Arginine Therapy, L-Arginine and Pulmonary Hypertension - Sickle Cell Disease

"A New Treatment for Pulmonary Hypertension in Sickle Cell Disease?

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. "

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http://ajrccm.atsjournals.org/cgi/content/full/168/1/63
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