Recurrent ischemic priapism is an erection disorder of non-willful, excessive penile erection, which afflictsapproximately 40% of male individuals with sickle cell disease. The disorder is not trivial, and itsconsequences include erectile tissue damage, erectile dysfunction, and psychological distress. Currently,satisfactory medical interventions to address the disorder are lacking, in large part because a rational basisfor its treatment remains obscure. We have recently elucidated a pathophysiologic mechanism, whichinvolves impairment in the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling (erectionmediatory) pathway, causing downregulation of phosphodiesterase type 5 (PDEs) function in the penis.PDEs, which serves a regulatory role in NO signaling as a cGMP-specific degradative phosphodiesterase, istherefore insufficiently active in controlling corporal smooth muscle relaxation, resulting in priapism. Wehave also shown that chronic PDEs inhibitor administration causes PDEs expressional upregulation inpenile tissues. These preclinical observations have supported a proposal to use continuous, long-term PDEsinhibitor therapy as an intervention for recurrent priapism in humans. We hypothesize that the therapyreverses downregulated PDEs functional levels in the penis toward normative ranges, thereby protectingagainst episodes of the disorder. To test this hypothesis, we propose a translational project, which includesboth preclinical investigation of the mechanism of action of this treatment and clinical assessment of itsutility for treating sickle cell disease-associated priapism. The preclinical component will consist ofmolecular and physiologic erection experiments following treatment with the prototypical PDEs inhibitorsildenafil in an experimental mouse model of sickle cell disease. The clinical component will be a singlecenter,randomized, double-blind, placebo-controlled study, in which sildenafil will be administeredcontinuously to patients with sickle cell disease and priapism. By way of this translational approach, thisproject may provide a critical step in introducing an effective, secondary prevention program for patientswith sickle cell disease-associated priapism, supported by a rational basis for its use. The project may lead toa major advance in the preservation of the sexual health and psychological well-being of individuals withsickle cell disease afflicted by priapism.
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