The effect of PDE5 inhibition on the erectile function in streptozotocin-induced diabetic rats.
The aim of this study was to assess the effect of phosphodiesterase 5 inhibitor, DA-8159, on erectile function throughout the quantitative analysis of vascular endothelial cell, smooth muscle (SM), TGF-beta1 expression in rat corpus cavernosum and measurement of intracavernous pressure (ICP) in diabetic rats. DA-8159 (0, 5, 10, 20 mg/kg) was administered orally once a day to diabetic rats. After 8 weeks, immunohistochemistry and computerized image analysis were performed to quantify the percent area within the Corpora Cavernosa occupied by the endothelial cells, SM cells and fibrotic tissues. ICP/mean arterial pressure (MAP) was also measured by electrostimulation of the cavernous nerve. Diabetic rats showed a significant decrease in the SM and endothelial cell content, and an increase in the TGF-beta1 expression level within the cavernosa areas compared to the normal rats. The mean cavernous SM, endothelial cell content and TGF-beta1 expression level were 9.7+/-0.7, 4.5+/-0.7 and 17.9+/-2.1%, respectively. DA-8159 prevented reduction of SM (12.3+/-0.4% (5 mg/kg), 13.8+/-0.4% (20 mg/kg)) and endothelial cell content (5.6+/-0.5% (5 mg/kg), 6.3+/-0.6% (20 mg/kg)). Immunoreactivity of TGF-beta1 and intracorporal fibrosis were also significantly lower in DA-8159-treated groups (11.8+/-1.2% (5 mg/kg), 9.5+/-1.1% (20 mg/kg)). Electrostimulation of the cavernous nerve induced significant increase in maximum ICP (62.2+/-13.6 mmHg in 10 mg/kg vs 37.5+/-17.5 mmHg in diabetic group) and area under the curve of the ratio of ICP/MAP (8891.09+/-1957 in 10 mg/kg vs 6315.87+/-2272 in diabetic group). These results suggest that subchronic treatment of DA-8159 can prevent the development of erectile dysfunction (ED), and provides a rationale for the use of DA-8159 as treatment of diabetic ED.
Ahn
G J
GJ
Department of Efficacy and Toxicology, Preclinical Division, Research Laboratories, Dong-A Pharmaceutical Company Ltd, Kyunggi, Republic of Korea.
Sohn
Y S
YS
Kang
K K
KK
Ahn
B O
BO
Kwon
J W
JW
Kang
S K
SK
Lee
B C
BC
Hwang
W S
WS
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology*; D004558:Electric Stimulation; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D010410:Penile Erection / Q000187:drug effects / Q000502:physiology*; D010413:Penis / Q000187:drug effects / Q000473:pathology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D013449:Sulfonamides; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D000096926:Benzenesulfonamides
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D010726:Phosphodiesterase Inhibitors; D011743:Pyrimidines; D013311:Streptozocin; D013449:Sulfonamides; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C508962:Tgfb1 protein, rat; C517384:Pde5a protein, rat; C419664:udenafil; D000096926:Benzenesulfonamides