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Nitric Oxide (Prong-2)

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Clinical Autonomic and Mitochondrial Disorders

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Abstract

Nitric oxide is a small molecule gas that is primarily produced by epithelial cells throughout the body (e.g., the inner lining of blood vessels, the blood-brain barrier, and barriers in the gut and around reproductive structures). Nitric oxide is known as the universal messenger, made in ubiquitous quantities to signal both defense mechanisms blocking harmful substances from entering the body and the mechanisms that permit helpful substances to enter the body. As such it is involved in many processes, for example, detoxification and the urea cycle, tissue regeneration, blood flow, prevention of atherosclerosis, and regulation of inflammation and oxidation. A large reservoir of nitric oxide is very important to health and wellness, but not too large. As with everything else in life, there still needs to be a proper balance. However, with the typical Western lifestyle, most do not have nearly as large a reservoir as is needed for wellness. Therefore, supplements are strongly recommended.

There are two processes by which supplemental nitric oxide may enter the body. The primary pathway is through the gut by consuming foods that are rich in the precursors to nitric oxide (e.g., L-arginine, L-citrulline, and L-carnitine). However, this pathway is limited. The secondary pathway is not rate limited and is assisted by friendly bacteria in the mouth. The secondary pathway is supplemented by products such as beetroot powder. Granted eating red beets is very healthful and does help, but it is not possible for the average person to eat enough red beets to match the nitric oxide-producing potential of one serving of beetroot powder.

The benefits of beetroot powder are discussed in examples involving heart failure, erectile dysfunction, and the nervous system. Also, there is a “dark side” to nitric oxide. Again, too much is not good either. The dark side of nitric oxide and how it may be avoided will also be discussed.

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Notes

  1. 1.

    Telomeres are nucleoprotein complexes located at both ends of eukaryotic chromosomes. These complexes consist of a six-base-pair DNA repeat (TTAGGG) and a growing list of associated proteins [69,70]. Telomeres are important structures involved in cell cycle control and essential for maintaining genome stability and integrity and for an extended proliferative life span in both cultured cells and the whole organism [71,72].

  2. 2.

    L-Arginine is the substrate for the endothelial nitric oxide synthase (eNOS) to generate nitric oxide. The L-arginine paradox refers to the phenomenon that exogenous L-arginine causes nitric oxide-mediated biological effects despite the fact that NOS are saturated with the substrate L-arginine.

  3. 3.

    Small (50–100 nanometer) flask-shaped invaginations of the plasma membrane in many vertebrate cell types, especially in endothelial cells

  4. 4.

    When fatty acids undergo beta oxidation in mitochondria, L-carnitine facilitates transports of fatty acids into the matrix of the mitochondria, and this is called the “L-carnitine fatty acid shuttle,” see Fig. 4.37.

  5. 5.

    Ischemia is an inadequate blood supply to an area of the body. Infarct is an obstruction of a blood vessel, which can cause ischemia. If the blockage is near the heart, it may cause a heart attack. If the heart attack is due to ischemia, it is usually not as severe. If the heart attack is due to an infarct (called a myocardial infarct), it can lead to sudden (cardiac) death. If the ischemia or infarct is near the brain, it is known as a stroke. As with the brain or the heart, ischemia anywhere in the body may cause the death of cells being supplied by the blocked blood vessel, and this can cause disease, including sepsis.

  6. 6.

    True, once Nitric oxide give up an electron, it then becomes a free radical. However, Nitric Oxide has a very short half-life and breaks down quickly, so it little time if any to oxidize anything else.

  7. 7.

    One to two 4 oz. glasses a day for men and one 4 oz. glass a day for women is recommended.

  8. 8.

    CAPON is an nNOS-associated protein which is highly enriched in the brain and has numerous co-localizations with nNOS. CAPON interacts with the nNOS PDZ domain through its C-terminus. CAPON competes with PSD95 for interaction with nNOS, and overexpression of CAPON results in a loss of PSD95/nNOS complexes in transfected cells. CAPON may influence nNOS by regulating its ability to associate with PSD95/NMDA receptor complexes.

  9. 9.

    PIN is a protein inhibitor of nNOS known to dissociate nNOS dimers into monomers.

  10. 10.

    Cerebral vasodilation is the vasodilation of the vessels in the meninges and in the circle of Willis. In the brain itself, there are no blood vessels, and, normally, there is no blood. Blood carries different salts, also known as electrolytes. The introduction of blood into the brain will change the electrical environment of that area of the brain and cause a change in brain patterns and damage cells (which will change brain patterns permanently). The meninges are the protective tissues surrounding the brain. They help to maintain proper pressures within the brain and contain the cerebral spinal fluid which bathes the brain in the nutrients it needs to function. The circle of Willis is the blood vessels supplying “blood to the brain.” In actuality, they bring blood close to the brain so that the nutrients needed may diffuse into the cerebral spinal fluid. Also, the brain has “sensors” that monitor the blood so that the brain “knows” what is needed by the rest of the body, as it works to help maintain homeostasis. Cerebral vasodilation helps to facilitate the delivery of nutrients to the brain and allows the meninges to be more flexible, thereby relieving pressure in the brain.

  11. 11.

    Dynamic PE is an abnormal, “hidden” parasympathetic excess. It is hidden in a sympathetic challenge. Normally with a sympathetic challenge, the parasympathetics first decrease then the sympathetics react, increase. With a dynamic PE, the parasympathetics instead increase abnormally. This forces a (secondary) sympathetic excess (SE), causing abnormal increases in heart rate, blood pressure, and cardiac output, as well as anxiety and exaggerated pain and stress responses. The secondary SE also often masks the (primary) PE. If the SE responses are treated, often the PE is exacerbated. Rather treat the PE [192], then the SE is relieved, and then the results of SE are eventually relieved.

  12. 12.

    The L-arginine-ADMA competition: while there is typically plenty of L-arginine (the rate limiter in the production of nitric oxide) in the cell, ADMA is promoted under conditions of too much nitric oxide (during prolonged illness or prolonged inflammation).

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  1. Franklin Cardiovascular Associates, PA and Autonomic Dysfunction and POTS Center, Sewell, NJ, USA

    Nicholas L. DePace MD, FACC

  2. TMCAMS, Inc., Franklin Cardiovascular Associates, PA and Autonomic Dysfunction and POTS Center, Richboro, PA, USA

    Joseph Colombo

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DePace, N.L., Colombo, J. (2019). Nitric Oxide (Prong-2). In: Clinical Autonomic and Mitochondrial Disorders. Springer, Cham. https://doi.org/10.1007/978-3-030-17016-5_4

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