Sildenafil Citrate-Restored eNOS and PDE5 Regulation in Sickle Cell Mouse Penis Prevents Priapism Via Control of Oxidative/Nitrosative Stress

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From: PLoS ONE(Vol. 8, Issue 7)
Publisher: Public Library of Science
Document Type: Report
Length: 5,390 words
Lexile Measure: 1510L

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Author(s): Trinity J. Bivalacqua 1, Biljana Musicki 1, Lewis L. Hsu 2,3, Dan E. Berkowitz 4, Hunter C. Champion 5, Arthur L. Burnett 1,*


Recurrent ischemic priapism, a disorder of non-willful, excessive penile erection, occurs commonly in the sickle cell disease (SCD) patient population and is associated with significant adverse consequences including erectile tissue damage, erectile dysfunction, and psychological distress [1]. The molecular pathophysiology of this erection disorder has only recently been scientifically investigated. Current advances in this field suggest the prominent role of aberrant function of the nitric oxide (NO)-based signal transduction pathway, which is well-described as the main mediatory system for penile erection [2]. Exaggerated erectile responses consistent with priapism are observed in mice lacking the gene for endothelial NO synthase (eNOS), which catalyzes endothelial NO production [3], [4]. Defective phosphodiesterase type 5 (PDE5) regulatory function in the penis accounts for these responses, resulting from altered endothelial NO signaling with detrimental effects on downstream pathway effector molecules, cGMP and cGMP-regulatory protein kinase G (PKG), which regulate PDE5 expression and activity [4], [5]. PDE5 dysregulation also occurs in the penis of a transgenic mouse model of severe sickle cell disease (sickle cell mice) [4], which show a priapism phenotype [6]-[8]. Penile overproduction of adenosine [9], [10] and upregulation of opiorphins (enzymes involved in the polyamine synthesis) [11] in sickle cell mouse penes also may contribute to the priapism phenotype observed in this experimental animal model.

Given the emerging central role of altered NO signaling in the pathophysiology of priapism associated with SCD, we hypothesized that restored normal NO/cGMP/PKG/PDE5-mediated penile vascular homeostasis in the penis via sustained pharmacotherapeutic inhibitory targeting of PDE5 would attenuate this disorder. In uncontrolled clinical studies involving men with SCD, PDE5 inhibitor therapy administered by continuous, long-term dosing unassociated with sexual stimulation proved efficacious in reducing priapism-related events [12], [13]. However, the precise pathogenic mechanisms resulting in altered NO signaling in the penis leading to SCD-associated priapism are unknown. Moreover, the mechanism of action of regimented PDE5 inhibitor therapy as an intervention for priapism has not been fully defined. Therefore, this study was designed, using the sickle cell mouse model, to: 1) investigate the pathogenic mechanisms in the penis causing endothelial NO/cGMP/PKG/PDE5 derangements that predispose priapism, and 2) identify a pharmacologic mechanism by which PDE5 inhibitors potentially serve as a therapy for priapism related to SCD.

Materials and Methods

Mouse Model of Human Sickle Cell Disease

Transgenic sickle cell (Sickle) mice with knockout of all mouse hemoglobin genes and expressing exclusively human sickle hemoglobin were developed at Lawrence Berkeley National Laboratory [14]. A breeding colony at the National Institutes of Health (NIH) generated animals for this study by mating sickle male mice to hemizygous females (approximately 15 generations). Because C57BL/6 is one of the background strains for the transgenic sickle mice, C57BL/6 was chosen as WT control. Additional control animals were hemizygous (Hemi) littermates. All were males ages 4 to 6 months old. Mice were pathogen free and received routine NIH rodent chow and water....

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Gale Document Number: GALE|A478444269