FK506 and erectile function preservation in the cavernous nerve injury model: optimal dosing and timing.
BACKGROUND
The immunophilin-ligand FK506 has been shown to ameliorate erectile function and preserve cavernous nerve (CN) architecture in short-term-studies using rat models of CN injury.


OBJECTIVE
The aim of this series was to ascertain the optimal dose and timing of FK506 administration in this animal model.


METHODS
Rats underwent bilateral CN crush and were treated with FK506 at different time points. There were control (C) and sham groups for each time point. Based on preliminary experiments, the CN-crush rats had no treatment (C) or either FK506 1 mg/kg (BL) or 3.2 mg/kg (BH) for 3 days prior to and the day of CN crush (PRE), on the day of and for 3 days following CN crush (POST) and for 3 days pre-, on the day of, and 3 days post-CN crush (PP).


METHODS
All animals had measurement of intracavernosal pressure/mean arterial blood pressure (ICP/MAP) ratios at 28 days post-CN crush. Structural analysis was conducted in the POST groups. Penile tissue was assessed for apoptosis with terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling assay and immunohistochemically for neural factors (growth associated protein 43 [GAP43], nerve growth factor [NGF], and neural nitric oxide synthase [nNOS]). The CN architecture was examined by transmission electron microscopy (TEM).


RESULTS
Sham animals had an ICP/MAP ratio of 70%. Only the BH-POST group revealed an improved ICP/MAP ratio compared with C (50 +/- 9% vs. 32 +/- 8%, P < 0.01). nNOS staining was significantly restored reaching sham levels in BL-POST and BH-POST groups vs. C (P < 0.05). NGF and GAP43 staining displayed no significant differences between C and treatment groups (P < 0.05). Apoptosis was significantly reduced in BL-POST and BH-POST groups compared with C (16 +/- 4%, 21 +/- 9%, and 63 +/- 7%, P < 0.001). TEM exhibited preservation of CN architecture for BH-POST compared with C.


CONCLUSIONS
These results suggest that short-term treatment with doses of FK506 higher than previously utilized preserves erectile function in the rat CN-injury model. Pretreatment appears to offer no advantage. However, FK506 administration just prior to CN injury and for a short-time post-injury achieves the best functional and structural preservation outcomes.
Mulhall
John P
JP
Weill Medical College of Cornell University-Department of Urology, New York, NY, USA. jpm2005@med.cornell.edu
Müller
Alexander
A
Donohue
John F
JF
Golijanin
Dragan
D
Tal
Raanan
R
Akin-Olugbade
Yemi
Y
Kobylarz
Keith
K
Cohen-Gould
Leona
L
Bennett
Nelson E
NE
Scardino
Peter
P
D000818:Animals; D017209:Apoptosis; D001794:Blood Pressure; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019922:GAP-43 Protein / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D046529:Microscopy, Electron, Transmission; D023421:Models, Animal; D020932:Nerve Growth Factor / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010410:Penile Erection / Q000187:drug effects*; D010413:Penis / Q000293:injuries* / Q000294:innervation* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016559:Tacrolimus / Q000008:administration & dosage*
D019922:GAP-43 Protein; D018696:Neuroprotective Agents; D020932:Nerve Growth Factor; D019001:Nitric Oxide Synthase; D016559:Tacrolimus