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Just Say NO! (Nitric Oxide that is)

March 12, 2000 | 41,101 views
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by Cory Mermer

Excess NO may be responsible for causing glaucoma and possibly other conditions: how to address this naturally: There has been much publicity in the press recently about a finding that many people suffering with chronic open angle glaucoma (COAG) have excessive levels of Nitric Oxide (NO) (Neufeld 97).

By reducing these levels through drugs, researchers were able to reduce the damage caused by increased intraocular pressure to the optic nerves in rats (Neufeld 99). There is now a rush by pharmaceutical companies, to get a NO-blocking drug approved for the treatment of COAG. However, there seems to be little interest in finding out what is really causing these levels to be so high in the first place. Since artificially suppressing any natural physiological response of the body is bound to have unintended consequences, wouldn't it make sense to look for the cause and address that instead?

Nitric Oxide: a brief description

Information about this neurotransmitter is still not fully known, since it was only first identified in 1987 (Ignarro, 1987), resulting in the authors receiving the 1989 Nobel Prize in Science. Nitric Oxide is made, at various sites in the body, from L-arginine. It serves many functions, such as inducing vasodilatation, controlling intragastric pressure, facilitating dilation of the uterus during pregnancy, inhibiting bone resorption, is essential for producing and maintaining an erection, and kills bacteria, fungi, and even tumor cells. However, it is also very dangerous at high levels, being a potent nitrogen free radical. It actually has the capacity to kill neurons and is thought to be responsible for much of the degeneration that occurs after strokes and in some diseases of the nervous system.

What are some of the possible causes of increased NO levels?

Based on current knowledge and available research, there are several factors which may cause or contribute to elevated NO levels:

  • Allergies (histamine)
  • Poor iron status
  • Hypoxia (oxygen deficiency)
  • Carbon monoxide exposure
  • Excess estrogen or 'estrogen dominance'
  • Others

Allergies

How can allergies cause increased NO levels? The answer is quite simple. It is common knowledge that allergies can cause elevated histamine levels, which is why antihistamine medications are such popular drugs. What is not widely known, is that histamine, in turn, stimulates a release of NO from various cells in the body (Mannaioni 97a, Mannaioni 97b, Champion 98).

It is actually proposed that some of the adverse effects of histamine, such as increasing permeability of the blood/brain barrier, are actually mediated by NO (Mayhan 96). Therefore, in individuals with allergies causing elevated histamine levels, addressing this problem may abrogate the need for pharmacologically reducing NO levels. Additionally, high histamine levels have been associated with of circulatory hypoxia, a condition that will be discussed further in another section (Sumina 78).

The question of how to address this problem can be done in several ways, the merits of which will not be explored now, since this is a topic which deserves more attention than can be given here:

  • Avoidance or reduction of allergens (e.g., dietary change, air filters, etc.)
  • Use of natural antihistamines (e.g., quercitin) (Bronner, Pearce)
  • Use of conventional antihistamine medications
  • Alternative allergy treatment (homeopathy, enzyme-potentiated desensitization)
  • Conventional allergy treatment

For those people with allergies, some of whom may not even know they have them, one or a combination of the above choices might help improve not just their allergic symptoms, but their overall health as well. Of course, in order to adequately address the allergy problem, it must be properly diagnosed by a qualified clinician.

Poor iron status

Another possible cause of increased NO is decreased iron levels. One of the reasons for this is that hemoglobin and other iron-containing compounds bind to NO in the blood, rendering it inactive.

Poor iron status and anemia may result from dietary insufficiency, not only of iron, but of folic acid and vitamin B-12 as well. Particularly in the elderly, B-12 deficiency is not uncommon. This is most likely due to an age-related decline in the production of Intrinsic Factor, a glycoprotein secreted by cells in the gastric mucosa, necessary for the proper absorption of B-12. Those at greatest risk for a deficiency of iron and B-12 are vegetarians and those with a diet very low in meat, the best source of B-12. However, deficiencies can be pharmacologically induced as well. As an example, drugs taken for gastrointestinal problems, such as the popular omeprazole (Prilosec in the US, Losec in Canada), are known to reduce B-12 absorption significantly, possibly by reducing IF levels (Marcuard 94).

Even in people with normal hemoglobin levels, their iron stores may be less than optimal. Many physicians feel that this is more accurately assessed through the evaluation of serum ferritin levels. Ferritin is the major iron storage protein, conserving it for use as needed, in the cells. It also serves other functions, such as protecting against certain free radicals, such as oxidized iron and peroxides, and is essential for proper cell growth and proliferation.

Therefore, it is likely that adequate ferritin levels act to reduce some of the negative effects of excess NO through its antioxidant function. NO in turn, helps to protect against the release of oxidative free iron from iron-containing compounds (Puntarulo 97, Juckett 96)

Hypoxia

In addition to resulting in reduced hemoglobin and ferritin levels, iron deficiency may cause elevated NO levels through another physiological mechanism by causing anemic hypoxia, or subnormal oxygen content in the blood. Hypoxia is known to cause a stimulation of NO production, which is most likely a defense or survival mechanism of the body, which produces the NO to relax the blood vessels in order to supply more oxygenated blood to the tissues.

Other forms of hypoxia may also be present and have this effect as well. For example, diffusional hypoxia results from damaged pulmonary membranes and impaired lung function, as occurs with chronic obstructive pulmonary disease (e.g., emphysema). Therefore lung diseases may cause elevated NO levels by causing chronic hypoxia.

As for natural treatments, some nutrients have been shown to enhance lung function. The most notable of these is N-acetylcysteine, commonly referred to as NAC.

Impaired lung function may also be pharmacologically induced with the use of common medications such as beta-blockers. These drugs have the potential to promote broncho-spasm and broncho-constriction. This class of drugs is often used for conditions such as hypertension, cardiac arrhythmia, chronic angina pectoris, and others. Natural treatments of these conditions and elimination of the necessity of these drugs may therefore reduce NO levels.

Ironically, the most popular drugs in the treatment of COAG are beta-blocker eye-drops (e.g., Timolol). Therefore, it is possible that this type of treatment could raise NO levels and actually increase the risk of damage to the optic nerve. Additionally, if those glaucoma subjects in the study by Neufeld et al were being treated with these medications, it is possible that the elevated NO was not a result of the condition, but rather the treatment.

A condition of circulatory hypoxia, resulting from excessive vasoconstriction or myocardial insufficiency, can also cause an increase in NO levels. Magnesium has been shown to ease vasoconstriction, and other cardio-protective nutrients, such as coenzyme Q10, L-Carnitine, Taurine, etc. may prove helpful for myocardial insufficiency.

Carbon Monoxide

Carbon monoxide (CO) exposure can cause circulatory hypoxia, a condition previously discussed, by attaching to hemoglobin and inhibiting its oxygen-carrying capacity. As a matter of fact, it attaches more than 200 times stronger to hemoglobin than oxygen (Walker 99). Low levels of CO exposure may not present any obvious symptoms and therefore, may go undetected.

These low levels of exposure may also cause symptoms, mimicking those of the common cold or flu, and may therefore be misdiagnosed by even the best physicians. This is unfortunate, since there are now simple breath meters which can detect carbon monoxide levels (Walker 99), but which are probably rarely used by general practitioners. Exposure in an industrial work environment is probably the most common scenario, but can occur in the home as well. This is especially true in the winter, when heating units are in use and windows are usually shut tight.

Interestingly, in a study recently published in a Chinese medical journal, the intraocular pressure in glaucoma patients has been shown to increase during the winter months (Qureshi 97). Whether this effect is due to the colder weather, carbon monoxide exposure, reduced level of physical activities, or some other factor is not yet known.

However, it would seem prudent to have carbon monoxide detectors installed in the home and even at work in order to reduce the chances of exposure. These devices are especially important since CO is odorless and colorless, and low levels of exposure may not present any immediately obvious symptoms. Proper ventilation is crucial to avoiding CO, especially when there is any combustion taking place, such as with heating units, gas stoves, and fireplaces.

It should be noted that those people with higher levels of hemoglobin and red blood cells should be somewhat less susceptible to damage from low levels of CO, due to their greater oxygen-carrying capacity.

Estrogen

Recently, estrogen has been shown to enhance the bioactivity of NO (Blum 98). There are several ways that women can wind up with excessive estrogen levels or an imbalance in the hormonal system, causing an "estrogen dominance" situation.

One is that women on hormone replacement therapy (HRT) may not have their hormone levels properly monitored and may be given doses that cause levels to rise too high. Also, the most popular estrogen used, Premarin, is obtained from horses and has a completely different composition than human estrogen, with much more potent estrogenic effects. There are an increasing number of doctors who are using "natural" hormone replacement therapy and custom tailoring the composition and dosages to their patients.

It is also possible that excessive estrogenic activity is being induced in the body through estrogen-mimicking environmental pollutants. There may be some detoxification and lifestyle modification procedures (e.g., eating organically, avoidance of plastics, etc.) that can reduce these effects. Another possibility is a hormonal imbalance between estrogen and progesterone.

If progesterone levels are low, a woman can become "estrogen dominant". Along with the many other adverse effects of this condition, NO may become too active. Many nutritionally-oriented doctors routinely check for this, using either salivary or blood tests, and where needed may prescribe a natural progesterone to be administered either orally or more commonly, transdermally.

Other factors

Fluoride poisoning has been shown to cause circulatory hypoxia (discussed previously), possibly resulting from a tremendous increase (8 to 9 fold) in histamine levels (Sumina 78). Therefore, it is not out of the realm of possibilities that lower doses of fluoride could result in a slight decrease in oxygen carrying capacity. People could reduce this possibility by not drinking fluoridated water or commercially prepared beverages, since many of these are made using fluoridated water.

One final possibility is that some elevated NO levels may be pharmacologically induced. As an example, it was discussed previously about this possibility with beta-blocking agents. It is beyond the scope of this paper to discuss all of the drugs which could possibly elevate NO levels, but clinicians and patients should be aware that any drug can have unintended and unwanted consequences.

Possible Dangers of Suppressing Nitric Oxide

Any drug that is developed to suppress NO production, in the hope of treating COAG or any other condition, could have many adverse effects, due to the many functions of the neurotransmitter. For example, NO plays an important role in controlling feto-placental circulation during pregnancy (Izumi 96), making it's use during pregnancy potentially dangerous. Suppression of NO could theoretically cause other problems such as impotence or sexual dysfunction, elevated blood pressure, digestive disturbances, increased susceptibility to infection, and even increased risk of cancer.

Summary

Nitric Oxide plays a vital role in normal physiological function. However, in addition to being an antioxidant, it is also a free radical and can have unwanted negative effects when levels are abnormally high. It may be possible to ascertain and treat the cause of this situation through various means, only some of which have been discussed here. As more becomes known about NO, other conditions beside COAG may be identified as being caused or exacerbated by excess NO, thereby opening up new avenues of treatment and hope for many sufferers of chronic health problems. (2058 words)

 

Dr. Mercola's Comments:

Nitric oxide is an important part of biochemical regulation, understanding and controlling its formation has the potential for profound influences on our health. Many thanks to Corey for providing this helpful piece of research.

References

1. Neufeld AH; Hernandez MR; Gonzalez M. Nitric oxide synthase in the human glaucomatous optic nerve head. Arch Ophthalmol 1997; 115: 497-503.

2. Neufeld AH, Sawada A, Becker B. Inhibition of nitric-oxide synthase 2 by aminoguanidine provides neuroprotection of retinal ganglion cells in a rat model of chronic glaucoma. Proc Natl Acad Sci USA 1999; 96: 9944-9948.

3. Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chauduri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Nat Acad SCI USA 1987; 84: 9265-9269.

4. Mannaioni PF; Bello MG; Di Bello MG; Schunack W; Masini E. Histamine up-regulates the generation of nitric oxide, and nitric oxide down-regulates the release of histamine in cardiovascular preparations. Inflamm Res 1997a; 46 Suppl 1: S97-98.

5. Mannaioni PF; Bello MG; DI Bello MG; Mirabella C; Gai P; Schunack W; Masini E. Interaction between histamine and nitric oxide in rat mast cells and in isolated guinea pig hearts. Int Arch Allergy Immunol 1997b; 113: 297-299.

6. Champion HC; Kadowitz PJ. R-(-)-alpha-methyl-histamine has nitric oxide-mediated vasodilator activity in the mesenteric vascular bed of the cat. Eur J Pharmacol 1998; 343: 209-216.

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8. Sumina EN, Shugaev VA, Shugaev VA. [The mechanism of circulatory hypoxia in acute with sodium fluoride poisoning]. Farmakol Toksikol 1978; 41: 480-482.

9. Bronner C, Landry Y. Kinetics of the inhibitory effect of flavonoids on histamine secretion from mast cells. Agents Actions 1985; 16: 147-151.

10. Pearce FL, Befus AD, Bienenstock J. Mucosal mast cells. III. Effect of quercitin and other flavonoids on antigen-induced histamine secretion from rat intestinal mast cells. J Allergy Clin Immunol 1984; 73: 819-823.

11. Marcuard SP, Albernaz L, Khazanie PG. Omeprazole therapy causes malabsorption of cyanocobalamin (vitamin B-12). Ann Intern Med 1994; 120: 211-215.

12. Juckett M, Zheng Y, Yuan H, Pastor T, Antholine W, Weber M, Vercellotti G. Nitric oxide donors modulate ferritin and protect endothelium from oxidative injury. Free Radic Biol Med, 20(1):63-73 1996.

13. Walker, H. Carbon monoxide poisoning is still an underrecognised problem. British Medical Journal 1999; 319: 1082-1083.

14. Kozma F, Johnson RA, Zhang F, Yu C, Tong X, Nasjletti A. Contribution of endogenous carbon monoxide to regulation of diameter in resistance vessels. Am J Physiol 1999; 276: Pt 2 R1087-1094.

15. Qureshi IA, Xi XR, Khan IH, Wu XD, Huang YB. Monthly measurements of intraocular pressure in normal, ocular hypertensive, and glaucoma male subjects of same age group. Chang Keng I Hsueh 1997; 20: 195-200.

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17. Izumi H; Makino Y; Mohtai H; Shirakawa K; Garfield RE. Comparison of nitric oxide and prostacyclin in endothelium-dependent vasorelaxation of human umbilical artery at midgestation. Am J Obstet Gynecol, 175(2):375-81 1996 Aug.


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