Nitric oxide (NO) is the master molecule and optimizer of blood flow to the whole body and our brain too! The main function of this amazing little molecule is to dilate blood vessels, improve blood flow everywhere, stimulate formation of new blood vessels for tissue repair and wound healing, and to regulate platelet aggregation and reduce the risk of blood clots.
Nitric oxide is truly nature’s super optimizer of health! Most people don’t realize the role that hormone and dietary imbalances and stress play to decrease nitric oxide production and impair health! I first wrote about this molecule and its role in women’s health in my 1994 book, Screaming to Be Heard: Hormone Connections Women Suspect and Doctor’s Ignore (2001 edition available on Amazon). The unknown molecule at the time was called endothelium-derived releasing factor or EDRF. Then in 1998, three scientists discovered the EDRF molecule to actually be nitric oxide, which led to their receiving a Nobel Prize.
The simple but powerful molecule we now know as Nitric oxide (nitrogen monoxide, NO) is composed of one nitrogen atom and one oxygen atom. At room temperature, it is an odorless and colorless gas. It used to be thought of as simply the “foundation of heart health” until we realized it’s “master” effects on blood vessels throughout the brain and body as a vasodilator controlling blood flow to help support healthy blood flow pressure and endothelium health (the inner lining of blood vessels).
NO is synthesized in the body through a process of converting L-arginine (a “semi-essential” amino acid) into nitric oxide and citrulline. Once synthesized, NO is released to diffuse freely across cell membranes to exert its effects. In this health tip, we will explore nitric oxide’s functions, its wide range of health benefits and what you need to know before you choose a NO supplement.
SUMMARY OF KEY FUNCTIONS OF NITRIC OXIDE:
- Vasodilation – relaxing and widening of blood vessels to help blood flow, to better deliver oxygen and nutrients to muscles and organs, and regulating blood pressure. NO causes vasodilation by inhibiting smooth muscle contraction. Increased blood flow results in increased nutrient uptake and glucose utilization in muscle, especially during exercise.
- Angiogenesis – the formation of new blood vessels important for tissue repair and wound healing.
- Platelet function – Helps to regulate platelet aggregation to prevent blood clots and maintain heart health.
- Relaxation of smooth muscle in gastrointestinal tract, airways, urinary bladder, uterus, etc.…) to regulate the processes of digestion, breathing, urination, menstruation and pregnancy, for example.
- Immune response – Helps to regulate inflammation and can also be made by the immune cells to kill bacteria, viruses and parasites.
- Neurotransmission – Serves as a signaling molecule for the nervous system.
- Mitochondrial regulation – Modulates mitochondrial respiration and energy production in cells by acting as a molecular switch that activates PGC-1α, the master regulator of mitochondrial biogenesis and energy metabolism.
- Gene expression regulation – NO acts as a signaling molecule within cells to regulate gene expression and other cellular processes including cell proliferation (cell growth and division), differentiation (cell specialization), and apoptosis (programmed cell death).
IMPRESSIVE HEALTH BENEFITS OF NITRIC OXIDE:
Male Hormones and Erectile Dysfunction
- Testosterone – Nitric oxide (NO) and testosterone have a complex, bidirectional relationship: Testosterone can positively regulate NO production, while NO can also influence testosterone secretion. Each one influences the other’s levels and effects, particularly in the context of sexual health and endothelial function.
- Erectile Dysfunction – NO is a key mediator of penile erection by stimulating the relaxation of smooth muscle cells in the erectile tissue leading to increased blood flow for the attainment of erection.
- Testosterone promotes production of NO, especially in the corpus cavernosum (the tissue responsible for penile erection) through various mechanisms, including activation of the eNOS (endothelial nitric oxide synthase) enzyme, which is crucial for NO production.
- Sexual Excitation – In some animal studies, both testosterone and NO levels increase during sexual excitation, and there’s a correlation between their levels and sexual behavior.
- NOTE: NO can have a dual effect on testosterone secretion. At low concentrations, NO can stimulate testosterone production, while at higher concentrations, it can inhibit it.
Female Hormones and Sex
- Estrogen (in particular, 17-beta estradiol, the primary pre-menopausal estrogen) and nitric oxide work together to maintain healthy blood vessels, reducing risk of stroke, protecting the brain and cognitive function, and maintaining healthy blood pressure. Declining NO production as estradiol declines in menopause is one of the main reasons menopausal women have higher blood pressure, and memory, mood, sleep and concentration problems.
- Increased NO production – Estrogen, especially 17β-estradiol, can boost the expression and activity of nitric oxide synthase (NOS), the enzyme responsible for NO production.
- Sexual Function – NO is involved in sexual arousal and function, with links to improved blood flow to the genital area.
Brain and Cognitive Health
Nitric oxide (NO) plays a multifaceted role in brain function, acting as a signaling molecule with both neuroprotective and neurotoxic effects. It’s involved in regulating cerebral blood flow, synaptic plasticity, learning, memory, and even influences the sleep-wake cycle. However, excessive NO production can contribute to neurodegeneration.
- Neurovascular Coupling – NO helps regulate blood flow in the brain, ensuring that blood supply matches neuronal activity. This is crucial for providing neurons with the necessary oxygen and glucose for proper function.
- Synaptic Plasticity – NO acts as a retrograde neurotransmitter, influencing synaptic transmission and contributing to processes like long-term potentiation (LTP), which is important for learning and memory.
- Neuroprotection – In appropriate concentrations, NO can protect neurons from damage by influencing various cellular processes like protein modification, dendritic spine growth, and myelination.
- Neurodegeneration – Excessive NO production, particularly by iNOS, can lead to oxidative stress, neuronal damage, and neurodegeneration. This is observed in conditions like Alzheimer’s disease and other neurodegenerative disorders.
- Neurotransmitters – NO can modulate the release and reuptake of neurotransmitters like dopamine, influencing their availability in the synapse.
- NO is essential for normal brain function, contributing to neurovascular coupling, synaptic plasticity, and other vital processes.
- In various diseases, such as stroke, traumatic brain injury, and neurodegenerative disorders, NO can become dysregulated, contributing to neuronal damage and disease progression.
- Targeting the NO pathway is a potential therapeutic strategy for various neurological conditions. For example, NO donors (chemical compounds that release nitric oxide) have shown promise in treating secondary brain injury after trauma.
PTSD
- Nitric oxide (NO) plays a significant role in the development and progression of PTSD, particularly in the context of fear and memory. Studies suggest that alterations in NO signaling, especially involving the enzyme neuronal nitric oxide synthase (nNOS), are linked to PTSD symptoms and related behaviors. Furthermore, manipulating NO levels, such as through nitrous oxide inhalation has shown promise as a potential therapeutic approach for some individuals with PTSD.
- The “global arginine bioavailability ratio” (GABR), reflects NO synthesis capacity, is decreased in veterans with PTSD. Increasing NO bioavailability through nutritional interventions (e.g., increasing arginine intake) helps reduce PTSD symptom severity.
- In my medical experience, PTSD treatment adding proper testosterone therapy for men and optimal estradiol therapy for women has a synergistic effect to improve NO levels, improve sleep and reduce PTSD anxiety and depressed mood.
Heart Health
- NO plays an important role in protection against the onset and progression of cardiovascular disease. The heart protective roles of NO include blood pressure regulation, vascular tone, inhibiting platelet aggregation and leukocyte adhesion, and prevention of smooth muscle cell proliferation.
- Low NO levels are linked to hypertension, atherosclerosis, cardiomyopathy, congestive heart failure and heart attacks fundamentally via endothelial dysfunction, impaired blood flow and oxygen delivery to heart and lungs.
Diabetes
- Nitric oxide is a critical molecule in glucose metabolism. In diabetes, dysregulation of nitric oxide pathways can contribute to complications like kidney disease and blindness.
- NO deficiency impairs blood vessel function and insulin sensitivity.
- NO excess can be detrimental. High glucose levels in diabetes can lead to increased production of ROS which inactivate NO and contribute to oxidative stress and tissue damage.
- Medications that release nitric oxide are being explored as potential therapies for improving insulin sensitivity and glucose control in diabetes.
COPD
- Studies show L-arginine metabolism is disturbed in individuals with COPD. With less L-arginine available for nitric oxide synthase (NOS) activity, less nitric oxide is produced.
- A recent randomized controlled trial published in the European Journal of Internal Medicine has shown that supplementing with L- arginine and liposomal vitamin C improves self-reported shortness of breath and the ability to perform daily activities in individuals’ chronic obstructive pulmonary disease.
ADDITIONAL BENEFITS:
- Hair and skin health, repair and even protection from sun damage.
- Improved exercise performance, including endurance, delayed fatigue, better muscle recovery and growth, less muscle soreness.
- Reduced inflammation throughout the body.
- Improved immune function.
FACTORS THAT DECREASE NITRIC OXIDE:
- Aging: As we get older, NO oxide production declines, which is a big reason to consider supplements that increase NO levels, as I will describe further below. Age effects are due to several factors: reduced synthesis, increased breakdown, and impaired signaling.
- Endothelium damage with age: impairs blood vessel lining’s ability to synthesize NO because nitric oxide synthase (NOS) the enzyme responsible for producing NO declines with age. There is also an increase in levels of reactive oxygen species (ROS) that react with NO forming peroxynitrite to inactivates NO.
- Older people also have diminished levels of nitrate-reducing bacteria in the mouth, and impaired NO transport pathways to name a few of age-related changes in the body that reduce levels of NO.
- Hypothalamic hypogonadism – i.e. stress-induced ovarian suppression in women and testicular suppression in men. MANY factors cause this in younger men and women: competitive athletics, anorexia, bulimia, use of psychotropic medicines (especially SSRIs, SNRIs, and atypical antipsychotics such as for PTSD, depression, anxiety, etc), marijuana/alcohol/narcotic use, nutritional deficiencies, COVID vaccines, COVID and other infectious illnesses (especially if chronic and subclinical residual effects).
- Menopause (natural or surgical) that leads to decline in estradiol
- Male Andropause and decline in testosterone
- Prescription medicines (via several mechanisms): big culprits are SSRIs, SNRIs, atypical antipsychotics, narcotics, beta blockers, chemotherapy drugs.
- Stress, COVID injections, severe illnesses and major surgeries also decrease NO production and increase inflammation that damages vascular pathways and immune function.
ACTION STEPS TO RAISE NITRIC OXIDE LEVELS:
- Regular exercise
- Stress management
- Eat a balanced diet rich in vegetables and focus on those that increase NO production: leafy greens, spinach, arugula, kale, beets and beet root juice, ginger, and celery.
- Add more fruits that increase NO: citrus, pomegranate, and watermelon that contain citrulline that is converted into arginine.
- Dark chocolate contains flavonoids that increase NO production.
SUPPLEMENTS TO BOOST NITRIC OXIDE LEVELS:
Nitric Oxide supplements contain precursors for the body to make more NO, such as L-arginine (the most common) and L-citrulline. They DO NOT contain actual nitric oxide gas. Several factors affect L-arginine being utilized for NO production:
- The above steps to improve overall health help the body’s natural L-arginine saturate the enzyme NOS, so taking extra L-arginine may not significantly increase NO production.
- Age and stress increase the need for L-arginine to make NO.
- L-arginine supplements have additional benefits beyond increasing NO: protein synthesis, ammonia detoxification, hormone secretion, and immune function. Athletes often use L-arginine to increase “muscle pump” during a workout and for several hours afterward, and to increase in overall workout capacity (muscular endurance) and an increase in post-exercise recovery.
Optimizing Benefits of L-Arginine Supplementation:
- I recommend our TruNitricOxide SR™ which has a unique patented extended-release form of L-arginine to prolong bioavailability of L-arginine to make NO.
- TruNitricOxide SR™ also contains ACTINOS2®, a mixture of both high- and low-molecular weight fractions of proteins and peptides that activate NOS to boost nitric oxide production, enhance transcription of the NOS gene and support its role in reducing the negative feedback mechanism for NO production.
- Studies found ACTINOS2 increases NO production in human endothelial cells in vitro from 9.5 to 12.7 times compared to a control.
I also selected our TruNitricOxide SR™ product because it is manufactured in the United States using the highest purity (>98.0%) of L-arginine alpha Ketoglutarate that is commercially available. This formulation is designed to deliver L-arginine alpha ketoglutarate in a controlled manner over a period of approximately 4-6 hours.
CAUTIONS:
NO is dose dependent as with many medications, drugs or supplements. Too little (deficiency) can cause many unwanted health effects, and lead to chronic fatigue and chronic illness. But too much can cause unwanted side effects also. Some of the side effects of excessive NO include inflammation and oxidative stress, hypotension, headaches, bleeding risk, worsening of respiratory conditions like asthma, respiratory distress, lung damage and even death in rare cases of nitric oxide toxicity usually only in occupational settings.
Nitric oxide can also interact with other drugs and medications and enhance their effects, which could possibly lead to unwanted results. Check with your physician before combining ANY Nitric Oxide supplement when you take these RX medicines:
- Blood pressure medications. Adding NO can lower blood pressure further, which means your doctor may need to lower your Rx dose to avoid dropping blood pressure too much.
- Erectile Dysfunction drugs – Viagra, Cialis, Levitra
- Anticoagulants and antiplatelet drugs -warfarin, heparin, aspirin, clopidogrel
- Alpha-blockers used to treat benign prostatic hyperplasia (BPH) and hypertension
- Any Rx medicines that affect cytochrome P450 enzymes
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As always, we urge you to avoid supplements without checking knowledgeable sources to evaluate your medical situation, proper lab tests to verify what is needed, and to make sure to avoid adverse interactions with prescription medicines and other supplements you take.
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To Your good health and improving resilience!
Elizabeth Lee Vliet, MD
