The functional and structural consequences of cavernous nerve injury are ameliorated by sildenafil citrate.
BACKGROUND
Radical prostatectomy (RP) is associated with erectile dysfunction (ED). A single, placebo-controlled, human study has assessed the effects of regular sildenafil use after RP and demonstrated an increased chance of preservation of preoperative erectile function. Aim. This study was undertaken to define the effects of such a regimen in an animal model.


METHODS
Using the cavernous nerve (CN) crush injury model, animals were divided into a number of groups: no CN injury (sham), bilateral CN injury exposed to either no sildenafil (control) or sildenafil at two doses (10 and 20 mg/kg) subcutaneously daily for three different durations (3, 10, 28 days).


METHODS
At these time points, CN electrical stimulation was used to assess erectile function by mean intracavernosal pressure (ICP)/mean arterial pressure (MAP) ratio. For the structural analyses, whole rat penes were harvested. Staining for Masson's trichrome was utilized to calculate the smooth muscle-collagen ratio. Immunohistochemical antibody staining was performed for endothelial (CD31 and eNOS) and neural (GAP43, NGF, and nNOS) factors and immunoblotting was performed to analyze the AKT/eNOS pathway. Terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) assay was used for the assessment of apoptotic indices and the CN architecture was evaluated by transmission electron microscopy (TEM).


RESULTS
Erectile function was improved with sildenafil in a time- and dose-dependent fashion with maximization of erectile function recovery occurring with daily 20 mg/kg at the 28-day time point. Sildenafil use resulted in smooth muscle-collagen ratio protection and CD31 and eNOS expression preservation. Sildenafil reduced apoptotic indices significantly compared with control. Animals exposed to sildenafil had increased phosphorylation of akt and eNOS. Tem demonstrated distinct differences in architecture between control and sildenafil groups toward an increased amount of myelinized nerve fibers.


CONCLUSIONS
Sildenafil use in the CN crush injury model preserves erectile function that appears to be mediated predominantly through preservation of smooth muscle content and endothelial function as well as through reduction in apoptosis.
Mulhall
John P
JP
Department of Urology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Urology, Weill Cornell Medical Center, New York, NY, USA. Electronic address: jpm2005@med.cornell.edu.
Müller
Alexander
A
Department of Urology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Donohue
John F
JF
Department of Urology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Mullerad
Michael
M
Department of Urology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Kobylarz
Keith
K
Department of Urology, Weill Cornell Medical Center, New York, NY, USA.
Paduch
Darius A
DA
Department of Urology, Weill Cornell Medical Center, New York, NY, USA.
Tal
Raanan
R
Department of Urology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Li
Philip S
PS
Department of Urology, Weill Cornell Medical Center, New York, NY, USA.
Cohen-Gould
Leona
L
Department of Pathology, Electron Microscopy Laboratory, Weill Cornell Medical Center, New York, NY, USA.
Scardino
Peter T
PT
Department of Urology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004558:Electric Stimulation; D007172:Erectile Dysfunction / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009409:Nerve Crush; D009413:Nerve Fibers, Myelinated / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010413:Penis / Q000293:injuries* / Q000294:innervation* / Q000473:pathology; D010766:Phosphorylation; D010879:Piperazines / Q000008:administration & dosage*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011687:Purines / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage*; D014665:Vasodilator Agents / Q000008:administration & dosage*
D010879:Piperazines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D003094:Collagen; D000068677:Sildenafil Citrate; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt