Arginine Offers the Power of Nitric Oxide
The Benefits of Arginine Keep on Coming
Nitric oxide release is the key to this amazing amino acid’s role in our health
By Will Block
ome things in science are surpassingly strange, and one of them is the fact that nitric oxide (NO), a poisonous gas and air pollutant, plays a key role in many important functions in the human body. We couldn’t be healthy without it—indeed, we couldn’t live without it. We need our NO in the right amounts, in the right places, at the right times.
Therein lies the rub, as it does with many nutrient molecules we rely on for optimizing our health. NO is not, however, a nutrient that we take, like a vitamin. It is, after all, a gas, and breathing it in high concentrations would be fatal.* Instead, we get our NO chemically bound (but ready to be released) in the form of arginine, an amino acid that is a true nutrient champion. For biochemical versatility in the cardiovascular, immune, central nervous, and neuroendocrine systems, no other amino acid can match its wide spectrum of benefits. It is arginine’s role as the direct chemical precursor of NO that makes it of such great scientific interest and such great value as a nutritional supplement.
NO News Is Good News
The good news about nitric oxide (NO) continues to pile up—and from some unexpected quarters. Following are three recent examples of benefits that have tumbled out of the arginine cornucopia.
Tuberculosis kills about 1.5 million people each year, primarily in Third World countries, where malnutrition, poor sanitation, and inadequate medical care are common. Recently, Swedish scientists studied 120 young adults (average age 30) in Ethiopia, where the incidence of TB and HIV is high. All the patients had active pulmonary tuberculosis, and about half were HIV-positive, which is both a risk factor and an exacerbating factor for TB. In addition to their regular TB drug therapy, the patients received 1 g/day of arginine or placebo for 4 weeks.
Arginine produced no signs of improvement, compared with placebo, in the HIV-positive TB patients. The HIV-negative TB patients, however, did improve significantly. The authors stated, “The improved clinical outcome observed in HIV–/TB+ patients was probably mediated by augmented production of NO induced by increased arginine intake.” They explained the lack of improvement in the HIV-positive patients on the basis of arginine’s being used up at the site of other (HIV-related) infections besides the lungs.
Whereas TB is caused by a bacterium and is spread primarily by coughing, malaria is caused by a tiny parasite transmitted by the bite of a female mosquito. The disease causes fever, headache, muscle ache, chills, sweating, and shaking. It kills more than 1 million people annually, most of them young African children. The most painful and deadly form of the disease is cerebral malaria, which entails high fever, severe headache, drowsiness, confusion, and delirium.
Based on prior knowledge of the antiparasitic activity of NO, researchers from the United States, 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 died); the other 19 were healthy and served as controls.
When the researchers measured the children’s plasma arginine levels, they found 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 very low in those with cerebral malaria. This suggested to the researchers that increasing NO levels through arginine supplementation might prove beneficial in the treatment of malaria. (For more information, see page 13 of this issue.)
Sickle Cell Anemia
Sickle cell anemia is a hereditary blood disease that affects millions of people worldwide, primarily blacks and Hispanics. 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 lead to pileups of the sickled cells, depriving tissues in the affected areas of vital oxygen. The result is pain, sometimes severe, which is the hallmark symptom of the disease. Because these abnormal cells die off much faster than normal ones, there is a chronic shortage of red blood cells—anemia.
During episodic flare-ups called sickle cell crises, which are extremely painful, the blood levels of arginine and NO have been found to be abnormally low and are inversely correlated with the severity of the pain. So researchers at Harvard Medical School decided to try NO inhalation therapy (80 parts per million in air, using a face mask) for 4 hours to see whether it would provide relief. The patients were 20 youngsters (average age 16, and all of them black). They reported significant pain reduction compared with placebo (which was just plain air), reaching a maximum at 3 hours. The researchers concluded that NO may be a viable therapy for sickle cell crisis and said that “. . . arginine, which produce[s] NO, may have the same NO-mediated benefits as inhaled NO.”
Sickle-cell anemia, by the way, was the first human disease ever to be explained at the purely molecular level. This great milestone in medical history was achieved in 1949 by Linus Pauling, who should have received the Nobel Prize in Medicine and Physiology for it.
- Schön T, Elias D, Moges F, Melese E, Tessema T, Stendahl O, Britton S, Sundqvist T. Arginine as an adjuvant to chemotherapy improves clinical outcome in active tuberculosis. Eur Respir J 2003;21:483-8.
- Lopansri BK, Anstey NM, Weinberg JB, Stoddard GJ, Hobbs MR, Levesque MC, Mwaikambo ED, Granger DL. Low plasma arginine concentrations in children with cerebral malaria and decreased nitric oxide production. Lancet 2003;361:676-8.
- Weiner DL, Hibberd PL, Betit P, Cooper AB, Botelho CA, Brugnara C. Preliminary assessment of inhaled nitric oxide for acute vaso-occlusive crisis in pediatric patients with sickle cell disease. JAMA 2003;289:
Arginine Benefits the Cardiovascular System
Far from injuring us, NO—when it is made inside the body from arginine—does many things to ensure our good health. It helps regulate our blood pressure, for one thing, when it’s synthesized in the vascular endothelium, the layer of smooth cells (called epithelial cells) that line the inside walls of blood vessels. There it exerts its characteristic vasodilating effect, i.e., it triggers the cellular responses that relax and dilate the vessel walls when needed, so as to lower blood pressure and increase blood flow. Men see (and perhaps admire) the result of this process every time they have an erection, and women benefit similarly, although the effect is not so readily visible.
Arginine’s benefits derive primarily from its ability to release nitric oxide when it undergoes a chemical transformation to the amino acid citrulline; the reaction is catalyzed by the enzyme nitric oxide synthase (NOS). It takes place 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. As a result, NO 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 that it stimulates the release of human growth hormone, a molecule that serves vital functions in our bodies even long after we’ve stopped growing. Growth hormone and nitric oxide play very different roles in human physiology, but at least one thing they have in common is a tendency to counteract atherogenesis. This is the process by which lesions form in our arteries and begin to accumulate fatty deposits of plaque, which leads to atherosclerosis. Here nitric oxide takes center stage.
Blood Flow Can Harm Your Arteries
The formation of atherosclerotic plaque is a very complex process that is influenced by many different factors. One that appears to be essential is inflammation of the vascular endothelium. That can be brought about in various ways, some of which are purely biochemical. But the physics of blood flow (called hemodynamics) also plays a role. When blood flows through an artery, surface forces called shear stress are generated at the arterial wall (the endothelium). Analysis of such forces is straightforward when the blood flows smoothly, but when it becomes turbulent, the analysis is very difficult.
Turbulence is likely to occur where the artery departs from a simple, straight tube shape, such as at a bend or in the vicinity of a branch point where the artery splits in two. At such places, the blood may swirl about forcefully and cause severe shear stress on the arterial wall. (The hemodynamics is not like that of hydrodynamics, by the way, because blood is unlike water in certain fundamental respects; in 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 that was considerably greater
than that of either the antioxidants
alone or arginine alone.
The upshot is that shear-stress damage at such sites makes them more vulnerable to inflammation than others, and research has shown that, sure enough, that is where atherosclerotic plaque is most likely to form. In the inflammatory process, the vascular endothelial cells release destructive free radicals and reactive oxygen species, which further damage the cells and make them hospitable to plaque deposits.
Researchers Try Antioxidants and Arginine
A team of researchers in the United States and Italy investigated whether it would be possible to inhibit such damage through the combined use of antioxidants (vitamins C and E) and arginine. Arginine was included, 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 (two types of white blood cells) to adhere to the inflamed epithelial cells. Furthermore, NO inhibits blood-platelet aggregation, which is desirable because such aggregates (clots) also contribute to plaque formation. And, of course, NO causes vasodilation, which tends to reduce the shear stress by giving the blood more space in which to flow.
So how did the researchers make the difficult measurements of shear stress at areas of inflammation? Well, not in human beings, but in laboratory apparatus, where human coronary artery cells and aorta cells from hypercholesterolemic mice were subjected to carefully controlled forces and tested under different conditions, the details of which are too complicated to go into here. The cells were tested alone, in the presence of vitamins C and E, in the presence of arginine, and in the presence of all three compounds.
Antioxidants and Arginine Work Synergistically
The application of shear stress to the cells did cause inflammatory damage, resulting in numerous biochemical responses, including the desirable release of increased amounts of endothelial NOS (to help synthesize more NO). And the application of antioxidants and arginine (providing more NO) blunted the deleterious effects of the shear stress, especially when these nutrients were combined—there was a synergistic effect that was considerably greater than that of either the antioxidants alone or arginine alone.* The authors noted that this is consistent with the impressive 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 take place in the cerebellum. There is also evidence that it enhances cognitive functions throughout the brain and that it may be necessary for long-term potentiation, the mechanism involved in long-term memory. It plays a vital role in kidney function, helping to protect the kidney’s basement membrane (its filtering system) from age-related degradation, and it is believed to have immune-system-enhancing properties. When its production is increased through supplementation with arginine, it is responsible for an improvement in insulin sensitivity (a reduction in insulin resistance) in diabetics.
Well, we could go on and on, but you get the idea. So . . . get arginine.
- de Nigris F, Lerman LO, Ignarro SW, Sica G, Lerman A, Palinski W, Ignarro LJ, Napoli C. Beneficial effects of antioxidants and l-arginine on oxidation-sensitive gene expression and endothelial NO synthase activity at sites of disturbed shear stress. Proc Natl Acad Sci 2003;100(3):1420-25.
Will Block is the publisher and editorial director of Life Enhancement magazine.