Phosphodiesterase Inhibition Increases Fetal Hemoglobin in Sickle Cell Disease; L-Arginine Supplementation Does Not.
Authors: Little Jane A. , Hauser Kristina Partovi , Martyr Sabrina E. , Kato Gregory J. , Machado Roberto , Castro Oswaldo , Taylor James , Gladwin Mark T. 
Published: October 2019

Nitric oxide- and cyclic nucleotide-linked pathways have been proposed to regulate fetal hemoglobin expression in sickle cell disease (SCD), and phosphodiesterase-5 (PDE5) inhibition and arginine supplementation can enhance these pathways. In an open-label gender-biased study (due to earlier concerns about sildenafil-induced priapism), we examined HbF and markers of disease activity in 12 patients with SCD (HbSS,) who had confirmed hematologic stability on hydroxyurea therapy and who had been treated with three months of thrice daily L-arginine supplementation (0.1–0.2 g/Kg, n=6, 4 male) or sildenafil (PDE5 inhibitor, 25–100 mg, n=6, all female). An additional 12 patients received study drug but did not have stable lead-in HbF levels; their data, where available, is included in analyses of amino acid levels, tricuspid regurgitant (TR) jet measurements, and 6-minute walk (6MW) distance. 25 mg of sildenafil increased cGMP by an average of 2 pM/ml at 2 hours (n=5). Statistics between groups are 2-way repeated measures ANOVA, while within groups are 1-way RMA, from data collected every 2 weeks. L-arginine increased serum arginine and ornithine concentrations while sildenafil did not. Percent change in HbF (%) and F-cells (%) from baseline rose with sildenafil, but did not change with L-arginine. Reticulocytes (K/μL) and arginase, markers of hemolysis, dropped with sildenafil, but LDH(IU/L) and MCHC rose with both treatments, although only modestly. TR jet velocity and 6-MW distance improved markedly in patients treated with sildenafil, whose parameters had suggested somewhat more severe disease at the start of therapy. We conclude that HbF and F-cell levels are modestly increased in patients on HU who also receive sidlenafil, consistent with prior studies suggesting that HU in part operates via NO-cGMP signaling pathways. Sildenafil, but not L-Arginine, improves physiologic, and some hematologic, parameters in SCD. These clinical data, while limited by small numbers, support earlier genetic data from other investigators that implicate members of the PDE family in the modulation of HbF in SCD.

Measurement L-Arg, baseline L-Arg, week 12 Sildenafil, baseline Sildenafil, week 12 Arginine [mM], 47±16 96±58 35.0±15.6 28.6±11.3 p<.005 2-way RMA n=7 n=8 Ornithine [mM], 74±13 128±77 68±11 61±7 p<.05 2-way RMA n=7 n=8 TR jet (m/s) 2.57±0.32 2.72±0.40 2.79±0.38 2.68±0.32 n=9, p=n.s., 1-way RMA n=13, p<.05, 1-way RMA 6-minute walk (meters) 494±109 511±116 400±89 491±110 n=9, p=n.s., 1-way RMA n=13, p<.05, 1-way RMA HbF (% Total Hgb) % change from baseline 0±0 2.9±16.1 0±0 9±16 n=6, p=n.s., 1-way RMA n=6, p<.05 1-way RMA F-cells (% total RBCs), % change 0±0 4.2±16.8 0±0 11±17 n=6, p=n.s., 1-way RMA n=6, p<.05 1-way RMA Reticulocytes, K/μL 186±38 190±23 244±129 177±92 n=6, rose and fell, p<.05 1-way RMA n=6, p<.05 1-way RMA LDH (IU/L) 305±96 327±62 324±153 351±260 n=6, p<.05 1-way RMA n=5, p<.05 1-way RMA Mean corpuscular Hgb concentration, MCHC (g/dL) 34.4±0.9 34.8±1.0 35.1±1.6 35.6±2.7 n=6, p<.05 1-way RMA n=6, p<.05 1-way RMA