Sustained nitric oxide (NO)-releasing compound reverses dysregulated NO signal transduction in priapism.
We evaluated the therapeutic potential of a sustained nitric oxide (NO)-releasing compound to correct the molecular hallmarks and pathophysiology of priapism, an important but poorly characterized erectile disorder. 1,5-Bis-(dihexyl-N-nitrosoamino)-2,4-dinitrobenzene (C6') and an inactive form of the compound [1,5-bis-(dihexylamino)-2,4-dinitrobenzene (C6)] were tested in neuronal cell cultures and penile lysates for NO release (Griess assay) and biological activity (cGMP production). The effect of local depot C6' or C6 was evaluated in mice with a priapic phenotype due to double neuronal and endothelial NO synthase deletion (dNOS(-/-)) or human sickle hemoglobin transgenic expression (Sickle). Changes in NO signaling molecules and reactive oxygen species (ROS) surrogates were assessed by Western blot. The physiological response after C6' treatment was assessed using an established model of electrically stimulated penile erection. C6' generated NO, increased cGMP, and dose dependently increased NO metabolites. C6' treatment reversed abnormalities in key penile erection signaling molecules, including phosphodiesterase type 5, phosphorylated endothelial nitric oxide synthase, and phosphorylated vasodilator-stimulated phosphoprotein. In Sickle mice, C6' also attenuated the increased ROS markers gp91(phox), 4-hydroxynonenal, and 3-nitrotyrosine. Finally, C6' corrected the excessive priapic erection response of dNOS(-/-) mice. Exogenous sustained NO release from C6' corrects pathological erectile signaling in mouse models of priapism and suggests novel approaches to human therapy.
1Department of Urology, The Johns Hopkins Hospital, 600 N. Wolfe St., Marburg 407, Baltimore, MD 21287-2411, USA. aburnett@jhmi.edu.
Gwen
G
Lagoda
Sena F
SF
Sezen
K Joseph
KJ
Hurt
Marcelo R
MR
Cabrini
Dillip K
DK
Mohanty
Arthur L
AL
Burnett
D000818:Animals; D002478:Cells, Cultured; D004136:Dinitrobenzenes / Q000627:therapeutic use*; D006451:Hemoglobin, Sickle / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011317:Priapism / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D051381:Rats
D004136:Dinitrobenzenes; D006451:Hemoglobin, Sickle; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III
NO bioavailability; oxidative stress; sickle cell