Sustained nitric oxide (NO)-releasing compound reverses dysregulated NO signal transduction in priapism

Gwen Lagoda, Sena F. Sezen, K. Joseph Hurt, Marcelo R. Cabrini, Dillip K. Mohanty, Arthur Burnett

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)76-84
Number of pages9
JournalFASEB Journal
Volume28
Issue number1
DOIs
StatePublished - 2014

Fingerprint

Priapism
Signal transduction
Signal Transduction
Nitric Oxide
Penile Erection
Nitric Oxide Synthase Type III
Reactive Oxygen Species
Type 5 Cyclic Nucleotide Phosphodiesterases
Sickle Hemoglobin
Nitric Oxide Synthase Type I
Molecules
Metabolites
Bioactivity
Cell culture
Biological Assay
Assays
Cell Culture Techniques
Western Blotting
Phenotype
Therapeutics

Keywords

  • NO bioavailability
  • Oxidative stress
  • Sickle cell

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology
  • Medicine(all)

Cite this

Sustained nitric oxide (NO)-releasing compound reverses dysregulated NO signal transduction in priapism. / Lagoda, Gwen; Sezen, Sena F.; Hurt, K. Joseph; Cabrini, Marcelo R.; Mohanty, Dillip K.; Burnett, Arthur.

In: FASEB Journal, Vol. 28, No. 1, 2014, p. 76-84.

Research output: Contribution to journalArticle

Lagoda, Gwen ; Sezen, Sena F. ; Hurt, K. Joseph ; Cabrini, Marcelo R. ; Mohanty, Dillip K. ; Burnett, Arthur. / Sustained nitric oxide (NO)-releasing compound reverses dysregulated NO signal transduction in priapism. In: FASEB Journal. 2014 ; Vol. 28, No. 1. pp. 76-84.
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