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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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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 precapillary secondary pulmonary hypertension. Cardiopulmonary exercise tests were performed to measure peak oxygen consumption (peak 
O2) and the ventilatory response to carbon dioxide production ( E- CO2 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 O2 (831 ± 88 to
896 ± 92 ml/min, p < 0.05) and a significant decrease in the E-
CO2 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 precapillary pulmonary hypertension.
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Nitric oxide (NO) is a potent vasodilator that also inhibits platelet adhesion and smooth muscle cell proliferation (1). Earlier studies have shown that inhaled NO ameliorates pulmonary hypertension with pulmonary selectivity (2, 3). In addition, NO inhalation has been shown to improve exercise capacity in patients with pulmonary hypertension (4). This treatment, however, requires a continuous inhalation device; hence, it is more uncomfortable and expensive than receiving oral medications.
Because NO is synthesized from the amino acid L-arginine by NO synthase (5), supplementation of L-arginine may have beneficial effects on cardiovascular diseases. In fact, oral supplementation of L-arginine improves endothelial-dependent vasodilation and exercise capacity in patients with congestive heart failure (6). An experimental study has shown that long-term intraperitoneal infusion of L-arginine attenuates progressive pulmonary hypertension and medial thickening of the pulmonary arteries in rats (7). In humans, intravenous administration of L-arginine has been shown to decrease pulmonary vascular resistance in patients with pulmonary hypertension by increasing the endogenous production of NO (8). However, there has been no clinical study to address the effects of oral L-arginine in patients with pulmonary hypertension.
Thus, the purpose of this study was to investigate the effects of short-term oral supplementation of L-arginine on hemodynamics and exercise capacity in patients with precapillary pulmonary hypertension in a randomized, double-blind, placebo-controlled fashion.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Study Patients
This study was made up of 19 patients with precapillary pulmonary
hypertension (mean pulmonary arterial pressure 
25 mm Hg; four
men and 15 women 49 ± 3 yr of age). The cause of pulmonary hypertension was primary pulmonary hypertension in 11 patients, chronic
thromboembolic pulmonary hypertension in seven, and residual pulmonary hypertension after correction of an interatrial shunt in one.
All patients had a thorough evaluation to identify the cause of their
pulmonary hypertension; the studies included chest radiography, lung
scanning, pulmonary function tests, Doppler echocardiography, and
cardiac catheterization, according to the protocol of the National Institutes of Health registry on primary pulmonary hypertension (9).
These patients were randomized to receive orally L-arginine (L-arginine group, n = 10) or placebo (Placebo group, n = 9). There were no significant differences in demographic, clinical, or hemodynamic data at baseline between the L-arginine group and the Placebo group (Table 1). The study was approved by the ethical committee of the National Cardiovascular Center, and all patients gave written informed consent.
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Study Protocol
Acute hemodynamic responses to supplemental L-arginine or placebo administered orally were assessed in all patients with pulmonary hypertension, in a randomized, double-blind fashion. All cardiovascular drugs were withdrawn at least 24 h before the start of hemodynamic studies. A 7.5 French Swan-Ganz catheter (TOO21H-7.5F; Baxter Co., Irvine, CA) was positioned in a pulmonary artery through a jugular vein. A 22-gauge cannula was inserted into a radial artery for hemodynamic measurements and blood sampling. After an equilibration period of 30 min, L-arginine (0.5-g capsule/10 kg body weight) or placebo (galactose at the same dose) was administered orally. Hemodynamic parameters were measured at 30-min intervals starting 30 min before L-arginine administration until 120 min after administration. Blood samples were taken at 30-min intervals starting immediately before oral administration until 120 min after administration.
The effects of L-arginine or placebo on exercise capacity were examined in 16 of 19 patients with pulmonary hypertension (L-arginine group, n = 9; Placebo group, n = 7). The remaining three patients were excluded from the exercise protocol because they could not tolerate the maximum exercise test. The initial cardiopulmonary exercise test was performed 5 to 7 d after the hemodynamic studies. Patients were instructed to take the same medication, L-arginine or placebo (0.5-g capsule/10 kg body weight), three times a day (7:00 A.M., 1:00 P.M., and 7:00 P.M.). The second cardiopulmonary exercise test was performed 7 d after treatment with L-arginine or placebo. All exercise tests were performed between 2:00 and 3:00 P.M. after at least a light lunch.
Hemodynamic Studies
Heart rate, mean systemic arterial pressure, mean pulmonary arterial pressure, mean right atrial pressure, and pulmonary capillary wedge pressure were measured in all patients. Cardiac output was measured by Fick's method (10). Oxygen consumption per body surface area was estimated by age, sex, and heart rate. Pulmonary vascular resistance and systemic vascular resistance were calculated using standard formulas.
Cardiopulmonary Exercise Testing
Patients first pedaled at 55 rpm without any added load for 1 min. The
work rate was then increased by 15 watts/min until their symptom-limited maximum. Heart rate was monitored with standard electrocardiographic leads, and blood pressure was measured at the brachial
artery with a sphygmomanometer. Breath-by-breath gas analysis was
performed using an AE280 (Minato Medical Science, Osaka, Japan).
Peak oxygen consumption (peak O2) was defined as the value of averaged data during the final 15 s of exercise. The E-CO2 slope, an indicator of dead-space ventilation, was determined as the linear regression slope of E and CO2 from the start of exercise until the RC point
(the time at which ventilation is stimulated by CO2 output and end-tidal CO2 tension begins to decrease).
Blood Sampling and Assay
Blood samples were drawn from a radial artery at catheterization and from a peripheral vein soon before each cardiopulmonary exercise test. Plasma L-arginine and L-citrulline were determined by high-performance liquid chromatography with an amino acid analyzer. For noninvasive assessment of right ventricular function, plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were measured directly with specific immunoradiometric assay kits (Shiono RIA ANP assay kit and Shiono RIA BNP assay kit, Shionogi Co., Ltd., Osaka, Japan) (11). Plasma norepinephrine and epinephrine were measured by high-performance liquid chromatography combined with the trihydroxyindole fluorometric procedure (HLC8030; Tosoh Co., Tokyo, Japan).
Statistical Analysis
All data were expressed as mean ± SEM unless otherwise indicated. Comparisons of baseline patient characteristics between the two groups were made by Fisher's exact test or Student's unpaired t test. Comparisons of the time course of parameters between the L-arginine group and the Placebo group were made by two-way analysis of variance (ANOVA) for repeated measures, followed by the Newman-Keuls test. Comparisons of parameters at baseline and after a 1-wk supplementation of L-arginine or placebo were analyzed by Student's paired t test. A p value < 0.05 was considered statistically significant.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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All subjects tolerated this study protocol, although L-arginine caused transient gastric discomfort in one subject. Clinically significant systemic hypotension or orthostatic hypotension was not observed in any patients.
L-arginine Metabolism
Baseline plasma levels of L-arginine and L-citrulline did not significantly differ between the L-arginine group and the Placebo group (Figure 1). A single oral administration of L-arginine significantly increased plasma L-arginine level twofold and resulted in an increase in plasma L-citrulline (32 ± 3 to 41 ± 4 nmol/ml, p < 0.05), which indicated enhancement of NO production. The elevation of both amino acids lasted longer than 120 min after oral administration. These parameters remained unchanged in the Placebo group.
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Acute Hemodynamic Responses to L-arginine
Oral supplementation of L-arginine significantly decreased mean pulmonary arterial pressure (53 ± 4 to 48 ± 4 mm Hg, p < 0.05) (Figure 2) 60 min after administration. L-arginine tended to increase cardiac index (2.0 ± 0.1 to 2.2 ± 0.1 L/min/ m2, p = 0.057). Thus, oral supplementation of L-arginine resulted in a 16% decrease in pulmonary vascular resistance (14.8 ± 1.5 to 12.4 ± 1.4 Wood units, p < 0.05) 60 min after administration. Although these effects of L-arginine were relatively modest, four of the 10 patients in the L-arginine group showed a greater than 20% decrease in pulmonary vascular resistance. L-arginine also decreased mean systemic arterial pressure (92 ± 4 to 87 ± 3 mm Hg, p < 0.05) but did not significantly alter heart rate. L-arginine produced an 11% decrease in systemic vascular resistance (28.3 ± 2.0 to 25.2 ± 1.8 Wood units, p < 0.05) 60 min after administration. No significant change in pulmonary capillary wedge pressure or right atrial pressure was observed (data not shown). There was no significant change in systemic arterial oxygen saturation (90 ± 3% to 89 ± 2%) or pulmonary arterial oxygen saturation (60 ± 3% to 62 ± 3%). Hemodynamic and blood gas parameters remained unchanged in the Placebo group.
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Effects of L-arginine on Exercise Capacity
Baseline peak O2 in the L-arginine group was significantly
lower than the normal value, which was determined from
pooled data of 20 age-matched healthy subjects (831 ± 88 versus 1,615 ± 100 ml/min, p < 0.05). One-wk supplementation
of L-arginine resulted in a significant increase in peak O2
(831 ± 88 to 896 ± 92 ml/min, p < 0.05) (Figure 3), associated
with a significant increase in peak work load (82 ± 6 to 92 ± 7 W, p < 0.05). Baseline E-CO2 slope in the L-arginine group
was markedly higher than the normal value (43 ± 4 versus 23 ± 1, p < 0.05). One-wk supplementation of L-arginine significantly decreased the E-CO2 slope (43 ± 4 to 37 ± 3, p < 0.05). Supplemental L-arginine did not alter heart rate or
blood pressure both at rest and at peak exercise. These parameters of exercise capacity remained unchanged during placebo
administration.
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Hormonal Effects of L-arginine
Plasma ANP and BNP tended to decrease after 1-wk supplementation of L-arginine, associated with significant increases in plasma L-arginine and L-citrulline (Table 2). Supplemental L-arginine did not alter plasma norepinephrine or epinephrine. These parameters remained unchanged in the Placebo group.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This is the first randomized, placebo-controlled study to examine the effects of short-term oral administration of L-arginine on hemodynamics and exercise capacity in patients with
precapillary pulmonary hypertension. In this study, we demonstrated that (1) oral L-arginine significantly decreased mean
pulmonary arterial pressure and pulmonary vascular resistance, associated with a significant increase in plasma citrulline, and that (2) L-arginine improved exercise capacity in patients with pulmonary hypertension, as indicated by an increase
in peak O2 and a decrease in the E-CO2 slope.
Abnormalities in endogenous vasodilator substances such as NO have been proposed as important in the development of pulmonary hypertension (12). Recently, the biologic actions of L-arginine, the precursor of NO, have been examined in a variety of cardiovascular diseases (6, 15). However, the therapeutic potential of orally administered L-arginine in patients with pulmonary hypertension remains unknown. In the present study, plasma L-citrulline, a metabolite of L-arginine in NO production, increased significantly after oral supplementation of L-arginine, indicating enhancement of endogenous NO production. The consequence of the oral supplementation was significant decreases in mean pulmonary arterial pressure and pulmonary vascular resistance. These results suggest that L-arginine may cause pulmonary vasodilation at least partly via a NO-mediated mechanism. These hemodynamic effects of L-arginine may be relatively small compared with those of intravenous prostacyclin (18) or oral prostacyclin analogue (22, 23). Nevertheless, four of the 10 patients in the L-arginine group showed a greater than 20% decrease in pulmonary vascular resistance. Furthermore, NO and prostacyclin cause pulmonary vasodilation by independent mechanisms: cyclic guanosine monophosphate-dependent and cyclic adenosine monophosphate-dependent mechanisms, respectively. Thus, oral administration of L-arginine may have a supplemental effect in patients who have already received prostacyclin or its analogue.
In the present study, baseline peak O2 was significantly
lower in patients with pulmonary hypertension than in healthy
subjects. Peak O2 is determined mainly by the maximal cardiac output during exercise and the potential for O2 extraction
by the exercising muscle (24). Thus, the decreased peak O2
may reflect insufficient oxygen delivery to the body during exercise, at least in part due to an inadequate increase in cardiac
output under conditions of severe pulmonary hypertension.
One-wk supplementation of L-arginine resulted in a significant
increase in peak O2. Acute hemodynamic studies at rest
demonstrated that L-arginine tended to increase cardiac index
and significantly decreased pulmonary vascular resistance. These results raise the possibility that L-arginine may cause an
increase in cardiac output during exercise through decreasing right ventricular afterload. Previous studies have shown that short-term administration of L-arginine can improve endothelial dysfunction, which is related to reduced exercise capacity
in patients with congestive heart failure (6, 25). Thus, it is also
possible that the increase in exercise capacity with L-arginine may be partly attributable to improvement in endothelium-dependent peripheral vasodilation in patients with pulmonary
hypertension. In the present study, the baseline E-CO2
slope was markedly increased in patients with precapillary
pulmonary hypertension. This steeper slope is considered to
be associated with increased physiologic dead space resulting
from an impaired increase in pulmonary perfusion during exercise (26). One-wk supplementation of L-arginine resulted in
a significant decrease in the E-CO2 slope. Thus, it is possible
that the decrease in the E-CO2 slope with L-arginine may be
attributable to a decrease in physiologic dead space resulting
from ameliorated pulmonary hypertension during exercise.
One-week supplementation of L-arginine tended to decrease plasma ANP and BNP, potential markers of right ventricular dysfunction (11, 27). It is interesting to speculate that the decrease in pulmonary vascular resistance by L-arginine may decrease wall stress in the right ventricle and improve right ventricular dysfunction in patients with pulmonary hypertension. Further long-term studies are necessary to clarify the hormonal effects of L-arginine in patients with pulmonary hypertension.
Study Limitations
First, three patients with severe pulmonary hypertension were unable to perform the cardiopulmonary exercise study. Thus, the effects of orally administered L-arginine in the most severe forms of pulmonary hypertension remain unknown. Second, medication that included vasodilators and anticoagulant agents was not controlled in this study. Nevertheless, there was no significant difference in medication use between the L-arginine group and the Placebo group. It is interesting to examine the effect of orally administered L-arginine in new patients with pulmonary hypertension who have not received any vasodilators. Finally, hemodynamic effects of L-arginine and the sample size of the study population were relatively small. The therapeutic potential of oral L-arginine in patients with precapillary pulmonary hypertension should be confirmed by long-term, large-scale studies.
In conclusion, short-term oral administration of L-arginine modestly decreased pulmonary vascular resistance and improved exercise capacity without serious adverse effects in patients with precapillary pulmonary hypertension.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Noritoshi Nagaya, M.D., Division of Cardiology, Department of Medicine, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
(Received in original form August 24, 2000 and in revised form October 16, 2000).
Acknowledgments:
Supported in part by the Japan Intractable Diseases Research Foundation.
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References |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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J. P. Cooke Asymmetrical Dimethylarginine: The Uber Marker? Circulation, April 20, 2004; 109(15): 1813 - 1818. [Full Text] [PDF]
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J. P. Cooke A Novel Mechanism for Pulmonary Arterial Hypertension? Circulation, September 23, 2003; 108(12): 1420 - 1421. [Full Text] [PDF]
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S. Sharma Treatment of Pulmonary Arterial Hypertension: A Step Forward Chest, July 1, 2003; 124(1): 8 - 11. [Full Text] [PDF]
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R. Budhiraja and P. M. Hassoun Portopulmonary Hypertension: A Tale of Two Circulations Chest, February 1, 2003; 123(2): 562 - 576. [Abstract] [Full Text] [PDF]
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M. M. Hoeper, N. Galie, G. Simonneau, and L. J. Rubin New Treatments for Pulmonary Arterial Hypertension Am. J. Respir. Crit. Care Med., May 1, 2002; 165(9): 1209 - 1216. [Full Text] [PDF]
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M. J. TOBIN Chronic Obstructive Pulmonary Disease, Pollution, Pulmonary Vascular Disease, Transplantation, Pleural Disease, and Lung Cancer in AJRCCM 2001 Am. J. Respir. Crit. Care Med., March 1, 2002; 165(5): 642 - 662. [Full Text] [PDF]
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