Vasodialators, vasoconstrictors, and decompression

[Duke Dive Medicine]

Dr. P says he's trying to get funding from DARPA to study this. A few general notes about inhaled nitric oxide: first, in a clinical setting, it's used primarily to dilate pulmonary vessels. It is rapidly scavenged by hemoglobin, which delivers it to areas of local tissue hypoxia, so it doesn't really have systemic effects. Also, it binds with the superoxide anion to produce peroxynitrite, which can be further changed to peroxynitrous acid (chemical formula ONOOH), which if present in sufficient quantities can damage the lung's surfactant. The dosing isn't entirely clear, either.

So, Dr. P's short answer is "not ready for prime time", but we may see something coming out in the next couple of years. Thanks for starting this discussion!

Best regards,
DDM

 

[t-mac]

Very interesting idea. NO is very short-lived -- I believe the endogenous sites of production and action are usually very nearby (this is why it took so long to sort this puzzle out). When I saw this I wondered if inhaled it would stick around long enough to have systemic effects or whether it would only work locally in the lungs, but I just looked and there is literature showing systemic vasodilatory effects. Definitely worth looking at this idea. Given the short half-life, I wonder, though, if you get a sort-of gradient from the pulmonary circulation to more distal areas and whether ultimately to have a meaninful effect in distal areas you need pulmonary concentrations that could become toxic. Anyway, please keep us posted if you explore this.

 

[Duke Dive Medicine]

Hi t-mac,

I think we're so close to the cutting edge here that the answer depends on who you ask. I've had some good talks with one of our scientists, Dr. Barry Allen, which have helped increase my own understanding of this subject. I can't write at his level so I'll just link some of the articles he gave me.

One you probably found already:
Endocrine Nitric Oxide Bioactivity and Hypoxic Vasodilation by Inhaled Nitric Oxide
Endocrine nitric oxide bioactivity and hypoxic vaso... [Circ Res. 2012] - PubMed - NCBI
Dr. Allen disagrees with the characterization of nitric oxide as an endocrine molecule and instead refers to its activity as paracrine.

Hemoglobin, nitric oxide, and molecular mechanisms of hypoxic vasodilation:
Endocrine nitric oxide bioactivity and hypoxic vaso... [Circ Res. 2012] - PubMed - NCBI

Two faces of nitric oxide: implications for cellular mechanisms of O2 toxicity:
Two faces of nitric oxide: implications for c... [J Appl Physiol. 2009] - PubMed - NCBI
if the above link doesn't work, try this one:
Two faces of nitric oxide: implications for cellular mechanisms of oxygen toxicity

Inhalation of Nitric Oxide Prevents Ischemic Brain Damage in Experimental Stroke by Selective Dilation of Collateral Arterioles:
Inhalation of nitric oxide prevents ischemic brain ... [Circ Res. 2012] - PubMed - NCBI

Extracellular superoxide dismutase, nitric oxide, and central nervous system O2 toxicity:
Extracellular superoxide dismutase,... [Proc Natl Acad Sci U S A. 1992] - PubMed - NCBI

Phosphodiesterase-5 inhibitors oppose hyperoxic vasoconstriction and accelerate seizure development in rats exposed to hyperbaric oxygen:
Phosphodiesterase-5 inhibitors oppose hyperox... [J Appl Physiol. 2009] - PubMed - NCBI

I'll come back here and post if we get funding for the study.

Best,
DDM

 

[t-mac]

Thanks for the references, DDM. I'm hoping you get your funding so we can learn more about this. Interesting how things come around in life -- I recall the NO/NOS story started coming out while I was doing my doctoral work at Duke back in the late 1980s. Of course, my wife, a "real" Dukie, would contend that all things ultimately come back to Duke.

 

[Duke Dive Medicine]

Of course they do! Looking at your profile it appears that you do some interesting and vital work yourself. Hats off to you. We may end up in parallel fields if the TBI and hyperbarics study has good results.

 

[KellyAsh]

Thank you guys for your insight and thoughts. It's exciting to hear this has been thought of before. It would be great if this turned out to be the next generation of accelerated decompression. I hope someone with the proper resources will take the ball, run with the idea, and turn it into reality, then name it after me, lol.