Citation
Tonelli AR, Aulak KS, Ahmed MK, Hausladen A, Abuhalimeh B, Casa CJ, Rogers SC, Timm D, Doctor A, Gaston B, Dweik RA. A pilot study on the kinetics of metabolites and microvascular cutaneous effects of nitric oxide inhalation in healthy volunteers. PLoS One. 2019 Aug 30;14(8):e0221777. doi: 10.1371/journal.pone.0221777. PMID: 31469867; PMCID: PMC6716644.
4 FUNDAMENTALS
1. Essential Background Material
Inhaled nitric oxide (NO) has many body-wide impacts. For example, it can protect against brain injury and cause vasodilation and increased blood flow in distant regions. However, it has remained unclear how inhaled NO exerts these effects.
In general, inhaled NO is believed to react away quickly after reaching the lungs. Thus, the systemic benefits of NO could simply be due to improved gas exchange in the lungs, which then has positive downstream impacts. However, another explanation could be that metabolites of NO transport it around the body, where bioactive NO can then reform under specific conditions (for instance, in areas of low oxygen).
Interestingly, despite its widespread clinical use, there have been very few studies testing this hypothesis to truly discover how inhaled NO exerts its systemic effects. This paper sought to fill that gap.
2. What Did this Research Do?
The researchers recruited 15 healthy volunteers. They had them inhale NO at concentrations of 40 ppm (the maximum produced in the paranasal sinuses is on the order of ~20 ppm, but typically much less). They inhaled the added NO for 15 minutes. Blood samples were collected before inhalation, at the end of the 15 minutes of inhalation, and then at 5, 15, and 30 minutes post-inhalation.
3. What Were the Major Findings?
The results were quite striking. They found that NO inhalation significantly increased circulating levels of SNO-Hb and nitrite. This is important because SNO-Hb plays a significant role in whole-body oxygenation. For example, a 2015 PNAS study discovered that SNO-Hb “senses” areas of low oxygen, and then releases bioactive NO to increase blood flow and oxygenation. This discovery led to breathing be considered as a three-gas system involving oxygen, carbon dioxide, and NO. All of this is to say that if inhaling NO increases SNO-Hb, it could be playing a critical role in whole-body oxygenation.
They also observed increases in circulating nitrite. This is important because, like SNO-Hb, nitrite can also release bioactive NO in regions of hypoxia. However, nitrite can do this independent of the hemoglobin, thus providing a “back-up mechanism” for increasing blood flow in regions of low oxygen.
Lastly, another interesting finding from this study was that nitrite levels were most significant at the 5-min post inhalation mark. In contrast, SNO-Hb continued rising throughout the 30 minutes. This led the authors to believe that the lungs might be acting as an SNO-Hb reservoir, releasing it "as needed."
4. Why Do These Results Matter?
When we breathe through our nose, we carry NO into the lungs (although not at concentrations as high as those studied here). Based on these findings, we can now be reasonably confident this NO enters the bloodstream and is carried as SNO-Hb and nitrite. Thus, breathing through your nose might not just improve gas exchange in the lungs. It might also help make sure oxygen gets delivered where it is needed most throughout the body.
Additionally, their finding that SNO-Hb levels continued increasing after NO inhalation is intriguing. It might support the idea that nose breathing provides a baseline level of NO that keeps SNO-Hb in its normal range. Then, when excess NO is inhaled, the body stores that "just in case." This is speculative, but interesting to think about.
1 BIG TAKEAWAY
For the first time, it has been shown that metabolites of inhaled nitric oxide enter the blood stream and are carried systemically throughout the body in forms that can convert back to bioactive NO. This provides a mechanism for how inhaled NO has distant effects.
1 PRACTICAL APPLICATION
This is one study, and it’s relatively new. So, we’ll need more to confirm/deny that NO inhalation consistently increases SNO-Hb and nitrite across different populations. In the meantime, the one application here is to simply breathe through our noses as much as possible. It may just be the key to whole-body oxygenation.