Sunday, November 07, 2010

Another suppressed cardiovascular treatment?

In the course of trying to decide whether pomegranate is worth its cost, I realized that pomegranate's main benefit to the cardiovascular system is its ability to protect an important chemical compound known as nitric oxide, so that it has a better chance of doing something useful before it is destroyed by oxidation. The discovery of nitric oxide and its functions earned Louis J. Ignarro, PhD, the 1998 Nobel prize in medicine. Shortly after this discovery was announced, there was an explosion of research into nitric oxide, and approximately 7000 papers were published on the subject within a year. (Yet I had to stumble onto the subject a decade later in the course of studying the benefits of pomegranate, and I suspect that the lack of publicity on this subject is deliberate. I even found apparent disinformation about NO in a 2007 article still posted on the Life Extension Foundation website. There is no excuse for its false implications to be left hanging on a supposedly authoritative website. The relevant passage is copied below.) Searching under Dr. Ignarro's name, I found his website and his 2008 article entitled Nobel Prize Winner’s Breakthrough – Prevent Heart Attack and Stroke with Nitric Oxide, which provide guidance on boosting nitric oxide levels. I found another good introduction to the importance of nitric oxide on Dr. Mercola's site. It plugs Dr. Mercola's nitric oxide-boosting formula, but I couldn't find how much of the critical ingredient (arginine) it contains. As of this writing, Doctor's Best appears to offer the most cost-effective arginine supplement. Dr. Ignarro strongly recommends using citrulline to enhance the absorption of arginine.

NO, which has a fleeting existence on the order of seconds, is critical to cardiovascular function, and the NO which is used by the cardiovascular system is produced by an enzyme known as "endothelial nitric oxide synthase" (eNOS) in the inner layer (the endothelium) of the arteries. This enzyme converts arginine into NO. Dr. Ignarro recommends taking L-citrulline along with arginine in order to facilitate its cellular uptake.

Without intervention, NO production declines with "biological age"

Due to wear and tear on the cardiovascular system, a substance known as ADMA, which resembles arginine, is produced by the body and ends up competing with arginine for uptake by eNOS. The result is a deficiency of NO, which has several seriously detrimental effects, potentially leading to a death spiral. By supplementing arginine in sufficient quantities, it is supposedly possible to swamp out the ADMA, restore NO production, and undo the damage caused by NO deficiency. [I haven't seen any indications that suppressing ADMA is a feasible solution.]

One of my sources for this information was The Real Reason Why Health Canada Banned Arginine posted to an alternative medicine website. The basic contention of the article, which is actually a scientific paper, is that boosting arginine sufficiently will overcome a substance known as ADMA (which increases with wear and tear on the cardiovascular system, and which because of its similarity to arginine is often taken up by eNOS, thus effectively blocking a significant portion of NO production). Arginine supplementation increases the ratio of arginine to ADMA, and consequently NO production increases up to a point which I assume approximates youthful levels, or at least sufficient levels. Once sufficient NO levels are restored, the arterial health improves. There is little risk of a toxic dose of arginine, so, to answer the question implied by the title, it seems that arginine was banned in Canada to deprive Canadians of sufficient nitric oxide. I've copied the more relevant portions of the paper below and translated some of the medical terminology:

(Altern Med Rev 2005;10(1):14-23)

[Title:] L-arginine improves vascular function by overcoming the deleterious effects of ADMA, a novel cardiovascular risk factor
Alternative Medicine Review, March, 2005 by Rainer H. Boger, Eyal S. Ron

[Rainer H. Boger, MD Professor and Head, Clinical Pharmacology Unit Institute of Experimental and Clinical Pharmacology and Toxicology Center of Experimental Medicine University Hospital Hamburg-Eppendorf Martinistr. 52 D-20246 Hamburg Germany; Eyal S Ron, Ph.D.: see]

The endothelium [inner layer of arteries] plays a crucial role in the maintenance of vascular tone and structure. One endothelium-derived vasoactive mediator with major importance is nitric oxide (NO), which is formed from the amino acid precursor L-arginine by the enzyme endothelial nitric oxide synthase (eNOS). NO is involved in a wide variety of regulatory mechanisms of the cardiovascular system, including vascular tone (it is the major mediator of endothelium-dependent vasodilation), vascular structure (inhibition of smooth muscle cell proliferation), and cell-cell interactions in blood vessels (inhibition of platelet adhesion and aggregation; inhibition of monocyte adhesion).

Dysfunction of the endothelial L-arginine/ nitric oxide pathway is a common mechanism by which several cardiovascular risk factors mediate certain deleterious effects on the vascular wall. [Low nitric oxide allows arteries to be damaged by the following.] Among these are hypercholesterolemia, hypertension, smoking, diabetes mellitus, homocysteine, and vascular inflammation.
Circulating L-arginine concentrations have been found to be within the normal range in most clinical conditions associated with endothelial dysfunction. Few patients experience pathologically low L-arginine concentrations. However, clinical and experimental evidence suggests elevation of ADMA can cause a relative L-arginine deficiency, even in the presence of "normal" L-arginine levels (which may, in fact, be too low in these conditions). AS ADMA IS A COMPETITIVE INHIBITOR OF eNOS, ITS INHIBITORY ACTION CAN BE OVERCOME BY INCREASING THE CONCENTRATION OF THE ENZYME'S SUBSTRATE, L-ARGININE (Figure 2). The studies cited above indicate ADMA levels may be increased in conditions associated with cardiovascular diseases. Elevated ADMA concentration is one possible explanation for endothelial dysfunction and decreased NO production in these diseases. [emphasis added]
Beneficial Effects of Supplemental Sustained-release L-Arginine

From the above-mentioned studies of L-arginine, it appears an effective method of improving endothelial function would be to supplement with L-arginine. Oral L-arginine, however, is absorbed and metabolized quickly; the half-life of L-arginine in human circulating plasma is less than one hour. (66) A controlled-release formulation of L-arginine would increase the length of time in which L-arginine achieves an effective concentration.


In a preliminary study of five patients with coronary artery disease in whose myocardial perfusion [blood-flow to the heart muscle] had been maximized and stabilized on conventional cardiovascular medications, 3 g sustained-release L-arginine was given twice daily for 12 weeks. Significant improvements in heart function and myocardial perfusion were seen via PET imaging. (68)


ADMA is an endogenous and competitive inhibitor of NO synthase. [ADMA occurs naturally in the body and competes with arginine for uptake by nitric oxide synthase, the "factory" which produces nitric oxide.] Plasma levels of this inhibitor [ADMA] are elevated in patients with atherosclerosis and in those with risk factors for atherosclerosis. (34,36) In these patients, plasma ADMA levels are correlated with the severity of endothelial dysfunction and atherosclerosis. By inhibiting the production of NO, ADMA can impair blood flow, accelerate atherogenesis [the development of atherosclerosis], and interfere with angiogenesis [the growth of new capillary blood vessels].

Supplemental L-arginine improves endothelial function, myocardial perfusion [blood-flow to the heart muscle], angina, erectile dysfunction, and exercise tolerance, regardless of ADMA status. However, many patients exhibiting one of these impairments demonstrate elevated blood ADMA. Therefore, testing for plasma ADMA levels may give the physician a better idea of those patients who may respond best to prolonged L-arginine supplementation, as data are accumulating to show that patients with elevated ADMA are the most likely to benefit. The ratio of L-arginine to ADMA is considered to be the most accurate measure of eNOS substrate availability. This ratio will increase during L-arginine supplementation, regardless of initial ADMA concentration. Due to the pharmacokinetics of oral L-arginine and the positive results from preliminary studies, it appears supplementation with a sustained-release L-arginine preparation will achieve positive therapeutic results at lower dosing levels. [end of excerpts from paper by Boger & Ron]

Life Extension Foundation article implies that ADMA limits NO production

As I indicated above, I don't think it's an accident that this information has not received wider publicity. There is an enormous amount of money to be made in treating people with cardiovascular disease. I found a prime example of the apparent suppression of this information on the Life Extension Foundation's website, which I previously considered to be a trustworthy source of information on nutritional supplements. This erroneous and potentially deliberately false information is contained in the following passage from The Intimate Link Between Erectile Dysfunction and Heart Disease:

Disruption in Nitric Oxide Synthesis

The body’s source for nitric oxide production is the amino acid L-arginine, which is naturally found in many foods. The average American ingests about 3,000–5,000 mg of L-arginine per day, as it is an amino acid naturally contained in many foods. Meats of all varieties, nuts, and dairy products are rich in L-arginine, so the body is accustomed to intake levels of several thousand milligrams every day.

A deficiency of L-arginine, however, does not generally disrupt nitric oxide synthesis because L-arginine availability is not the rate-limiting step in this process. [Actually, a deficiency of arginine RELATIVE to rising ADMA levels is the culprit, so this is a half-truth.] In fact, research over the past five years has identified an endogenous (occurs in the body naturally) inhibitor called “asymmetric dimethylarginine” or ADMA, an amino acid which blocks the production of nitric oxide. By acting as an L-arginine mimic, this damaging look-alike effectively elbows out L-arginine and pushes it off to the side in the biochemical pathway leading to the synthesis of nitric oxide. ADMA is relatively elevated in patients with hypertension, high levels of cholesterol, triglycerides, homocysteine and low-density lipoprotein (LDL), and low levels of high-density lipoprotein (HDL), as well as with aging itself. This inhibitor of nitric oxide synthesis may very well be the common factor shared by all of these abnormal conditions. Increased levels of this detrimental inhibitor (ADMA) block nitric oxide production, leading to endothelial dysfunction.

[Note that the article "neglects" to mention that sufficient arginine can swamp out the ADMA and restore nitric oxide production, perhaps because doing so would make several of LEF's pricey supplements obsolete.]