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Published ahead of print on March 5, 2003, doi:10.1164/rccm.200208-967OC

Am. J. Respir. Crit. Care Med., Volume 168, Number 1, July 2003, 63-69

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Submitted on August 30, 2002
Accepted on February 25, 2003

Arginine Therapy: A New Treatment for Pulmonary Hypertension in Sickle Cell Disease?

Claudia R Morris1*, Sidney M Morris2, Ward Hagar3, Jane van Warmerdam4, Susan Claster5, Diane Kepka-Lenhart2, Lorenzo Machado6, Frans A Kuypers6, and Elliott P Vichinsky3

1 Emergency Medicine, Children's Hospital and Research Center at Oakland, Oakland, CA, USA, 2 Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, 3 Hematology/Oncology, Children's Hospital and Research Center at Oakland, Oakland, CA, USA, 4 Pediatric Clinical Research Center, Children's Hospital and Research Center at Oakland, Oakland, CA, USA, 5 Hematology, University of California, San Francisco, San Francisco, CA, USA, 6 Children's Hospital Oakland Research Institute, Oakland, CA, USA

* To whom correspondence should be addressed. E-mail: claudiamorris{at}attbi.com.

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 L-arginine produced a 15.2 % mean reduction in estimated pulmonary artery systolic pressure (63.9±13 to 54.2±12 mmHg, p=0.002) after five days of therapy in ten patients. Arginase activity was elevated almost two fold, (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




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