People take nitric oxide for a variety of reasons, many of which do not have any scientific research to support them. Most of these benefits are anecdotal, meaning that people may have reported a benefit, but there is no proof backed up by a scientific study.
For most people, taking nitric oxide supplements does not cause side effects. When side effects do occur, they are often mild and may include:. However, some people should not take the supplements because of the risk of potential side effects. These include people with:. Doctors also have some concerns that taking nitric oxide supplements could make some conditions worse. These include kidney disease, herpes , and after a person has had a heart attack.
A study published in in JAMA found that people taking L-arginine after a heart attack had a higher chance of death, experiencing a repeat heart attack, and being hospitalized than people who did not. This article does not give a comprehensive list of potential conditions where a person should not take nitric oxide supplements. The supplements may also interfere with medications, such as those for diabetes and high blood pressure.
Anyone thinking about taking nitric oxide supplements should talk to their doctor first to ensure they will not interfere with existing conditions or any other medications they are taking. Nitric oxide supplements have been available for decades, but as there is little scientific evidence to back up their use for specific health benefits, doctors do not routinely recommend them. Instead, doctors may prefer to recommend lifestyle modifications or medications that scientists have proven to treat medical conditions effectively.
Nitric oxide supplements do not cause many side effects in most people, so some people might choose to try them. However, individuals should make sure that they do not have specific medical conditions that nitric oxide could harm. A person should always talk to their doctor before taking nitric oxide or any other supplement to make sure they are making a safe, healthful choice. Resveratrol is a plant compound with antioxidant-like properties.
It comes from red grapes. Learn more. Herbal remedies are a form of traditional medicine that use plants to treat illness. Here are examples of remedies for common conditions. Ginseng, an oval-shaped root, is among the most popular herbal remedies. Learn more about possible benefits and risks of using ginseng. Historically, people have used the bark of the slippery elm tree to treat many different conditions.
Topical application of nitrite is an effective treatment for skin infections and ulcerations. Furthermore, in the stomach, nitrite-derived NO plays an important role in host defense and in regulation of gastric mucosal integrity. More recently, these investigators reported that intermittent administration of a low-dose nitrite aerosol could attenuate pulmonary vascular remodeling in rodent models of pulmonary arterial hypertension [ 1 ].
In addition to the oxidation of NO, nitrite is also derived from reduction of salivary nitrate by commensal bacteria in the mouth and GI tract as well as from dietary sources such as meat, vegetables and drinking water.
The metabolic activation of nitrate from dietary or endogenous sources requires its initial reduction to nitrite, and because mammals lack nitrate reductase enzymes, this conversion is dependent upon oral commensal bacteria as well as bacteria in the GI tract and on body surfaces [ 11 ]. Human nitrate reduction requires the presence of these bacteria, revealing a functional symbiotic relationship, since mammalian cells cannot effectively metabolize this anion.
The salivary nitrate levels can approach 10 mM and nitrite levels 1—2 mM after a dietary nitrate load. When saliva enters the acidic stomach 1—1. The discovery of this mammalian nitrogen cycle has led researchers to explore the role of nitrate and nitrite in physiological processes that are known to be regulated by NO.
Much of the recent focus on nitrite physiology is due to its ability to be reduced to NO during ischemic or hypoxic events. Nitrite reductase activity in mammalian tissues has been linked to the mitochondrial electron transport system, protonation, deoxyhemoglobin and xanthine oxidase. There are also a number of natural products that have been shown to be oxygen-independent nitrite reducers [ 13 ] that can provide an effective system for generating NO from nitrite. Nitrite and nitrate therapy or supplementation may restore NO homeostasis from endothelial dysfunction providing benefit in a number of diseases characterized by NO insufficiency.
If so, this will provide the basis for new therapeutic or preventive strategies, and new dietary guidelines for optimal health. Studies using a patented nitrite formulation US patents 8,,, 8,,, 8,, and 8,, marketed as a nutraceutical in the form of an orally disintegrating tablet found that it could modify cardiovascular risk factors in patients over the age of 40, significantly reduce triglycerides and reduce blood pressure [ 14 ]. Single administration of this lozenge leads to peak plasma levels of nitrite around 1.
This same lozenge was used in a pediatric patient with argininosuccinic aciduria and significantly reduced his blood pressure when prescription medications were ineffective [ 15 ].
A more recent clinical trial using the NO lozenge reveals that a single lozenge can significantly reduce blood pressure, dilate blood vessels, improve endothelial function and arterial compliance in hypertensive patients [ 16 ]. The same lozenge was used in an exercise study and was found to lead to a significant improvement in exercise performance [ 18 ].
These studies clearly demonstrate the safety and efficacy of low doses of nitrite in humans. From a public health perspective, we may be able to provide better dietary recommendations and dramatically affect the severity and incidence of cardiovascular disease and the subsequent clinical events.
Nitrite itself may provide therapeutic benefit embedded in certain materials. NO donors were really the first class of NO-based therapies. NO donors broadly speaking are a heterogeneous group of different chemical classes of compounds that either decompose spontaneously in a pH dependent manner or are metabolized in cells and tissues to generate NO. These different classes of NO donating drugs all have different pharmacodynamic, pharmacokinetic, and toxicological properties.
A common feature of all of these compounds is that they can release NO and lead to NO dependent biological effects such as relaxation of blood vessels. Nitrovasodilators, such as nitroglycerin are used in the management of various acute and chronic cardiovascular pathologies.
Once liberated, NO activates sGC in the smooth muscle, increases the concentrations of the secondary messenger cyclic GMP, alters calcium flux and ultimately causes relaxation. There are a select few nitrovasodilators that are in clinical use today, however, all these drugs have been used in medicine long before the discovery of NO as a biological signaling molecule. Nicorandil and molsidomine which is converted to the active moiety, 3-morpholinosydnonimine [linsidomine, SIN-1], in vivo are not approved for use in the US, but, like PETN, are available abroad.
These drugs are administered both orally and transdermally. Although nitrovasodilators are very effective in acute care situation, the long term use is severely limited by the rapid development of tolerance to their vasodilatory effects. In order for organic nitrates to maintain their vasodilatory effects when used chronically, they must be cycled off for an 8—hour period.
This interruption complicates organic nitrate therapy in patients who may require around-the-clock angina protection. Interestingly, in contrast to the vasodilatory effects, tolerance development to the platelet anti-aggregatory effects of organic nitrates does not appear to be significant [ 19 ].
Chronic organic nitrate therapy has been associated with reduced survival when used in patients with coronary artery disease [ 21 ] but the underlying mechanisms are still not known. It is clear however that use of organic nitrate therapy leads to increased vascular oxidative stress which in turn can produce endothelial dysfunction.
As a result, use of these compounds is limited to acute treatments, such as acute angina or for emergency hypertensive crises. NONOates are generated by exposing various nucleophile compounds to NO gas at a few atmospheres of pressure.
The resulting compounds are stable as a solid and highly soluble in aqueous solution, releasing 2 moles of NO per mole of donor compound. Decomposition rates are dependent upon pH, temperature and the chemical characteristics of the donor compound, generating compounds whose NO generation rate can be predicted and adjusted.
A distinct advantage of this class of NO donors is that they generate NO spontaneously, without any need for electron transfer, co-factors, metabolic activation, or oxidation-reduction activation. A disadvantage is the spontaneous NO release which presents a challenge for targeted delivery. In order to provide a mechanism for targeted NO release, photosensitive precursors to diazeniumdiolates have been developed.
There are three different classes of photo-triggered diazeniumdiolates: 2-nitrobenzyl derivatives, meta-substituted benzyl derivatives, and naphthylmethyl and naphthylallyl derivatives. This photo-triggered diazeniumdiolate derivative may prove useful in future pharmacological investigations. Potential applications include inhibition of restenosis after angioplasty, preparation of thromboresistant medical devices, reversal of vasospasm, and relief of pulmonary hypertension.
Beneficial effects of diazeniumdiolate therapy have been reported in a patient with acute respiratory distress syndrome but these compounds have not entered clinical trials in humans as yet. This innovative strategy has produced hybrid drugs, with a dual mechanism of action that captures its original mechanism along with the slow release of NO. These drugs are synthesized by inserting appropriate NO-donor chemical groups i.
This strategy has opened up the possibility of designing new classes of drugs that are capable of delivering NO into tissues and the bloodstream in a sustained and controlled manner and perhaps offset many of the unwanted side effects. The approach has led to the synthesis of several new chemical entities whose pharmacologic profile provides a better safety profile than the parent drug.
These hybrids offer the advantage of combining a basic mechanism of action from the parent drug e. NSAIDs, including those that are selective for cyclooxygenase-2, were among the most widely used drugs until they were recalled by the FDA due to an increased risk of serious cardiovascular events, including heart attacks and strokes.
The combination of COX inhibition with controlled release of NO yields a series of drugs that exert anti-inflammatory and analgesic activities in a wide range of settings, and have reduced gastrointestinal and cardiorenal toxicity. Many pharmaceutical companies have invested millions of dollars in this strategy and although the preclinical and clinical data looked very promising, the FDA outright rejected the first of its kind Naproxcinod, a NO-naproxen drug developed by NicOx.
The FDA review recommended further trials in humans to assess the safety on a cardiovascular and gastrointestinal level. This ruling was a major blow to the strategies and pipeline products of big pharma and small biotech. It is currently unclear how industry will respond to further development of this technology. S-nitrosation is a ubiquitous redox-related modification of cysteine thiol which affects protein structure and function and can elicit cGMP-independent NO signaling [ 23 ].
As early as , Ignarro's group demonstrated that the activation of organic nitrates was attributed to reactions with cellular thiols [ 24 ], which is several years before making the observation that NO is actually synthesized endogenously in mammalian cells. There is now a large body of literature that implicates S-nitrosothiol SNO as an intermediate in nitric oxide dependent and guanylyl cyclase independent signaling processes.
S-nitrosothiols may be NO carriers that have vasodilatory properties and may also be integral to the regulation of platelet aggregation. In addition, it can exist in the plasma as an S-nitroso adduct of circulating albumin. Consequently, it has been generally assumed that naturally occurring S-nitrosothiols act as in vivo storage sites for NO, which can be released upon demand. S-nitrosothiols are susceptible to decomposition by numerous mechanisms, giving rise to NO and the corresponding disulfide.
S-nitrosothiols are actively metabolized by cells [ 25 ]. S-nitrosothiols are biologically active as vasodilators and inhibitors of platelet aggregation. Due to the fact that these low molecular weight nitrosothiols act similarly to EDRF with a longer circulating half-life than NO, make them an ideal candidate for drug development. However, the therapeutic use of S-nitrosothiols such as S-nitroso-N-acetyl-D, L-penicillamine SNAP has been limited by their potent vasodilatory effects leading to hypotension.
Nanotechnology has emerged as a revolutionary new science. It has the potential to be used as the basis for new, more effective drug delivery systems.
Part of the innovation lies in the synthesis of different size particles that may be used for targeted delivery to specific tissue beds or even cancer cells.
The use of nanotechnology allows for the effective delivery of a very reactive substance such as NO gas in a way that circumvents many of the limitations associated with other NO delivery systems. Furthermore, precisely and accurately engineered particle constructs can be uniquely manufactured that may eliminate architectural randomness and allow for site-specific targeted distribution.
The use of silicon in nanoparticle constructs has been shown to be effective as a continuous and tunable multistage drug delivery system [ 27 ]. This is a very promising strategy to allow for targeted delivery of NO without the unwanted systemic side effects of conventional NO-based therapeutics. Specific technologies will be discussed in much greater detail in the other articles in the issue. There are numerous benefits to this phenomenon. Specifically, nitric oxide production on the skin is important for three key reasons: wound healing, dermal immune response, and dermal vasodilation.
Learn more about the endless benefits of getting the right amount of sun to boost nitric oxide levels.
Increased stress lowers nitric oxide levels, and lower nitric oxide levels increase stress. It's feedback systems that spiral health out of control. Symptoms of low nitric oxide include anxiety, depression, and fatigue, which are all made worse by stress.
Stressful events can engage the parasympathetic nervous system, which causes the heart to pump and adrenal glands to engage. Try to put plans in place and use tools to prevent stress from reaching this level.
Find more about how the body uses nitric oxide to reduce stress and ways you can manage stress levels for achieving optimal health. It keeps us alive, but mostly we don't think about the way we breathe. But the way we choose to breathe makes a big difference in our quality of life and our health. One key difference is that breathing through the nose allows nitric oxide production in the nasal cavity. When we breathe through our mouth, there are no nitric oxide production benefits.
Nose breathing helps produce nitric oxide that relaxes the muscle around blood vessels and arteries helping the body relax. SKY meditation is an example of a popular breathing practice that increases nitric oxide and one that drastically:.
Most people don't know that the wrong turn in oral health can mean depleted benefits from exercise. For a long time, researchers didn't understand how post-workout hypotension occurred. After studies were conducted, it was found that anti-bacterial mouthwash is to blame for reduced nitrate levels and thus reduced nitric oxide levels. You don't have to skip the dental floss, and there are natural mouthwashes you can switch to if you're at risk. Don't waste the cardiovascular benefits of your next workout by using harmful mouthwashes.
Fluoride use in municipal drinking water has become the norm. Toothpaste brands have made it a staple ingredient. The claim is that fluoride is important to prevent cavities. However, you can choose which toothpaste you use and opt for non-fluoridated toothpaste. Those who drink municipal water are subjected to fluoride, whether they want to ingest it or not. Regardless of your take on fluoride, studies show that fluoride poses a threat to health and suppresses nitric oxide synthesis.
Excessive exposure can deplete nitric oxide production capabilities. Look for toothpaste that avoids fluoride as an ingredient. Natural alternatives to fluoride that protect teeth from cavities include Neem, coconut oil, ozonated olive oil, oregano oil, and myrrh. Heavy salt use or "salt loading" episodes have been connected to a subsequent decrease in nitric oxide production.
Both groups of people who are salt sensitive and who are not salt-sensitive displayed depleted nitric oxide production capabilities after heavy salt usage. This study tells us that if you want to keep your nitric oxide levels up, avoid salty foods. That means reducing the amount of salt you use or opting for an alternative altogether like miso paste which is soy-based. Diets rich in saturated fats impact the body's ability to produce nitric oxide.
Reduced nitric oxide production means there will be less nitric oxide available to do its job and relax the smooth muscle around arteries.
It is suspected that this might be the process by which saturated fats contribute to disturbed endothelial tissue. The reduction of saturated fats helps avoid this reduction in nitric oxide and will undoubtedly contribute to overall health. It's no surprise that smoking is bad for you, but did you know that smoking drastically reduces your oxid nitric levels. Smoking impairs endothelial vasodilation and restricts circulation. Exposure to cigarette smoke extract displays irreversible, permanent nitric oxide synthase inhibition in the pulmonary artery endothelial cells.
As a result of this permanent damage, it's suspected that this is the cause of high rate pulmonary and cardiovascular disease in cigarette smokers. If you want to increase your nitric oxide levels, try decreasing your cholesterol.
Studies show that high cholesterol levels reduce the bioavailability of nitric oxide, which is part of why this impacts heart health.
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