Tadalafil increases Akt and extracellular signal-regulated kinase 1/2 activation, and prevents apoptotic cell death in the penis following denervation.
OBJECTIVE
Despite techniques to preserve the cavernous nerves during radical prostatectomy erectile dysfunction remains a complication. We determined whether bilateral cavernous nerve resection induces apoptosis in the penis. We also determined whether treatment with the phosphodiesterase-5 inhibitor tadalafil prevents apoptosis as well as the specific mechanisms involved.


METHODS
Mice were subjected to cavernous nerve resection or sham surgery. Penises were processed for the identification of apoptotic cells, changes in phosphorylation of several protein kinases and immunolocalization of specific kinases. Mice were also placed on tadalafil or vehicle after cavernous nerve resection and the penises were processed as described. Statistical analysis was performed with the Mann-Whitney U test for comparisons among groups or Student's t test.


RESULTS
An increase in apoptotic cavernous smooth muscle and endothelial cells was evident by 2 weeks, which further increased 4 and 6 weeks after cavernous nerve resection. Apoptosis coincided with an increase in the phosphorylation of c-jun N-terminal kinase and p38 mitogen activated protein kinase. Phospho-c-jun N-terminal kinase was immunolocalized to endothelial and smooth muscle cells. Treatment with tadalafil decreased the number of apoptotic cells and increased the phosphorylation of the 2 survival associated kinases Akt and extracellular signal-regulated kinase 1/2.


CONCLUSIONS
These results provide a rationale for the early use of phosphodiesterase-5 inhibition following radical prostatectomy or extensive pelvic surgery, during which there may be injury to the cavernous nerves, to aid in the return of erectile function.
Lysiak
Jeffrey J
JJ
Department of Urology, University of Virginia, Charlottesville, Virginia, USA.
Yang
Sang-Kuk
SK
Klausner
Adam P
AP
Son
Hwancheol
H
Tuttle
Jeremy B
JB
Steers
William D
WD
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002243:Carbolines / Q000494:pharmacology*; D003714:Denervation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010413:Penis / Q000187:drug effects* / Q000294:innervation* / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000068581:Tadalafil
D002243:Carbolines; D010726:Phosphodiesterase Inhibitors; D000068581:Tadalafil; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases