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J Am Coll Cardiol, 2000; 35:271-276
© 2000 by the American College of Cardiology Foundation
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CLINICAL STUDIES

Effects of oral L-arginine on endothelium-dependent vasodilation and markers of inflammation in healthy postmenopausal women

Arnon Blum, MD*, Londa Hathaway, RN*, Rita Mincemoyer, RN*, William H. Schenke, BA*, Martha Kirby, BA{dagger}, Gyorgy Csako, MD§, Myron A. Waclawiw, PhD{ddagger}, Julio A. Panza, MD, FACC* and Richard O. Cannon, III, MD, FACC*

* Cardiology Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA
{dagger} Hematology Branch Branches, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA
{ddagger} Office of Biostatistics Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA
§ Clinical Pathology Department, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA

Manuscript received January 20, 1999; revised manuscript received September 3, 1999, accepted October 21, 1999.

Reprint requests and correspondence: Dr. Richard O. Cannon, National Institutes of Health, Building 10, Room 7B15, 10 Center Drive MSC-1650, Bethesda, Maryland 20892-1650
cannonr{at}nih.gov


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES

We examined whether oral administration of L-arginine, the substrate for nitric oxide (NO) synthesis, increases NO bioactivity in healthy postmenopausal women.

BACKGROUND

Nitric oxide may protect arteries against atherosclerosis, as suggested by experimental studies in animals. Estrogen therapy, which has been shown to increase NO bioactivity in the vasculature of healthy postmenopausal women, is not acceptable for long-term use by many women.

METHODS

In a randomized, double-blind, crossover study, 10 postmenopausal women without additional risk factors for atherosclerosis received L-arginine 9 g or placebo daily for one month, with treatment periods separated by one month. Nitric oxide levels in serum (as an index of endothelial NO release), brachial artery endothelium-dependent dilator responses to hyperemia by ultrasonography (as an index of vascular NO bioactivity) and markers of inflammation in blood that are inhibited by NO in cell culture experiments were measured at the end of each treatment period.

RESULTS

L-arginine levels in plasma were increased in all women during L-arginine treatment compared with placebo (136.8 ± 63.1 vs. 75.2 ± 16.2 µmol/liter, p = 0.009). However, there was no change in serum nitrogen oxide levels (42.1 ± 24.5 vs. 39.1 ± 16.6 µmol/liter, p = 0.61), nor was there an effect of L-arginine on flow-mediated dilation during hyperemia (3.8 ± 3.0% vs. 4.9 ± 4.8%, p = 0.53) compared with placebo. Our study had sufficient power (ß = 0.80) to detect a true absolute treatment difference in flow-mediated brachial artery dilation of 1.7% or larger as statistically significant at alpha = 0.05. There was no effect of L-arginine on serum levels of soluble cell adhesion molecules compared with placebo: E-selectin (50.6 ± 14.8 vs. 52.1 ± 17.0 ng/ml, p = 0.45), intercellular adhesion molecule-1 (230 ± 51 vs. 230 ± 52 ng/ml, p = 0.97) and vascular cell adhesion molecule-1 (456 ± 62 vs. 469 ± 91 ng/ml, p = 0.53).

CONCLUSIONS

Oral administration of L-arginine may not augment endothelial NO synthesis and release in postmenopausal women and is thus unlikely to be of general benefit to healthy postmenopausal women in protection from the development of atherosclerosis.

Abbreviations and Acronyms
  ADMA = asymmetric dimethylarginine
  CRP = C-reactive protein
  FITC = fluorescein isothiocyanate
  ICAM-1 = intercellular adhesion molecule-1
  L-NMMA = NG-monomethyl-L-arginine
  NO = nitric oxide
  NOS = nitric oxide synthase
  VCAM-1 = vascular cell adhesion molecule-1

Nitric oxide (NO), an important regulator of vascular homeostasis, is synthesized continuously in endothelial cells by the constitutive enzyme nitric oxide synthase (NOS III) from the substrate L-arginine (1). Normally, L-arginine is not rate-limiting in this reaction; the Km for NOS is in the micromolar range, whereas intracellular levels of arginine are in the millimolar range. Under certain conditions, however, L-arginine administration can enhance the synthesis of NO. In the hypercholesterolemic rabbit model, dietary supplementation with L-arginine reduced atheroma formation, improved endothelium-dependent dilation (2,3), decreased platelet aggregation (4) and decreased monocyte adherence to aortic endothelium (5). In hypercholesterolemic humans, intravenous or oral L-arginine improved endothelium-dependent dilation of forearm vasculature (6,7). L-arginine has also been shown (in vitro) to reduce human monocyte adhesion to endothelial cells and decrease expression of endothelial cell adhesion molecules (8).

Estrogen therapy improves vascular NO bioactivity in the coronary and systemic circulations of postmenopausal women (9–13), but it is unacceptable for long-term use by many because of side effects and concerns regarding cancer risk. Based on experimental studies and the limited human experience to date, we reasoned that L-arginine may also increase NO bioactivity in postmenopausal women. Accordingly, we measured the effects of L-arginine on vascular NO bioactivity and on markers of inflammation potentially affected by NO in postmenopausal women in a randomized, double-blind, placebo-controlled study.


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
Study population and design.   Twelve healthy postmenopausal women (55 ± 5 years) who had not taken hormone replacement, antioxidant vitamin (A, C, E) or lipid-lowering therapies in the preceding two months were enrolled in the study. All had plasma 17ß-estradiol levels below 50 pg/ml and follicle stimulating hormone levels >50 pg/ml. No subject was hypertensive, diabetic or a current cigarette smoker. The baseline lipid profile was as follows: total cholesterol, 199 ± 22 (range, 171 to 222) mg/dl; low-density lipoprotein cholesterol, 124 ± 22 (range, 78 to 152) mg/dl; high-density lipoprotein cholesterol, 60 ± 9 (range, 46 to 76) mg/dl; and triglycerides, 97 ± 49 (range, 48 to 187) mg/dl. Treatment with all nonsteroidal anti-inflammatory agents (including aspirin) was discontinued during the study. Women were randomly assigned to L-arginine 9 g (3 g in 500-mg capsules three times a day) or identical placebo capsules daily, with each treatment period one month in duration and separated by one-month off treatment. All study participants returned to the Clinical Center for blood drawing and brachial artery reactivity measurements at the end of each treatment period. Subjects were placed on a nitrate-restricted diet (≤15 mg/day) for three days before each visit in order to reduce the contribution of dietary nitrates to serum nitrogen oxide levels (14). The study was approved by the Institutional Review Board of the National Heart, Lung, and Blood Institute, and all participants gave written, informed consent. One woman stopped the study during the first treatment period (placebo) because of abdominal pain, and one woman was excluded from further participation after completing the first treatment period (L-arginine) because of bullous pemphigoid that required steroid treatment. Thus, 10 women completed both phases of the study and serve as the source of data for this report.

Laboratory assays.   Blood samples for laboratory assays were obtained between 8 and 9 AM following overnight fasting and immediately coded, so that investigators performing laboratory assays would be blinded to subject identity or study sequence. Plasma and serum were separated by centrifugation and stored at –80°C until analysis. C-reactive protein (CRP) in the serum was measured by a fluorescence polarization immunoassay (TdxFLEX Analyzer, Abbott, Abbott Park, Illinois). L-arginine was quantitated in plasma by high-pressure liquid chromatography (at Mayo Medical Laboratories, Rochester, Minnesota). Serum nitrogen oxide (nitrate/nitrite) levels were measured by conversion of nitrate to nitrite by nitrate reductase, followed by addition of Griess reagents and photometric measurement of absorbance (Oxford Biomedical Research, Oxford, Michigan). E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) levels were measured by enzyme-linked immunosorbent assays (R&D Systems, Inc., Minneapolis, Minnesota).

Blood samples for flow cytometry were processed using the Coulter Q Prep workstation (Beckman Coulter Corp., Miami, Florida). Expression of the following integrin adhesion molecules was measured on monocytes, lymphocytes and granulocytes: 1) LFA-1 (CD11a); 2) Mac-1 (CD11b); and 3) VLA-4 (CD49d), and the selectin adhesion molecule L-selectin (CD62L) (15). All monoclonal antibodies to cell surface adhesion molecules were directly conjugated to fluorescein isothiocyanate (FITC) and were obtained from Immunotech (Beckman Coulter Company, Miami, Florida). Flow cytometry was performed by the EPICS XL-MCL Flow Cytometer (Beckman Coulter Company) equipped with a 15-mW, 488-nm argon ion laser. A total of at least 50,000 events per sample were analyzed. The lymphocytes, monocytes and granulocytes were electronically isolated by collection of a dual-parameter histogram of log 90° light scatter versus forward angle light scatter. Fluorescence intensity of the measured adhesion molecule was expressed as mean channel units. Relative FITC log fluorescence was calculated using the histogram data. Flow cytometry settings remained constant for all data generated, and standard beads were used to calibrate the instrument.

Vascular studies.   Imaging studies of the left brachial artery were performed using a high-resolution ultrasound 7.5-MHz linear-array transducer (Hewlett-Packard) following 30 min of rest, based on the technique reported by Celermajer et al. (16). After finding the clearest view of the brachial artery, the skin was marked and the arm kept in the same position throughout the study. Baseline measurements included brachial artery diameter and flow velocity measured by pulsed-Doppler with the range gate (1.5 mm) in the center of the artery. The system permitted a direct assessment of the angle between the bloodstream and the intersecting ultrasound beam, which was then used to calculate blood flow velocity. Endothelium-dependent vasodilation was assessed by measuring the change in diameter of the brachial artery during reactive hyperemia created by an inflated cuff (250 mm Hg for 5 min) on the forearm, a response previously shown to be mediated primarily by NO (17). After cuff deflation, flow velocity was measured for the first 15 s, then the arterial diameter was recorded continually for the next 60 s. Fifteen minutes later, repeat baseline diameter and flow velocity measurements were made, followed by nitroglycerin spray (0.4 mg) under the tongue to assess endothelium-independent vasodilation. Three minutes later, arterial diameter and flow velocity measurements were recorded. Arterial diameter was measured in millimeters from the intima-blood interface on both the anterior and posterior walls, coincident with the R wave on the ECG, at two sites along the artery and for three cardiac cycles, with these six measurements averaged. During hyperemia, six measurements of arterial diameter were averaged during maximum dilation between 50 and 70 s following cuff deflation. Blood flow was calculated by multiplying the velocity-time integral of the Doppler flow signal by the heart rate and the cross-sectional area of the vessel.

Reproducibility of study parameters.   In a recently completed study of 28 healthy postmenopausal women who underwent studies off all hormone and other therapies on three occasions (18), each separated by 12 weeks, coefficients of variation for study parameters were computed as the square root of the pooled within-subject variance divided by the mean of the averages over all subjects for each parameter: flow-mediated brachial artery dilation = 0.623; nitrogen oxides = 0.365; E-selectin = 0.226, ICAM-1 = 0.159, VCAM-1 = 0.178.

Statistical analysis.   Measurements are expressed as mean ± SD. The two-sided paired Student t test was used to compare changes in vascular responses and laboratory values between L-arginine and placebo treatments, with p < 0.05 an indicator of statistical significance. The primary study comparison predefined in advance of data collection was flow-mediated dilation of the brachial artery with L-arginine treatment compared with placebo. All other comparisons were regarded as secondary, and no adjustments to p values for multiple comparisons were performed.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
Effects of L-arginine on vasomotor function.   L-arginine treatment for one month nearly doubled serum L-arginine levels compared with placebo treatment (136.8 ± 63.1 vs. 75.2 ± 16.2 µmol/liter, p = 0.009). Despite the significantly higher L-arginine levels following one month of L-arginine treatment, there was no significant change in serum nitrogen oxide levels compared with placebo treatment (42.1 ± 24.5 vs. 39.1 ± 16.6 µmol/liter, p = 0.61). There was no significant effect of L-arginine treatment on brachial artery diameters, flow, flow-mediated dilation with hyperemia or nitroglycerin-induced dilation compared with placebo treatment (Table 1, Fig. 1). In our study of 10 women, we could detect a true treatment difference in flow-mediated dilation (primary end point) of 1.7% or larger between L-arginine and placebo treatment as statistically significant with a two-sided paired t test at alpha = 0.05 and 80% power. We observed a 1.1% absolute difference in flow-mediated dilation between the two treatments (from 3.8% to 4.9%), with the dilation actually being greater during placebo treatment.


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  		Table 1 Effects of L-Arginine on Brachial Artery Endothelial Function

 


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  		Figure 1 Bar graphs show percent increase in brachial artery diameter from baseline measurements following forearm ischemia (flow-mediated dilation) in the left panel, and following nitroglycerin administration in the right panel. Data = mean ± SEM.

 
Effects of L-arginine on markers of inflammation.   There was no effect of L-arginine treatment on serum levels of markers of inflammation compared with placebo treatment: E-selectin, 50.6 ± 14.8 vs. 52.1 ± 17.0 ng/ml, p = 0.45; ICAM-1, 230 ± 51 vs. 230 ± 52 ng/ml, p = 0.97; VCAM-1, 456 ± 62 vs. 469 ± 91 ng/ml, p = 0.53; and CRP, 0.5 ± 0.8 vs. 0.5 ± 0.7 mg/dl, p = 0.9. Flow cytometry measurements for all adhesion molecules on monocytes, lymphocytes and granulocytes are provided in Table 2. L-arginine treatment was associated with a change in levels only with Mac-1 on monocytes, with a decreased expression compared with placebo treatment (12.7 ± 5.7 vs. 17.4 ± 6.4 mean fluorescence units, p = 0.015).


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  		Table 2 Effects of L-Arginine on Cell Adhesion Molecule Expression on Leukocytes

 

   Discussion
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 Abstract
 Methods
 Results
 Discussion
References
 
Studies in humans and in animals have shown that acute infusion and oral administration of L-arginine improve endothelium-dependent vasorelaxation of arteries with previously impaired dilator responses, and in animal models, protect against diet-induced atherosclerosis (2–7). We and others have shown previously that the acute infusion and oral administration of estrogen to postmenopausal women improve endothelium-dependent vasodilation of the coronary and systemic circulations (9–13). In this regard, flow-mediated dilation in our subjects receiving placebo was similar to the placebo or pretreatment measurements in two studies, both of which showed a doubling of this response after oral estrogen treatment (11,12). We previously found that enhancement by estrogen of acetylcholine-stimulated vasodilation in the coronary circulation was inhibited by NG-monomethyl-L-arginine (L-NMMA) (13), a competitive inhibitor of NOS (19). Further, flow-mediated dilation of the brachial artery is largely inhibited by L-NMMA (17). These observations suggest that estrogen enhances NO bioactivity either through increased synthesis or protection from oxidative degradation.

We reasoned that long-term administration of the substrate for NO synthesis might accomplish the same effects as estrogen on endothelium-dependent vasodilation. Such a finding could be of considerable interest to postmenopausal women at risk for atherosclerosis, but who cannot or choose not to take estrogen therapy because of concerns regarding side effects and cancer risk. However, in contrast to the robust effects of estrogen and statin lipid-lowering therapies on brachial artery flow-mediated dilation in healthy postmenopausal women (11,12), L-arginine treatment (9 g daily for one month) did not augment nitrogen oxide levels in serum, and did not improve endothelium-dependent vasodilation, as compared with placebo treatment in our postmenopausal study participants.

Because NO donors have been shown in endothelial cell culture experiments to prevent activation of proinflammatory genes by inhibition of an important nuclear transcription factor (NF{kappa}B) (20–23), we measured the effect of L-arginine on soluble cell adhesion molecules. Cell adhesion molecules, once expressed on the surfaces of endothelial cell or leukocytes in culture following cytokine stimulation, are shed into the supernatant within 24 h and are measurable in the sera of humans using the same immunoassay (24–26). Levels of VCAM-1, ICAM-1, E-selectin and L-selectin are increased in sera from patients with atherosclerosis (27–31). However, L-arginine did not reduce levels of cell adhesion molecules in our postmenopausal subjects as compared with placebo treatment. This contrasts with estrogen treatment, which reduced levels of cell adhesion molecules in sera of healthy and hypercholesterolemic postmenopausal women (12,18,32).

We reasoned that if L-arginine suppressed inflammatory cytokine expression by vascular cells as a result of increased NO, then the expression of leukocyte integrin and selectin adhesion molecules, the counter-ligands to cell adhesion molecules on the vascular endothelium, might also be reduced. Mac-1 expression on monocytes, as measured by flow cytometry, was significantly lowered with L-arginine treatment relative to placebo. However, L-arginine had no effect on Mac-1 integrin expression on other leukocyte cell lines, nor on the other leukocyte integrins and selectin adhesion molecule expression, raising the possibility that the change in Mac-1 expression was due to chance.

Study limitations.   A possible explanation for failure to demonstrate a vascular effect of L-arginine is that the dose used (9 g daily) in our study was insufficient. However, higher doses have been associated with side effects of nausea, stomach cramps and diarrhea (7). Further, in this study of hypercholesterolemic subjects, administration of L-arginine 21 g daily caused the same relative increase in serum L-arginine levels as was seen in our study with 9 g daily for the same duration of administration. A second potential limitation of our study is the relatively small number of participants. However, our study had sufficient power (80%) to detect an absolute improvement in flow-mediated brachial artery dilation of 1.7%, which is less than the 4% to 5% absolute improvement in flow-mediated dilation observed with estrogen treatment in healthy postmenopausal women (11,12,18). Indeed, flow-mediated dilation was actually greater while receiving placebo in our study, decreasing the likelihood that a larger number of subjects might have shown benefit from L-arginine treatment. The coefficients of variations for the parameters measured in our study are sufficiently low that an inability to show L-arginine treatment benefit due to poor measurement reproducibility over time seems unlikely. A third potential limitation of the study is that brachial artery endothelial function could have been normal in our study participants, and thus unlikely to be improved by L-arginine, similar to the absence of L-arginine effect in healthy young men given L-arginine 21 g daily for three days (33). In this regard, oral L-arginine 21 g daily for one month significantly improved brachial artery flow-mediated dilator responsiveness in 27 young hypercholesterolemic men and women in a randomized, double-blind, placebo-controlled study (7). However, we have recently shown that estrogen and vitamin E, alone and in combination, improve endothelium-dependent brachial artery responsiveness in healthy postmenopausal women with similar magnitude of brachial artery flow-mediated dilation without therapy as was measured in our study participants during the placebo phase (18). A fourth potential limitation of our study is that levels of asymmetric dimethylarginine (ADMA) were not measured in the plasma of our participants. Miyazaki and coworkers (34) reported elevated levels of this competitive inhibitor of NOS in patients with risk factors for atherosclerosis. Thus, it is possible that had levels of ADMA been found to be low in our patients, improvement in endothelial function with L-arginine would not have been expected. However, given the current interest in L-arginine as a therapeutic supplement to prevent atherosclerosis, our study suggests that L-arginine may not benefit the general population of healthy postmenopausal women.

In conclusion, we did not find evidence that L-arginine, when administered for one month to healthy postmenopausal women, augments endothelial NO synthesis and release or lower soluble cell adhesion molecule levels in contrast to the effects of estrogen therapy. Thus, our study suggests that L-arginine is unlikely to be of general benefit to healthy postmenopausal women in protection from the development of atherosclerosis.


   Acknowledgments
 
We appreciate the assistance of Maureen Leser, RD, for preparing the low-nitrate diet, Rene Costello, MT, for his excellent technical assistance, and Toni Julia for typing the manuscript.


   References
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 Discussion
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