Nitric Oxide, a case for the nasal pathway for breathing

Paranasal Sinuses:

Hollow air filled spaces in the skull’s facial bones and around the nose that connect to the nasal cavity. Sinuses consist of frontal, ethmoid, maxillary, and sphenoid sinuses. In theory the paranasal sinuses have ducts that contain nitric oxide synthase that reacts to the oxygen pulled in through the nasal cavity. This in turn accelarates the processing of Nitric oxide from a metabloic reaction

Nitric Oxide: Colorless reactive gas, vasodilator (Vasodilation is the widening of blood vessels due to the relaxation of the blood vessel's muscular walls.)

Signaling: NO acts as a messenger molecule in the cardiovascular, nervous, and immune systems. 

Muscle relaxation: NO promotes vasodilation by relaxing vascular smooth muscle. 

Inflammation: NO has anti-inflammatory effects by inhibiting the adhesion of platelets and leukocytes to endothelial surfaces via vasodilatory properties.

(vasodilation itself does not not imply anti-inflammation, the adhesion of wbc onto the mechanism of inflammation)

Exercise performance: NO may help improve exercise performance and endurance. 

Key points about NO as a neuromodulator:

• Unique diffusion property:

  Unlike most neurotransmitters, NO is a gas that can easily diffuse across cell membranes, allowing it to reach multiple neurons in a wider area. 

• Modulatory effects:

  NO primarily modulates neuronal activity by influencing the production of cyclic GMP (cGMP) within the cell, which can then impact various cellular processes. 

• Roles in brain function:

  • Learning and memory: NO is implicated in long-term potentiation (LTP), a process crucial for memory consolidation. 

  • Sensory perception: NO plays a role in olfactory processing and may be involved in other sensory modalities. 

  • Neurovascular coupling: NO regulates blood flow in the brain by relaxing blood vessels, ensuring adequate oxygen supply to active neurons. 

• Potential implications in disease:

  Dysregulation of NO production has been linked to neurodegenerative diseases like Alzheimer's and Parkinson's, as well as conditions like stroke. 

The synthesis of L-Arginine is the known pathway to nitric oxide occurring within the body. But as recent as a study done in 2020 is the hypothetical implication of the nasal breathing being the most significant pathway in the creation of nitric oxide. It makes sense, athletes have been told from a young age to utilize breathing in through the nose and out through the mouth as the primary mechanism of breath especially while under the state of rest before enacting another bout, set, or repetition to the physical endeavor the athlete is partaking in. Seemingly I’m putting the science to the mechanism of how and why nasal breathing is the superior method of oxygen/nitric oxide intake.

Until recently, NO has been considered just an air pollutant as a byproduct of fuel combustion (metabolic reactions within the body). In 1987, Ignarro et al. [19] and Palmer et al. [20] independently demonstrated that the previously recognized endothelial derived relaxing factor (EDRF) which is released from the vascular walls is essentially Nitric Oxide.

He (Negus) has stated, “There does not appear to be any functional reason for the appearances of the paranasal sinuses, and the irregularity of their distribution, often with complete absence, suggests that they are only unwanted residual spaces.”

With this being said nitric oxide isn’t created by thin air (literally) moving through the nasal cavity and traveling all the way down to the alveoli. Nitric oxide in theory is synthesized in passing through the paranasal ducts… RESEARCH THE PATHWAY OF NO VIA THE PARANASAL SINUS AND THE METABOLIC PATHWAY VIA L-ARGININE:

Nitric oxide synthase (NOS) is an enzyme that catalyzes the production of nitric oxide (NO) from L-arginine, with oxygen as a key substrate. In the context of the paranasal sinuses, nitric oxide synthase enzymes in the sinus lining use this process to produce NO, which is critical for various physiological functions. Here's a detailed explanation of the process:

Step-by-Step Process of Nitric Oxide Synthesis

1. Enzyme and Location:

   • Nitric oxide synthase (NOS) is present in the epithelial cells lining the paranasal sinuses. The specific isoform involved in this region is typically inducible NOS (iNOS) or endothelial NOS (eNOS).

2. Substrates and Cofactors:

   • The enzyme uses L-arginine (an amino acid) as the primary substrate.

   • Oxygen (O₂) acts as a co-substrate and is essential for the oxidative reaction.

   • Several cofactors are required for the reaction to proceed, including:

     • NADPH: Provides the reducing power needed for the reaction.

     • FAD (Flavin adenine dinucleotide) and FMN (Flavin mononucleotide): Transfer electrons to assist in the reduction of molecular oxygen.

     • Tetrahydrobiopterin (BH4): Stabilizes the enzyme and facilitates the production of NO.

3. Reaction Mechanism:

   • NOS catalyzes a two-step oxidation reaction:

     • Step 1: L-arginine is hydroxylated to form N-hydroxy-L-arginine (NHA).

     • Step 2: NHA is further oxidized to produce L-citrulline and nitric oxide (NO).

   • Both steps involve the incorporation of oxygen atoms from molecular oxygen (O₂) into the products.

4. Electron Transport:

   • NADPH donates electrons, which are transferred through FAD and FMN within NOS.

   • These electrons reduce molecular oxygen (O₂), enabling it to participate in the oxidative reaction with L-arginine.

5. Nitric Oxide Release:

   • The produced nitric oxide (NO) diffuses into the nasal airways and bloodstream, exerting its physiological effects:

     • Vasodilation in the respiratory tract and other tissues.

     • Antimicrobial activity to protect against pathogens.

     • Improvement of oxygen exchange in the lungs.

Importance of Oxygen in the Reaction

• Oxygen is critical because NOS requires it to carry out the oxidation of L-arginine. Without sufficient oxygen, the production of nitric oxide is impaired.

• This highlights why nasal breathing, which optimizes airflow through the sinuses and ensures an adequate oxygen supply to the epithelial cells, is essential for efficient NO production.

In summary, nitric oxide synthase in the paranasal sinuses uses oxygen to oxidize L-arginine into nitric oxide and L-citrulline. The NO produced has multiple health benefits, including improved oxygen exchange, immune defense, and vascular health.

Oxygen passing through the paranasal sinuses does not directly create nitric oxide; instead, the oxygen acts as a necessary component in the biochemical reaction within the sinus lining where the enzyme nitric oxide synthase (NOS) converts L-arginine into nitric oxide (NO), using oxygen as a reactant in this process; essentially, the sinuses have specialized cells that use oxygen to produce nitric oxide from L-arginine, not that oxygen itself transforms into nitric oxide. 

Holden et al. [41] found that NO concentration within the nasal cavity is approximately 3-fold greater during inhalation compared with exhalation, and NO concentration increases nearly 6-fold as air moves from the nasal sill to the posterior oropharynx. Collectively, these findings suggest that high output of NO produced by the paranasal sinuses travels during inspiration to the lower respiratory tract.

In 1991, Frostel et al. [42] demonstrated in an animal model of pulmonary hypertension that inhaled NO acts as a vasodilator which decreases pulmonary vascular pressure. Subsequent research consolidated this finding [43,44,45,46,47] and has led to FDA approval of inhaled NO as a treatment modality for neonatal pulmonary hypertension in 1999 [48, 49]. It is well documented in the literature that chronic oral breathing secondary to adeno-tonsillar hypertrophy induces pulmonary hypertension, right ventricular strain, and eventually right heart failure [50,51,52,53,54,55]. This entity has been termed “hypoxic corpulmonale” and has been erroneously attributed to alveolar hypoventilation [56]. Neither the amount of inhaled oxygen nor the alveolar ventilation should vary if air is inhaled from the mouth instead of the nose. However, breathing through the mouth deprives the lungs from the endogenously produced NO and is likely to result in the observed increase in the pulmonary vascular pressure and right ventricular strain.

Bazak, R., Elwany, S., Mina, A. et al. Nitric oxide unravels the enigmatic function of the paranasal sinuses: a review of literature. Egypt J Otolaryngol 36, 8 (2020). https://doi.org/10.1186/s43163-020-00011-7

Ramanlal R, Gupta V. Physiology, Vasodilation. [Updated 2023 Jan 23]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK557562/