The effects of a sustained-release L-arginine formulation on blood pressure and vascular compliance in 29 healthy individuals

Alternative Medicine Review, March, 2006 by Alan L. Miller

Abstract

Vascular endothelial function is crucial to cardiovascular function and thus to blood perfusion to the heart and throughout the body. A number of substances are produced and secreted by vascular endothelial cells, the most important of which is nitric oxide, a potent regulator of vascular function. Nitric oxide diffuses from endothelial cells into underlying smooth muscle, causing relaxation, which results in vasodilation. When this process is inhibited or inadequate the arteries cannot dilate as necessary, resulting in hypertonicity and reduced blood flow. Such endothelial dysfunction also causes increased platelet and monocyte adhesiveness and smooth muscle proliferation, processes thought to be at the genesis of atherosclerotic plaque formation. Since L-arginine is the body's only substrate for nitric oxide synthesis, adequate L-arginine must be present for proper nitric oxide production.

In this open label trial, a group of 29 asymptomatic individuals were given L-arginine (1,050 mg, as Perfusia-SR[R], a sustained-release preparation) twice daily (total 2.1 g daily) for one week. Systolic blood pressure was reduced in 62 percent of participants compared to baseline, with a non-significant mean decrease in all patients of 4 mmHg. Diastolic blood pressure was reduced in 69 percent of participants, with a mean reduction of 3.7 mmHg (p=0.005). In the 10 individuals who were borderline or hypertensive (systolic >130 or diastolic >85), there was a mean systolic reduction of 11 mmHg (p=0.05), while normotensives (n=19) had a mean systolic decrease of only 0.22 mmHg. Diastolic blood pressure was decreased a non-significant 4.9 mmHg in borderline or hypertensives and 4.5 mmHg in normotensives (p=0.026).

Vascular elasticity relates to endothelial function, and can be measured non-invasively. At baseline and follow-up, vascular compliance was assessed via digital pulse wave analysis (DPA; Meridian Medical). After one week, pulse wave analysis showed a significant increase in large artery compliance (mean 23% improvement; p=0.02) and a non-significant increase in small artery compliance (mean 23% improvement; p=0.15).

This study demonstrates blood pressure reductions, especially in patients with borderline or frank hypertension, as well as improved vascular compliance--an indicator of improved endothelial function and perfusion--after a one-week trial of sustained-release L-arginine. Poor endothelial function due to inadequate endothelial nitric oxide production is present in hypertension, as well as in numerous other aspects of cardiovascular disease, including angina, erectile dysfunction, cerebrovascular disease, and peripheral vascular disease. This is the first study showing a moderate dose of sustained-release L-arginine can improve endothelial function and blood pressure.

Introduction

The healthy function of vascular endothelial cells is crucial to cardiovascular health. It was previously thought this single layer of cells that lines the lumen of blood vessels was merely a physical barrier between blood and the underlying tissue. However, about 20 years ago researchers began to understand that the vascular endothelium acts not only as a barrier, but also as a vital regulator of blood vessel activity, with far-reaching implications. At that time it was discovered that an endothelium-derived substance could stimulate the underlying smooth muscle to relax, thus causing vasodilation. The substance was dubbed endothelium-derived relaxing factor (EDRF). Subsequently, Robert Furchgott, Louis Ignarro, and Ferid Murad determined the identity of EDRF as nitric oxide (NO), and were honored in 1998 with the Nobel Prize in Physiology of Medicine. This discovery has resulted in thousands of papers being published on the subject of nitric oxide and endothelial function.

Nitric oxide, a simple gaseous compound consisting of one molecule of nitrogen and one molecule of oxygen, is a potent regulator of vascular function. NO is produced in vascular endothelial cells in response to a number of stimuli, including sheer stress and acetylcholine. NO diffuses into underlying vascular smooth muscle and acts as a messenger molecule, activating guanylate cyclase, which elevates the concentration of cyclic guanosine monophosphate (cGMP), which in turn causes relaxation of smooth muscle and vasodilation (Figure 1). (1)

[FIGURE 1 OMITTED]

In addition to its role in the regulation of vascular tone, NO has other significant vascular benefits. NO decreases platelet aggregation and adhesiveness, reduces monocyte adhesiveness and inflammatory cytokine release, and inhibits smooth muscle proliferation. (2) There is also evidence that adequate NO inhibits LDL oxidation. (3) These events are at the genesis of the atherosclerotic process and, without adequate nitric oxide, occur unabated. Loss of sufficient endothelial NO production appears early in the development of atherosclerosis, evidenced by impaired acetylcholine-induced vasorelaxation in hypercholesterolemic patients. (2,4) Impaired NO synthesis is a component of a number of cardiovascular conditions, including hypertension, (5-7) hyperlipidemia, (7,8) peripheral vascular disease, (9 hyperhomocysteinemia, (10,11) congestive heart failure, (12) erectile dysfunction (13) and cerebrovascular events. (14) Poor NO production in vascular endothelial cells is also seen post balloon angioplasty. (15)

Nitric oxide is produced in vascular endothelial cells from a single natural substrate--the amino acid L-arginine. L-arginine is considered a non-essential amino acid because, in addition to being present in dietary proteins, it can be produced in the body from another amino acid, L-citrulline, in an ATP-dependent process. However, adequate dietary or supplemental L-arginine appears to be the key to sufficient NO production.