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Arginine and the Cardiovascular System

The amino acid arginine is the substrate of endothelial nitric oxide synthase and the main precursor of nitric oxide (NO) in the vascular endothelium. Compromised production of NO may cause serious problems in endothelial equilibrium; therefore, numerous therapies have been investigated to assess the possibility of reversing endothelial dysfunction by enhancing the release of nitric oxide from the endothelium. Among such therapies, arginine treatment remains the most studied. Since the 1990s, it has been shown that arginine improves endothelial function in patients with hypercholesterolemia and hypertension, and has potential roles in diabetes (Siasos G, Tousoulis D, Antoniades C et al. Arginine, the substrate for NO synthesis: an alternative treatment for premature atherosclerosis? Int J Cardiol. 2007;116(3):300-308). This amino acid also improves endothelial function in patients with coronary artery disease and dilates human epicardial atheromatous coronary arteries (Tousoulis D, Böger RH, Antoniades C et al. Mechanisms of disease: L-arginine in coronary atherosclerosis--a clinical perspective. Nat Clin Pract Cardiovasc Med. 2007;4(5):274-283).

The effects of dietary or supplemental arginine on endothelial function were observed not only in patients (i.e, Bednarz B, Chamiec T, Maciejewski P et al. Kardiol. Pol. 2005;62:421-426 and Clarkson P1, Adams MR, Powe AJ et al. Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults. J Clin Invest. 1996;97(8):1989-1994), but also in healthy humans. A single oral dose of 6 g arginine given to healthy people led to a significant vasodilator effect and concomitantly increased the plasma levels of both arginine itself and NO (Bode-Boger SM, Boger RH, Galland A et al. L-arginine-induced vasodilation in healthy humans: pharmacokinetic-pharmacodynamic relationship. Br J Clin Pharmacol. 1998;46(5):489-497). The positive effect of arginine appears age-independent, since it was observed in both young and elderly humans (Bode-Böger SM, Muke J, Surdacki A et al. Oral L-arginine improves endothelial function in healthy individuals older than 70 years. Vasc Med. 2003;8(2):77-81).

Understandably, the effectiveness of arginine was more pronounced in situations associated with compromised cardiovascular function(s) in otherwise healthy people. Among such situations, cigarette smoking is perhaps most relevant. In smokers, arginine, but not vitamin C, reversed the deleterious effects of smoking on vasodilation (Adams MR, Jessup W, Celermajer DS. Cigarette smoking is associated with increased human monocyte adhesion to endothelial cells: reversibility with oral L-arginine but not vitamin C. J Am Coll Cardiol. 1997;29(3):491-497). From a practical perspective of the supplemental use of arginine, it is noteworthy that the vascular functions of arginine are correlated to its circulating levels in the blood, which is a positive indicator of oral arginine treatment efficacy.

A question emerged whether traditionally recommended physical exercise or nutraceutical treatments (mainly arginine-based treatments) are more effective for improving endothelial functions. This question was addressed in 40 patients with chronic heart failure, and it was shown that dietary arginine supplementation, as well as regular physical exercise, improved endothelium-dependent vasodilation to a similar extent. Both interventions together seemed to produce additive effects with respect to endothelium-dependent vasodilation (Hambrecht R, Hilbrich L, Erbs S et al. 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):706-713). In line with this clinical observation, animal studies indicated that arginine increased muscle capillary blood flow even if animals were not performing exercise.

Supplementation with arginine might provide additional blood flow at rest and during exercise and improve exercise capacity, and thus, additively enhance the positive effects of exercise on heart function (Ohta F, Takagi T, Sato H et al., Low-dose L-arginine administration increases microperfusion of hindlimb muscle without affecting blood pressure in rats. Proc Natl Acad Sci U S A. 2007;104(4):1407-1411).

Finally, it is worth noting that arginine is a very safe amino acid, and oral doses up to 15 - 20 g per day are well tolerated.