Increased phosphodiesterase type 5 levels in a mouse model of type 2 diabetes mellitus.
BACKGROUND
Diabetes mellitus (DM) is a major risk factor for developing erectile dysfunction (ED) and men with DM are often less responsive to phosphodiesterase type 5 (PDE5) inhibitors than ED due to other causes.


OBJECTIVE
The aim of this study was to explore potential mechanisms whereby PDE5 inhibitors may have reduced efficacy in type 2 DM.


METHODS
At 4 weeks of age, mice were either fed a high-fat diet (HFD) for 22-36 weeks or fed regular chow (control). An additional group of mice in the same genetic background had a genetic form of type 1 DM.


METHODS
Glucose tolerance testing, intracorporal pressures (ICPs), oxidative stress (OS), apoptotic cell death (active caspase-3 and apostain), PDE5, p53, and cyclic guanosine monophosphate (cGMP) levels, and histological examination of inflow arteries were performed in mice fed a HFD and control mice. A group of mice with type 1 DM were studied for PDE5 expression levels.


RESULTS
All mice fed a HFD had impaired glucose tolerance compared with the age-matched mice fed on standard chow diet (control). HFD fed mice had reduced maximum ICPs following in vivo cavernous nerve electrical stimulation and increased apoptotic cell death, OS, and p53 levels in the corporal tissue. Interestingly, PDE5 levels were increased and cGMP levels were decreased. In contrast, mice with type 1 DM did not have increases in PDE5.


CONCLUSIONS
Taken together, our results suggest that type 2 DM-induced ED is associated with findings that could lead to reduced cGMP and may account for reduced efficacy of PDE5 inhibitors.
Department of Urology, University of Virginia Health System, Charlottesville, VA 22908, USA.
Riyad T
RT
Ellati
Ayotunde O
AO
Dokun
Parviz K
PK
Kavoussi
William D
WD
Steers
Brian H
BH
Annex
Jeffrey J
JJ
Lysiak
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000097:blood*; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000473:pathology; D059305:Diet, High-Fat; D007172:Erectile Dysfunction / Q000201:enzymology* / Q000473:pathology; D005951:Glucose Tolerance Test; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010413:Penis / Q000098:blood supply / Q000473:pathology; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*
D058986:Phosphodiesterase 5 Inhibitors; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5