In the past five years we have seen much wider acceptance of several naturopathic interventions and perspectives relevant to vascular health. Mainstream medicine has come to recognize the importance of inflammation in cardiovascular disease, and the sensitivity of C-Reactive Protein as a marker for cardiovascular risk. Both of these were once considered “alternative” notions.
Likewise, omega-3 versus omega-6 fatty acids, folic acid to counteract homocysteine, coenzyme Q10, niacin and extended-release niacin, Monascus purpureus (red rice yeast), policosanol, garlic, hawthorne, ginkgo, systemic enzymes, nattokinase, red wine, and heart rate variability, have begun to enter mainstream cardiovascular care. All of these advances have been chronicled in past issues of Holistic Primary Care. Their wider use reflects both a maturing of naturopathic and nutritional science, as well as a greater willingness from allopathic physicians to look beyond the realm of pharmacotherapy and surgical interventions.
The most recent breakthrough is the development of a sustained-release form of L-arginine, which makes it possible to improve vascular function in ways that have not previously been practical with this amino acid.
In 1998 Furchgott, Ignaro and Murad were awarded the Nobel Prize in Medicine for their discovery of nitric oxide as a signaling molecule in the cardiovascular system. Since then, nitric oxide (NO) has been the focus of intense research (more than 27,000 references in Pub Med are found for “arginine” and “nitric oxide”).
L-arginine is converted by endothelial nitric oxide synthase (eNOS) into NO. Another form of arginine, asymmetric dimethylarginine (ADMA) inhibits eNOS. ADMA competes with arginine to bind with eNOS, down-regulating this enzyme. This is clinically important because elevated ADMA is common in patients with hyperlipidemia, hyperhomocysteinemia, coronary artery disease, angina pectoris, congestive heart failure, peripheral vascular disease, hypertension, diabetes mellitus, chronic renal failure, preeclampsia, and erectile dysfunction (Boger et al. Circulation 1998; 98: 1842–1847).
By inhibiting production of NO, ADMA can stimulate atherosclerosis and impair vascular flow. L-arginine significantly mitigates these effects, independent of ADMA status. However, plasma ADMA is a good marker for vascular risk, giving physicians a means to predict which patients are most likely to benefit from L-arginine supplementation.
Ordinary L-arginine, while helpful, is rapidly absorbed and metabolized; its half-life in humans is less than one hour. Therefore it does not have a sustained effect unless it is taken in frequent doses throughout the day (and night). A controlled-release form of L-arginine has been developed which allows twice-daily dosing to maintain an effective serum concentration. This is available in the U.S. and Canada as “Perfusia-SR” and is available at perfusia-sr.com or from Thorne Research (www.thorne.com). Cost of a month’s supply is just over $30.
NO can only be produced by the vascular endothelial cells when they contain adequate amounts of L-arginine, since this amino acid is the only substrate for creation of NO. NO in turn is responsible for a number of critical vascular functions, including smooth muscle relaxation and subsequent vasodilation, inhibition of platelet aggregation, monocyte adhesiveness, and smooth muscle proliferation. NO is also vital to maintaining normal blood pressure, myocardial function, inflammatory response, apoptosis, and antioxidant function (Wu G, Meininger CJ. J Nutr 2000; 130: 2626–2629). Arginine also stimulates the release of catecholamines, insulin, glucagons, prolactin, and growth hormone. It stimulates immune function (e.g. natural killer cell activity) and decreases pro-inflammatory cytokines.
Myocardial PET scans have shown significant improvement in myocardial perfusion following supplementation with sustained-release L-arginine (preliminary results from a study by K. Loance Gould, MD, U Texas Medical School, Houston, TX). Sustained-release L-arginine has demonstrated synergistic endothelium-dependent vasodilatory effects when taken with simvastatin (Boger et al. J Am Coll Cardiol 2004: Suppl: 525A). The vascular benefits of HMG-Co-A reductase inhibitors (i.e., “statins”) are in part due to their ability to up-regulate eNOS gene expression (Laufs et al. Circulation 1998; 97: 1129–1135).
Erectile dysfunction (ED) affects an estimated 54 percent of men aged 65–70, and is considered an indicator of vascular compromise. Existing research on arginine and ED appears promising; at least some men will experience improved erectile function from arginine supplementation (Zorgniotti et al. Int J Impot Res 1994; 6: 33–35). Arginine also markedly increases sperm count, motility and pregnancy rates (Tanimura J. Bull Osaka Med School 1967; 13: 84–89).
Most arginine studies to date have used a non-sustained release form; once a clinical trial is completed with the controlled-release formulation, the vascular effects of arginine will be more fully appreciated.
No significant adverse effects have been noted with arginine supplementation. Patients with hepatic or renal disease should be closely monitored since their ability to metabolize and clear arginine may be compromised. It has been suggested, based on fairly old in vitro evidence (Tankersley RW. J Bacteriol 1964; 87: 609–613), that arginine may be contraindicated in patients with herpes simplex, due to stimulation of viral replication, although this has not been observed in controlled clinical trials. Lysine supplementation may be recommended to inhibit herpes virus replication if recurrences of herpes become more frequent.
There is also a theoretical possibility that arginine may stimulate growth factors for cancers via polyamine synthesis. However, arginine, in the dose of 30 g per day for three days has also been shown to significantly increase natural killer cell activity in patients with advanced breast cancer (Brittenden J, et al. Eur J Surg Oncol 1994; 20: 467–472). Until definitive data is available, arginine should be used with caution in cancer patients.”
Michael Traub, ND, is past-president of the American Association of Naturopathic Physicians. He practices in Kailua-Kona, Hawaii.
