Nitric Oxide (NO)
Not to be confused with nitrous oxide (N2O, laughing gas). To keep them straight, check out the nitrous oxide mascot.
Nitric Oxide as a Vasodilator
The Nobel Prize was awarded In 1998 for the discovery that nitric oxide (NO) acts as a signaling molecule in the cardiovascular system, causing vasodilation.
Decrease of NO levels with age may be a major contributor to erectile dysfunction.
Nitric oxide gas is FDA-approved only for treatment of persistent pulmonary hypertension of the newborn.
NO is the direct cause of septic shock by vasodilation, when triggered by cytokine storm.
Nitric Oxide as a Neurotransmitter
Nitric oxide serves as a gaseous neurotransmitter, synthesized postsynaptically and acting presynaptically, i.e., retrograde neurotransmission. Other examples of retrograde neurotransmission involve endocannabinoids and nerve growth factor.
As a neurotransmitter, nitric oxide is involved in long term potentiation and hence is likely to be important in memory and learning.
Nitric Oxide Synthases
Bacteria make NO from nitrate. Humans make NO from L-arginine, catalyzed by nitric oxide synthase (NOS) enzymes.
NOS-1
The neuronal isoform (nNOS) is involved in the development of the nervous system. Nitric oxide functions as a retrograde neurotransmitter important in long term potentiation and hence is likely to be important in memory and learning. nNOS is also involved in cardiac function, peristalsis, and sexual arousal in males and females.
NOS-2
The cytokine-inducible isoform (iNOS) produces nitric oxide as an immune defense mechanism. It is the cause of septic shock via vasodilation.
NOS-3
The endothelial isoform (eNOS) is important for cardiovascular health.
Bacterial NOS
Nitric oxide produced in the mouth by bacterial NOS (bNOS) from nitrate is protective against oxidative damage.
Nitric Oxide and Mental Health
Nitric oxide is involved in neurodevelopment and has been implicated in essentially all psychiatric conditions (Kumar & Chanana, 2017).
Depressed patients have decreased NOS activity that improves after antidepressant treatment and predicts drug response (Loeb et al, 2020).
Although all SSRIs cause erectile dysfunction, paroxetine (Paxil) is especially likely to do so—the putative mechanism being inhibition of NOS by paroxetine. As a consequence of inhibiting NOS, one would expect paroxetine to decrease NO levels. To the contrary, the net effect of paroxetine is increased NO like the other SSRIs.
Electroconvulsive therapy (ECT) decreases serum nitric oxide, resulting in transient blood pressure elevation (Atagun et al, 2021). It is unknown whether ECT is associated with decreased nitric oxide in the brain—if so that would theoretically oppose the antidepressant benefit.
In patients with schizophrenia, nitric oxide level in cerebrospinal fluid is decreased (Ramirez et al, 2004). Antipsychotics normalize nitric oxide levels in the prefrontal cortex (Morales-Medina et al, 2021).
NMDA receptor hyperactivation or ischemic events lead to higher concentration of nitric oxide that can lead to neurodegeneration, contributing to Alzheimer’s and Parkinson’s disease (Jankovic et al, 2024).
Inhibition of nitric oxide signaling by PCP is involved in its behavioral effects (Fejgin et al, 2007).
Mouthwash and Nitric Oxide
Nitric oxide bioavailability is thought to be modulated systemically by oral microbes, which produce NO from dietary nitrate (NO3-). Antiseptic mouthwash may destroy nitric oxide-producing bacteria. Regular use of antiseptic mouthwash is associated with a slight but significant elevated risk of hypertension, and a strong association was found between antiseptic mouthwash use and cardiovascular disease (Bagabir et al, 2024). Endothelial dysfunction resulting from deficient nitric oxide production is the earliest event in the development of hypertension (Nathan S Bryan, 2022).
Supplementation
L-citrulline is converted to L-arginine, which is used to produce nitric oxide. Supplemental L-citrulline and L-arginine are taken for mild to moderate erectile dysfunction, although evidence is insufficient. NOS activity can be indirectly measured by the L-Citrulline/L-Arginine ratio. The problem with arginine/citrulline supplements is that individuals who are deficient in NO have adequate arginine but cannot convert it to NO due to loss of function of NOS.
Humans cannot convert nitrate to NO, so supplementing nitrate (e.g., beetroot juice) will increase NO only if the proper bacteria are present in the mouth. Nitric oxide guy Nathan S. Bryan PhD estimates that nitrate based products may work in less than a third of the population due to widespread disruption of the oral microbiome, e.g., from antiseptic mouthwash.
Nitric oxide synthase (NOS) enzymes are present in the nasal cavity and paranasal sinuses. Nasal breathing produces higher levels of nitric oxide in exhaled air compared to mouth breathing (Tomberg et al, 2002). Increase of NO availability has been cited as a reason for mouth taping while sleeping.
Don't confuse Nitric Oxide with Nitrous Oxide
Nitrous oxide mnemonic here
Recommendation
To be determined. Maybe don't use mouthwash? Tape your mouth at night?
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