Chronic administration of sildenafil modified the impaired VEGF system and improved the erectile function in rats with diabetic erectile dysfunction.
BACKGROUND
Men frequently develop diabetic erectile dysfunction (DMED), as a result of endothelial dysfunction. DMED patients often have reduced efficacy with phosphodiesterase type 5 inhibitors therapy.


OBJECTIVE
To determine whether chronic sildenafil administration can modify the impaired vascular endothelial growth factor (VEGF) system and improve the erectile function in rats with diabetic erectile dysfunction.


METHODS
A group of Sprague Dawley rats (n = 30) with DMED were induced by intraperitoneal injection of streptozotocin (40 mg/kg) and screened by subcutaneous injection of Apomorphine (100 mg/kg). They were then exposed to either vehicle or sildenafil (prescribed in our hospital, 5 mg/kg and 10 mg/kg, respectively) for 10 weeks. An additional nondiabetic and age-matched control group (n = 10) was also allocated and given the routine diet for the same period. Assessments were performed to both groups at 36 hours after the last dose of sildenafil. Penile intracavernous pressure (ICP), mean arterial pressure (MAP), penile tissue morphology, immunohistologic analysis, and Western blot analysis of VEGF, VEGFR1, and eNOS were determined.


METHODS
Functional, morphological, and proteomical changes on penile structures by the chronic Sildenafil (5 mg/kg and 10 mg/kg, respectively) administration were determined.


RESULTS
A significant increase of ICP, ICP/MAP ratio, and area under the curve were observed in the both groups treated by sildenafil (5 mg/kg and 10 mg/kg, respectively), compared with the DMED rats without receiving Sildenafil. Immunohistochemical staining of their penile tissue showed a decrease in VEGF, VEGFR1, and eNOS staining in the controlled group compared with an improvement in the chronic sildenafil administration group. Western blot analysis demonstrated exactly the same results.


CONCLUSIONS
We demonstrated that daily sildenafil administration can restore the impaired VEGF system in the penis of DMED rats and progressively improve both erectile function and endothelial function, suggesting a potential general mechanism of improved signaling through the VEGF/eNOS signaling cascade.
Liu
Guihua
G
Department of Urology, First Affiliated Hospital of Sun Yet-Sen University, Guangzhou, China.
Sun
Xiangzhou
X
Dai
Yuping
Y
Zheng
Fufu
F
Wang
Daohu
D
Huang
Yanping
Y
Bian
Jun
J
Deng
Chunhua
C
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental; D004334:Drug Administration Schedule; D004558:Electric Stimulation; D007172:Erectile Dysfunction / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010413:Penis / Q000294:innervation / Q000378:metabolism*; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D000068677:Sildenafil Citrate; D013194:Staining and Labeling; D013450:Sulfones / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000378:metabolism*
D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D042461:Vascular Endothelial Growth Factor A; D000068677:Sildenafil Citrate; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D040262:Receptors, Vascular Endothelial Growth Factor