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.

A Review of Nasal Nitric Oxide's Powerful Effects

Key Points

• Nasal nitric oxide (NO) acts as our first line of defense against airborne pathogens by sterilizing incoming air and enhancing cilia movement

• Nasal NO plays a role in warming the air we breathe as it travels into the lungs

• Humming significantly increases nasal NO and could be used as a test for sinus disorders
  

The Breathing Diabetic Summary

I spend a lot of time reading about nitric oxide (NO).  But, the more I learn, the more interested I become. It seems to pop up everywhere I look. Sometimes I wonder what it can’t do.

Nitric oxide’s physiological relevance was discovered in 1987, the same year I was born. Its effects were known several years prior, but it wasn’t until two separate papers (both in prestigious journals, PNAS and Nature) were published that NO’s benefits became “official.”

In the respiratory system, the primary source of NO is the upper airways. The paranasal sinuses, in particular, produce ~90% of the NO measured in exhaled air.  

Previously, we have learned that NO acts as our first line of defense against airborne pathogens by sterilizing incoming air.  The breathing community often touts aspect of NO.  Here, we learn there is more to it: nitric oxide also increases the cilia motility.  

Cilia are tiny hairs lining the back of your nose and respiratory tract. They oscillate back and forth to move mucus out of the upper and lower airways, bringing pathogens and other potentially harmful agents along for the ride.  Cilia are your lung’s first defense against inhaled particles and nitric oxide enhances their activity.  

Nitric oxide also plays a role in warming incoming air. The precise mechanism is unclear, but increased nasal NO release is associated with increased temperature in the nasal airways.

Here is my speculation: NO increases blood flow in your nose, which warms the nasal passages and airways. As air travels through, it extracts this warmth before entering the lungs. Makes sense, but is just a hypothesis and likely oversimplifies what is going on…

Nasal nitric oxide also redistributes blood flow in the lungs when in the upright position, leading to better oxygen uptake. (Nasal NO might even be an adaptation to gravity, allowing us to walk upright.)  

Finally, humming causes a significant increase in nasal NO. However, some sinus disorders inhibit this enhanced NO release. Therefore, the measurement of nasal NO after humming might be a way to test for sinus disorders.

To summarize, nasal nitric oxide is a powerful gas. It acts as our first line of defense against airborne pathogens by sterilizing incoming air and by improving cilia motility. Additionally, NO helps warm the air we breathe as it travels into our lungs. NO also redistributes blood flow in the lungs, resulting in better oxygen uptake. Lastly, humming increases NO significantly and might provide a way to test for sinus disorders.

Abstract

Exhaled nitric oxide (NO) originates from the upper airways, and takes action, to varying extents, in regulation, protection and defense, as well as in noxious processes. Nitric oxide retains important functions in a wide range of physiological and pathophysiological processes of the human body, including vaso-regulation, antimicrobial activity, neurotransmission and respiration. This review article reports the ongoing investigations regarding the source, biology and relevance of NO within upper respiratory tract. In addition, we discuss the role of NO, originating from nasal and paranasal sinuses, in inflammatory disorders such as allergic rhinitis, sinusitis, primary ciliary dyskinesia, and cystic fibrosis.

Journal Reference:

Maniscalco M, Bianco A, Mazzarella G, Motta A.  Recent Advances on Nitric Oxide in the Upper Airways.  Curr Med Chem. 2016;23(24):2736-2745.