Cellular Signaling
with Nitric Oxide (NO)


Nitric Oxide (NO) is synthesized endogenously and plays a central role in cell-to-cell signaling.

NO is synthesized from L-arginine by the action of nitric oxide synthases (NOS) in a two-step oxidation process, with a half-life of a mere 5 seconds.

NO has the ability to cross cellular membranes under a very fast diffusion rate, and functions as one of the most primary components of human health.

The main issue related to the utilization of NO donors in humans is based on the fact that most investigators could not envision how a molecule as toxic as NO could function in a biological setting. NO functions as both a toxic and non-toxic agent, depending on its biosynthesis.

NO acts as a highly reactive, diffusible, and unstable radical under certain circumstances. Thus, researchers have sought stable NO donors with potential therapeutic value.

A stable NO donor must be capable of controlling the amount and rate of NO release in the human body in order to avoid potential toxic side-effects. The by-products of a programmed NO-reaction must possess minimal side-effects, or it cannot be used without danger of negative reactions.

The NO-delivery-dose must be sufficient to induce health benefits without triggering negative physiological effects. This elemental dose ranges from 3 grams to 20 grams per day of a NO-donor. Said doses are appropriate in cases of impotence and fertility.

A targeted-release of NO by a NO-donor requires a Low Glycemic delivery system that contains a Blind Amino Acid® Rider (BAAR).

The most stable non-drug NO-donor is FF L-Arginine bound to a BAAR, which is the substrate for nitric oxide synthase. This form of L-Arginine reverses the inhibition of nitric oxide synthase caused by arginine analogs, and is proven safe in humans long-term in doses of 3g - 20g daily.



 
Nitric Oxide (NO)
and its relation to:
• Insulin Resistance
• Metabolic Syndrome
• C-Reactive Protein
• Cardiovascular Risk



NITRIC OXIDE (NO) plays a significant role in reducing inflammation and platelet aggregation. When the endothelium is healthy, Nitric Oxide (NO) controls vascular tone (particularly vascular dilation), and protects the endothelium from damage due to increased pressure or flow.[1]

Two of the primary health issues on the rise globally, metabolic syndrome and insulin resistance, are related to NO. Increased C-reactive protein (CRP) levels seen in insulin resistance correlate with decreased NO levels.

CRP levels are shown to increase with each additional component of metabolic syndrome, and recent reviews have shown that elevated CRP levels correlate with increased cardiovascular risk.[2,3]

CRP is a recognized marker of vascular health and inflammation, and there is evidence that CRP is also an important inflammatory agent.[4]

1.
Nesto R. C reactive protein, its role in inflammation, type 2 diabetes and cardiovascular disease, and the effects of insulin-sensitizing treatment with thiazolidinediones. Diabetes Med. 2004;21:810-817.
2.
Festa A, D'Agostino R, Howard G et al. Chronic subclinical inflammation as part of the insulin resistance syndrome. The Insulin Resistance Atherosclerosis Study. Circulation. 2000;102:42-47.
3.
Ridker PM, Rifai N, Rose L, et al. Comparison of C reactive protein and low density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347:1557-1565.
4.
Nissen SE, Murat Tuzcu E, Schoenhagen P, et al, for the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) Investigators. Statin therapy, LDL cholesterol, C-reactive protein and coronary artery disease. N Engl J Med. 2005;352:29-38.

 




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Understanding Nitric Oxide
Physiology in the Heart:
A Nanomedical Approach


American J Cardiology
2005 Oct 10;96(7B):13i-24i.
Epub 2005 Aug 8.


Malinski T
Department of Biochemistry, Ohio University, Athens, Ohio 45710, USA. malinski@ohio.edu

Nitric oxide (NO) is a ubiquitous signaling molecule synthesized from L-arginine and oxygen.

The process is catalyzed by NO synthase (NOS), an enzyme expressed in both constitutive (endothelial, neuronal) and inducible forms.

Uncoupling of constitutive NOS leads to overproduction of superoxide (O2-) and peroxynitrite (ONOO-), 2 potent oxidants.

Nanosensing techniques have been developed to monitor the physiology of NO in the beating heart in vivo.

These methods involve the application of nanosensors to monitor real-time dynamics of NO production in the heart as well as the dynamics of oxidative species (oxidative stress) produced in the failing heart.

Results of a recent study using nanotechnology demonstrated that African Americans have an inherent imbalance of NO, O2-, and ONOO- production in the endothelium.

The overproduction of O2- and ONOO- triggers the release of aggressive radicals and damages cardiac muscle (necrosis), which may explain why African Americans are at greater risk for developing cardiovascular diseases, such as hypertension and heart failure, and are more likely to have complications than European Americans.

Potential therapeutic strategies to prevent or ameliorate damage to the heart during cardiac events are prevention of O2- and ONOO- production, supplementation of NO (NO donors), and scavenging of O2- (antioxidants).






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