FK506 and sildenafil promote erectile function recovery after cavernous nerve injury through antioxidative mechanisms.
BACKGROUND
Immunophilin ligands and phosphodiesterase type 5 (PDE5) inhibitors are touted to promote erectile function recovery after cavernous nerve (CN) injury. However, the mechanisms for their effects remain unclear.


OBJECTIVE
To compare the erection recovery effects of the immunophilin ligand FK506 and the PDE5 inhibitor sildenafil after CN injury and determine whether they involve antioxidative and/or antiapoptotic mechanisms.


METHODS
Initial experiments established conditions of our CN injury model in adult male Sprague-Dawley rats. Subsequently, we evaluated treatment effects 14 days after: (i) unilateral CN injury (UNI) + saline (vehicle control); (ii) UNI + FK506 (5 mg/kg once daily, subcutaneous x 5 days); (iii) UNI + sildenafil (20 mg/kg every 8 hours, subcutaneous x 7 days); (iv) UNI + FK506/sildenafil; and (v) sham surgery.


METHODS
Intracavernous pressure (ICP) measurement after CN electrical stimulation to assess erectile function and Western blot analysis of expressions of glutathione peroxidase (GPX; antioxidant enzyme), nitrotyrosine (NT; oxidative stress marker), and phosphorylated and total Akt (antiapoptotic factor) in penes.


RESULTS
In the UNI model, GPX expression was increased at Days 1 and 7, while p-Akt expression decreased at Day 1 and returned to baseline at Day 7. GPX expression was significantly higher in the UNI + FK506 group compared with the saline-treated group (P < 0.05). ICP increased in all treatment groups compared with that of the saline-treated group (P < 0.05). NT levels were increased after saline treatment (P < 0.05) but not after FK506 and sildenafil treatment, alone or in combination. GPX was localized to nerves coursing through the penis and to smooth muscle and endothelium of the dorsal vein and arteries.


CONCLUSIONS
Both FK506 and sildenafil protect erectile function after CN injury by decreasing oxidative stress-associated tissue damage. FK506 may act through increased GPX activity. Further research is required to elucidate mechanisms associated with the beneficial effect of sildenafil.
Lagoda
Gwen
G
Department of Urology, The James Buchanan Brady Urological Institute, The Johns Hopkins Hospital, 600 N. Wolfe Street/Marburg 407, Baltimore, MD 21287, USA.
Jin
Liming
L
Lehrfeld
Todd J
TJ
Liu
Tongyun
T
Burnett
Arthur L
AL
D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005979:Glutathione Peroxidase / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D009416:Nerve Regeneration / Q000187:drug effects*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010410:Penile Erection / Q000187:drug effects*; D010413:Penis / Q000293:injuries* / Q000294:innervation / Q000473:pathology; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage / Q000494:pharmacology*; D016559:Tacrolimus / Q000008:administration & dosage / Q000494:pharmacology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; C002744:3-nitrotyrosine; D014443:Tyrosine; D000068677:Sildenafil Citrate; D005979:Glutathione Peroxidase; D019001:Nitric Oxide Synthase; D016559:Tacrolimus