerin and sodium nitroprusside directly dilate vascular smooth muscle by nitric oxide induces activation of guanylate cyclase.  NO also has been shown to inhibit adhesion and aggregation of platelets and leukocytes in the vessel lumen by the production of NO-hemoglobin or methemoglobin.   The stimulatory effect of NO on guanylate cyclase is inhibited by hemoglobin and by methylene blue.
 

Vasodilators Vasoconstrictors
Nitric Oxide(EDRF) 
Endothelial-derived hyper-polarization factor (EDHF) 
Atrial Natiuretic Peptide (ANP) 
L-arginine (precursor of NO) 
Adenosine (ADO) 
Serotonin (5-HT)[stimulates NO release] 
 
Angiotensin II 
Endothelin 
Thromboxanes 
Endothelial-derived contracting factor (EDCF) 
Norepinephrine(NE) 
Serotonin(5-HT)[during platelet aggregation] 
 
 Table 1 Substances which constrict or dilate vessels
 

In the central nervous system, NO is a neuronal mediator that may be involved in neurotransmitter release and even memory function.  Synthesis of NO in the CNS is carried out by the same mediator as in the endothelium, NO synthase (NOS).  NO formation in the CNS appears to be triggered by stimulation of Glutamate receptors and influx of Ca++. Glutamate is an excitatory amino acid and has been implicated in cerebral ischemia and tissue necrosis during stroke.  It appears that the prolonged stimulation of the Glutamate receptor may cause the accumulation of NO in toxic levels with subsequent cellular damage.  Thus, NO has both a beneficial (protecting, enhancing and mediating the activity of neurons) and toxic (indiscriminately destroying neurons) effects in the brain.

In the peripheral nervous system, NO functions as a transmitter.  It can be found in the so-called nitrogenic neurons -- where it is involved with peristalsis and sexual excitation/vasocongestion. This is thought to be as a result of its role in regulation of potassium channels.   NO may also play a role in regulation of insulin release from pancreatic beta cells and has also been implicated as the destruction of these same beta cells at the onset of Type I diabetes.

NO plays an important role in immune defense.  Activation of the immune system results in the stimulation of large amounts of NO to be produced by macrophages.  When a macrophage encounters a pathogen, it surrounds it and encapsulates it using the process of endocytosis.  The pathogen, now inside a vacuole, is showered with NO.  The NO causes massive oxidative damage through the production of oxygen, copper, iron, and hyrdroxyl radicals.  These reactions may escalate until extremely high levels of NO derivatives, such as nitrogen dioxide and peroxynitrites, cause severe oxidative damage to cellular membranes, hypotension, and shock.

Study of this simple, yet complex chemical will continue into the next millennium.  As further research adds to our understanding of the molecular nature of both physiology and pathophysiology, it will remain crucial to keep abreast of developments that will effect how we practice, as well as unlock new medications for the treatment or prevention of disease.
 

Resources:

1.  Free Radicals:  Nature's way of saying NO or Molecular murder, 1995 Gray laboratories reviews
2.  "Endothelial Derived Relaxant Factor": NITRIC OXIDE, 1997, University of Michigan, Department of Anesthesia Web Project
3.  Egashira, et al., Basal Release of Endothelium-Derived Nitric Oxide at site of Spasm in Patients with Variant Angina., J Am Coll Cardiol 1996;27:1444-9
4.  Katayama, Yoshiki: Nitric Oxide: Mysterious Messenger, 1995, Dojundo Newsletter No 1.
5.  Hoogerwerf, N: Responses of Peripheral Arteries to Physical Stimuli and the Role of the Endothelium (summary of thesis, defended 17-12-93 at the Free University, Amsterdam, The NETHERLANDS)
6.  Goodman and Gilman: Pharmacological Basis of Therapeutics, 6th Ed,  1980 Macmillan
7.  Singh, et al:  Cardiovascular Pharmacology and Therapeutics, 1st Ed, 1995, Churchill-Livingstone
8.  Haber, E: Molecular Cardiovascular Medicine, 1995, Scientific American
 

 


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Updated: Sept. 15, 1999
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