Chronic Phosphodiesterase Type 5 Inhibitor Therapy Reduces Priapic Activity in Transgenic Sickle Cell Mice: Restoring Nitric Oxide/Redox Balance in the Penis.

Sickle cell disease (SCD)-associated priapism is characterized by aberrant nitric oxide (NO) regulatory pathway signaling and reduced endothelial NO bioavailability resulting in phosphodiesterase type 5 (PDE5) dysregulation in the penis. Our objective was to determine the effect of chronic PDE5 inhibitor therapy on in vivo erectile responses as well as on NO signaling and redox actions in the penis in an animal model of SCD in order to identify mechanisms associated with this therapeutic effect. Our animal model comprised transgenic sickle cell (SS) mice, expressing human sickle hemoglobin.

Five groups of mice were used: 1) wild type (WT), 2) sickle cell heterozygotes (Hemi), 3) sickle cell homozygotes (Sickle), 4) WT + sildenafil (100 mg/kg per day), and 5) Sickle + sildenafil (100 mg/kg per day). All experimental groups underwent cavernous nerve electrical stimulation (CNS; 0.5 - 6 V) to assess erectile function (intracavernous pressure; ICP), and their responses were compared to WT. The frequency of erectile responses (erections/hr) pre- and post-stimulation was also determined. Analyses of penes were: total endothelial NOS (eNOS) and its phosphorylated/activated form (p-eNOS, Ser-1177), and PDE5 expressions; eNOS uncoupling (ratio of active eNOS dimer vs. inactive monomer); reactive oxygen species (ROS) generation; cGMP, NOS and PDE5 activities; and electron microscopy.

Erectile responses to CNS were significantly enhanced (P<0.05) in the Sickle when compared to Hemi and WT at all voltage settings. Sickle mice treated with sildenafil had a reduction (P<0.05) in spontaneous erections and reduced erectile responses to CNS, while sildenafil therapy had no effect on erectile responses in WT. EM showed endothelial cell interruption with loss of normal endothelial architecture and increased smooth muscle cell hyperplasia in Sickle mice penes. Sickle mice penes had reduced eNOS activity, p-eNOS expression, cGMP level, and PDE5 activity and increased eNOS uncoupling and ROS generation. Sildenafil therapy restored cGMP, NOS and PDE5 activities, improved p-eNOS expression, prevented eNOS uncoupling, and reduced ROS generation in Sickle mice penes compared to WT.

The priapic activity in the Sickle mouse is associated with a reduction in the functions of NOS and PDE5 and an NO/redox imbalance in the penis, and chronic PDE5 inhibitor therapy reverses this phenotype by restoring normal NO-mediated penile vascular homeostasis. These data support the use of PDE5 inhibitors for the treatment of priapism associated with hematologic dyscrasias.

Burnett:Pfizer Inc: Research Funding; Lilly LLC: Research Funding. Off Label Use: Sildenafil and tadalafil are FDA approved for treating erectile dysfunction.