--- title: Exploring the Dual Pathways and Nutrients for Enhanced Nitric Oxide Production description: Nitric oxide production relies on two distinct pathways, the endogenous and enterosalivary routes, each needing specific nutrient cofactors. image: https://www.casi.org/hubfs/casi/featured/2-1-nitric-oxide.jpeg --- An **educational publication of Designs for Health** [For Practitioners →](https://www.designsforhealth.com) [![casilogoresize2-2](https://www.casi.org/hubfs/casilogoresize2-2.png)](https://www.casi.org/) [Home](https://www.casi.org/) [Science Update](https://www.casi.org/articles/tag/science-update) [Research & Education](https://www.casi.org/articles/tag/research-education) [Archive](https://www.casi.org/articles/all) Search articles Search Research & Education # Exploring the Dual Pathways and Nutrients for Enhanced Nitric Oxide Production DM Danielle C. Male, MS, CNS, LDN Jan 30, 2024 ![Exploring the Dual Pathways and Nutrients for Enhanced Nitric Oxide Production](https://www.casi.org/hs-fs/hubfs/casi/featured/2-1-nitric-oxide.jpeg?width=960) Nitric oxide (NO) is a messenger molecule that plays a role in [nearly every organ system in the body](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390088/). Nitric oxide regulates [hormone secretion](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9340976/), [nutrient metabolism](https://pubmed.ncbi.nlm.nih.gov/34251644/), [cardiac contractility, smooth muscle relaxation](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683098/), [immune function](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390088/), and [cognitive health](https://pubmed.ncbi.nlm.nih.gov/34251644/), and supports a [healthy microbial balance](https://pubmed.ncbi.nlm.nih.gov/34251644/). Healthy NO levels may promote [athletic performance](https://pubmed.ncbi.nlm.nih.gov/30895562/), as [clinical trials](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282262/) have shown that NO [increases](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282262/) blood flow and helps with healthy muscle contraction, oxygen supply to muscles, glucose uptake, muscle fatigue, mitochondrial respiration, and oxidative phosphorylation.  One of NO’s primary functions is to serve as a [vasodilator](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683098/) to promote increased blood supply to tissues and to relax the inner muscles of blood vessels. As a result, NO helps to promote [normal blood pressure and blood flow](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683098/), increasing the delivery of oxygen and nutrients to tissues and facilitating the clearance of metabolic by-products. Clinical studies suggest impaired NO production, activity, or bioavailability is associated with endothelial dysfunction in [cardiovascular disease, hypertension, hyperlipidemia, and diabetes mellitus.](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390088/)  Despite its vital functions for overall health, [NO status naturally declines with age](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390088/) or in cases of [certain metabolic conditions](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390088/). Fortunately, throughout the aging process, the body utilizes two major pathways that work [in tandem](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/) to maintain healthy NO homeostasis: [the endogenous pathway and the enterosalivary pathway](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/). The steps and required nutrients for the dual pathways of NO are explained below.  **The Endogenous Pathway –** Requires L-arginine and healthy vascular endothelial structure and function.  Nitric oxide is endogenously produced as a by-product of the oxidation of the amino acid [L-arginine](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/) (Arg), catalyzed by [endothelial nitric oxide synthase](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/) (eNOS) – an [isoform of NO synthase (NOS) enzymes](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3345541/). Once produced, NO can form [nitrosothiols](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/) or become [oxidized to nitrite and nitrate](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390088/), which can be [recycled to regenerate NO](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390088/), thus promoting sustained and healthy NO homeostasis.  As Argis a [precursor](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9340976/) to NO, it may [increase NO bioavailability](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9340976/). Arg can be obtained from dietary sources or endogenous metabolism. Human studies suggest that Arg may help promote [healthy blood pressure](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9340976/) and may support [athletic performance](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282262/) through its role in NO production.  L-citrulline (Cit) can serve as an endogenous precursor to Arg, thereby increasing NO production. Some research suggests that Cit supplementation may be [more effective than Arg supplementation](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683098/) in promoting healthy NO levels due to [different metabolic pathways](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683098/). Arginine undergoes gastrointestinal and hepatic extraction. Unlike Arg, Cit [bypasses](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683098/) the metabolism by the intestine and liver, where it reaches the [kidneys and gets converted into Arg](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683098/). On the other hand, [human and animal studies](https://pubmed.ncbi.nlm.nih.gov/31977835/) suggest that the combined effect of Cit and Arg supplementation may be more beneficial than each individual amino acid alone.  The NOS enzymes require [multiple nutrient cofactors](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3345541/) – relying on the adequate nutritional status of riboflavin (vitamin B2), glutathione, niacin (vitamin B3), folate (promotes the cofactor [tetrahydrobiopterin \[BH4\] bioavailability](https://pubmed.ncbi.nlm.nih.gov/27974600/)), and calcium. [Thiamine](https://www.sciencedirect.com/science/article/abs/pii/S030698771100017X) may also modulate [eNOS-dependent](https://www.sciencedirect.com/science/article/abs/pii/S030698771100017X) NO production. In [rodent models](https://pubmed.ncbi.nlm.nih.gov/24103804/), a thiamine deficiency led to reduced NO production and increased vascular dysfunction.  Under [healthy conditions](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390088/), the endogenous pathway proceeds normally and can support proper NO status. However, during the aging process or in the presence of metabolic conditions, several [problems](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390088/) can disrupt this pathway. One is [insufficient nutrient cofactor availability](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390088/). Two, a reduction in the [expression of total eNOS](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390088/). Lastly, limited L-arginine availability, transport, and conversion to NO [due to eNOS enzyme uncoupling](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390088/).  Uncoupling of eNOS from [electron transfer](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3345541/) occurs as a result of cellular damage from [oxidative stress or insufficient cofactor availability](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3345541/). If uncoupling occurs, eNOS switches from preferentially producing NO to, instead, generating [superoxide](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390088/), which contributes to [oxidative stress and endothelial dysfunction](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390088/). For instance, inadequate levels of [BH4](https://pubmed.ncbi.nlm.nih.gov/27974600/) (a cofactor for eNOS) may generate [superoxide radicals from eNOS rather than NO](https://pubmed.ncbi.nlm.nih.gov/27974600/). NOS-derived superoxide reacts with NO to produce highly reactive [peroxynitrite radicals](https://pubmed.ncbi.nlm.nih.gov/27974600/), which rapidly oxidize BH4 and trigger the [uncoupling](https://pubmed.ncbi.nlm.nih.gov/27974600/) of NOS. Depletion of BH4 and uncoupling of NOS are associated with [cardiovascular disease](https://pubmed.ncbi.nlm.nih.gov/27974600/).  Consequently, it is vital to support [antioxidant status](https://pubmed.ncbi.nlm.nih.gov/26097441/) during the endogenous production of NO. Research suggests that supplementing with L-arginine and antioxidants, such as [vitamin C and glutathione](https://pubmed.ncbi.nlm.nih.gov/26097441/), may be more effective in promoting [NO production](https://pubmed.ncbi.nlm.nih.gov/26097441/) and [sustained NO release](https://pubmed.ncbi.nlm.nih.gov/26097441/) in the body than supplementing with Arg and Cit alone. [In vivo and in vitro](https://pubmed.ncbi.nlm.nih.gov/26097441/), the combination of glutathione and L-citrulline was shown to help promote plasma levels of NO.  Due to the potential limitations of the endogenous pathway of NO production, the body simultaneously utilizes the second pathway, the [enterosalivary pathway](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/).  **The Enterosalivary Pathway –** Requires dietary nitrates and a healthy oral microbiome.  The enterosalivary pathway produces the same [biologically active NO](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390088/) produced through the endogenous pathway but with [dietary nitrite](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390088/) as the precursor rather than L-arginine. The enterosalivary pathway is associated with elevations in [plasma nitrite and cyclic guanosine monophosphate](https://pubmed.ncbi.nlm.nih.gov/25421976/) (cGMP), a sensitive marker of bioactive NO production. This pathway may be a [protective measure](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390088/) to compensate for insufficient eNOS activity or NO insufficiency. Additionally, this route is [not impacted by age](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390088/). Instead, it requires two necessary elements: one, the [dietary intake of nitrates](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/) through food or supplements, and two, a [healthy oral microbiome](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/).  The enterosalivary pathway starts when an [exogenous source of inorganic dietary nitrate](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/) (NO3-) is digested through nitrate-rich foods, such as beets and green, leafy vegetables. The [gastrointestinal tract](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/) rapidly absorbs nitrate, where it enters circulation and is either excreted through the kidneys (~70%) or transported to the saliva glands (~25%), forming [salivary nitrate](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/). This explains why salivary nitrate levels are [ten to twentyfold higher](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/) than in the blood.  Next, salivary NO3- is [reduced](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/) to nitrite (NO2-) by the action of [nitrate reductases](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/) found in certain [commensal oral bacteria](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/), such as *Rothia mucilaginosa, Haemophilus parainfluenzae, Neisseria flavescens,* and *Neisseria subflava.* Therefore, healthy oral microbial balance is vital for proper NO conversion through the enterosalivary pathway.  The saliva containing NO2- is swallowed into the [stomach](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/), where it is reduced to NO by the [acidic environment](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/) and in the presence of endogenous reductants, such as [vitamin C](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/). In addition to vitamin C, human studies suggest that [berry polyphenolic compounds](https://pubmed.ncbi.nlm.nih.gov/19778575/) may promote NO production in the stomach. Interestingly, nitrite-derived NO may support the [host immune defense](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390088/) and regulate [gastric mucosal integrity](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390088/). It is important to note that the conversion of nitrite into NO in the stomach is [pH-dependent](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390088/), where insufficient stomach acid may disrupt this process.  Various [clinical trials](https://pubmed.ncbi.nlm.nih.gov/23596162/) have investigated the general clinical benefits of dietary nitrates to promote [healthy blood pressure](https://pubmed.ncbi.nlm.nih.gov/25421976/) (BP). A [meta-analysis](https://pubmed.ncbi.nlm.nih.gov/23596162/) of 16 randomized, placebo-controlled trials with 254 participants examined the effects of dietary nitrate (between 157 mg and 1,488 mg per day) on BP. The researchers concluded that inorganic nitrate and beetroot juice consumption was associated with a statistically significant 4.4 mmHg reduction in systolic BP, with a non-significant, modest 1.1 mmHg decrease in diastolic BP.  ## Supportive Nutrients for Both Pathways Recent literature has explored the role of [hydrogen sulfide](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/) (H2S), a [gaseous transmitter](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/), to promote healthy [NO homeostasis and vasodilation](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/). H2S can be produced endogenously or obtained dietarily. Compounds in [garlic](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/), including [allicin and S-allyl-L-cysteine](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10490347/), act as [H2S donors](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/). H2S may promote [NO synthesis](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10490347/) through [eNOS-dependent](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/) and [enterosalivary pathways](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/) to maintain elevated cGMP levels in several ways. [First](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/), it may promote eNOS function and the bioavailability of NO-derived cGMP. [Second](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/), H2S may promote the conversion of nitrite into NO by shifting the activity of xanthine oxidoreductase (XOR) enzymes to nitrite reductases to form NO. [Third](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/), H2S may also interact with oxidized forms of NO to produce stable intermediates that serve as reservoirs for NO, such as in the muscles.  [Vitamin C](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869438/) is necessary for collagen synthesis, endothelial health, and promoting antioxidant status. As a potent antioxidant, vitamin C may help attenuate the [oxidative stress and inflammation](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869438/) associated with vascular dysfunction. Moreover, vitamin C helps the [conversion of nitrite to NO](https://pubmed.ncbi.nlm.nih.gov/33115598/) in the enterosalivary pathway in the stomach. Vitamin C, [alone](https://pubmed.ncbi.nlm.nih.gov/33642340/) or [in combination](https://pubmed.ncbi.nlm.nih.gov/30930132/) with nitrate consumption, has been shown in clinical trials to support NO production, healthy BP, and endothelial health in older adults and individuals with [hypertension](https://pubmed.ncbi.nlm.nih.gov/33183558/), [type 2 diabetes mellitus](https://pubmed.ncbi.nlm.nih.gov/33642340/), or [hypercholesterolemia](https://pubmed.ncbi.nlm.nih.gov/33115598/).  A small [open-label clinical trial with 12 hypertensive participants](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/) aged 52 to 73 examined the effects of a supplement that contained dietary nitrates, black garlic extract, and vitamin C on NO bioavailability and blood pressure. After four weeks, the subjects exhibited a decrease in systolic BP by ~11 mmHg (p \< 0.001) at two weeks, which persisted until the end of the trial. Diastolic BP decreased up to 11 mmHg (p \< 0.01) in the patients with elevated diastolic BP, but no decrease was observed in the participants with normotensive diastolic BP. All 12 participants had consistent, rapid increases of salivary NO2- concentrations (from [fourfold to forty-fourfold times higher](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/) than baseline) at two hours post-administration, which slowly decayed but remained above baseline in all participants after 24 hours. This suggests combining these nutrients may promote [sustained, healthy NO status](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/), potentially up to 24 hours daily, for longer-lasting clinical benefits. However, these are [preliminary results](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578647/), and further research is required on this subject.  ## Conclusion Promoting sustained NO production and bioavailability is vital for overall health, particularly for cardiovascular health, brain health, immune health, and supporting athletic performance. The body utilizes two complex yet important pathways to help ensure proper NO status. However, both pathways require specific precursors and nutrient cofactors for enhanced and sustained production. Supporting antioxidant status, promoting a healthy oral microbial environment, and consuming nitrate-rich food or supplements can help maintain healthy NO levels.  On this page Share [LinkedIn](https://www.linkedin.com/shareArticle?mini=true&url=https%3A%2F%2Fwww.casi.org%2Farticles%2Fdual-pathways-nutrients-enhanced-nitric-oxide-production) [X](https://twitter.com/intent/tweet?url=https%3A%2F%2Fwww.casi.org%2Farticles%2Fdual-pathways-nutrients-enhanced-nitric-oxide-production&text=Exploring+the+Dual+Pathways+and+Nutrients+for+Enhanced+Nitric+Oxide+Production) [Email](mailto:?subject=Exploring%20the%20Dual%20Pathways%20and%20Nutrients%20for%20Enhanced%20Nitric%20Oxide%20Production&body=https%3A%2F%2Fwww.casi.org%2Farticles%2Fdual-pathways-nutrients-enhanced-nitric-oxide-production) DM ### Danielle C. Male, MS, CNS, LDN Clinical Application ## Clinical Considerations in Practice In clinical practice, practitioners considering the topics discussed above may also weigh nutrient form, delivery and formulation, alongside individual patient variability. ### Practitioner Formulation Example ![NOx Synergy™](https://cdn.sanity.io/images/lemtscrs/production-www/da4dbaab6ba8b223ea8e0072c3b267de088bf84c-2000x2000.png?w=128&h=128&fit=max&auto=format) NOx Synergy™ L-arginine, L-citrulline, taurine and creatine · Powder [Explore Formulations →](https://www.designsforhealth.com/products/nox-synergy) ## Continue your research #### [Research & Education B Vitamins 101: Functions, Food Sources, and Daily Requirements Jun 25, 2026](https://www.casi.org/articles/b-vitamins-101-functions-food-sources-and-daily-requirements) #### [Research & Education Magnesium Supplementation 101: Choosing the Best Form for Your Patient’s Needs Jun 02, 2026](https://www.casi.org/articles/magnesium-supplementation-101-choosing-the-best-form-for-your-patients-needs) #### [Research & Education Magnesium Glycinate Chelate Buffered: A Smart Approach to Magnesium Supplementation May 21, 2026](https://www.casi.org/articles/magnesium-glycinate-chelate-buffered-a-smart-approach-to-magnesium-supplementation) #### [Research & Education Overcoming the Anaerobic Barrier: A New Approach to Probiotic Manufacturing May 12, 2026](https://www.casi.org/articles/overcoming-the-anaerobic-barrier-a-new-approach-to-probiotic-manufacturing) ![casilogoresize2-2](https://www.casi.org/hubfs/casilogoresize2-2.png) An educational publication of [**Designs for Health**](https://www.designsforhealth.com). 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