More Healthy Uses for Arginine
Arginine Keeps Kidneys in the Pink
New Evidence for the Nitric Oxide Amino Acid's Ability
to Protect and Preserve Kidney Function

he human body is filled with surprises and paradoxes. Not many years ago, anyone who said that nitric oxide would turn out to be one of the body's most vital messenger molecules would have been thought absolutely crazy. Nitric oxide (NO), after all, is a poisonous gas - inhaling it in concentrated form will destroy your lungs and kill you. It's used in the manufacture of nitric acid, and it spews from automobile tailpipes, fouling our atmosphere by initiating chemical reactions that produce smog and acid rain. This doesn't exactly make you want to run right out and get some, does it?

Believe it or not, however (Ripley would have loved this), that nasty little molecule is also one of life's chemical jewels, a biochemical neurotransmitter that - in just the right amounts and in just the right places - mediates a host of vital bodily functions, not the least of which is getting erections. Through its action as a vasodilator (a substance that causes blood vessels to relax and thus become wider), it lowers blood pressure, and it is also mobilized by the immune system to help defend against infection and cancer.

The discoveries leading to these stunning conclusions led to a Nobel Prize in medicine for three scientists, who were as amazed as anyone else by what they had found. By defying conventional wisdom and embracing the hard evidence that led inexorably to a seemingly preposterous conclusion, they upheld one of the cardinal rules of good science: keep an open mind. Science, as that subgenius Forrest Gump might have said if he were a tad smarter, is "like a box of chocklit-covered amino acids. You never know whatchu gonna git."

ARGININE IS WHAT YOU SHOULD "GIT"
While there is no doubt that nitric oxide wields incredible biochemical power, few people know how we get it. Truth is, it's the unexpected offspring of a nice, mild-mannered amino acid we have learned to love and admire - none other than arginine. Arginine, believe it or not, is the nearly exclusive source of nitric oxide in our bodies. That alone makes arginine one of the most important nutrients there is, period.

But arginine does much more than generate nitric oxide (which it does via a reaction between one of its four nitrogen atoms with oxygen). Arginine is nothing if not versatile as a biochemical mediator of a variety of important physiological functions occurring in the cardiovascular, immune, central nervous, and neuroendocrine systems (see Arginine's Cornucopia of Benefits).

When we speak of arginine, by the way, it should be understood that we mean L-arginine, the biologically active form of this molecule; the other form, D-arginine, is biologically inactive and is not found in human proteins - or in any Life Enhancement product.

ARGININE - ALMOST AN ESSENTIAL AMINO ACID
Although arginine is generally not classified as an essential amino acid - i.e., not one that must be obtained through the diet because the body can't synthesize it in sufficient amounts - some nutritionists classify it as "conditionally essential," meaning that it is sometimes difficult for the body to synthesize it rapidly enough to maintain good health.1 In other words, it's a borderline case. Among the foods that tend to be rich in arginine are turkey, chicken, nuts, fish, chocolate, and garlic.

We will focus, in what is to follow, mainly on new evidence of arginine's importance in maintaining normal, healthy function of the kidneys, those marvelous but vulnerable waste-disposal and regulatory organs, about which we have not previously published any feature articles (see Figure 1).

Figure 1.
A kidney glomerulus, one of about one million microscopic "knots" of thin-walled capillaries through which waste molecules pass out of the blood and into the urine. This vital process is called glomerular filtration.

ARGININE RETARDS GLYCOSYLATION, AND THEREFORE AGING
In an interview (How to Get the Health Benefits of Growth Hormone) with life-extension scientists Durk Pearson and Sandy Shaw®, whose writings and products are familiar to readers of this magazine, Pearson said, "One very important thing about arginine is that it is a very powerful sacrificial target for cross-linkers. [See explanation below.] If nothing else gets you, you're going to end up having to go on kidney dialysis at the age of 90 or 100 or 120, because, throughout your lifetime, cross-linking reactions are taking place in the collagen in the basement membrane of your kidneys." (See Figure 2.)

Figure 2.
The vital filtering component of the glomerulus is the basement membrane, which "encases" the capillary walls. Among the benefits of arginine are protecting this membrane from age-related degradation (glycosylation reactions) and providing the nitric oxide needed by the capillary epithelial cells for optimal functioning.

Translation: By chemically "sacrificing" itself, arginine interferes with a kind of reaction that tends to damage the proteins in certain membranes by cross-linking them. This reaction, called glycosylation, causes the membranes to thicken and harden, a classic symptom of aging. By inhibiting glycosylation, arginine protects and preserves the membranes, and thus the functions of the organs of which they are a part - in this case, the kidneys, whose basement membranes are involved in the filtration of metabolic waste products (mostly urea) from the blood.

WHAT KIDNEYS DO
The kidneys are very complex organs that process about one liter of blood every minute, filtering out wastes and delivering them to the bladder as urine to be excreted. They maintain the correct balance of fluids, minerals, nutrients, and acid in the body. Of particular importance is their role in regulating the body's water balance and salt balance, both of which are critical for good health and for life itself. If either one gets thrown far enough off, you die. Chronic kidney failure - the gradual loss of kidney function, resulting in potassium retention (which can cause cardiac arrest) and the buildup of metabolic wastes in the blood - is most often caused by diabetes or high blood pressure. It is a serious problem, and anything that can forestall it is worth investigating.

ARGININE IS AVAILABLE IN CONVENIENT FORM
As readers of this magazine know, we have devoted ourselves to ensuring that, as Pearson put it, "nothing else gets you" (such as heart disease or cancer). Now we take up the challenge of trying to ensure that kidney failure doesn't get you either. After all, what is life extension but the systematic elimination (or diminution, at least at first) of "things that can get you"? And if, along the way, you can make yourself feel better and have enhanced energy and libido - which arginine can "git" for you - well, that's life enhancement.

Pearson and Shaw were among the first to draw public attention to the nutrient value of arginine as a dietary supplement with a myriad of health benefits. Since 1979 they have been advocating arginine - and taking it daily themselves.

NEW RESEARCH ON ARGININE'S ROLE IN KIDNEY FUNCTION
At the Teikyo University Ichihara Hospital in Chiba, Japan, researchers set out to study the effect of oral arginine on blood flow in the kidneys, as well as on the kidneys' ability to maintain sodium balance and water balance.2 They were also interested in neurohormonal factors involved in both kidney and cardiac function. The subjects of this study were not healthy individuals, but rather those with chronic heart failure (also called congestive heart failure, or CHF in either case), a debilitating, degenerative disease in which the heart gradually loses its ability to pump blood sufficiently to serve all the body's needs. Common symptoms are chronic shortness of breath and fluid retention in the lungs and legs, where the ankles typically become swollen and puffy.

In CHF, kidney function is typically impaired, and the resulting kidney failure can, in turn, exacerbate the CHF, leading to a vicious cycle. It was already known from previous research that arginine is beneficial for systemic hemodynamics (the forces involved in the circulation of blood throughout the body) in patients with CHF,3,4 but the Japanese researchers wanted to know in particular what its effect would be on renal (kidney) hemodynamics. And because the management of sodium and water balance is critical in the treatment of CHF, this too was a key aspect of the study.

Furthermore (and here we come back to our favorite gas), it is now known that arginine's offspring, nitric oxide, plays a pivotal role in regulating kidney function in patients with high blood pressure or various renal disorders.5-7 NO is produced in the vascular endothelium - that is, in the layer of smooth cells (called epithelial cells) that line the inside walls of blood vessels - where it exerts its vasodilating effect. Impairment of NO production in these vascular epithelial cells is a characteristic feature of heart failure, and it can harm the kidneys as well.

Most laypeople don't realize how intimately connected, biochemically speaking, their hearts and their kidneys really are. It is yet another example of the ingenious ways in which Mother Nature has finessed our physiology with balancing and counterbalancing mechanisms that serve to keep us in good health - as long as we do our part by exercising and providing ourselves with the nutrients we really need, especially as we grow older.

ARGININE FOUND TO HAVE BENEFICIAL EFFECTS
To test the effect of arginine on kidney function, the Japanese researchers devised a double-blind crossover trial - one in which the patients serve as their own controls by being "crossed over" from experimental group to control group, and vice versa, at a certain point. Seventeen CHF patients (14 men and 3 women) ranging in age from 29 to 71, with a mean of 56, were selected for the study, which entailed two five-day treatment periods separated by a two-day "washout" period of no treatment. The patients were hospitalized for the duration and were closely monitored. Blood and urine tests and other diagnostic procedures were used to evaluate the effects of the treatment regimen.

The amount of arginine given was 15 grams per day, orally in the form of a pineapple-flavored drink. The placebo was the same drink, but without the arginine; the patients could presumably not tell the difference. Although 15 grams (slightly more than half an ounce) may sound like a lot by most nutritional-supplement standards, it is well tolerated with virtually no side effects. Indeed, infusions of twice that amount of arginine, 30 grams, are routinely used in tests of the human pituitary gland's ability to release growth hormone, an endocrine process that is stimulated by arginine. Medically monitored subjects have even been given up to 60 grams (2.1 oz) of arginine without reports of serious problems.

From the analysis of their results, the Japanese researchers concluded that arginine does have beneficial effects on the kidneys - specifically, on their ability to filter wastes, to maintain sodium and water balance, and to maintain neurohormonal balance - in patients with chronic heart failure. They believe that their results support the hypothesis that the beneficial effects of arginine on renal function are related to the production of nitric oxide in the vascular endothelium.

THE BENEFITS OF ARGININE AND EXERCISE ARE ADDITIVE
From Japan we go to Germany, where researchers at the University of Leipzig have shed new light on the ability of arginine, in conjunction with physical exercise, to improve endothelial function in patients with chronic heart failure.8 A hallmark of CHF is the inability of the vascular endothelium to respond appropriately to the need for dilation of the blood vessels, especially in response to the neurotransmitter acetylcholine, which triggers the synthesis of nitric oxide from arginine. This dysfunction can lead to exercise intolerance.

Since it was known that both arginine alone9 and judicious exercise alone10 improve endothelial function and that they do so via the release of nitric oxide, the researchers set out to determine whether the effects of arginine and exercise together are additive.

They randomly divided 40 male CHF patients not more than 70 years old into four groups of ten each: (1) a control group that continued their sedentary lifestyle unchanged; (2) a group that received 8 grams per day of oral arginine; (3) a group that was put on a carefully controlled regimen of forearm-strengthening exercises; and (4) a group that received both the arginine and the exercise training.

All the men continued their usual cardiac medications unchanged, and, except for the control group, all stayed in the hospital for the four-week duration of the study. A variety of diagnostic procedures was used to assess the response of endothelial function to stimulation by acetylcholine at the beginning of the study (the baseline value) and again at the end.

Two of the men in the control group dropped out, so the final number of subjects was 38. The results of the tests led the researchers to two main conclusions: (1) supplemental oral arginine and localized exercise both led separately to a significant increase in endothelium-dependent vasodilation, most likely through the increased endothelial release of NO; and (2) the effects of arginine and exercise do seem to be additive, i.e., combining them gives the best results.

This study shows yet again - not that there has ever been any serious doubt - that whatever else we may do to optimize our health, we will always benefit from regular exercise, the value of which is seemingly limitless. But it also shows - and this has been doubted in some quarters - that the potential for augmenting our health through nutritional supplements is also seemingly limitless, in light of the vast array of safe and effective natural substances available in Mother Nature's pharmacopoeia.

References

  1. Visek WJ. Arginine needs, physiological state, and usual diets. J Nutr 1986;116:36-46.
  2. Watanabe G, Tomiyama H, Doba N. Effects of oral administration of L-arginine on renal function in patients with heart failure. J Hypertens 2000 Feb;18(2):229-34.
  3. Koifman B, Wollman Y, Bogomolny N, Chernichowsky T, Finkelstein A, Peer G, Scherez J, Blum M, Laniado S, Iaina A, et al. Improvement of cardiac performance by intravenous infusion of l-arginine in patients with moderate congestive heart failure. J Am Coll Cardiol 1995 Nov 1;26(5):1251-6.
  4. Rector TS, Bank AJ, Mullen KA, Tschumperlin LK, Sih R, Pillai K, Kubo SH. Randomized, double-blind, placebo-controlled study of supplemental oral L-arginine in patients with heart failure. Circulation 1996 Jun 15;93(12):2135-41.
  5. Bachmann S, Mundel P. Nitric oxide in the kidney: synthesis, localization, and function. Am J Kidney Dis 1994 Jul;24(1):112-29.
  6. Aiello S, Remuzzi G, Noris M. Nitric oxide/endothelin balance after nephron reduction. Kidney Int Suppl 1998 Apr;65:S63-7.
  7. Drexler H. Endothelial dysfunction: clinical implications. Prog Cardiovasc Dis 1997 Jan-Feb;39(4):287-324.
  8. Hambrecht R, Hilbrich L, Erbs S, Gielen S, Fiehn E, Schoene N, Schuler G. Correction of endothelial dysfunction in chronic heart failure: additional effects of exercise training and oral L-arginine supplementation. J Am Coll Cardiol 2000;35(3):706-13.
  9. Rector TS, Bunk AJ, Mullen KA et al. Randomized, double-blind, placebo-controlled study of supplemental oral L-arginine in patients with heart failure. Circ 1996;93:2135-41.
  10. Hambrecht R, Fiehn E, Weigl C, et al. Regular physical exercise corrects endothelial dysfunction and improves exercise capacity in patients with chronic heart failure. Circ 1998;98:2709-15.
  11. Wascher et al. Effects of low-dose L-arginine on insulin-mediated vasodilation and insulin sensitivity. Eur J Clin Invest 1997;27:690-5.
  12. Beale RJ, Bryg DJ, Bihari DJ. Immunonutrition in the critically ill: a systematic review of clinical outcome. Crit Care Med 1999 Dec;27(12):2799-805.

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