A Concise Review of Inhaled Nitric Oxide’s Systemic Impacts

Key Points

• The classical viewpoint that inhaled nitric oxide (NO) only has local effects cannot explain observations.

• For example, inhaled NO has many systemic effects, including the ability to selectively increase blood flow where it is needed most.

• SNO-Hb might be the likely candidate for how inhaled NO is transferred into the blood and transported throughout the body while retaining its bioactivity.

The Breathing Diabetic Summary

This paper presented a concise review of inhaled NO’s systemic effects.  So, I’ll keep the summary brief as well. 

The classical view that inhaled NO only has local effects in the airways and lungs is not supported by observations.  It turns out that inhaled NO has many systemic effects.  Notably, inhaled NO selectively increases blood flow where it is needed most.  Thus, our bodies have a way of using inhaled NO other than just in the airways and lungs.  It can also be transported to distant regions where blood flow is restricted, resulting in vasodilation and increased blood flow.  This was also shown in the Cannon et al. (2001) study.   

Here, as in that study and others, the precise mechanism for how this is done is unknown.  However, there is one pathway that has been brought up repeatedly, which is SNO-Hb.  As we learned in a 2015 PNAS study, SNO-Hb is critical to blood flow regulation and oxygen delivery.  It “senses” regions of hypoxia, releases bioactive NO, and improves blood flow to get more oxygen to the tissues.

The authors suspect that this is also the mechanism by which inhaled NO is selectively improving blood flow, stating that this pathway “likely represents an important mechanism by which inhaled NO can cause systemic effects.”  The difficulty is that SNO-Hb is hard to measure; therefore, there have been no conclusive studies to show that this is the mechanism by which inhaled NO works. 

Altogether, this paper shows that the traditional view of inhaled NO is not adequate to explain its systemic effects.  It’s selective vasodilating effects suggest that SNO-Hb is the mechanism by which inhaled NO is transported throughout the body.  Still, more studies are needed to support this hypothesis.

Abstract

Many effects of inhaled nitric oxide (NO) are not explained by the convention that NO activates pulmonary guanylate cyclase or is inactivated by ferrous deoxy- or oxyheme. Inhaled NO can affect blood flow to a variety of systemic vascular beds, particularly under conditions of ischemia/reperfusion. It affects leukocyte adhesion and rolling in the systemic periphery. Inhaled NO therapy can overcome the systemic effects of NO synthase inhibition. In many cases, these systemic-NO synthase-mimetic effects of inhaled NO seem to involve reactions of NO with circulating proteins followed by transport of NO equivalents from the lung to the systemic periphery. The NO transfer biology associated with inhaled NO therapy is rich with therapeutic possibilities. In this article, many of the whole-animal studies regarding the systemic effects of inhaled NO are reviewed in the context of this emerging understanding of the complexities of NO biochemistry.

Journal Reference:

Gaston B. Summary: systemic effects of inhaled nitric oxide. Proc Am Thorac Soc. 2006 Apr;3(2):170-2. doi: 10.1513/pats.200506-049BG. PMID: 16565427.

Nitric Oxide Might Outweigh All Other Benefits of Nose Breathing

Key Points

• Nasal nitric oxide (NO) acts as our body’s first line of defense against airborne pathogens

• Nasal NO reduces blood pressure, redistributes blood flow, and increases gas exchange

• The humidifying effects of the nose might not be as important as NO

The Breathing Diabetic Summary

Nitric oxide (NO) has, somewhat quietly, become a staple of breathing science.  NO is produced in the nasal airways and carried into the lungs with each (nasal) breath we take.  This review discussed nasal NO, its origins, and its physiological effects in the body.

The general consensus is that NO is produced in the paranasal sinuses and is continuously released into the nasal airways.  Because of this continuous release, NO’s concentration is dependent on flow rate.  A lower flow rate will allow more NO to build up, thus bringing higher concentrations down into the lungs with each breath.   

This could be yet another benefit of slow breathing: Slower flow rates will increase NO. Each breath then brings in a higher concentration of NO, redistributing blood flow, increasing gas exchange, and potentially increasing infection-fighting capabilities.

Which brings us to the next physiological effect of nasal NO: Host defense.  Some bacteria die when NO concentrations are as low as 100 parts per billion (ppb).  In the paranasal sinuses, the concentration can be as great as 30,000 ppb(!).  Thus, nasal NO might be the first line of defense against airborne bacteria, acting to sterilize the incoming air and reduce infection. 

Nasal NO also increases arterial oxygenation and reduces blood pressure in the lungs.  For example, one study showed that nasal breathing increased tissue oxygenation by 10% when compared to mouth breathing.  That’s pretty remarkable.

For example, one study showed that nasal breathing increased tissue oxygenation by 10% when compared to mouth breathing.

Another study showed that when mouth breathers were given supplemental NO, arterial oxygenation increased and and lung blood pressure decreased similar to nose breathing.  Interestingly, if the mouth breathers were just given moistened air (without NO), these effects did not occur.  Thus, the main benefits of nasal breathing might be due to NO, not the warming and humidifying effects that are typically touted (although they clearly help).

Finally, widening the nostrils via nasal tape also increases arterial oxygenation during breathing at rest.  This could partially be due to an increased delivery of NO to the lungs.  We can naturally unblock our noses using simple breath hold techniques or use something like Intake Breathing for assistance.

Overall, this study highlighted several important aspects of nasal NO.  It acts as our body’s first line of defense against airborne pathogens by sterilizing incoming air.  Then, as NO travels into the lungs, it reduces blood pressure, redistributes blood flow, and increases gas exchange, leading to greater arterial oxygenation.  Finally, we learned that the humidifying effects of the nose might not be as important as NO. 

I am continually amazed by the many roles of nitric oxide in the body.  I believe it might be the most important aspect of nasal breathing. 

Journal Reference:

Lundberg JO, Weitzberg E.  Nasal nitric oxide in man.  Thorax.  1999;54(10):947-52.