Extrapulmonary effects of inhaled nitric oxide: Role of Reversible S-Nitrosylation of Erythrocytic Hemoglobin - McMahon and Doctor (2006)

Key Points

  • Inhaled nitric oxide (iNO), previously thought to have a short lifetime, has positive impacts outside of the lungs in the peripheral areas of the body

  • The most plausible mechanism for these peripheral effects is through SNO-Hb (see Zhang et al., 2015)

The Breathing Diabetic Summary

This paper is all about inhaled NO (iNO) and its effects outside of the lungs.  This is relevant to us because we know that the nose is a reservoir of NO, and so each time we breathe through our nose, we get some iNO.  Traditionally, it was thought that iNO only acted as a vasodilator in the lungs.  Once it encountered a red blood cell (RBC), it was terminated.  However, iNO has also been shown to have peripheral effects, which were not completely understood.  Now, with our knowledge of SNO-Hb (Zhang et al., 2015), we better understand the mechanism behind how iNO can have effects outside of the lungs.

(Note that this paper was written almost a decade before Zhang et al. (2015). The mechanism behind SNO-Hb was discovered, I believe, back in the mid 1990s.  Therefore, the idea of NO “riding” on RBCs has been established for quite a while, but the Zhang et al. (2015) study was the first to really emphasized the importance of this mechanism for blood flow regulation.  That is why I commonly refer to that paper in reference to the SNO-Hb mechanism of blood flow regulation.)

An interesting perspective from this paper was that RBCs basically regulate their own action of oxygen delivery.  As the Hb oxygen saturation drops, the RBC itself causes vasodilation via the SNO-Hb mechanism, thus increasing blood flow to increase oxygen delivery.  So, it essentially monitors itself, and when it realizes its running low on oxygen, it increases blood flow to make sure enough oxygen is available to the tissues and organs.  That’s pretty amazing!

SIDE NOTE:  This is completely unrelated, but since my wife is pregnant with our first child, I found this fascinating.  We know the SNO-Hb mechanism is important for whole body oxygenation, but this really emphasizes its importance.  This study cites papers that have found that umbilical blood flow going toward the fetus is rich in SNO-Hb whereas blood flow going away from the fetus had relatively less SNO-Hb.  The body is an amazing thing!

One really important takeaway from this paper was that there was no direct evidence of iNO increasing SNO-Hb.  Obviously, if SNO-Hb is so important, we would like to know that iNO is increasing it.  But, because this is a relatively new discovery (in the science world), and it is very difficult to measure, it will still take time to confirm that this is occurring.  However, the tone of the authors was very optimistic toward this point, for example, citing a paper that showed iNO did in fact increase SNO-Hb, but that it was not “statistically significant.”  In any case, because there are so many benefits of nose breathing aside from the NO, I think it’s a safe bet to breathe this way and wait for the science to catch up.  And if it turns out iNO cannot be converted to SNO-Hb, we’ll still be better oxygenated and in better health from this one small change.

Finally, and importantly for us diabetics, this paper describes how high HbA1c has negative effects on the SNO-Hb mechanism.  Briefly, high HbA1c causes the RBC to “hold on” to more NO in a non-bioactive form, thus disrupting the SNO-Hb mechanism and disrupting blood flow regulation in diabetics.  See the notes on James et al. (2004) for more information.

Overall, this paper shows that iNO does in fact have peripheral effects.The most plausible mechanism for these effects is through SNO-Hb, however, more research needs to be done to confirm this.

Abstract from Paper

Early applications of inhaled nitric oxide (iNO), typically in the treatment of diseases marked by acute pulmonary hypertension, were met by great enthusiasm regarding the purported specificity of iNO: vasodilation by iNO was specific to the lung (without a change in systemic vascular resistance), and within the lung, NO activity was said to be confined spatially and temporally by Hb within the vascular lumen. Underlying these claims were classical views of NO as a short-lived paracrine hormone that acts largely through the heme groups of soluble guanylate cyclase, and whose potential activity is terminated on encountering the hemes of red blood cell (RBC) Hb. These classical views are yielding to a broader paradigm, in which NO-related signaling is achieved through redox-related NO adducts that endow NO synthase products with the ability to act at a distance in space and time from NOsynthase itself. Evidence supporting the biological importance of such stable NO adducts is probably strongest for S-nitrosothiols (SNOs), in which NO binds to critical cysteine residues in proteins or peptides. The circulating RBC is a major SNO reservoir, and RBC Hb releases SNO-related bioactivity peripherally on O2 desaturation. These new paradigms describingNOtransport also provide a plausible mechanistic understanding of the increasingly recognized peripheral effects of inhaled NO. An explanation for the peripheral actions of inhaled NO is discussed here, and the rationale and results of attempts to exploit the “NO delivery” function of the RBC are reviewed.

Journal Reference:

Timothy J. McMahon and Allan Doctor, (2006) Extrapulmonary effects of inhaled nitric oxide, Proc Am Thorac Soc, 3, 153–160, DOI:10.1513/pats.200507-066BG.