Published online before print June 25, 2007, doi: 10.1161/CIRCULATIONAHA.106.683656
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(Circulation. 2007;116:188-195.)
© 2007 American Heart Association, Inc.
Vascular Medicine |
L-Arginine Supplementation in Peripheral Arterial Disease
No Benefit and Possible Harm
From the Division of Cardiovascular Medicine (A.M.W., R.H., N.N., J.P.C.) and Department of Biostatistics (N.B.), Stanford University School of Medicine, Stanford, Calif.
Correspondence to John P. Cooke, MD, PhD, Division of Cardiovascular Medicine, Stanford University Medical Center, Falk Cardiovascular Research Institute, 300 Pasteur Dr, Stanford, CA 94305. E-mail john.cooke{at}stanford.edu
Received December 20, 2006; accepted May 3, 2007.
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Abstract |
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Background— L-Arginine is the precursor of endothelium-derived nitric oxide, an endogenous vasodilator. L-Arginine supplementation improves vascular reactivity and functional capacity in peripheral arterial disease (PAD) in small, short-term studies. We aimed to determine the effects of long-term administration of L-arginine on vascular reactivity and functional capacity in patients with PAD.
Methods and Results— The Nitric Oxide in Peripheral Arterial Insufficiency (NO-PAIN) study was a randomized clinical trial of oral L-arginine (3 g/d) versus placebo for 6 months in 133 subjects with intermittent claudication due to PAD in a single-center setting. The primary end point was the change at 6 months in the absolute claudication distance as assessed by the Skinner-Gardner treadmill protocol. L-Arginine supplementation significantly increased plasma L-arginine levels. However, measures of nitric oxide availability (including flow-mediated vasodilation, vascular compliance, plasma and urinary nitrogen oxides, and plasma citrulline formation) were reduced or not improved compared with placebo. Although absolute claudication distance improved in both L-arginine- and placebo-treated patients, the improvement in the L-arginine-treated group was significantly less than that in the placebo group (28.3% versus 11.5%; P=0.024).
Conclusions— In patients with PAD, long-term administration of L-arginine does not increase nitric oxide synthesis or improve vascular reactivity. Furthermore, the expected placebo effect observed in studies of functional capacity was attenuated in the L-arginine-treated group. As opposed to its short-term administration, long-term administration of L-arginine is not useful in patients with intermittent claudication and PAD.
Key Words: amino acids • atherosclerosis • endothelium • nitric oxide • peripheral vascular disease
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Introduction |
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Endothelium-derived nitric oxide (NO) is a potent endogenous vasodilator with vasoprotective properties.1 In patients with cardiovascular risk factors or disease, inactivation or reduced synthesis of NO impairs endothelium-dependent vasodilation.2–4 Furthermore, the vasoprotective actions of NO are attenuated by cardiovascular risk factors.2–4
Clinical Perspective p 195
L-Arginine is the precursor of NO. In animal models of cardiovascular disease, supplementation with L-arginine improves vasodilation and increases vascular NO synthesis.5,6 In preclinical studies, long-term administration of L-arginine inhibits atherosclerosis and myointimal hyperplasia and enhances angiogenesis.7–9 More importantly, short-term studies in patients with cardiovascular risk factors or disease indicated that L-arginine supplementation may increase NO synthesis and improve vasoreactivity. In patients with severe peripheral arterial disease (PAD), intravenous infusion of L-arginine (30 g over 30 minutes) increases limb blood flow 2-fold and to the same extent as prostaglandin E1.10 The increase in limb blood flow is associated with parallel increases in urinary nitrogen oxides, as well as plasma and urinary cGMP, consistent with increased NO synthesis.10
There are limited options for medical management of intermittent claudication. A nutritional adjunct to PAD therapy seems low risk, and the scientific rationale for L-arginine supplementation seems sound. Accordingly, we initiated a randomized clinical trial of L-arginine supplementation with the aim of improving vascular reactivity and functional capacity in patients with PAD.
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Methods |
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Trial Design
The Nitric Oxide in Peripheral Arterial Insufficiency (NO-PAIN) trial was a prospective, single-center, randomized, double-blind, placebo-controlled National Heart, Lung, and Blood Institute-funded study of the efficacy and safety of oral L-arginine supplementation in patients with intermittent claudication. The trial was approved by the institutional review board at Stanford University; registered at www.clinicaltrials.gov (No. NCT00284076); and monitored by an external Data and Safety Monitoring Board and a National Heart, Lung, and Blood Institute program officer. Written informed consent was obtained from each patient.
Patients
Inclusion criteria were age of at least 45 years, unilateral or bilateral PAD confirmed by a resting ankle-brachial index (ABI) <0.9, stable intermittent claudication for the previous 3 months, and the ability to walk 1 to 12 minutes on a treadmill. Variability of maximum walking distances between 2 consecutive screening treadmill tests was <25%. Exclusion criteria included ischemic rest pain, ulceration or gangrene, history in the previous 3 months of acute coronary syndrome or revascularization involving the peripheral or coronary arteries, major amputation, malignancy within the previous 5 years (except for treated nonmelanoma skin cancer), proliferative retinopathy, uncontrolled hypertension, or active inflammatory, infectious, or autoimmune diseases. A 1-month washout period was also required before enrollment for patients taking pentoxifylline, cilostazol, prostanoids, L-carnitine, or L-arginine. Patients were advised to maintain their current lifestyle habits related to diet, tobacco, and exercise during study participation.
Eligible patients were randomly assigned to either L-arginine (1 g TID with meals) or placebo. L-Arginine was manufactured by Ajinomoto Inc and encapsulated by Cosmo-Pharm Inc. Bioavailability studies before study initiation confirmed that active study drug increased plasma arginine levels. Amino acid analysis (Beckman 6300 analyzer; Beckman) at the Stanford Clinical Laboratory after the completion of the study showed 95.8% and 97.9% recovery of L-arginine in randomly selected capsules from the remaining lot of L-arginine and 0% recovery of L-arginine from randomly selected capsules from placebo.
Study Procedures
Assessment of Functional Capacity
Graded treadmill tests were performed at 3 and 6 months after randomization, according to the Skinner-Gardner protocol.11 Initial claudication distance (ICD) and absolute claudication distance (ACD) were recorded. Two consecutive treadmill tests were performed within 1 week at baseline (before administration of study drug); 1 test was performed at 3 months; and 2 treadmill tests were performed after 6 months on study drug. Functional status was also assessed by the Walking Impairment Questionnaire and the Health Status Survey SF-36 questionnaire (SF-36).
Vascular Studies
ABI was measured after 10 minutes of supine rest with a hand-held Doppler. Systolic pressures were measured at the dorsalis pedis, posterior tibial, and brachial arteries bilaterally. The right and left ABI values were calculated by taking the higher pressure of the 2 arteries at each ankle, respectively, divided by the higher of the 2 brachial arterial systolic pressures. The index ABI was defined as the ABI of the extremity with the lowest value.
Flow-mediated vasodilation of the brachial artery was measured with the use of an Acuson Sequoia C256 high-resolution ultrasound unit with a 14-mHz probe (Siemens Inc). Vascular studies were performed in a quiet, darkened room with the patient in a fasting state. After measurement of the brachial artery diameter, a blood pressure cuff on the forearm was inflated to a pressure of 50 mm Hg above systolic pressure for 5 minutes. After deflation, measurements of the brachial artery diameter were performed at 30, 45, and 60 seconds during reactive hyperemia. Electronic calipers were used for the measurement of artery diameter. Flow-mediated vasodilation was expressed as the maximal percent change in diameter from the resting condition during the period of reactive hyperemia.
Vascular compliance was measured with the use of a CVProfilor DO 2020 (Hypertension Diagnostics Inc). A tonometer was positioned over the radial artery to obtain a stable waveform. The measurement of oscillatory compliance has been shown to be at least partially dependent on NO availability,12 and it correlates with measures of flow-mediated vasodilation in the same subjects.13 Coefficients of variation for these tests performed in our laboratory have been published previously.14
Patients ingested a low-nitrite diet for 24 hours before testing, fasted overnight, and were given low-nitrate water to consume for 12 hours before blood samples and urine were collected for safety laboratory studies; urinary and plasma nitrogen oxides; amino acid analysis; and plasma asymmetrical dimethylarginine (ADMA) levels. Venous blood was collected into EDTA-coated tubes on ice and plasma stored at –80°C. Nitrogen oxide measurements were performed by Greiss reaction with a colorimetric assay; plasma arginine, ornithine, and citrulline were measured with an amino acid analyzer; and plasma ADMA was measured by immunoassay.15
A questionnaire to elicit adverse events, a pill count to assess compliance, and a treadmill test were conducted at 3- and 6-month follow-up. Secondary measures such as ABI, flow-mediated vasodilation, vascular compliance, and basic clinical laboratories were repeated at 6 months.
Statistical Analysis
The change in ACD was prespecified as the primary end point. ACD values were log transformed. Secondary efficacy end points included changes in ICD, SF-36 and Walking Impairment Questionnaire measures, ABI, flow-mediated vasodilation, vascular compliance, urinary and plasma nitrogen oxides, and plasma amino acid levels. Sample size calculation for the primary end point was based on the results of a pilot, dose-ranging study.16 These calculations indicated that 120 patients randomized into 2 treatment groups would provide 90% power at a 1-sided 
level of 0.05 to reject the null hypothesis assuming a 20% increase in ACD over placebo in the L-arginine group. Thus, we sought to enroll at least 132 patients to allow for an anticipated dropout of 10%.
Baseline characteristics in the 2 groups were compared by Student t test or Mann-Whitney test. The primary efficacy analysis, based on a modified intention-to-treat principle, included all patients who received at least 1 dose of blinded study treatment and had at least 1 valid postrandomization treadmill test. A last observation carried forward method was applied to missing 6-month data. Comparisons of 6-month changes from baseline in efficacy and laboratory values between the 2 groups were conducted with an ANCOVA model with terms for treatment and baseline values. All statistical comparisons between mean treatment-related changes from baseline were performed with the model-adjusted (least-squares) mean values rather than unadjusted raw means. Nonparametric tests were used to analyze nonnormally distributed data when appropriate. In all cases, P<0.05 was used to indicate statistical significance. All analyses were performed with SPSS software, version 12.0.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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A total of 2365 people presented for the study. After initial telephone screening, 687 provided consent and underwent further onsite screening. Most exclusions from those providing consent were due to normal ABI. Thus, 133 patients were randomized (67 subjects randomized to placebo and 66 to L-arginine). The numbers of discontinuations were similar between the groups, resulting in 61 patients in the placebo group and 58 patients in the L-arginine group. Baseline characteristics of the 2 treatment groups were not different (Tables 1 and 2
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Laboratory Measures
Plasma arginine increased in the group receiving the active study drug, as did plasma ornithine (Figure 1) and blood urea nitrogen (from 20.3±6.8 to 22.9±9.8 mg/dL at 6 months; P=0.005). Surprisingly, plasma citrulline levels did not increase in the arginine group (Figure 1). In the placebo group, no changes occurred in plasma levels of arginine, ornithine, or urea.
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Plasma and urinary nitrogen oxides rose slightly in the placebo group but not with L-arginine treatment (Figure 2 and Table 3). Plasma ADMA levels were high in both groups at baseline (Table 3) but did not change significantly over 6 months, nor were there any significant changes in clinical chemistry, hematology, lipid measures, glucose, or insulin in either group (data not shown).
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Vascular Studies
No group differences existed for ABI or vascular compliance measurements (Table 4). ABI increased slightly in both groups (Table 4). No correlation existed between change in ABI and ACD (r=–0.116, P=0.23). Surprisingly, mean flow-mediated vasodilation in the L-arginine group decreased after 6 months, whereas flow-mediated vasodilation in the placebo group increased. This resulted in a significant difference in the mean change of flow-mediated vasodilation between the 2 groups (Figure 2), although the changes within the groups did not reach statistical significance (Figure 2).
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Functional Capacity
Walking distances (ICD and ACD) increased in both groups from baseline to last observation carried forward through 6 months (Table 5). In the placebo group, ACD increased significantly from baseline to 3 months and baseline to 6 months, whereas no significant change occurred in the L-arginine group between baseline and 3 months (Figure 3). The change in baseline to 6 months reached significance (P=0.04). No significant intragroup differences existed between 3- and 6-month time points. Subjects receiving L-arginine manifested significantly less improvement in ACD (mean improvement of 11.5% in the L-arginine group versus 28.3% in the placebo group) (Figure 4). The change in ICD in the L-arginine group tended to be less than in the placebo group (39.6% versus 47.1%; P=0.06). Quantitative composite measures of quality of life with the use of the Walking Impairment Questionnaire or SF-36 were similar between the treatment groups (data not shown).
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Adverse Events
The adverse event profile for the safety population is summarized in Table 6. Of these, 9 in each group were considered serious events. No group differences existed in serious or total adverse events.
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Discussion |
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The major observation of the present study is that long-term administration of L-arginine does not improve walking distance in patients with PAD. Furthermore, the data indicate that long-term administration of L-arginine may even impair functional capacity, perhaps through an adverse effect on vascular reactivity. Specifically, significant group differences were observed in flow-mediated vasodilation and in plasma and urinary nitrogen oxide elaboration.
Rationale for L-Arginine Supplementation
These findings were unexpected. In previous studies, we and others have shown that short-term administration of L-arginine (the NO precursor) improves endothelial vasodilator function of coronary or peripheral arteries in patients with cardiovascular disease.17 The improvement in vascular reactivity is likely due to the metabolism of L-arginine to NO because it is associated with increases in urinary or plasma nitrogen oxides and cGMP.18
We hypothesized that administration of L-arginine would enhance NO synthesis and, by so doing, improve calf blood flow and functional capacity in patients with PAD. This hypothesis was based on the observation that patients with PAD have elevated plasma levels of ADMA.18,19 ADMA is a methylated arginine analogue and an endogenous competitive inhibitor of NO synthase.20 ADMA is metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). In conditions in which DDAH is impaired or deficient, ADMA accumulates.21 Vascular DDAH is impaired by the oxidative stress associated with elevated levels of cholesterol, blood glucose, triglycerides, or homocysteine.19,22,23 Preclinical and human studies indicate that ADMA adversely affects angiogenesis and vascular regeneration and accelerates vascular disease.9,24–26 ADMA correlates with the severity of arterial disease27 and is predictive of cardiovascular events.27,28 Infusion of ADMA increases systemic resistance, reduces cardiac output and vascular compliance, and lessens cerebral blood flow in humans.29,30
Other Studies of L-Arginine Supplementation and Functional Capacity
This is the largest randomized clinical trial, of the longest duration, to assess the effect of L-arginine on functional capacity. Several small studies of relatively brief duration have shown a beneficial effect of L-arginine on functional capacity. In patients with PAD (n=39), Boger and colleagues18 showed that intravenous administration of L-arginine (8 g BID) for 2 weeks improved femoral endothelium-dependent vasodilation, increased urinary nitrogen oxides and cGMP, and increased walking distance compared with placebo. Maxwell and colleagues31 reported that oral L-arginine supplementation (3 g BID, as part of a nutraceutical supplement) for 2 weeks improved ACD in patients with PAD (n=41). Previously, we performed a pilot study to establish the lowest effective oral dose of L-arginine to improve walking distance.16 Patients with PAD and intermittent claudication (n=80) were randomly assigned to oral doses of 0, 3, 6, or 9 g of L-arginine daily in 3 divided doses for 12 weeks. We observed a trend for a greater increase in walking distance in the group treated with 3 g L-arginine daily and a trend for an improvement in walking speed in patients treated with L-arginine. Similar observations related to the beneficial effects on functional capacity of L-arginine have been made in patients with coronary artery disease32–34 and in patients with congestive heart failure.35
Although these studies were typically small and of short duration, they are consistent with mechanistic preclinical studies. In hypercholesterolemic mice, plasma ADMA levels are elevated, and endothelial vasodilator function is impaired. In these animals, L-arginine supplementation increases exercise capacity in association with an increase in limb blood flow and urinary nitrogen oxides.36 In addition to its action as a vasodilator, NO mediates angiogenesis. In the NO synthase-deficient mouse, angiogenesis in response to limb ischemia is impaired, as demonstrated by capillary densitometry.37 By contrast, in the DDAH transgenic mouse, plasma ADMA levels are low, NO synthesis is increased, and the angiogenic response to limb ischemia is augmented.38 In New Zealand White rabbits, L-arginine enhances the angiogenic response to surgically induced limb ischemia.37 Thus, by improving vascular reactivity and/or vascular regeneration, augmenting the synthesis of endothelial NO improves limb blood flow and exercise capacity.
L-Arginine Tolerance?
The discordance between the results of the present study and those of previous work might be explained by the fact that the present study was of longer duration. Perhaps counterregulatory mechanisms are activated in response to prolonged administration of the NO precursor. This is true of sustained administration of exogenous NO donors such as nitroglycerin, which causes nitrate tolerance. Multiple mechanisms may be involved in nitrate tolerance, including neurohormonal adjustments, oxidative stress, or inhibition of nitroglycerin bioactivation.39 Could similar mechanisms exist to counter an upregulated synthesis of endogenous NO? Of relevance to this question, Moncada and coworkers40 found that NO synthase inhibitors enhanced vascular responsiveness to exogenous nitrates. They suggested that removal of endogenous NO induced a supersensitivity to nitrovasodilators at the level of soluble guanylate cyclase.
Induction of arginase expression is a mechanism that could be involved in "arginine tolerance." Arginase metabolizes L-arginine to ornithine and urea. Arginase in the intestine and liver is responsible for extensive first-pass metabolism of L-arginine.41 In our study, ornithine and urea levels were increased in the arginine-treated individuals, consistent with the action of arginase. However, we also observed a significant elevation of plasma arginine levels, and therefore arginase cannot be invoked as the sole cause of counterregulation.
We had anticipated that arginine administration would increase both NO and citrulline levels by the action of NO synthase. We observed no increase in either. Perhaps L-arginine administration triggers a mechanism to inhibit NO synthase. A transient increase in vascular NO levels could inhibit DDAH and cause ADMA to increase.42 However, we did not observe an increase in plasma ADMA levels in the arginine-treated patients. Alternatively, it is possible that a transient increase in NO levels could inhibit NO synthase activity by nitrosylation of NO synthase itself43 or the arginine transporter to counter any arginine-induced increase in NO production.
Potential Adverse Effects of Long-Term L-Arginine Therapy
In our study, the improvement in ACD in the placebo-treated patients was 28.3%, similar to the placebo effect in other studies.44 By contrast, long-term L-arginine therapy was associated with only an 11.5% increase in ACD. The improvement in ACD was significantly different between the 2 groups and might indicate an adverse effect of L-arginine on functional capacity. The reduced improvement might be due to an arginine-induced derangement of the NO synthase pathway, with a paradoxical reduction in NO production.
In a recent randomized clinical trial, long-term therapy with oral L-arginine supplementation in patients after myocardial infarction (6 g/d for 6 months; n=150) did not improve ejection fraction or vascular compliance, and the study was terminated prematurely for safety concerns.45 By contrast, in a larger study of shorter duration (6 g/d for 30 days; n=750), L-arginine tended to reduce major adverse cardiovascular events.46 Taken together, these studies are also consistent with a benefit of short-term administration, which is lost with long-term administration (ie, arginine tolerance).
The present study was based on the hypothesis that L-arginine would reverse the competitive inhibition of NO synthase by ADMA. Accumulating evidence indicates that ADMA contributes to endothelial dysfunction in cardiovascular disease and may be an independent predictor of cardiovascular events. In mice, overexpression of DDAH reduces plasma ADMA, increases NO synthesis, and reduces systemic vascular resistance.47 The reduction in ADMA is associated with vascular protection, as shown by a greater capacity for angiogenesis, and a resistance to vascular lesion formation.24,38,48 Agents that increase DDAH expression or activity may be useful in the treatment of cardiovascular disease. Indeed, there are currently several disease-modifying drugs that reduce ADMA, including metformin, rosiglitazone, converting enzyme inhibitors, and angiotensin receptor antagonists.21 Of course, each of these agents has other metabolic and hemodynamic effects that are antiatherogenic.
Conclusion
In a randomized, double-blind, placebo-controlled trial in patients with intermittent claudication, oral L-arginine supplementation (3 g/d for 6 months) was less effective than placebo in improving measures of endothelial function and treadmill exercise. L-Arginine is not a useful nutritional adjunct in patients with intermittent claudication and PAD.
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Acknowledgments |
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We gratefully acknowledge the careful monitoring of the study by Drs Jeffrey Olin and Joshua Beckman (Data and Safety Monitoring Board) and the National Heart, Lung, and Blood Institute program officer Dr Diane Reid; Drs Richard Olshen and Iain Johnstone for biostatistical support; Homa Tavana, Bonnie Chung, and Scott Reiff for administrative support, recruitment efforts, and data collection; the staff of the Stanford General Clinical Research Center for nursing and laboratory support; and the participants in this study for their time and effort.
Sources of Funding
This study was supported in part by grants (to Dr Cooke) from the National Institutes of Health (R01 HL63685, R01 HL075774, P01AI50153, P50HL083800, and T32 HL007708) and from Ajinomoto Inc. Dr Wilson is supported by a postdoctoral fellowship from the National Health and Medical Research Council of Australia and the Royal Australasian College of Physicians Bayer Fellowship.
Disclosures
Dr Cooke is the inventor of patents owned by Stanford University for diagnostic and therapeutic applications of the NO synthase pathway from which he receives royalties. Dr Cooke is a consultant to Ajinomoto and United Therapeutics. The other authors report no conflicts.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
- Napoli C, de Nigris F, Williams-Ignarro S, Pignalosa O, Sica V, Ignarro LJ. Nitric oxide and atherosclerosis: an update. Nitric Oxide. 2006; 15: 265–279.[CrossRef][Medline]
[Order article via Infotrieve]
- Ludmer PL, Selwyn AP, Shook TL, Wayne RR, Mudge GH, Alexander RW, Ganz P. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med. 1986; 315: 1046–1051.[Abstract]
- Creager MA, Cooke JP, Mendelsohn ME, Gallagher SJ, Coleman SM, Loscalzo J, Dzau VJ. Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest. 1990; 86: 228–234.[Medline]
[Order article via Infotrieve]
- Cooke JP, Dzau VJ. Nitric oxide synthase: role in the genesis of vascular disease. Annu Rev Med. 1997; 48: 489–509.[CrossRef][Medline]
[Order article via Infotrieve]
- Cooke JP, Andon NA, Girerd XJ, Hirsch AT, Creager MA. Arginine restores cholinergic relaxation of hypercholesterolemic rabbit thoracic aorta. Circulation. 1991; 83: 1057–1062.
[Abstract/Free Full Text] - Tsao PS, McEvoy LM, Drexler H, Butcher EC, Cooke JP. Enhanced endothelial adhesiveness in hypercholesterolemia is attenuated by L-arginine. Circulation. 1994; 89: 2176–2182.
[Abstract/Free Full Text] - Cooke JP, Singer AH, Tsao P, Zera P, Rowan RA, Billingham ME. Antiatherogenic effects of L-arginine in the hypercholesterolemic rabbit. J Clin Invest. 1992; 90: 1168–1172.[Medline]
[Order article via Infotrieve]
- Wang BY, Candipan RC, Arjomandi M, Hsiun PT, Tsao PS, Cooke JP. Arginine restores nitric oxide activity and inhibits monocyte accumulation after vascular injury in hypercholesterolemic rabbits. J Am Coll Cardiol. 1996; 28: 1573–1579.[Abstract]
- Jang JJ, Ho HK, Kwan HH, Fajardo LF, Cooke JP. Angiogenesis is impaired by hypercholesterolemia: role of asymmetric dimethylarginine. Circulation. 2000; 102: 1414–1419.
[Abstract/Free Full Text] - Bode-Boger SM, Boger RH, Alfke H, Heinzel D, Tsikas D, Creutzig A, Alexander K, Frolich JC. 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] - Hiatt WR, Hirsch AT, Regensteiner JG, Brass EP; Vascular Clinical Trialists. Clinical trials for claudication: assessment of exercise performance, functional status, and clinical end points. Circulation. 1995; 92: 614–621.
[Free Full Text] - McVeigh GE, Allen PB, Morgan DR, Hanratty CG, Silke B. Nitric oxide modulation of blood vessel tone identified by arterial waveform analysis. Clin Sci (Lond). 2001; 100: 387–393.[Medline]
[Order article via Infotrieve]
- Wilson AM, O’Neal D, Nelson CL, Prior DL, Best JD, Jenkins AJ. Comparison of arterial assessments in low and high vascular disease risk groups. Am J Hypertens. 2004; 17: 285–291.[CrossRef][Medline]
[Order article via Infotrieve]
- Nair N, Oka RK, Waring LD, Umoh EM, Taylor CB, Cooke JP. Vascular compliance versus flow-mediated vasodilation: correlation with cardiovascular risk factors. Vasc Med. 2005; 10: 275–283.
[Abstract/Free Full Text] - Schulze F, Wesemann R, Schwedhelm E, Sydow K, Albsmeier J, Cooke JP, Boger RH. Determination of asymmetric dimethylarginine (ADMA) using a novel ELISA assay. Clin Chem Lab Med. 2004; 42: 1377–1383.[CrossRef][Medline]
[Order article via Infotrieve]
- Oka RK, Szuba A, Giacomini JC, Cooke JP. A pilot study of L-arginine supplementation on functional capacity in peripheral arterial disease. Vasc Med. 2005; 10: 265–274.
[Abstract/Free Full Text] - Drexler H, Zeiher AM, Meinzer K, Just H. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine. Lancet. 1991; 338: 1546–1550.[CrossRef][Medline]
[Order article via Infotrieve]
- Boger RH, Bode-Boger SM, Thiele W, Creutzig A, Alexander K, Frolich JC. Restoring vascular nitric oxide formation by L-arginine improves the symptoms of intermittent claudication in patients with peripheral arterial occlusive disease. J Am Coll Cardiol. 1998; 32: 1336–1344.
[Abstract/Free Full Text] - Stuhlinger MC, Tsao PS, Her JH, Kimoto M, Balint RF, Cooke JP. Homocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine. Circulation. 2001; 104: 2569–2575.
[Abstract/Free Full Text] - Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet. 1992; 339: 572–575.[CrossRef][Medline]
[Order article via Infotrieve]
- Cooke JP. Asymmetrical dimethylarginine: the Uber marker? Circulation. 2004; 109: 1813–1818.
[Free Full Text] - Ito A, Tsao PS, Adimoolam S, Kimoto M, Ogawa T, Cooke JP. Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase. Circulation. 1999; 99: 3092–3095.
[Abstract/Free Full Text] - Lin KY, Ito A, Asagami T, Tsao PS, Adimoolam S, Kimoto M, Tsuji H, Reaven GM, Cooke JP. Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation. 2002; 106: 987–992.
[Abstract/Free Full Text] - Achan V, Ho HK, Heeschen C, Stuehlinger M, Jang JJ, Kimoto M, Vallance P, Cooke JP. ADMA regulates angiogenesis: genetic and metabolic evidence. Vasc Med. 2005; 10: 7–14.
[Abstract/Free Full Text] - Cooke JP Asymmetric dimethylarginine (ADMA): an endogenous inhibitor of angiogenesis. Eur J Clin Pharmacol. 2006; 62 (suppl 13): 115–121.[CrossRef]
- Thum T, Tsikas D, Stein S, Schultheiss M, Eigenthaler M, Anker SD, Poole-Wilson PA, Ertl G, Bauersachs J. Suppression of endothelial progenitor cells in human coronary artery disease by the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine. J Am Coll Cardiol. 2005; 46: 1693–1701.
[Abstract/Free Full Text] - Mittermayer F, Krzyzanowska K, Exner M, Mlekusch W, Amighi J, Sabeti S, Minar E, Muller M, Wolzt M, Schillinger M. Asymmetric dimethylarginine predicts major adverse cardiovascular events in patients with advanced peripheral artery disease. Arterioscler Thromb Vasc Biol. 2006; 26: 2536–2540.
[Abstract/Free Full Text] - Thum T, Bauersachs J. ADMA, endothelial progenitor cells, and cardiovascular risk. Circ Res. 2005; 97: e84.
[Free Full Text] - Kielstein JT, Tsikas D, Fliser D. Effects of asymmetric dimethylarginine (ADMA) infusion in humans. Eur J Clin Pharmacol. 2006; 62 (suppl 13): 39–44.[CrossRef]
- Kielstein JT, Impraim B, Simmel S, Bode-Boger SM, Tsikas D, Frolich JC, Hoeper MM, Haller H, Fliser D. Cardiovascular effects of systemic nitric oxide synthase inhibition with asymmetrical dimethylarginine in humans. Circulation. 2004; 109: 172–177.
[Abstract/Free Full Text] - Maxwell AJ, Anderson BE, Cooke JP. Nutritional therapy for peripheral arterial disease: a double-blind, placebo-controlled, randomized trial of HeartBar. Vasc Med. 2000; 5: 11–19.
[Abstract/Free Full Text] - Ceremuzynski L, Chamiec T, Herbaczynska-Cedro K. Effect of supplemental oral L-arginine on exercise capacity in patients with stable angina pectoris. Am J Cardiol. 1997; 80: 331–333.[CrossRef][Medline]
[Order article via Infotrieve]
- Bednarz B, Wolk R, Chamiec T, Herbaczynska-Cedro K, Winek D, Ceremuzynski L. Effects of oral L-arginine supplementation on exercise-induced QT dispersion and exercise tolerance in stable angina pectoris. Int J Cardiol. 2000; 75: 205–210.[CrossRef][Medline]
[Order article via Infotrieve]
- 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] - Bednarz B, Jaxa-Chamiec T, Gebalska J, Herbaczynska-Cedro K, Ceremuzynski L. L-Arginine supplementation prolongs exercise capacity in congestive heart failure. Kardiol Pol. 2004; 60: 348–353.[Medline]
[Order article via Infotrieve]
- Maxwell AJ, Ho HV, Le CQ, Lin PS, Bernstein D, Cooke JP. L-Arginine enhances aerobic exercise capacity in association with augmented nitric oxide production. J Appl Physiol. 2001; 90: 933–938.
[Abstract/Free Full Text] - Murohara T, Asahara T, Silver M, Bauters C, Masuda H, Kalka C, Kearney M, Chen D, Symes JF, Fishman MC, Huang PL, Isner JM. Nitric oxide synthase modulates angiogenesis in response to tissue ischemia. J Clin Invest. 1998; 101: 2567–2578.[Medline]
[Order article via Infotrieve]
- Jacobi J, Sydow K, von Degenfeld G, Zhang Y, Dayoub H, Wang B, Patterson AJ, Kimoto M, Blau HM, Cooke JP. Overexpression of dimethylarginine dimethylaminohydrolase reduces tissue asymmetric dimethylarginine levels and enhances angiogenesis. Circulation. 2005; 111: 1431–1438.
[Abstract/Free Full Text] - Sydow K, Daiber A, Oelze M, Chen Z, August M, Wendt M, Ullrich V, Mulsch A, Schulz E, Keaney JF Jr, Stamler JS, Munzel T. Central role of mitochondrial aldehyde dehydrogenase and reactive oxygen species in nitroglycerin tolerance and cross-tolerance. J Clin Invest. 2004; 113: 482–489.[CrossRef][Medline]
[Order article via Infotrieve]
- Moncada S, Rees DD, Schulz R, Palmer RM. Development and mechanism of a specific supersensitivity to nitrovasodilators after inhibition of vascular nitric oxide synthesis in vivo. Proc Natl Acad Sci U S A. 1991; 88: 2166–2170.
[Abstract/Free Full Text] - Morris SM Jr. Arginine metabolism in vascular biology and disease. Vasc Med. 2005; 10 (suppl 1): S83–S87.
[Abstract/Free Full Text] - MacAllister RJ, Parry H, Kimoto M, Ogawa T, Russell RJ, Hodson H, Whitley GS, Vallance P. Regulation of nitric oxide synthesis by dimethylarginine dimethylaminohydrolase. Br J Pharmacol. 1996; 119: 1533–1540.[Medline]
[Order article via Infotrieve]
- Erwin PA, Lin AJ, Golan DE, Michel T. Receptor-regulated dynamic S-nitrosylation of endothelial nitric-oxide synthase in vascular endothelial cells. J Biol Chem. 2005; 280: 19888–19894.
[Abstract/Free Full Text] - Dawson DL. Comparative effects of cilostazol and other therapies for intermittent claudication. Am J Cardiol. 2001; 87: 19D–27D.[Medline]
[Order article via Infotrieve]
- Schulman SP, Becker LC, Kass DA, Champion HC, Terrin ML, Forman S, Ernst KV, Kelemen MD, Townsend SN, Capriotti A, Hare JM, Gerstenblith G. L-Arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial. JAMA. 2006; 295: 58–64.
[Abstract/Free Full Text] - Bednarz B, Jaxa-Chamiec T, Maciejewski P, Szpajer M, Janik K, Gniot J, Kawka-Urbanek T, Drozdowska D, Gessek J, Laskowski H. Efficacy and safety of oral L-arginine in acute myocardial infarction: results of the multicenter, randomized, double-blind, placebo-controlled ARAMI pilot trial. Kardiol Pol. 2005; 62: 421–427.[Medline]
[Order article via Infotrieve]
- Dayoub H, Achan V, Adimoolam S, Jacobi J, Stuehlinger MC, Wang BY, Tsao PS, Kimoto M, Vallance P, Patterson AJ, Cooke JP. Dimethylarginine dimethylaminohydrolase regulates nitric oxide synthesis: genetic and physiological evidence. Circulation. 2003; 108: 3042–3047.
[Abstract/Free Full Text] - Tanaka M, Sydow K, Gunawan F, Jacobi J, Tsao PS, Robbins RC, Cooke JP. Dimethylarginine dimethylaminohydrolase overexpression suppresses graft coronary artery disease. Circulation. 2005; 112: 1549–1556.
[Abstract/Free Full Text]
CLINICAL PERSPECTIVE
L-Arginine is a semiessential amino acid and is the precursor for nitric oxide (NO). The vasodilator action of NO resembles that of nitroglycerin. Its vasodilator and vasoprotective effects are attenuated in patients with cardiovascular disease or risk factors. Previous studies in cardiovascular patients reveal that short-term administration of L-arginine restores endothelium-dependent, NO-mediated vasodilation. Small pilot studies of brief duration indicate that L-arginine supplementation improves vascular function as well as symptoms in patients with peripheral arterial disease. Accordingly, we performed a randomized clinical trial to determine whether long-term L-arginine supplementation (1 g TID for 6 months) is useful in patients with symptomatic peripheral arterial disease. The primary end point was walking distance by treadmill testing. Secondary end points included measures of vascular function, including flow-mediated vasodilation and vascular compliance, and biochemical measures of NO synthase activity. L-Arginine supplementation increased plasma L-arginine levels but did not increase metabolites of NO synthase (plasma citrulline and nitrogen oxides). Furthermore, L-arginine supplementation did not improve measures of vascular function. Surprisingly, the increment in walking distance in the placebo group was greater than that in the group treated with L-arginine. As opposed to its short-term use, long-term L-arginine supplementation does not improve vascular function or symptoms in patients with peripheral arterial disease. The absence of a long-term benefit might be explained by "arginine tolerance."
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Clinical trial registration information—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00284076.
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  T. Teerlink Letter by Teerlink Regarding Article, "L-Arginine Supplementation in Peripheral Arterial Disease: No Benefit and Possible Harm" Circulation, February 12, 2008; 117(6): e157 - e157. [Full Text] [PDF]
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A. M. Wilson, R. K. Harada, N. Nair, N. Balasubramanian, and J. P. Cooke Response to Letter Regarding Article, "L-Arginine Supplementation in Peripheral Arterial Disease: No Benefit and Possible Harm" Circulation, February 12, 2008; 117(6): e158 - e158. [Full Text] [PDF]
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