title: Separate or combined treatments with daily sildenafil, molsidomine, or muscle-derived stem cells prevent erectile dysfunction in a rat model of cavernosal nerve damage.
abstract: BACKGROUND
  Long-term daily administration of phosphodiesterase type 5 (PDE5) inhibitors in the rat prevents or reverses corporal veno-occlusive dysfunction (CVOD) and smooth muscle cell (CSMC) loss and fibrosis, in both aging and bilateral cavernosal nerve resection (BCNR) models for erectile dysfunction. In the aging rat model, corporal implantation of skeletal muscle-derived stem cells (MDSC) reverses CVOD. Nitric oxide (NO) and cyclic guanosine monophosphate can modulate stem cell lineage.
  
  
  OBJECTIVE
  To investigate in the BCNR model the effects of sildenafil at lower doses, alone or in combination with MDSC or the NO donor molsidomine, on CVOD and the underlying corporal histopathology.
  
  
  METHODS
  CVOD, histological, and biochemical markers in rat corporal tissue. Methods.  Rats subjected to BCNR were maintained for 45 days either untreated, or received sildenafil in the water or retrolingually at 10, 2.5, and 1.25 mg/kg/day (medium, low, and very low doses), or intraperitoneal molsidomine, or MDSC implantation into the corpora cavernosa separately or in combination. Cavernosometry evaluated CVOD. Histopathology was assessed on penile sections by Masson trichrome, immunohistochemistry for α-smooth muscle actin (ASMA), or immunofluorescence for neuronal nitric oxide synthase (nNOS)/neurofilament 70, and in fresh tissue by Western blot for various markers and picrosirius red for collagen.
  
  
  RESULTS
  All treatments normalized erectile function (drop rate), and most increased the CSMC/collagen ratio and ASMA expression in corporal tissue sections, and reduced collagen content in the penile shaft. MDSC also increased nNOS and brain-derived neurotrophic factor. The combination treatment was not superior to MDSC or sildenafil given alone, and upregulated PDE5.
  
  
  CONCLUSIONS
  Lowering the dose of a continuous long-term sildenafil administration still maintained the prevention of CVOD in the BCNR rat previously observed, but it was less effective on the underlying histopathology. As in the aging rat model, MDSC also counteracted CVOD, but supplementation with very low-dose sildenafil did not improve the outcome.
authors.affiliation: Department of Surgery, Division of Urology, Los Angeles Biomedical Research Institute (LABioMed) at Harbor-UCLA Medical Center, Torrance, CA, USA.
authors.forename: Istvan
authors.initials: I
authors.lastname: Kovanecz
authors.forename: Steve
authors.initials: S
authors.lastname: Rivera
authors.forename: Gaby
authors.initials: G
authors.lastname: Nolazco
authors.forename: Dolores
authors.initials: D
authors.lastname: Vernet
authors.forename: Denesse
authors.initials: D
authors.lastname: Segura
authors.forename: Sahir
authors.initials: S
authors.lastname: Gharib
authors.forename: Jacob
authors.initials: J
authors.lastname: Rajfer
authors.forename: Nestor F
authors.initials: NF
authors.lastname: Gonzalez-Cadavid
mesh_terms: D000818:Animals; D003131:Combined Modality Therapy; D018783:Impotence, Vasculogenic / Q000503:physiopathology* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008981:Molsidomine / Q000494:pharmacology*; D009121:Muscle Denervation; D018485:Muscle Fibers, Skeletal / Q000637:transplantation*; D010410:Penile Erection / Q000187:drug effects / Q000502:physiology; D010413:Penis / Q000294:innervation*; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D000068677:Sildenafil Citrate; D033581:Stem Cell Transplantation; D013450:Sulfones / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate; D008981:Molsidomine