Nitric Oxide and COVID19
Third in a Series Concerning the Non-Pharmaceutical Work-Arounds to COVID19: Use and Feed Your Body Well -- or Lose It...
Introduction
The last post (October 29th) discussed how zinc and its ionophores interfere with COVID19 viral entry via the ACE2 receptor molecules found on the outside of many different kinds of human cells. Unlike current mRNA vaccines, this chemical interference with the actions of the invading virus minimizes, if not actually prevents, personal COVID19 (SARS-CoV-2) virus infestations and their subsequent spread to other people.
The last post also provided some data that showed differences in human exposure to geographic variations in natural and/or dietary sources of zinc and its ionophores in the USA apparently explains much of the observed variation in state-by-state COVID19 mortality rates. These data suggest that comparatively high consumption of fruits and vegetables, relatively high consumption of craft-type beers, and high outdoor and indoor exposure to dusts rich in zinc, all inadvertently but very materially reduce state-level COVID19 mortality in the USA.
Note that the two maps below originally published elsewhere (on November 23rd) indicate that geographic controls of COVID19 mortality dominate the effects of all other cultural and political factors (including vaccination and boosters) over time.
The current post will relate how nitric oxide (“NO”), an important cellular-signaling and immunological agent, functions very similarly to zinc and its ionophores in minimizing infection, replication, and spread of COVID19 by, once again, interfering with the virus at and near human ACE2 cellular receptor sites. Such interference, of course, represents an early action of the innate immunity system.
As in the cases of zinc and its ionophores, there are also dietary sources of substances that promote and help sustain NO production in the human body, the ingestion of some of which varies from state to state in the US. In addition, personally-favored mode of breathing (i.e., by mouth or nose), frequency and intensity of physical exercise and a person’s relative degree of obesity and/or chronic inflammation, also govern the generation and level of nitric oxide in the human body. Accordingly, these other NO exogenous controls on endogenous processes and systems may also affect geographic COVID19 mortality rate.
Multifunctional Nitric Oxide
According to Ignarro (2000), nitric oxide gas dissolved in extracellular fluid and cytoplasm is one of the smallest, most ubiquitous, and simplest biologically active molecules found in mammals -- and is involved in nearly all cell and organ functions in those mammalian bodies. Internally generated following a few different biochemical pathways and associated enzymes, it functions as neurotransmitter, locally active hormone, innate immunity barrier to infection, inducible mediator and cellular protective molecule, and – in some circumstances – can even act as a harmful cellular toxin.
Given that NO has numerous important functions in organ and cell performance and regulation, faults in the various NO-dependent biochemical systems can lead to the development of numerous pathological conditions. Among many other health problems, these include high blood pressure, atherosclerosis, coronary artery disease, heart failure, stroke, erectile dysfunction, diabetes-related vascular dysfunction, ulcers, Alzheimer’s Disease, insulin resistance, and asthma.1 The graphic below illustrates the extremely wide field of functional importance of NO in human biological systems.
Besides being exceedingly small and therefore able to pass in and out of cells and tissues without the need for special active transport mechanisms or associated special molecular structures, nitric oxide gas is a quite reactive free radical so exerts its biological and chemical effects quickly and vigorously. Being so chemically reactive, however, half-life of NO molecules inside the human body is very brief, on the order of 2-6 seconds. Much of this short half-life is explained by the (fortunately) high chemical affinity NO has for the superoxide reactive oxygen species, the heme portion of red blood cells, and the heme portion of the enzyme guanylate cyclase.
Nitric Oxide Versus the SARS Viruses
A small clinical trial carried out in China during the 2003 outbreak of SARS-CoV-1 showed that inhaled NO gas very effectively corrected breathing problems in people with severe SARS-CoV-1. Moreover, this improvement persisted permanently after cessation of the NO inhalation therapy. Those conducting the trial treatment interpreted this latter finding to mean that NO’s positive effects were not restricted only to immediate improvement in the pulmonary system of the afflicted but that NO somehow also acted to reverse or extinguish the troublesome SARS infection itself.
Following this lead, in vitro ‘test tube’ studies completed in the years after the initial 2003 SARS-CoV-1 outbreak showed that SARS-CoV and SARS-CoV-2 replication is, in fact, directly hindered in a dose-dependent manner2 by the presence of NO in the extracellular fluid (e.g., blood):3
“Firstly, NO or its derivatives causes a reduction in the palmitoylation of the S protein which results in the inhibition of membrane fusion mediated by the interaction between S protein and the ACE2 receptor. Secondly, NO or its derivatives have an inhibitory effect on the production of viral RNA, which can be observed as early as 3 hours post-infection.”
NO in this 2009 study, its 2004 predecessor, and a later 2020 study of the new COVID19/SARS-CoV-2 virus, was supplied to the in vitro cells by the naturally occurring dissociation of a weak (200 to 600 micro-molar) aqueous solution of NO-containing S-nitroso-N-acetylpenicillamine (“SNAP”). At ~200 micro-molar solution strength, the SNAP solution steadily provided concentrations of 30-55 micro-molar free NO to the experimental cells for a run period of up to 4 hours.
That such micro-molar magnitudes of free NO can actually be reached in natural (in vivo) systems was confirmed at about the same time as the first lab studies with SARS-CoV-1 virus and the SNAP NO donor solutions were being carried out. Jeong and Kim (2002) showed that macrophages, for example, could be triggered to produce NO concentrations in the range of 1-30 micro-molar NO.
NO-Dependent System Problems
Problems in NO-dependent systems generally come from one or both of the two following directions: an increase in the biological demand for NO, and/or a decrease in the normal biological accessible supply and reserves of the molecule.4 Changes in both of these major factors are causally related to the development of immune system dysfunction, age-related or age-independent.
The apparently dominant origin5 of human NO-related difficulties derives from enzymatic competition for arginine, the amino acid used to produce NO in the body. The enzyme arginase and the several cell and tissue-specific molecular forms of the enzyme nitric oxide synthase (“NOS”) both utilize arginine to produce entirely different end products. See graphic below. Especially at low physiological concentrations of arginine commonly found in older people, arginase can gain the upper hand in the competition between the two opposing enzyme systems, reducing NO production by nitric oxide synthases and instead favoring the production of urea and ornithine by arginase.
With increasing age and attendant gradually reduced metabolic turnover of proteins, endogenous (recycled from body proteins) arginine levels tend to decrease, while activity of the arginase enzyme is upregulated.6 Both influences usually work to reduce NO production and arginine levels, which in turn leads to a vicious cycle of increased production of reactive oxygen species (“ROS”), development of acute and/or chronic inflammation, and a consequently even greater paucity of needed NO and arginine.
Workarounds to Ordinary Human Problems Involving NO-Dependent Systems
If NO production is so important to general human health and to protecting against microbial invaders like COVID19, the question is, of course, what – if anything – can be done to compensate for these NO-related ‘weaknesses of the flesh’? Apparently, natural and cultural evolution both have, willy-nilly, long worked out numerous ‘optional’7 fixes for the problem. In addition, science itself has also much more recently come up with further non-pharmaceutical workarounds.
Kobayashi’s (2021) paper, “Lifestyle-mediated nitric oxide boost to prevent SARS-CoV-2 infection: A perspective”, reviews most of the recognized natural and cultural means for compensating for shortfalls in ‘normal’ processes of NO production. According to Kobayashi, each of the following factors can eventually, through NO-mediated biochemical means, potentially inhibit the activity and progression of COVID19 viruses:
Eating ‘greens’ and other rich vegetable sources of nitrates and nitrites. Commensal bacteria8 in the mouth convert nitrates to nitrite. The nitrites in the saliva (and in dietary substances) are reduced to nitrous acid in the stomach, which then decomposes to NO and other nitrogen-containing molecules. Interestingly, it is beginning to appear that nitrite – whatever its initial source form – represents the largest single intravascular and tissue storage form of NO in the human body.
Physical exercise. Frequent aerobic physical exercise upregulates and maintains the activity of vascular system-related nitric oxide synthase. On the other hand, relatively anaerobic resistance exercise reportedly serves to reduce nitrate and nitrate in muscle and blood to NO and less reactive intermediate nitrogen-bearing species without the express need of NO synthase assistance.
Nose-breathing (versus mouth-breathing). Kobayashi provides references indicating that the simple expedient of inhaling through the nose, rather than the mouth, significantly and favorably affects pulmonary vasculature, raising arterial oxygenation and pulmonary arterial pressure levels by causing NO-mediated bronchodilation. He suggests that this manner of breathing therefore could have much the same positive effects with regard to the COVID19 respiratory virus as was seen with experimental NO inhalation therapy in 2003 with the SARS-CoV-1 virus. In this same regard, Navarro (2020) recommends exhaling through the mouth rather than the nose in order to maximize internally-generated concentrations of NO in the air inhaled into potentially COVID19-infected lungs.
Summary Figure 2 from Kobayashi’s paper is pasted below.
Exogenous L-arginine supplementation, on the other hand, is a recent example of a scientifically-established method of boosting biological levels of NO (and arginine). It has been found that in many instances of reduced NO generation, especially that caused by NO synthase competition with arginase, arginine supplementation can reverse the physiological problems concerned. See references.9 More recent research indicates, however, that citrulline10 supplementation is biochemically more efficient in meeting NO (and arginine) needs, and is less potentially biochemically problematic than arginine supplementation.11 Both arginine and citrulline are amino acids freely and cheaply available in the US supplement market.
Another recent scientific finding is that arginase-related NO and arginine deficiency problems can be improved through the use of orally taken arginase-inhibitors that have the net effect of increasing NO production, especially in older people. While prescription arginase inhibitors represent a growth market for the pharmaceutical industry, these molecular substances are also quite common in everyday food stuffs. Epicatechin, for example, abundantly found in cocoa, and catechin, abundantly found in green and black teas, have been determined to inhibit arginase activity, activate NO synthase, and materially increase vascular dilation caused by NO. Indeed, it appears to be a general rule that zinc ionophores also function as arginase inhibitors. Besides epicatechin and catechin, other zinc ionophores like chloroquine and quercetin also function as arginase inhibitors promoting NO production and thus further strengthening innate immunity against COVID19 by employing a complementary biochemical pathway.
Is There Any Possible Evidence of Geographic Control of Individual Biological NO Generation Capability and USA State Level COVID19 Mortality Data?
Eating vegetables, especially beets and nitrate-rich green leafy vegetables like spinach, arugula, and bok choy, is a notable way of maintaining biochemical NO-generating capacity by taking advantage of the commensal bacteria found in the human mouth. The following graph taken from the last post shows again the state level COVID19 mortality data as a function of state average frequency of vegetable eating. Clearly, the more often that NO-generating vegetables are eaten by the members of a state population, the lower is that state’s overall COVID19 mortality rate.
Obese people generally generate lower levels of NO in their bodies. According to Masi et al., 2018:
“On the cardiovascular system, obesity accelerates atherosclerosis progression, inducing pathophysiological changes that are detectable already from young adults and are similar to those observed in aging. Among these, a reduced NO availability represents one of the earliest vascular alterations observed in obesity and leads to altered vascular homeostasis and accelerated remodeling.”
The following graph suggests that the usually reduced NO availability consequent of obesity may also have a significant influence on state level COVID19 mortality rate.
The next graph in this posting makes eminent great sense given that, among other things, physical activity increases and maintains the ability to generate COVID19-protective NO in human muscles and the human vascular system. Of course, the desire and ability to be physically active is dependent on all around current health status, and not only just the single factor of how much NO a person’s organs, tissues, and cells typically generate. However, the direction of causality goes both ways in this general, multi-factorial case. Cultivating health, by paying attention to diet and consciously engaging in regular physical activity at any age, for example, simultaneously helps build, maintain, and employ, a relatively strong human immune system. This graph very clearly shows that those who -- for cultural, personal, or economic reasons -- evidently use their bodies as if they are only depletable, non-renewable resources, and do little or nothing to compensate for the passage of time, and for the wear and tear of everyday use, don’t do so well at all in our world dominated by microbial life and viruses.
Which brings up a final bit of information to consider. Given the evident importance of physical activity in establishing and maintaining immunity to viruses like COVID19 (see the graph above again), data in the final graph of this post illustrating the huge plunge in physical activity of UK residents over the course of the COVID19 ‘excitement’ suggests that mandated lockdowns may have been a really great way to strongly increase overall population susceptibility to COVID19 infection and mortality. Extreme centralization of government and associated abdication of personal decision-making certainly introduce very pronounced hazards to human life. See the Darwin Awards. Oops.
https://pubmed.ncbi.nlm.nih.gov/21244363/; https://pubmed.ncbi.nlm.nih.gov/15866322/; https://www.researchgate.net/publication/229072659_Nitric_oxide_and_geriatrics_Implications_in_diagnostics_and_treatment_of_the_elderly/fulltext/002b617b0cf25be734cc6734/Nitric-oxide-and-geriatrics-Implications-in-diagnostics-and-treatment-of-the-elderly.pdf
The higher the dose, the greater the hindrance of viral replication.
http://cology4u.blogspot.com/2011/06/nitric-oxide.html provides a concise summary of nitric oxide behavior in biological systems, and the factors influencing its production and subsequent chemical behavior. NO problems can also occur when too much NO is being produced, as in the cytokine storms associated with severe COVID19 infections. This particular problem will be addressed in the next post.
There are other complications and factors involved – see Box 2 in https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC4461463/ and https://pubmed.ncbi.nlm.nih.gov/21244363/
Not all humans take advantage of these fixes.
https://pubmed.ncbi.nlm.nih.gov/15158604/ Note that using mouthwash kills these bacteria and that there is some evidence that such a practice is therefore harmful to cardiovascular and metabolic health: https://www.ahajournals.org/doi/10.1161/JAHA.119.013324.
Citrulline is a sweet-tasting amino acid found in very high amounts in watermelon.
Wow. This is incredibly info-rich, thank you! I will be combing it more thoroughly. Interesting about the nose breathing. Yogis have clearly been on to something!
An excellent write up. Thanks.