HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) All Versions of this Article: 89/1/77    most recent ajcn.2008.26544v1 Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bai, Y. Articles by Hui, R. Search for Related Content PubMed PubMed Citation Articles by Bai, Y. Articles by Hui, R. Agricola Articles by Bai, Y. Articles by Hui, R.

Increase in fasting vascular endothelial function after short-term oral L-arginine is effective when baseline flow-mediated dilation is low: a meta-analysis of randomized controlled trials^1,2,3

¹ From the Key Laboratory for Clinical Cardiovascular Genetics & Sino-German Laboratory for Molecular Medicine, Cardiovascular Institute & FuWai Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China (YB, TY, KS, JC, and RH); the Hypertension Division, Cardiovascular Institute & FuWai Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China (YB and RH); and the National Center for Pharmaceutical Screening, Institute of Materia Medica Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China (LS).

² Supported by grant no. 2006CB503805 from the Ministry of Science and Technology of China (to RH).

³ Address requests for reprints and correspondence to R Hui, Cardiovascular Institute & FuWai Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 167 Beilishilu, Beijing 100037, PR China. E-mail: huirutai{at}gmail.com.

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
Background: Previous trials suggest that oral L-arginine administration affects endothelial function. However, most of these studies were small, the conclusions were inconsistent, and the precise effects are therefore debatable.

Objective: The objective was to assess the effect of oral L-arginine supplementation on endothelial function, as measured with the use of fasting flow-mediated dilation (FMD).

Design: We conducted a meta-analysis of randomized, placebo-controlled L-arginine supplementation trials that evaluated endothelial function. Trials were identified in PubMed, Cochrane Library, Embase, reviews, and reference lists of relevant papers. The weighted mean difference (WMD) was calculated for net changes in FMD by using random-effect models. Previously defined subgroup analyses and meta-regression analyses were performed to explore the influence of study characteristics.

Results: Thirteen trials were included and evaluated. Because there was only one long-term study, we focused on short-term effects of L-arginine (12 studies, 492 participants). In an overall pooled estimate, L-arginine significantly increased FMD (WMD: 1.98%; 95% CI: 0.47, 3.48; P = 0.01). Meta-regression analysis indicated that the baseline FMD was inversely related to effect size (regression coefficient = –0.55; 95% CI: –1.00, –0.1; P = 0.016). A subgroup analysis suggested that L-arginine supplementation significantly increased FMD when the baseline FMD levels were <7% (WMD: 2.56%; 95% CI: 0.87, 4.25; P = 0.003), but had no effect on FMD when baseline FMD was >7% (WMD: –0.27%; 95% CI: –1.52, 0.97; P = 0.67).

Conclusion: Short-term oral L-arginine is effective at improving the fasting vascular endothelial function when the baseline FMD is low.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
Cardiovascular disease (CVD), the biggest burden and dominant chronic disease in many parts of the world, has been predicted to be the main cause of disability and death worldwide in the 21st century (1). Endothelial dysfunction is an early pathophysiological feature and an independent predictor of poor prognosis in most forms of CVD (2–4). Endothelial function has been shown to be influenced by several vascular risk factors. Treatment of these risk factors can restore endothelial function (5, 6). The L-arginine/nitric oxide (NO) pathway plays a critical role in maintaining normal endothelial function by causing blood vessel relaxation (vasodilatation). The semiessential amino acid L-arginine is the only substrate for NO synthesis in vascular endothelial cells. Therefore, this amino acid has the potential to improve endothelial function and is expected to play a role in the prevention or treatment of CVD and other vascular disorders (7). Preliminary reports suggest that arginine may be useful at improving medical conditions, including angina, atherosclerosis, coronary artery disease (CAD), erectile dysfunction, heart failure, and intermittent claudication/peripheral vascular disease (8–10).

Previously published trials have suggested that oral L-arginine supplementation affects endothelial function in hypercholesterolemic individuals, patients with CAD, healthy elderly individuals, and healthy young individuals who smoke (11–38). However, the sample size of these studies was small and the conclusions were inconsistent. As a result, the precise effects of arginine administration are still under debate.

In most of these studies, endothelial function was measured by fasting flow-mediated dilation (FMD), which represents the ability of the brachial artery to dilate in response to ischemia-induced hyperemia and reflects the local bioavailability of NO under a physiologic stimulation (38). The aim of the present review was to identify and combine all published randomized controlled trials that investigated the effects of L-arginine supplementation on FMD.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
Literature search
We systematically searched PubMed, Cochrane Library, Embase, reviews, and reference lists of relevant papers with the strategy of using the term "arginine" paired with the following: "endothelial," "endothelium," "coronary heart disease," "CVD," "stroke," "cerebrovascular disease," "ischemia," and "trial."

Study selection
We selected completed, published, and nonconfounded randomized placebo-controlled trials of oral L-arginine supplementation studies in which endothelial function was evaluated by estimating the fasting FMD in the brachial artery. Participants must have been treated with L-arginine for 3 d. Trials evaluating endothelial function with other methods were also included for systematic review but were not selected for meta-analysis, because these data could not be combined and compared quantitatively.

Quality assessment
Studies were assessed for quality of randomization, blinding, reporting of withdrawals, generation of random numbers, and concealment of allocation. Trials scored one point for each area addressed, with a possible score of between 0 and 5 (highest level of quality) (39).

Data extraction
All literature searches were independently reviewed by 2 authors (YB and LS) to identify relevant trials that met the inclusion criteria. Disparities were resolved by discussion. Data on trial size, population characteristics (age, sex, and baseline comorbidities), treatment regimen (dose of L-arginine, duration of treatment), and change in FMD levels were extracted.

Statistics and analysis
Our primary outcome was the net change in FMD due to L-arginine supplementation. Weighted mean differences (WMDs) and 95% CIs were calculated for net changes in FMD by using random-effect (DerSimonian and Laird) models (40). Statistical heterogeneity of treatment effects between studies was formally tested with Cochran's test (P < 0.1). The I² statistic was also examined, and we considered I² >50% to indicate significant heterogeneity between the trials (41). Previously defined subgroup analyses and meta-regression analyses were performed to explore heterogeneity in effects and the influence of study characteristics. Publication bias was assessed with funnel plots, Egger regression test (42), and fail-safe N test (43). Statistical analyses were performed with Stata software (version 9.0; Stata Corporation, College Station, TX) and REVMAN software (version 5.0; Cochrane Collaboration, Oxford, United Kingdom).

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
Search results
A total of 1466 articles were identified in a combined search of the PubMed, Embase, and Cochrane Library databases and from a manual approach (search of previous studies cited in previous reviews and of reference lists from the identified articles); 1438 articles were excluded because they were not randomized controlled trials or their interventions were not relevant to the purpose of this meta-analysis (such as vitamin C or other agents intended to improve endothelial function). Full text assessment of the 28 potentially relevant articles resulted in 13 eligible randomized controlled studies (Figure 1). The most common reasons for exclusion were as follows: L-arginine was not supplied orally but intravenously in 5 trials (24–28) and intraarterially in 2 studies (23, 29) and that FMD levels were not reported. Four studies (20, 32–34) were not included because they were not placebo-controlled. One trial (22) was excluded because participants were only given one dose of L-arginine (15 g) together with a high-fat meal.

View larger version (24K): [in this window] [in a new window]   FIGURE 1. Flow diagram of the trial selection process Flow chart shows the number of citations retrieved by individual searches and the number of trials included in the review. FMD, flow-mediated dilation.

Effects of oral supplementation of L-arginine on FMD
Thirteen trials evaluated the effect of oral L-arginine supplementation on FMD level. The work of Bode-Böger et al (38) was separated into 2 trials (effect of L-arginine on subjects with high and low asymmetric dimethylarginine concentrations) for analysis. One study (12) did not directly report FMD in the placebo-controlled group directly, but the data were able to be calculated from the information provided in the article. One study (18) reported the baseline and postsmoking FMD levels on the first, second, and third follow-up days. We extracted the postsmoking FMD data from the third day for meta-analysis to meet our inclusion criteria (3 d of L-arginine treatment).

The trial reported by Wilson et al (19) was the only study that evaluated the long-term effectiveness of L-arginine supplementation. The results of this trial were quite distinct from those of the short-term studies (heterogeneity test: ² = 1538.28, I² = 99%, P < 0.00001).

First, the data were pooled from the 12 short-term studies. FMD levels were significantly higher in the L-arginine–supplemented subjects than in the placebo-treated subjects (13 comparisons, 493 participants; WMD: 1.98%; 95% CI: 0.47, 3.48; P = 0.01) (Figure 2). Significant heterogeneity for this outcome was found (heterogeneity ² = 636.06, I² = 98%, P < 0.0001). The sources of heterogeneity were investigated by meta-regression methods. Meta-regression analysis of the data showed that the baseline FMD was negatively related to effect size (regression coefficient = –0.55; 95% CI: –1.00, –0.1; P = 0.016), which largely explained the heterogeneity of the effect. The dose of L-arginine (range: 3–24 g/d) and the average age of the participants were not effect modifiers.

View larger version (34K): [in this window] [in a new window]   FIGURE 2. Random-effects meta-analysis of weighted mean differences (95% CI) in flow-mediated dilation (FMD) with L-arginine treatment compared with placebo. Sizes of data markers indicate the weight of each study in the analysis. The subgroups were differentiated by FMD at baseline (<7% and 7%). Böger GI-1: study in subjects with high asymmetric dimethylarginine; Böger GI-2: study in subjects with low asymmetric dimethylarginine.

The intake of L-arginine seemed to have no significant effect on FMD (14 comparisons, 589 participants; WMD: 1.57%; 95% CI: –0.32, 3.46; P = 0.1) when the trial by Wilson et al (19) was included in the analysis.

Publication bias
Funnel plots of all short-term studies and 10 studies in the low baseline FMD group seemed asymmetric through visual examination, whereas a statistical analysis of funnel plots suggested no publication bias (Egger test, P = 0.49, Figure 3; Egger test, P = 0.71, Figure 4). A fail-safe N test indicated that it would take 2427 (for all studies) or 2383 (for the low baseline FMD subgroup) unpublished null result studies to bring the combined P to a nonsignificant level.

View larger version (5K): [in this window] [in a new window]   FIGURE 3. Begg's funnel plot (with pseudo 95% CIs) of all individual studies in the meta-analysis. Studies that evaluated the effect of L-arginine supplementation on flow-mediated dilation were plotted with weighted mean differences (WMDs) on the vertical axis and the SEs of the WMDs along the horizontal axis. Graph symbols were sized by weights.

View larger version (5K): [in this window] [in a new window]   FIGURE 4. Begg's funnel plot (with pseudo 95% CIs) of studies in the meta-analysis with low baseline flow-mediated dilation (FMD) levels (<7%). Studies that evaluated the effect of L-arginine supplementation on FMD were plotted with weighted mean differences (WMDs) along the vertical axis and the SEs of the WMDs along the horizontal axis. Graph symbols were sized by weights.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

A subsequent subgroup analysis showed that the effect of L-arginine intake was positive when FMD was low at baseline but negative when FMD was high at baseline. These data suggest that the intervention was able to restore the dysfunctional endothelium but could not further improve the endothelium function. The consistent results of the meta-regression and subgroup analyses reported herein add credence to the contrasting results in the different subgroups and suggest that the effect of arginine supplementation was greatly influenced by baseline FMD. This may influence the decisions of doctors, funding authorities, or medical institutions on the use of L-arginine in populations with different levels of endothelial function. Ultimately, this result appears to support the idea that we should provide L-arginine to those targeted patients who would benefit most rather than to all individuals.

To ensure comparability of the trials, we excluded trials in which the effect of L-arginine on endothelial function was not evaluated on the basis of FMD. Three studies (44–46) indicated that acetylcholine-induced increases in blood flow were enhanced with L-arginine therapy. Interestingly, one of these studies (45) documented that administration of L-arginine augmented the forearm blood flow response to acetylcholine in individuals with impaired endothelium-dependent vasodilatation, but not in healthy subjects. This finding is consistent with our results from the FMD study, which suggests that the effect of L-arginine supplementation was influenced by the baseline endothelial profile.

The mechanism whereby L-arginine may improve endothelial function, especially when baseline FMD is low, remains uncertain. Low FMD may result from decreased NO synthesis and is therefore reversible with L-arginine supplementation, whereas subjects with a high FMD may already have sufficient NO activity, which explains the failure of L-arginine supplementation to increase FMD in such subjects (36). Furthermore, L-arginine may have additional favorable effects on endothelial function that are not mediated by an increase in the concentration of substrate. Studies have shown that oral L-arginine can enhance insulin and prolactin secretion (47–49), influence the immune system, and inhibit LDL oxidation (17, 50). It is uncertain whether any or all of these changes might contribute to the modulation of an individual's response to oral L-arginine therapy.

The present study had several potential limitations. First, only 3 studies were combined for analysis in the high FMD group, which meant that the result of this group was less conclusive than that of the first group. Thus, before we ignore a beneficial effect of L-arginine supplementation on endothelial function in subjects with a high FMD, additional studies in healthy persons with normal vascular function are needed. Second, although a positive trend was documented, it was statistically nonsignificant when 4% and 6% were used as cutoffs for subgroup analysis. The lack of statistical significance might be due to the small number of studies in the low and high FMD strata. Therefore, we must be careful with the interpretation of the subgroup analysis until the rationale of the cutoffs is confirmed by additional large-scale, high-quality trials.

Third, because significant heterogeneity was observed in the treatment effects of all studies and in the subgroup with low FMD at baseline, both visual examination and statistical analysis of funnel plots did not provide sufficient evidence against a publication bias. However, a fail-safe N test was also performed to evaluate publication bias, which suggested that it would take 2427 (for all studies) or 2383 (for the subgroup with low FMD at baseline) unpublished null result studies to bring the combined P value to a nonsignificant level. The existence of that many unpublished studies is improbable; hence, this fail-safe N added greatly to the confidence of the results of our meta-analysis. Fourth, only one study evaluated the association between long-term L-arginine treatment (>6 mo) and FMD levels. Therefore, the effectiveness and safety of long-term supplementation with L-arginine on endothelial function could not be quantitatively evaluated in our systematic review. When Wilson et al's (19) data were pooled with the short-term studies, a negative overall effect and a large degree of heterogeneity were found. Potential mechanisms of the unexpected findings in this trial should be examined carefully, and the long-term effects of L-arginine supplementation should be sought by more high-quality, double-blind, randomized clinical trials.

Fifth, the dose of L-arginine and mean age were statistically different between groups with high and low baseline FMD levels (Table 2) and varied largely in all studies. The potential influence of these factors was estimated by the sensitivity analysis and the meta-regression analysis, which indicated that the dose of L-arginine (range: 3–24 g/d) and the average age of the participants were not effect modifiers. It is an interesting point that low-dose L-arginine has been as effective as large doses, which suggests that daily nutritional doses may be enough to induce a favorable effect. Other explanations may be that either the dose range or the sample size was not large enough, which resulted in a relative lack of power to detect the effect. This phenomenon needs to be investigated in future studies. Sixth, a major limitation of the existing evidence was that none of these trials showed an association between baseline L-arginine supplementation and endothelial function in unstable CAD patients. Furthermore, soft endpoints (net change of FMD) were used in these studies, whereas the effects of treatment on clinical outcomes were not examined.

Our meta-analysis suggests that individuals with apparently impaired endothelial function (low baseline FMD) are likely to benefit from short-term oral L-arginine intake. This beneficial effect seems not to be dose-dependent when the dose of L-arginine ranges from 3 to 24 g/d. However, its long-term effectiveness and safety are not clear. Future research efforts should concentrate on higher-quality and more rigorous randomized trials with longer follow-ups to resolve the uncertainty regarding the clinical effectiveness and safety of this type of intervention.

	ACKNOWLEDGMENTS

 
We thank Junhao Liu, J Isenburg, and BioMed Proofreading for their text editing.

The authors' responsibilities were as follows—YB, LS, and RHui: conceived the idea for the study and developed the search strategy; and YB and LS: summarized the data and conducted the data analyses. All authors contributed to the data analysis, verification, and writing and revision of the manuscript. The authors had no conflict of interests to declare.

	REFERENCES

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 

1. Report, WH. Reducing risks, promoting healthy life. World Health Organization: Geneva, Switzerland, 2002..
2. Perez-Vizcaino, F, Duarte, J & Andriantsitohaina, R. Endothelial function and cardiovascular disease: effects of quercetin and wine polyphenols. Free Radic Res 2006;40:1054–65..[Medline]
3. Cai, H & Harrison, DG. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 2000;87:840–4..[Abstract/Free Full Text]
4. Suwaidi, JA, Hamasaki, S, Higano, ST, et al.. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 2000;101:948–54..[Abstract/Free Full Text]
5. Wang, J, Brown, MA, Tam, SH, et al.. Effects of diet on measurements of nitric oxide metabolites. Clin Exp Pharmacol Physiol 1997;24:418–20..[Medline]
6. Huggins, G.S, Pasternak, RC, Alpert, NM, et al.. Effect of short term treatment of hyperlipidemia on coronary vasodilator function and myocardial perfusion in regions having substantial impairment of baseline dilator reverse. Circulation 1998;98:1291–6..[Abstract/Free Full Text]
7. Lerman, A, Suwaidi, JA & Velianou, JL. l-Arginine: a novel therapy for coronary artery disease? Expert Opin Investig Drugs 1999;8:1785–93..[Medline]
8. Tousoulis, D, Böger, RH, Antoniades, C, Siasos, G, Stefanadi, E & Stefanadis, C. Mechanisms of disease: L-arginine in coronary atherosclerosis-a clinical perspective. Nat Clin Pract Cardiovasc Med 2007;4:274–83..[Medline]
9. Stanislavov, R, Nikolova, V & Rohdewald, P. Improvement of erectile function with Prelox: a randomized, double-blind, placebo-controlled, crossover trial. Int J Impot Res 2008;20:173–80..[Medline]
10. Miller, AL. The effects of sustained-release-L-arginine formulation on blood pressure and vascular compliance in 29 healthy individuals. Altern Med Rev 2006;11:23–9..[Medline]
11. Adams, MR, McCredie, R, Jessup, W, Robinson, J, Sullivan, D & Celermajer, DS. Oral L-arginine improves endothelium-dependent dilatation and reduces monocyte adhesion to endothelial cells in young men with coronary artery disease. Atherosclerosis 1997;129:261–9..[Medline]
12. 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;35:706–13..[Abstract/Free Full Text]
13. Blum, A, Hathaway, L, Mincemoyer, R, et al.. Oral L-arginine in patients with coronary artery disease on medical management. Circulation 2000;101:2160–4..[Abstract/Free Full Text]
14. Maxwell, AJ, Zapien, MP, Pearce, GL, MacCallum, G & Stone, PH. Randomized trial of a medical food for the dietary management of chronic, stable angina. J Am Coll Cardiol 2002;39:37–45..[Abstract/Free Full Text]
15. Bennett-Richards, KJ, Kattenhorn, M, Donald, AE, et al.. Oral L-arginine does not improve endothelial dysfunction in children with chronic renal failure. Kidney Int 2002;62:1372–8..[Medline]
16. Bode-Böger, SM, Muke, J, Surdacki, A, Brabant, G, Böger, RH & Frölich, JC. Oral L-arginine improves endothelial function in healthy individuals older than 70 years. Vasc Med 2003;8:77–81..[Abstract/Free Full Text]
17. Yin, WH, Chen, JW, Tsai, C, Chiang, MC, Young, MS & Lin, SJ. L-Arginine improves endothelial function and reduces LDL oxidation in patients with stable coronary artery disease. Clin Nutr 2005;24:988–97..[Medline]
18. Siasos, G, Tousoulis, D, Vlachopoulos, C, et al.. Short-term treatment with L-arginine prevents the smoking-induced impairment of endothelial function and vascular elastic properties in young individuals. Int J Cardiol 2008;126:394–9..[Medline]
19. Wilson, AM, Harada, R, Nair, N, Balasubramanian, N & Cooke, JP. L-Arginine supplementation in peripheral arterial disease: no benefit and possible harm. Circulation 2007;116:188–95..[Abstract/Free Full Text]
20. Marchesi, S, Lupattelli, G, Siepi, D, et al.. Oral L-arginine administration attenuates postprandial endothelial dysfunction in young healthy males. J Clin Pharm Ther 2001;26:343–9..[Medline]
21. Martina, V, Masha, A, Gigliardi, VR, et al.. Long-term N-acetylcysteine and L-arginine administration reduces endothelial activation and systolic blood pressure in hypertensive patients with type 2 diabetes. Diabetes Care 2008;31:940–4..[Abstract/Free Full Text]
22. Lin, CC, Tsai, WC, Chen, JY, Li, YH, Lin, LJ & Chen, JH. Supplements of L-arginine attenuate the effects of high-fat meal on endothelial function and oxidative stress. Int J Cardiol 2008;127:337–41..[Medline]
23. Hirooka, Y, Egashira, K, Imaizumi, T, et al.. Effect of L-arginine on acetylcholine-induced endothelium-dependent vasodilation differs between the coronary and forearm vasculatures in humans. J Am Coll Cardiol 1994;24:948–55..[Abstract]
24. Angdin, M, Settergren, G, Liska, J & Astudillo, R. No effect of L-arginine supplementation on pulmonary endothelial dysfunction after cardiopulmonary bypass. Acta Anaesthesiol Scand 2001;45:441–8..[Medline]
25. Bode-Böger, SM, Böger, RH, Alfke, H, et al.. L-Arginine induces nitric oxide-dependent vasodilation in patients with critical limb ischemia: a randomized, controlled study. Circulation 1996;93:85–90..[Abstract/Free Full Text]
26. Quyyumi, AA. Does acute improvement of endothelial dysfunction in coronary artery disease improve myocardial ischemia? A double-blind comparison of parenteral D- and L-arginine. J Am Coll Cardiol 1998;32:904–11..[Abstract/Free Full Text]
27. Pernow, J, Bohm, F, Beltran, E & Gonon, A. L-Arginine protects from ischemia-reperfusion-induced endothelial dysfunction in humans in vivo. J Appl Physiol 2003;95:2218–22..[Abstract/Free Full Text]
28. Piatti, P, Fragasso, G, Monti, LD, et al.. Acute intravenous L-arginine infusion decreases endothelin-1 levels and improves endothelial function in patients with angina pectoris and normal coronary arteriograms: correlation with asymmetric dimethylarginine levels. Circulation 2003;107:429–36..[Abstract/Free Full Text]
29. Hirooka, Y, Imaizumi, T, Tagawa, T, et al.. Effects of L-arginine on impaired acetylcholine-induced and ischemic vasodilation of the forearm in patients with heart failure. Circulation 1994;90:658–68..[Abstract/Free Full Text]
30. Walker, HA, McGing, E, Fisher, I, et al.. Endothelium-dependent vasodilation is independent of the plasma L-arginine/ADMA ratio in men with stable angina: lack of effect of oral L-arginine on endothelial function, oxidative stress and exercise performance. J Am Coll Cardiol 2001;38:499–505..[Abstract/Free Full Text]
31. Rector, TS, Bank, AT, Mullen, KA, et al.. Randomized, double-blind, placebo-controlled study of supplemental oral L-arginine in patients with heart failure. Circulation 1996;93:2135–41..[Abstract/Free Full Text]
32. Regensteiner, JG, Popylisen, S, Bauer, TA, et al.. Oral L-arginine and vitamins E and C improve endothelial function in women with type 2 diabetes. Vasc Med 2003;8:169–75..[Abstract/Free Full Text]
33. Koga, Y, Akita, Y, Junko, N, et al.. Endothelial dysfunction in MELAS improved by L-arginine supplementation. Neurology 2006;66:1766–9..[Abstract/Free Full Text]
34. Sozykin, AV, Noeva, EA, Balakhonova, TV, Pogorelova, OA & Men'shikov, MI. Effect of L-arginine on platelet aggregation, endothelial function adn exercise tolerance in patients with stable angina pectoris. Ter Arkh 2000;72:24–7..[Medline]
35. Clarkson, P, Adams, MR, Powel, AJ, et al.. Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults. J Clin Invest 1996;97:1989–94..[Medline]
36. Adams, MR, Forsyth, CJ, Jessup, W, Robinson, J & Celermajer, DS. Oral L-arginine inhibits platelet aggregation but does not enhance endothelium-dependent dilation in healthy young men. J Am Coll Cardiol 1995;26:1054–61..[Abstract]
37. Abdelhamed, AI, Reis, SE, Sane, DC, Brosnihan, KB, Preli, RB & Herrington, DM. No effect of an L-arginine-enriched medical food (HeartBars) on endothelial function and platelet aggregation in subjects with hypercholesterolemia. Am Heart J 2003;145:E15..[Medline]
38. Böger, GI, Rudolph, TK, Maas, R, et al.. Asymmetric dimethylarginine determines the improvement of endothelium-dependent vasodilation by simvastatin: effect of combination with oral L-arginine. J Am Coll Cardiol 2007;49:2274–82..[Abstract/Free Full Text]
39. Moher, D, Pham, B, Jones, A, et al.. Does quality of reports of randomized trials affect estimates of intervention efficacy reported in meta-analyses? Lancet 1998;352:609–13..[Medline]
40. DerSimonian, R & Laird, N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177–88..[Medline]
41. Higgins, JP, Thompson, SG, Deeks, JJ & Altman, DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557–60..[Free Full Text]
42. Egger, M, Davey Smith, G, Schneider, M & Minder, C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629–34..[Abstract/Free Full Text]
43. Rosenthal, R. The "file drawer problem" and tolerance for null results. Psychol Bull 1979;86:638–41..
44. Drexler, H, Fischell, TA, Pinto, FJ, et al.. Effect of L-arginine on coronary endothelial function in cardiac transplant recipients: relation to vessel wall morphology. Circulation 1994;89:1615–23..[Abstract/Free Full Text]
45. Creager, MA, Gallagher, SJ, Girerd, XJ, Coleman, SM, Dzau, VJ & Cooke, JP. L-Arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans. J Clin Invest 1992;90:1248–53..[Medline]
46. Otsuji, S, Nakajima, O, Waku, S, et al.. Attenuation of acetylcholine-induced vasoconstriction by L-arginine is related to the progression of atherosclerosis. Am Heart J 1995;129:1094–100..[Medline]
47. Besset, A, Bonardet, A, Rondouin, G, Descomps, B & Passouant, P. Increase in sleep related GH and Prl secretion after chronic arginine aspirate administration in man. Acta Endocrinol (Copenh) 1982;99:18–23..[Abstract/Free Full Text]
48. Elsair, J, Khelfat, K, Ghouini, A & Ikhlef, F. Effects of arginine, administered orally, on the endogenous secretion of the STH-somatomedin complex in young human volunteers. C R Seances Soc Biol Fil 1985;179:608–14..[Medline]
49. Isidori, A, Lo Monaco, A & Cappa, M. A study of growth hormone release in man after oral administration of amino acids. Curr Med Res Opin 1981;7:475–81..[Medline]
50. Hayde, M, Vierhapper, H, Lubec, B, et al.. Low-dose dietary L-arginine increases plasma interleukin 1 alpha but not interleukin 1 beta in patients with diabetes mellitus. Cytokine 1994;6:79–82..[Medline]

This Article Abstract Full Text (PDF) All Versions of this Article: 89/1/77    most recent ajcn.2008.26544v1 Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bai, Y. Articles by Hui, R. Search for Related Content PubMed PubMed Citation Articles by Bai, Y. Articles by Hui, R. Agricola Articles by Bai, Y. Articles by Hui, R.