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Published ahead of print on March 5, 2003, doi:10.1164/rccm.200208-967OC
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American Journal of Respiratory and Critical Care Medicine Vol 168. pp. 63-69, (2003)
© 2003 American Thoracic Society

Original Article

Arginine Therapy

A New Treatment for Pulmonary Hypertension in Sickle Cell Disease?

Claudia R. Morris, Sidney M. Morris, Jr., Ward Hagar, Jane van Warmerdam, Susan Claster, Diane Kepka-Lenhart, Lorenzo Machado, Frans A. Kuypers and Elliott P. Vichinsky

Departments of Emergency Medicine and Hematology/Oncology and Pediatric Clinical Research Center, Children's Hospital and Research Center at Oakland, Oakland; Department of Hematology, University of California at San Francisco, San Francisco; Children's Hospital, Oakland Research Institute, Oakland, California; and Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Correspondence and requests for reprints should be addressed to Claudia R. Morris, M.D., Department of Emergency Medicine, Children's Hospital Oakland, 747 52nd Street, Oakland, CA 94609. E-mail: cmorris{at}mail.cho.org


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Pulmonary hypertension is a life-threatening complication of sickle cell disease. L-Arginine is the nitrogen donor for synthesis of nitric oxide, a potent vasodilator that is deficient during times of sickle cell crisis. This deficiency may play a role in pulmonary hypertension. The enzyme arginase hydrolyzes arginine to ornithine and urea, and thus, it may compete with nitric oxide synthase, leading to decreased nitric oxide production. Nitric oxide therapy by inhalation has improved pulmonary hypertension associated with acute chest syndrome in sickle cell disease, and several studies demonstrate therapeutic benefits of arginine therapy for primary and secondary pulmonary hypertension. We sought to determine the effects of arginine therapy on pulmonary hypertension in patients with sickle cell disease. Arginase activity was also determined. Oral arginine produced a 15.2% mean reduction in estimated pulmonary artery systolic pressure (63.9 ± 13 to 54.2 ± 12 mm Hg, p = 0.002) after 5 days of therapy in 10 patients. Arginase activity was elevated almost twofold (p = 0.07) in patients with pulmonary hypertension and may limit arginine bioavailability. With limited treatment options and a high mortality rate for patients with sickle cell disease who develop pulmonary hypertension, arginine is a promising new therapy that warrants further investigation.

Key Words: pulmonary hypertension • L-arginine • nitric oxide • sickle cell disease • arginase

Pulmonary hypertension is a life-threatening complication of sickle cell disease (1) that has been reported to occur in up to 30% of adult patients (1, 2). With improved medical care and a longer life expectancy, the number of affected patients will likely increase with time. The etiology of sickle cell disease–related pulmonary hypertension is unclear. Treatment options are limited, and the prognosis is poor (3). Patients who develop this complication have a shortened survival period (4). Its presence is an independent predictor of death, with an average time to death after diagnosis being as short as 12 months (2). Anecdotal treatments with vasodilators, oxygen, anticoagulants, and transfusion have been tried but remain unproven (3, 5).

Several studies in non–sickle cell disease patients demonstrate therapeutic benefits of L-arginine therapy for pulmonary hypertension (6, 7). Low plasma L-arginine concentrations have been discovered in infants with persistent pulmonary hypertension of the newborn (8) correlating with low nitric oxide metabolite levels (9). L-Arginine infusion has decreased pulmonary vascular resistance and improved blood oxygenation in infants with this disease process (10). L-Arginine supplementation also improves pulmonary artery pressures and hemodynamics in patients with primary and secondary pulmonary hypertension (7), and one recent study demonstrates these effects after only 1 week of therapy (6).

Inhalation of nitric oxide also lowers pulmonary artery pressures in both adults and infants with pulmonary hypertension (11, 12). Recent studies suggest that rapid scavenging of nitric oxide by cell-free hemoglobin, which is found in high concentrations under conditions of hemolysis, may limit nitric oxide bioavailability in sickle cell disease (13), whereas inhaled nitric oxide augments nitric oxide transport on sickle cell hemoglobin (14). Several case reports have also demonstrated significant improvement in pulmonary hypertension in children with acute chest syndrome after inhaled nitric oxide therapy (15, 16).

Recent studies found that oral L-arginine normalizes red blood cell density and induces Gardos channel inhibition in sickle cell transgenic mice (17). There is otherwise limited information available on the impact of L-arginine supplementation in sickle cell disease (18). However, improvement in pulmonary artery pressures has been described after treatment with arginine-butyrate in patients with sickle cell disease and pulmonary hypertension who were on hydroxyurea therapy (19). L-Arginine is the nitrogen donor for synthesis of nitric oxide, a potent vasodilator that is deficient during times of sickle cell crisis (20–22). Because nitric oxide generation is increased by hydroxyurea (23–26), treatment with hydroxyurea may deplete arginine stores even further. Therefore, it is possible that the arginine component of arginine-butyrate may possess therapeutic properties by replenishing the deficient substrate for nitric oxide production.

There is growing evidence that pulmonary hypertension is a disease process that involves altered arginine metabolism or decreased bioavailability. Arginase, an enzyme that converts L-arginine to ornithine and urea (27, 28), may limit nitric oxide bioavailability in sickle cell disease through increased use of its substrate. Because arginine supplementation improves pulmonary artery pressures in nonsickle cell patients with pulmonary hypertension (6, 7, 10), arginine may also be therapeutic for sickle cell disease patients with pulmonary hypertension by providing increased substrate for nitric oxide production.

Some results of this study have been previously reported in abstract form (29–32).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Ten sickle cell disease patients with documented pulmonary hypertension at steady state were enrolled in the study. All known patients with pulmonary hypertension receiving care at the Northern California Comprehensive Sickle Cell Center were approached for participation in this study. Patients with renal or liver dysfunction were not eligible for enrollment. Eight patients were homozygous for hemoglobin S. One patient had hemoglobin type SC, and one patient had hemoglobin S ß-thalassemia. The mean age of patients was 32.7 ± 15 years, with a range of 13 to 63 years. There were four women enrolled. Although one patient was determined to be noncompliant with taking the oral L-arginine supplements, he was still included in the statistical analysis based on the intention to treat. Compliance was determined by a statistically significant rise in Day 6 plasma L-arginine levels compared with pretreated Day 0 levels. Ten ethnically matched normal nonsickle cell disease volunteers were enrolled as a control group to compare amino acid levels and arginase activity. The mean age was 20.6 ± 10 years, ranging from 10 to 34 years. There were four females and six males enrolled. Pulmonary hypertension was defined as estimated pulmonary artery pressures of more than 30 mm Hg by echocardiogram (or tricuspid regurgitant jet velocity of greater than 2.5 m/second), more than 2 months of duration, not associated with acute chest syndrome. A chart review was performed on all patients to obtain tricuspid regurgitant jet velocity data from previous echocardiograms before arginine therapy for comparison to study results. The study protocol was approved by the Institutional Review Board at Children's Hospital and Research Center at Oakland, and informed consent was obtained for all patients.

Study Design
Patients with sickle cell disease and documented pulmonary hypertension by echocardiography were treated with oral L-arginine–HCl (supplied by Tyson and Associates, Hawthorne, CA) at a dose of 0.1 g/kg three times a day for 5 days. Echocardiograms were performed before and after L-arginine administration on Days 0 and 6 and at 1 month or more follow-up after completion of arginine therapy. Blood samples for determination of amino acid levels were drawn in the morning of Day 0 (pretreatment), Day 3, and Day 6 of the study. Arginase activity levels were determined on Day 0. No patients were being concurrently treated with vasodilators or anticoagulant agents, and no patients received a red blood cell transfusion during the 5-day study period. Cardiologists involved in the interpretation of echocardiograms were unaware of the therapy given.

Amino Acid Measurement
Plasma amino acid levels were determined by ion exchange chromatography (Li-Ion Exchange Column; Pickering Laboratories, Inc., Mountain View, CA) at the Molecular Structure Facility, University of California (Davis, CA).

Arginase Activity
Arginase activity was determined as the conversion of [14C-guanidino]-L-arginine to [14C]urea, which was converted to 14CO2 by urease and trapped as Na214CO3 for scintillation counting as described previously (33). For these determinations, 50-µl aliquots of serum samples were incubated at 37°C for 2 hours.

Co-oximetry
Analyses of methemoglobin levels and venous oxygen saturation were done on venous blood by co-oximetry (Chiron Diagnostics model #845, Emeryville, CA).

Statistical Analysis
Tricuspid regurgitant jet velocity was estimated by echocardiography and was used to calculate the pressure gradient across the pulmonic valve according to the Bernoulli equation (p = 4V2) added to a central venous pressure estimated at 14 mm Hg in all patients (34). Tricuspid regurgitant jet velocity was measured using both the parasternal long axis and four-chamber view to confirm a concurrent value. Estimated pulmonary artery systolic pressures (mm Hg) based on changes in mean tricuspid regurgitant jet velocity were compared before and after treatment with oral L-arginine. Results are expressed as means ± SD. The paired Student's t test and one-way analysis of variance for repeated measures was used to evaluate for significant differences. A p value of less than 0.05 was considered statistically significant (35).

Sample Size Calculation
Assuming a type 1 error rate of 5%, a within-group pulmonary artery systolic pressure SD of 14, and a prepost pulmonary artery systolic pressure correlation of 0.80, a matched pair t test design with a sample size of n = 10 would have 90% power to detect a mean change of 9.1 (e.g., approximately a 15% decrease in pulmonary artery systolic pressure).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Outcome Measures Before and After L-arginine Therapy
Echocardiography.
Oral L-arginine supplementation significantly reduced pulmonary artery systolic pressure by a mean of 15.2% (63.9 ± 13 to 54.2 ± 12 mm Hg, p = 0.002) after 5 days of therapy (Figure 1) . One patient was determined to be noncompliant based on the plasma L-arginine concentration at the end of the study (61.5 µM at Day 0 versus 44.9 µM at Day 6). He was the only patient found to not show an improvement in pulmonary hypertension by echocardiogram.



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  		Figure 1. Changes in the estimated mean pulmonary artery systolic pressures (mm Hg) measured by echocardiography in patients with sickle cell disease and pulmonary hypertension. Measurements are taken before arginine therapy is started (pretreatment) and after completion of 15 doses of arginine (post-treatment). Male patients are represented by circles, and females are represented by triangles. The dotted line represents the only patient found to be noncompliant based on post-treatment plasma arginine levels. Arginine supplementation significantly decreases pulmonary artery systolic pressures (n = 10, p < 0.005).

 
The tricuspid regurgitant jet velocity from echocardiograms obtained more than 2 months before study enrollment demonstrated stable estimated pulmonary artery systolic pressures in five patients and worsening pulmonary hypertension in two patients. Results were unavailable from outside hospitals in three patients. Follow-up echocardiography was obtained at 1 month or more after arginine therapy in the nine compliant patients, with mixed results (Table 1) . The noncompliant patient was lost to follow-up. Four patients reverted to their previous baseline pulmonary artery systolic pressures. Four patients exhibited persistent improvement, and one patient demonstrated a worsening of pulmonary hypertension (echocardiography done while admitted for acute chest syndrome). Two of the patients demonstrating persistent improvement had also been started on transfusion therapy because of the severity of their disease, and one of these two patients had continued arginine therapy (at a dose of 0.1 g/kg twice a day).


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  		TABLE 1. Effect of arginine therapy on echocardiography

 
Amino acid levels.
Plasma L-arginine levels were low in patients with pulmonary hypertension compared with normal control subjects (50.8 ± 19 versus 114 ± 27 µM, p < 0.0001) but were similar to levels found in sickle cell patients at steady state who did not have pulmonary hypertension (18, 20). Ornithine levels were similar in both groups (53.4 ± 13 versus 57.0 ± 20 µM, pulmonary hypertension versus normal control subjects, respectively); however, the arginine-to-ornithine ratio was significantly lower in patients with pulmonary hypertension (0.95 ± 0.3 vs. 2.0 ± 0.6, p < 0.0001), probably reflecting increased arginase activity and decreased arginine bioavailability. Both L-arginine and ornithine concentrations increased significantly after 5 days of oral L-arginine supplementation (n = 10, p < 0.05; Figure 2) .



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  		Figure 2. Changes in plasma L-arginine and ornithine concentration (µM) after oral L-arginine administration (0.1 g/kg, TID) in sickle cell disease patients with pulmonary hypertension. Measurements of L-arginine (black solid) and ornithine (black pattern) are taken before arginine therapy is started (Day 0), midtreatment (Day 3), and after completion of 15 doses (Day 6). Arginine administration significantly increases plasma L-arginine and ornithine concentrations by Day 3 and Day 6 (n = 10, p < 0.05).

 
Arginase activity.
Arginase converts L-arginine to ornithine and urea (Figure 3) . Arginase activity in serum trended higher in sickle cell patients with pulmonary hypertension compared with normal control subjects but did not reach statistical significance in this limited sample population (0.82 ± 0.6 versus 0.43 ± 0.2 µmol/ml/hour, p = 0.07). Of interest, the patients with the two highest levels of arginase activity (1.22 and 2.46 µmol/ml/hour) have died within 1 year of enrollment.



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  		Figure 3. Arginase competes with nitric oxide synthase for available L-arginine substrate. L-Arginine (L-Arg) produces nitric oxide (NO) and citrulline (cit) in the presence of the nitric oxide synthase enzyme (NOS). NO release causes vasodilation through the activation of soluble guanylate cyclase (GTP) to the intracellular messenger cGMP (82, 83). Arginase converts L-arginine to ornithine and urea (67–69). Both L-arginine and ornithine use the same cationic amino acid transporter molecule (CAT) for cellular uptake (84, 85). Ornithine can competitively inhibit L-arginine transport into the endothelial cell, thereby limiting substrate availability for nitric oxide synthase and regulating nitric oxide production. NG-hydroxyl-L-arginine is the intermediate product of the L-arginine-NO pathway and is a potent inhibitor of arginase activity (86, 87). Accumulation of both intracellular and extracellular NG-hydroxyl-L-arginine would favor the continued conversion of L-arginine to nitric oxide by maintaining adequate arginine availability. Under conditions of low L-arginine concentration, nitric oxide synthase is uncoupled and reduces oxygen (O2) to superoxide (O2-) instead of generating NO (61, 62). NO reacts rapidly with superoxide to form reactive NOS (RNOS) that could lead to oxidative stress and cellular damage (64). Pathologic conditions of increased arginase activity could have a negative impact on nitric oxide bioavailability.

 
Other effects.
Arginine catabolism generates urea, which is excreted by the kidneys. Similar to the effects of a large protein load, high doses of L-arginine may cause a transient increase in blood urea nitrogen levels, and adequate hydration is necessary to avoid adverse effects to the kidneys. Liver function tests and renal function were followed with no significant changes noted. Commonly described side effects of oral arginine are associated with the gastrointestinal tract, including cramping and diarrhea (36). Arginine supplementation was well tolerated, and no adverse effects were reported.

A statistically significant increase in methemoglobin occurred (0.55 ± 0.4 vs. 1.10 ± 0.3, p < 0.05). Although this change is not clinically relevant, it suggests an increase in nitric oxide production. Venous oxygen saturation measured by co-oximetry (37) increased from 56.8 ± 18 to 76.4 ± 9% after L-arginine supplementation (n = 6, p = 0.066). The single patient to demonstrate a decrease in venous oxygen saturation also experienced a decrease in his blood pressure. This patient had a history of hypertension treated with enalapril. His blood pressure normalized on L-arginine therapy, necessitating a temporary discontinuation of enalapril while on study. Otherwise, vital signs, including blood pressure, remained stable in all other patients. One patient described subjective improvement in a chronic leg ulcer after treatment with arginine, and two patients described improved exercise tolerance and energy level after therapy.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This is the only study to date that evaluates a potential new therapy for secondary pulmonary hypertension associated with sickle cell disease. As an increasingly recognized pulmonary complication of adulthood (2, 4, 38), our study demonstrates that children are also affected. We currently have a 20% mortality rate within 2 years of the study's conclusion, consistent with the shortened survival described for this disease process (2, 4). With a mean reduction in pulmonary artery systolic pressures of 15.2%, our results are consistent with previously reported experiences with arginine supplementation for pulmonary hypertension in nonsickle cell disease patients (6, 7, 10). We also describe a new model of pathophysiology involving increased arginase activity that limits both arginine and nitric oxide bioavailability.

Endothelial dysfunction may contribute to the pathogenesis of pulmonary hypertension through impaired production of nitric oxide (7, 39–41). It is likely that arginine's effects are linked to nitric oxide generation. Nitric oxide metabolism is altered during acute chest syndrome (42), a common pulmonary complication of sickle cell disease (43) associated with low plasma arginine (20) and nitric oxide metabolite levels (20, 44) that is also often accompanied by pulmonary hypertension. Reported benefits of inhaled nitric oxide for acute chest syndrome (15, 16) suggest that nitric oxide–based therapies may be useful (45). L-Arginine may be a safer and more easily administered alternative to inhaled nitric oxide gas.

Plasma levels of endothelin-1, the most potent endothelial-derived vasoconstrictor (46, 47), are elevated in patients with sickle cell disease (48) and may contribute to the development of acute chest syndrome (49) and pulmonary hypertension (50, 51). Nitric oxide directly inhibits endothelin-1 production and release (46). L-Arginine also decreases circulating plasma endothelin-1 levels (52, 53) and is likely an added benefit for pulmonary hypertension. Conditions of decreased nitric oxide bioavailability may allow for the upregulation of adhesion molecules (13, 54) and endothelin-1 (55), leading to a clinical scenario of pulmonary hypertension in the susceptible patient. It is possible that genetics play a role in this susceptibility, as low exhaled nitric oxide and a polymorphism in the nitric oxide synthase gene have been linked to acute chest syndrome (56).

The rationale for arginine therapy has been questioned, as the low Km of nitric oxide synthase for L-arginine (less than 10 µM) (57) should prohibit arginine concentration from becoming rate limiting, even when circulating levels are below normal (20, 58, 59). However, rates of nitric oxide production vary according to extracellular arginine concentration, even when intracellular arginine levels are in apparent excess, a phenomenon termed the "arginine paradox" (60). The mechanisms of this paradox are undefined but likely involve decreased substrate bioavailability and attenuated nitric oxide synthesis, compounded by increased nitric oxide consumption. It has recently been recognized that scavenging of nitric oxide by elevated cell-free hemoglobin is a mechanism by which nitric oxide bioavailability is limited in sickle cell disease (13). This, in turn, could lead to increased arginine metabolism in a compensatory attempt to produce more nitric oxide, thereby depleting arginine stores further during times of hemolysis, a hallmark of sickle cell crisis. Also, nitric oxide synthase will produce superoxide in lieu of nitric oxide when arginine concentration is low (61). Superoxide, already increased in sickle cell disease (62) and augmented further by circulating xanthine oxidase (63), will consume nitric oxide to form the potent oxidant peroxynitrite (64), further limiting nitric oxide bioavailability and possibly inducing cellular injury. Studies in transgenic sickle cell mice demonstrate that nitric oxide synthase activity is paradoxically increased (65, 66), again suggesting in a futile compensatory attempt to replenish the deficient nitric oxide pool. Our data support a mechanism whereby arginase activity would further limit arginine bioavailability and translate to decreased nitric oxide production.

Found predominantly in the liver and kidneys, arginase is also present in human red blood cells (67), and it can be induced in many cell types by a variety of cytokines and inflammatory stimuli (27, 28, 68). Arginase activity may play a regulatory role in nitric oxide production, as it can limit availability of arginine for nitric oxide synthase (69) (Figure 3). Under pathologic conditions of elevated arginase activity, a higher than expected increase in arginine concentration may be necessary to induce a therapeutic effect. Elevated plasma arginase activity has been described in patients with sickle cell disease (59), but its role in pulmonary hypertension has not been previously explored. We observed that oral arginine supplementation significantly increased ornithine levels. Plasma arginase activity trended higher in patients with pulmonary hypertension compared with nonsickle cell normal control subjects, and the two patients with the highest levels have died within 1 year of enrollment. Elevated arginase activity may therefore be a marker of greater disease severity or end-organ damage. Arginase activity present in the serum of patients probably does not accurately reflect whole-body arginase activity, as the arginases are intracellular enzymes that appear in the circulation after cell damage or cell death. The arginine-to-ornithine ratio may therefore be a superior reflection of total arginase activity. This ratio would also be helpful in evaluating arginine bioavailability, as ornithine competes with L-arginine for cellular uptake. The arginine-to-ornithine ratio was significantly lower in sickle cell patients with pulmonary hypertension compared with normal control subjects, suggesting a role for arginase in the "arginine paradox."

None of our patients underwent a cardiac catheterization, the gold standard for evaluation of pulmonary hypertension. This may be considered a major limitation in our study. However, echocardiography is a noninvasive measurement shown to reliably predict pulmonary artery pressures in patients with chronic heart failure (70, 71) and those with pulmonary hypertension awaiting lung transplant, correlating with results of cardiac catheterization (72). Gladwin and colleagues recently confirmed this strong correlation between the two techniques (r = 0.98; p < 0.001) in patients with sickle cell disease and pulmonary hypertension (38). Although the sample size of our study population was relatively small, we were sufficiently powered to detect a difference in pulmonary pressures of 15% or more in 10 patients. Eligible patients who had not yet developed renal or liver dysfunction were scarce. This implies that the diagnosis is often being determined late in the clinical course. It is possible that patients develop pulmonary hypertension as a manifestation of more severe disease; however, a broader screening of asymptomatic patients by echocardiography may reveal occult pulmonary hypertension preceding complications, thus allowing for earlier intervention (73).

In conclusion, arginine is a well tolerated, nontoxic nutritional supplement with few side effects (52, 74–81). With the high mortality rate and limited treatment options available for these patients, L-arginine supplementation is a promising new therapy that warrants further investigation. In addition, these data suggest that elevated arginase activity may contribute to the pathogenesis of pulmonary hypertension in sickle cell disease. The correlation of disease severity and the arginine-to-ornithine ratio should also be explored, as it may represent an easily measured, objective marker that could identify patients at risk and allow for earlier intervention. Blinded, controlled studies with longer duration of therapy are needed to extend our preliminary findings and determine the safety and efficacy of arginine therapy in sickle cell disease.


   Acknowledgments
 
The authors acknowledge Dr. Mark Hudes, Ph.D., Senior Statistician from the Department of Nutritional Sciences and Toxicology, University of California, Berkeley, for his assistance with statistical analysis and Jeni Gardner for her help with data processing.


   FOOTNOTES
 
Supported in part by National Institute of Health grants HL-04386–02 and RR01271–19, the Pediatric Clinical Research Center, and GM57384 (to S.M.M.).

Received in original form August 30, 2002; accepted in final form February 25, 2003


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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
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