Therein lies the rub, as it does with many nutrient molecules we rely on for maximizing our health. NO isn’t, however, a nutrient that people take, like a mineral. It’s, after all, a gasoline, and breathing it at high concentrations will be fatal. * Rather we get our own NO chemically bound (although ready to be published) in the form of arginine, an amino acid that is a genuine nutrient champion. For biochemical versatility from the cardiovascular, immunesystem, central nervous, and neuroendocrine systems, no other amino acid may match its broad spectrum of advantages. It’s arginine’s function as direct chemical precursor of NO that makes it of these great scientific interest and such great value as a nutritional supplement. One may, however, safely breathe NO in extremely dilute form, and inhalation NO therapy is used for a number of serious ailments, such as pulmonary hypertension, severe respiratory failure, reperfusion injury in cardiac ischemia, and also, perhaps, sickle cell anemia (see the sidebar). NO News Is Good NewsThe fantastic news about nitric oxide (NO) has been stack up–and from some unexpected quarters. Following are three recent examples of advantages that have tumbled from the arginine cornucopia.
Tuberculosis kills approximately 1.5 million people each year, primarily in Third World countries, where malnutrition, inadequate sanitation, and inadequate medical care are common. Besides their routine TB drug treatment, the patients received 1 g/day of either arginine or placebo for 4 weeks. Arginine produced no signs of progress, in comparison to placebo, in the HIV-positive TB patients. The HIV-negative TB patients, however, did raise significantly. The authors stated, “The improved clinical outcome found in HIV–TB+ patients was likely mediated by augmented production of NO induced by increased arginine consumption” They explained that the lack of improvement in the HIV-positive patients on the basis of arginine’s being consumed in the site of other (HIV-related) diseases besides the lungs.
It kills more than 1 million people annually, the majority of them young African children. The very painful and deadly form of the disease is cerebral malaria, which entails high fever, severe headache, drowsiness, confusion, and delirium. Based on prior understanding of the antiparasitic action of NO, researchers in the USA, Australia, and Tanzania recently collaborated in a study on 75 young Tanzanian children (average age 4), of whom 17 had “uncomplicated” malaria and 39 had cerebral malaria (18 of the latter expired); another 19 were healthful and served as commands.2 Once the researchers measured the children’s plasma arginine levels, they found that a striking inverse correlation with the severity of the children’s condition: arginine levels were normal from the controls, so low in those with uncomplicated malaria, and also quite low in those with cerebral malaria. This suggested to the researchers who raising NO degrees through arginine supplementation may prove beneficial in the treatment of malaria. (For additional information, see page 13 of this matter) Sickle Cell Anemia
Linus PaulingSickle cell anemia is a hereditary blood disease which affects millions of individuals worldwide, mostly blacks and Hispanics. The red blood cells, which are normally smooth and doughnut-shaped (although without the hole), eventually become distorted into a sickle shape that impairs their ability to squeeze through tiny capillaries. This can lead to pileups of the sickled cells, depriving tissues from the affected regions of critical oxygen. The result is pain, sometimes severe, which is the hallmark symptom of this disease. Because these abnormal cells die off much quicker than normal ones, there is a chronic lack of red blood cells–anemia. During episodic flare-ups called sickle cell crisesthat are extremely debilitating, the blood levels of arginine and NO have been proven to be abnormally low and are inversely correlated with the severity of the pain. So researchers at Harvard Medical School chose to try out NO inhalation treatment (80 parts per million in air, using a face mask) for 4 hours to check whether it would provide relief.3 The patients had been 20 children (average age 16, and all of them black). They reported significant pain reduction compared with placebo (which was just plain atmosphere), reaching a maximum in 3 hours. The researchers reasoned that NO might be a viable treatment for sickle cell crisis and said that “… arginine, which create[s] NO, might have the exact same NO-mediated advantages as inhaled NO.” Sickle-cell anemia, by the way, was the first human disorder ever to be clarified at the only molecular level. This wonderful milestone in medical history has been achieved in 1949 by Linus Pauling, who should have received the Nobel Prize in Medicine and Physiology for it. References
Far from pushing us, NO–when it’s made within the body from arginine–does lots of things to make sure our great health. It helps regulate our blood pressure, for one thing, when it’s synthesized in the vascular endothelium, the layer of smooth cells (known as epithelial cells) that line the inside walls of arteries. There it consumes its feature vasodilating effect, i.e., it triggers the cellular reactions that relax and dilate the vessel walls when needed, so as to decrease blood pressure and increase blood flow. Men view (and maybe admire) the result of this process every time that they have an erection, and girls benefit alike, even though the effect isn’t so easily observable. It occurs in many different tissues and cells, most notably the vascular endothelium, but also in many types of white blood cells and also in blood platelets, the small cell-like structures which are responsible for blood clotting, or thrombosis. Consequently, zero functions in the cardiovascular system as a central regulator of vascular tone, cellular endothelial adhesion, platelet aggregation, and thrombosis. Arginine’s other claim to fame, biochemically speaking, is the fact that it also stimulates the release of human growth hormone, a molecule which functions vital functions in our bodies even long after we have stopped growing. Growth hormone and nitric oxide play very different roles in human physiology, but at least one thing that they have in common is a tendency to counteract atherogenesis. This is the procedure by which lesions form in our arteries and start to accumulate fatty deposits of plaque, which leads to atherosclerosis. Blood Flow Could Harm Your Arteries The creation of atherosclerotic plaque is a very complex process that’s influenced by many distinct factors. One which seems to be crucial is inflammation of the vascular endothelium. That can be brought about in a variety of ways, some of which are purely biochemical. But the physics of blood flow (known as hemodynamics) also plays a role. When blood flows through an artery, surface forces called shear pressure are created in the anterior wall (the endothelium). Investigation of these forces is straightforward once the blood flows easily, but when it becomes disruptive, the analysis is very hard. Turbulence is likely to happen where the artery departs from a simple, straight tubing contour, like in a bend or in the vicinity of a division point where the artery splits in 2. At such places, the bloodstream may swirl about forcefully and cause severe shear pressure on the arterial wall. (The hemodynamics isn’t like that of hydrodynamics, by the way, because blood is unlike water in certain fundamental respects; at the jargon of physics, it’s a non-Newtonian fluid, whereas water is a Newtonian fluid.) Whenever these nutrients were united, there was a synergistic effect which has been much larger than that of either the antioxidants. The upshot is that shear-stress damage at such websites makes them more vulnerable to inflammation compared to others, and research has proven that, sure enough, that is where atherosclerotic plaque is the most likely to form. In the inflammatory process, the vascular endothelial cells discharge destructive free radicals and reactive oxygen species, which further damage the tissues and make them hospitable to plaque deposits. Researchers Try Antioxidants and Arginine A group of researchers in the USA and Italy investigated whether it would be possible to inhibit such harm during the combined use of antioxidants (vitamins E and C) along with arginine.1 Arginine was contained, of course, as an external source of NO, to augment the NO formed naturally in the vascular endothelium. NO is known to inhibit the undesirable tendency of monocytes and leukocytes (2 types of white blood cells) to adhere to this inflamed endothelial tissues. What’s more, NO inhibits blood-platelet aggregation, which is desirable because these aggregates (clots) also contribute to plaque formation. And, of course, NO causes vasodilation, which tends to reduce the shear stress by giving the bloodstream more space to flow. So how can the researchers make the difficult measurements of shear stress at areas of inflammation? Well, not in human beings, but also in lab devices, where human coronary artery cells and aorta cells in hypercholesterolemic mice were subjected to carefully controlled forces and examined under different conditions, the details of which are too complex to go into here. The cells were examined independently, in the presence of vitamins C and E, at the presence of arginine, and in the presence of all three chemicals. Antioxidants and Arginine Work Synergistically The application of shear stress to the tissues failed to cause inflammatory harm, leading to numerous biochemical responses, including the desirable release of increased amounts of endothelial NOS (to help synthesize more NO). Along with the application of antioxidants along with arginine (supplying more NO) blunted the deleterious effects of the shear stress, especially when these nutrients were united–there was a synergistic effect that was much greater than that of either the antioxidants alone or arginine alone. * The authors noted that this is in accord with the striking body of evidence that arginine supplementation reduces the symptoms of coronary heart disease in patients.
With Arginine, There’s Always More In the central nervous system, NO is essential for motion-related learning processes that happen in the cerebellum. There is also evidence that it improves cognitive functions through the brain and it may be necessary for long-term potentiation, the mechanics involved in memory. It plays a vital role in kidney function, helping to protect the kidney’s basement membrane (its own filtering system) from age-related degradation, and it’s believed to have immune-system-enhancing properties. When its production is increased through supplementation with arginine, it’s in charge of an improvement in insulin sensitivity (a reduction in insulin resistance) in diabetics.