Nitric Oxide

Dr Thanh-Tam Pham - 7/3/2021


Dr Louis Ignarro was awarded a Nobel prize in 1998 for the discovery of Nitric oxide and cardiovascular health.

Nitric oxide NO has a very short half life and is identified to be an endothelial derived relaxing factor modulating the vascular tone of blood vessels and blood pressure. Apart from vasodilation it has other powerful antioxidant, anti-inflammatory, anti-thrombotic and anti-atherogenic actions.

NO is produced naturally in the body and its most important function is vasodilation to increase circulation. It is essential for overall health because it allows blood, nutrients and oxygen to travel to every part of the body effectively and efficiently.

Nitric oxide production is decreasing with aging.

Nitric oxide deficient states are associated with cell senescence, oxidative stress, inflammation, endothelial dysfunction, vascular disease, insulin resistance and type 2 diabetes.

1-   Vegetables high in Nitrates: celery, lettuce, beetroots, spinach…

Diet is a safe and inexpensive mode of increasing NO bioavailability. Nitrates from vegetables are harmless whereas nitrates in processed meat could be carcinogenic when consumed in excess over a long period of time.

2-   Increase intake of anti-oxidant: vitamin C, Vitamin E, red wine polyphenols resveratrol, quercetin, dark chocolate…

NO is an unstable molecule that degrades quickly in the bloodstream so it must be constantly replenished. One way to increase its stability and limit its breakdown by free radicals is by consuming anti-oxidants.

3-   Limit use of mouth wash.

Mouth wash kills microbiome in the back of the tongue that convert nitrates to Nitric oxide. In fact, humans cannot produce NO from nitrates without these bacteria.

4-   Breathing through the nose increases Nitric oxide comparing to breathing through the mouth.


5-   NO boosting supplements

-      L- Arginine: however evidence to increase blood flow remains mixed

-      L- Citrulline: studies showed it increases blood flow, improves exercise performance and lower blood pressure.


6-   Exercise:

Since skeletal muscle is the most abundant tissue in the body, exercise training augments endothelial and skeletal Nitric oxide synthase activation matching the energy supply with increased demand. Exercise increases blood flow and improves endothelial cell production of NO. Exercise attenuates norepinephrine mediated abnormal coronary vasoconstriction even in coronary heart disease patients and raises para-sympathetic input to the heart. Exercise mediated increases in NO also enhance telomeric integrity and mitochondrial efficiency reducing oxidative stress and pro-inflammatory signalling. Exercise effects are greatest in the vascular bed of the working muscles but due to the changes in heart rate, blood viscosity and flow, pulse pressure , the vascular stress enhances NO bioactivity systemically also in hypertensive, coronary heart disease and heart failure patients.

Intensity: moderate exercise enhances plasma nitrite/nitrate levels and endothelial function. Mild exercise has no impact. However strenuous exercise increases oxidative stress, undermining the benefits of exercise.

The benefits of exercise can be seen to reduce blood pressure at 10 weeks when exercising for 30min at least 3 times a week. With the longer term effects (weeks to years), there is Nitric oxide mediated vascular remodelling such as increases in blood vessel diameter.

Studies also showed exercise increases anti-oxidant activity which helps to inhibit the breakdown of NO caused by free radicals.

7-   Drugs to increase Nitric oxide:

Nitric oxide inhalation is used in limited applications such as in pulmonary hypertension in neonates. There are studies of NO inhalation to treat the severe Covid 19 cases with pulmonary problems.

Nitric oxide donor drugs including nitrates and nitroprusside are used for the stable delivery of NO in angina, heart failure, pulmonary hypertension, hypertension crisis. Their long term use has been limited by the development of nitrate tolerance and toxicity issues.

Drugs that increase NO bioavailability: ACE inhibitors, ARB, Beta Adrenergic blockers (third generation vasodilating Beta blockers such as nebivolol, carvedilol), PDE-5 inhibitors sildenafil, tadalafil, HMACoA reductase inhibitors statins.


Insulin Resistance

Deficiency in Nitric oxide is implicated in the pathogenesis of Insulin resistance

Both the insulin receptor and Nitric oxide synthase are expressed in the vascular endothelium where they regulate vascular tone as well as involved in metabolic processes in skeletal and cardiac muscles. In fact, the Insulin receptor and NOS are closely linked anatomically and functionally. In reciprocal fashion, insulin activates NOS while NO signalling enhances insulin sensitivity. Preservation of normal NO signalling correlates with Insulin mediated glucose homeostasis. In contrast, stress and inflammation are catabolic processes. Inflammation causes resistance to anabolic action of Insulin and also vascular dysfunction with impaired nutrient delivery. Endothelial dysfunction compromises insulin sensitivity and insulin resistance worsens endothelial function. Chronic stress and inflammation, aging can manifest in dysfunctional NO signalling and Insulin resistance in many tissues including the blood vessels, the myocardium and skeletal muscles. The vascular dysfunction and the metabolic disturbances will evolve over time into cardiometabolic disease.





-      Charaterisation of the role of NO and its clinical applications. Levine A,B et al- Cardiology 2012 Vol 122

-      Healthline- Gavin Van De Walle- MS,RD 26 April 2018

Dr Louis Ignarro ‘s interview  by Dhru Purohit.: The Miracle Molecule will supercharge your Health