Hematologic, biochemical, and cardiopulmonary effects of l-arginine supplementation or phosphodiesterase 5 inhibition in patients with sickle cell disease who are on hydroxyurea therapy

Objectives: Fetal hemoglobin (HbF) induction involves NO-cGMP signaling pathways. l-arginine, an NO precursor, and the phosphodiesterase (PDE) 5 inhibitor sildenafil, which potentiates cGMP, were studied in adults with sickle cell disease (SCD) who were stably on HU. Methods: Twenty four courses of l-arginine (0.1-0.2 g/kg divided TID) or sildenafil (25-100 mg TID), assigned based on gender due to concerns about sildenafil-related priapism, were successfully completed. Biochemical assays, pulmonary pressures, and cardiopulmonary exercise capacity are reported from patients in whom serial values are available. Hematologic responses are reported in 14 subjects with HbSS who had stable baseline HbF levels. Results: l-arginine increased plasma arginine and ornithine, but not citrulline, suggesting diversion by plasma arginase from NO, and citrulline, generation. Glutathione increased only in patients on l-arginine. Sildenafil increased plasma cGMP and citrulline, but not other amino acids. Pulmonary pressures and 6-min walk distances improved only in patients on sildenafil. In subjects with stable baseline HbF levels, HbF levels changed little from a normalized baseline on l-arginine, decreasing by 2.9 ± 16.1%, n = 6; P = n.s., but increased on sildenafil, by 7.5 ± 11.7%, n = 8, P \u3c 0.05. Absolute reticulocyte counts initially decreased in patients on sildenafil. Conclusions: l-arginine, at doses that increase plasma arginine levels, altered redox potential in red cells. The lack of clinically detectable efficacy of l-arginine may be due to increased arginine metabolism in SCD patients. In vivo augmentation of the cyclic nucleotide pathway by PDE inhibition may induce HbF slightly, but strikingly improves hemodynamic and functional status in SCD. © 2009 John Wiley & Sons A/S