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.