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Molecular Mechanisms of Sickle Cell-Associated Priapism: Effect of Chronic PDE5 Inhibitor Therapy
Trinity J Bivalacqua, Biljana Musicki*, Hunter Champion*, Arthur Burnett
Johns Hopkins Hospital, Baltimore, MD

Introduction: Mechanisms governing priapism in sickle cell disease are not understood. Our objective was to determine the effect of PDE5 inhibitor therapy on NO/cGMP/PDE5 signaling and erectile responses in a mouse model of sickle cell disease.
Methods: Transgenic sickle cell (SS) mice, expressing human sickle hemoglobin, were utilized. Five groups were used: 1) wild type (WT), 2) sickle cell heterozygotes (SS+/-), 3) sickle cell homozygotes (SS -/-), 4) WT + sildenafil (100 mg/kg per day x 1 mth), and 5) SS -/- + sildenafil. Groups underwent cavernous nerve stimulation (CNS) to assess erectile function. The frequency of erectile responses (erections/hr) pre- and post-stimulation was determined. Electron microscopy (EM), histological analysis, NOS, eNOS uncoupling, cGMP, and PDE5 activities were determined.
Results: Erectile responses to CNS were significantly enhanced in SS -/- when compared to SS +/- and WT. SS-/- spontaneous erections pre- and post stimulation were increased. SS-/- mice treated with sildenafil had a reduction in spontaneous erections and reduced erectile responses, while sildenafil therapy had no effect on WT. EM showed endothelial cell interruption and penile fibrosis. Sildenafil therapy restored NOS, cGMP, PDE5 activity, and prevented eNOS uncoupling in SS -/-.
Conclusions: Priapic activity in SS -/- mice is associated with a reduction in NOS/PDE5 expression and significant eNOS uncoupling with chronic PDE5 inhibitor therapy restoring NO/cGMP/PDE5 signaling cascade. This therapy reduces priapic activity by restoring normal penile homeostasis. Molecular findings suggest that abnormalities in the penile endothelium may account for changes observed in NOS/PDE5 expression and eNOS uncoupling.

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