Subacute Hemolysis in Sickle Cell Mice Causes Priapism Secondary to NO Imbalance and PDE5 Dysregulation.
BACKGROUND
Recent research suggests that priapism in sickle cell disease (SCD) is due to dysregulation of penile erection homeostasis including alteration of nitric oxide synthase (NOS) and phosphodiesterase type 5 (PDE5) activities by excessive levels of reactive oxygen species (ROS) released during hemolysis. It is unknown if subacute exposure to hemolysis is sufficient or if chronic reconditioning of erectile tissues is required for perturbation of homeostatic pathways and whether PDE5 inhibitor (PDE5I) treatment can restore erectile homeostasis in the subacute setting.


OBJECTIVE
The aim of this study was to investigate the effects of subacute hemolysis (3-month exposure) on priapism and NO pathway regulation.


METHODS
Mice underwent bone marrow transplantation with either SCD (BM-SS) or wild-type (WT) bone marrow. BM-SS mice were treated with sildenafil 100 mg/kg/day. We measured intracavernous pressure (ICP) measurements with or without cavernous nerve stimulation following bone marrow transplantation to assess for priapism.


METHODS
ICP and frequency of erections were assessed. Penile tissues were analyzed for NOS, protein kinase G (PKG), PDE5, and ROS activities.


RESULTS
BM-SS mice demonstrated a priapism phenotype. PDE5I treatment reduced the frequency of erections in BM-SS mice (1.7 ± 1.1 vs. 5.5 ± 2.8 erections per hour, P < 0.05). Penile tissues from BM-SS mice demonstrated decreased NOS, PKG, PDE5 and elevated ROS activities compared with that of control mice. PDE5I treatment increased NOS (11.6 ± 1.3% vs. 7.8 ± 2.3%, P < 0.05) and PDE5 (76.3 ± 9.8% vs. 52.3 ± 11.1%, P < 0.05) activities and decreased ROS activity (137.8 ± 12.1% vs. 199.1 ± 11.3%, P < 0.05) compared with non-PDE5I treated BM-SS mice. PKG activity was increased beyond control levels with PDE5I treatment (158.4 ± 10.3%, P < 0.05).


CONCLUSIONS
Short-term hemolysis is sufficient to establish a priapism phenotype and results in loss of erectile function. PDE5I treatment ameliorates priapism, in part, because of restored NO balance with decreased ROS generation and increased PDE5 activity.
The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
Nikolai A
http://orcid.org/0000-0003-4913-0570
NA
Sopko
The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
Hotaka
H
Matsui
The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
Johanna L
JL
Hannan
Department of Anesthesiology and Critical Care Medicine, and Biomedical Engineering, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Dan
D
Berkowitz
Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Hunter C
HC
Champion
Department of Pediatrics, University of Illinois, Chicago, IL, USA.
Lewis L
LL
Hsu
The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
Biljana
B
Musicki
The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
Arthur L
AL
Burnett
The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
Trinity J
TJ
Bivalacqua
D000208:Acute Disease; D000755:Anemia, Sickle Cell / Q000150:complications* / Q000378:metabolism; D000818:Animals; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D004195:Disease Models, Animal; D006461:Hemolysis; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D010410:Penile Erection / Q000187:drug effects*; D010413:Penis / Q000187:drug effects; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011317:Priapism / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000068677:Sildenafil Citrate / Q000494:pharmacology*
D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D000068677:Sildenafil Citrate; D019001:Nitric Oxide Synthase; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517382:Pde5a protein, mouse
Endothelial Nitric Oxide Synthase; PDE5 Inhibitor; Phosphodiesterase 5; Priapism; Reactive Oxygen Species; Sickle Cell Disease