Treatments in Respiratory Medicine

, Volume 5, Issue 1, pp 31–45 | Cite as

New Strategies for the Treatment of Pulmonary Hypertension in Sickle Cell Disease

The Rationale for Arginine Therapy
Review Article


Nitric oxide (NO) is inactivated in sickle cell disease (SCD), while bioavailability of arginine, the substrate for NO synthesis, is diminished. Impaired NO bioavailability represents the central feature of endothelial dysfunction, and is a key factor in the pathophysiology of SCD. Inactivation of NO correlates with the hemolytic rate and is associated with erythrocyte release of cell-free hemoglobin and arginase during hemolysis. Accelerated consumption of NO is enhanced further by the inflammatory environment of oxidative stress that exists in SCD. Based upon its critical role in mediating vasodilation and cell growth, decreased NO bioavailability has also been implicated in the pathogenesis of pulmonary arterial hypertension (PHT). Secondary PHT is a common life-threatening complication of SCD that also occurs in most hereditary and chronic hemolytic disorders. Aberrant arginine metabolism contributes to endothelial dysfunction and PHT in SCD, and is strongly associated with prospective patient mortality. The central mechanism responsible for this metabolic disorder is enhanced arginine turnover, occurring secondary to enhanced plasma arginase activity. This is consistent with a growing appreciation of the role of excessive arginase activity in human diseases, including asthma and PHT. Decompart-mentalization of hemoglobin into plasma consumes endothelial NO and thus drives a metabolic requirement for arginine, whose bioavailability is further limited by arginase activity. New treatments aimed at maximizing both arginine and NO bioavailability through arginase inhibition, suppression of hemolytic rate, or oral arginine supplementation may represent novel therapeutic strategies.



Supported in part by National Institutes of Health grants HL-04386-05 and MO1-RR01271, Pediatric Clinical Research Center.

The author wishes to acknowledge the contributions of Drs Sidney Morris, Jr and Mark Gladwin for helpful discussions and Dr Sidney Morris, Jr for critical review of the manuscript.

The author has no conflicts of interest directly relevant to the content of this review.


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© Adis Data Information BV 2006

Authors and Affiliations

  1. 1.Department of Emergency MedicineChildren’s Hospital and Research Center at OaklandOaklandUSA

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