NATRIC OXID

Why Nitric Oxide Won the Nobel Prize?

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Every year, the Nobel Prize is given out in 6 pre-defined categories:

  • Chemistry
  • Economic Sciences
  • Literature
  • Medicine or Physiology
  • Physics
  • Peace

For Medicine or Physiology this prestigious award is awarded after careful deliberation on the two basic criteria that have to be fulfilled before someone becomes eligible for a Nobel Prize nominee:

  • It has to be an original discovery
  • It has to benefit the humankind

The “original discovery” in this case was the fact that Nitric Oxide is naturally present in and produced by all mammalian species. This discovery was made in the 1986 by Dr. Lois J. Ignarro. Further studies led to the find that nitric oxide is indeed beneficial to the humankind. The molecule was found to be monumental in regulating and maintaining a healthy cardiovascular function, brain and cognitive function, joint function, erectile function, digestive function, exercise endurance and a lot more in the human body. This completed the second criterion of a Nobel Prize. The 1998 Nobel Prize in Medicine or Physiology was awarded to three independent pharmacologists for their work on Nitric Oxide.

This Nobel Prize was titled “Nitric Oxide as a Unique Signalling Molecule in the Cardiovascular System”. Today almost two decades later, nitric oxide is commonly recognized as a powerful, naturally-occurring signalling molecule present in every organ of the human body. This molecule is not limited to the cardiovascular system alone.

This website contains carefully selected authentic information on the fundamentals of Nitric Oxide that can help you learn about how this tiny molecule packs the ability to protect the human body against a number of disorders and diseases.

Check Out These Fascinating Links to Learn More About the Nobel Prize:

Nobel Prize website: www.nobelprize.org
Nobel Prize in Physiology or Medicine website: http://www.nobelprize.org/nobel_prizes/medicine/
1998 Nobel Prize for Nitric Oxide: http://www.nobelprize.org/nobel_prizes/medicine/laureates/1998/
Video of Dr. Lou and the other Laureates receiving the Nobel Prize:
http://www.nobelprize.org/nobel_prizes/medicine/laureates/1998/award-video.html

Who Needs Dietary Supplements for Nitric Oxide?

As established, nitric oxide (NO) is essential for healthy existence. Hence, the use of nitric oxide boosting dietary supplements is more or less necessary for everyone. We age through life. The process begins the minute you’re born. Newborn infants have the highest levels of nitric oxide, but as they grow these levels start depleting. The momentum gains speed as you age.
The rate at which these nitric oxide levels decline is usually determined by the lifestyle you lead. A healthy lifestyle, clean eating, regular physical activity works as insurance of sustaining healthy levels of nitric oxide. On the contrary, someone who lives a sedentary lifestyle and pays little attention to nutrition will end up depleting their nitric oxide levels at a pace faster than the others. It is therefore extremely important to live a healthy lifestyle and you need to start young for that.

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A healthy lifestyle needs to be supplemented by consuming the right form and amounts of food. These foods include colorful fruit and vegetables that are rich in antioxidants and protein. However, it is highly unlikely that the food we consume will provide us with all the essential nutrients required for the optimal functioning of the body. This is where nutritional supplements come in. Your routine diet may not be providing you with the right amounts of nitric oxide, which is why it is important to invest in supplements. These nutritional supplements include ones that contain antioxidants and specific amino acids.
The two specific amino acids that should be present in the nutritional supplements you consume include L-arginine and L-citrulline. These, as explained previously in other sections of this website, are the amino acids used by the human body to produce nitric oxide. The presence of antioxidants in the supplements you consume will ensure that the newly produced nitric oxide is properly protected against any form of oxidative damage.

Nitric oxide is an essential element of achieving optimal health. It is therefore prudent for everyone to consume nutritional supplements that boost NO production in the body every day for a lifetime. The health benefits of nitric oxide are countless. This is one reason why there are no age limitations on the use of such supplements. Still, since we tend to lose NO levels as we age, it is suggested that both men and women start taking nutritional supplements somewhere between the ages of 20 and 35 years. Remember: The younger you are, the better it is.

With that explained, it is imperative that we point out the fact that you’re never too late for making amends. Whether you’re 20 or 40 at this moment, taking the right step can actually help you enjoy the various health benefits that nitric oxide has to offer. For women especially, it is ideal to begin using nitric oxide boosting products several years before the anticipated menopausal period. The prime reason for this is the estrogen levels in women that sharply decline during and following the menopause.

Estrogen is a well known stimulant for the production of nitric oxide and before women enter their menopause phase, they produce more nitric oxide compared to men of similar age. This happens to be one of the major reasons behind the fact that women are less susceptible to cardiovascular diseases like heart attacks and strokes – it’s simply because their systems are protected by the high levels of nitric oxide.

However, once menopause begins a woman’s body undergoes major changes. The estrogen levels sharp decline sharply and eventually cause a corresponding decline in the amount of nitrogen oxide produced by the body. This increases their risk of getting a heart or stroke more than the risk faced by men of comparable age for the same. Most women hit their menopause between the ages of 40 and 55. Therefore, it is recommend that they start taking nitric oxide boosting nutritional supplements between the ages of 20 and 35 years and continue it on a daily basis for as long as they live.

The History: How Was Nitric Oxide Discovered

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Nitric oxide (NO) today is one of the most effective universal signalling molecules that occur naturally in mammalian species. Almost 3 decades ago when its presence was first discovered in mammalian cells, nobody knew anything about nitric oxide.
There wasn’t one rational scientist who could have considered the presence of a reactive, chemically unstable free radical gas in mammalian tissues – Why? Because of the chemistry of nitric oxide! Consider this: let’s suppose nitric oxide is an extremely lipophilic molecule which easily filters through all sorts of biologic membrane barriers.

Would anyone in this scenario spare a thought to the possibility that the same molecule can be accumulated in the cellular organelles just like other recognized signalling molecules? Obviously not! The natural characteristics of nitric oxide make it a reactive free radical that biologically has a limited half-life. Given that, it was nearly impossible to gauge the length of time nitric oxide could remain effectively active, if it was somehow actually stored in the human body.

These basic facts about nitric oxide were the reasons why a majority of the scientist community didn’t consider the possibility of nitric oxide functioning in mammals as a common and ubiquitous signaling molecule. It appears that this consideration didn’t occur to anyone until 1986 – this was when nitric oxide was found hidden in the arteries – as the endothelium-derived relaxing factor (EDRF), something that was long sought after by the scientist community.
By 1989, there was major headway made into the explication of the mechanism and biosynthesis of nitric oxide and the way it works. The groundbreaking discovery clarified that nitric oxide is indeed a signaling molecule enzymatically produced from L-arginine, which immediately stimulates cytosolic guanylate cyclase through heme-dependent mechanisms that raise cyclic GMP.
Cyclic GMP is the second emissary articulating nitric oxide’s vasorelaxant effect. Following this breakthrough of endogenous nitric oxide, Dr. Ignarro revisited the fundamental chemical properties of nitric oxide and separately addressed each reason scientists originally alleged to be behind the belief that nitric oxide could possibly not exist in mammals as a potent signaling molecule.

Nitric oxide is its original state is a gaseous molecule that is reasonably soluble in most water-based mediums, which makes nitric oxide a soluble molecule. Nitric oxide when subjected to biosynthesis, innately interacts with guanylate cyclase receptor owing to its lipophilic nature, which doesn’t pose an issue related to the organelle storage of the molecule. In fact, it is the lipophilic properties of nitric oxide that enable the molecule to easily diffuse through the cell membranes and arrive at the intracellular guanylate cyclase. One thing was established beyond doubt at this point – it is the lipophilic characteristics of nitric oxide that make it a powerful signaling molecule.
The next thing Dr. Ignarro addressed was nitric oxide’s short half-life. What he discovered was an intriguing fact related to the level of nitric oxide concentration. Dr. Ignarro found that biologically low concentrations (nM range) of nitric oxide react rather sluggishly with oxygen as compared to the rapid reaction of high concentrations (mM range) of nitric oxide when subjected to 2nd order kinetics. This gives the endogenous nitric oxide sufficient time to extract its physiological properties. Also, the stability of nitric oxide nM concentrations in the oxygenated watery medium facilitated the classification of EDRF as nitric oxide.
By now, we’re all aware of the fact that nitric oxide is a reactive free radical. The study on reactivity of nitric oxide with other genus revealed that nitric oxide particularly reacted with the heme prosthetic group found in cytosolic guanylate cyclase that causes a 400-fold activation of enzyme. Nitric oxide also chemically interacts with sulfur species found in catalytic locations (ornithine decarboxylase) and other locations of protein to physiologically mutate their function. The super-fast reaction between superoxide anion and nitric oxide is what helps terminate the natural action of nitric oxide.

It was therefore concluded that the fundamental chemical properties of nitric oxide are actually contributors to the substance’s efficient functioning as a signalling molecule.
Before 1986, there was absolutely no credible scientific discussion or published evidence backing the fact that nitric oxide could act as an endogenic molecule in mammals. That said, in 1976 Ferid Murad with his team successfully proved that commercially available or laboratory generated nitric oxide had the ability to trigger cytosolic guanylate cyclase activation and increase tissue levels in cyclic GMP. This was the first major discovery in the field of nitric oxide biological sciences.

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Following that, it was found that nitrovasodilators like nitroglycerin, nitroprusside, and other nitrite esters and organic nitrate could activate the production of tissue cyclic GMP. This was the report that sparked the interest of Dr. Ignarro and his team. Soon after, Dr. Ignarro reported that nitroglycerin – representative of all the nitrite esters and organic nitrate properties – serves as a vasodilator when it metabolizes into the vascular muscle cells to reach the nitric oxide.
In ascertaining how the process works, Dr. Ignarro discovered the role played by S-nitrosothiols and related species that are exceptional nitric oxide donor molecules. They then established the purpose of S-nitroso-N-acetylpenicillamine (SNAP). SNAP is a steady crystalline donor agent for nitric oxide. The chain of studies on niric oxide by then had already started. Next in line was an independent study by Dr. Ignarro in which they found that nitric oxide is a powerful inhibitor of platelet aggregation occurring in the human body. It worked by stimulating plate guanylate cyclase that eventually led to elevated platelet cyclic GMP.
By 1980, there was considerable breakthrough in the study of pharmacological properties of nitric oxide. The two most prominent properties established so far included the NO were nonvascular and vascular smooth muscle relaxation and the inhibition of human platelet aggregation. However, the scientific world wasn’t convinced with just that. What came next was Robert Furchgott’s provocative discovery that seemed unrelated but held importance nonetheless. Robert Furchgott and team uncovered that to relax the smooth muscle cells, acetylcholine needed arterial endothelial cells.

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Next came a series of classic pharmacological experiments. These were aimed at demonstrating how acetylcholine somehow works together with the vascular endothelium in order to produce a chemically unstable genus that eventually interacts with the surrounding smooth muscle cells to obtain relaxation. Unsure of what this specific relaxant genus was back then, the scientists agreeably named it the “endothelium-derived relaxing factor” (EDRF).

ERDF was the actual powerhouse that fueled the studies and researches on the subject that continued for the next 6 years. The world of science was determined to identify this mysterious relaxing factor. There were a series of reports that suggested an extensive range of possibilities – these ranged from amino acids, to peptides, potassium, and polyunsaturated fatty acids.

Dr. Ignarro took a different approach. He emphasized on systematically considering every possibility that the cyclic GMP could be concerned with. So far, none of the substances and molecules suggested by others as possible EDRF had the ability to increase the levels of arterial cyclic GMP. Dr. Ignarro’s lab used a sensitive radioimmunoassay to find that acetylcholine had the ability to elevate the levels of arterial smooth muscle cyclic GMP, but that was only possible in the presence of endothelium-dependent mechanisms. The question that now needed an answer was: does cyclic GMP actually cause the relaxation obtained by acetylcholine?

To find out if that really was the case, Dr. Ignarro’s team began studying the possibility that the activation of guanylate cyclise might actually be the reason behind acetylcholine led GMP production. They tested the impacts of methylene blue – a common cytosolic guanylate cyclise inhibitor. During the experiment, when acetylcholine was added to methylene blue, the inhibitor eliminated both the vascular relaxation and cyclic GMP accumulation.

These observations clearly proposed that acetylcholine educes endothelium-dependent relaxation through processes that involved guanylate cyclase activation and the resulting formation of cyclic GMP in the smooth muscle cells of human arteries. In the series of similar experiments that followed, the labs incubated the endothelium-intact arterial rings using a physiological solution in order to monitor the guanylate cyclase activity.

It was then discovered that adding acetylcholine triggered the visible guanylate cyclise activation. However, the same didn’t happen in the endothelium-denuded arterial ring arrangements. It was hence, obvious that guanylate cyclase cannot be activated directly by acetylcholine. Now the next question that had Dr. Ignarro and his team curious was: What is the missing link between the smooth muscle cells and endothelial cells that facilitated acetylcholine to trigger cyclic GMP and consequently cause the smooth muscles to relax?

Since Dr. Ignarro’s labs have been studying both nitric oxide and EDRF for years by then, they were familiar with the pharmacological and chemical properties of each. It was in a group meeting at the laboratory when it suddenly dawned on the team the nitric oxide and EDRF shared several identical properties.

This was the new lead they were looking for! Despite the chemical and physiological reasons that restricted the scientist community to consider the likelihood of the existence of nitric oxide in mammalian bodies, Dr. Ignarro decided to think differently for a change.
They next designed a series of biochemical, pharmacological, and chemical experiments to determine and quantify the presence of nitric oxide in mammals. It was in 1986 that the team was able to successfully demonstrate that nitric oxide is actually EDRF. It was the first ever demonstration of its kind.

The Basics of Nitric Oxide

Nitric Oxide or NO as it is scientifically known, is a naturally occurring signaling molecule found in the brains, arteries, and several other organs of the mammalian bodies. The natural composition of nitric oxide makes it an unstable gaseous molecule that barely lasts a second after being produced within the cells.
However, this duration still gives nitric oxide enough time to impart its miraculous effects inside the body. Nitric oxide originates from L-arginine – one of the 23 amino acids found in proteins. L-citrulline, another amino acid is first converted by the body into L-arginine, which then produces nitric oxide. Hence, both L-citrulline and L-arginine are natural sources of nitric oxide. Taking an optimum level of protein through proper diet and supplements will result in increased production of nitric oxide in the body.

Vasolidation was the first impact of nitric oxide on the body to be discovered. It established the solid grounds for the fact that nitric oxide improves the circulation of blood in the body by allowing it to smoothly flow through veins and arteries to reach the organs. Vasodilation is also effective in regulating normal blood pressure.
In addition to that, nitric oxide also has anti-inflammatory properties that prevent unnecessary blood clot formation in the arteries and reduces the risk of heart attack and stroke.
The health benefits of nitric oxide aren’t limited to the cardiovascular system. The molecule has proven essential for the well-being and development of the brain and cognitive function, improving the overall learning, recalling, and memory capacity.

Medical science has now established that reduced nitric oxide levels in the brain can lead to Dementia, as well as the Alzheimer’s disease. As mentioned earlier, nitric oxide helps maintain normal flow of blood to the brain and prevents the chances of blood clot formation that may possibly lead to strokes.
The interesting thing is that the brain produces more nitric oxide than any other body organ. This is a major reason why one cannot rule out the other unknown benefits of nitric oxide for the brain. The anti-inflammatory properties of nitric oxide also benefit the digestive system and joints function in our bodies. It prevents pain and excessive swelling in multiple body organs.

Nitric oxide maintains the normal flow of blood in the skin and protects it against the UV radiation of the sun. When the skin is exposed to sunlight, the body produces more nitric oxide. This leads to melanin pigment dispersion (skin darkening) and acts as a shield against the dangerous effects of UV light.
Nitric oxide has also been found to be the chief moderator of the erectile function in both men and women. Sexual arousal in healthy, normal individuals stimulates the production of nitric oxide which consequently triggers the erectile function. Drugs like Viagra and others treat erectile dysfunction in men by recovering the nitric oxide action to improve the flow of blood to the erectile tissue.

As obvious by now, nitric oxide is no ordinary signaling molecule. It is essential for the optimal functioning of the human body and its organs. But that’s not all – nitric oxide is called the “magic anti-aging molecule”. Aging causes the nitric oxide levels in our bodies to decline sharply. A developing fetus has the highest amount of nitric oxide in it. The level remains high for around 10 to 15 years of a child’s life – after that, it starts to drop.
Aging and the decline in nitric oxide levels combined become the leading cause of several diseases and disorders. These risks further increase if an individual lives an unhealthy lifestyle – lack of physical activity and poor nutrition.

References

  • Nutrition and Cardiovascular Disease: Putting a Pathogenic Framework Into Focus (Napoli C, Stanley WC, Ignarro LJ.) Cardiovasc Res. 2007 Jan 15; 73(2):253-6.
  • Nitric Oxide and Pathogenic Mechanisms Involved In the Development of Vascular Diseases (Napoli C, Ignarro LJ.) Arch Pharm Res. 2009 Aug; 32(8):1103-8.
  • Novel Features of Nitric Oxide, Endothelial Nitric Oxide Synthase, and Atherosclerosis (Ignarro LJ, Napoli C.) Curr Diab Rep. 2005 Feb; 5(1):17-23.
  • Long-Term Combined Beneficial Effects of Physical Training And Metabolic Treatment On Atherosclerosis In Hypercholesterolemic Mice (Napoli C, Williams-Ignarro S, De Nigris F, Lerman LO, Rossi L, Guarino C, Mansueto G, Di Tuoro F, Pignalosa O,De Rosa G, Sica V, Ignarro LJ.) Proc Natl Acad Sci USA. 2004 Jun 8; 101(23):8797-802.
  • W. Effect of Oral L-Arginine Supplementation on Blood Pressure: A Meta-Analysis Of Randomized, Double-Blind, Placebo-Controlled Trials (Dong JY, Qin LQ, Zhang Z, Zhao Y, Wang J, Arigoni F, Zhang) Am Heart J. 2011 Dec; 162(6):959-65.
  • Nitric Oxide: Biology and Pathobiology. 2nd Edition (Louis J. Ignarro, Editor. Elsevier, Inc.,) Copyright 2010. 26 Chapters; 845 pages.
    Nitric Oxide as a Mediator of Relaxation of the Corpus Cavernosum in Response to Nonadrenergic, Noncholinergic Neurotransmission (Rajfer J, Aronson WJ, Bush PA, Dorey FJ, Ignarro LJ.) N Engl J Med. 1992 Jan 9; 326(2):90-4.
  • Protective Effects of Physical Exercise in Alzheimer’s Disease and Parkinson’s Disease: A Narrative Review (Paillard T, Rolland Y, de Souto Barreto P.) J Clin Neurol. 2015 Jul; 11(3):212-9.
  • Nitric Oxide Signaling Is Recruited As A Compensatory Mechanism For Sustaining Synaptic Plasticity In Alzheimer’s Disease Mice (Chakroborty S, Kim J, Schneider C, West AR, Stutzmann GE.) J Neurosci. 2015 Apr 29; 35(17):6893-902.
  • S-Nitrosylation In Neurogenesis And Neuronal Development (Okamoto S, Lipton SA.) Biochim Biophys Acta.2015 Aug; 1850(8):1588-93.

Nitric Oxide for Health Management and Disease Prevention

Nitric oxide is a potent signaling molecule, widespread in the body. This naturally occurring molecule has some vital functions that it performs in the body. These include:

Vasodilation – it maintains optimal blood pressure and promotes blood flow to the organs.

  • It stops the unwanted clotting of blood that may lead to an obstruction in the blood flow.
  • It prevents inflammation in the arteries and regulates healthy arterial lining by reducing the cholesterol plaque buildup.
  • It improves the memory, learning, and recalling functions of the brain
    It promotes healthy functioning of the digestive process through optimal movement of the digested foods and regulated discharge of digestive enzymes and hormones
  • It supports the bladder function by enabling the expansion of the bladder for increased urine holding capacity.
  • It regulates healthy sexual arousal and erectile function in both men and women
  • It shields the skin from the ionizing radiation of the sun.

In addition to all this, nitric oxide together with hormones and other molecules in the body ensure the normal functioning of the body.

There are a number of diseases and disorders that are linked with the decline in the levels of nitric oxide that occurs consequential to the aging process. There are cases which explicitly link the condition directly to the fall in nitric oxide levels; others are being researched by the medical world. An individual’s lifestyle has been declared the leading determinant of the nitric oxide levels in their bodies. Many unhealthy lifestyle habits adversely impact the body’s nitric oxide levels and put the individual at a risk of:

  • High blood pressure and/or hypertension
  • Stroke
  • Heart attack or myocardial infarction
  • Dementia, including Alzheimer’s
  • Irritable bowel syndrome and other digestive tract disorders
  • Urinary incontinence (more likely affect elderly women)
  • Sexual arousal disorders such as erectile dysfunction in both men and women

An individual is at greater risk of contracting other diseases and disorders as well. For example, poor nutrition and eating habits lead to obesity. This in the long-run will contribute to the decline in the level of nitric oxide and will expose the individual to the risk of getting type-2 diabetes, heart attack, and/or stroke. As mentioned earlier, it is also believed that this decrease in the production of nitric oxide will lead to an increased risk of erectile dysfunction, dementia, and other disorders.

In contrast to that, someone who works regular exercise and physical activity into their routine is likely to have both chronic and acute increases in the nitric oxide levels in their body.

Here’s how it works: When you indulge in exercise of physical activity, your heart pumps blood at an increase rate and quantity through your arteries. This increased flow and force of blood stimulates the endothelial cells found in the inner arterial layer to generate more nitric oxide.

Since nitric oxide is a vasodilator, it will immensely improve the flow of blood to the exercising muscles – delivering more nutrients and oxygen to the muscle cells from the blood. Nitric oxide levels increase every time your heart rate increases by minimum 20 heartbeats per minute.

There is no need to cycle uphill or run a marathon to achieve increase nitric oxide production. A simple brisk walk, slow jog, playing tennis, climbing stairs, or swimming will suffice. The nitric oxide your body uses to level up your exercise performance happens to be the same nitric oxide that imparts immeasurable health benefits to you over time.
Hence, the key to healthy living and maintaining optimal nitric oxide levels in the body is to exercise regularly for a lifetime!