Arginine, Growth Hormone and NO Supplements

Arginine is considered a semi-essential amino acid. It’s one of three amino acids (the others being methionine and glycine) that are the precursors, or starting substances, of creatine synthesis in the body. Arginine also plays a pivotal role in the urea cycle, which involves the elimination of protein metabolic by-products—toxic protein by-product ammonia converts into harmless urea in the liver, enabling the kidneys to excrete it.

In recent years arginine supplements have been associated with boosting nitric oxide. Arginine is the immediate precursor of NO synthesis in the body by way of NO synthase enzymes. Before the advent of NO supplements, however, the most popular bodybuilding use of arginine was as a growth hormone booster.

Providing arginine in an infusion of 30 grams so reliably promoted GH release that it was used as a provocative challenge to determine GH deficiency. GH release is controlled by two opposing substances. The first, growth-hormone-releasing hormone, as the name implies, promotes the release of GH from the anterior portion of the pituitary gland; GH makes up 8 percent of the gland’s weight. In the body’s typical yin-yang balancing fashion, another substance, somatostatin, puts the brakes on GH release. GH release decreases in most people as they age because the release of growth-hormone-releasing hormone dwindles, allowing somatostatin to dominate; hence the lowered GH release when people get past age 40.

Arginine blocks somatostatin activity. That means it should set in motion a rapid and significant release of GH, and it does—when provided in infusion form. But studies that have examined the fate of orally taken arginine in relation to GH release have largely been equivocal, with the majority showing little or no effect.

Various explanations have been suggested. First, whatever you eat must be processed in the liver before it’s released into the blood. The liver contains high levels of the enzyme arginase, which degrades arginine. Some have tried to overcome that formidable liver barrier by taking bigger doses of arginine in an effort to mimic the 30-gram-dose arginine infusions that we know lead to GH release. The problem is that large doses of arginine produce nausea and gastrointestinal discomfort. (If you vomit that huge oral dose of arginine, you can’t realistically expect a GH response.)

There are other problems too. For example, you can’t take any other amino acids or protein with arginine, since free amino acids compete for uptake. The presence of other amino acids in the blood is enough to blunt GH release. The same holds true for fat and carbohydrate, as GH is best released when your blood glucose and blood fat are low. That explains why taking a GH-boosting supplement before bed with any type of food renders it useless.

Even under the best conditions, only 60 percent of orally taken arginine is absorbed, and of that 10 percent is rapidly metabolized in the liver, which leaves 50 percent of the dose in the blood plasma. That’s seven times less than the dose you need to induce GH secretion.

Recent research examining the relationship between arginine and GH has produced interesting results. For example, one study looked at what happened when rats were given consistently high levels of arginine in their drinking water.1 The rats showed an increase in the gene expression of GH in the pituitary gland, along with an increase in insulin resistance. GH promotes insulin resistance by opposing the actions of insulin. Yet paradoxically, from an anabolic perspective, insulin is synergistic with GH, since GH promotes protein synthesis, while insulin prevents excess protein breakdown in muscle.

Arginine itself promotes insulin release, and that may have been a factor in the insulin resistance that turned up in the study subjects. As indicated in the rat study, arginine aids in the synthesis of GH in the pituitary gland by increasing the gene activity that governs the process. That’s significant because it shows that arginine, besides blocking somatostatin release, also favors GH release.

Another new study also looked at the effects of taking arginine prior to a weight-training workout.2 Eight healthy males were observed under four conditions:

ALL1) Placebo

2) Arginine alone

3) Placebo and exercise

4) Arginine and exercise

The subjects provided blood samples every 10 minutes for 3 1/2 hours. After giving a baseline sample, they took either seven grams of arginine or a placebo in a random, blinded protocol. On the exercise days the subjects did three sets of nine exercises, using weights equal to 80 percent of their one-rep-maximum lifts.

Exercise promotes GH release via several mechanisms. One involves the heightened release of a brain neurotransmitter called acetylcholine. That blunts the release of somatostatin, leading to higher GH levels. In addition, intense exercise promotes the release of growth-hormone-increasing hormone from the hypothalamus, further increasing GH release.

In the new study, oral arginine increased GH release when the subjects were at rest (double baseline levels), but training alone produced a greater release of GH than arginine alone (sixfold over resting levels).

Interestingly enough, the amino acid offers significant benefits to humans with diabetes, as a new study demonstrates.3 Thirty-three obese diabetic patients followed a low-calorie diet and trained on an exercise program for 21 days. They were divided into two groups, with one group on a placebo, the other on 8.3 grams of arginine a day.

Both groups lost bodyfat, but the arginine group lost more. They also experienced improved glucose metabolism and insulin sensitivity; better endothelial, or blood vessel, function; less oxidative stress and a greater sparing of lean mass during the diet. Diabetics, because of damage to the endothelium, often are deficient in NO, which leads to high blood pressure and various cardiovascular complications. Being on arginine seemed to lower blood pressure, likely the result of an improved NO profile.

The authors note that they chose the dose of 8.3 grams a day of arginine because nine grams is the minimum effective dose that avoids side effects. Doses that are too high can lead to cardiovascular problems because of fat oxidation and production of peroxynitrate free radicals that form when high levels of NO are exposed to hydrogen peroxide in the tissues.

An additional and important benefit is that arginine increased the subjects’ adiponectin levels. Adiponectin, which is secreted by fat cells, is a very useful substance because it increases insulin sensitivity and promotes the use of bodyfat as a fuel source. Diabetics and those who are obese usually lack sufficient adiponectin release, which leads to the cluster of symptoms known as the metabolic syndrome.

Speaking of adiponectin, another new study found that giving subjects the B-complex vitamin niacin dramatically increased adiponectin levels.4 Twenty-four people took an extended-release version of niacin. During the first four weeks the daily dose was increased at weekly intervals from 375 milligrams to 1,000 milligrams. The dose was maintained for a month, then increased to 1,500 milligrams a day for another six weeks. Those doses led to a 54 and 94 percent increase in adiponectin levels. Adiponectin not only helps with fat burning but also prevents metabolic syndrome, diabetes and cardiovascular disease.

Niacin, however, should never be taken before a workout, since it blocks the use of fat for fuel, prematurely exhausting limited glycogen stores. The extended-release niacin used in the study has also been linked to liver problems.

What about the NO-boosting supplements? They’re popular, but do they work as advertised? The advertisements suggest they would prove useful by promoting NO synthesis and release, which are involved in the release of various anabolic hormones, such as testosterone, growth hormone and insulin. Since NO dilates blood vessels, using the supplements should also provide greater blood flow to muscle, along with the psychological benefits of having a greater muscle pump. Boosting NO may also upgrade muscle protein synthesis while blunting catabolic effects in muscle.

A new study looked at the absorption, safety and beneficial effects of NO supplements.5 The primary ingredients are arginine and alpha-ketoglutarate, AKG being a by-product of the citric acid energy cycle in cells. Past studies show that when it’s combined with amino acids, such as ornithine, it provides anticatabolic effects in muscle. In most such studies, however, subjects got the combination through feeding tubes rather than orally.

In the first part of the study the safety and absorption characteristics of arginine and alpha-ketoglutarate, or AAKG, as the combination is called, were examined in 10 healthy men, aged 30 to 50. The men fasted for eight hours, then took four grams of either a timed-release or a regular form of AAKG. That portion of the study, as expected, led to a peak in blood levels of arginine, which were higher in the subjects who got the regular than the timed-release form.

The second part of the study involved a training component, in which 35 experienced weight-trained men were randomly assigned to take either a placebo or 12 grams of AAKG daily in three doses of four grams each. They trained four days a week for eight weeks.

The AAKG proved safe, with no effects on liver enzymes, kidney function or blood composition. Those in the AAKG group showed significantly greater gains in their one-rep bench press and anaerobic power tests than those in the placebo group.

The authors can’t explain the strength increase but suggest that it may have been because of an increase in muscle creatine levels—a highly dubious explanation at best. My view is that the strength increase was related to the high arginine intake afforded by the supplement. That may have resulted in a greater NO synthesis, which may have supported the strength gains.

References

1 Barbosa, T., et al. (2006). Chronic oral administration of arginine induces GH gene expression and insulin. Life Sci. 79(15):1444-9.

2 Collier, S., et al. (2006). Oral arginine attenuates the growth hormone response to resistance exercise. J Appl Physiol. 101(3):848-52.

3 Lucotti, P.C., et al. (2006). Beneficial effects of oral L-arginine treatment added to a hypocaloric diet and exercise training program in obese, insulin resistant type-2 diabetic patients. Am J Physiol Endocrin Metab. In press.

4 Westphal, S., et al. (2006). Adiponectin and treatment with niacin. Metabolism. 55:1283-1285.

5 Campbell, B., et al. (2006). Pharmacokinetic, safety, and effects on exercise performance of L-arginine a-ketoglutarate in trained adult men. Nutrition. 22:872-81. IM