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

Abstract

There is abundant evidence that the endothelium plays a crucial role in the maintenance of vascular tone and structure. One of the major endothelium-derived vasoactive mediators is nitric oxide (NO), an endogenous messenger molecule formed in healthy vascular endothelium from the amino acid precursor L-arginine. Endothelial dysfunction is caused by various cardiovascular risk factors, metabolic diseases, and systemic or local inflammation. One mechanism that explains the occurrence of endothelial dysfunction is the presence of elevated blood levels of asymmetric dimethylarginine (ADMA)--an L-arginine analogue that inhibits NO formation and thereby can impair vascular function. Supplementation with L-arginine has been shown to restore vascular function and to improve the clinical symptoms of various diseases associated with vascular dysfunction.

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

Introduction

The endothelium 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. Among these are hypercholesterolemia, hypertension, smoking, diabetes mellitus, homocysteine, and vascular inflammation? (1-6)

Supplementation with L-arginine in animals with experimentally-induced vascular dysfunction atherosclerosis improves endothelium-dependent vasodilation. (7-10) Moreover, L-arginine supplementation results in enhanced endothelium-dependent inhibition of platelet aggregation, inhibition of monocyte adhesion, and reduced vascular smooth muscle proliferation. (11-13) The mechanism by which dietary L-arginine brings about these beneficial effects has long been poorly understood. Experimental evidence derived from studying cloned, purified eNOS in a cell-free system in vitro, and in the presence of optimal concentrations of all co-factors, suggests L-arginine concentrations as low as 3 [micro]mol/L are sufficient to induce half-maximal activity of this enzyme. (14) In contrast, circulating L-arginine measured in plasma of healthy humans as well as in plasma of patients with vascular disease is in the range of 40-100 [micro]mol/L (15,16)--which is 15- to 30-fold higher.

ADMA is a Novel Cardiovascular Risk Factor

In 1992, Vallance et al first described the presence of asymmetric dimethylarginine (ADMA) as an endogenous inhibitor of eNOS in human plasma and urine. (17) Since then, the role of this molecule in the regulation of eNOS has attracted increasing attention. ADMA inhibits vascular NO production within the concentration range found in patients with vascular disease. ADMA also causes local vasoconstriction when infused intra-arterially, and increases systemic vascular resistance and impairs renal function when infused systemically. Currently available experimental and clinical evidence suggests even small modifications of ADMA levels significantly change vascular NO production, vascular tone, and systemic vascular resistance (for review, see Boger (18). Thus, elevated ADMA levels may explain the "L-arginine paradox;" i.e., the observation that supplementation with exogenous L-arginine improves NO-mediated vascular functions in vivo, although its baseline plasma concentration is about 25-fold higher than the Michaelis Constant (Km) of the isolated, purified endothelial NO synthase in vitro (Figure 1).

[FIGURE 1 OMITTED]

Elevated ADMA concentration has a high prevalence in hypercholesterolemia, hyperhomocysteinemia, diabetes mellitus, peripheral arterial occlusive disease, hypertension, chronic heart failure, coronary artery disease, pregnancy-induced hypertension and preeclampsia, erectile dysfunction, and other clinical conditions (Table 1). (1,19-28)

Several recent studies have supplied evidence to support a pathophysiological role of ADMA in the pathogenesis of vascular dysfunction and cardiovascular disease. High ADMA levels were found to be associated with carotid artery intima-media-thickness in a study with 116 clinically healthy human subjects. (29) Taking this observation further, another study performed with hemodialysis patients reported that ADMA prospectively predicted the progression of intimal thickening during one year of follow-up. (30) In a nested, case-control study involving 150 middle-aged, non-smoking men, high ADMA levels were associated with a 3.9-fold elevated risk for acute coronary events. (31)