Arginine, Amino Ammo

Proteins are composed of various combinations of the 22 amino acids, nine of which are considered essential for adults. Essential means that they cannot be synthesized in the body and must be obtained from outside sources, mainly food. The other, so-called nonessential, aminos are categorized as such because they can be synthesized in the body from other aminos, not because they are unimportant. Among the aminos that fall into that category are tyrosine, which makes up two-thirds of thyroid hormone, glutamine and arginine.

Studies conducted over the past few years have discovered that many of the nonessential amino acids may be considered essential under certain conditions, including stress, trauma, wounds and various catabolic conditions that accelerate protein breakdown, or catabolism, such as serious burns. Glutamine falls into that category. Most bodybuilders are aware that glutamine may help promote anabolic, or muscle-building, effects. Thus, although glutamine is deemed a nonessential amino acid, for bodybuilders and others who are subjected to high stress levels, it becomes conditionally essential. The same holds true for arginine.

Extensive recent research shows that athletes and other people whose bodies are subjected to high-stress conditions may benefit from taking in increased levels of arginine. Arginine may be helpful in maintaining immune system competence under stressful conditions, such as high-intensity training; may promote the release of anabolic hormones, including insulin and growth hormone; and is a precursor for creatine synthesis in the body, as well as for other growth factors such as polyamines. The most interesting effect of arginine, however, is its role as a direct precursor for the synthesis of nitric oxide, a substance that affects many vital functions in the body, including protein synthesis and muscle repair after training.

The use of arginine as an anabolic aid and immune-system stimulant was popularized in the 1982 best-seller Life Extension by Durk Pearson and Sandy Shaw. In that book Shaw described how she took 10 grams of oral L-arginine on an empty stomach to speed the healing of her broken foot. As a side effect, she said, she lost 25 pounds of fat while gaining five pounds of muscle in six weeks. Shaw and Pearson attributed Shaw's significantly improved body composition to an increased rate of growth hormone release due to her arginine intake.

While Pearson and Shaw may have popularized the use of oral arginine supplements, the amino was well known to scientists long before any concept of life extension existed. Researchers first isolated arginine from seedlings in 1886, and nine years later it was identified as a component of animal proteins. The realization that arginine can be synthesized by mammals occurred in 1930, and at around the same time it was found to be essential for creatine synthesis in the body. Further studies showed that arginine was needed for the growth of chicks but not adult birds, thus indicating it was essential for young, growing animals but not for adults.

The designation that arginine was unessential lasted until the 1980s, when research showed that it was conditionally essential in situations involving trauma or disease. The excitement over the capabilities of arginine reached a fever pitch in scientific circles in 1987, when it was identified as the precursor for the synthesis of nitric oxide in the body.

Arginine can be synthesized in the intestine from another amino acid called citrulline, which, in turn, can be synthesized from glutamine. Citrulline also exists naturally in watermelon and casein, the major milk protein, but under high-stress conditions the body's synthesis of arginine may not suffice. Sixty percent of the arginine produced in the body occurs due to the conversion of citrulline by enzymes in the kidneys.

Much of arginine's benefit is based on its being the precursor to nitric oxide; however, arginine has several other functions and benefits that are independent of that relationship.ALL

Cardiovascular Benefits

Most of the cardiovascular benefits of arginine are related to its role in the production of nitric oxide (NO). NO used to be referred to as 'endothelial relaxation factor' because of its potent effects on relaxing and dilating the endothelium, the smooth muscle found in the linings of blood vessels, an effect that leads to a lowering of blood pressure.1 It's also known to inhibit the aggregation of platelets, the elements needed for blood clotting. Under certain conditions, however, excessive clotting can lead to heart attacks and strokes.

While NO is normally produced in the endothelium, its production is impaired in people who have atherosclerosis, and that leads to reduced dilation of blood vessels. That, in turn, leads to a vicious circle, in which the blood vessel linings narrow, increasing the risk of heart attacks and strokes. Based on that effect, arginine may increase local production of NO and thus help prevent atherosclerosis.

In a study introduced at the 1995 meeting of the American Heart Association, researchers found that giving older people supplemental L-arginine restored lost elasticity in aged blood vessels. The mechanism involves long-term damage to the endothelium, which causes a local deficiency of nitric oxide. Providing arginine restores nitric oxide production in the vessels, leading to increased dilation and flexibility. Another study found that giving rats L-arginine relieved the adverse effects of hypertension, or high blood pressure, on heart function.2

Arginine may also lower blood pressure by inhibiting the production of a substance called angiotensin-converting enzyme.3 An entire class of drugs used to treat hypertension works by inhibiting the same enzyme; however, the study with arginine used intravenous doses of the amino acid.

The effects of arginine on blood vessels are due to its role as a direct precursor to nitric oxide. NO works by increasing the release of cyclic GMP, which leads to blood vessel relaxation. That's also the way the popular drug Viagra works, which brings up the question, Does arginine have a positive effect on sexual function?

Natural Viagra?

We've known about the effects of arginine on sexual function since 1944. In a study published that year, feeding an arginine-deficient diet to nine men decreased sperm counts by 90 percent while increasing the percentage of nonmotile sperm 10-fold.4 Arginine is essential for sperm formation, so it plays a vital role in male fertility. Another study found that giving infertile men only 500 milligrams of arginine a day for six to eight weeks markedly increased sperm counts and motility in the men, which led to successful pregnancies (in the men's wives, of course).5

Viagra works by increasing the level of cyclic GMP in the blood vessels of the penis, enabling the user to get an erection. Nitric oxide does that naturally, which indicates that men who respond to Viagra have deficient nitric oxide production in that area. Since arginine is the direct precursor to nitric oxide, the question is, Would taking supplemental arginine have a Viagralike effect?

In a 1994 study conducted at the New York University School of Medicine, six of 15 men who took 2,800 milligrams of arginine daily for two weeks had improved erectile function, while none of the subjects taking placebos got any effect. A more recent study that used the scientific gold standard of a double-blind, randomized, placebo-controlled protocol showed that impotent men who took five grams of arginine orally a day had significantly improved sexual function. In other words, they were able to get it up. The mechanism was thought to be enhanced nitric oxide production, coupled with nitric oxide'induced release of luteinizing-hormone-releasing hormone from the hypothalamus in the brain.6

On the other hand, another study found no significant difference in impotence scores in 32 patients who took either 500 milligrams of arginine or a placebo three times a day. It may be that arginine only works in cases involving a lack of localized nitric oxide production.7 Arginine and Immune Function

As with glutamine, arginine is required for optimal functioning of the immune system. That's important for athletes or anyone engaged in regular intense training. Vigorous training is known to depress immune function, leaving trainees open to increased incidence of infections. Taking amino acids such as glutamine and arginine may counteract that immunity effect.

Arginine is essential for the function of various immune cells, such as macrophages, neutrophils and lymphocytes. The immune cells use the nitric oxide produced as a result of arginine ingestion to destroy bacteria and other invading organisms. When combined with oxygen, nitric oxide functions in that manner as a free radical.

Other studies show that arginine increases the effect of chemotherapy drugs on tumor cells while reducing their immune suppressive effects. Arginine also aids healing of various tissues, including tendons and bone, and taking supplemental arginine leads to quicker healing of wounds, burns and the gastrointestinal tract. Much of that effect is attributed to increased nitric oxide synthesis as well as upgraded activity of the arginine-activated enzyme, arginase, which produces a favorable environment for fibroblast and collagen production, both of which are needed for connective tissue repair.8

Arginine may also help protect kidney function as people age. That's significant because most older people retain only 40 percent of kidney function. One study found that supplemental arginine protected against age-related destruction of the internal filtering units of the kidneys while increasing their function by 50 percent.9

Arginine and Athletic Enhancement

The most familiar use for supplemental arginine is as a growth hormone releaser. It's controversial, since not all studies show a significant effect of arginine in promoting growth hormone release. What isn't argued is the fact that intravenous doses averaging 30 grams of arginine do invariably provoke a significant GH release within 30 to 60 minutes. In fact, giving intravenous arginine was formerly used as a direct test for GH-releasing function. Arginine promotes GH secretion by inhibiting the release of somatostatin, a substance produced in the brain that inhibits GH release.10 The most quoted study finding a favorable effect of arginine on GH release involved an oral dose of 1.2 grams of L-arginine and 1.2 grams of L-lysine, which led to a 700 percent increase in GH levels and a 200 percent increase in insulin levels.11 An interesting aspect of the study was that neither amino acid alone, even in larger doses, had any effect on GH release.

A study of bodybuilders who took ornithine, which is made in the body from arginine, found that a 12-gram oral dose increased GH levels by 300 percent without affecting insulin release.12 Lower doses had no effect. In a follow-up study 11 competitive weightlifters, ages 19 to 35, took two grams a day of ornithine, arginine and lysine for four days, but there was no effect on either GH or insulin.13 In another study involving seven male bodybuilders, researchers likewise found no effect on GH release when the subjects took 2.4 grams of arginine and 2.4 grams of lysine,14 while yet another study found that giving subjects 1,500 milligrams each of arginine and lysine didn't affect exercise-induced release of GH but did increase GH release under resting conditions.15

Adding to the confusion was a study presented at the 1998 Experimental Biology meeting. Eight men, ages 20 to 42, took three-, six- or nine-gram oral doses of arginine or a placebo. Two of them showed zero response at any dose, while another two showed GH elevations of 200 to 1,000 percent. The four remaining men averaged 70 to 120 percent increases in GH levels. The only factor that appeared to affect GH release in this study was body mass index, with a higher body mass index, or more fat, leading to a reduced rate of GH release.

Still another study involved giving five grams of arginine to older and younger subjects under both resting and weight-training conditions.16 Arginine had no effect on increasing GH release during exercise, but for unknown reasons it did appear to blunt GH during exercise in the younger subjects. One reason arginine isn't as effective orally as it is intravenously in producing a GH-release effect is that oral doses of 10 grams average only 20 percent absorption.17 Arginine taken orally is catabolized extensively by intestinal cells, as is glutamine taken orally. Another barrier to oral absorption is the liver enzyme arginase, which degrades arginine. The greater the oral intake of arginine, the more active arginase becomes. A low-sodium diet leads to lower plasma levels of arginine due to upgraded arginase activity.18

Even if oral arginine isn't an effective GH releaser, it still offers beneficial effects for athletes. One study found that arginine stimulated insulin-mediated glucose uptake.19 The body also needs arginine to synthesize creatine. Normal creatine synthesis in the body requires 2.3 grams of arginine daily.20 A recent study of mice found that arginine increased aerobic capacity in both nitric oxide'deficient and normal mice by increasing oxygen delivery to muscles.21 The researchers also indicated that prolonged exercise may induce a state of relative nitric oxide deficiency in hard-training athletes. Finally, recent studies show that nitric oxide is involved in both strength increases after training and muscle repair that leads to muscular growth.22,23 Arginine is also important for its role in the urea cycle, a process occurring in the liver involving protein metabolism by-products such as ammonia being converted into urea and then excreted through the kidneys.

Side effects are rare with arginine taken orally, though doses of more than 30 grams may cause nausea and diarrhea. Cases of herpes simplex type 1, or cold sores in the mouth area, may become worse in some people after using oral doses of arginine, since the herpes virus favors arginine as a replication substrate. That's easily controlled, however, if you also take the amino acid L-lysine, which nullifies the effect.

Editor's note: Due to its effect on muscle glycogen storage and blood flow via nitric oxide production, arginine is being included in many postworkout supplements, such as Muscle-Link's RecoverX. For more information, see page 138 of the Nov \'01 issue of IRONMAN. References

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2 Susic, D., et al. (1999). Prolonged L-arginine on cardiovascular mass and myocardial hemodynamics and collagen in aged spontaneously hypertensive rats and normal rats. Hypertension. 33:451-455.

3 Higashi, Y., et al. (1995). Intravenous administration of L-arginine inhibits angiotensin-converting enzyme in humans. J Clin Endocrinol Metab. 80:2198-2202.

4 Holt, L.E., et al. (1944). Observations on amino acid deficiencies in man. Trans Assoc Am Physicians. 58:143-156.

5 Tanimura, J. (1967). Studies on arginine in human semen. Part 2. The effects of medication with L-arginine HCL on male infertility. Bull Osaka Med School. 13:84-89.

6 Chen, J., et al. (1999). Effect of oral administration of high-dose nitric oxide donor L-arginine in men with organic erectile dysfunction: results of a double-blind, randomized, placebo-controlled study. BJU Int. 83:269-73.

7 Klotz, T., et al. (1999). Effectiveness of oral L-arginine in first-line treatment of erectile dysfunction in a controlled crossover study. Urol Int. 63:220-23.

8 Shearer, J., et al. (1997). Differential regulation of macrophage arginine metabolism: a proposed role in wound healing. Am J Physiol. 272:E181-90.

9 Beckelhoff, J.F., et al. (1997). Long-term dietary supplementation with L-arginine prevents age-related reduction in renal function. Am J Physiol. 272:R1768-R1774.

10 Gianotti, L., et al. (2000). Arginine counteracts the inhibitory effect of recombinant human insulinlike growth factor 1 on the somatotroph responsiveness to growth-hormone-releasing hormone in humans. J Clin Endocrinol Metab. 85:3604-3608.

11 Isidori, A., et al. (1981). A study of growth hormone release in man after oral administration of amino acids. Cur Med Res Opin. 7:475-481.

12 Bucci, L., et al. (1990). Ornithine ingestion and growth hormone release in bodybuilders. Nutr Res. 10:239-245.

13 Fogelholm, G.M., et al. (1993). Low-dose amino acid supplementation: no effects on serum human growth hormone or insulin in male weightlifters. Int J Sports Nutr. 3:290-97.

14 Lambert, M.I., et al. (1993). Failure of commercial oral amino acid supplements to increase serum growth hormone concentrations in male bodybuilders. Int J Sports Nutr. 3:298-305.

15 Suminski, R.R., et al. (1997). Acute effect of amino acid ingestion and resistance exercise on plasma growth hormone concentration in young men. Int J Sports Nutr. 7:48-60.

16 Marcell, T.J., et al. (1999). Oral arginine does not stimulate basal or augment exercise-induced GH secretion in either young or old adults. J Gerontol. 54A:M395-M399.

17 Yangphao, O., et al. (1999). Pharmacokinetics of intravenous and oral L-arginine in normal volunteers. Br J Clin Pharm. 47:261-66.

18 Kitiyakara, C., et al. (2001). Effects of dietary salt intake on plasma arginine. Am J Physiol. 280:R1069-R1075.

19 Paolisso, G., et al. (1997). L-arginine but not d-arginine stimulates insulin-mediated glucose uptake. Metabolism. 46:1068-1073.

20 Guoyao, W.U., et al. (1998). Arginine metabolism: nitric oxide and beyond. Biochem J. 336:1-17.

21 Maxwell, A.J., et al. (2001). L-arginine enhances aerobic exercise capacity in association with augmented nitric oxide production. J Appl Physiol. 90:933-938.

22 Folland, J.P., et al. (2000). The influence of nitric oxide on in vivo human skeletal muscle properties. Acta Physiol Scand. 169:141-148.

23 Anderson, J. (2000). A role for nitric oxide in muscle repair: nitric oxide'mediated activation of muscle satellite cells. Molecular Biol Cell. 11:1859-74. IM