Nitric oxide


NO More Heart Disease (National Best Seller 2005) Dr. Louis J. Ignarro


Book by Nobel prize winner (1998) extols the virtue of NO on cleaning plaques from blood vessels, improving circulation, and preventing heart disease.


“At extraordinarily high concentrations, NO is toxic. These levels however, cannot be reached through the body’s internal mechanisms for producing NO from either food and supplement intake or from exercise. At relatively low levels within the body- the kind that can be attained through foods, supplements, and exercise –NO can dramatically influence our health in positive ways.” P. 9


When the body is at rest, less NO is formed. P. 50

NO is not produced during sleep, so prior to going to sleep is a good time to take the supplement.


A combination of  an NO friendly diet, exercise, and the proper amino acids and antioxidants will provide cardiovascular health benefits, often in a little as two weeks. P. 69


L-arginine and L-citrulline, as well as other amino acids,  and vitamins C, E, folic acid, and alpha lipoic acid supplements are recommended. P 70f.


L-arginine supplement: 4-6 grams/day

L-citroline supplement: 200-1000 mg/day

Vitamin C supplement: 500 mg/day

Vitamin E supplement: 200 IU/day

Folic acid supplement: 400-800 mcg/day

Alpha lipoic acid supplement: 10 mg/day


p. 91-115



“NO is a potent antioxidant and also an anti-inflamatory. It can minimize oxidative stress” p. 195 


“Some research shows that as NO levels decline…. There is a marked acceleration of the formation of plaques associated with altzheimer’s disease. “ p. 202



Links on the topic:


The statements made in the book are supported from studies posted on the internet. But these studies also suggest that NO can be toxic to neurons, and that too much NO can be toxic to neurons. Dr. Ignarro states that toxic levels “cannot be reached through the body’s internal mechanisms for producing NO from either food and supplement intake or from exercise.” P. 9, referenced above.

The studies stating that NO can be toxic to neurons is assumed to mean that too much NO can be toxic to neurons.




Green text supports claims in the book

Red text contradicts claims in the book; says NO toxic

Magenta text finds that too much NO is extremely toxic


Nitric Oxide Inhibition Slows Alzheimer's Disease in Mice, Weill Cornell Team Reports (2005)


A toxic gas appears to speed neurological decline in mice bred to mimic Alzheimer's disease, and inhibiting the production of this gas -- called nitric oxide -- led to dramatic slowdowns in the rodents' disease-related brain damage, according to a new study by researchers at the Weill Medical College of Cornell University.


The "i" in iNOS (so named by Dr. Nathan after its discovery in 1992) stands for "inducible." "It's an enzyme that is induced into action to produce nitric oxide during infection, inflammation, or an immune response," Dr. Nathan said.

As such, iNOS has no place in the healthy brain, but scientists have long noticed high levels of the enzyme in the brains of Alzheimer's patients.

"It shouldn't be there -- it seems to be causing trouble without providing any benefit," Dr. Beal said.

He and Dr. Nathan suspected that an abnormal form of a protein called amyloid-beta -- a hallmark of Alzheimer's disease -- may serve as an irritant, "fooling" the body into thinking that an infection-like process is underway, and spurring iNOS to begin producing nitric oxide.

They also suspected that rising concentrations of nitric oxide in the brain accelerate Alzheimer's disease progression.



Nitric oxide pathways in Alzheimer's disease and other neurodegenerative dementias.


Abstract Nitric oxide (NO) is an enzymatic product of nitric oxide synthase (NOS). NO has significant physiological functions and an increasing body of evidence suggests that NO pathways are implicated in a number of neurological disorders, including Alzheimer's disease (AD) and other neurodegenerative dementias. NO is continuously released by endothelial cells in the vascular system, whereas advanced age in the presence of vascular risk factor causes a decrease in cerebral blood flow, involving microvasculopathy with impaired NO release, which in turn results in regional metabolic dysfunction. This finding suggests that vascular pathology plays a crucial role in the pathogenesis of so-called neurodegenerative dementias. Inflammatory responses are commonly found in the brain under a variety of neurodegenerative dementias, including AD and dementia with Lewy bodies, in which up-regulation of NOS expression, suggesting overproduction of NO, is found in neurons and glia. NO is thought to be involved in such neuroinflammation due to its free radical properties, which compromise cellular integrity and viability via mitochondrial damage. Further studies to elucidate NO pathways in neurodegenerative dementias could lead to a better understanding of their pathogenesis and improved therapeutic strategies, and therefore are certainly warranted.

(The statements in green and red appear to contradict one another)

Alzheimer's Plaques Lead to Loss of Nitric Oxide in Brain (Jan 2011)


Levels of nitric oxide (NO) -- a signaling molecule that helps regulate blood flow, immune and neurological processes -- are known to be low in the brains of people who have Alzheimer's disease, but the reason for that hasn't been clear, said study co-author Jeffrey S. Isenberg, M.D., M.P.H., associate professor, Division of Pulmonary, Allergy, and Critical Care Medicine, Pitt School of Medicine.

"’There is evidence that suggests enhancing NO levels can protect neurons from degenerating and dying.’"


Photomodulation, Nitric Oxide, and Alzheimer’s Disease

Clarimedix, a company out of Boulder, Colorado has taken an alternative approach to the traditional “plaques and tangles” theory and is focusing on the effect of light as a biomodulator and the idea that this cognitive syndrome may be the result of problems with perfusion to the brain.
The idea is that a light, emitted from a patch placed on the skin over the carotid artery, helps to modulate the release of nitric oxide, which is capable of increasing blood flow, reducing inflammation and triggering gene expression changes in the brain. This type of treatment would have many advantages over typical pharmacotherapy, especially the non-invasive, locally-delivered nature of the device.


Nitric Oxide Can Alter Brain Function

"Nitric oxide is a chemical messenger which cannot be stored and can rapidly diffuse across cell membranes to act at remote sites (in contrast to conventional neurotransmitters which cannot pass across cell membranes).

"It is broadly localized in the central nervous system, where it influences synaptic transmission and contributes to learning and memory mechanisms. However, because it is normally released in such minute quantities and is so labile, it is very difficult to study.

"We show that NO is made in response to incoming synaptic activity (activity generated by sound received by the ear) and that it acts to suppress a key potassium ion-channel (Kv3). Normally these ion-channels keep electrical potentials very short-lived, but nitric oxide shifts their activity, slowing the electrical potentials and reducing information passage along the pathway, acting as a form of gain control.

"Surprisingly, the whole population of neurons were affected, even those neurons which had no active synaptic inputs, so indicating that nitric oxide is a 'volume transmitter' passing information between cells without the need for a synapse. Such a function is ideal for tuning neuronal populations to global activity. On the other hand, too much nitric oxide is extremely toxic and will cause death of nerve cells; so within the kernel of this important signaling mechanism are the potential seeds for neurodegeneration, which if left unchecked contribute to the pathologies of stroke and dementias."


Nitric Oxide and Related Substances as Neural Messengers


While NO mediates normal synaptic transmission, excess levels of NO may be neurotoxic.


Blood vessel/nitric oxide health may affect Alzheimer's risk

Researchers at the Mayo Clinic have published an intriguing paper explaining why exercise may help reduce the risk of Alzheimer's disease. For years, exercise has been linked to reduced risk of heart disease and reduced dementia risk.

The study focused on the layer of cells, known as the endothelium, that line the inside of blood vessels. In that lining nitric oxide is produced. Nitric oxide is a crucial chemical that long has been associated with the ability of blood vessels to widen as well as reduced risk of cardiovascular disease. But it appears to have another function, according to the paper, which was published in Circulation Research, a journal of the American Heart Association.

Using endothelial cells from tiny blood vessels from the human brain, the researchers chemically inhibited the production of an enzyme needed to produce nitric oxide. That caused a biochemical reaction that led to an increase in levels of amyloid precursor protein (APP), the basic substance involved in the formation of amyloid plaques that build up around brain cells and are the hallmark of Alzheimer's disease. The reaction also increased production of another enzyme needed to transform APP into the plaques.

The reseachers also looked at mice that had been genetically engineered to lack the enzyme involved nitric oxide production. Those mice had naturally higher blood pressure, more insulin resistance as well as higher levels of APP.

"There is a lot of literature showing that every time you exercise, you stimulate the endothelium to produce more nitric oxide," senior author Zvonimir Katusic, a professor of anesthesiology and pharmacology at the Mayo Clinic, said in a statement. "What we have identified in this paper may help explain the reported cognitive benefit of exercise."