L‑arginine Research Trial: Abstract 1

Am J Respir Crit Care Med. 2001 Mar;163(4):887-91.

Short-term oral administration of L‑arginine improves hemodynamics and exercise capacity in patients with pre-capillary pulmonary hypertension.

Nagaya NUematsu M, Oya H, Sato N, Sakamaki F, Kyotani S, Ueno K, Nakanishi N, Yamagishi M, Miyatake K.

Source

Department of Internal Medicine and Department of Pharmacy, National Cardiovascular Center, and Osaka Seamen's Insurance Hospital, Osaka, Japan.

Abstract

We sought to assess the effects of oral supplementation of L‑arginine, the precursor of nitric oxide (NO), on hemodynamics and exercise capacity in patients with pulmonary hypertension. Acute hemodynamic responses to oral L‑arginine (0.5 g/10 kg body weight) or placebo were examined in 19 patients with primary or pre-capillary secondary pulmonary hypertension.

Cardiopulmonary exercise tests were performed to measure peak oxygen consumption (peak V O(2)) and the ventilatory response to carbon dioxide production (V E-V CO(2) slope) before and 1 wk after treatment with L‑arginine (1.5 g/10 kg body weight/d) or placebo. Oral supplementation of L‑arginine significantly increased plasma L‑citrulline, which indicated enhancement of NO production. Supplemental L‑arginine produced a 9% decrease in mean pulmonary arterial pressure (53 +/- 4 to 48 +/- 4 mm Hg, p < 0.05) and a 16% decrease in pulmonary vascular resistance (14.8 +/- 1.5 to 12.4 +/- 1.4 Wood units, p < 0.05). L‑arginine modestly decreased mean systemic arterial pressure (92 +/- 4 to 87 +/- 3 mm Hg, p < 0.05). A 1-wk supplementation of L‑arginine resulted in a slight increase in peak V O(2) (831 +/- 88 to 896 +/- 92 ml/min, p < 0.05) and a significant decrease in the V E- V CO(2) slope (43 +/- 4 to 37 +/- 3, p < 0.05) without significant systemic hypotension. Hemodynamics and exercise capacity remained unchanged during placebo administration. These results suggest that oral supplementation of L‑arginine may have beneficial effects on hemodynamics and exercise capacity in patients with pre-capillary pulmonary hypertension.

L‑arginine Research Trial: Abstract 2

[NOTE from MoreLyfe: This study found that L‑arginine improves coronary and systemic endothelial function, i.e. better blood flow to the heart and everywhere else. However, though others’ research the 6g daily dose mentioned in the last paragraph below is insufficient to gain the results required to reverse CVD. A 5g dose 6—8 times a day for the first three months then gradually reducing the number of doses (the number of times taking it throughout the day, not the amount of L‑arginine in each dose) gradually over the following months until a maintenance dose of 1–2 doses (5g each dose) per day about 6—8 months later. Following the dosage used below in this trial is insufficient to reverse CVD.]

J Am Coll Cardiol, 2002; 39:46-48

EDITORIAL COMMENT
Oral L‑arginine (and other active ingredients) for ischemic heart disease

Richard O. Cannon, III, MD, FACCa,*
a Cardiology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.

The endothelium maintains a non thrombotic surface for blood flow, prevents platelet and leukocyte activation and adhesion, modulates cellular composition of the arterial wall, and promotes dilator tone of arteries and veins, homeostatic properties regulated in part by the endothelial synthesis of nitric oxide (NO). Endothelial release of NO is reduced or absent in patients with coronary artery disease (CAD) or its risk factors (1) and may contribute to myocardial ischemia by limiting appropriate blood flow during stress (2).

Furthermore, reduced NO bioactivity—as evidenced by abnormal dilator responsiveness to acetylcholine, cold pressor testing or shear stress during hyperemia—has been reported by several groups to indicate increased risk of serious cardiovascular events in the few years that follow (3,4). Strategies for increasing endothelial NO synthase activity that may be amenable to pharmacologic intervention include enhanced transcription of the gene for this enzyme, stabilization of messenger RNA (mRNA) for greater enzyme synthesis, provision of cofactors for the enzyme and administration of the substrate, L‑arginine. This last approach, in particular, has generated considerable interest and controversy in recent years. Normally, L‑arginine is not rate-limiting in the enzymatic conversion of this semi-essential amino acid to L‑citrulline and NO: the cytosolic concentration of L‑arginine within endothelial cells exceeds by a factor of 1,000 the maximum substrate utilization rate by NO synthase. However, under specific conditions, administration of L‑arginine might be expected to enhance NO synthesis. First reported by Vallance et al. (5) a decade ago, methylated L‑arginines such as asymmetric dimethylL‑arginine (ADMA), enzymatically generated from proteins that regulate RNA processing and transcriptional control, may compete with L‑arginine for the active substrate binding site on NO synthase. Because ADMA cannot be converted to NO, NO synthesis could be reduced if sufficient L‑arginine were displaced. Elevated levels of ADMA have been measured in serum samples from patients with hypercholesterolemia and peripheral arterial disease, possibly a consequence of reduced catabolism by the enzyme dimethylL‑arginine dimethylaminohydrolase (68). The relevance of endogenous NO synthase inhibitors to human atherosclerosis was suggested by a strong association between ADMA levels and carotid artery intimal-medial thickness measured by ultrasound in a Japanese population (9). Additional proposed mechanisms by which L‑arginine bioavailability may be reduced include excess enzymatic conversion to ornithine via enhanced activity of arginase in plasma or within endothelial cells (10), and inhibition of L‑arginine transport into endothelial cells (11).

Several groups have reported that intravascular infusion of L‑arginine in patients with CAD and hypercholesterolemic subjects improves coronary and systemic endothelial function, often evidenced by prevention of constriction or enhanced dilation in response to intra-arterial acetylcholine (1215). Although improved endothelial function in these studies is consistent with enhanced substrate availability for NO synthase, other effects of L‑arginine may account for augmented NO synthesis. In this regard, intravenous infusion of L‑arginine stimulates the release of insulin, which in turn activates endothelial NO synthase and promotes NO release (16).

Furthermore, Nagase et al. (17) reported that L‑arginine or D-L‑arginine reacts nonenzymatically with H2O2—likely present at least transiently in the high-oxidant environment of the atherosclerotic arterial wall—to form NO. These mechanisms of L‑arginine-mediated increase in NO that are independent of L‑arginine substrate availability for NO synthase may explain why intra-brachial arterial infusion of D-L‑arginine, which is not a substrate for this enzyme, improved forearm blood flow responses to acetylcholine to the same degree as L‑arginine in patients with CAD (18). Regardless of the mechanism of L‑arginine effect on endothelial function, two groups reported that intravenous infusion of L‑arginine failed to improve exercise tolerance or ST segment responses in patients with CAD (18,19).

It is possible that longer duration of treatment with L‑arginine is required to improve endothelial function enough that coronary blood flow increases during stress, preventing myocardial ischemia. Oral administration of L‑arginine has been reported to improve brachial artery endothelial function in young hypercholesterolemic subjects and young patients with CAD, and coronary microvascular endothelial function in patients without angiographically significant CAD (2022). Furthermore, studies including small numbers of patients with CAD reported improved exercise performance with delayed appearance of ST-segment depression and maximum ST-depression after three days of oral L‑arginine (6 g daily) compared with exercise stress testing on placebo (23), and reduced angina after three months of oral L‑arginine (24).

L‑arginine Research Trial: Abstract 3

[NOTE from MoreLyfe: This study is typical of the kind of trial quoted by my cardiologist when I enquired why he wasn't prescribing L‑arginine to his patients. He said tests show that results show that that L‑arginine is not effective (even though I was standing in front of him a testament that it is!). The trial below lasted only two weeks, nowhere near long enough to achieve any conclusive result. The nominated dosage was also insufficient.]

J Am Coll Cardiol, 2001; 38:499-505

American College of Cardiology Foundation

Clinical Study

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.

Hamish A. Walker, MRCP*, Elaine McGing*, Ian Fisher, BSc, Rainer H. Böger, MD, Stefanie M. Bode-Böger, MD, Graham Jackson, FRCP*, James M. Ritter, FRCP and Philip J. Chowienczyk, FRCP

* Cardiothoracic Centre, St. Thomas' Hospital, London, United Kingdom

Department of Clinical Pharmacology, Centre for Cardiovascular Medicine and Biology, King’s College, London, St. Thomas’ Hospital, London, United Kingdom Department of Pharmacology, University Hospital, Hamburg-Eppendorf, Hamburg, Germany, Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany.

Manuscript received December 14, 2000; revised manuscript received March 29, 2001, accepted April 10, 2001.

Objectives

This study was designed to determine the effect of two weeks' treatment with L‑arginine on the ratio of plasma L‑arginine to asymmetric dimethylL‑arginine (ADMA), oxidative stress, endothelium-dependent vasodilatation to acetylcholine, exercise performance and heart rate variability in men with stable angina.

Background

The ratio of plasma L‑arginine:ADMA has been proposed as a determinant of endothelium-dependent dilation; dietary supplementation with L‑arginine has been shown to improve endothelium-dependent vasodilation and symptoms in some conditions.

Methods

Men (n = 40) with stable angina, at least one epicardial coronary artery with a stenosis >50% and a positive exercise test were randomized to receive L‑arginine (15 g daily) or placebo for two weeks according to a double-blind parallel-group design. Plasma L‑arginine, ADMA, 8-epi prostaglandin F2 (a marker of oxidative stress) and forearm vasodilator responses to brachial artery infusion of nitroprusside and acetylcholine (±L‑arginine) were measured. A standard Bruce protocol exercise test was performed before and at the end of the treatment period.

Results

Plasma L‑arginine increased after oral L‑arginine, whereas ADMA remained unchanged, leading to an increase in the L‑arginine/ADMA ratio of 62 ± 11% (mean ± SE, p < 0.01). Despite a significant enhancement in acetylcholine response by intra-arterial L‑arginine at baseline, this response remained unchanged after oral L‑arginine. Measures of oxidative stress and exercise performance after L‑arginine/placebo were similar in placebo and active groups.

Conclusions

In men with stable angina, an increase in plasma L‑arginine/ADMA ratio after two weeks' oral supplementation with L‑arginine is not associated with an improvement in endothelium-dependent vasodilatation, oxidative stress or exercise performance.

L‑arginine Research Trial: Abstract 4

[NOTE from MoreLyfe: This trial concludes that exercise assists the effectiveness of supplementing L‑arginine.

J Am Coll Cardiol, 2000; 35:706-713

Clinical Studies

Correction of endothelial dysfunction in chronic heart failure: additional effects of exercise training and oral L‑arginine supplementation.

Rainer Hambrecht, MDa, Lutz Hilbrich, MDa, Sandra Erbs, BSca, Stephan Gielen, MDa, Eduard Fiehn, MDa, Nina Schoene, MDa and Gerhard Schuler, MDa a University of Leipzig, Heart Center, Division of Cardiology, Leipzig, Germany a Manuscript received October 13, 1998; revised manuscript received October 5, 1999, accepted November 17, 1999.

Objectives

The aim of this study was to analyze whether L‑arginine (L-arg.) has comparable or additive effects to physical exercise regarding endothelium-dependent vasodilation in patients with chronic heart failure (CHF).

Background

Endothelial dysfunction in patients with CHF can be corrected by both dietary supplementation with L-arg. and regular physical exercise.

Methods

Forty patients with severe CHF (left ventricular ejection fraction 19 ± 9%) were randomized to an L-arg. group (8 g/day), a training group (T) with daily handgrip training, L-arg. and T (L-arg. + T) or an inactive control group (C). The mean internal radial artery diameter was determined at the beginning and after four weeks in response to brachial arterial administration of acetylcholine (ACh) (7.5, 15, 30 μg/min) and nitroglycerin (0.2 mg/min) with a transcutaneous high-resolution 10 MHz A-mode echo tracking system coupled with a Doppler device. The power of the study to detect clinically significant differences in endothelium-dependent vasodilation was 96.6%.

Results

At the beginning, the mean endothelium-dependent vasodilation in response to ACh, 30 μg/min was 2.54 ± 0.09% (p = NS between groups). After four weeks, internal radial artery diameter increased by 8.8 ± 0.9% after ACh 30 μg/min in L-arg. (p < 0.001 vs. C), by 8.6 ± 0.9% in T (p < 0.001 vs. C) and by 12.0 ± 0.3% in L-arg. + T (p < 0.005 vs. C, L-arg. and T). Endothelium-independent vasodilation as assessed by infusion of nitroglycerin was similar in all groups at the beginning and at the end of the study.

Conclusions

Dietary supplementation of L-arg. as well as regular physical exercise improved agonist-mediated, endothelium-dependent vasodilation to a similar extent. Both interventions together seem to produce additive effects with respect to endothelium-dependent vasodilation.

L‑arginine Research Trial: Abstract 5

[NOTE from MoreLyfe: This paper concludes that L‑arginine supplementation improves symptoms of intermittent claudication in patients with peripheral arterial occlusion, i.e. cramping pain caused by the obstruction of the arteries (similar to angina).]

J Am Coll Cardiol, 1998; 32:1336-1344

Clinical Studies

Restoring vascular nitric oxide formation by L‑arginine improves the symptoms of intermittent claudication in patients with peripheral arterial occlusive disease.

Rainer H. Böger, MD*, Stefanie M. Bode-Böger, MD*, Wolfgang Thiele*, Andreas Creutzig, MD, Klaus Alexander, MD and J.ürgen C. Frölich, MD* *Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany.

Department of Angiology, Hannover Medical School, Hannover, Germany. Manuscript received February 12, 1998; revised manuscript received June 17, 1998, accepted July 6, 1998.

Background

Administration of L‑arginine improves nitric oxide (NO) formation and endothelium-dependent vasodilation in atherosclerotic patients.

Objectives

We investigated in this double-blind, controlled study whether prolonged intermittent infusion therapy with L‑arginine improves the clinical symptoms of patients with intermittent claudication, as compared with the endothelium-independent vasodilator prostaglandin E1, and control patients.

Methods

Thirty-nine patients with intermittent claudication were randomly assigned to receive 2 x 8 g L‑arginine/day, or 2 x 40 μg prostaglandin E1 (PGE1)/day or no hemodynamically active treatment, for 3 weeks. The pain-free and absolute walking distances were assessed on a walking treadmill at 3 km/h, 12% slope, and NO-mediated, flow-induced vasodilation of the femoral artery was assessed by ultrasonography at baseline, at 1, 2 and 3 weeks of therapy and 6 weeks after the end of treatment. Urinary nitrate and cyclic guanosine-3', 5'-monophosphate (GMP) were assessed as indices of endogenous NO production.

Results

L‑arginine improved the pain-free walking distance by 230 ± 63% and the absolute walking distance by 155 ± 48% (each p < 0.05). Prostaglandin E1 improved both parameters by 209 ± 63% and 144 ± 28%, respectively (each p < 0.05), whereas control patients experienced no significant change. L‑arginine therapy also improved endothelium-dependent vasodilation in the femoral artery, whereas PGE1 had no such effect. There was a significant linear correlation between the L‑arginine/asymmetric dimethylL‑arginine (ADMA) ratio and the pain-free walking distance at baseline (r = 0.359, p < 0.03). L‑arginine treatment elevated the plasma L‑arginine/ADMA ratio and increased urinary nitrate and cyclic GMP excretion rates, indicating normalized endogenous NO formation. Prostaglandin E1 therapy had no significant effect on any of these parameters. Symptom scores assessed on a visual analog scale increased from 3.51 ± 0.18 to 8.3 ± 0.4 (L‑arginine) and 7.0 ± 0.5 (PGE1; each p < 0.05), but did not significantly change in the control group (4.3 ± 0.4).

Conclusions

Restoring NO formation and endothelium-dependent vasodilation by L‑arginine improves the clinical symptoms of intermittent claudication in patients with peripheral arterial occlusive disease.