(Circulation. 1996;93:85-90.)
© 1996 American Heart Association, Inc.
Articles |
L-Arginine Induces Nitric Oxide–Dependent Vasodilation in Patients With Critical Limb Ischemia
A Randomized, Controlled Study
From the Institute of Clinical Pharmacology (S.M.B.-B., R.H.B., D.H., D.T., J.C.F.) and Department of Angiology (H.A., A.C., K.A.), Medical School, Hannover, Germany.
Correspondence and reprint requests to Dr Stefanie M. Bode-Böger, Institute of Clinical Pharmacology, Hannover Medical School, Konstanty-Gutschow-Str 8, 30625 Hannover, Germany.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background L-Arginine is the precursor of endogenous nitric oxide (NO), which is a potent vasodilator acting via the intracellular second-messenger cGMP. In healthy humans, L-arginine induces peripheral vasodilation and inhibits platelet aggregation due to an increased NO production. Prostaglandin E1 (PGE1) induces peripheral vasodilation via stimulating prostacyclin receptors.
Methods and Results We investigated the effects of one intravenous infusion of L-arginine (30 g, 60 minutes) or PGE1 (40 µg, 60 minutes) versus those of placebo (150 mL 0.9% saline, 60 minutes) on blood pressure, peripheral hemodynamics, and urinary NO3- and cGMP excretion rates in patients with critical limb ischemia (peripheral arterial occlusive disease stages Fontaine III or IV). Blood flow in the femoral artery was significantly increased by L-arginine (+42.3±7.9%, P<.05) and by PGE1 (+31.0±10.2%, P<.05) but not by placebo (+4.3±13.0%, P=NS). Urinary NO3- excretion increased by 131.8±39.5% after L-arginine (P<.05) but only by 32.3±17.2% after PGE1 (P=NS). Urinary cGMP excretion increased by 198.7±84.9% after L-arginine (P<.05) and by 94.2±58.8% after PGE1 (P=NS). Both urinary index metabolites were unchanged by placebo.
Conclusions We conclude that intravenous L-arginine induces NO-dependent peripheral vasodilation in patients with critical limb ischemia. These effects are paralleled by increased urinary NO3- and cGMP excretion, indicating an enhanced systemic NO production. Increased urinary NO3- excretion may be a sum effect of NO synthase substrate provision (L-arginine) and increased shear stress (PGE1 and L-arginine).
Key Words: L-arginine • prostaglandins • peripheral vascular disease • nitric oxide
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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The endothelium has been identified as a source of mediators that protect the vascular wall against vasospasm and thrombotic occlusion.1 These mediators include prostacyclin, a vasodilator and antiaggregatory prostaglandin,2 and nitric oxide (NO), which is synthesized from the terminal guanidino nitrogen of the amino acid precursor L-arginine.3 NO has been shown to account for the biological activity of the endothelium-derived relaxing factor in the cardiovascular system.4 These actions, mainly relaxation of vascular smooth muscle and inhibition of platelet aggregation and adhesion, are mediated by the intracellular second-messenger cGMP.5 NO is very rapidly oxidized to NO3- in vivo,6 which is subsequently excreted into the urine.7 8 As NO itself can hardly be measured in vivo, NO3- has been suggested to be a suitable index metabolite for the determination of NO formation rates in vivo.8 9 We have recently shown that intravenous L-arginine induces peripheral vasodilation, inhibits platelet aggregation, and concomitantly increases urinary NO3- and cGMP excretion rates in healthy humans.10 The release and/or biological activity of endothelium-derived relaxing factor/NO has been shown to be impaired in atherosclerotic arteries,11 12 which is in accordance with the endothelial injury hypothesis of atherosclerosis.13 Exogenous administration of L-arginine restores endothelium-dependent relaxations in experimental atherosclerosis.14 15 16 However, although L-arginine was also shown to enhance acetylcholine-induced, endothelium-dependent vasodilation in hypercholesterolemic or atherosclerotic patients,17 it has been disputed whether L-arginine is capable of inducing vasodilation in these patients.18
The biological activity of prostacyclin is also decreased in atherosclerosis, as the homeostasis between the vasoconstrictor thromboxane A2 and prostacyclin is shifted in favor of thromboxane.19 20 Infusion of prostaglandin (PG)E1, which stimulates prostacyclin receptors and thus substitutes its deficient biological activity, has been used as pharmacotherapy for peripheral arterial occlusive disease in Germany and several other countries.21 22
In the present study, we investigated whether L-arginine, given as a single intravenous infusion, induces vasodilation in the more severely affected lower limb of patients with critical limb ischemia and whether the possible hemodynamic effects are related to an increased NO production (using the urinary excretion rates of NO3- and cGMP as index parameters for systemic NO formation in vivo). We compared the effects of L-arginine with those of PGE1 as an NO/cGMP-independent vasodilator and with those of placebo.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Patients and Study Design
Ten male patients with critical limb ischemia (peripheral arterial occlusive disease stages Fontaine III or IV) received a single intravenous infusion of L-arginine (Fresenius AG; 30 g dissolved in 150 mL 0.9% saline, pH 6.5) or PGE1 (Prostavasin, Schwarz Pharma; 40 µg dissolved in 150 mL 0.9% saline) into an antecubital vein over 60 minutes. Both substances were administered in randomized order with a washout period of at least 2 days between them. Another group of six patients with critical limb ischemia received a single intravenous infusion of placebo (150 mL 0.9% saline, 60 minutes). All patients had angiographically proven femoropopliteal occlusions and additional distal stenoses of the crural arteries. None had proximal hemodynamically relevant stenoses of the iliac vessels. The cardiovascular risk factors and parallel diseases of the two groups of patients are given in Table 1
, and the
mean plasma cholesterol and triglyceride levels
are given in Table 2. Each patient gave written informed
consent to participation in the study, which had been approved by the
Hannover Medical School Ethics Committee. Comedication, which was kept
constant throughout the study period, is given in Table 3. At
the beginning of each study day, each patient
emptied his bladder. A mild oral volume loading (using demineralized
water) was started with 3 mL/kg body wt initially and continued during
the study period with 1 to 2
mL·kg-1·h-1
adjusted to the individual hourly urine volumes. Each participant
remained in the supine position for 60 minutes before and 30 minutes
after the infusion.
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During 1 hour before and 3 hours after the beginning of the infusion, urine was collected in hourly intervals and immediately frozen for the determination of urinary NO3- and cGMP concentrations. At baseline and at the end of the infusions, a venous blood sample was drawn with EDTA for the determination of plasma arginine levels.
At 60 minutes before, during, and for 20 minutes after the end of the infusion, blood pressure and heart rate were recorded every 5 minutes by the standard sphygomanometric method with an automatic device (Boso digital II, Bosch & Sohn).
Duplex Measurements of Femoral Arterial Blood
Flow
Blood flow velocity was measured by image-directed duplex
ultrasonography before the infusion and at its end in a segment of the
common femoral artery with a circular cross section. Measurements were
made with a DRF 400 image-directed duplex ultrasound system
(Diasonics-Sonotron) with a transducer combining 7.5-MHz B-mode imaging
and 3-MHz pulsed Doppler beams. Blood flow volume was automatically
calculated as the product of the cross-sectional area and the
time-averaged blood velocity from seven repeated
measurements.23 The investigator performing the duplex
measurements was blinded to the treatment.
Biochemical Assays
Urinary
NO2-/NO3-
was determined as its pentafluorobenzyl derivative by gas
chromatography–mass spectrometry (GC-MS) as
described previously.24 25 Briefly, 100-µL
aliquots of
urine were spiked with 250 ng of
[15N]NO3- (MSD Isotopes
Merck Frosst) as internal standard, acidified with 20 µL of 0.1 N
HCl, and treated with 5 mg cadmium for 10 minutes at room temperature.
The suspension was then centrifuged; the supernatant decanted
and alkalinized with 10 µL of 4 N NaOH, treated with 500 µL of cold
acetone (-20°C), and centrifuged. Then, 5 µL of
pentafluorobenzyl bromide was added to the decanted supernatant, and
the mixture was allowed to react for 75 minutes at 50°C. After being
cooled to room temperature, acetone was removed under nitrogen, and the
residue was extracted with 1 mL of toluene. The toluene phase was taken
up and dried over Na2SO4. Then 1-µL aliquots
were injected into the GC-MS device.
GC-MS was carried out on a triple-stage quadrupole mass spectrometer TSQ 45 interfaced with a gas chromatograph 9611 (Finnigan MAT). An OV-1 fused silica capillary column (25x0.25 mm ID, 0.25-µm film thickness) from Machery-Nagel was used with helium as the carrier gas (55 kPa). Negative ions were produced by chemical ionization using methane as the reactant gas (65 Pa) at an electron energy of 90 eV and an electron current of 0.2 mA. Quantification was performed by selected ion monitoring at m/z 46 for endogenous NO2-/NO3- and m/z 47 for the internal standard. The detection limit of the method was 20 fmol nitrite or nitrate. Intra-assay variability was less than 3.8%.
For the determination of cGMP levels, urine samples were thawed and centrifuged at 2500g (4°C; 10 minutes). Supernatants were diluted 1:500 in phosphate buffered saline and acetylated by a mixture of acetic acid anhydride/triethylamine. cGMP content was measured by radioimmunoassay using [125I]cGMP as a tracer and globulin precipitation. The detection limit of the assay was 160 fmol/mL.
Urinary creatinine was determined spectrophotometrically with the alkaline picric acid method in an automatic analyzer (Beckman). The urinary excretion rates of NO3- and cGMP were corrected by urinary creatinine concentration.
Plasma arginine levels were determined spectrophotometrically after conversion to urea according to the method of Bacchus and London.26
Calculations and Statistical Analysis
All values are given as
mean±SEM. The statistical comparison of
hemodynamic data was performed by two-way ANOVA for
repeated measurements followed by the Scheffé F test. For
statistical comparison of the time course of urinary
NO3- and cGMP excretion, the area under
the curve was calculated for each infusion, and
area-under-the-curve values were compared using Student's
paired t test. Statistical significance was assumed for
P<.05.
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Results |
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Femoral arterial blood flow was enhanced by 42.3±7.9% during L-arginine infusion (P<.05) and by 31.0±10.2% during PGE1 infusion (P<.05) but remained unchanged during placebo infusion (+4.3±13.0%, P=NS) (Fig 1
). There
was
no significant difference between both active treatments. However,
blood flow further increased until 30 minutes after the end of
L-arginine infusion, whereas after the end of
PGE1 infusion blood flow immediately began to decrease.
This effect was due to an increased blood flow velocity (+56% after
L-arginine, +29% after PGE1), whereas the
femoral artery diameter remained unchanged (Table 4).
Furthermore, L-arginine had a more pronounced effect on
systolic and diastolic blood pressures than
PGE1, as assessed by comparison of the area under
the blood pressure–time curves (P<.05), and placebo
had no affect on blood pressure (Fig 2). Neither of the
infusions significantly affected heart rates.
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During L-arginine administration, plasma arginine levels increased from 84.6±14.1 to 3780.3±380.5 µmol/L (P<.05). During the infusion of PGE1 or placebo, plasma arginine levels were not significantly changed.
Urinary NO3- excretion significantly
increased during L-arginine administration
(+131.8±39.5%, P<.05), whereas during PGE1
infusion urinary NO3- excretion
increased by only 32.3±17.2% (P=NS versus baseline;
P<.05 between both treatments for
area-under-the-curve analysis) (Fig 3A). Urinary cGMP excretion
significantly increased (by
198.7±84.9%) after L-arginine infusion
(P<.05) but only by 94.2±58.8% after PGE1
(P=NS versus baseline). Area-under-the-curve
analysis revealed no statistically significant difference in
urinary cGMP excretion between both active infusions (Fig 3B).
Placebo
infusion induced no significant change in urinary
NO3- or cGMP excretion rates (Fig
3).
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No qualitative differences could be detected in the hemodynamic or biochemical responses to the infusions in subgroups of patients with or without diabetes, hypertension, or hypercholesterolemia.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The present study suggests that intravenous infusion of L-arginine, the precursor of endothelium-derived NO, induces peripheral vasodilation in the diseased limb of patients with severe peripheral arterial occlusive disease. This hemodynamic reaction is comparable to the one induced by a therapeutic dose of PGE1, a prostaglandin used in the treatment of critical limb ischemia. Flow-induced vasodilation of conduit arteries is not involved in this hemodynamic effect, as femoral artery diameter remained constant during both L-arginine and PGE1 infusion. However, infusion of L-arginine more strongly increased urinary nitrate and cGMP excretion rates, indicating that endogenous NO formation was enhanced during and after L-arginine infusion.
Evidence has been presented that the abnormal endothelium-dependent vasodilation in atherosclerosis is related to a reduced ability of the endothelium to produce and/or release biologically active vasorelaxant mediators NO11 27 28 and prostacyclin.19 Recently, we found that intravenous infusion of L-arginine induces vasorelaxation and inhibits platelet aggregation in healthy humans.10 A hypotensive effect of L-arginine has also been shown by others in normal subjects29 and in hypertensive and hypercholesterolemic patients.17 30 These effects are suggested to be due to enhanced NO production, as assessed by quantification of NO3-, the major urinary metabolite of endogenous NO,10 29 31 and of cGMP, the second messenger involved in NO-mediated effects.10 Our present results suggest that in patients with severe peripheral arterial occlusive disease, intravenous L-arginine induces peripheral vasorelaxation in the diseased limb.
PGE1, which binds to prostacyclin receptors and induces cAMP-dependent vasodilation, has been used in the pharmacotherapy of end-stage peripheral arterial occlusive disease.21 22 32 Our present results showing a 31% increase in femoral artery blood flow confirm earlier findings by Hirai et al,33 who found a ~38% increase in calf blood flow during intravenous PGE1 infusion in patients with intermittent claudication.
Urinary nitrate excretion significantly increased during and after infusion of L-arginine and, less pronounced, of PGE1. The urinary excretion rates of nitrate and cGMP have been found to be useful indicators of systemic NO production during physiological24 or pharmacological8 10 29 modulation of NO formation. Our present observation that urinary nitrate excretion was also enhanced by PGE1, but not by placebo, may indicate that vasodilation may be a stimulator of NO production, probably via increased shear stress at the endothelial surface.34 This suggests that the increased nitrate excretion may be a sum effect of NO synthase substrate provision (L-arginine) and increased shear stress (L-arginine and PGE1).
Endothelium-dependent cholinergic relaxations in the forearm vascular bed of hypercholesterolemic patients have previously been shown to be improved by acute intravenous infusion of L-arginine,17 but not by intra-arterial infusion.18 In both studies, L-arginine had no effect on basal blood flow. In contrast to these studies in which local blood flow responses were monitored in the upper extremities, we investigated blood flow responses in the more severely diseased lower limb in patients with advanced atherosclerosis, and we observed a significant increase in blood flow with L-arginine. It is important to note that the defect in the endothelial L-arginine/NO/cGMP pathway appears to be reversible not only in early hypercholesterolemia17 but also in advanced atherosclerosis, as shown here. Therefore, NO synthase substrate provision may be a new therapeutic approach to correct endothelial function in advanced peripheral arterial occlusive disease.
The pharmacological mechanism underlying the vasodilator effect of L-arginine remains unclear. Our present results strongly suggest that exogenously administered L-arginine stimulates NO formation. Others have shown that different mechanisms like vasodilator prostanoids,35 histamine,36 or insulin17 are improbable to have contributed to this effect. In our present study, the hemodynamic effects of L-arginine were not different in the subgroups of patients with or without insulin-dependent diabetes mellitus, although this evidence is not conclusive, as we did not measure insulin secretion rates.
It is still unclear by which mechanism exogenous L-arginine increases NO formation, as intracellular L-arginine levels have been shown to be high enough (in the millimolar range) to saturate NO synthase, whose Km has been determined in a cell-free enzyme preparation to be 2.9 µmol/L.37 Based on this value, restitution of intracellular L-arginine levels alone seems improbable as a cause of increased NO production. However, it is not known whether the intracellular Km is in the same order of magnitude in living tissues and whether other factors like cellular L-arginine uptake or intracellular compartimentalization affect L-arginine levels in the vicinity of the NO synthase. Moreover, the Km may be different in cardiovascular disease. A recent report38 suggested that an endogenous inhibitor of NO synthesis, NG,NG-dimethylarginine, is increased in serum from hypercholesterolemic rabbits. Dimethylarginine has previously been shown by Vallance and coworkers to be an endogenous inhibitor of NO synthase.39 This inhibitory action might be competitively overcome by L-arginine, thereby stimulating NO production. However, data on plasma concentrations of dimethylarginines in hypercholesterolemic patients are not available.
In conclusion, results from the present study suggest that intravenous infusion of L-arginine induces peripheral vasodilation, which is probably mediated via NO, in patients with critical limb ischemia. Our study gives no conclusive evidence for any direct effect of L-arginine on the atherosclerotic process. Further studies will be needed to assess a potential therapeutic role of L-arginine in atherosclerotic disease and to elucidate its mechanism of action.
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Acknowledgments |
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This work was supported in part by a grant from the Else-Kröner-Fresenius foundation. The authors are indebted to A. Otten, F.-M. Gutzki, M.-Th. Suchy, W. Thiele, and K. Schnalle for their excellent technical assistance.
Received February 6, 1995; revision received August 16, 1995; accepted August 20, 1995.
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 J. Chen, P. Kuhlencordt, F. Urano, H. Ichinose, J. Astern, and P. L. Huang L-Arginine on Atherosclerosis in ApoE Knockout and ApoE/Inducible NO Synthase Double-Knockout Mice Arterioscler Thromb Vasc Biol, January 1, 2003; 23(1): 97 - 103. [Abstract] [Full Text] [PDF]
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 H. Masuda, T. Tsujii, T. Okuno, K. Kihara, M. Goto, and H. Azuma Accumulated endogenous NOS inhibitors, decreased NOS activity, and impaired cavernosal relaxation with ischemia Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2002; 282(6): R1730 - R1738. [Abstract] [Full Text] [PDF]
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 K. Nakamura, I. Schmidt, C. C. Gray, A. Dewar, S. Rothery, N. J. Severs, M. H. Yacoub, and M. Amrani The effect of chronic L-arginine administration on vascular recovery following cold cardioplegic arrest in rats Eur. J. Cardiothorac. Surg., April 1, 2002; 21(4): 753 - 759. [Abstract] [Full Text] [PDF]
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 M. Condorelli and G. Brevetti Intermittent claudication: an historical perspective Eur. Heart J. Suppl., March 1, 2002; 4(suppl_B): B2 - B7. [Abstract] [PDF]
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A. Silvestro, G. Oliva, and G. Brevetti Intermittent claudication and endothelial dysfunction Eur. Heart J. Suppl., March 1, 2002; 4(suppl_B): B35 - B40. [Abstract] [PDF]
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H. A. Walker, E. McGing, I. Fisher, R. H. Boger, S. M. Bode-Boger, G. Jackson, J. M. Ritter, and P. J. Chowienczyk 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., August 1, 2001; 38(2): 499 - 505. [Abstract] [Full Text] [PDF]
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J. J. Jang, H.-K. V. Ho, H. H. Kwan, L. F. Fajardo, and J. P. Cooke Angiogenesis Is Impaired by Hypercholesterolemia : Role of Asymmetric Dimethylarginine Circulation, September 19, 2000; 102(12): 1414 - 1419. [Abstract] [Full Text] [PDF]
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C. M. Oomen, M. J. van Erk, E. J. M. Feskens, F. J. Kok, and D. Kromhout Arginine Intake and Risk of Coronary Heart Disease Mortality in Elderly Men Arterioscler Thromb Vasc Biol, September 1, 2000; 20(9): 2134 - 2139. [Abstract] [Full Text] [PDF]
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A. J Maxwell, B. E Anderson, and J. P Cooke Nutritional therapy for peripheral arterial disease: a double-blind, placebo-controlled, randomized trial of HeartBar(R) Vascular Medicine, February 1, 2000; 5(1): 11 - 19. [Abstract] [PDF]
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Y. Higashi, S. Sasaki, K. Nakagawa, T. Ueda, A. Yoshimizu, S. Kurisu, H. Matsuura, G. Kajiyama, and T. Oshima A comparison of angiotensin-converting enzyme inhibitors, calcium antagonists, beta-blockers and diuretic agents on reactive hyperemia in patients with essential hypertension: a multicenter study J. Am. Coll. Cardiol., February 1, 2000; 35(2): 284 - 291. [Abstract] [Full Text] [PDF]
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 Y Kanaya, M Nakamura, N Kobayashi, and K Hiramori Effects of L-arginine on lower limb vasodilator reserve and exercise capacity in patients with chronic heart failure Heart, May 1, 1999; 81(5): 512 - 517. [Abstract] [Full Text]
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R. H. Boger, S. M. Bode-Boger, A. Szuba, P. S. Tsao, J. R. Chan, O. Tangphao, T. F. Blaschke, and J. P. Cooke Asymmetric Dimethylarginine (ADMA): A Novel Risk Factor for Endothelial Dysfunction : Its Role in Hypercholesterolemia Circulation, November 3, 1998; 98(18): 1842 - 1847. [Abstract] [Full Text] [PDF]
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R. H. Boger, S. M. Bode-Boger, W. Thiele, A. Creutzig, K. Alexander, and J.u. C. Frolich 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., November 1, 1998; 32(5): 1336 - 1344. [Abstract] [Full Text] [PDF]
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J. Mair, B. Puschendorf, R. H. Boger, and S. M. Bode-Boger Is Measurement of Cyclic Guanosine Monophosphate in Plasma or Urine Suitable for Assessing In Vivo Nitric Oxide Production? • Response Circulation, March 31, 1998; 97(12): 1209 - 1210. [Full Text] [PDF]
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 S. M Bode-Boger, R. H Boger, S. Kienke, M. Bohme, L. Phivthong-ngam, D. Tsikas, and J. C Frolich Chronic dietary supplementation with L-arginine inhibits platelet aggregation and thromboxane A2 synthesis in hypercholesterolaemic rabbits in vivo Cardiovasc Res, March 1, 1998; 37(3): 756 - 764. [Abstract] [Full Text] [PDF]
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G. Theilmeier, J. R. Chan, C. Zalpour, B. Anderson, B.-y. Wang, A. Wolf, P. S. Tsao, and J. P. Cooke Adhesiveness of Mononuclear Cells in Hypercholesterolemic Humans Is Normalized by Dietary L-Arginine Arterioscler Thromb Vasc Biol, December 1, 1997; 17(12): 3557 - 3564. [Abstract] [Full Text]
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 Y. Higashi, T. Oshima, R. Ozono, H. Matsuura, and G. Kajiyama Aging and Severity of Hypertension Attenuate Endothelium-Dependent Renal Vascular Relaxation in Humans Hypertension, August 1, 1997; 30(2): 252 - 258. [Abstract] [Full Text]
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R. H. Boger, S. M. Bode-Boger, W. Thiele, W. Junker, K. Alexander, and J. C. Frolich Biochemical Evidence for Impaired Nitric Oxide Synthesis in Patients With Peripheral Arterial Occlusive Disease Circulation, April 15, 1997; 95(8): 2068 - 2074. [Abstract] [Full Text]
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S. P. Schwarzacher, T. T. Lim, B. Wang, R. S. Kernoff, J. Niebauer, J. P. Cooke, and A. C. Yeung Local Intramural Delivery of L-Arginine Enhances Nitric Oxide Generation and Inhibits Lesion Formation After Balloon Angioplasty Circulation, April 1, 1997; 95(7): 1863 - 1869. [Abstract] [Full Text]
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Y. Higashi, T. Oshima, N. Sasaki, N. Ishioka, Y. Nakano, R. Ozono, M. Yoshimura, K. Ishibashi, H. Matsuura, and G. Kajiyama Relationship Between Insulin Resistance and Endothelium-Dependent Vascular Relaxation in Patients With Essential Hypertension Hypertension, January 1, 1997; 29(1): 280 - 285. [Abstract] [Full Text] [PDF]
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