Production and storage of nitric oxide in adaptation to hypoxia - Manukhina et al. (1999)

Key Points

  • Adaptation to hypoxia significantly increases production & storage of nitric oxide

  • Production and storage are balanced to ensure blood pressure remains normal and nitric oxide reserves are available if needed

The Breathing Diabetic Summary

In 2015, a pivotal paper was published showing that breathing can no longer be thought of as a two-gas system and that nitric oxide (NO) plays an important role in the respiratory cycle.

Here’s how.  Nitric oxide binds to the hemoglobin in a form called SNO-Hb where it is transported within the red blood cells.  Critically, in areas of hypoxia, the NO is released to open up the blood vessels and increase blood flow and oxygenation.

From that statement, we see the importance of NO in response to hypoxia.  However, I personally did not consider this mechanism with respect to intermittent hypoxia training.  Then I read this paper.

Here, they gradually adapted mice to hypoxia in an altitude chamber simulating ~5000 m.  The mice completed 40 sessions.  They started at 10 min the first session, then 20 min the second session, and so on until they reached 5 hours of simulated altitude per session.

Note that this gradual acclimation was a key component of their study.  If the change had been too severe or too quick, the response might have been detrimental.

After acclimation, they found that NO metabolites (nitrite and nitrate) increased significantly.  This indicates that the mice were either generating more NO or releasing more NO from storage.

However, at the same time, the mice also were increasing their NO storage.  The increase in NO storage correlated significantly with the increase in NO metabolites.

Thus, these results indicate that adaptation to intermittent hypoxia increases NO synthesis and storage. 

The storage rate was higher than the synthesis rate, which the authors hypothesize is a protective mechanism to ensure blood pressure does not drop too low.  However, the large storage also ensures that NO can be readily released if needed.

Abstract from Paper

Adaptation to hypobaric hypoxia is known to exert multiple protective effects related with nitric oxide (NO). However the effect of adaptation to hypoxia on NO metabolism has remained unclear in many respects. In the present work we studied the interrelation between NO production and storage in the process of adaptation to hypoxia. The NO production was determined by the total nitrite/nitrate concentration in rats plasma. The volume of NO store was evaluated in vitro by the magnitude of isolated aorta relaxation to diethyldithiocarbamate. It was shown that both the nitrite/nitrate level and the NO store increased as adaptation to hypoxia developed. Furthermore, the NO store volume significantly correlated with plasma nitrite/nitrate. Therefore, adaptation to hypoxia stimulates NO production and storage and these effects can potentially underlie NO-dependent beneficial effects of adaptation.

Journal Reference:

Manukhina EB, Malyshev IY, Smirin BV, Mashina SY, Saltykova VA, Vanin AF.  Production and storage of nitric oxide in adaptation to hypoxia.  Nitric Oxide.  1999;3(5):393-401.