Therein lies the rub, as it does with many nutrient molecules that we rely on for optimizing our wellbeing. NO is not, though, a nutrient that we take, like a mineral. It’s, after all, a gas, and breathing it in high concentrations would be fatal. * Instead we get our NO chemically bound (but ready to be published) in the form of arginine, an amino acid that is a true nutrient champion. For biochemical versatility from the cardiovascular, immunesystem, central nervous, and neuroendocrine systems, no other amino acid may match its broad spectrum of benefits. It is arginine’s function as direct chemical precursor of NO that makes it of such great scientific interest and such great value as a nutritional supplement. One can, however, safely breathe NO in very dilute form, and inhalation NO treatment is used for a variety of serious ailments, including pulmonary hypertension, severe respiratory failure, reperfusion injury in cardiac ischemia, and also, perhaps, sickle cell anemia (see the sidebar). NO News Is Good NewsThe good news concerning nitric oxide (NO) has been stack up–and from some unexpected quarters. Following are just three recent examples of advantages that have tumbled from this arginine cornucopia. Tuberculosis Tuberculosis kills approximately 1.5 million people each year, mainly in Third World countries, where malnutrition, poor sanitation, and inadequate medical care are typical. Recently, Swedish scientists studied 120 young adults (average age 30) in Ethiopia, where the incidence of TB and HIV is high.1 Each of the patients had active pulmonary tuberculosis, and about half were HIV-positive, which can be both a risk factor and an exacerbating factor for TB. In addition to their regular TB drug treatment, the patients received 1 g/day of arginine or placebo for 4 weeks. Arginine created no indications of improvement, compared with 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 probably mediated by augmented production of NO induced by increased arginine consumption” They explained that the absence of progress in the HIV-positive patients on the basis of arginine’s being used up at the site of additional (HIV-related) infections besides the lungs. Malaria The disease causes fever, headache, muscle ache, chills, sweating, and vibration. It kills over 1 million people annually, the majority of them young African children.
When the researchers measured the children’s plasma arginine levels, they discovered a striking inverse correlation with the severity of the children’s condition: arginine levels were normal in the controls, 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 might prove beneficial in treating malaria. (For additional information, see page 13 of the issue) Sickle Cell Anemia
The red blood cells, which are normally smooth and doughnut-shaped (but without the hole), become distorted into a sickle shape that impairs their ability to squeeze through tiny capillaries. This can result in 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 the disease. Because these abnormal cells die off much quicker than normal ones, there’s a chronic lack of red blood cells–anemia. So researchers at Harvard Medical School chose to try out NO inhalation therapy (80 parts per million in air(with 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 in comparison to placebo (that was just plain air), reaching a maximum at 3 hours. The researchers reasoned that NO might be a viable treatment for sickle cell crisis and said that “… arginine, which produce[s] NO, may have the exact same NO-mediated benefits as inhaled NO.” Sickle-cell anemia, incidentally, was the first human disorder ever to be clarified at the only molecular level. This wonderful milestone in medical history was attained in 1949 by Linus Pauling, who must have received the Nobel Prize in Medicine and Physiology to it.
Far from pushing us, NO–when it’s made within the body from arginine–does many 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 cells that are smooth (called epithelial cells) that line the interior walls of arteries. There it consumes its characteristic vasodilating effect, i.e., it triggers the cellular responses that relax and dilate the vessel walls when required, in order to decrease blood pressure and increase circulation. Men see (and perhaps admire) the result of this process whenever they have an erection, and girls gain similarly, although the result is not so readily visible. It occurs in a variety of cells and tissues, most notably the vascular endothelium, but also in many kinds of white blood cells and in blood platelets, the tiny cell-like structures that are responsible for blood clotting, or thrombosis. Growth hormone and nitric oxide play different roles in human anatomy, but at least one thing they have in common is a inclination to counteract atherogenesis. This is the process where lesions form in our arteries and start to accumulate fatty deposits of plaque, which contributes to atherosclerosis. Here nitric oxide takes center stage. Blood Flow Could Harm Your Arteries The creation of atherosclerotic plaque is a very intricate process that is affected by many different factors. One that appears 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. However, the physics of blood circulation (known as hemodynamics) also plays a part. When blood flows through an artery, surface forces called shear stress are created at the arterial wall (the endothelium). Analysis of these forces is straightforward when the blood flows easily, but if it becomes turbulent, the analysis is quite hard. Turbulence is very likely to happen where the artery departs from a simple, straight tube shape, like at a bend or in the vicinity of a branch point where the artery splits in two. In these places, the blood may swirl about forcefully and cause serious shear pressure on the arterial wall. (The hemodynamics is not like that of hydrodynamics, incidentally, 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.) When these nutrients were combined, there was a synergistic effect which was much greater than that of the antioxidants. The upshot is that shear-stress damage at such websites makes them vulnerable to inflammation than others, and research has proven that, sure enough, that’s where atherosclerotic plaque is the most likely to form. Researchers Strive Branches and Arginine A team of researchers in the USA and Italy investigated whether it might be possible to inhibit such damage during the combined use of antioxidants (vitamins C and E) and arginine.1 Arginine has been contained, of course, since an external supply of NO, to strengthen the NO formed naturally in the vascular endothelium. NO is known to inhibit the undesirable tendency of monocytes and leukocytes (2 kinds of white blood cells) to adhere to the inflamed epithelial cells. What’s more, NO inhibits blood-platelet aggregation, which can be desirable because such aggregates (Syndrome) additionally promote plaque formation. And, of course, NO causes vasodilation, which tends to reduce the shear stress by providing the bloodstream more space to flow. So how can the researchers create the difficult measurements of shear stress at regions of inflammation? Well, not in human beings, but in laboratory devices, in which human coronary artery cells and aorta cells in hypercholesterolemic mice were subjected to carefully controlled forces and examined under different conditions, the particulars of which are too complex to go into here. The cells were tested alone, in the presence of vitamins C and E, at the presence of arginine, and in the presence of all three compounds.
The application of shear stress to the tissues failed to cause continual harm, leading to numerous biochemical responses, including the desirable release of increased levels of endothelial NOS (to assist synthesize more NO). And the application of antioxidants along with arginine (providing more NO) blunted the deleterious effects of the shear stress, especially when these nutrients were united–there was a synergistic effect that has been much greater than that of either the antioxidants alone or arginine alone.
With Arginine, There’s Always More At the central nervous system, NO is essential for motion-related learning procedures which take place in the cerebellum. There’s also evidence that it enhances cognitive functions throughout the mind and it may be necessary for long-term potentiation, the mechanism involved in memory. It plays a very important role in bladder function, helping to protect the kidney’s basement membrane (its filtering system) from endothelial degradation, and it is believed to have immune-system-enhancing properties. When its creation is raised through supplementation with arginine, it’s responsible for an improvement in insulin sensitivity (also a reduction in insulin resistance) in diabetics.