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

Abstract

Objectives-Fetal hemoglobin (HbF) induction involves NO-cGMP signaling pathways. Larginine, 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-24 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 and Conclusions-L-arginine increased plasma arginine and ornithine, but not citrulline, suggesting diversion by plasma arginase from NO, and citrulline, generation. Glutathione (GSH) increased only in patients on L-arginine. Sildenafil increased plasma cGMP and citrulline, but not other amino acids. Pulmonary pressures and 6-minute 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<.05. Absolute reticulocyte counts initially decreased in patients on sildenafil.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 †

Peroxisome Proliferator-Activated Receptor γ Regulates the V-Ets Avian Erythroblastosis Virus E26 Oncogene Homolog 1/microRNA-27a Axis to Reduce Endothelin-1 and Endothelial Dysfunction in the Sickle Cell Mouse Lung

“…Although several potential therapeutic strategies have been investigated in SCD-PH, none have significantly affected SCD-PH outcomes (11,(75)(76)(77)(78)(79). The importance of ET-1 in the pathogenesis of SCD-PH is well established (80)(81)(82)(83).…”

A randomized, placebo-controlled trial of arginine therapy for the treatment of children with sickle cell disease hospitalized with vaso-occlusive pain episodes

“…In transgenic mouse models of SCD, L-arginine supplementation inhibits the red cell Gardos channels, 24 reduces red cell density, 24 improves perfusion, and reduces lung injury, microvascular vaso-occlusion and mortality. [25][26][27] Arginine also increases erythrocyte glutathione levels in both mice 25 and humans, 28 and may down-regulate inflammatory pathways. 29 In addition, arginine is a key substrate in creatine synthesis, an important metabolic pathway not yet sufficiently studied in SCD that may be affected by an arginine-deficient state.…”

“…Experience with arginine therapy in SCD is growing, 20,22,25,28,33,34 and no safety issues have emerged. We learned through this study that intravenous administration is preferred by patients and improves feasibility of study drug delivery compared to oral administration in the acute setting.…”

Pharmacological Value of Caffeine, Taurine and Arginine in Nutritional Supplements and their Relation to Well Known Socially Important Diseases

“…However, fetal hemoglobin levels were insignificantly reduced by 2.9% ± 16.1% from baseline in patients receiving L-arginine. In those treated with sildenafil, fetal hemoglobin levels increased [66].…”