title: Sildenafil citrate-restored eNOS and PDE5 regulation in sickle cell mouse penis prevents priapism via control of oxidative/nitrosative stress.
abstract: Sildenafil citrate revolutionized the practice of sexual medicine upon its federal regulatory agency approval approximately 15 years ago as the prototypical phosphodiesterase type 5 inhibitor indicated for the treatment of male erectile dysfunction. We now provide scientific support for its alternative use in the management of priapism, a clinical disorder of prolonged and uncontrolled penile erection. Sildenafil administered continuously to sickle cell mice, which show a priapism phenotype, reverses oxidative/nitrosative stress effects in the penis, mainly via reversion of uncoupled endothelial nitric oxide synthase to the functional coupled state of the enzyme, which in turn corrects aberrant signaling and function of the nitric oxide/cyclic GMP/protein kinase G/phosphodiesterase type 5 cascade. Priapism tendencies in these mice are reverted partially toward normal neurostimulated erection frequencies and durations after sildenafil treatment in association with normalized cyclic GMP concentration, protein kinase G activity and phosphodiesterase type 5 activity in the penis. Thus, sildenafil exerts pleiotropic effects in the penis that extend to diverse erection disorders.
authors.affiliation: The James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland, United States of America.
authors.forename: Trinity J
authors.initials: TJ
authors.lastname: Bivalacqua
authors.forename: Biljana
authors.initials: B
authors.lastname: Musicki
authors.forename: Lewis L
authors.initials: LL
authors.lastname: Hsu
authors.forename: Dan E
authors.initials: DE
authors.lastname: Berkowitz
authors.forename: Hunter C
authors.initials: HC
authors.lastname: Champion
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Burnett
mesh_terms: D000755:Anemia, Sickle Cell / Q000150:complications* / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D015538:Nitrosation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D010413:Penis / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011317:Priapism / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D011687:Purines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D017382:Reactive Oxygen Species; D013450:Sulfones; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D052250:Nitric Oxide Synthase Type III; D017869:Cyclic GMP-Dependent Protein Kinases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006152:Cyclic GMP